Cynnamide compound

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

 

The scope of the invention

The present invention relates to a pharmaceutical agent, in particular to the means of reducing the production of amyloid beta (hereinafter indicated as Aβ), which is effective for the treatment of neurodegenerative disease caused by Aβ such as Alzheimer's disease and down syndrome.

Background of the invention

Alzheimer's is a disease characterized by degeneration and loss of neurons and the formation of senile plaques and neurofibrillary changes. Currently, the treatment of Alzheimer's disease is limited to therapy aimed at reducing symptoms through reducing the symptoms of funds represented by the acetylcholinesterase inhibitor, and basic drug, preventing the development of this disease, is still not developed. To create a basic medicines for Alzheimer's disease is a need to develop a way to control the early development of pathological conditions.

Believe that the Aβ protein, which is a metabolite of amyloid protein precursor (hereinafter indicated as APP), largely associated with degeneration and loss of neurons, as well as with the early development of the States of dementia (for example, see non-Patent Document 1 and non-Patent Document 2). The main components of Aβ b the LCA are Aβ40, consisting of 40 amino acids, and Aβ42, which contains two additional amino acids at the C-terminal part. Aβ40 and Aβ42 have a tendency to aggregation (for example, see non-Patent Document 3) and constitute the main components of senile plaques (for example, non-Patent Document 3, non-Patent Document 4 and non-Patent Document 5), and moreover, it is known that mutations in the APP gene and presenilin that look at family Alzheimer's disease increase production of Aβ40 and Aβ42 (for example, see non-Patent Document 6, Patent Document 7 and non-Patent Document 8). Therefore, compounds that reduce the production of Aβ40 and Aβ42, as expected, will be a tool for monitoring the development of Alzheimer's disease or for the prevention of this disease.

These Aβ are produced when there is a splitting of the APP under the action of beta-secretase, followed by their separation under the action of gamma-secretase. With this in mind, attempts have been made to create inhibitors of γ-secretase and β-secretase in order to reduce the production of Aβ. Many of these known inhibitors secrets are peptides or peptidomimetics, such as L-685,458 (for example, see non-Patent Document 9) and LY-411575 (for example, see non-Patent Document 10, non-Patent Document 11 and Patent Document 12).

Non-patent Document 1: Klein WL and 7 others, connected the with this article, connects brain damage in Alzheimer's disease with the following: the presence of ligands oligomeric Aβ (ADDL) suggests a molecular basis for reversible memory loss, Proceeding National Academy of Science USA, 2003, Sep 2, 100(18), p. 10417-10422;

Non-patent Document 2: Nitsch RM, and 16 others, Antibodies against β-amyloid gradually slow the decline of cognitive abilities in Alzheimer's disease, Neuron, 2003, May 22, 38(4), p. 547-554;

Non-patent Document 3: Jarrett JT, and the other 2, the Carboxyl end of the β-amyloid protein is critical for the nucleation of amyloid formation: involvement in the pathogenesis of Alzheimer's disease, Biochemistry, 1993, May 11, 32(18), p. 4693-4697;

Non-patent Document 4: Glenner GG, and others, Alzheimer's Disease: initial report of the purification and identification of a new cerebrovascular amyloid protein, Biochemical and Biophysical Research Communications, 1984, May 16, 120(3), p. 885-890;

Non-patent Document 5: Masters CL, and 6 other protein core of amyloid plaques in Alzheimer's disease and down syndrome, Proceeding National Academy of Science USA, 1985, Jun, 82(12), p. 4245-4249;

Non-patent Document 6: Gouras GK, and 11 others, Vnutrennyaya the Aβ42 accumulation in human brain, American Journal of Pathology, 2000, Jan, 156(1), p. 15-20;

Non-patent Document 7: Scheuner D, and 20 others, the Levels of secreted amyloid β-protein similar to the protein found in senile plaques in Alzheimer's disease, increased in vivo as the result of mutations presenilin and 2 and APP associated with familial Alzheimer's disease, Nature Medicine, 1996, Aug, 2(8), p. 864-870;

Non-patent Document 8: Forman MS, and 4 others, Differential effects containing the Swedish mutation of amyloid protein precursor on β-amyloid accumulation and secretion in neurons and non-neural cells, Journal of Biological Chemistry, 1997, Dec 19, 272(51), p. 32247-32253;

Non-patent Document 9: Shearman MS, and 9 others, L-685458, mimic the transition state of aspirinplease, is a strong inhibitor of the activity of γ-secretase precursor of amyloid β-protein, Biochemistry, 2000, Aug 1,39(30), p. 8698-8704;

Non-patent Document 10: Shearman MS, and 6 other Comprehensive inhibitors of the catalytic site-directed γ-secretase, no pharmacological differences between Notch S3 and β-APP-splitting, Biochemistry, 2003, Jun 24, 42(24), p. 7580-7586;

Non-patent Document 11: Lanz TA, and 3 others, Study the pharmacodynamics Aβ in the brain, cerebrospinal fluid, and plasma in young (no plaques) Tg2576 mice using an inhibitor of γ-secretase N2-[(2S)-2-(3,5-differenl)-2-hydroxyethanoic]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninemia (LY-411575), Journal of Pharmacology and Experimental Therapeutics, 2004, Apr, 309(1), p. 49-55;

Non-patent Document 12: Wong GT, and 12 others, Prolonged treatment with an inhibitor of γ-secretase LY-411575 inhibits the production of β-amyloid peptide and alters lymphopoiesis and differentiation of intestinal cells, Journl of Biological Chemistry, 2004, Mar 26, 279(13), p. 12876-12882.

Disclosure of invention

Task, which is aimed at solving the present invention

As indicated above, compounds that prevent the production of Aβ40 and Aβ42 from APP, it has been proposed as a means for prevention or treatment of diseases caused by Aβ, represented by Alzheimer's disease. However, dipeptide compounds that prevent the production of Aβ40 and Aβ42 and with excellent medical action, up to this time were not known. So you need a new low-molecular-weight compound that inhibits the production of Aβ40 and Aβ42.

Means for solving problems

The authors of the present invention have conducted extensive research and first discovered ones cinnamene compounds that inhibit the production of Aβ40 and Aβ42 from APP, and found a means for the prevention or treatment of diseases caused by Aβ, represented by Alzheimer's disease, which was created by the present invention.

Thus, the present invention relates to the objects listed below:

1) the Compound or its pharmacologically acceptable salt represented by formula (I):

Formula 1

(where Ar1represents imidazolidinyl group which may be substituted by 1-3 will replace the guides and selected from the group of substituents A1 below; Ar2represents pyridinyl group, pyrimidinyl group or a phenyl group which may be substituted by 1-3 substituents selected from the group of substituents A2 below; X1represents (1) -C≡C - or - (2) -CR3=CR4- (where R3and R4is a Deputy selected from the group of substituents A3, below); and

(1) R1and R2represent a group selected from the group of substituents A4 below, or

R1and R2together with the nitrogen atom to which they are attached, form one of the following groups:

(2-1) 5-11-membered non-aromatic heterocyclic group represented by the formula (II):

Formula 2

(where Y1represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -SO2-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5=CR6- (where R5and R6represent substituents selected from the group of substituents A4 below), (11) a simple link or (12) >C=CR13R14(where R13and R14represent substituents selected from the group of substituents A4 shown below); and

maand mbrepresent an integer having a value of from 0 to 4)which may be substituted by 1-4 cover the firs, selected from the group of substituents A4;

(2-2) 6-20-membered non-aromatic heterocyclic group represented by the formula (III):

Formula 3

(where Y2represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -SO2-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5= CR6- (where R5and R6represent substituents selected from the group of substituents A4 below, or R5and R6together with the carbon atom to which they are bound, form a 6-14-membered aromatic hydrocarbon ring group or a 6-14-membered non-aromatic hydrocarbon ring group)or (11) a simple link; and

ma, mb, mcand mdrepresent an integer having a value of from 0 to 4)which may be substituted by 1-4 substituents selected from the group of substituents A4;

(2-3) 9-16-membered non-aromatic heterocyclic group represented by the formula (IV):

Formula 4

(where Y3represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -SO2-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO - or (10) a simple link; and

maand mbhave the meaning given above), which may be substituted by 1-4 substituents selected from the group of substituents A4;

(2-4) a group represented by the following formula:

Formula 5

which may be substituted by 1-4 substituents selected from the group of substituents A4 shown below;

(2-5) a group represented by the following formula:

Formula 6

which may be substituted by 1-4 substituents selected from the group of substituents A4 shown below;

or

R1and R2together with the-X1-CO-N - form one of the following ring structures:

(3-1) a cyclic group represented by the formula (V):

Formula 7

(where Z1represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -SO2-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO - or (10) a simple bond; Z2represents (1) a methine group or (2) a nitrogen atom; R7is a Deputy selected from the group of substituents A3 shown below; and nanband ncrepresent an integer having a value of from 0 to 4)which may be substituted by 1-4 substituents selected from the group of substituents A4;

(3-2) a cyclic group represented by the formula (VI):

Formula 8

(where Z3represents (1) a simple link, (2) -CO-, (3) -(CH2nd- (where ndis an integer having a value of from 1 to 3) or (4) -CR8R9- (where R8and R9represent a Deputy selected from the group of substituents A4, below;

Z4represents (1) a simple link, (2) -O-, (3) -NRCO-, (4) -CONR-, (5) -CSNR- (6)-NRCS-(where R represents a Deputy selected from the group of substituents A4 below) or (7) -S-;

Z5represents (1) a simple link, (2) aminogroup, which can be substituted by the Deputy selected from the group of substituents A4 below (3) -(CH2ne- (where neis an integer having a value of from 1 to 3), (4) -CR8R9- (where R8and R9have the meanings defined above) or (5) -O-; and

R1and R7have the meaning given above); or

(3-3) a cyclic group represented by the following formula:

Formula 9

(where R1and R7have the meaning given above), which may be substituted by 1-4 substituents selected from the group of substituents A4 below.

The group of substituents A1: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) the nitro-group, (5) C3-8-cycloalkyl group, (6) C2-6-Alchemilla group, (7) C2-6-Alchemilla group, (8) C1-6-alkoxygroup, (9) C3-8-cycloalkanes, (10) formyl group, (11) C1-6-acylcarnitine group and (12) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of a halogen atom, hydroximino group, ceanography, C1-6-alkoxygroup, C3-8-cycloalkyl group and C1-6-alkylcarboxylic group).

Group Vice A2: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-3 substituents selected from the group consisting of a halogen atom, ceanography, C1-6-alkoxygroup, C2-6-alkenylphenol group, C2-6-alkenylphenol group and C3-8-cycloalkyl group), (6) C3-8-cycloalkanes, (7) C2-6-alkenylacyl and (8) C2-6-alkyloxy.

Group Vice A3: (1) hydrogen atom, (2) halogen atom, (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of formyl group, halogen atom, hydroxyl group, hydroxyl group containing protective group, ceanography, C2-6-alkenylphenol group, C2-6-alkenylphenol group, C3-8-cycloalkyl group, C1-6-alkoxygroup, C1-6-allylthiourea, C1-6-alkylsulfonyl group, C1-6-alkylsulfonyl group, C1-6-alkylcarboxylic group, amino is the group (where this amino group may be substituted by C1-6-alkyl groups, not necessarily containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group Vice-A4, and-X-A (where X represents aminogroup, -O - or-S - and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4) and (6) C1-6-CNS group.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyI kinogruppa, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-5 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S - and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic Goethe is acyclically group, which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above).

2) the Compound or its pharmacologically acceptable salt according to the above p. 1), where Ar1represents imidazolidinyl group which may be substituted by 1-2 substituents selected from the group consisting of (1) hydrogen atom, (2) halogen atom, (3) C3-8-cycloalkyl group, (4) C2-6-alkenylphenol group, (5) C2-6-alkenylphenol group, (6) C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1-3 halogen atoms).

3) the Compound or its pharmacologically acceptable salt according to the above p. 1), where Ar2represents a phenyl group which may be substituted by 1-3 substituents selected from the group consisting of (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) ceanography, (6) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-3 substituents selected from C2-6-alkenylphenol group, C2-6-alkenylphenol group and C3-8-cycloalkyl group), (7) C2-6-alkenylacyl and (8) C2-6-alkyloxy.

4) the Compound or its pharmacologically acceptable salt according to the above p. 2)where Ar1represents imidazolidinyl group, to ora may be substituted by 1-2 substituents, selected from the group consisting of (1) hydrogen atom, (2) halogen atom, (3) C3-8-cycloalkyl group and (4) C1-6-alkyl groups.

5) the Compound or its pharmacologically acceptable salt according to the above p. 3)where Ar2represents a phenyl group which may be substituted by 1-3 substituents selected from the group consisting of (1) hydrogen atom, (2) halogen atom, (3) ceanography and (4) C1-6-alkoxygroup.

6) the Compound or its pharmacologically acceptable salt according to the above p. 1), where X1represents-C≡C-.

7) the Compound or its pharmacologically acceptable salt according to the above p. 1), where X1represents-CR3=CR4- (where R3and R4represent substituents selected from the group of substituents A3 below).

Group Vice A3: (1) hydrogen atom, (2) halogen atom, (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of formyl group, halogen atom, hydroxyl group, the hydroxyl group containing protective group, ceanography, C2-6-alkenylphenol group, C2-6-alkenylphenol group, C3-8-cycloalkyl group, C1-6-alkoxygroup, C1-6-allylthiourea, C1-6-alkylsulfonyl group, C1-6-alkylsulfonyl group, C1-6-alkylcarboxylic group, an amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted 1-3 substituents selected from the group of substituents A4, 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group Vice-A4, and-X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4) and (6) C1-6-alkoxygroup.

Group Vice A4: (1) atom of water is an ode, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group, which can to be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group, which is may be substituted by 1-3 substituents, selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above).

8) the Compound or its pharmacologically acceptable salt according to the above p. 7), where X1represents-CR31=CR41- (where R31represents a group selected from the group consisting of (1) hydrogen atom, (2) halogen atom, (3) C1-6-alkyl groups and (4) C1-6-alkoxygroup; and R41represents a group selected from the group consisting of (1) hydrogen atom, (2) halogen atom, (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A5, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A5, and (5) C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1-3 what zamestitelyami, selected from the group consisting of a halogen atom, a hydroxyl group, ceanography, C3-8-cycloalkyl group, C1-6-alkyl groups, C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A5, 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A5, 5-14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A5, and-O-A1(where A1is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A5, or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A5))).

Group Vice-A5: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) C3-8-cycloalkyl group, (6) C3-8-cycloalkanes, (7) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-5 halogen atoms), (8) C1-6-alkoxygroup (where is the th C1-6-alkoxygroup may be substituted by 1-5 halogen atoms) and (9) amino group (where this amino group may be substituted by C1-6-alkyl groups, not necessarily containing 1 to 5 halogen atoms).

9) the Compound or its pharmacologically acceptable salt according to the above p. 8), where X1represents-CR32=CR42- (where R32represents a hydrogen atom or halogen atom, and R42is a Deputy selected from the group consisting of hydrogen atom, halogen atom, C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted C3-8-cycloalkyl group or phenyl group) and phenyl group).

10) the Compound or its pharmacologically acceptable salt according to the above p. 1), where R1and R2represent a group selected from substituents selected from the group of substituents A4.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which can the be substituted by 1-3 substituents, selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above.

11) the Compound or its pharmacologically acceptable salt according to the above p. 10), where R1represents a group selected from the group of substituents A8 below, and R2represents a group selected from the group of substituents A6 below.

Group Vice A6: (1) hydrogen atom, (2) C3-8-cycloalkyl group, (3) C3-8-cycloalkanes, (4) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-allylthiourea, hydroxyimino, C1-6-alkoxyamino, C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, PR is stavlennii below, and-O-A2(where A2is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below or a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 below)and (5) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-allylthiourea, hydroxyimino, C1-6-alkoxyamino, C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, a 5 to 14-membered non-aromatic heterocyclic group, which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, and-O-A 2(where A2shall have the meaning given above)).

Group Vice A7: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) C3-8-cycloalkyl group, (6) C3-8-cycloalkanes, (7) C1-6-acylcarnitine group, (8) C1-6-allylthiourea, (9) C1-6-alkylsulfanyl group, (10) C1-6-alkylsulfonyl group, (11) C1-6-alkyl group (where specified C1-6 is an alkyl group may be substituted by 1-5 substituents selected from the group consisting of halogen atom, C1-6-alkyl groups, 6-14-membered aromatic hydrocarbon ring group, a 5 to 14-membered aromatic heterocyclic group and -- O-A3(where A3is a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group)), (12) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 halogen atoms, or together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group), (13) amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), (14) 6-14-membered aromatic hydrocarbon ring group, which may be substituted by 1-3 substituents selected from the group of substituents A7, (15) 5-14-membered aromatic heterocyclic the Skye group, which may be substituted by 1-3 substituents selected from the group of substituents A7, (16) 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 and (17) -CO-A3(where A3shall have the meaning given above).

Group Vice A8: (1) hydrogen atom, (2) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous the group and the two C1-6-alkyl groups together with the carbon atom to which they are bound, may form a cyclic group (where a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-5 substituents selected from the group of substituents A7, a 5 to 14-membered aromatic heterocyclic group, to the which may be substituted by 1-3 substituents, selected from the group of substituents A7, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, and-X-A2(where X represents aminogroup, -O - or-S-, and A2is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-5 substituents selected from the group of substituents A7 or a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7)), (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, and (5) -X-A2(where X and A2have the meanings defined above).

12) the Compound or its pharmacologically acceptable salt according to the above p. 11)where R1represents a C1-6-alkyl group (where specified C1-6-alkyl group represents a hydrogen atom, C3-8-cycloalkanes, C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous group and the two C1-6-alkyl groups together with the carbon atom, with which they are linked, may form a cyclic group (where a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), C1-6-alkoxygroup, 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A9, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9, and-O-A4(where A4is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A9, or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9)), and R2represents (1) hydrogen atom or (2) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group, C3-8-cycloalkyl group, C3-8-cycloalkanes, C1-6-allylthiourea, an amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents, is selected from group Vice-A9, 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9, and 5-14 membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9).

Group Vice A9: (1) hydrogen atom, (2) halogen atom, (3) C3-8-cycloalkyl group, (4) C3-8-cycloalkanes, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-5 substituents selected from the group consisting of halogen atom and C1-6-alkyl groups), (6) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 halogen atoms, or together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group), (7) an amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), (8) 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9, (9) -CO-A3(where A3is a 6-14-membered aromatic hydrocarbon ring group), (10) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A9, and (11) 5-Ana aromatic heterocyclic group, which may be substituted by 1-3 substituents selected from the group of substituents A9.

13) the Compound or its pharmacologically acceptable salt according to the above p. 1), where R1and R2together with the nitrogen atom to which they are bound, form a 5-11-membered heterocyclic group represented by the formula (II):

Formula 10

(where Y1represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -SO2-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5=CR6- (where R5and R6represent a group selected from the group of substituents A4 below), (11) a simple link or (12) >C=CR13R14(where R13and R14represent substituents selected from the group of substituents A4 shown below); and maand mbrepresent an integer having a value of from 0 to 4)which may be substituted by 1-4 substituents selected from the group of substituents A4 below.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-member is nnow aromatic heterocyclic group, which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above).

14) the Compound or its pharmacologically acceptable salt according to the above p. 13)where 5-11-membered heterocyclic group is piperidinyloxy group, pyrrolidinyl group, sepanlou group, atenilol group, piperazinilnom group, 1,4-diazepino group, morpholinyl group or thiomorpholine group.

15) the Compound or its pharmacologically acceptable salt according to the above p. 14)where R1and R2together with the nitrogen atom to which they are bound, form piperidinyl group, pyrrolidinyl group, sepanlou group, atenilol group, piperazinilnom group, 1,4-diazepino group, morpholinyl group or thiomorpholine group which may be substituted by 1-3 substituents selected from the group consisting of (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) formyl group, (5) hydroxyisopropyl, (6) C1-6-alkoxyimino, (7) C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1-3 hydroxy groups or 1-3 substituents selected from the group consisting of 6-14-membered aromatic carbohydrate is native ring group, which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below or a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 below), (8) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, (9) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, (10) -O-A2(where A2is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below or a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 below), (11) -CO-A2(where A2shall have the meaning given above), and (12) =CH-A2(where A2shall have the meaning given above).

Group Vice A7: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) C3-8-cycloalkyl group, (6) C3-8-cycloalkanes, (7) C1-6-acylcarnitine group, (8) C1-6-allylthiourea, (9) C1-6-alcalali nilina group, (10) C1-6-alkylsulfonyl group, (11) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-5 substituents selected from the group consisting of halogen atom, C1-6-alkyl groups, 6-14-membered aromatic hydrocarbon ring group, a 5 to 14-membered aromatic heterocyclic group and -- O-A3(where A3is a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group)), (12) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 halogen atoms, or together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group), (13) amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), (14) 6-14-membered aromatic hydrocarbon ring group, which may be substituted by 1-3 substituents selected from the group of substituents A7, (15) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, (16) 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 and (17) -CO-A3(where A3has the meaning given in the above).

16) the Compound or its pharmacologically acceptable salt according to the above p. 15)where R1and R2together with the nitrogen atom to which they are bound, form piperidinyl group, pyrrolidinyl group, sepanlou group, atenilol group, piperazinilnom group, 1,4-diazepino group, morpholinyl group or thiomorpholine group which may be substituted by 1-4 substituents selected from the group consisting of (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1-3 hydroxy groups or 1-3 substituents selected from the group consisting of 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A10 below), (5) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A10 below (6) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A10 below (7) -O-A6(where A6is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituent and, selected from the group of substituents A10 below), (8) =CH-A6(where A6shall have the meaning given above).

Group Vice A10: (1) hydrogen atom, (2) halogen atom, (3) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-5 halogen atoms), (4) C1-6-alkoxygroup and (5) 6-14-membered aromatic hydrocarbon ring group.

17) the Compound or its pharmacologically acceptable salt according to the above p. 1), where R1and R2together with the nitrogen atom to which they are attached, form a 6 to 20-membered non-aromatic heterocyclic group represented by the formula (III):

Formula 11

(where Y2represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -SO2-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5= CR6- (where R5and R6represent a group selected from the group of substituents A4 below, or R5and R6together with the nitrogen atom to which they are bound, form a 6-14-membered aromatic hydrocarbon ring group or a 6-14-membered non-aromatic hydrocarbon ring group) or (11) a simple bond; and ma, mb, mcand mdrepresent an integer having a value of from 0 to 4)which may be substituted by 1-4 substituents selected from the group of substituents A4, depict allenou below.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (25) 5-14-membered neuromath the ical heterocyclic group, which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above).

18) the Compound or its pharmacologically acceptable salt according to the above p. 1), where R1and R2together with the nitrogen atom to which they are bound, form 9 to 16-membered non-aromatic heterocyclic group represented by the formula (IV):

Formula 12

(where Y3represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -SO2-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO - or (10) a simple bond; and maand mbrepresent an integer having a value of from 0 to 4)which may be substituted by 1-4 substituents selected from the group of substituents A4.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group is a, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group Vice-A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (7) C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above).

19) the Compound or its pharmacologically acceptable salt according to the above p. 1), where R1and R2together with the nitrogen atom to which they are attached, form a group represented by the following formula:

Formula 13

which may be substituted by 1-4 substituents selected from the group of substituents A4.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents, who swear from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-5 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents, selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has A value which, defined above) and (32) =CH-A (where A has the meaning given above).

20) the Compound or its pharmacologically acceptable salt according to the above p. 1), where R1and R2together with the nitrogen atom to which they are attached, form a group represented by the following formula:

Formula 14

which may be substituted by 1-4 substituents selected from the group of substituents A4.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic coal is Ogorodnaya ring group, which may be substituted by 1-5 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above).

21) the Compound or its pharmacologically acceptable salt according to the above p. 20)where R1and R2together with the nitrogen atom to which they are attached, form a group represented by the following formula:

Formula 15

which may be substituted by 1-4 mixing what italiani, selected from the group of substituents A4.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group is amestitelj A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above).

22) the Compound or its pharmacologically acceptable salt according to the above p. 21), where the group formed by R1and R2together with the nitrogen atom to which they are connected, may be substituted by 1 to 4 fluorine atoms.

23) the Compound or its pharmacologically acceptable salt according to the above p. 1), where R1and R2together with the-X1-CO-N may form a cyclic group represented by the formula (V):

Formula 16

(where Z1represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -SO2-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO - or (10) a simple bond; Z2represents (1) a methine group or (2) a nitrogen atom; R7 is a Deputy selected from the group of substituents A3 shown below; and nanband ncrepresent an integer having a value of from 0 to 4)which may be substituted by 1-4 substituents selected from the group of substituents A4.

Group Vice A3: (1) hydrogen atom, (2) halogen atom, (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of formyl group, halogen atom, hydroxyl group, hydroxyl group containing protective group, ceanography, C2-6-alkenylphenol group, C2-6-alkenylphenol group, C3-8-cycloalkyl group, C1-6-alkoxygroup, C1-6-allylthiourea, C1-6-alkylsulfonyl group, C1-6-alkylsulfonyl group, C1-6-alkylcarboxylic group, an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the groups of the substituents A4, 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group Vice-A4, and-X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group, which may be substituted by 1-3 substituents selected from the group of substituents A4)and (6) C1-6-alkoxygroup.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which can be substituted 1 - substituents, selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-5 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above.

24) the Compound or its pharmacologically acceptable salt according to the above p. 1), where R1and R2together with the-X1-CO-N may form a cyclic group represented by the formula (VI):

Formula 17

(where Z3represents (1) a simple link, (2) -CO-, (3) -(CH2nd- (where ndis an integer having a value of from 1 to 3) or (4) -CR8R9- (where R8and R9represent a Deputy selected from the group of substituents A4 shown below;

Z4represents (1) a simple link, (2) -O-, (3) -NRCO-, (4) -CONR-, (5) -CSNR-, (6)-NRCS- (where R represents a Deputy selected from the group of substituents A4 below) or (7) -S-;

Z5represents (1) a simple link, (2) aminogroup, which can be substituted by the Deputy selected from the group of substituents A4 below (3) -(CH2ne- (where neis an integer having a value of from 1 to 3), (4) -CR8R9- (where R8and R9have the meanings defined above) or (5) -O-; and R1is a Deputy selected from the group of substituents A4, and R7is a Deputy selected from the group of substituents A3), which may be substituted by 1-4 substituents selected from the group replace what she A4.

Group Vice A3: (1) hydrogen atom, (2) halogen atom, (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of formyl group, halogen atom, hydroxyl group, hydroxyl group containing protective group, ceanography, C2-6-alkenylphenol group, C2-6-alkenylphenol group, C3-8-cycloalkyl group, C1-6-alkoxygroup, C1-6-allylthiourea, C1-6-alkylsulfonyl group, C1-6-alkylsulfonyl group, C1-6-alkylcarboxylic group, an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents, select nimi from the group of substituents A4, 5-14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group Vice-A4, and-X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4)and (6) C1-6-alkoxygroup.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic is practical hydrocarbon ring group, which may be substituted by 1-5 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above).

25) the Compound or its pharmacologically acceptable salt according to the above p. 24), where Formula (VI) is a cyclic group:

Formula 18

(where R1and R51is a Deputy selected from the group of substituents A4, and R7is a Deputy, selected from the group of substituents A3), which may be substituted by 1-4 substituents selected from the group of substituents A7.

Group Vice A3: (1) hydrogen atom, (2) halogen atom, (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of formyl group, halogen atom, hydroxyl group, hydroxyl group containing protective group, ceanography, C2-6-alkenylphenol group, C2-6-alkenylphenol group, C3-8-cycloalkyl group, C1-6-alkoxygroup, C1-6-allylthiourea, C1-6-alkylsulfonyl group, C1-6-alkylsulfonyl group, C1-6-alkylcarboxylic group, an amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group for whom estately A4, 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4 and -- X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4)and (6) C1-6-alkoxygroup.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from gruppesamtale A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-5 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group, which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above).

Group Vice A7: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) C3-8-cycloalkyl group, (6) C3-8-kloeckera, (7) C1-6-acylcarnitine group, (8) C1-6-allylthiourea, (9) C1-6-alkylsulfanyl group, (10) C1-6-alkylsulfonyl group, (11) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-5 substituents selected from the group consisting of halogen atom, C1-6-alkyl groups, 6-14-membered aromatic hydrocarbon ring group, a 5 to 14-membered aromatic heterocyclic group and -- O-A3(where A3is a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group)), (12) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 halogen atoms, or together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group), (13) amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), (14) 6-14-membered aromatic hydrocarbon ring group, which may be substituted by 1-3 substituents selected from the group of substituents A7, (15) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, (16) 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents, selected isgroup Vice-A7, and (17) -CO-A3(where A3shall have the meaning given above).

26) the Compound or its pharmacologically acceptable salt according to the above p. 1), where R1and R2together with the-X1-CO-N, may form a cyclic group represented by the following formula:

Formula 19

(where R1and R7have the meaning given above), which may be substituted by 1-4 substituents selected from the group of substituents A4.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from g is uppy Vice A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-5 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the value defined above) and (32) =CH-A (where A has the meaning given above).

27) the Compound or its pharmacologically acceptable salt in accordance with the above paragraphs. 24) and 26), where R1is a Deputy selected from the group of substituents A8.

Group Vice A8: (1) hydrogen atom, (2) C1-6-alkylene the group (where this C1-6-alkyl group may be substituted by 1-3 substituents, selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous group and the two C1-6-alkyl groups together with the carbon atom to which they are bound, may form a cyclic group (where a methylene group in the cyclic group which forms the ring may be substituted with one oxygen atom)), C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, and-X-A2(where X represents aminogroup, -O - or-S-, and A2is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents, selected isgroup Vice-A7, or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7)), (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, and (5) -X-A2(where X and A2have the meanings defined above).

Group Vice A7: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) C3-8-cycloalkyl group, (6) C3-8-cycloalkanes, (7) C1-6-acylcarnitine group, (8) C1-6-allylthiourea, (9) C1-6-alkylsulfanyl group, (10) C1-6-alkylsulfonyl group, (11) C1-6-alkyl group (where specified C1-6 is an alkyl group may be substituted by 1-5 substituents selected from the group consisting of halogen atom, C1-6-alkyl groups, 6-14-membered aromatic hydrocarbon ring group, a 5 to 14-membered aromatic heterocyclic group and -- O-A3(where A3is a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group), (12) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 halogen atoms, or together with the atom is m carbon bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group), (13) amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), (14) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7, (15) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, (16) 5 to 14-membered non-aromatic heterocyclic group, which may be substituted by 1-3 substituents selected from the group of substituents A7 and (17) -CO-A3(where A3shall have the meaning given above).

28) the Compound or its pharmacologically acceptable salt according to the above p. 27), where R1represents a C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous group and the two C1-6-alkyl group together with the carbon atom, to the which they are associated, may form a cyclic group (where a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A9, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9, and-X-A4(where X represents aminogroup, -O - or-S - and A4is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A9, or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9)).

Group Vice A9: (1) hydrogen atom, (2) halogen atom, (3) C3-8-cycloalkyl group, (4) C3-8-cycloalkanes, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-5 substituents, selected the C group, consisting of halogen atom and C1-6-alkyl groups), (6) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 halogen atoms, or together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group), (7) an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), (8) 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents, selected from the group of substituents A9, (9) -CO-A3(where A3is a 6-14-membered aromatic hydrocarbon ring group), (10) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A9, and (11) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9.

29) the Compound or its pharmacologically acceptable salt in accordance with the above paragraphs. 10), 24) and 26), where R1represents-X21-X22-Ar3(where X21represents 1), C1-6-alkylenes group (where specified C1-6-Allenova group may be substituted by 1-3 substituents selected from the group consisting of hydrogen atom, halogen atom, hydroxyl the Oh group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous group and the two C1-6-alkyl groups together with the carbon atom to which they are bound, may form a cyclic group (where a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), a C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl), a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7) or (2) a simple link, and X22represents a simple bond, aminogroup, which can be substituted by the Deputy selected from the group of substituents A7, -O - or-S-, and Ar3is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 or a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7).

Group Vice A7: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) C3-8-cycloalkyl group, (6) C3-8-cycloalkenyl the PA, (7) C1-6-acylcarnitine group, (8) C1-6-allylthiourea, (9) C1-6-alkylsulfanyl group, (10) C1-6-alkylsulfonyl group, (11) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-5 substituents selected from the group consisting of halogen atom, C1-6-alkyl groups, 6-14-membered aromatic hydrocarbon ring group, a 5 to 14-membered aromatic heterocyclic group and -- O-A3(where A3is a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group), (12) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 halogen atoms, or together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group), (13) amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), (14) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7, (15) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, (16) 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected is from the group of substituents A7, and (17) -CO-A3(where A3shall have the meaning given above).

30) the Compound or its pharmacologically acceptable salt according to the above p. 29), where R1represents-X21a-X22a-Ar3a(where X21arepresents a C1-6-alkylenes group (where specified C1-6-Allenova group may be substituted by 1-3 substituents selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous group and the two C1-6-alkyl group together with the carbon atom to which they are bound, may form a cyclic group (where a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom))), C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9), and X22arepresents a simple bond or an oxygen atom and Ar3ais a 6-14-membered aromatic coal is hydrogen ring group, which may be substituted by 1-3 substituents selected from the group of substituents A9, or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9).

Group Vice A9: (1) hydrogen atom, (2) halogen atom, (3) C3-8-cycloalkyl group, (4) C3-8-cycloalkanes, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-5 substituents selected from the group consisting of halogen atom and C1-6-alkyl groups), (6) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 halogen atoms, or together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group), (7) an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), (8) 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9, (9) -CO-A3(where A3is a 6-14-membered aromatic hydrocarbon ring group), (10) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A9, and (11) 5-14-membered aromatic heterocyclic group to which I may be substituted by 1-3 substituents, selected from the group of substituents A9.

31) the Compound or its pharmacologically acceptable salt according to the above p. 30)where Ar3ais a 6-14-membered aromatic hydrocarbon ring group selected from the group consisting of phenyl groups, naftilos group and fluorenyl group, or a 5-14-membered aromatic heterocyclic group selected from the group consisting of thienyl group, peredelnoj group, chinoline group, isohynolines group, indolines group, benzothiazolyl group, benzoxazolyl group and shriley group which may be substituted by 1-3 substituents selected from the group of substituents A9.

Group Vice A9: (1) hydrogen atom, (2) halogen atom, (3) C3-8-cycloalkyl group, (4) C3-8-cycloalkanes, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-5 substituents selected from the group consisting of halogen atom and C1-6-alkyl groups), (6) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 halogen atoms, or together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group), (7) an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), (8) 5-14-the Lenna non-aromatic heterocyclic group, which may be substituted by 1-3 substituents selected from the group of substituents A9, (9) -CO-A3(where A3is a 6-14-membered aromatic hydrocarbon ring group), (10) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A9 and (11) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9.

32) the Compound or its pharmacologically acceptable salt according to the above p. 1), where R1is a 6-14-membered non-aromatic hydrocarbon ring group or 5 to 14-membered non-aromatic heterocyclic group represented by the formula (VII):

Formula 20

(where R8- R12represent 1) a simple link, 2) -CO-, 3) a methylene group which may be substituted by 1 or 2 substituents selected from the group of substituents A4, 4) -O-, 5) aminogroup, which may contain a Deputy selected from the group of substituents A4 or 6) -S-, and Ar4is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4 shown below or a 5 to 14-membered aromatic heterocycle which economic group, which may be substituted by 1-3 substituents selected from the group of substituents A4 below).

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-5 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents, selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above).

33) the Compound or its pharmacologically acceptable salt according to the above p. 32)where Ar4represents a phenyl group or 5 to 14-membered aromatic heterocyclic group selected from the group consisting of pyridinoline group, pyrimidinyl group, personalni group, thienyl group, oxazoline group, pyrrolidino group, thiazolidine group and shriley group which may be substituted by 1-3 substituents selected from the group consisting of halogen atom, C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of and the Ohm halogen and C1-6-alkyl groups), C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1 to 3 halogen atoms), amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from group Vice-A7 and-CO-A2(where A2is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below or a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 below).

Group Vice A7: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) C3-8-cycloalkyl group, (6) C3-8-cycloalkanes, (7) C1-6-acylcarnitine group, (8) C1-6-allylthiourea, (9) C1-6-alkylsulfanyl group, (10) C1-6-alkylsulfonyl group, (11) C1-6-alkyl group (where the decree is fair C1-6-alkyl group may be substituted by 1-5 substituents, selected from the group consisting of halogen atom, C1-6-alkyl groups, 6-14-membered aromatic hydrocarbon ring group, a 5 to 14-membered aromatic heterocyclic group and -- O-A3(where A3is a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group), (12) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 halogen atoms, or together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group), (13) amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), (14) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7, (15) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, (16) 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 and (17) -CO-A3(where A3shall have the meaning given above).

34) the Compound or its pharmacologically acceptable salt according to the above p. 33), where R1is the Wallpaper indenolol group, isanganiro group, tetrahydronaphthyl group, asterolecaniidae group, romanello group, azihromycin group, tetrahydrofuranyl group or tetrahydroisoquinoline group which may be substituted by 1-3 substituents selected from the group consisting of (1) halogen atom, (2) hydroxyl group, (3) ceanography, (4) C3-8-cycloalkyl group, (5) C3-8-cycloalkanes, (6) C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1-3 halogen atoms or C1-6-alkyl groups), (7) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1 to 3 halogen atoms), (8) amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms)and (9) 5-14-membered non-aromatic heterocyclic group.

35) the Compound or its pharmacologically acceptable salt according to the above p. 1), selected from the following groups:

1) (E)-N-biphenyl-3-ylmethyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide,

2) (E)-N-((1S)-indan-1-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylamide,

3) (E)-N-(chroman-4-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylamide,

4) (E)-1-(3,4-diferensial)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it,

5) (E)-1-indan-2-yl-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzilic is n)piperidine-2-it,

6) (E)-1-(chroman-4-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it,

7) (E)-1-((1S)-1-(4-forfinal)ethyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it,

8) (E)-1-((6-chloropyridin-2-yl)methyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it,

9) (E)-1-(4-tert-butylbenzyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it,

10) (E)-1-(3,4-diferensial)-3-((5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-yl) methylene)piperidine-2-it,

11) (E)-1-((1H-indol-3-yl)ethyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it,

12) (E)-1-(5-Florinda-2-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it,

13) (E)-1-(7-ferroman-4-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it,

14) (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)piperidine-2-he

15) (E)-1-((2,4-differenl)ethyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it.

36) the Agent for the prevention or treatment of a disease caused by beta-amyloid, comprising as active ingredient a compound represented by the General formula (I)or its pharmacologically acceptable salt.

37) the Agent for the prevention or treatment in accordance with the above p. 36), where the disease is caused by beta-amyloid, is a Alzheimer's disease, senile d is manciu, down's syndrome or amyloidosis.

The compound of General formula (I) according to the present invention or its pharmacologically acceptable salt and agent for the prevention or treatment of diseases caused by Aβ are new inventions that are not described in the documents.

Below is an explanation of the symbols, terms, etc. used in the present description, and detailed description of the present invention.

Although the structural formula of the compound may represent a specific isomer, as it is convenient to represent in the present description, the present invention includes all isomers such as geometrical isomers that can be formed from the structure of the compound, optical isomers based on the chiral carbon (carbon), stereoisomers and tautomers, and a mixture of isomers, and the present invention is not limited to the formula described for convenience, and may represent either one of the isomers or a mixture of isomers. Therefore, although some molecules may contain a chiral carbon atom in its structure and can be optically-active substance and the racemate, the present invention is not limited to such a specific connection and includes any of these compounds. Moreover, crystalline polymorphs that may exist, is not limited, and may represent either one of the Fe crystals, or their mixture can be in the form of a hydrate or may be an anhydride.

The term "disease (s)caused by Aβ" covers a broad range of diseases, including Alzheimer's disease (for example, see Klein WL, and seven others, Alzheimer's disease-affected brain: presence of oligomeric Aβ ligands (ADDLs) suggests molecular basis for reversible memory loss, Proceeding National Academy of Science USA, 2003, Sep 2, 100(18), p. 10417-10422;

Nitsch RM, and 16 others, Antibodies against β-amiloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22, 38(4), p. 547-554;

Jarrett JT, and 2 others, The carboxy terminus of the β-amiloid protein is critical for the seeding of amiloid formation: implications for the pathogenesis of Alzheimer's disease, Biochemistry, 1993, May 11, 32(18), p. 4693-4697;

Glenner GG, and another, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amiloid protein, Biochem Biophys Res Commun, 1984, May 16, 120(3), p. 885-890;

Masters CL, and six others, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceeding National Academy of Science USA, 1985, Jun, 82(12), p. 4245-4249;

Gouras GK, and eleven others, Intraneuronal Aβ42 accumulation in human brain, American Journal of Pathology, 2000, Jan, 156(1), p. 15-20;

Scheuner D, and twenty others, Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine, 1996, Aug, 2(8), p. 864-870; and

Forman MS, and 4 others, Differential effects of the swedish mutant amyloid precursor protein on β-amyloid accumulation and secretion in neurons and nonneuronal cells, Journal of Biological Chemistry, 1997, Dec 19, 272(51), p. 32247-32253.), senile dementia (for example, see Blass JP, Brain metabolism and brain disease: is metabolic deficiency = MKD the proximate cause of Alzheimer dementia? Journal of Neuroscience Research, 2001, Dec 1, 66(5), p. 851-6.), frontotemporal dementia (for example, see Evin G, and eleven others, Alternative ranscripts of presenilin-1 associated with frontotemporal dementia, Neuroreport, 2002, Apr 16, 13(5), p. 719-723.), Pick disease (for example, see Yasuhara O, and three others, Accumulation of amyloid precursor protein in brain lesions of patients with Pick disease, Neuroscience Letters, 1994, Apr 25, 171(1-2), p. 63-66.), Down syndrome (for example, see Teller JK, and ten others, Presence of soluble amyloid β-peptide precedes amyloid plaque formation in Down''s syndrome, Nature Medicine, 1996, Jan, 2(1), p. 93-95; and

Tokuda T, and six others, Plasma levels of amyloid β proteins Aβ1-40 and Aβ1-42(43) are elevated in Down''s syndrome, Annals of Neurology, 1997, Feb, 41(2), p. 271-273.), cerebral amyloid angiopathy (for example, see Hayashi Y, and nine others, Evidence for presenilin-1 involvement in amyloid angiopathy in the Alzheimer's disease-affected brain, Brain Research, 1998, Apr 13, 789(2), p. 307-314;

Barelli H, and fifteen others, Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid β peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer's disease and cerebral amyloid angiopathy cases, Molecular Medicine, 1997, Oct, 3(10), p. 695-707;

Calhoun ME, and ten others, in Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid, Proceeding National Academy of Science USA, 1999, Nov 23, 96(24), p. 14088-14093; and

Dermaut B, and ten others, Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation, Brain, 2001, Dec, 124(Pt 12), p. 2383-2392.), hereditary cerebral hemorrhage with amyloidosis-Dutch type (for example, see Cras p. and nine others, Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala-->Gly mutation, Acta Neuropathologica (Berl), 1998, Sep, 96(3), p. 253-260;

Herzig MC, and fourteen others, Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis, Nature Neuroscience, 2004, Sep, 7(9), p. 954-960;

Van Duinen SG, and five others, Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer's disease, Proceeding National Academy of Science USA, 1987, Aug, 84(16), p. 5991-994; and

Levy E, and eight others, Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type, Science, 1990, Jun 1, 248(4959), p. 1124-1126.), his or her cognitive (for example, see Laws SM, and seven others, Association between the presenilin-1 mutation Glu318Gly and complaints of his or her memory, Neurobiology of Aging, 2002, Jan-Feb, 23(1), p. 55-58.), memory disorder/ learning disorder (for example, see Vaucher E, and five others, Object recognition memory and cholinergic parameters in mice expressing human presenilin 1 transgenes, Experimental Neurology, 2002, Jun, 175(2), p. 398-406;

Morgan D, and fourteen others, Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease, Nature, 2000, Dec 21-28, 408(6815), p. 982-985; and

Moran PM, and three others, Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human β-amyloid precursor protein, Proceeding National Academy of Science USA, 1995, Jun 6, 92(12), p. 5341-5345.), amyloidosis, cerebral ischemia (for example, see Laws SM, and seven others, Association between the presenilin-1 mutation Glu318Gly and complaints of his or her memory, Neurobiology of Aging, 2002, Jan-Feb, 23(1), p. 55-58;

Koistinaho M, and ten others, β-amyloid precursor protein transgenic mice that harbor diffuse Aβ deposits but do not form plaques show increased ischemic vulnerability: role of inflammation, Proceeding National Academy of Science USA, 2002, Feb 5, 99(3), p. 1610-1615; and

Zhang F, and four others, Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein, " Journal of Neuroscience, 1997, Oct 15, 17(20), p. 7655-7661.), vascular dementia (for example, see Sadowski M, and six others, Links between the pathology of Alzheimer's disease and vascular dementia, Neurochemical Research, 2004, Jun, 29(6), p. 1257-1266.), ophthalmoplegia(eye muscle paralysis) (for example, see O'riordan S, and seven others, Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities, Neurology, 2002, Oct 8, 59(7), p. 1108-1110.), multiple sclerosis (for example, see Gehrmann J, and four others, Amyloid precursor protein (APP) expression in multiple sclerosis lesions, Glia, 1995, Oct 15(2), p. 141-151; and

Reynolds, WF, and six others, Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer's disease, Experimental Neurology, 1999, Jan, 155(1), p. 31-41.), head trauma, cranial damage (for example, see Smith DH, and four others, Protein accumulation in traumatic brain injury, Neuromolecular Medicine, 2003, 4(1-2), p. 59-72.), apraxia (for example, see Matsubara-Tsutsui M, and seven others, Molecular evidence of presenilin 1 mutation in familial early onset dementia, American Journal of Medical Genetics, 2002, Apr 8, 114(3), p. 292-298.), prion disease, familial amyloid neuropathy, triplet repeat disease (for example, see Kirkitadze MD, and two others, Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies, Journal of Neuroscience Research, 2002, Sep 1, 69(5), p. 567-577;

Evert BO, and eight others, Inflammatory genes are upregulated in expanded ataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains, Journal of Neuroscience, 2001, Aug 1, 21(15), p. 5389-5396; and

Mann DM, and another, Deposition of amyloid (A4) protein within the brains of persons with dementing disorders other than Alzheimer's disease and Down''s syndrome, Neuroscience Letters, 1990, Feb 5, 109(1-2), p. 68-75.), PA's disease (for example, see the Primavera J, and four others, Brain Accumulation of Amyloid-β in Non-Alzheimer Neurodegeneration, Journal of Alzheimer's Disease, 1999, Oct, 1(3), p. 183-193.), Dementia with Lewy bodies (for example, see Giasson BI, and two others, Interactions of amyloidogenic proteins, Neuromolecular Medicine, 2003, 4(1-2), p. 49-58;

Masliah E, and six others, β-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and PA's disease, Proceeding National Academy of Science USA, 2001, Oct 9, 98(21), p. 12245-12250;

Barrachina M, and six others, Amyloid-β deposition in the cerebral cortex in Dementia with Lewy bodies is accompanied by a relative increase in AβPP mRNA isoforms containing the Kunitz protease inhibitor, Neurochemistry International, 2005, Feb, 46(3), p. 253-260; and

Primavera J, and four others, Brain Accumulation of Amyloid-β in Non-Alzheimer Neurodegeneration,Journal of Alzheimer's Disease, 1999, Oct, 1(3), p. 183-193.), Parkinsonism-dementia complex (PDC) (for example, see Schmidt ML, and six others, Amyloid plaques in Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex contain species of Aβ similar to those found in the amyloid plaques of Alzheimer's disease and pathological aging, Acta Neuropathologica (Berl), 1998, Feb, 95(2), p. 117-122; and

Ito H, and three others, Demonstration of β amyloid protein-containing neurofibrillary tangles in parkinsonism-dementia complex on Guam, Neuropathology and Applied Neurobiology, 1991, Oct, 17(5), p. 365-373.), frontotemporal dementia-parkinsonism linked to chromosome 17 (FTDP-17) (for example, see Rosso SM, and three others, Coexistent tau and amyloid pathology in hereditary frontotemporal dementia with tau mutations, Annals of the New York Academy of Science, 2000, 920, p. 115-119.), dementia with argyrophilic grains (for example, see Tolnay M, and four others, Low amyloid (Aβ) plaque load and relative predominance of diffuse plaques distinguish argyrophilic grain disease from Alzheimer's disease, Neuropathology and Applied Neurobiology, 1999, Aug, 25(4), p. 295-305.), Niemann-Pick disease (for example, see Jin LW, and three others, Intracellular accumulation of amyloidogenic fragments of amyloid-β precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities, American Journal of Pathology, 2004, Mar, 164(3), p. 975-985.), amyotrophic lateral scleraosis (for example, see Sasaki S, and another, Immunoreactivity of β-amyloid precursor protein in amyotrophic lateral sclerosis, Acta Neuropathologica (Berl), 1999, May, 97(5), p. 463-468;

Tamaoka A, and four others, Increased amyloid β protein in the skin of patients with amyotrophic lateral sclerosis, Journal of Neurology, 2000, Aug, 247(8), p. 633-635;

Hamilton RL, and another, Alzheimer's disease pathology in amyotrophic lateral sclerosis, Acta Neuropathologica (Berl), 2004, Jun, 107(6), p. 515-522; and

Turner BJ, and six others, Brain β-amyloid accumulation in transgenic mice expressing mutant superoxide dismutase 1, Neurochemical Research, 2004, Dec, 29(12), p. 2281-2286.), hydrocephalus (for example, see Weller RO, Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer's disease, pion disorders and multiple sclerosis, Journal of Neuropathology and Experimental Neurology, 1998, Oct, 57(10), p. 885-894;

Silverberg GD, and four others, Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory discrimination: a hypothesis, Lancet Neurology, 2003, Aug, 2(8), p. 506-511;

Weller RO, and three others, Cerebral amyloid angiopathy: accumulation of Aβ in interstitial fluid drainage pathways in Alzheimer's disease, Annals of the New York Academy of Sciences, 2000, Apr, 903, p. 110-117;

Yow HY, and another, A role for cerebrovascular disease in determining the pattern of β-amyloid deposition in Alzheimer's disease, Neurology and applied neurobiology, 2002, 28, p. 149; and

Weller RO, and four others, Cerebrovascular disease is a major factor in the failure of elimination of A from the aging human brain, Annals of the New York Academy of Sciences, 2002, Nov, 977, p.162-168.), incomplete parapalegia (for example, see O'riordan S, and seven others, Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities, Neurology, 2002, Oct 8, 59(7), p. 1108-10;

Matsubara-Tsutsui M, and seven others, Molecular evidence of presenilin 1 mutation in familial early onset dementia, American Journal of Medical Genetics, 2002, Apr 8, 114(3), p. 292-8;

Smith MJ, and eleven others, Variable phenotype of Alzheimer's disease with spastic paraparesis, Ann Neurol. 2001 Jan, 49(1), p. 125-129; and

Crook R, and seventeen others, A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1, " Nature Medicine, 1998, Apr, 4(4), p.452-455.), progressive supranuclear palsy (PSP) (for example, see Masliah E, and six others, β-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and PA's disease, Proceeding National Academy of Science USA, 2001,Oct 9, 98(21), p. 12245-12250; and

Primavera J, and four others, Brain Accumulation of Amyloid-β in Non-Alzheimer Neurodegeneration, Journal of Alzheimer's Disease, 1999, Oct, 1(3), p. 183-193.), cerebral hemorrhage (for example, see Atwood CS, and three others, Cerebrovascular requirement for sealant, anti-coagulant and remodeling molecules that allow for the maintenance of vascular integriy and blood supply, Brain Research Review, Sep 2003, 43(1), p. 164-178; and

Lowenson JD, and 2 others, Protein Aging: increasing interest among amyloid formation and intracellular repair, Trends in Cirdiovascular medicine, 1994, 4(1), p. 3-8.), spasm (for example, see Singleton AB, and thirteen others, Pathology of early-onset Alzheimer's disease cases bearing the Thr113-114ins presenilin-1 mutation, Brain, 2000, Dec, 123 Pt 12, p. 2467-2474.), mild cognitive his or her (for example, see Gattaz WF, and four others, Platelet phospholipase A(2) activity in Alzheimer's disease and mild his or her cognitive, Journal of Neural Transmission, 2004, May, 111(5), p. 591-601; and

Assini A, and four others, Plasma levels of amyloid β-protein 42 are increased in women with mild his or her cognitive, Neurology, 2004, Sep 14, 63(5), p. 828-831.), atherosclerosis (for example, see De Meyer GR, and eight others, Platelet phagocytosis and processing of β-amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis, Circulation Research, 2002, Jun 14, 90(11), p. 1197-1204.), etc.

"6-14-membered aromatic hydrocarbon ring group," "5 to 14-membered aromatic heterocyclic group," "6-14-membered non-aromatic hydrocarbon ring group" and "5 to 14-membered non-aromatic heterocyclic group" in the above formula (I)contained in the agent for the prevention or treatment of diseases caused by Aβ, according to the present invention, have the following meanings.

"6-14-membered aromatic hydrocarbon ring group" means a monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring group containing 6-14 carbon atoms and preferable groups include monocyclic, bicyclic or tricyclic 6-14-the Lenna aromatic hydrocarbon ring group, for example, a phenyl group, indenolol group, naftalina group, azulinebloo group, heptylaniline group, biphenylene group, fluorenyl group, phenalenyl group, phenanthroline group, antarctilyne group, etc.

"5 to 14-membered aromatic heterocyclic group" refers to a monocyclic, bicyclic or tricyclic aromatic heterocyclic group containing 5 to 14 atoms and preferable groups include, for example, (1) nitrogen-containing aromatic heterocyclic groups such as pyrrolidine group, Peregrina group, pyridazinyl group, pyrimidinyl group, piratininga group, piratininga group, imidazolium, indayla group, isoindolyl group, indolizinyl group, polylina group, indazolinone group, kinolinna group, izochinolina group, hyalinella group, phthalazinone group, naphthylethylene group, khinoksalinona group, hinazolina group, indolenine group, peridiniella group, imidazolidinyl group, pirazinamida group, accidenily group, phenanthridinone group, carbazolyl group, pyrimidinone groups, phenanthroline group and penicilina group; (2) sulfur-containing aromatic heterocyclic groups such as thienyl group and b is satanella group; (3) oxygen-containing aromatic heterocyclic groups such as furilla group, Pernilla group, cyclopentadienyl group, benzofuranyl group and isobenzofuranyl group; (4) aromatic heterocyclic groups containing two or more heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, such as thiazolidine group, isothiazolinone group, benzothiazolyl group, benzothiadiazole group, phenothiazinyl group, isoxazolyl group, furazolidine group, phenoxypyridine group, pyrazoloquinoline group, imidazothiazole group, thienopyridine group, properally group, pyridoxamine group, etc.

"6-14-membered non-aromatic hydrocarbon ring group" refers to a cyclic aliphatic hydrocarbon group containing 6-14 carbon atoms, and means, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, Spiro[3.4]octanediol group, deganello group, indenolol group, 1-acenaphthylene group, Cyclopentasiloxane group, benzocyclobutene group, indenolol group, tetrahydronaphthyl group, 6,7,8,9-tetrahydro-5H-benzocycloheptene group, 1,4-digitron talinolol group and other cyclic aliphatic hydrocarbon group, containing 6-14 carbon atoms.

"5 to 14-membered non-aromatic heterocyclic group" means not only a 5-14-membered non-aromatic heterogenities group, but also saturated heterocyclic group condensed with an aromatic hydrocarbon ring group, or a saturated hydrocarbon ring group or a saturated heterocyclic group condensed with an aromatic heterocyclic group(or groups), which 1) contains 5-14 forming ring atoms, 2) contains 1-5 heteroatoms such as a nitrogen atom, -O - or-S-, from forming ring atoms, and (3) may contain one or more carbonyl groups, double bonds, or triple bonds in the ring. Specific examples 5-14-membered non-aromatic heterocyclic groups include azetidinone ring, pyrrolidinyl ring, piperidinyl ring, aspenlea ring, atconline ring, tetrahydropyrimidine ring, tetrahydropyrimidine ring, morpholinyl ring, thiomorpholine ring, piperazinilnom ring, thiadiazolidine ring, dioxinlike ring, imidazolidine ring, thiadiazolidine ring, 1,2-benzopyranyl ring, isopropanole ring, chromaline ring, indolenine ring, isoindoline ring, isoindoline group, asterolecaniidae gr the PPU, azihromycin group, tetrahydrofuranyl group, tetrahydroisoquinoline group, 2,3,4,5-tetrahydrobenzo[b]thienyl group, a 3,4-dihydro-2H-benzo[b][1,4]dioxyphenyl group, indan-1-onlineu group, 6,7-dihydro-5H-cyclopentadienyl group, 6,7-dihydro-5H-[1]-pyridinyl group, 6,7-dihydro-5H-[1]-pyridinyl group, 5,6-dihydro-4H-cyclopent[b]thienyl group, 4,5,6,7-tetrahydrobenzo[b]thienyl group, a 3,4-dihydro-2H-Naftali-1-onlineu group, 2,3-dihydroindol-1-onlineu group, 3,4-dihydro-2H-isoquinoline-1-onlineu group, 3,4-dihydro-2H-benzo[1,4]examinining group, etc.

The group of substituents A1, group Vice A2, group Vice A3, group Vice A4, group Vice A5, group Vice A6, group Vice A7, group Vice A8, group Vice-A9 and a group of deputies A10 represent the following groups.

The group of substituents A1 refers to the following groups: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) the nitro-group, (5) C3-8-cycloalkyl group, (6) C2-6-Alchemilla group, (7) C2-6-Alchemilla group, (8) C1-6-alkoxygroup, (9) C3-8-cycloalkanes, (10) formyl group, (11) C1-6-acylcarnitine group or (12) C1-6 is an alkyl group (where the above C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of a halogen atom, hydro is a strong group, ceanography, C1-6-alkoxygroup, C3-8-cycloalkyl group and C1-6-alkylcarboxylic group).

Group Vice A2 refers to the following groups: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-3 substituents selected from the group consisting of a halogen atom, ceanography, C1-6-alkoxygroup, C2-6-alkenylphenol group, C2-6-alkenylphenol group and C3-8-cycloalkyl group), (6) C3-8-cycloalkanes, (7) C2-6-alkenylacyl or (8) C2-6-alkyloxy.

Group Vice A3 refers to the following groups: (1) hydrogen atom, (2) halogen atom, (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of formyl group, of halogen atom, hydroxyl group, hydroxyl group containing protective group, ceanography, C2-6-alkenylphenol group, C2-6-alkenylphenol group, C3-8-cycloalkyl group, C1-6-alkoxygroup, C1-6-allylthiourea, C1-6-alkylsulfonyl group, C1-alkylsulfonyl group, C1-6-alkylcarboxylic group, an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A4, 5 to 14-membered non-aromatic heterocyclic group which may to be substituted by 1-3 substituents selected from the group Vice-A4, and-X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4)or (6) C1-6-alkoxygroup.

Group Vice A4 refers to the following groups: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl gr is the PAP (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 substituents selected from the group of substituents A4, (20) amino group which may be substituted by 1-2 substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-5 substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 substituents, selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X submitted is aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above), or (32) =CH-A (where A has the meaning given above).

Group Vice A5 refers to the following groups: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) C3-8-cycloalkyl group, (6) C3-8-cycloalkanes, (7) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-5 halogen atoms) (8) C1-6-alkoxygroup (where specified alkoxygroup may be substituted by 1-5 halogen atoms) or (9) an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms).

Group Vice A6 refers to the following groups: (1) hydrogen atom, (2) C3-8-cycloalkyl group, (3) C3-8-cycloalkanes, (4) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of halogen atom, hydroxyl group, cyano groups, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-alkylthio, hydroxyimino, C1-6-alkoxyimino, C1-6-alkoxygroup, amino (glaucosoma amino group may be substituted by C1-6-alkyl groups, not necessarily containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, and-O-A2(where A2is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below or a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 below), or (5) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-allylthiourea, hydroxyimino, C1-6-alkoxyamino, C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl groups is, not necessarily containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, and-O-A2(where A2shall have the meaning given above)).

Group Vice A7 refers to the following groups: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) C3-8-cycloalkyl group, (6) C3-8-cycloalkanes, (7) C1-6-acylcarnitine group, (8) C1-6-allylthiourea, (9) C1-6-alkylsulfanyl group, (10) C1-6-alkylsulfonyl group, (11) C1-6-alkyl group (where mentioned C1-6-alkyl group may be substituted by 1-5 substituents selected from the group consisting of halogen atom, C1-6-alkyl groups, 6-14-membered aromatic hydrocarbon ring group, a 5 to 14-membered aromatic heterocyclic group and -- O-A3(where A3is a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic hetaeras the cyclic group)), (12) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 halogen atoms, or together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group), (13) amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), (14) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7, (15) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, (16) 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, or (17) -CO-A3(where A3shall have the meaning given above).

Group Vice A8 refers to the following groups: (1) hydrogen atom, (2) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous the group and the two C1-6-alkyl groups together with the carbon atom, with which they are linked, may form a cyclic group (where a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, 5-14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, and-X-A2(where X represents aminogroup, -O - or-S-, and A2is a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7)), (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7, is whether (5) -X-A 2(where X and A2have the meanings defined above).

Group Vice A9 applies to the following groups: (1) hydrogen atom, (2) halogen atom, (3) C3-8-cycloalkyl group, (4) C3-8-cycloalkanes, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-5 substituents selected from the group consisting of halogen atom and C1-6-alkyl groups), (6) C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 by halogen atoms or together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group), (7) an amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), (8) 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9, (9) -CO-A3(where A3is a 6-14-membered aromatic hydrocarbon ring group), (10) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A9, or (11) a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9.

Group Vice A10 refers to the following GRU is pam: (1) a hydrogen atom, (2) halogen atom, (3) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-5 halogen atoms), (4) C1-6-alkoxygroup and (5) 6-14-membered aromatic hydrocarbon ring group.

The term "halogen atom" refers to fluorine atom, chlorine atom, bromine, iodine, etc. and preferably to fluorine atom, chlorine and bromine.

The term "C1-6-alkyl group" refers to an alkyl group containing 1-6 carbon atoms and preferable groups include linear or branched alkyl groups such as methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, tert-boutelou group, n-pentelow group, isopentyl group, neopentyl group, n-hexoloy group, 1-methylpropyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, etc.

The term "C1-6-alkoxygroup" refers to a group in which a hydrogen atom in the alkyl group containing 1-6 carbon atoms has been replaced by an oxygen atom, and preferable groups include the indicate, for example, a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, n-phenoxypropan, isobutoxy, sec-phenoxypropan, tert-phenoxypropan, n-hexachrome, isohexadecane, 1,2-DIMETHYLPROPANE, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropyl, 1,1,2-trimethylpropyl, 1,1-Dimethylbutane, 2,2-Dimethylbutane, 2-ethylbutane, 1,3-Dimethylbutane, 2-methylphenoxy, 3-methylphenoxy, hexyloxy etc.

The term "C1-6-alkylsulfonyl group" refers to a group in which a hydrogen atom in the alkyl group containing 1-6 carbon atoms has been replaced by sulfonyloxy group, preferred groups include, for example, methanesulfonyl group, ethanolgasoline group, etc.

The term "amino group which may be substituted by C1-6-alkyl group" refers to an amino group which may be substituted by alkyl groups containing 1-6 carbon atoms and preferable groups include, for example, an amino group, methylaminopropyl, ethylamino, propylamino, dimethylaminopropyl etc.

The term "C2-6-Alchemilla group" refers to alkenylphenol group containing 2-6 carbon atoms, and prepact the positive group include linear or branched alkeneamine group, for example, vinyl group, allyl group, 1-propenyloxy group, Isopropenyl group, 1-butene-1-ilen group, 1-butene-2-ilen group, 1-butene-3-ilen group, 2-butene-1-ilen group, 2-butene-2-ilen group, etc.

The term "C2-6-Alchemilla group" refers to alkenylphenol group containing 2-6 carbon atoms and preferable groups include linear or branched alkyline group, for example etinilnoy group, 1-propenyloxy group, 2-propenyloxy group, butenyloxy group, pantanillo group, hexylamino group, etc.

The term "C3-8-cycloalkyl group" refers to a cyclic alkyl group containing 3 to 8 carbon atoms and preferable groups include, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, etc.

The term "C1-6-allylthiourea" refers to a group in which a hydrogen atom in the alkyl group containing 1-6 carbon atoms has been replaced by a sulfur atom, and preferable groups include, for example, methylthiourea, ethylthiourea, n-PropertyGroup, isopropylthio, n-butylthiourea, isobutylthiazole, tert-butylthiourea, n-intelligroup, isopentype, pointertype, n-vexillographer, 1-methylpropyloxy etc.

The term "C1-6-alkylsulfonyl the group" refers to a group, in which the hydrogen atom in the alkyl group containing 1-6 carbon atoms has been replaced by sulfanilic group, preferred groups include, for example, methylsulfinyl group, ethylmethylamino group, n-propylsulfonyl group, isopropylphenyl group, n-butylsulfonyl group, isobutylamino group, tert-butylsulfonyl group, n-pentylaniline group, isopentenyladenine group, neopentylene group, n-hexylaniline group, 1-methylpropyl sulfonyloxy group, etc.

The term "C1-6-acylcarnitine group" refers to a group in which a hydrogen atom in the alkyl group containing 1-6 carbon atoms has been replaced by a carbonyl group, and preferred groups include, for example, acetyl group, propionyl group, butyryloxy group, etc.

The term "C3-8-cycloalkanes" refers to a group in which a hydrogen atom in the cyclic alkyl group containing 3-8 carbon atoms has been replaced by an oxygen atom, and preferable groups include, for example, cyclopropane, cyclobutanes, cyclopentamine, cyclohexamide, cycloheptylamine, cyclooctylamine etc.

The term "C3-8-cycloalkylation" refers to a group in which a hydrogen atom in the cyclic alkyl group containing 3-8 atmosukarto, was replaced by a sulfur atom, and preferable groups include, for example, cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexylprop, cycloheptylamine, cyclooctylamine etc.

The term "C1-6-alkoxyimino" refers to a group in which a hydrogen atom in aminogroup was substituted C1-6-alkoxygroup, and preferred groups include, for example, methoxyimino, toksikologiya etc.

The term "C2-6-alkenylacyl" refers to a group in which a hydrogen atom in alkenylphenol group containing 2-6 carbon atoms has been replaced by an oxygen atom, and preferable groups include linear or branched alkenylacyl, such as vinyloxy, allyloxy, 1-propenyloxy, isopropenylacetate, 1-butene-1-lexigraphy, 1-butene-2-lexigraphy, 1-butene-3-lexigraphy, 2-butene-1-lexigraphy, 2-butene-2-lexigraphy.

The term "C2-6-alkyloxy" refers to a group in which a hydrogen atom in alkenylphenol group containing 2-6 carbon atoms has been replaced by an oxygen atom, and preferable groups include linear or branched alkyloxy, such as atenololviagrawp, 1-propenyloxy, 2-propenyloxy, butenyloxy, pentyloxy, hexyloxy etc.

The term "C3-8-cycloalkylcarbonyl group" regarding the priority for the group, in which the hydrogen atom in the cyclic alkyl group containing 3-8 carbon atoms, was substituted sulfanilic group, preferred groups include, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylcarbonyl group, cycloheptylmethyl group, cyclooctylmethyl group, etc.

The term "C3-8-cycloalkylcarbonyl group" refers to a group in which a hydrogen atom in the cyclic alkyl group containing 3-8 carbon atoms, was substituted sulfonyloxy group, preferred groups include, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylcarbonyl group, cycloheptylmethyl group, cyclooctylmethyl group, etc.

Preferred examples of the "hydroxyl group-containing protective group" include methoxyethylamine group, tetrahydropyranyloxy group, tert-butylamino group, allylamino group, benzoate group, an acetate group, formatnew group, crotonate group, p-phenylbenzoate group or pivaloate group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, trityloxy group, benzyl group, etc.

Preferred examples of C1-6-alkoxy PPI in the "C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-5 halogen atoms, or together with the carbon atom, bound to the specified adjacent C1-6-alkoxygroup may form a cyclic group)" include C1-6-alkoxygroup substituted by 1-5 halogen atoms, or a cyclic group can be formed together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup. The expression "cyclic group may be formed together with the carbon atom is bound to the specified adjacent C1-6-alkoxygroup" means, for example, methylenedioxy, Ethylenedioxy etc. and can be specifically illustrated, for example, by the formula:

Formula 21

etc.

The substituent in the "C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous group and the two C1-6-alkyl groups together with the carbon atom to which they are bound, may form a cyclic group (where a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom))" can be specifically illustrated, for example, by the formula:

Formula 22

etc.

The following compound of formula (I) according to the present invention.

Of the compounds represented by formula (I), preferred is a compound or its pharmacologically acceptable Sol is, in which Ar1represents imidazolidinyl group which may be substituted by 1-2 substituents selected from the group of substituents A1;

more preferred is a compound or its pharmacologically acceptable salt, in which Ar1represents imidazolidinyl group which may be substituted by 1-2 substituents selected from a hydrogen atom, halogen atom, C3-8-cycloalkyl group, C2-6-alkenylphenol group, C2-6-alkenylphenol group and C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1 to 3 halogen atoms); and

most preferred is a compound or its pharmacologically acceptable salt, in which Ar1represents imidazolidinyl group which may be substituted by 1-2 substituents selected from the group consisting of hydrogen atom, halogen atom, C3-8-cycloalkyl group and C1-6-alkyl groups.

Of the compounds represented by formula (I), preferred is a compound or its pharmacologically acceptable salt, in which Ar2represents pyridinyl group, pyrimidinyl group or a phenyl group which may be substituted by 1-3 substituents selected from the group of substituents A2;

more preferred is a compound or its pharmacologically acceptable salt, in which Ar2p is ecstasy pyridinyl group, pyrimidinyl group or a phenyl group which may be substituted by 1-3 substituents selected from the group consisting of hydrogen atom, halogen atom, ceanography, hydroxyl group, C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1-3 substituents selected from C2-6-alkenylphenol group, C2-6-alkenylphenol group and C3-8-cycloalkyl group), C2-6-alkenylacyl and C2-6-alkyloxy; and

most preferred is a compound or its pharmacologically acceptable salt, in which Ar2represents pyridinyl group, pyrimidinyl group or a phenyl group which may be substituted by 1-3 substituents selected from the group consisting of (1) hydrogen atom, (2) halogen atom, (3) ceanography and (4) C1-6-alkoxygroup.

Of the compounds represented by formula (I), preferred is a compound or its pharmacologically acceptable salt in which X1represents (1) -C≡C - or - (2) -CR3=CR4- (where R3and R4represent a Deputy selected from the group of substituents A3;

more preferred is a compound or its pharmacologically acceptable salt in which X1represents-CR31=CR41- (where R31represents a group selected from the group consisting of (1) hydrogen atom, (2) and the Ohm halogen, (3) C1-6-alkyl groups and (4) C1-6-CNS group; and R41represents a group selected from the group consisting of (1) hydrogen atom, (2) halogen atom, (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A5, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A5, and (5) C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of of halogen atom, hydroxy-group, ceanography, C3-8-cycloalkyl group, C1-6-alkyl groups, C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl groups, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A5, 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A5, 5 to 14-membered non-aromatic heterocyclic group, which may be substituted by 1-3 substituents selected from the group of substituents A5, and-O-A1(where A1is a 6-14-membered aromatic hydrocarbons is the same ring group, which may be substituted by 1-3 substituents selected from the group of substituents A5, or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A5))); and

most preferred is a compound or its pharmacologically acceptable salt in which X1represents-CR32=CR42- (where R32represents a hydrogen atom or halogen atom and R42is a Deputy selected from the group consisting of hydrogen atom, halogen atom and C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted C3-8-cycloalkyl group or phenyl group) and phenyl group).

Of the compounds represented by formula (I), the compound or its pharmacologically acceptable salt, in which R1and R2represent a group selected from the group of substituents A4, or a group formed by R1and R2together with the nitrogen atom, is a 5-11-membered heterocyclic group represented by the formula (II), which may be substituted by 1-4 substituents selected from the group of substituents A4; 6-20-membered non-aromatic heterocyclic group represented by the formula (III), which may be substituted by 1-4 substituents selected from the group of substituents A4, 9-16-membered NEA is ematichesky heterocyclic group, represented by formula (IV), which may be substituted by 1-4 substituents selected from the group of substituents A4, a group represented by the following formula:

Formula 23

which may be substituted by 1-4 substituents selected from the group of substituents A4, a group represented by the following formula:

Formula 24

which may be substituted by 1-4 substituents selected from the group of substituents A4, the cyclic group represented by formula (V), which may be substituted by 1-4 substituents selected from the group of substituents A4, the cyclic group represented by formula (VI), which may be substituted by 1-4 substituents selected from the group of substituents A4, and the cyclic group represented by the following formula:

Formula 25

which may be substituted by 1-4 substituents selected from the group of substituents A4, one can cite as an example the preferred connection.

Of the compounds represented by formula (I), preferred is a compound or its pharmacologically acceptable salt, in which R1and R2represent a group selected from the group of substituents A4;

more preferred is a compound or its pharmacologically acceptable salt, in which Rsup> 1represents a group selected from the group of substituents A8, and R2represents a group selected from the group of substituents A6; and

most preferred is a compound or its pharmacologically acceptable salt, in which R1represents a C1-6-alkyl group (where specified C1-6-alkyl group represents a hydrogen atom, C3-8-cycloalkanes, C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous group and the two C1-6-alkyl groups together with the carbon atom to which they are bound, may form a cyclic group (where a methylene group in the cyclic group which constitutes the ring may be substituted one oxygen atom)), C1-6-alkoxygroup, 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A9, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9,and-O-A4(where A4is a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9)), and R2predstavljaet a (1) hydrogen atom or (2) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 substituents, selected from the group consisting of hydroxyl group, C3-8-cycloalkyl group, C3-8-cycloalkanes, C1-6-allylthiourea, an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A9, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A9, and 5-14 membered non-aromatic heterocyclic group, which may be substituted by 1-3 substituents selected from the group of substituents A9).

In the compounds represented by formula (I), 5-11-membered heterocyclic group represented by the formula (II), formed R1and R2together with the nitrogen atom to which they relate, refers to a heteroatom-containing cyclic group, containing in the whole, 5-11 members, and preferred examples include piperidinyl group, pyrrolidinyl group, sepanlou group, atenilol group, piperazinilnom group, 1,4-diazepino group, morpholinyl group or thiomorpholine group.

Of the compounds represented by formula (I), preferred is a compound or its pharmacologically acceptable salt, inwhich R 1and R2together with the nitrogen atom to which they are bound, form a 5-11-membered heterocyclic group represented by the formula (II), which may be substituted by 1-4 substituents selected from the group of substituents A4;

more preferred is a compound or its pharmacologically acceptable salt, in which R1and R2together with the nitrogen atom to which they are bound, form a 5-11-membered heterocyclic group represented by the formula (II), which may be substituted by 1-4 substituents selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, formyl group, hydroxyimino, C1-6-alkoxyamino, C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group, 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 below), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below, a 5 to 14-membered aromatic is practical heterocyclic group, which may be substituted by 1-3 substituents selected from the group of substituents A7, below-O-A2(where A2is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A7 shown below or a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A7 below), -CO-A2(where A2shall have the meaning given above) and =CH-A2(where A2shall have the meaning given above); and

most preferred is a compound or its pharmacologically acceptable salt, in which R1and R2together with the nitrogen atom to which they are bound, form a 5-11-membered heterocyclic group represented by the formula (II), which may be substituted by 1-4 substituents selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1-3 substituents selected from the group consisting of a hydroxyl group or a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A10), 6-14-membered aromatic hydrocarbon is a ring group, which may be substituted by 1-3 substituents selected from the group of substituents A10, 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituents selected from the group of substituents A10, -O-A6(where A6is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 substituents selected from the group of substituents A10 below) and =CH-A6(where A6shall have the meaning given above).

In the compounds represented by formula (I), "6-20-membered non-aromatic heterocyclic group"represented by formula (III), formed R1and R2together with the nitrogen atom to which they relate, relates to heteroatom-containing spiritlessly group containing generally 6-20 members, and preferred examples include

Formula 26

etc.

In addition, the compounds represented by formula (I), preferred is a compound or its pharmacologically acceptable salt, in which R1and R2together with the nitrogen atom to which they are attached, form a 6 to 20-membered non-aromatic heterocyclic group represented by the formula (III), which may be substituted by 1-4 substituents selected from the group of substituents A4.

Of the compounds represented forms the Loy (I), preferred is a compound in which the group formed by R1and R2together with the nitrogen atom to which they relate, is a 9-16-membered non-aromatic heterocyclic group represented by the formula (IV), which may be substituted by 1-4 groups substituents selected from the group of substituents A4, or its pharmaceutically acceptable salt.

"9-16-membered non-aromatic heterocyclic group"represented by formula (IV), refers to a heteroatom-containing cyclic group, containing in the whole 9-16 members.

Of the compounds represented by formula (I), preferred is a compound in which the group formed by R1and R2together with the nitrogen atom to which they are attached, represents a group represented by the following formula:

Formula 27

which may be substituted by 1-4 groups substituents selected from the group of substituents A4, or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), preferred is a compound in which the group formed by R1and R2together with the nitrogen atom to which they are attached, represents a group represented by the following formula:

Formula 28

which may be substituted by 1-4 groups Zam is stitely, selected from the group of substituents A4, or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), more preferred is a compound in which R1and R2together with the nitrogen atom to which they are attached, form a group represented by the following formula:

Formula 29

which may be substituted by 1-4 groups substituents selected from the group of substituents A4, or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), preferred is a compound in which the group formed by R1and R2together with the nitrogen atom to which they are connected, may be substituted by 1-4 groups substituents selected from the group of substituents A4, or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), more preferred is a compound in which the group formed by R1and R2together with the nitrogen atom to which they are connected, may be substituted by 1 to 4 fluorine atoms and the like, or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), preferred is a compound in which the group formed by R1and R2together with the-X1-CO-N is a cyclic group (where R7is a Deputy, wybran the th from the group of substituents A3), represented by formula (V), which may be substituted by 1-4 substituents selected from the group of substituents A4, or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), preferred is a compound in which the group formed by R1and R2together with the-X1-CO-N is a cyclic group represented by the formula (VI), which may be substituted by 1-4 substituents selected from the group of substituents A4 (where R1 represents a Deputy selected from the group of substituents A4, and R7is a Deputy selected from the group of substituents A3), or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), more preferred is a compound in which the group formed by R1and R2together with the-X1-CO-N is a cyclic group represented by the following formula:

Formula 30

which may be substituted by 1-4 groups substituents selected from the group of substituents A7 (where R1 represents a Deputy selected from the group of substituents A4, and R7 represents a group of deputies A3) or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), preferred is a compound in which R1the op is pulling above cyclic group is a Deputy, selected from the group of substituents A4, or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), more preferred is a compound in which R1in the above-described cyclic group is a Deputy selected from the group of substituents A8, or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), preferred is a compound in which R1in the above-described cyclic group is a Deputy selected from the group consisting of C1-6-alkalai group (where specified C1-6-alkyl group may be substituted by 1-3 groups of the substituents selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous group and the two C1-6-alkyl groups together with the carbon atom to which they are bound, may form a cyclic group (where a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally with the holding 1-5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9, and-X-A4(where X represents aminogroup, -O - or-S-, and A4is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9, or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9)), or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), preferred is a compound in which the group formed by R1and R2together with the-X1-CO-N is a cyclic group represented by the following formula:

Formula 31

which may be substituted by 1-4 groups substituents selected from the group of substituents A4, or its pharmaceutically acceptable salt.

Of the compounds, the pre is raised by the formula (I), preferred is a compound in which R1in the above-described cyclic group is a Deputy selected from the group of substituents A4, or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), more preferred is a compound in which R1in the above-described cyclic group is a Deputy selected from the group of substituents A8, or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), preferred is a compound in which R1in the above-described cyclic group is a Deputy selected from the group consisting of C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1-3 groups of the substituents selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous group and the two C1-6-alkyl groups together with the carbon atom to which they are bound, may form a cyclic group (where a methylene group in the cyclic group which constitutes the ring may be substituted by one atom is of ikorodu)), C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9, and-X-A4(where X represents aminogroup, -O - or-S-, and A4is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9, or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9)), or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), preferred is a compound in which R1in the Formula (I), R1in the Formula (VI) and R1in the cyclic group represented by the following formula:

Formula 32

represents-X21-X22 -Ar3

where X21represents a C1-6-alkylenes group (where specified C1-6-Allenova group may be substituted by 1-3 groups of the substituents selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous group and the two C1-6-alkyl group together with the carbon atom to which they are bound, may form a cyclic group (where a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl), a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A7), or a simple bond, and X22represents a simple bond, aminogroup, which can be substituted by the Deputy selected from the group of substituents A7, -O - or-S-, and Ar3is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A7 or a 5 to 14-membered aromatic Goethe is acyclically group, which may be substituted by 1-3 groups of the substituents selected from the group of substituents A7, or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), more preferred is a compound in which R1represents-X21a-X22a-Ar3awhere X21arepresents a C1-6-alkylenes group (where specified C1-6-Allenova group may be substituted by 1-3 groups of the substituents selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, formyl group, C1-6-alkyl group (where 1 or 2 of the above C1-6-alkyl groups may substitute the same carbon atom in C1-6-alkalinous group and the two C1-6-alkyl group together with the carbon atom to which they are bound, may form a cyclic group (where a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), C1-6-alkoxygroup, an amino group (where this amino group may be substituted by C1-6-alkyl containing 1 to 5 halogen atoms), a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9), and X22arepresents a simple bond or an oxygen atom, and Ar 3ais a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9, or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A9, or its pharmaceutically acceptable salt.

Moreover, Ar3ain the "-X21a-X22a-Ar3a" is a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group, and preferably a group selected from phenyl group, naftilos group and fluorenyl group, or a group selected from a thienyl group, pyridinoline group, hyalinella group, ethanolamines group, indolines group, benzothiazolyl group, benzoxazolyl group and shriley group.

Of the compounds represented by formula (I), preferred is a compound in which R1is a 6-14-membered non-aromatic hydrocarbon ring group or 5 to 14-membered non-aromatic heterocyclic group represented by the formula (VII), or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), preferred is a compound in which R1represented by formula (VII), g is e Ar 4represents a phenyl group, pyridinyl group, pyrimidinyl group, personilnya group, thienyl group, oxazolidinyl group, pyrrolidino group, thiazolino group and follow group which may be substituted by 1-3 groups of the substituents selected from the group consisting of halogen atom, C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1-3 groups of the substituents selected from the group consisting of halogen atom and C1-6-alkyl groups), C1-6-alkoxygroup (where specified C1-6-alkoxygroup can be substituted by 1 to 3 halogen atoms), amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A7, a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A7, a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A7 and-CO-A2(where A2is a 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups the Deputy is, selected from the group of substituents A7 or a 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A7), or its pharmaceutically acceptable salt.

Of the compounds represented by formula (I), preferred is a compound in which R1represented by formula (VII), where R1represents indenolol group, isoindoline group, tetrahydronaphthyl group, asterolecaniidae group, romanello group, azihromycin group, tetrahydrofuranyl group or tetrahydroisoquinoline group which may be substituted by 1-3 groups of the substituents selected from the group consisting of, for example, halogen atom, hydroxyl group, ceanography, C3-8-cycloalkyl group, C3-8-cycloalkanes, C1-6-alkyl groups (where specified C1-6-alkyl group may be substituted by 1-3 halogen atoms or C1-6-alkyl groups), C1-6-alkoxygroup (where specified C1-6-alkoxygroup may be substituted by 1 to 3 halogen atoms), amino group (where this amino group may be substituted by C1-6-alkyl containing 1 to 5 halogen atoms) and a 5-14-membered non-aromatic heterocyclic group, or its pharmaceutically acceptable salt.

Especially preferred are compounds selected, voltage is emer, from the following group, or their pharmaceutically acceptable salts which are useful as a means for prevention or treatment of diseases caused by beta-amyloid, such as Alzheimer's disease, senile dementia, down's syndrome, amyloidosis, etc.

1) (E)-N-Biphenyl-3-ylmethyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide,

2) (E)-N-((1S)-Indan-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide,

3) (E)-N-(Chroman-4-yl)-3[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide,

4) (E)-1-(3,4-Diferensial)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it,

5) (E)-1-Indan-2-yl-3[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it,

6) (E)-1-(Chroman-4-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it,

7) (E)-1-[(1S)-1-(4-Forfinal)ethyl]-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it,

8) (E)-1-[(6-Chloropyridin-2-yl)methyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it,

9) (E)-1-(4-Tert-butylbenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it,

10) (E)-1-(3,4-Diferensial)-3-{[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-yl]methylene}piperidine-2-it,

11) (E)-1-[(1H-Indol-3-yl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it,

12) (E)-1-(5-Florinda-2-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it,

13) (E)-1-(7-Ferroman-4-is)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it,

14) (E)-3-[3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-(1,2,3,4-tetrahydronaphthalen-2-yl)piperidine-2-he,

15) (E)-1-[(2,4-Differenl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it.

Although the above preferred variants of the embodiment of the compounds of the above General formula (I), the active ingredient of the pharmaceutical agents of the present invention is not limited to a specific compound described in the present description, and can be selected any variant of realization of the full amount within the compounds of General formula (I).

The method of obtaining compounds of General formula (I) according to the present invention are described below.

The connection represented by the General formula (I)

Formula 33

(where Ar1, Ar2X1, R1and R2have the above specified values, and if necessary, Ar1and Ar2may contain a protective group(s) for functional groups, such as hydroxy-group(group), amino group(group) or carbonisation the group(s))can be synthesized in accordance with the following General Ways of Obtaining 1-5.

A common way of obtaining 1

A typical way to obtain (a Common way to obtain 1) compounds of General formula (I) according to the present invention are described below.

Formula 34

(where Ar1, Ar2and X1have the meanings defined above; V represents a protective group for carboxyl group, such as methyl group, ethyl group, benzyl group, allyl group, triphenylmethyl group, tert-bucilina group, methoxymethyl group or tert-butyldimethylsilyl group, and

(1) R1and R2represent a group selected from the group of substituents A4 below, or

R1and R2together with the nitrogen atom to which they are attached, form one of the following groups:

(2-1) 5-11-membered non-aromatic heterocyclic group represented by the formula (II):

Formula 35

(where Y1represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -SO2-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5=CR6- (where R5and R6represent a group selected from the group of substituents A4 below), (11) a simple link or (12) >C=CR13R14(where R13and R14represent a group selected from the group of substituents A4 shown below); and

maand mbrepresent an integer having a value of from 0 to 4)which may be substituted by 1-4 groups substituents selected from the group of substituents A4;

(2-2) 6-20-membered non-aromatic heterocyclic GRU is PU, represented by formula (III):

Formula 36

(where Y2represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -SO2-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5= CR6- (where R5and R6represent a group selected from the group of substituents A4 below, or R5and R6together with the carbon atom to which they are bound, form a 6-14-membered aromatic hydrocarbon ring group or a 6-14-membered non-aromatic hydrocarbon ring group) or (11) a simple link; and

ma, mb, mcand mdrepresent an integer having a value of from 0 to 4)which may be substituted by 1-4 groups substituents selected from the group of substituents A4;

(2-3) 9-16-membered non-aromatic heterocyclic group represented by the formula (IV):

Formula 37

(where Y3represents (1) -NH-, (2) -O-, (3) -S-, (4)-SO-, (5) -SO2-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO - or (10) a simple link; and

maand mbrepresent an integer having a value of from 0 to 4)which may be substituted by 1-4 groups substituents selected from the group of substituents A4;

(2-4) a group represented by the following formula:

Formula 38

which may be substituted by 1-4 groups mixing is of Italy, selected from the group of substituents A4;

(2-5) a group represented by the following formula:

Formula 39

which may be substituted by 1-4 groups substituents selected from the group of substituents A4 below.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) formyl group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 groups substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 groups of the substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-5 groups substituents selected from the group of substituents A4, (23) 5-14-membered the romantic heterocyclic group, which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl group, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above).

The above-described General method of obtaining 1" is an example of a method of obtaining compounds of General formula (I), in which the ester derivative (1a) is subjected to reaction removal of protection in stage 1-1 to convert in carbonisation connection (2) and then carbonisation connection (2) is subjected to amidation reaction with aminoven compound (3).

Obtaining compounds of carboxylic acids is (2)

Connection carboxylic acid (2) can be obtained, for example, subjecting ester (1a) "stage 1-1". That is, although the reaction of the removal of protection in stage 1-1" may vary depending on the source of the substance, there are no particular restrictions, provided that the reaction is carried out in conditions similar to those used for the reaction in the methods known from the prior art (for example, the methods described in T.W. Green. "Protective Groups in Organic Synthesis" John Wiley & Sons. Inc., 1981, p154-186). Preferably this reaction is the hydrolysis of ester compounds, and you can use the methods described in many known reference documents (for example, you can use such methods, which are described in "Composition and Reaction of Organic Compound [II]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1978, p.930-943). Preferably the desired connection carboxylic acid (2) can be obtained by interaction of ester (1a) using aqueous solvent (a mixture of solvents consisting of water, for example, with methanol, ethanol and/or tetrahydrofuran, etc.) at a temperature of from room temperature to 100ºC in the presence of 1.0 to 5.0 equivalents of a metal hydroxide (preferably, for example, sodium hydroxide, potassium hydroxide or lithium hydroxide, etc.). Moreover, depending on the respective complex is Thira (1a) compound carboxylic acid (2) can also be appropriately obtained in acidic conditions, preferably using triperoxonane acid). In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods. Undesirable side products can be removed by methods known from the prior art, such as the traditionally used methods, chromatography, extraction and/or crystallization.

Obtaining compounds of General formula (I)

The compound of General formula (I) can be obtained, for example, by subjecting compound carboxylic acid (2) "stage 1-2". That is, although the amidation reaction "stage 1-2" may vary depending on the source of the substance, there are no particular restrictions, provided that the reaction is carried out in conditions similar to those used for the reaction in the methods known from the prior art, described in many reference documents (for example, such methods are described in "Composition and Reaction of Organic Compound [II]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1978, p.1136-1162). Preferred examples include (i) a process comprising converting a carboxylic acid (2) in gelegenheid acid with subsequent interaction of gelegenheid acid aminoven compound in alkaline conditions (for example, the method described in "Composition and Reaction of Organic Compound [II]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 197, p.1142-1145), (ii) a process involving the interaction carbonbearing compounds (2) and amine compounds using a condensing agent (for example, the method described in the "Guide to Organic Chemistry Experiment (4)," KagakuDojin, September, 1990, p.27-52), etc.

In the case described above in (i), used a base, a solvent and the reaction temperature may vary depending on the source of the substance and is not specifically limited, and can be used (i) method using, for example, pyridine, lutidine, quinoline, isoquinoline, etc. as the primary solvent; (ii) a method using, for example, pyridine, triethylamine, N,N-diisopropylethylamine etc. as the base, and preferred, for example, tetrahydrofuran, 1,4-dioxane, etc. as a solvent, which dissolves the starting material(substance in some extent, but does not hinder the reaction, or a mixture of these solvents; or (iii) a method using a two-layer distribution system, consisting of the alkaline solution, preferably, for example, an aqueous solution of a base such as sodium hydroxide, potassium hydroxide, etc. and halogenated solvent, preferably, for example, methylene chloride, 1,2-dichloroethane, etc. the reaction Temperature should be a temperature which is sufficient to complete the reaction, n is giving to the formation of unwanted side products, and preferably it is within the temperature cooling with ice up to 100ºC. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods. Although the procedures used to convert carboxylic acid (2) in gelegenheid acid can vary depending on the source of the substance, there are no particular restrictions, provided that the reaction is carried out in conditions similar to those used for the reaction in the methods known from the prior art. Preferably, you can use gloriouse agent, such as thionyl chloride and oxalicacid, in an inert solvent such as methylene chloride, toluene and tetrahydrofuran. For more effective implementation of the response is appropriate, the addition of catalytic amounts of N,N-dimethylformamide, etc. the reaction Temperature must be a such a temperature which is sufficient to complete the reaction, without giving effect to the formation of unwanted side products, and preferably it is within the temperature cooling with ice up to 100ºC.

In the case described above in (ii), used the condensing agent may vary depending on the source of the substance and is not specifically limited, and predpochtitelno appropriate to use for example, from 1.0 equivalent to 2.0 equivalents of 1,3-dicyclohexylcarbodiimide, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide, hexaflurophosphate benzotriazol-1-yloxytris(dimethylamino) phosphonium etc. per carbonisation connection (2). For more effective implementation of the reaction can be added, for example, from 1.0 equivalent to 2.0 equivalents of N-hydroxysuccinimide, N-hydroxybenzotriazole, etc. It is preferable from the viewpoint of operability and work efficiency of mixing for the implementation of this reaction in the presence of a solvent, although the solvent used may vary depending on the source of the substance and used condensing agent and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not prevent the implementation of the reaction, a halogen solvent such as methylene chloride and 1,2-dichloroethane, or a polar solvent, such as tetrahydrofuran and N,N-dimethylformamide are preferred. The reaction temperature should be a such a temperature which is sufficient to complete the reaction, without giving effect to the formation of unwanted side products, and preferably it is within the temperature cooling with ice up to 100ºC. In the preferred reaction conditions which x the reaction is completed in 1-24 hours and the development of the reaction can be monitored known chromatographic methods. Undesirable side products can be removed by any method known from the prior art, such as traditional chromatographic method and/or crystallization. It is also possible to obtain the desired compounds of General formula (I) by amide bond formation with subsequent conversion of R1and R2the usual way using well-known techniques, and it is also possible to obtain the desired compounds of General formula (I) by appropriate modification of the groups of the substituents Ar1, Ar2and X1.

Getting amine compound (3)

Amine compound (3) is commercially available or can be obtained by a method known from the prior art. Preferred examples of such method include i) a method of converting a corresponding alcohol compound or alkylhalogenide connection amine compound known method; (ii) method of conversion of the corresponding nitro compounds, nitrile compounds, Aksenova compounds, azide compounds or amide acid using known reaction recovery, iii) the method of conversion of the corresponding carbonyl compounds using known reactions reductive amidation, iv) the method of receiving am the new compounds by the reaction of removal of the protection of the nitrogen atom protected by a protective group, etc.

In the case described above in (i), the conversion can be performed by methods described in many known reference documents, and, for example, are preferred methods of obtaining amine compounds from the corresponding alcohol using Mitsunobu (see, for example, O. Mitsunobu, "Synthesis," p.1, 1981) or from alkylhalogenide connection method Gabriel (Gabriel) (see, for example, M.M.S. Gibson et al., "Angew. Chem.," vol. 80, p.986, 1968). In the case of using the method of Mitsunobu effective to obtain the desired amine compounds can be performed preferably by a two-step reaction involving the condensation of the corresponding alcohol compounds with emenim connection with the use of 1.0-3.0 equivalents of diethylazodicarboxylate simultaneous presence of 1.0 to 3.0 equivalents of triphenylphosphine and processing of the product obtained in the first stage, for example, of 1.0 to 3.0 equivalents of hydrazine. The reaction temperature should be a such a temperature which is sufficient to complete the reaction, without giving effect to the formation of unwanted side products, and it is preferably the temperature of the cooling with ice up to 100°C for the condensation reaction with emenim connection at the first stage and 50ºC-100ºC for treatment with hydrazine in the second stage. Although the solvent used in this reaction may vary is encoded depending on the source of the substance and used condensing agent and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not prevent the implementation of the reaction, diethyl ether, tetrahydrofuran, etc., for example, are preferred for the reaction of the first stage, and methanol, ethanol, etc., for example, are preferred for the reaction of the second stage. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods. Undesirable side products can be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization. In the case of using the method of Gabriel effective to obtain the desired amine compounds can be performed preferably by a two-step reaction involving the condensation of the corresponding alkylhalogenide connection with the imide by any method known from the prior art, and the processing of the product obtained in the first stage, for example, of 1.0 to 3.0 equivalents of hydrazine. The reaction temperature should be a such a temperature which is sufficient to complete the reaction, without giving effect to the formation of unwanted side products, and it is preferably the temperature of the cooling with ice up to 100ºC for the reaction of condenser and with emenim connection at the first stage and 50ºC-100ºC for treatment with hydrazine in the second stage. Although the solvent used in this reaction may vary depending on the source of the substance and used condensing agent and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not prevent the implementation of the reaction, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, etc., for example, are preferred for the reaction of the first stage, and methanol, ethanol, etc., for example, are preferred for the reaction of the second stage. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods. Undesirable side products can be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization.

In the case described above in (ii), you can use the recovery methods described in many known reference documents (for example, the method described in "Composition and Reaction of Organic Compound [III]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1978, p.1333-1341), and effective at getting the desired amine compounds can be made by the method of catalytic hydrogenation, which is preferably used, for example, a catalyst based on metal, by way of no is of using a metal hydride, etc. Method of catalytic hydrogenation is preferably carried out at a pressure of from normal to 100 atmospheres in the atmosphere of hydrogen. Catalysts based on metal used in the reaction, preferably represents, for example, platinum, platinum oxide, platinum black, Raney Nickel, palladium on carbon, etc. Although the solvent used in this reaction may vary depending on the source of the substance and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not prevent the implementation of the reaction, methanol, ethanol, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate and so on, for example, are preferred. For more effective implementation of the response, you can add an acidic substance such as acetic acid or hydrochloric acid. As for the restore method using a metal hydride, effective to obtain the desired amine compound (3) is carried out preferably using sociallyengaged or DIBORANE. The solvent used in this reaction may vary depending on the source of the substance and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not prevent the implementation of react and, for example, preferred are diethyl ether, tetrahydrofuran, etc. the Temperature for the reaction of recovery described in (ii), shall constitute such a temperature which is sufficient to complete the reaction, without giving effect to the formation of unwanted side products, and it is preferably the temperature of the cooling with ice up to 100ºC. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods. Undesirable side products can be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization.

In the case described above in (iii), it is possible to use the reaction of reductive amination, known from the prior art (for example, the method described in "Composition and Reaction of Organic Compound [III]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1978, p.1380-1384), and the preferred method includes obtaining iminovogo compounds by the reaction of dehydration of the corresponding carbonyl compounds and amine compounds by heating to the boiling point under reflux in the presence of an acid catalyst (preferably, for example, inorganic acids such as chloritoid the native acid or sulfuric acid, organic acids, as methanesulfonate acid, p-toluensulfonate acid and camphorsulfonic acid, or salts of organic acids such as p-toluensulfonate pyridinium), and recovery iminovogo connection using a metal hydride, such as sociallyengaged, borohydride sodium and so on, to give the desired amine compounds. An alternative method that includes processing iminovogo compounds in an inert solvent, such as tetrahydrofuran, in the presence of a catalyst based on a Lewis acid (preferably of isopropoxide titanium (IV)) and restore iminovogo connection using a metal hydride, such as borohydride sodium is preferred. Alternatively, for example, the method of recovery of carbonyl compounds and 0.5-5.0 equivalents of amine compounds using metal hydride, such as acetoxyvalerenic sodium and cyanoborohydride sodium, in an inert solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, methanol and ethanol, to give the desired amine compound is also preferred. For more effective implementation of the reaction preferably corresponding adding an acidic substance such as acetic acid or hydrochloric acid. The development of the reaction restorative Mininova the Oia iii) can be traced known chromatographic methods. Undesirable side products can be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization.

In the case described above in (iv), it is possible to use the reaction of removal of protection described in many known reference documents (see, for example, T.W. Green, "Protective Groups in Organic Synthesis," John Wiley & Sons. Inc., 1981), and preferred are a method of obtaining the desired amine compounds from the corresponding urethane compounds (preferably, for example, tert-BUTYLCARBAMATE connection benzylcarbamoyl connection, 9-fluorenylmethoxycarbonyl connection etc), or a method of obtaining such a desired amine compounds from the corresponding amide compounds (preferably, for example, formamide connection, acetamide compounds trifurcating connection etc). An alternative way to remove protection from the appropriate amidnogo connection in accordance with the above described method of Gabriel to give the desired amine compound is also preferred. Although the reaction conditions for the removal of protection can vary depending on the source of the substance and there are no particular restrictions, provided that the reaction is carried out in conditions similar to those used in this reaction, can the use of any known method. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods. Undesirable side products can be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization.

Receive-1 ester compound (1a)

Formula 40

(where Ar1, Ar2X1and V have the meanings defined above;

V, V1and V2are the same or different from each other and represent a protective group for carboxyl group, such as methyl group, ethyl group, benzyl group, allyl group, triphenylmethyl group, tert-bucilina group or tert-butyldimethylsilyl group;

L1, L2, L3and L4are the deleted group, such as a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a sulfonate, such as triflate, group triamcinolone, baronova acid or ester Bronevoy acid (B(OV1)2);

L7represents an ester group, such as methyl ester, complex ethyl ester or complex benzyl ether, or cyano;

W represents diethylphosphino group, diphenylphosphino the function group or bis(2,2,2-triptorelin)postonline group;

R13and R14represent a group selected from the group of substituents A1 below; and

R11and R12represent a group selected from the group of substituents A3, below.

The group of substituents A1: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) the nitro-group, (5) C3-8-cycloalkyl groups, (6) C2-6-Alchemilla groups, (7) C2-6-Alchemilla group, (8) C1-6-alkoxygroup (9) C3-8-cycloalkanes, (10) formyl group, (11) C1-6-acylcarnitine group and (12) C1-6-alkyl group (where mentioned C1-6-alkyl group may be substituted by 1-3 groups of the substituents selected from the group consisting of a halogen atom, a hydroxyl group, ceanography, C1-6-alkoxygroup, C3-8-cycloalkyl group and C1-6-alkylcarboxylic group).

Group Vice A3: (1) hydrogen atom, (2) halogen atom, (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 groups of the substituents selected from the group consisting of formyl group, an atom halogen, a hydroxyl group, Hydra is Xylenol group, containing a protective group, ceanography, C2-6-alkenylphenol group, C2-6-alkenylphenol group, C3-8-cycloalkyl group, C1-6-alkoxygroup, C1-6-allylthiourea, C1-6-alkylsulfonyl group, C1-6-alkylsulfonyl group, C1-6-alkylcarboxylic group, an amino group (where this amino group may be substituted by C1-6-alkyl group(or groups), optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups of deputies selected from the group of substituents A4, 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group Vice-A4, and-X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 substituted by groups selected from the group of substituents A4) and (6) C1-6-CNS group.

Although the ester compound(1a) can vary depending on the source of the substance, it can be obtained by the method known from the prior art. Preferably, for example, the ester compound (1a) can be obtained, as shown in the diagram, the reaction above, but getting it is not limited. Namely, the ester compound (1a) can be obtained, for example, by reacting the compound (4a) and compound (5a) in Stage 2-1 with getting carbonyl compounds (6a) and subjecting a carbonyl compound reaction, Horner-Emmons in Stage 2-2" with obtaining the ester compound (1a). Alternative based on the carbonyl compound (6a) through the "stage 2-9" get connection (6c) and subjecting the compound (6c) reaction, Horner-Emmons with compound (7a') in Stage 2-2" with obtaining the ester compound (1a). Alternative ester compound (1a) can also be obtained through a three-stage reaction stage 2-4" using amino compounds (5b) as the starting material for formation of groups Ar1compound (6b) with the subsequent reaction mix with compound (7b) or (7b') in accordance with stage 2-5". Ester compound (1a) can also be obtained by using the compound (5d) as the source of matter and convert it into a compound (6b) in accordance with the "Stage 2-1 with obtaining the ester compound (1a) in Stage 2-5".

Getting carbonyl with the unity (6a)

Carbonyl compound (6a) is commercially available or can be obtained by a method known from the prior art. If it is not available on the market, the carbonyl compound (6a) can be obtained in accordance with Stage 2-1 using, for example, compound (5a) as educt. Namely, the reaction of Stage 2-1" can vary depending on the source of the substance, and there are no particular restrictions, provided that the reaction is carried out in conditions similar to those used in this reaction, and you can use any method known from the prior art. For example, preferably, when the response of the combination of compounds (4a) and compound (5a) is carried out in a neutral or alkaline conditions (see, for example, D.D. Davey et al., "J. Med. Chem.," vol. 39, p.2671-2677, 1991). Namely, preferably, when used 1.0 to 5.0 equivalents of compound (4a) in the calculation of the compound (5a). For the effective implementation of the reaction preferably, when the base is used in an amount of from 1.0 to 5.0 equivalents, and preferred examples include sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, barium carbonate, etc. of the Solvent used in this reaction may vary depending on the source of the substance and is not specifically limited, provided that on which dissolves the original substance(substances) to a certain extent, but it does not preclude the implementation of the reaction, preferred are, for instance, acetonitrile, tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidine etc. the reaction Temperature must be a such a temperature which is sufficient to complete the reaction, without giving effect to the formation of unwanted side products, and it is preferably in the range from 50ºC to 200ºc is manageable. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods. Undesirable side products can be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization.

Carbonyl compound (6a) can be obtained in accordance with Stage 2-8 using the compound (6b) as educt. Namely, the reaction Stage 2-8" can vary depending on the source of the substance, and there are no particular restrictions, provided that the reaction is carried out in conditions similar to those used in this reaction, and you can use any method known from the prior art. For example, you can also use the two-stage method in which the compound (6b) (where L2preferably represents the Wallpaper, a chlorine atom, a bromine atom, an iodine atom and a sulfonate, such as triflate) and the connection vinilla subjected to reaction combinations Stille for converting the first vinyl compound and obtained the vinyl compound is subjected to oxidation with ozone (see, for example, S.S. Chandran et al., "Bioorg. Med. Chem. Lett.," vol. 11, p.1493-1496, 2001). Alternative you can also use the reaction injection of carbon dioxide (see, for example, T. Okano et al., "Bull. Chem. Soc. Jpn.," vol. 67, p.2329-2332, 1994) using a catalyst based on a transition metal.

Also, for example, in the case when the carbonyl compound (6b) contains L7 group, compound 6a can be obtained by using a redox reaction by methods known from the prior art.

Obtaining the compound (5a)

The compound (5a)is used at this stage, is commercially available or can be obtained by a method known from the prior art. If it is not available on the market, the preferred compound (5a) (where L1represents a fluorine atom, a chlorine atom or a bromine atom) can be obtained in the form of the corresponding alcohol by oxidation reactions, known from the prior art, and can be subjected to ester-known reduction reaction of obtaining carbonyl compounds.

Obtaining the compound (4a)

The compound (4a)is used at this stage, is commercially available is, or it can be obtained by the method known from the prior art (see, for example, M. Komoto et al., "Agr. Biol. Chem.," vol. 32, p.983-987, 1968, or J.M. Kokosa et al., "J. Org. Chem.," vol. 48, p.3605-3607, 1983).

Conversion of the carbonyl compound (6a) in the ester compound (1a)

Although the conversion of the carbonyl compound (6a) in the ester compound (1a) can vary depending on the source of the substance, it is possible to use known methods described in many reference documents (such method is described, for example, in H.O. House, Modern synthetic reactions," W.A. Benjamin Inc., p629-733, 1972, or W. Carrthers, "Some modern methods of organic synthesis,Cambridge University press, p.125-144, 1986). For example, the ester compound (1a) can be obtained by conversion of the carbonyl compound (6a) in accordance with the "Stage 2-2". Namely, although the reaction Horner-Emmons "Stage 2-2" can vary depending on the source of the substance, there are no particular restrictions, provided that the reaction is carried out in conditions similar to those used in this reaction, and you can use methods known from the prior art (see, for example, W.S. Wadsworth, Jr. "Org. Reactions.," vol. 25, p.73, 1997). Namely, the carbonyl compound (6a) and ether alkylphosphines acid (7a) can be subjected to the condensation reaction with the conversion into the corresponding ester compound (1a) in alkaline conditions. The basis is preferred for the use in an amount of from 1.0 to 2.0 equivalents based on the carbonyl compound (6a), and preferred examples include sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, n-utility, diisopropylamide lithium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide, sodium, triethylamine, diisopropylethylamine etc. the Solvent used in this reaction may vary depending on the source of the substance and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not hinder the reaction, preferred are, for instance, diethyl ether, tetrahydrofuran, dimethylsulfoxide, toluene, benzene, ethanol, methanol and so on, the reaction Temperature must be a such a temperature which is sufficient to complete the reaction, without giving effect to the formation of unwanted side products, and it is preferably in the range from-78ºC to 100ºC and more preferably from-78ºC to room temperature. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods. As for the geometrical isomers formed during this reaction, the desired geometric isomer can be selectively obtained by a suitable choice of connection of ester alkylphosphines acid (7a), the base, the temperature of the reaction and/or solvent, and unwanted side products and geometrical isomers can be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization.

For example, converting a carbonyl compound (6a) in the ester compound (1a) can be accomplished through connection (6c), subjecting the compound (7a') reaction, Horner-Emmons "Stage 2-2" with obtaining the ester compound (1a). For example, to obtain the compound (6c) in Stage 2-9 you can use well-known methods described in many reference documents (for example, described in O. Pamies et al., J. Org. Chem., p.4815-4818, 2003, etc). Namely, preferably using carbonyl compounds (6a) and phosphate compounds, such as diethylphosphate etc. in alkaline conditions. As for bases, preferably from 1.0 to 2.0 equivalents based on the carbonyl compound (6a), preferred examples of such bases include 1,8-diazabicyclo[5,4,0]undec-7-ene, triethylamine, pyridine, sodium methoxide, etc. the Solvent used in this reaction may vary depending on the source of the substance and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not prevent the reaction. Preferred examples include diethyl-the new ether, tetrahydrofuran, dimethylsulfoxide, toluene, benzene, ethanol, methanol, etc. the reaction Temperature must be a such a temperature which is sufficient to complete the reaction, without giving effect to the formation of unwanted side products, and it is preferably in the range from-78ºC to 100ºC and more preferably from-78ºC to room temperature. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods. Undesired by-products formed in this reaction, may be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization. Moreover, the obtained compound (6c) can be modified by the method well known to specialists in this field, the desired compound (for example, as described in T.-J.Tsai. Tetrahedron Letters, vol. 37, No. 5, p.629-632, 1996).

Obtaining compounds (7a')

The compound (7a'), used at this stage, is commercially available or can be obtained by a method known from the prior art. If it is not available on the market, the preferred compound (7a') can be obtained by subjecting the corresponding alcohol oxidation reactions, well known to experts in the field, or exposing sootvetstvujushij ester is well known oxidation reactions with obtaining α-keeeping connection.

Getting amine compound (5b)

Amine compound (5b) is commercially available or can be obtained by a method known from the prior art. Preferably it can be obtained in accordance with Stage 2-3" using nitro compounds (5c) as educt. Namely, although the reaction recovery "Stage 2-3" may vary depending on the source of the substance, there are no particular restrictions, provided that the reaction is carried out in conditions similar to those used in this reaction, and you can use methods known from the prior art (for example, the method described in "Composition and Reaction of Organic Compound [III]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1978, p.1333-1341). Preferably such methods are a way catalytic hydrogenation, which is preferably used, for example, a catalyst based on metal, or the recovery method using metal etc. Way catalytic hydrogenation is preferably carried out at a pressure of from normal to 100 ATM hydrogen atmosphere. Catalysts based on metals used in this reaction, preferably represents, for example, platinum, platinum oxide, platinum black, Raney Nickel, palladium on carbon, etc. Although the solvent, the COI is Leshey in this reaction, may vary depending on the source of the substance and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not prevent the implementation of the reaction, methanol, ethanol, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate and so on, for example, are preferred. For more effective implementation of the response, you can add an acidic substance such as acetic acid or hydrochloric acid. As for the restore method using metal, it is preferable to use zinc, iron, tin, etc. and preferably the operation of the process in acidic conditions using, for example, hydrochloric acid, acetic acid and ammonium chloride. Although the solvent used in this reaction may vary depending on the source of the substance and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not hinder the reaction, preferred are, for instance, methanol, ethanol, 2-propanol, etc. the reaction Temperature must be a such a temperature which is sufficient to complete the reaction, without giving effect to the formation of unwanted side products, and it is preferable in point is adelah from room temperature up to 100ºC. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods. Undesirable side products can be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization.

Preferred amine compound (5b) can also be obtained by means of combination reaction in stage 2-6" using as the starting material of the compound (5d), which is commercially available or can be obtained by a method known from the prior art. Namely, although the reaction mix "Stage 2-6 may vary depending on the source of the substance, there are no particular restrictions, provided that the reaction is carried out in conditions similar to those used in this reaction, and you can use methods known from the prior art. Preferably, you can use the two-stage method for making known reactions delete group benzophenone (reaction removal benzophenone) after the reaction of a combination of benzophenone-imine using a catalyst based on transition metal (see, for example, S.L. Buchwald et al., "Tetrahedron Lett.," vol. 38, p.6367-6370, 1997, or J.F. Hartwig et al., "J. Am. Chem. Soc.," vol. 120, p.827-828, 1998). In the reaction of a combination of benzophenone-imine in quality is the firmness of the catalyst is preferably possible to use a catalytic amount (0.01 to 0.2 equivalents per compound (5d)) traditional palladium catalyst, such as palladium(II)acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0) or Tris(dibenzylideneacetone)dipalladium(0), or traditional Nickel catalyst, such as (1, 5cyclooctadiene) Nickel (0), etc. in Addition, in order to promote more effective implementation of the reaction is also the preferred proper adding phosphorus ligand (preferably, for example, triphenylphosphine, tri-o-tolylphosphino, three-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1,2-bis(diphenylphosphino)ethane, or 1,1'-bis(diphenylphosphino)ferrocene, etc. moreover, the reaction can give the preferred result in the presence of a base, and though the base is not specifically limited, provided that it can be used in reactions combination, similar to the reaction, and preferred examples include sodium hydroxide, barium hydroxide, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, tert-piperonyl sodium, etc. This reaction preferably carried out in the presence of a solvent from the standpoint of efficiency of operation and efficiency of mixing, and although the solvent used in this reaction may vary depending on the source of the substance and of the used catalyst based on switched the aqueous metal and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not hinder the reaction, preferred are, for instance, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene , 1-methyl-2-pyrrolidone, N,N-dimethylformamide, etc. the reaction Temperature must be a such a temperature which is sufficient to complete the reaction combinations, and it is preferably in the range from room temperature up to 100ºC. It is preferable to conduct this reaction in an atmosphere of inert gas, and more preferably in an atmosphere of nitrogen or argon. After processing in the second stage can be used in the manner known from the prior art (see, for example, T.W. Green. "Protective Groups in Organic Synthesis" John Wiley & Sons. Inc., 1981). Undesirable side products can be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization.

With regard to the preferred amine compounds (5b), L2you can modify the way known from the prior art, and preferably the conversion of the hydrogen atom in the group halogen substituent may for L2(for example, as described in "Composition and Reaction of Organic Compound [I]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., November, 1977, p. 54-360).

Getting nitro compounds(5c)

Nitrosoaniline (5c)used at this stage, is commercially available or can be obtained by a method known from the prior art. If it is not available on the market, the efficient retrieval of preferred compounds (5c) (where L2represents a fluorine atom, chlorine atom, bromine atom or iodine atom) can be performed by subjecting the corresponding compound, the precursor of the nitration, as is well known to specialists in this field (e.g., as described in "Composition and Reaction of Organic Compound [III]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1978, p. 1261-1300).

Obtaining the compound (6b)

The compound (6b) can be obtained by a method known from the prior art. Preferably it is obtained through the above-mentioned "Stage 2-1 using the compound (5d) as a starting substance, or it can also be obtained in accordance with stage 2-4" using the amine compound (5b) as the starting material. For example, for efficient conversion of the compound (6b) stage 2-4" can be accomplished by treating compound (5b) a mixture of solvents consisting of acetic anhydride and formic acid, in the first phase of implementation of the condensation with α-halogenation (where L4represents a chlorine atom, a bromine atom or an iodine atom) in y is lacnych conditions in the second phase and heat treatment using ammonium acetate and acetic acid in the third phase. Preferably, when the first phase of the process a mixture of solvents consisting of 2.0 to 10.0 equivalents of acetic anhydride and 10.0 to 20.0 equivalents of formic acid based on the compound (5b) at a temperature from temperature cooling with ice up to 50ºC. The base used in the second phase, preferably used in quantities of from 1.0 to 5.0 equivalents based on the compound (5b), and preferred, for example, are sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, n-utility, diisopropylamide lithium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide, sodium etc. Although the solvent used in this reaction may vary depending on the source of the substance and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but not impede the exercise of the reaction, preferred are, for instance, diethyl ether, tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, etc. For more effective implementation of the reaction is preferably appropriately adding, for example, potassium iodide, sodium iodide, etc. the reaction Temperature must be a such a temperature which is sufficient to complete the reaction, without giving effect to the formation of unwanted side products, and she preferred the nutrient is in the range from room temperature up to 100ºC. Preferably, when the third phase of the process a mixture of solvents consisting of 5.0 to 10.0 equivalents of ammonium acetate and 10.0 to 20.0 equivalents of acetic acid per connection (5b) at a temperature of 50ºC-150 ° C. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods. Undesirable side products can be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization.

α-Halogenation used in the second phase of this stage, is commercially available or can be obtained by a method known from the prior art. If he never comes on the market, the efficient retrieval of preferred α-halogenation (where L4represents a chlorine atom, a bromine atom or an iodine atom) can be performed by subjecting the corresponding compound, the precursor reaction of halogenation, well-known specialists in this field (e.g., as described in "Composition and Reaction of Organic Compound [I]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1977, p. 307-450).

With regard to the compound (6b), L2you can modify the way known from the prior art, and preferably is a possible transformation in the group of iodine (see, n is the sample, S.L. Buchwald et al. "J. Am. Chem. Soc.," vol. 124, p.14844-14845, 2002), group (lower alkyl)tin (see, for example, J. Marti et al., "Synth. Commun.," vol. 30, p.3023-3030, 2000) and in the group of boron (see, for example, N. Miyaura et al., " J. Org. Chem.," vol. 60, p.7508-7510, 1995), etc.

The conversion from the compound (6b) of the ester compound (1a)

The conversion from the compound (6b) of the ester compound (1a) can be carried out using methods known from the prior art. For example, the ester compound (1a) can be obtained by subjecting the compound (6b) "Stage 2-5" together with the compound (7b) or compound (7b'). Namely, although the reaction mix "Stage 2-5 may vary depending on the source of the substance, there are no particular restrictions, provided that the reaction is carried out in conditions similar to those used in this reaction, and you can use methods known from the prior art, and preferred are reaction Mizoroki-Hake (see, for example, R.F. Heck, "Org. Reactions.," vol. 27, p.345, 1982), the reaction of the Suzuki-Miyaura (see, for example, A. Suzuki, Chem. Rev.," vol. 95, p.2457, 1995), the Sonogashira reaction (see, for example, K. Sonogashira, "Comprehensive Organic Synthesis," vol. 3, p.521, 1991), the Stille reaction mix (J.K. Stille, "Angew. Chem. Int. Ed. Engl.," vol. 25, p.508,1986), etc.

Preferred by reaction Mizoroki-Hake involves the reaction of a combination of a halide, triflate compounds (6b) (where L2represents a chlorine atom, a bromine atom, at the m of iodine, or triplet) alkanoyl compound (7b; L3represents a hydrogen atom), which is used in an amount of from 1.0 to 5.0 equivalents based on the compound (6b), in the presence of, for example, 0.01 to 0.2 equivalents of catalyst based on a transition metal. From the standpoint of efficiency of operation and efficiency of mixing this reaction is preferably carried out in the presence of a solvent, although a solvent used in this reaction may vary depending on the source of the substance and of the used catalyst based on a transition metal and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not hinder the reaction, preferred are, for instance, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone, N,N-dimethylformamide and so on, the reaction Temperature must be a such a temperature which is sufficient to complete the reaction combinations, and it is preferably in the range from room temperature to 150 ° C. Preferably, when this reaction is carried out in an atmosphere of inert gas, and more preferably in an atmosphere of nitrogen or argon. The catalyst based on transition metal preferably represents, for example,a complex of palladium and more preferably includes traditional palladium complex, such as palladium(II)acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0) or Tris(dibenzylideneacetone)dipalladium(0). In addition, for more effective implementation of the reaction is also the preferred proper adding phosphorus ligand (preferably, for example, triphenylphosphine, tri-o-tolylphosphino, three-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl, etc). Moreover, the reaction can give the preferred result in the presence of a base and, though the base is not specifically limited, provided that it can be used in reactions combination similar to this reaction, the preferred examples include triethylamine, N,N-diisopropylethylamine, N,N-dicyclohexylamine, tetrabutyltin ammonium, etc. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods.

The Suzuki reaction is Maura preferably carried out by combining, for example, halide or triflate compounds (6b), where L2represents a chlorine atom, a bromine atom, an iodine atom or triflate, with, for example, the connection Bronevoy acid or ester derivative Bronevoy acid (7b), where L3represents B(OH)2or B(OV1)2in the presence of 0.01 to 0.5 e is bivalent catalyst based on transition metal per triflate connection. In order for the reaction and the stirring was easy to implement, this reaction is preferably carried out in the presence of a solvent. Solvent used varies depending on the source of the substance and of the used catalyst based on a transition metal and is not specifically limited, provided that the solvent does not inhibit the reaction and allows dissolution therein of the original substance in some degree. Preferred examples include acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone and N,N-dimethylformamide and a mixture of water with such solvents. The reaction temperature should be a such a temperature, which can ensure the completion of combination reaction, and preferably is in the range from room temperature to 200ºc is manageable. Preferably the reaction is carried out in an atmosphere of inert gas, and more preferably in an atmosphere of nitrogen or argon. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored using known chromatographic methods. The catalyst based on transition metal is preferably a known palladium catalyst and more preferably a known palladium catalyst, such as,for example, the palladium(II)acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0) or Tris(dibenzylideneacetone)dipalladium(0). For the effective implementation of the process of the reaction may appropriate adding phosphorus ligand (preferably, for example, triphenylphosphine, tri-o-tolylphosphino, tricyclohexylphosphine or three-tert-butylphosphine) or the like, in Addition, for the effective implementation of the process of the reaction may appropriate salt of Quaternary ammonium, preferably, for example, tetraethyllead ammonium or tetrabutylammonium bromide. This reaction can give the preferred results in the presence of a base. Used in this case, the base varies depending on the starting substances used solvent, etc. and is not specifically limited. Preferred examples include sodium hydroxide, barium hydroxide, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored using known chromatographic methods. In this reaction, even if the compound (7b) represents, for example, a halide or triflate compound (7b), where L3represents a chlorine atom, a bromine atom, an iodine atom or trip is at, the compound (6b) represents, for example, the connection Bronevoy acid or ester derivative Bronevoy acid (6b), where L2represents B(OH)2or B(OV1)2can be effectively obtained the desired product combinations (1a).

The reaction conditions for the reaction Sonogashira vary depending on the source substance, a solvent and a catalyst based on a transition metal, but not specifically limited, provided that the reaction conditions are such that use in the reaction similar to the reaction. To implement this behavior you can use the techniques known to experts in this field. As starting substances are preferably used alcinoe connection (7b'). Examples of preferred solvents include acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone, N,N-dimethylformamide and dimethylsulfoxide. Examples of preferred solvents include tetrahydrofuran, 1,4-dioxane, 1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reaction temperature should be a such a temperature, which can ensure the complete reaction of the combination and preferably is in the range from room temperature up to 100ºC. Preferably the reaction is carried out is the atmosphere of inert gas, and more preferably in an atmosphere of nitrogen or argon. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored using known chromatographic methods. The catalyst based on transition metal preferably represents, for example, known palladium catalyst and more preferably, for example, such known palladievyh catalyst as palladium(II)acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0) or Tris(dibenzylideneacetone)dipalladium(0). For the effective implementation of the process of the reaction may appropriate to add, for example, phosphorus ligand (preferably, for example, triphenylphosphine, tri-o-tolylphosphino or three-tert-butylphosphine). In this reaction, you can add a metal halide, a salt of Quaternary ammonium, or the like, preferably, for example, copper iodide (I), lithium chloride, tetrabutylammonium fluoride or oxide of silver (I). The reaction can give the preferred results in the presence of a base. The base used in this case is not specifically limited, provided that the base can be used in the reaction combinations, such as this reaction. Preferred examples include basic solvents, such as diethylamine, triethylamine, N,N-diisopropylethylamine, piperidine and pyridine.

The reaction mix-still prefer the Ino carried out by reacting 1.0 equivalent or more connections triamcinolone (6b), where L2represents (V1)Sn, with a halide or a compound of the triflate (7b), where L3represents a chlorine atom, a bromine atom, an iodine atom or triflate, in the presence of 0.01 to 0.2 equivalent of a catalyst based on a transition metal. For the effective implementation of process reaction preferably, when appropriately used is 0.1 to 5.0 equivalents of a halide of copper(I) and/or lithium chloride. Examples of preferred solvents used in this reaction include toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone and dimethyl sulfoxide. The reaction temperature should be a such a temperature, which can ensure the complete reaction of the combination and preferably is in the range from room temperature up to 100ºC. The catalyst based on transition metal is preferably a palladium catalyst, more preferably a famous palladium catalyst, such as palladium(II)acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0) or Tris(dibenzylideneacetone)dipalladium(0) and, more preferably, for example, tetrakis(triphenylphosphine)palladium(0) or Tris(dibenzylideneacetone)dipalladium(0). Preferably the reaction is carried out in an atmosphere of inert gas, and more preferably in the atmosphere is ore of nitrogen or argon. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored using known chromatographic methods.

Obtaining the compound (7b) (7b')

The compound (7b) and the compound (7b'), used at this stage, are commercially available or can be obtained by a method known to specialists in this field. When such connection is not commercially available, the preferred compound (7b), where L3represents B(OH)2or B(OV1)2and V1shall have the meaning given above, can be effectively obtained, for example, from the corresponding precursor by reaction combinations, known to specialists in this field (e.g., as described in C.R. Deloge et al., "Bull. Soc. Chim. Fr.", 1992, vol.129, pp 285-290). Alternative effective obtain preferred compounds (7b), where L3represents triflate can be carried out, for example on the basis of the corresponding predecessor method, known to specialists in this field (e.g., as described in B. Dupre et al., "J. Org. Chem.", 1991, vol.56, pp,3197-3198.

Obtaining ester derived alkylphosphines acid (7a)

Formula 41

(9d)

(where V2and R12has the meaning defined above, W represents (EtO)sub> 2PO, (PhO)2PO or (CF3CH2O)2PO, and L3represents a chlorine atom, a bromine atom or an iodine atom.)

The above formula is an example of a method of obtaining ester derived alkylphosphines acid (7a). Namely, ester derived alkylphosphines acid (7a) is commercially available or can be obtained by a method known to specialists in this field, presented above as stage 3-1" - "stage 3-3 (see, for example, C.Patois et al., Synth.Commun., vol. 22, p.2391, 1991, or J.A.Jackson et al., J.Org.Chem., vol. 20, p.5556, 1989). For example, "stage 3-1 represents the way in which the desired ester derivative alkylphosphines acid (7a) are obtained by treatment of the ester derived alkylphosphines acid (9a) connection alkylhalogenide (8a), which is used in a quantity of 1.0 to 2.0 equivalents per ester derived alkylphosphines acid (9a), in alkaline conditions and the introduction of R12. Stage 3-2 represents the way in which the desired ester derivative alkylphosphines acid (7a) are obtained by treatment of the ester derived alkylphosphines acid (8b) halogenated ester derivatives of formic acid (9b), which is used in a quantity of 1.0 to 2.0 equivalents per ester derived alkyl spinaway acid (8b), in alkaline conditions. "Study 3-3 represents the way in which the desired ester derivative alkylphosphines acid (7a) obtained by processing gelegenheid alkylphosphines acid (8c) complex ester (9c), which is used in a quantity of 1.0 to 2.0 equivalents per gelegenheid alkylphosphines acid (8c), in alkaline conditions. "Stage 3-4" represents the way in which the desired ester derivative alkylphosphines acid (7a) are obtained by treatment of α-halogenated complex ester (9d) trialkylphosphites, which is used in the amount of 1.0 to 10.0 equivalents per α-halogenated ester (9d). Although the basic compounds used at this stage will vary depending on the starting substances, preferably, when using sodium hydride, n-utility, diisopropylamide lithium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide, sodium, etc. in the amount of, for example, from 1.0 to 1.5 equivalents. Although trialkylphosphine used at this stage will vary depending on the starting substances, preferably, when used trimethylphosphite, triethylphosphite, etc. in amounts of, for example, from 1.0 to 10.0 equivalents. The solvent used for this reaction may vary depending on the source of the substance and is not specifically limited, provided what he dissolves the original substance(substances) to a certain extent, but does not prevent the reaction. Preferred examples include hexane, toluene, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, triamide hexamethylphosphoric acid or mixture of such solvents. The reaction temperature should be a such a temperature which is sufficient to complete the reaction, without giving effect to the formation of unwanted side products, and preferably it ranges from-78ºC to about 150ºc. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromatographic methods. Undesired by-products formed in this reaction, may be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization. Moreover, with regard to ester derived alkylphosphines acid (7a), it is possible to carry out an effective modification of R12by the way, is well known to specialists in this field, the desired ester derivative alkylphosphines acid (7a).

Connection alkylhalogenide (8a), ester derived alkylphosphines acid (8b), halogenmethyl alkylphosphines acid (8c), ester derived alkylphosphines acid (9a), halogenated ester production is the initial formic acid (9b), ester compound (9c) and α-halogen-substituted ester derivative (9d)used at this stage, is commercially available or can be obtained by a method known from the prior art.

Receive-2 ester compound (1a)

Formula 42

(where Ar2X1V and L1have the same meanings as in the Formula (I);

V represents a methyl group, ethyl group, benzyl group, allyl group, triphenylmethyl group, tert-boutelou group or a protective group such as tert-butyldimethylsilyl group, methoxymethyl group;

L1represents a hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, and triplet, such as a sulfonate group triamcinolone, baronova acid or ester Bronevoy acid (B(OV1)2.)

The above formula represents an example of the method of obtaining the ester compound (1a) as an alternative method. Namely, it represents (i) a method in which the above-described compound (5a) is used as the starting material which is converted into an ester compound (1b), following the above "Stage 2-2", to obtain the ester compound (1a) above "Stage 2-1"; (ii) the way in which ester the compound (1b) conversion on the live in amine derivative (1d) in Stage 2-6", from which the ester derivative (1a) in accordance with the above-described "Stage 2-4", or (iii) the manner in which the above-described nitrosoaniline (5c) is used as the starting material, which is subjected to the three above stages: "Stage 2-5", "Stage 2-3" and "Stage 2-4" to obtain the ester compound (1a). In addition, it is shown that the amine compound (1d) can also be converted into ester derivative (1b) in response Sandmeyer "Stage 2-7, and then converted to the ester compound (1a) in accordance with the above mentioned "Stage 2-1".

The conversion of compounds of ester (1b) in the amine (1d)

Conversion to the amine compound (1d) of ester (1b) can be done using a method known from the prior art. Preferably, you can use the same method as described above for Stage 2-6".

Conversion of the amine (1d) in the ester derivative (1b)

Conversion of the amine (1d) in the ester derivative (1b) may vary depending on the source of the substance and is not specifically limited, provided that it can be done in conditions similar to the conditions of this method, and you can use methods known from the prior art. Preferably, you can use the reaction Sandmeyer "Stage 2-7", etc. and effectively gaining the ester derivative (1b), preferably, can be carried out using methods known from the prior art (for example, as described in "Composition and Reaction of Organic Compound [I]," New Experiment Chemistry Series, vol.14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., November, 1977, p. 383-388)

A common way to obtain 2

"A General method of obtaining 2" for typical compounds of General formula (I) described below.

Formula 43

(where Ar1, Ar2X1, R1, R2, R11, R12and L3shall have the meaning given above;

W1has the same meaning as defined for W, and L5represents a hydroxyl group, a chlorine atom and a bromine atom).

The compound of General formula (I) can be obtained, for example, by converting the compound (7c) in the compound (7d) in accordance with the above-described "Stage 1-2" with the subsequent implementation Stage 2-2" using a carbonyl compound (6a), as described above, or by converting compound (7e) in the compound (7f) in accordance with the above-described "Stage 1-2" with the subsequent implementation Stage 2-5 using carbonyl compounds (6b)as described above.

Obtaining the compound (7d)

The compound (7d) is commercially available or can be obtained by subjecting the compound (7c) stage, similar to that described above Stage 1-2, using Aminova what about the connection (3), as explained above.

Obtaining the compound (7c)

The compound (7c) is commercially available or can be obtained by a method known from the prior art. Preferably the efficient retrieval of compound (7c) can be made using as the starting material described above ester alkylphosphines acid (7a) and subjecting the reaction of removal of protection similar to that described above for stage 1-1".

Obtaining the compound (7f)

The compound (7f) is commercially available or can be obtained by subjecting compound (7e) stage, similar to that described above Stage 1-2", together with aminoven compound (3)as described above.

Obtaining compound (7e)

The compound (7e) is commercially available or can be obtained by a method known from the prior art. Preferably the efficient retrieval of compound (7e) can be carried out using as starting substances in the above compound (7b) and subjecting the reaction of removal of protection similar to that described above for stage 1-1".

A common method of obtaining 3

A typical receipt (General method of obtaining 3) compounds of General formula (I) described below.

Formula 44

(where, Ar1, Ar2 and X1shall have the meaning given above;

R1and R2together with the-X1-CO-N - clicks the form of one of the following ring structures:

(3-1) a cyclic group represented by the formula (V):

Formula 45

(where Z1represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -SO2-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO - or (10) a simple bond; Z2represents (1) a methine group or (2) a nitrogen atom; R7is a Deputy selected from the group of substituents A3 shown below; and nanband ncrepresent an integer having a value of from 0 to 4)which may be substituted by 1-4 groups substituents selected from the group of substituents A4;

(3-2) a cyclic group represented by the formula (VI):

Formula 46

(where Z3represents (1) a simple link, (2) -CO-, (3) -(CH2nd- (where ndis an integer having a value of from 1 to 3) or (4) -CR8R9- (where R8and R9represent a Deputy selected from the group of substituents A4 shown below;

Z4represents (1) a simple link, (2) -O-, (3) -NRCO-, (4) -CONR-, (5) -CSNR -, or (6)-NRCS- (where R represents a Deputy selected from the group of substituents A4 below) or (7) -S-;

Z5represents (1) a simple link, (2) aminogroup, which can be substituted by the Deputy selected from the group of substituents A4, presents no is e, (3) -(CH2ne- (where neis an integer having a value of from 1 to 3), (4) -CR8R9- (where R8and R9shall have the meaning given above), or (5) -O-; and

R1- R7have the meaning given above); or

(3-3) a cyclic group represented by the following formula:

Formula 47

(where R1and R7have the meaning given above)

which may be substituted by 1-4 groups substituents selected from the group of substituents A4 below.

Group Vice A3: (1) hydrogen atom, (2) halogen atom, (3) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (4) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (5) C1-6-alkyl group (where specified C1-6-alkyl group may be substituted by 1-3 groups of the substituents selected from the group consisting of formyl group, an atom halogen, a hydroxyl group, a hydroxyl group-containing protective group, ceanography, C2-6-alkenylphenol group, C2-6-alkenylphenol group, C3-8-cycloalkyl group, C1-6-alkoxygroup, C1-6-allylthiourea, C1-6-alkylsulfonyl group, C1-6-alkylsulfonyl the school group, C1-6-alkylcarboxylic group, an amino group (where this amino group may be substituted by C1-6-alkyl group, optionally containing 1 to 5 halogen atoms), 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group Vice-A4, and-X-A (where X represents aminogroup, -O - or-S - and is a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4), and (6) C1-6-CNS group.

Group Vice A4: (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano, (5) the nitro-group, (6) C3-8-cycloalkyl group, (7) C2-6-Alchemilla group, (8) C2-6-Alchemilla group, (9) C3-8-cycloalkanes, (10) C3-8-cycloalkylation, (11) fo the mile group, (12) C1-6-acylcarnitine group, (13) C1-6-allylthiourea, (14) C1-6-alkylsulfanyl group, (15) C1-6-alkylsulfonyl group, (16) hydroxyimino, (17) C1-6-alkoxyimino, (18) C1-6-alkyl group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (19) C1-6-alkoxygroup, which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (20) an amino group which may be substituted by 1-2 groups of the substituents selected from the group of substituents A4, (21) carnemolla group which may be substituted by 1-2 groups of the substituents selected from the group of substituents A4, (22) 6-14-membered aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (23) 5-14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (24) 6-14-membered non-aromatic hydrocarbon ring group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (25) a 5 to 14-membered non-aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4, (26) a C2-6-alkenylacyl, (27) a C2-6-alkyloxy, (28) a C3-8-cycloalkylcarbonyl GRU is PA, (29) a C3-8-cycloalkylcarbonyl group, (30) -X-A (where X represents aminogroup, -O - or-S-, and a represents a 6-14-membered aromatic hydrocarbon ring group or 5 to 14-membered aromatic heterocyclic group which may be substituted by 1-3 groups of the substituents selected from the group of substituents A4), (31) -CO-A (where A has the meaning given above) and (32) =CH-A (where A has the meaning given above).

The above formula is presented to illustrate an example method of using the compound (10a), the compound (10b), the compound (10c) or compound (10d) as starting substances in which they are subjected to dehydration reaction "Stage 4-1, using a carbonyl compound (6a'), to obtain compounds of General formula (I). Namely, although the reaction of dehydration Stage 4-1" can vary depending on the source of the substance and is not specifically limited, provided that it can be done in conditions similar to the conditions of this method, you can use methods known from the prior art (for example, as described in H.O. House."Modern synthetic reactions" W.A. Benjamin, Inc., p.629-653, 1972). Preferably the efficient retrieval of compounds of formula (I) can be done through the implementation of the dehydrating condensation reaction of the hydrogen of the acid group of the compound (10a), the compound (10b), the compound (10c) or compound (10d) and the Ohm oxygen of the carbonyl compound (6a') in alkaline conditions. Preferred examples of the base used in this reaction include piperidine, pyrrolidine, sodium methoxide, ethoxide sodium tert-piperonyl potassium, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, n-utility, diisopropylamide lithium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide, sodium etc. Equivalent can vary depending on the Foundation, the starting materials and solvent used and is not limited. The solvent used for this reaction may vary depending on the source of the substance and reason and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not prevent the reaction. Preferred examples include diethyl ether, tetrahydrofuran, benzene, toluene, xylene, methanol, ethanol or tert-butyl alcohol. The reaction temperature should be a such a temperature which is sufficient to complete the reaction, without giving effect to the formation of unwanted side products, and preferably is in the range from-78ºC to about 150ºc. In the preferred reaction conditions, the reaction is completed in 1-24 hours, and the development of the reaction can be monitored known chromate is a graphical methods.

In addition, the compound of General formula (I) can also be obtained by a two-step method where the compound (10a), (10b), (10c) and (10d), which was treated under alkaline conditions, and the carbonyl compound (6a') to form the alcohol through aldorino reaction, and then the hydroxyl group of this compound is removed in a known manner. As the base used in the first stage of this method, sodium hydride, n-butyl lithium, lithium aminobutiramida amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, ethoxide sodium tert-piperonyl etc. preferably specified. The equivalent of such grounds may vary depending on the source of the substance, and although it is not limited, from 1.0 to 2.0 equivalents are preferred. For more effective implementation of the reaction can be added, for example, isopropoxide titanium (IV) or boron TRIFLUORIDE. The solvent used in the first stage, can vary depending on the source of the substance and reason and is not specifically limited, provided that it dissolves the original substance(substances) to a certain extent, but does not prevent the reaction. Preferred examples include diethyl ether, tetrahydrofuran, etc. the reaction Temperature must be a such a temperature which is sufficient to complete the reaction, without giving this the m to the formation of undesirable side products, and preferably is in the range from-78ºC to room temperature. As the second stage of this reaction, you can use any method known from the prior art (for example, described in "Composition and Reaction of Organic Compound [I]," New Experiment Chemistry Series, vol.14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., November, 1977, p. 115-127). The development of the reaction can be monitored known chromatographic methods. Undesired by-products formed in this reaction, may be removed by any method known from the prior art, such as the traditionally used method of chromatography and/or crystallization.

Getting the carbonyl compound (6a')

Carbonyl compound (6a') can be obtained in the same way, as described above for the carbonyl compound (6a).

Obtaining compound (10a), the compound (10b), the compound (11c) (11d)

The compound (10a), the compound (10b), the compound (11c) and the compound (11d) are commercially available or can be obtained by a method known from the prior art. Preferably the efficient retrieval of these compounds can be accomplished by introducing R1group on the nitrogen of the secondary amide in alkaline conditions (see J.A. Campbell et al., J. Org. Chem., vol. 60, p.4602-4616, 1995).

A common way to obtain 4

A typical receipt (General method 4) compounds of General formula (I) described below.

Formula 48

(where, Ar1, Ar2X1, R1, R2, R7, Z1, Z2, Z3, Z4, Z5nanbncand W1have the meanings defined above).

The above formula illustrates an example method using a compound (11a), the compound (11b), the compound (11c) or compound (11d) as starting substances in which they are subjected to reaction Stage 2-2 with a carbonyl compound (6a') to obtain the compounds of General formula (I).

Obtaining compound (11a), the compound (11b), the compound (11c) (11d)

The compound (11a), the compound (11b), the compound (11c) and the compound (11d) are commercially available or can be obtained by a method known from the prior art. Preferably in accordance with the "Stage 3-3"described above (Receiving ester derived alkylphosphines acid (7a)), efficient production of these compounds can be performed using the corresponding amide compounds as source materials.

A common way to obtain 5

Typical receive (a common way of obtaining 5) compounds of General formula (I) described below.

Formula 49

(where, Ar1, Ar2X1, R1, R2, R7, Z3, Z4, Z5, W1and V2they shall have the value defined above, and

L6selected from the above group of substituents A4).

The above formula illustrates an example of a method of using compounds of ester (12a) as the source of the material where it is subjected to reaction Stage 4-1 with a carbonyl compound (6a') to convert the compound (13), which is then converted into a compound of General formula (I) by the reaction of cyclization Stage 5-1", or a method using a compound (12b) as the source of the material where it is subjected to reaction Stage 2-2 with a carbonyl compound (6a') to convert the compound (13), which then put "Stage 5-1". For example, the cyclization Stage 5-1" can vary depending on the source of the substance and is not specifically limited, provided that it can be done in conditions similar to the conditions of this method, and you can use methods known from the prior art. For example, the cyclization can be achieved by (i) interaction of the compound (13) with the amine (3b) through two of the above "stage 1-1" and "Stage 1-2" with the formation of amide linkages and implementation of cyclization in the removal process group Deputy L6or (ii) the introduction of the amine compound (3b) group Deputy L6where the formed product is then subjected to the above "stage 1-1" and 2 "With the adiya's 1-2" with the formation of intramolecular amide bond to the implementation of the cyclization. It is preferable for the effective implementation of the response at each stage of the group of substituents L6or V2can appropriately be modified using the method known to specialists in this field.

Obtaining compounds (12a)

The compound (12a) is commercially available or can be obtained by a method known from the prior art. If carbonisation connection is not available on the market, the corresponding connection, for example, can be obtained by subjecting the corresponding carboxylic acid, the reaction of introducing a protective group known from the prior art (see T.W. Green."Protective Groups in Organic Synthesis" John Wiley & Sons. Inc., 1981).

Getting amine compound (3b)

Amine compound (3b) is commercially available or can be obtained by a method known from the prior art. Preferably it can be obtained in the same manner as described above (Getting amine compound (3)).

Obtaining compound (12b)

The compound (12b) is commercially available or can be obtained by a method known from the prior art. Preferably it can be obtained in the same manner as described above (ester derived alkylphosphines acid (7a)).

The effect of the invention

To demonstrate the usefulness of the compounds of General formula (I) n the present invention, the authors of the present invention were carried out the following tests.

The test example 1 [Quantitative determination of Aβ peptide in the culture of neurons from the brain of fetal rat]

(1)

Primary culture of neurons of the rat

Primary culture neurons were obtained from the cerebral cortex 18-day-old embryos of Wistar rats (Charles River Japan, Yokohama, Japan). Embryos are aseptically removed from pregnant rats under ether anesthesia. The brain of embryos was separated and immersed in ice environment L-15 (e.g., Invitrogen Corp. Cat #11415-064, Carlsbad, CA, USA or SIGMA L1518, St. Louis. MO, USA). The cerebral cortex were collected from the brain under a stereoscopic microscope. The collected fragments of the cerebral cortex were subjected to enzymatic treatment in an enzyme solution containing 0.25% trypsin (e.g., Invitrogen Corp., Cat #15050-065, Carlsbad, CA, USA) and 0.01% Gnkazy (for example, Sigma D5025, St. Louis. MO, USA)at 37 degrees C for 30 minutes to obtain a dispersion of cells. The enzymatic reaction was stopped by adding the same volume V / V heat inactivated horse serum. After centrifugation at 1500 rpm for 5 minutes the supernatant was removed and 5-10 ml of medium was added to the cell precipitate. Wednesday Neurobasal mediumTM(Invitrogen Corp., Carlsbad, CA, USA), supplemented with 2% B-27 additional nutrient (Invitrogen Corp., Carlsbad, CA, USA), 25 μm 2-mercaptoethanol (2-ME, WAKO, 139-06861, Osaka, Japan, 0.5 mm L-glutamine (e.g., Invitrogen Corp., Cat # 25030-081, Carlsbad, CA, USA) and 1% antibiotic-antimycotic funds (Invitrogen Corp., Cat # 15240-062, Carlsbad, CA, USA) was used as culture medium (Neurobasal/B27/2-ME). When evaluating the connection used the medium of the same composition, but without the addition of 2-ME (Neurobasal/B27). The cell sediment was ground into powder by gently pipetting. The remaining cell precipitate was removed by filtration through a 40-μm nylon sieve (Cell Strainer, Cat # 35-2340, Becton Dickinson Labware, Franklin Lakes, NJ, USA) and obtained cell suspension neurons. Cell suspension neurons was diluted with medium Neurobasal/B27/2-ME and then sown in the plate at the density of 100 ml/well getting the initial density of the cells 5×105cells/cm2in 96-well polystyrene plate with pre-applied coating of poly-L-or D-lysine (e.g., cultural tablet Falcon MICROTESTTM, 96-well, flat bottom, with lid for low evaporation (Cat # 35-3075, Becton Dickinson Labware, Franklin Lakes, NJ, USA)coated with poly-L-lysine using the method below, or 96-well culture tablet BIOCOATTMwith a coating of poly-D-lysine, Cat # 35-6461, Becton Dickinson Labware, Franklin Lakes, NJ, USA). Coating of poly-L-lysine was carried out as follows. A solution of poly-L-lysine (SIGMA P2636, St. Louis, MO, USA) with a concentration of 100 mg/ml were obtained under aseptic conditions using 0,15M Bor the private buffer (pH 8.5). The solution was added to 96-well polystyrene incubator at a density of 50-100 ml/well and incubated at room temperature for one hour or more, or at 4ºC over night or longer. Washed 4 or more times with sterile water and then dried, or washed, for example, sterile PBS or medium and used for sowing cells. Cells were cultured for one day in the incubator in an atmosphere of 5% CO2- 95% air at 37 degrees C, the entire quantity of the medium was replaced with fresh medium Neurobasal/B27/2-ME and the cells were then cultured for another 3 days.

Adding connections

Drugs were added at day 4 of cultivation in the following way. All the amount of medium was removed from the containing culture wells, and was added to the medium Neurobasal/B27 at 180 μl/well. The solution of the test compound in dimethyl sulfoxide (hereinafter indicated as DMSO) was diluted in Neurobasal/B27 thus, to obtain a 10-fold dilution from the desired final concentration. The diluent was added at 20 μl/well and thoroughly mixed. The final concentration of DMSO was 1% or less. The control group was only added DMSO.

Sampling

After incubation for 3 days, the amount of medium was collected as a sample for ELISA. This environment was used without any dilution for the quantitative determination of Aβx-42 before it is used the I in the corresponding ELISA tests.

Evaluation of the survival rate of cells

Cell survival was assessed using the MTT assay. The MTT assay was carried out in accordance with the following protocols. Preheated medium with 100 ml/well was added to the wells after collecting environment. A solution of 8 mg/ml MTT (SIGMA M2128, St. Louis, MO, USA)dissolved in D-PBS(-) (phosphate buffered physiological saline, Dulbecco, SIGMA D8537, ST. Louis, MO, USA), was added 8 μl/well and incubated in an incubator in an atmosphere of 5% CO2- 95% air at 37°C for 20 minutes. Added MTT solubilizers buffer at 100 ml/well MTT formazane crystals were thoroughly dissolved in the incubator with an atmosphere of 5% CO2- 95% air at 37°C and measured spectral absorption capacity at 550 nm. MTT solubilizers buffer was prepared as follows. N,N'-dimethylformamide (e.g., WAKO 045-02916, Osaka, Japan) and distilled water, 250 ml each, were mixed together. The resulting mixture was dissolved 100 g of SDS (sodium dodecyl sulphate (for example, sodium lauryl sulfate, WAKO 191-07145, Osaka, Japan)). Added concentrated Hcl and concentrated acetic acid, 350 ál each, to achieve a final pH of about 4.7.

When measuring the wells, which were not sown any cells containing only medium and MTT solution was considered background (bkg). Each measured value was used for calculation of the decree which authorized the following formula to determine the relative content against the control group (group without treatment drugs CTRL) (% of CTRL) for comparison and evaluation of the survival rate of cells.

% CTRL=(Arc-A550_bkg)/(A550_CTRL-A550_bkg)×100

(AOR: spectral absorption capacity at 550 nm of the wells containing sample, A550_bkg: spectral absorption capacity at 550 nm background wells, A550_CTRL: spectral absorption capacity at 550 nm holes in the control group)

Analysis of Aβ by ELISA method

For analysis β using ELISA method used sets of Human Amyloid beta (1-42) Assay Kit (#17711 or #27711) from Measurement-Biological Laboratories, Co., Ltd. (IBL Co., Ltd.). Used the methods described in the protocols recommended by the manufacturer (methods described in the attached document), except that the calibration curve Aβ built using beta-amyloid peptide 1-42 rats (Calbiochem, #171596 [Aβ42]). The results are presented as percentage of the concentration of Aβ in the medium control group (% of CTRL). The results are presented in Table 1.

(2) Thus, it is proved that the compound of the present invention has the effect of reducing the production of Aβ42.

Accordingly, since the compound of General formula (I) or its pharmaceutically acceptable salt have the effect of reducing the production of Aβ42, in accordance with the present invention, they can provide a means for the prevention or treatment in particular, neurodegenerative disease caused by Aβ such as illness who ü Alzheimer's disease and down's syndrome.

Table 1-1
Test connectionThe effect of reducing the production of Aβ42 IC50(nm)
Example 153190
Example 12170
Example 173190
Example 17560
Example 186190
Example 86320
Example 122190
Example 139200
Example 398220
Example 96220
Example 338330
Example 90240
Example 40270
Example 40390
Example 366330
Example 353220

Table 1-2
Test connectionThe effect of reducing the production of Aβ42 IC50(nm)
Example 414130
Example 416100
Example 418109
Example 420120
Example 42580

Table 1-3
Test connectionThe effect of reducing the production of Aβ42 IC50(nm)
Example 427780
Example 430119
Example 611265
Example 63956
Example 90868
Example 97680
Example 101460
Example 102771
Example 96587
Example 99160
Example 102570
Example 621100

"Sol" means pharmaceutically acceptable salt and is not specifically limited, provided that forms a pharmaceutically acceptable salt with a compound of General formula (I), which can be an agent for the prevention or treatment of diseases caused by Aβ. Specific examples that can be specified include, for example, preferably salts of halogen acids (such as, for example, hydrohloride, hydrochloride, hydrobromide and hydroiodide), salts of inorganic acids (such as, for example, sulfates, nitrates, perchlorates, phosphates, carbonates, and bicarbonates), organic carboxylates (such as acetates, oxalates, maleate, tartratami, fumarate and citrate), organic sulfonates (such as, for example, methanesulfonate, triftoratsetata, econsultancy, bansilalpet, toluensulfonate and camphorsulfonate), salt, amino acids (such as, for example, aspartate and glutamate), solicitating amine, alkali metal salts (such as, for example, salts of sodium and potassium salts), salts of alkaline earth metals (such as magnesium salts and calcium salts), etc.

The agent for the prevention of diseases caused by Aβ, the present invention can be formulated into the composition in the usual way. Preferred dosage forms are, for example, tablets, powders, fine granules, granules, coated tablets, capsules, syrups, drops, pharmaceutical forms for inhalation, suppositories, injectable preparations, ointments, ophthalmic solutions, ophthalmic ointments, nasal drops, ear drops, poultices, lotions, etc. For the formulation of the composition can be used conventionally used excipients, such as binders, lubricants, dyes and corrigentov and, if necessary, stabilizers, emulsifiers, absorption material, surface-active agents, agents for adjusting pH, preservatives and antioxidants, and components traditionally used as ingredients for pharmaceutical preparations can be mixed to obtain compositions in traditional ways. Such components, which can be specified are animal fats and vegetable oils, such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such is AK, for example, liquid paraffin, squalene, paraffin wax; synthetic ester oils, such as, for example, octyldodecanol, isopropylmyristate; higher alcohols, such as, for example, cetosteatil alcohol, beganovic alcohol; silicone resin; for example, silicone oil; surfactants such as esters of fatty acids of polyoxyethylene, an ester of fatty acids sorbitan, esters of fatty acids of glycerol, esters of fatty acids and polyoxyethylene sorbitan, polyoxyethylene hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymer; water-soluble polymers, such as, for example, hydroxyethylcellulose, polyacrylate, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, methyl cellulose; lower alcohols, such as, for example, ethanol, isopropanol; polyols, such as glycerin, propylene glycol, dipropyleneglycol, sorbitol; sugars such as glucose, sucrose; inorganic powders such as silicic anhydride, aluminum silicate-magnesium aluminum silicate; and distilled water, etc. Used excipients are, for example, lactose, corn starch, white soft sugar, dextrose, lures, sorbitol, crystalline cellulose and silicon dioxide, etc. Used binder represents the t a, for example, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, Arabian gum, tragakant, gelatin, shellac, hypromellose, hydroxypropylcellulose, polyvinylpyrrolidone, block-copolymer polypropylenglycol/polyoxyethylene and meglumin etc. Used leavening agents are, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and calcium carboxymethyl cellulose, etc. Used lubricants are, for example, magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oils, etc. as dyes use dyes approved for use as additives for pharmaceutical preparations. Used corrigentov represent, for example, cocoa powder, pepper mint, camphor, mpasm (empasm), menthol oil, borneol and cinnamon powder, etc.

Compositions for oral administration formulate, for example, by adding the compound that is the active ingredient, or its salt or its hydrate and excipients, and then for example, binders, disintegrating agents, lubricants, dyes and corrigentov etc. as necessary, then traditional ways formulir the Ute, for example, powders, fine granules, granules, tablets, coated tablets and capsules, etc. In the case of tablets/granules, there is no need to mention that is an acceptable application of the appropriate coating, if necessary, for example sugar coating. In the case of syrups or injections add, for example, means regulating pH, solubilizing means and means to control toychest etc. and, if necessary, a tool to facilitate solubilization and stabilizers, etc. and formulated into a composition in traditional ways. In the case of preparations for external use methods of formulation are not specifically limited, and you can get them in traditional ways. As the main materials you can use various traditionally used substances, such as chemicals used for pharmaceutical preparations, quatercentennial tools and cosmetics. Examples of such substances that can be specified include animal and vegetable oils, mineral oils, synthetic ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyols, water-soluble polymers, clay mineral and distilled water, etc. and also, if e is about you, you can add a tool for pH control, antioxidant, chelating agents, preservatives and fungicides, dyes and fragrances and so on in Addition, if necessary, can be included in the composition of the ingredients that have differenziale-inducing effect, such as, for example, funds for improving blood circulation, microbicides, anti-inflammatory drugs, stimulants cells, vitamins, amino acids, moisturizers and keratolytic funds. The amount of injected therapeutic/prophylactic agent of the present invention varies depending on, for example, on the severity of symptoms, age, sex, weight, route of administration, type of salt and a specific type of disease, etc. Typical amount for an adult ranges from about 30 μg to 10 g, preferably from 100 μg to 5 g, more preferably from 100 μg to 3 g per day for oral administration, and from about 30 μg to 1 g, preferably 100 μg to 500 mg, more preferably from 100 μg to 30 mg for administration by injection that lead either single or multiple doses.

The most preferred method of carrying out the invention

The present invention will be described hereinafter in more detail with reference to examples. These examples are illustrative and are in no way intended to limit the means to prevent lilacine diseases, caused by Aβ, the present invention specific examples below. Specialists in this area with average skills can use various forms of referential examples and examples described below, as well as the claims in accordance with the present invention for carrying out the invention in its entirety. So the options are covered by the claims in accordance with the present invention.

In the examples presented here the following notation is used.

DMF: N,N'-dimethylformamide

THF: tetrahydrofuran

LAH: sociallyengaged

EDC: hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

HOBT: 1-hydroxybenzotriazole

IPEA: diisopropylethylamine

TEA: triethylamine

DPPF: 1,1-bis(diphenylphosphino)ferrocene

CDI: N,N'-carbonyldiimidazole

TBAF: tetrabutylammonium fluoride

PYBOP: ether benzotriazol-1-yloxytris(pyridine)phosphodiesteraseisozyme acid

DBU: 1,8-diazabicyclo[5,4,0]undec-7-ene

DAST: TRIFLUORIDE diethylaminoethyl

BOP: benzotriazol-1 yloxy-Tris(dimethylamino)fosfodiesterasa

DIBAL-H: diisobutylaluminium

Reagent Dess-Martin: periodinane Dess-Martin

Chromatography was performed using BW-300 (product of Fuji Silysia Chemical Ltd.) as the carrier, unless otherwise noted.

LC-MS: high-performance LM is bone chromatography for preparative separation of target compounds using mass spectrometry. As an eluting solvent used linear gradient 10-99%consisting of water containing 0.1% triperoxonane acid, and acetonitrile containing 0.1% triperoxonane acid.

Example 1

Synthesis of (E)-N-indan-1-yl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 50

Synthesis of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde and 3-methoxy-4-(5-methyl-1H-imidazol-1-yl)benzaldehyde

To a solution in DMF (50 ml) of 4-fluoro-3-methoxybenzaldehyde (3.00 g) and 4-methylimidazole (3,307 g) was added potassium carbonate (4,05 g) and the reaction mixture was stirred at 100ºC during the night. The resulting reaction mixture was concentrated under reduced pressure, to the residue were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent system hexane-ethyl acetate) and was obtained 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (856 mg) and 3-methoxy-4-(5-methyl-1H-imidazol-1-yl)benzaldehyde (44 mg).

Physical properties of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde:

1H-NMR (CDCl3) δ (ppm): 2,31 (s, 3H), of 3.97 (s, 3H), 7,02 (Sirs, 1H), 7,44 (d, J=8.0 Hz, 1H), 7,55 (DD, J=1.6 Hz, 8.0 a is C, 1H), 7,58 (d, J=1.6 Hz, 1H), 7,84 (Sirs, 1H), 10,00 (s, 1H).

Physical properties of 3-methoxy-4-(5-methyl-1H-imidazol-1-yl)benzaldehyde:

1H-NMR (CDCl3) δ (ppm): 2,10 (s, 3H), 3,90 (s, 3H), 6,91 (Sirs, 1H), 7,40 (d, J=8.0 Hz, 1H), 7,50 (d, J=1.2 Hz, 1H), EUR 7.57-to 7.59 (m, 1H), to 7.84 (s, 1H), of 10.05 (s, 1H).

In addition, 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde can also be synthesized in the following alternative way.

Synthesis of methyl ester of 3-methoxy-4-nitrobenzoic acid

Methyliodide (463 g) was added dropwise at room temperature to a mixture of 3-hydroxy-4-nitrobenzoic acid (199 g) and potassium carbonate (450 g) in DMF (1 l). After stirring the reaction solution at room temperature over night to the reaction mixture was added methyliodide (230 g) and the reaction mixture was then stirred at room temperature for 6 hours. The reaction mixture was added to ice water and the precipitated solids were collected by filtration. By drying the obtained solid substance at 50ºC during the night received 178 g specified in the connection header. The physical properties of this compound were consistent with values reported previously (CAS#5081-37-8).

Synthesis of methyl ester of 4-amino-3-methoxybenzoic acid

To a solution of methyl ester of 3-methoxy-4-nitrobenzoic acid (150 g) in methanol (600 ml) and THF (300 ml) was added 10% palladium on ug is erode (15 g) and the reaction mixture was stirred at 50ºC-64ºC when the hydrogen pressure of 0.9 MPa for 6.5 hours. After the reaction solution was allowed to cool to room temperature, received 134 g specified in the connection header by filtration of the reaction solution through celite and condensation of the obtained filtrate under reduced pressure. The physical properties of this compound were consistent with values reported previously (CAS#41608-64-4).

Synthesis of methyl ester of 4-formylamino-3-methoxybenzoic acid

Anhydrous acetic acid (268 ml) was added dropwise to formic acid (401 ml) at room temperature and the reaction solution was stirred for 40 minutes at room temperature. To this reaction solution was added dropwise at room temperature a solution of methyl ester 4-amino-3-methoxybenzoic acid (134 g) in THF (600 ml) and the reaction solution was stirred for 1 hour. To the reaction solution was added 3.8 l of ice water and the precipitated solids were separated by filtration and then washed with water (2 l). By drying the obtained solid substance at 50ºC during the night received 111 g specified in the connection header. The physical properties of this compound were consistent with values reported previously (CAS#700834-18-0).

Synthesis of methyl ester 4-[formyl-(2-oxopropyl)amino]-3-methoxybenzoic acid

Chloroacetone (84,5 ml) was added to paraply at room temperature to a mixture of methyl ester of 4-formylamino-3-methoxybenzoic acid (111 g), of cesium carbonate (346 g) and potassium iodide (8,78 g) in DMF (497 ml) and the reaction mixture was stirred for 3 hours. To the reaction mixture was added cesium carbonate (173 g) and chloroacetone (42,0 ml) and the reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture were added ice water and ethyl acetate and the organic layer was separated. To the aqueous layer was added ethyl acetate and the organic layer was separated. The organic layers were combined, washed with water and saturated saline solution in this order and the resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with toluene and the solution was concentrated under reduced pressure. To the obtained residue was added tert-butyl methyl ether and heptane, and the precipitated solids were separated by filtration and washed with 50% solution of tert-butyl methyl ether in heptane. Using air drying the obtained solid substance during the night received 118g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 2,19 (s, 3H), 3,91 (s, 3H), of 3.94 (s, 3H), of 4.49 (s, 2H), 7,31 (d, J=8.0 Hz, 1H), 7,63 (d, J=2.0 Hz, 1H), 7,69 (DD, J=8,0, 2.0 Hz, 1H), with 8.33 (s, 1H).

Synthesis of methyl ester of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoic acid

A solution of methyl ester 4-(formyl-(2-oxopropyl)amino)-3-methoxybenzoyl sour is s (118 g) and ammonium acetate (172 g) in acetic acid (255 ml) was heated under stirring at 140ºC for 1 hour. After completion of the reaction, the reaction solution was neutralized with aqueous ammonia under ice cooling. To the reaction solution were added ethyl acetate and the organic layer was separated. After drying over anhydrous magnesium sulfate the organic layer was filtered through a layer of silica gel and the filtrate was concentrated under reduced pressure. To the residue was added tert-butyl methyl ether and heptane, and the precipitated solids were separated by filtration and washed with 50% solution of tert-butyl methyl ether in heptane. After using air drying the obtained solid substance during the night got to 68.4 g specified in the connection header. In addition, crystallized mother liquor was concentrated under reduced pressure, the residue was purified column chromatography on silica gel (eluting solvent system heptane-ethyl acetate) and received 22,3 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 2,30 (s, 3H), of 3.94 (s, 3H), of 3.96 (s, 3H), 6,98 (Sirs, 1H), 7,32 (d, J=8,4 Hz, 1H), 7,71-7,73 (m, 2H), 7,79 (Sirs, 1H).

Synthesis of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde

To a solution in THF (60 ml) of sodium bis(2-methoxyethoxy) aluminiumhydride (65% solution in toluene, 56 ml) was added dropwise a solution of pyrrolidine (18 ml) in THF (45 ml) over 15 minutes at-5ºC or below. The reaction solution was stirred at room te is the temperature for 1 hour, to the reaction solution was added dropwise a suspension of tert-butoxide (2.10 g) in THF (15 ml) at room temperature and the reaction mixture was stirred for 15 minutes. The reaction mixture was added dropwise to a solution of methyl ester of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoic acid (20 g) in THF (50 ml) under cooling with ice for 30 minutes. The reaction mixture was stirred at room temperature for 2 hours and the reaction solution was added dropwise 5h. the sodium hydroxide solution (150 ml). To the reaction solution were added ethyl acetate and the organic layer was separated. The organic layer was washed with a saturated solution of ammonium chloride and saturated saline in this order. The organic layer was dried over anhydrous magnesium sulfate and after filtration through a layer of silica gel, the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and the precipitated solids were separated by filtration. After air drying the obtained solid substance during the night received 7,10 g specified in the connection header. In addition, crystallized mother liquor was concentrated under reduced pressure, the residue was purified column chromatography on silica gel (eluting solvent system heptane-ethyl acetate-2-propanol) and obtained 2.65 g is specified in the header connect the headphones.

Synthesis of diethyl ether indan-1-ylcarbonylglycine acid

After the addition of thionyl chloride (6,07 g) to a solution of diethoxyphosphoryloxy acid (5,00 g) in methylene chloride (20 ml) the reaction mixture was stirred at room temperature for 2 hours and the reaction solution was concentrated under reduced pressure. A solution of the obtained residue in THF (40 ml) was added dropwise to a solution in THF (80 ml), 1-aminoindane (3,40 g) and TEA (3.5 ml) under ice cooling and the reaction solution was stirred at the same temperature. To the obtained reaction mixture were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent system hexane-ethyl acetate) and received 4,2 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,31-of 1.36 (m, 6H), 1,79-1,89 (m, 1H), 2,56-2,63 (m, 1H), 2,83-3,03 (m, 4H), 4.09 to 4,18 (m, 4H), 5,47 (kV, J=7,6 Hz, 1H), 6,83-6,89 (shirt, 1H), 7,19-to 7.32 (m, 4H).

Synthesis of (E)-N-indan-1-yl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

The monohydrate of lithium hydroxide (9 mg) was added to a solution in THF (2 ml) of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (21 mg) and diethyl ether indan-1-icarb molecularbiological acid (30 mg), obtained above, and the reaction solution was stirred at room temperature overnight. After concentrating the reaction mixture under reduced pressure, the residue was purified column chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent system hexane-ethyl acetate) and received 13 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,86-of 1.95 (m, 1H), to 2.29 (s, 3H), 2,63-of 2.72 (m, 1H), 2,88-of 3.06 (m, 2H), 3,88 (s, 3H), 5,65 (kV, J=7,6 Hz, 1H), 5,88 (d, J=8,4 Hz, 1H), 6,41 (d, J=to 15.4 Hz, 1H), 6,92 (t, J=1.2 Hz, 1H), 7,13-7,35 (m, 7H), to 7.67 (d, J=to 15.4 Hz, 1H), 7,71 (d, J=1.6 Hz, 1H).

Example 1-1

Synthesis of (E)-3-[4-(4-bromo-1H-imidazol-1-yl)-3-methoxyphenyl]-N-(9H-fluoren-9-yl)acrylamide

Formula 51

Synthesis of 4-(4-bromo-1H-imidazol-1-yl)-3-methoxybenzaldehyde

Potassium carbonate (1,74 g) was added to a solution of 4-fluoro-3-methoxybenzaldehyde (1,94 g) and 4-bromoimidazo (1.85 g) in DMF and the reaction solution was stirred at 100ºC during the night. The resulting reaction mixture was concentrated under reduced pressure, to the obtained residue were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: hexane system:atilas the tat) and got to 1.21 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 3,93 (s, 3H), 7,24 (s, 1H), 7,43 (d, J=7,6 Hz, 1H), 7,52-of 7.55 (m, 2H), 7,74 (s, 1H), becomes 9.97 (s, 1H).

Synthesis of (E)-3-[4-(4-bromo-1H-imidazol-1-yl)-3-methoxyphenyl]-N-(9H-fluoren-9-yl)acrylamide

In the same way as described in example 121, specified in the title compound was synthesized from 3-(4-(4-bromo-1H-imidazol-1-yl)-3-methoxyphenyl)acrylic acid (100 mg)was obtained from hydrochloride of 4-(4-bromo-1H-imidazol-1-yl)-3-methoxybenzaldehyde and 9-fluoren-9-ylamine (81 mg).

1H-NMR (CDCl3) δ (ppm): 1,83-of 1.97 (m, 1H), 2,60-to 2.74 (m, 1H), 2,84-is 3.08 (m, 2H), with 3.89 (s, 3H), 5,64 (kV, J=7,6 Hz, 1H), equal to 6.05 (d, J=8,4 Hz, 1H), 6,46 (d, J=15.2 Hz, 1H), 7,10-7,30 (m, 7H), 7,34 (d, J=6,8 Hz, 1H), to 7.61 (d, J=6.0 Hz, 1H), to 7.67 (d, J=15.6 Hz, 1H).

Example 2

Synthesis of (E)-3-[3-ethoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 52

Synthesis of 4-fluoro-3-hydroxybenzaldehyde

Tribromide boron (1M solution in methylene chloride, 100 ml) was gradually added dropwise under ice cooling to a solution of 3-methoxy-4-forventelige (4.4 g) in methylene chloride (100 ml). After completion of adding dropwise, the reaction solution was stirred at room temperature for 2 hours. The reaction solution was again cooled with ice, the reaction solution was slowly added to ice water to stop the reaction and then added 5N. a solution of Ki is rochloride to reach pH 1. After condensing the reaction solution under reduced pressure, to the residue were added water and ethyl acetate and the organic layer was separated. The obtained organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 4:1) and received 3,18 g (79%) of 4-fluoro-3-hydroxybenzaldehyde. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 5,70 (s, 1H), 7,24 (DD, J=8,4, 10,0 Hz, 1H), 7,40-to 7.50 (m, 1H), 7,55 (DD, J=2.0 a, and 8.4 Hz, 1H), to 9.91 (s, 1H).

Synthesis of 3-ethoxy-4-forventelige

Sodium hydride (171 mg) was added at room temperature to a solution in DMF (10 ml) of 4-fluoro-3-hydroxybenzaldehyde (300 mg)obtained above, and the reaction solution was stirred for 30 minutes. Then to the reaction solution was added dropwise Iodate (0,26 ml) and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction to the reaction solution were added while cooling with ice water and ethyl acetate and the organic layer was separated. The obtained organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. According to the scientists the residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 5:1) and received 250 mg (70%) 3-ethoxy-4-forventelige. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,49 (t, J=6.8 Hz, 3H), 4,19 (kV, J=6,8 Hz, 2H), 7.23 percent (DD, J=8,0, 10.4 Hz, 1H), 7,43 (m, 1H), 7,50 (DD, J=2,0, 8.0 Hz, 1H), to 9.91 (s, 1H).

Synthesis of 3-ethoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde

4-Mei (244 mg) was added to a solution in DMF (3 ml), 3-ethoxy-4-forventelige (250 mg)obtained above, and the reaction solution was stirred at about 150ºc for 4 hours. After completion of the reaction, the resulting reaction solution was concentrated, the resulting reaction residue was added water and ethyl acetate and the organic layer was separated. The obtained organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 1:4) and received 60 mg (18%) 3 ethoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 1.46 (t, J=8,4 Hz, 3H), 2,31 (s, 3H), 4,20 (kV, J=8,4 Hz, 2H), 7,00-7,06 (m, 1H), 7,43 (d, J=8.0 Hz, 1H), 7,53 (DD, J=1,6, 8.0 Hz, 1H), 7,55 (d, J=1.6 Hz, 1H), of 7.90 (d, J=1.2 Hz, 1H), 9,99 (s, 1H).

Synthesis of (E)-3-[3-ethoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

To a solution in THF (8 ml), 3-ethoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (60 mg) was added diethyl-the new ether (indan-1-ylcarbonyl)alkylphosphines acid (81 mg) and the monohydrate of lithium hydroxide (22 mg) and the reaction mixture was stirred at room temperature for 14 hours. After completion of the reaction to the reaction solution were added water and ethyl acetate and the organic layer was separated. The obtained organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 1:4) and received 23 mg (23%) specified in the connection header. The physical properties of this compound are as follows.

ESI-MS; m/z 388 [M++H].1H-NMR (CDCl3) δ (ppm): of 1.41 (t, J=6.8 Hz, 3H), 1,82-of 1.97 (m, 1H), 2,30 (s, 3H), 2,60-to 2.74 (m, 1H), 2,84-3,10 (m, 2H), 4,10 (kV, J=6,8 Hz, 2H), 5,64 (kV, J=7,6 Hz, 1H), 5,88 (d, J=8,4 Hz, 1H), to 6.39 (d, J=15.6 Hz, 1H), to 6.95 (s, 1H), 7,10-7,19 (m, 2H), 7,20-7,31 (m, 4H), 7,34 (d, J=6,8 Hz, 1H), 7,66 (d, J=15.6 Hz, 1H), 7,78 (d, J=1.6 Hz, 1H).

Example 3

Synthesis of (E)-3-[3-cyclopropyl methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 53

In the same way as described in example 2, 22 mg (3.6 per cent) indicated in the title compound was obtained from 4-fluoro-3-hydroxybenzaldehyde (200 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 414 [M++H].1H-NMR (CDCl3) δ (ppm): 0.24 to 0,38 (m, 2H), 0.56 to 0.70 and (m, 2H), 1,16-1,32 (m, 1H), 1,82-to 1.98 (m, 1H), 2,30 (s, 3H), 2,60-to 2.74 (m, 1H), 2,84-3,10 (m, 2H),a 3.87 (d, J=6,8 Hz, 2H), 5,63 (kV, J=7,6 Hz, 1H), to 5.93 (d, J=8,4 Hz, 1H), to 6.39 (d, J=15.6 Hz, 1H), 6,98 (s, 1H), 7,11 (d, J=1.7 Hz, 1H), 7,16 DD, J=1,7, and 8.4 Hz, 1H), 7,19-7,30 (m, 4H), 7,34 (d, J=6,8 Hz, 1H), 7,65 (d, J=15.2 Hz, 1H), to 7.84 (m, 1H).

Example 4

Synthesis of (E)-3-[3-(2-butenyloxy)-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 54

In the same way as described in example 2, 58 mg (7.8 per cent) indicated in the title compound was obtained from 4-fluoro-3-hydroxybenzaldehyde (250 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 412 [M++H].1H-NMR (CDCl3) δ (ppm): 1,85 (t, J=3.0 Hz, 3H), 1,82-to 1.98 (m, 1H), of 2.45 (s, 3H), 2,62-to 2.74 (m, 1H), 2,86-3,10 (m, 2H), 4,71 (d, J=3.0 Hz, 2H), 5,65 (kV, J=7,6 Hz, 1H), to 5.93 (d, J=8.0 Hz, 1H), 6,41 (d, J=15.6 Hz, 1H), 6,92-6,97 (m, 1H), 7.18 in-7,32 (m, 6H), 7,35 (d, J=7,6 Hz, 1H), 7,69 (d, J=15.6 Hz, 1H), 7,74 (d, J=1.6 Hz, 1H).

Example 5

Synthesis of (E)-N-indan-2-yl-3-[4-(4-methyl-1H-imidazol-1-yl)-3-(2-propenyloxy)phenyl]acrylamide

Formula 55

In the same way as in example 2, 96 mg (9.5 per cent) indicated in the title compound was obtained from 4-fluoro-3-hydroxybenzaldehyde (350 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 398 [M++H].1H-NMR (CDCl3) δ (ppm): to 2.29 (d, J=1.0 Hz, 3H), by 2.55 (t, J=2.0 Hz, 1H), 2,99 (DD, J=4.0 a, and 16.4 Hz, 2H), 3,39 (DD, J=6,8, and 16.4 Hz, 2H), 4,73 (d, J=2.0 Hz, 2H), 4,85-of 4.95 (m, 1H), 5,94 (d, J=8.0 Hz, 1H), 6,33 (d, J=15.6 Hz, 1H), 6,91-to 6.95 (m, 1H), 7,16-to 7.32 (m, 7H), 7,63 (d, J=15.6 Hz, 1H), 7,71 (d, J=1.6 Hz, 1H).

Example 6

Synthesis of (E)-N-indan-1-yl-3-[4-(4-methyl-1H-imidazol-1-yl)-3-vinyloxyethyl]acrylamide

Fo the mule 56

Synthesis of 3-(2-bromoethoxy)-4-forventelige

Sodium hydride (1,14 g) was added to a solution of 4-fluoro-3-hydroxybenzaldehyde (2.00 g) in DMF (30 ml) at room temperature and the reaction solution was stirred for 30 minutes. Then to the reaction solution was added dropwise dibromethane (2,46 ml) and after adding dropwise, the reaction solution was heated at 140ºC for 3 hours. To the reaction solution under ice cooling was added water and ethyl acetate and the organic layer was separated. The obtained organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 6:1) and received 606 mg (20%) 3-(2-bromoethoxy)-4-forventelige. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): at 3.69 (t, J=6.4 Hz, 2H), 4,42 (t, J=6.4 Hz, 2H), 7,27 (DD, J=8,4, 9.6 Hz, 1H), 7,46-7,56 (m, 2H), 9,92 (s, 1H).

Synthesis of 4-fluoro-3-vinyloxyethyl

50% sodium hydroxide Solution (5 ml) and tetrabutylammonium bisulfate (859 mg) was added to a solution in toluene (8 ml) of 3-(2-bromoethoxy)-4-fermentacyjnego derived (606 mg)obtained above, and the reaction solution was stirred at room te is the temperature for 1 hour. To the reaction solution after completion of the reaction was added water and ethyl acetate and the organic layer was separated. The obtained organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 6:1) and obtained 200 mg (49%) of 4-fluoro-3-vinyloxyethyl. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 4,60 (DD, J=2.0 a, 6,0 Hz, 1H), 4,84 (DD, J=2,0, to 13.6 Hz, 1H), to 6.67 (DD, J=6,0, to 13.6 Hz, 1H), 7,30 (DD, J=8,4, 10,0 Hz, 1H), 7,50-of 7.70 (m, 2H), to 9.93 (s, 1H).

Synthesis of 4-(4-methyl-1H-imidazol-1-yl)-3-vinyloxyethyl

In the same way as described in example 2, 66 mg (24%) of 4-(4-methyl-1H-imidazol-1-yl)-3-vinyloxyethyl was obtained from 4-fluoro-3-vinyloxyethyl (200 mg)obtained above. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,31 (s, 3H), with 4.64 (DD, J=2.0 a, 6,0 Hz, 1H), 4,87 (DD, J=2,0, to 13.6 Hz, 1H), 6,63 (DD, J=6,0, to 13.6 Hz, 1H), 7,03 (s, 1H), 7,50 (d, J=8,4 Hz, 1H), of 7.64-7,74 (m, 2H), a 7.85 (s, 1H), 10,00 (s, 1H).

Synthesis of (E)-N-indan-1-yl-3-[4-(4-methyl-1H-imidazol-1-yl)-3-vinyloxyethyl]acrylamide

In the same way as described in Example 2, 60 mg (54%) of (E)-N-indan-1-yl-3-(4-(4-methyl-1H-imidazol-1-yl)-3-vinyloxyethyl)acrylamide was obtained from 4-(4-methyl-1H-imidazol-1-yl)-3-is unilaterally (66 mg), obtained above. The physical properties of this compound are as follows.

ESI-MS; m/z 386 [M++H].1H-NMR (CDCl3) δ (ppm): 1,89-to 1.98 (m, 1H), 2,30 (s, 3H), 2,60-to 2.74 (m, 1H), 2,84-3,10 (m, 2H), 4.53-in (DD, J=2,8, and 5.6 Hz, 1H), amounts to 4.76 (DD, J=2,8, of 14.0 Hz, 1H), 5,64 (kV, J=7.2 Hz, 1H), 5,91 (d, J=8,4 Hz, 1H), 6,41 (d, J=15.6 Hz, 1H), 6,55 (DD, J=6,4, of 14.0 Hz, 1H), 6,95 (s, 1H), 7,20-7,37 (m, 6H), 7,34 (d, J=6,8 Hz, 1H), 7,65 (d, J=15.6 Hz, 1H), 7,73 (d, J=1.6 Hz, 1H).

Example 7

Synthesis of (E)-3-[3-ethoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1-(4-indol-1-yl-piperidine-1-yl)propenone

Formula 57

In the same way as described in example 121, 60 mg (26%) indicated in the title compound was obtained from (E)-(3-ethoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (140 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 477 [M++Na].1H-NMR (CDCl3) δ (ppm): to 1.42 (t, J=6.8 Hz, 3H), 1,90-2,10 (m, 2H), 2,19-to 2.29 (m, 2H), 2,30 (s, 3H), 2,80-of 3.06 (m, 1H), 3,25-3,50 (m, 1H), 4,12 (kV, J=6,8 Hz, 2H), 4,24-and 4.40 (m, 1H), 4,46-4,60 (m, 1H), 4,90-5,08 (m, 1H), is 6.54 (DD, J=0,8, a 3.2 Hz, 1H), 6,92-6,97 (m, 1H), 7,08-7,30 (m, 7H), 7,39 (d, J=8.0 Hz, 1H), to 7.64 (d, J=7,6 Hz, 1H), 7,68 (d, J=15.6 Hz, 1H), 7,78 (d, J=1.6 Hz, 1H).

Example 8

Synthesis of (E)-3-[3-allyloxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-2-alacrimia

Formula 58

In the same way as described in example 121, 48 mg (17%) indicated in the title compound was obtained from (E)-(3-allyloxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (512 mg). Physical SV is istwa this connection the following.

1H-NMR (CDCl3) δ: to 2.29 (s, 3H), 2,89 (DD, J=4,0, 16.0 Hz, 2H), 3,38 (DD, J=6,8, 16.0 Hz, 2H), 4,58 (d, J=5,2 Hz, 2H), 4,82-to 4.98 (m, 1H), 5,27 (DD, J=1,2, and 10.8 Hz, 1H), 5,35 (DD, J=1,2, 15.6 Hz, 1H), 5,90-6,10 (m, 1H), 6,04 (d, J=8.0 Hz, 1H), 6,32 (d, J=15.2 Hz, 1H), 6,94 (s, 1H), 7,07-7,17 (m, 2H), 7.18 in-7,30 (m, 5H), to 7.59 (d, J=15.6 Hz, 1H), 7,74 (d, J=0.8 Hz, 1H).

Example 9

Synthesis of (E)-3-[3-cyano-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 59

Synthesis of 5-bromo-2-(4-methyl-1H-imidazol-1-yl)benzonitrile and 5-bromo-2-(5-methyl-1H-imidazol-1-yl)benzonitrile

Potassium carbonate (2,07 g) was added to a solution in DMF (20 ml) of 5-bromo-2-perbenzoate (2.00 g) and 4-methylimidazole (1,23 g) and the reaction solution was stirred at 100ºC for 4.5 hours. The reaction mixture was concentrated under reduced pressure, to the residue were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent system hexane-ethyl acetate) and received 5-bromo-2-(4-methyl-1H-imidazol-1-yl)benzonitrile (962 mg) and 5-bromo-2-(5-methyl-1H-imidazol-1-yl)benzonitrile (60 mg).

Physical properties of 5-bromo-2-(4-methyl-1H-imidazol-1-yl)benzonitrile following.

1H-NMR (CDCl3) δ (ppm): 2,32 (s, 3H), 7,05 (t, J=1.2 Hz, 1H), 7,31 (d, J=8,8 Hz, 1H), 7,74 (q, j =1.2 Hz, 1H), 7,83 (DD, J=2 Hz and 8.8 Hz, 1H), to 7.93 (d, J=1.2 Hz, 1H).

Physical properties of 5-bromo-2-(5-methyl-1H-imidazol-1-yl)benzonitrile following.

1H-NMR (CDCl3) δ (ppm): of 2.15 (s, 3H), 6,97 (t, J=1.2 Hz, 1H), 7,28 (d, J=8,4 Hz, 1H), 7,56 (d, J=1.2 Hz, 1H), 7,89 (DD, J=2,4 Hz and 8.4 Hz, 1H), of 7.97 (d, J=2.4 Hz, 1H).

Synthesis of N-indan-1-alacrimia

The solution floridamedia acrylic acid (2,04 g) in THF (10 ml) was added dropwise to a solution in THF (30 ml) of 1-aminoindane (3.00 g) and TEA (2.28 g) under ice cooling and the reaction solution was stirred for 20 minutes at the same temperature. To the obtained reaction mixture were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By adding to the residue a simple ether and filtering off insoluble materials were received of 2.23 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,81-1,90 (m, 1H), 2,61-2,69 (m, 1H), 2,86 was 3.05 (m, 2H), 5,58 (kV, J=7,6 Hz, 1H), of 5.68 (DD, J=1.6 Hz, 10.4 Hz, 1H), 5,70-5,78 (Sirs, 1H), 6,10 (DD, J=10.4 Hz, and 17.2 Hz, 1H), 6,34 (DD, J=1,6 Hz and 17.2 Hz, 1H), 7,20-to 7.32 (m, 4H).

Synthesis of (E)-3-[3-cyano-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

To a solution in DMF (2 ml) of 5-bromo-2-(4-methyl-1H-imidazol-1-yl)benzonitrile (50 mg) and N-indan-1-alacrimia (43 mg), obtained above, was added palladium acetate (2.2 mg), ortho-tritolyl spin (6 mg) and TEA (0.5 ml) and the reaction solution was stirred at 70ºC under nitrogen atmosphere over night. The reaction mixture was concentrated under reduced pressure, to the residue were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (Carrier: Chromatorex®NH, eluting solvent system hexane-ethyl acetate) and received 31 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,86-of 1.95 (m, 1H), 2,32 (s, 3H), 2,64-of 2.72 (m, 1H), 2,89-is 3.08 (m, 2H), 5,64 (kV, J=7,6 Hz, 1H), 5,96 (d, J=8,4 Hz, 1H), 6,44 (d, J=16 Hz, 1H), 7,10 (t, J=1.2 Hz, 1H), 7,22-7,30 (m, 3H), 7,34 (d, J=7,6 Hz, 1H), 7,43 (d, J=8,4 Hz, 1H), 7,69 (d, J=16 Hz, 1H), 7,78-7,80 (m, 2H), of 7.90 (d, J=2 Hz, 1H).

Example 10

Synthesis of (E)-N-biphenyl-3-ylmethyl-3-[3-cyano-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 60

Synthesis of (E)-3-[3-cyano-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

To a solution in DMF (10 ml) of 5-bromo-2-(4-methyl-1H-imidazol-1-yl)benzonitrile (700 mg) and ethyl ester of acrylic acid (362 mg) was added palladium acetate (31 mg), tri-ortho-tolylphosphino (85 mg) and TEA (2 ml) and the reaction solution was stirred at 80ºC under nitrogen atmosphere over night. The reaction mixture was concentrated under reduced pressure, to the residue were added water and ethyl acetate and the organic layer was separated. The organic layer industry is Ali saturated salt solution, was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent system hexane-ethyl acetate), the fraction of the target substance were combined and concentrated under reduced pressure. The resulting substance was dissolved using a 5h. of sodium hydroxide solution (5 ml) and ethanol (30 ml) and the reaction mixture was stirred at 60ºC for 3 hours. The reaction mixture was concentrated under reduced pressure, to the residue was added water and neutralized using 5N. of hydrochloric acid. Insoluble substances, which are then deposited was separated by filtration, washed with simple ether and received 498 mg specified in the connection header.

ESI-MS; m/z 254 [M++H].

Synthesis of (E)-N-biphenyl-3-ylmethyl-3-[3-cyano-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

To a solution in DMF (0.2 ml) of (E)-3-[3-cyano-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15 mg) and monohydrochloride 3-phenylendiamine (16 mg) were successively added TEA (0,007 ml), HOBT (10 mg) and EDC (14 mg) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified column chromatography on silica gel (Carrier: Chromatorex®NH, eluting solvent system hexane-ethyl acetate) and the floor is made of 5 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 2,32 (s, 3H), of 4.67 (d, J=6 Hz, 2H), 6,04-between 6.08 (m, 1H), of 6.49 (d, J=15.6 Hz, 1H), to 7.09 (s, 1H), 7,32-of 7.60 (m, 10H), to 7.68 (d, J=15.6 Hz, 1H), 7,76-7,79 (m, 2H), 7,89 (d, J=2 Hz, 1H).

Example 11

Synthesis of (E)-3-[3-chloro-4-(1H-imidazol-1-ylphenyl]-N-indan-1-alacrimia

Formula 61

Synthesis of 3-chloro-4-(1H-imidazol-1-yl)benzaldehyde

To a solution of DMF (20 ml) of 3-chloro-4-forventelige (500 mg) were successively added potassium carbonate (1.20 g) and imidazole (275 mg) and the reaction solution was stirred at 80ºC overnight. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:methanol=10:1) and received 548 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm)rating: 10.0 (s, 1H), of 8.09 (d, J=2.0 Hz, 1H), to $ 7.91 (DD, J=2,0, 8.0 Hz, 1H), 7,80 (s, 1H), 7,54 (d, J=8.0 Hz, 1H), 7.24 to 7,27 (m, 2H).

Synthesis of (E)-3-[3-chloro-4-(1H-imidazol-1-ylphenyl]acrylic acid

To a solution in THF (13 ml) of 3-chloro-4-(1H-imidazol-1-yl)benzaldehyde (545 mg) were successively added methyl ether dimethyltitanocene acid (513 ml) and monog the dratha of lithium hydroxide (133 mg) and the reaction solution was stirred over night. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 442 mg of the crude product of ester. To the reaction solution obtained by dissolving the obtained product of ester in THF (5.0 ml), was added 2n. the sodium hydroxide solution (5.0 ml) and the reaction solution was stirred at room temperature overnight. The reaction solution was cooled to 0ºC, to the reaction solution was added 2n. the hydrochloric acid and the formed precipitate was separated by filtration using a funnel of Kiriyama. The precipitate was washed with water and ethyl acetate and received 218 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 8,08 (d, J=2.0 Hz, 1H), to 7.93 (s, 1H), 7,82 (DD, J=2.0 a, and 8.4 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,56 (d, J=8,4 Hz, 1H), of 7.48 (s, 1H), 7,11 (s, 1H), 6,70 (d, J=16 Hz, 1H).

Synthesis of (E)-3-[3-chloro-4-(1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

17,0 mg specified in the title compound was obtained from (E)-3-[3-chloro-4-(1H-imidazol-1-yl)phenyl] acrylic acid (20.0 mg) and 1-aminoindane (15,0 μl) in the same way as described in example 324. The physical properties of this compound are as follows.

ESI-MS; m/z 364[M++H].

Example 12

Synthesis of (E)-3-[4(1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 62

Synthesis of (E)-3-[4(1H-imidazol-1-yl)phenyl]acrylic acid

To a solution in THF (3.0 ml) 4-imidazol-1-albenzaalbenza (100 mg) were added successively methyl ether dimethyltitanocene acid (103 ml) and the monohydrate of lithium hydroxide (27.0 mg) and the reaction solution was stirred over night. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 143 mg of the crude product of ester. To a solution in THF (2.0 ml) of the obtained product of ester was added 2n. the sodium hydroxide solution (2.0 ml) and the reaction solution was stirred at room temperature overnight. The reaction solution was cooled to 0ºC, to the reaction solution was added 2n. the hydrochloric acid and the formed precipitate was separated by filtration using a funnel of Kiriyama. The precipitate was washed with water and ethyl acetate and received 98,0 mg specified in the head of the connection. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 8,35 (s, 1H), 7,83 (d, J=8,4 Hz, 2H), 7,82 (s, 1H), 7,71 (d, J=8,4 Hz, 2H), 7,60 (d, J=16 Hz, 1H), 7,11 (s, 1H), return of 6.58 (d, J=16 Hz, 1H).

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

11.0 mg specified in the title compound was obtained from (E)-3-[4-(1H-imidazol-1-yl)phenyl]acrylic acid (20.0 mg) and 1-aminoindane (17,0 μl) in the same manner as described in example 324. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to $ 7.91 (s, 1H), of 7.70 (d, J=16 Hz, 1H), 7.62mm (d, J=8,4 Hz, 2H), 7,40 (d, J=8,4 Hz, 2H), 7,22-7,37 (m, 5H), 7,20 (s, 1H), gold 6.43 (d, J=16 Hz, 1H), 5,88 (d, J=7.2 Hz, 1H), 5,64 (kV, J=7.2 Hz, 1H), 3,03 (DDD, J=4,4, 8,8, 16 Hz, 1H), 2,92 (TD, J=8.0 a, 16 Hz, 1H), 2,64-of 2.72 (m, 1H), 1,86-of 1.95 (m, 1H).

Example 12-1

Synthesis of (E)-N-(9H-fluoren-9-yl)-3-[4-(1H-imidazol-1-yl)phenyl]acrylamide

Formula 63

In the same way as described in example 12, 3.6 mg specified in the title compound was obtained from (E)-3-[4-(1H-imidazol-1-ylphenyl)acrylic acid (13 mg), and hydrochloride of 9-aminofluorene (20 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 378 [M++H].

Example 13

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-triptoreline]-N-indan-1-alacrimia

Formula 64

To a solution of 4-fluoro-3-triftormetilfullerenov (400 mg) in DMF (2.0 ml) alternately add the Lyali potassium carbonate (414 mg) and imidazole (136 mg) and the reaction solution was stirred at 80ºC for 6 hours. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: hexane:ethyl acetate 3:1→ ethyl acetate) and got to 13.7 mg of 4-(1H-imidazol-1-yl)-3-triftormetilfosfinov. Then to ethanol (1.0 ml) solution of the obtained aldehyde compound (13,0 mg) was added malonic acid (11.0 mg) and piperidine (53,0 mg) and the reaction solution was boiled under reflux for 5 hours. To the reaction solution were added pyridine (2.0 ml) and malonic acid (11.0 mg) and the reaction solution was boiled under reflux for one and a half hours. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and was obtained by condensation under reduced pressure of 15.0 mg of the crude carboxylic acid. In the same way as described in example 324, 10,7 mg specified in the title compounds were obtained based on the obtained carboxylic acid and 1-aminoindane. The physical properties of this compound are as follows.

1H-NMR CDCl 3) δ (ppm): 7,94 (DD, J=2.0 a, and 8.4 Hz, 1H), 7,76 (d, J=16 Hz, 1H), 7,75 for 7.78 (m, 1H),to 7.64 (s, 1H), 7,41 (d, J=8,4 Hz, 1H), 7,34 (d, J=7.2 Hz, 1H), 7,26-7,31 (m, 3H), 7,21 (s, 1H), 7,13 (s, 1H), 6,53 (d, J=16 Hz, 1H), 5,97 (Sirs, 1H), 5,65 (kV, J=7,6 Hz, 1H), 3.04 from (DDD, J=4,4, 8,8, 16 Hz, 1H), 2.95 points (TD, J=8.0 a, 16 Hz, 1H), 2,69 (DTD, 4,4, 8,0, 13 Hz, 1H), 1,87 is 1.96 (m, 1H)

Example 14

Synthesis of amide (E)-N-biphenyl-3-ylmethyl-3-[3-hydroxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

Formula 65

To a solution in methylene chloride (3 ml) amide (E)-N-biphenyl-3-ylmethyl-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (100 mg)obtained in example 121 was added dropwise at-78ºC tribromide boron (1M solution in pentane, 1,18 ml) and the reaction solution was stirred at room temperature for 6 hours. The reaction solution was diluted with a saturated solution of sodium bicarbonate and ethyl acetate and the organic layer was separated. After drying over anhydrous magnesium sulfate the organic layer was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent system chloroform-methanol) and got to 16.5 mg specified in the connection header.

ESI-MS; m/z 410 [M++H].1H-NMR (DMSO-d6) δ (ppm): of 2.15 (s, 3H), of 4.49 (d, J=6.0 Hz, 1H), 6,63 (d, J=15.6 Hz, 1H), 7,11 (d, J=8.0 Hz, 1H), 7,19-7,20 (m, 2H), 7,30-7,66 (m, 11H), 7,86 (s, 1H), 8,72 (t, J=6.0 Hz, 1H), 10,43 (s, 1H).

Example 15

Synthesis of (E)-3-[4-(1H-imidazol-1-yl-2-methoxyphenyl]-N-indan-1-alacrimia

Formula 66

Synthesis of methyl ester of 4-(1H-imidazol-1-yl)-2-methoxybenzoic acid

To a solution in acetone (10 ml) of methyl ester of 4-fluoro-2-oksibenzoynoy acid (1.0 g) were successively added potassium carbonate (1.2 g) and itmean (732 μl) and after boiling under reflux for 4 hours the reaction solution was concentrated under reduced pressure. To a solution of the obtained residue (1.08 g) in DMF (10 ml) was added sequentially potassium carbonate (1.20 g) and imidazole (479 mg) and the reaction solution was stirred at 80ºC overnight. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: hexane:ethyl acetate=3:1→ ethyl acetate:methanol=10:1) and received 370 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,92-of 7.96 (m, 2H), 7,34 (s, 1H), 7.23 percent (s, 1H), 6,97? 7.04 baby mortality (m, 2H), 3,98 (s, 3H), 3,91 (s, 3H).

Synthesis of (E)-3-[4-(1H-imidazol-1-yl-2-methoxyphenyl]-N-indan-1-alacrimia

DIBAL-H (solution 1,0M in toluene, with 3.27 ml) was added to a solution of methyl ester 4-(1H-imidazol-1-yl)-2-methoxybenzoyl KIS is the notes (253 mg) in methylene chloride (5.0 ml) at-78ºC and the reaction solution was stirred for 1 hour. To the reaction solution was added saturated aqueous solution of salt Rochelle and the reaction solution was stirred at room temperature overnight. To the reaction solution were added ethyl acetate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and was obtained by condensation under reduced pressure 216 mg of the crude alcohol connection.

To a solution of oxalicacid (277 μl) in methylene chloride (4.0 ml) was added at-78ºC dimethyl sulfoxide (451 μl) and the reaction solution was stirred for 15 minutes. Then by the above reaction solution at-78ºC was added to the solution in methylene chloride (3.0 ml) of the alcohol compound (216 mg)obtained in the previous phase, and stirred for 25 minutes. Then to the reaction solution was added TEA (1.0 ml), was heated to 0ºC and was stirred for 3 hours. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and by condensation under reduced pressure received 214 mg of the crude aldehyde compounds. To a solution of the obtained aldehyde (25,5 mg) in THF (2.0 ml) was added at 0ºC sodium hydride (8.0 mg) and di is tilby ether (indan-1-ylcarbonyl)alkylphosphines acid (63,0 mg), obtained in example 1 and the reaction solution was stirred at room temperature for 1 hour and 40 minutes. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: hexane:ethyl acetate=1:1→ethyl acetate→ethyl acetate:methanol=10:1) and received 28,4 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,89 (d, J=16 Hz, 1H), 7,88 (s, 1H), 7,56 (d, J=8,4 Hz, 1H), 7,35 (d, J=6,4 Hz, 1H), 7,20-7,30 (m, 5H), 6,98 (DD, J=2.0 a, and 8.4 Hz, 1H), 6.89 in (d, J=2.0 Hz, 1H), to 6.57 (d, J=16 Hz, 1H), 5,93 (shirt, J=8.0 Hz, 1H), 5,65 (kV, J=8.0 Hz, 1H), 3,94 (s, 3H), to 3.02 (DDD, J=4,4, 8,8, 16 Hz, 1H), 2,87-2,96 (m, 1H), 2,67 (DTD, J=4,4, 8,0, 16 Hz, 1H), 1.85 to 1,95 (m, 1H).

Example 16

Synthesis of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)-5-methoxyphenyl]-N-indan-1-alacrimia

Formula 67

Synthesis of 1-(4-bromo-2-fluoro-6-methoxyphenyl)-1H-imidazole

To a solution of 5-bromo-2,3-differenoe (600 μl) in acetone (10 ml) were successively added potassium carbonate (1.10 g) and itmean (654 ml) and the reaction solution was boiled under reflux for 4 hours. The reaction solution was concentrated under reduced pressure and the floor is made of untreated promotergene connection. To a solution in DMF (10 ml) obtained prosteradlo connection (1,17 g) was added sequentially potassium carbonate (1.10 g) and imidazole (429 mg) and the reaction solution was stirred at 80ºC overnight. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: hexane:ethyl acetate=3:1→ethyl acetate:ethanol=10:1) and received 510 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 7.82 (s, 1H), 7,24 (s, 1H), 7,21 (s, 1H), 7,05-was 7.08 (m, 2H), 3,98 (s, 3H).

Synthesis of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)-5-methoxyphenyl]-N-indan-1-alacrimia

In the same way as described in example 9, was received of 3.80 mg specified in the header connection on the basis of 1-(4-bromo-2-fluoro-6-methoxyphenyl)-1H-imidazole (86,0 mg) and N-indan-1-alacrimia (90,0 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 7.84 (s, 1H), to 7.64 (d, J=16 Hz, 1H), 7,34 (d, J=7.2 Hz, 1H), 7.23 percent-7,29 (m, 5H), 7,11 (t, J=8.0 Hz, 1H), 6,40 (d, J=16.0 Hz, 1H), 5,95 (d, J=8.0 Hz, 1H), 5,64 (kV, J=8.0 Hz, 1H), 3,98 (s, 3H), totaling 3.04 (DDD, J=4,4, 8,8, 16.0 Hz, 1H), 2,93 (TD, J=8,0, 16.0 Hz, 1H), 2,64-of 2.72 (m, 1H), 1,86-of 1.95 (m, 1H).

Example 17

Synthesis of (E)-3-[3-(1H-they are the azole-1-yl)-4-methoxyphenyl]-N-indan-1-alacrimia

Formula 68

Synthesis of 3-(1H-imidazol-1-yl-4-methoxybenzaldehyde

To aqueous solution (15 ml), imidazole (5,69 g) was added 3-bromo-4-methoxybenzaldehyde (3.00 g) and copper powder (86 mg) and the reaction solution was stirred for three days at 100°C in nitrogen atmosphere. To the reaction mixture was added concentrated aqueous ammonia solution and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent: ethyl acetate) and received 321 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 3,98 (s, 3H), 7,11-7,28 (m, 3H), 7,84-to 7.93 (m, 3H), 9,94 (s, 1H).

Synthesis of (E)-3-[3-(1H-imidazol-1-yl)-4-methoxyphenyl]-N-indan-1-alacrimia

In the same way as described in example 1 was received 44 mg specified in the header connection on the basis of 3-imidazol-1-yl-4-methoxybenzaldehyde (33 mg).

1H-NMR (CDCl3) δ (ppm): 1,84-of 1.93 (m, 1H), 2,60 of 2.68 (m, 1H), 2,85 totaling 3.04 (m, 2H), a 3.87 (s, 3H), 5,61 (kV, J=7,6 Hz, 1H), 6,28 (d, J=8 Hz, 1H), 6,37 (d, J=15.6 Hz, 1H), 7,03 (d, J=8,8 Hz, 1H), 7,13-7,34 (m, 6H), 7,41 (d, J=2 Hz, 1H), 7,47 (DD, J=2,4 Hz and 8.8 Hz, 1H), to 7.64 (d, J=15.6 Hz, 1H), 7,72 (s, 1H).

Example 18

Synthesis of (E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

ormula 69

Synthesis of 4-bromo-5-fluoro-2-methoxyaniline

To a solution in THF (20 ml) of 5-fluoro-2-methoxyaniline (1,76 g) was added dropwise under ice cooling a solution of perbromide pyridinium bromide (4,36 g) in THF (30 ml) and the reaction solution was stirred for 30 minutes at room temperature. The solid which has precipitated from the reaction mixture, was isolated by filtration and the solid washed with THF. After the obtained solid substance was dissolved with water and ethyl acetate, the aqueous layer was neutralized using a saturated aqueous solution of sodium bicarbonate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent system hexane-ethyl acetate) and got to 1.83 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): is 3.82 (s, 3H), 3,91 (Sirs, 2H), 6,50 (d, J=9.6 Hz, 1H), at 6.84 (d, J=6.0 Hz, 1H).

Synthesis of 1-(4-bromo-5-fluoro-2-methoxyphenyl)-4-methyl-1H-imidazole

In the same way as described in example 23, received 326 mg specified in the header connection on the basis of 4-bromo-5-fluoro-2-methoxyaniline (500 mg).

1H-NMR (CDCl3) δ (ppm): to 2.29 (s, 3H), 3,85 (s, 3H), 6.89 in (s, 1H), to 7.09 (d, J=8,4 Hz, H), 7,19 (d, J=6.0 Hz, 1H), of 7.70 (s, 1H).

Synthesis of (E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

In the same way as described in example 9, received 31 mg specified in the header connection on the basis of 1-(4-bromo-5-fluoro-2-methoxyphenyl)-4-methyl-1H-imidazole (44 mg).

1H-NMR (CDCl3) δ (ppm): 1,86-of 1.95 (m, 1H), to 2.29 (s, 3H), 2,63-of 2.72 (m, 1H), 2,88-of 3.07 (m, 2H), 3,86 (s, 3H), 5,65 (kV, J=7,6 Hz, 1H), 5,97 (d, J=8,4 Hz, 1H), to 6.57 (d, J=15.6 Hz, 1H), 6,93 (s, 1H), 7,05 (d, J=10.4 Hz, 1H), was 7.08 (d, J=6,8 Hz, 1H), 7,21-7,27 (m, 3H), 7,34 (d, J=6,4 Hz, 1H), 7,71 (d, J=15.6 Hz, 1H), 7,76 (s, 1H).

Example 19

Synthesis of (E)-3-[2-fluoro-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 70

Synthesis of 2,4-debtor-3-methoxybenzaldehyde

Diisopropylamide lithium (solution 1,5M in cyclohexane, 5.6 ml) was added dropwise to a solution of 2,6-diferente (1,00 g) in THF (10 ml) at 72ºC in nitrogen atmosphere and the reaction solution was stirred for 30 minutes. To the reaction mixture was added DMF (2.7 ml), the reaction solution was stirred for 30 minutes at-78ºC and then stirred at room temperature for 1 hour. To the reaction mixture were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column of HRO what ecografia on silica gel (eluting solvent system hexane-ethyl acetate) and received 433 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): of 4.05 (s, 3H), 6,99-7,05 (m, 1H), 7,54-of 7.60 (m, 1H), 10,27 (s, 1H).

Synthesis of (E)-3-[2-fluoro-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

In the same way as described in example 1 received 5 mg specified in the header connection on the basis of 2,4-debtor-2-methoxybenzaldehyde (443 mg).

1H-NMR (CDCl3) δ (ppm): 1,86-of 1.95 (m, 1H), 2,30 (s, 3H), 2,64-by 2.73 (m, 1H), 2,89-of 3.07 (m, 2H), 3,81 (s, 3H), 5,65 (kV, J=7,6 Hz, 1H), 5,88 (d, J=8,4 Hz, 1H), is 6.54 (d, J=15.6 Hz, 1H), 6,98 (s, 1H), was 7.08 (DD, J=2 Hz, 8,4 Hz, 1H), 7,21-7,27 (m, 4H), 7,35 (d, J=7,6 Hz, 1H), 7,76 (d, J=15.6 Hz, 1H), 7,78 (s, 1H).

Example 20

Synthesis of (E)-3-[4-(2-chloro-1H-imidazol-1-yl)-3-methoxyphenyl]-N-indan-1-alacrimia

Formula 71

Synthesis of 4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde and 4-(5-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde

To a solution in chloroform (3 ml) of 4-(1H-imidazol-1-yl)-3-methoxybenzaldehyde (50 mg)obtained in example 111 was added N-chlorosuccinimide (35 mg) and the reaction solution was heated to boiling point under reflux for 1.5 hours. The reaction mixture was allowed to cool and then was purified column chromatography on silica gel (eluting solvent system hexane-ethyl acetate) and received 4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde (13 mg) and 4-(5-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde (14 mg).

Physical properties of 4-(2-chloro-1H-imidazo the-1-yl)-3-methoxybenzaldehyde following.

1H-NMR (CDCl3) δ (ppm): to 3.92 (s, 3H),? 7.04 baby mortality (d, J=1.4 Hz, 1H), 7,10 (d, J=1.4 Hz, 1H), of 7.48 (d, J=8 Hz, 1H), EUR 7.57-to 7.59 (m, 2H), or 10.6 (s, 1H).

Physical properties of 4-(5-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde following.

1H-NMR (CDCl3) δ (ppm): to 3.92 (s, 3H), 7,10 (s, 1H), 7,47 (d, J=8 Hz, 1H), 7,58-of 7.60 (m, 3H), or 10.6 (s, 1H).

Synthesis of (E)-3-[4-(2-chloro-1H-imidazol-1-yl)-3-methoxyphenyl]-N-indan-1-alacrimia

In the same way as described in example 1 received 18 mg specified in the header connection on the basis of 4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde (13 mg).

1H-NMR (CDCl3) δ (ppm): 1,86 is 1.96 (m, 1H), 2,63-of 2.72 (m, 1H), 2,88-of 3.07 (m, 2H), of 3.84 (s, 3H), 5,64 (kV, J=7,6 Hz, 1H), 5,94 (d, J=8,4 Hz, 1H), 6,46 (d, J=to 15.4 Hz, 1H), 7,00 (d, J=1.0 Hz, 1H), 7,06 (d, J=1.0 Hz, 1H), 7,14 and 7.36 (m, 7H), of 7.70 (d, J=to 15.4 Hz, 1H).

Example 21

Synthesis of (E)-3-[4-(5-chloro-1H-imidazol-1-yl)-3-methoxyphenyl]-N-indan-1-alacrimia

Formula 72

In the same way as described in example 1 received 19 mg specified in the header connection on the basis of 4-(5-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde (14 mg).

1H-NMR (CDCl3) δ (ppm): 1,86 is 1.96 (m, 1H), 2,63-of 2.72 (m, 1H), 2,86-of 3.07 (m, 2H), of 3.84 (s, 3H), 5,65 (kV, J=7,6 Hz, 1H), 6,01 (d, J=8,4 Hz, 1H), 6,47 (d, J=to 15.4 Hz, 1H), 7,05 (s, 1H), 7,15 and 7.36 (m, 7H), 7,53 (s, 1H), 7,70 (d, J=to 15.4 Hz, 1H).

Example 22

Synthesis of (E)-N-indan-1-yl-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-yl]acrylamide

Formula 73

<> Synthesis of ethyl ester of (E)-3-(5-methoxy-6-nitropyridine-3-yl)acrylic acid

To a solution in DMF (20 ml) of 5-bromo-3-methoxy-2-nitropyridine (726 mg)synthesized in accordance with the method described in Acta Chemica Scandinavica vol.47, p.805, 1993, was added to the acrylate (of 0.44 ml), palladium acetate (35 mg), 2-(di-tert-butylphosphino)biphenyl (93 mg) and TEA (of 0.87 ml) and the reaction solution was stirred at 80ºC for 3 hours. After the reaction solution was allowed to cool to room temperature, to the reaction solution were added ethyl acetate and a saturated solution of ammonium chloride to separate the organic layer. After the obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 2:1) and received 787 mg (69%) of ethyl ester of (E)-3-(5-methoxy-6-nitropyridine-3-yl)acrylic acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 1.35 (t, J=7,6 Hz, 3H), 4,01 (s, 3H), 4,28 (kV, J=7,6 Hz, 2H), return of 6.58 (d, J=16.4 Hz, 1H), 7,56 (d, J=1.6 Hz, 1H), to 7.67 (d, J=16.4 Hz, 1H), to 8.20 (d, J=1.6 Hz, 1H).

Synthesis of ethyl ester of (E)-3-(6-amino-5-methoxypyridine-3-yl)acrylic acid

Iron (1.6 g) and ammonium chloride (3 g) was added to a suspension of ethyl ester of (E)-3-(5-methoxy-6-nitropyridine-3-yl)acrylic acid (787 mg), the scientists above, in ethanol (40 ml) and water (8 ml) and the reaction solution was heated to boiling point under reflux for 1 hour. After the reaction solution was allowed to cool to room temperature, the precipitated substance was filtered through celite. To the filtrate was added ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was separated. After drying the organic layer through anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 2:1) and received 506 mg (66%) of ethyl ester of (E)-3-(6-amino-5-methoxypyridine-3-yl)acrylic acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 1.33 (t, J=7.2 Hz, 3H), 3,88 (s, 3H), 4,25 (kV, J=7.2 Hz, 2H), 5,02 (Sirs, 2H), 6,23 (d, J=16.0 Hz, 1H), 7,06 (d, J=1.6 Hz, 1H), 7,60 (d, J=16.0 Hz, 1H), 7,78 (d, J=1.6 Hz, 1H).

Synthesis of ethyl ester of (E)-3-(6-chloro-5-methoxypyridine-3-yl)acrylic acid

Sodium nitrite (124 mg) was added to a solution of ethyl ester of (E)-3-(6-chloro-5-methoxypyridine-3-yl)acrylic acid (200 mg)obtained above, in concentrated hydrochloric acid (10 ml) at 0ºC. The reaction solution was stirred for 1 hour and 30 minutes at 0ºC, and then for 1 hour and 30 minutes at room temperature. For the eat the reaction solution was neutralized with the help of 8h. the sodium hydroxide solution and was extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 2:1) and obtained 57 mg (26%) of ethyl ester of (E)-3-(6-chloro-5-methoxypyridine-3-yl)acrylic acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 1.35 (t, J=7.2 Hz, 3H), of 3.96 (s, 3H), 4,28 (kV, J=7.2 Hz, 2H), 6.48 in (d, J=16.4 Hz, 1H), 7,29 (d, J=1.6 Hz, 1H), to 7.64 (d, J=16.4 Hz, 1H), 8,11 (d, J=1.6 Hz, 1H).

Synthesis of ethyl ester of (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-yl]acrylic acid

4-Mei (39 mg) and potassium carbonate (65 mg) was added to a solution in DMF (5 ml), ethyl ether (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-yl]acrylic acid (57 mg)obtained above and stirred at 120ºC for 32 hours. After the reaction solution was allowed to cool to room temperature, to the reaction solution were added ethyl acetate and the organic layer was washed saturated aqueous sodium bicarbonate. After drying the organic layer over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: ethyl is Etat) and received 12 mg (18%) of ethyl ester of (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-yl]acrylic acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 1.35 (t, J=7.2 Hz, 3H), to 2.29 (s, 3H), Android 4.04 (s, 3H), 4,29 (kV, J=7.2 Hz, 2H), 6.48 in (d, J=15.6 Hz, 1H), 7,45 (d, J=1.6 Hz, 1H), 7,56 (s, 1H), to 7.67 (d, J=15.6 Hz, 1H), 8,18 (d, J=1.6 Hz, 1H), 8,39 (s, 1H).

Synthesis of (E)-N-indan-1-yl-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-yl]acrylamide

1H. a solution of sodium hydroxide (0.2 ml) was added to a solution of ethyl ester of (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-yl]acrylic acid (12 mg)obtained above in methanol (0.5 ml) and stirred at room temperature for 12 hours. After adding to the reaction solution 1N. aqueous hydrochloric acid (0.2 ml) to neutralize the reaction solution, the solution was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and received 11 mg (100%) of (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-yl]acrylic acid by evaporation of the solvent under reduced pressure. 4 mg (23%) indicated in the title compound was obtained by condensation of 1-aminoindane (7.5 mg) with a compound of acrylic acid obtained in the same manner as described in example 121. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,86-of 1.97 (m, 1H), to 2.29 (s, 3H), 2,63-to 2.74 (m, 1H), 2,88-to 3.09 (m, 2H), 3,99 (s, 3H), 5,65 (kV, J=7,6 Hz, 1H), by 5.87 (sird, J=7,6 Hz, 1H), 6,46 (d, J=15.6 Hz, 1H), 7,20-7,35 (m, 4H), 7,42 (d, J=1,6 Hz, 1H), 7,56 (s, H), to 7.68 (d, J=15.6 Hz, 1H), to 8.20 (d, J=1.6 Hz, 1H), 8,39 (s, 1H).

Example 23

Synthesis of (E)-N-indan-1-yl-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide

Formula 74

Synthesis of 6-chloro-2-methoxy-3-nitropyridine

The sodium methoxide (1.40 g) was gradually added to a solution of 2,6-dichloro-3-nitropyridine (of 5.00 g) in THF (50 ml) over 30 minutes under ice cooling. Then the reaction solution was stirred at 0ºC for 1 hour and stirred at room temperature for 12 hours. The reaction solution was poured into a saturated solution of ammonium chloride (50 ml) and was extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 2:1) and received 2,90 g (58%) 6-chloro-2-methoxy-3-nitropyridine. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 4,16 (s, 3H), 7,03 (d, J=8,8 Hz, 1H), 8,25 (d, J=8,8 Hz, 1H).

Synthesis of tert-butyl methyl ether (E)-3-(6-methoxy-5-nitropyridine-2-yl)acrylic acid

To a solution of 6-chloro-2-methoxy-3-nitropyridine (440 mg)obtained above in DMF (10 ml) was added tert-butyl ester of acrylic acid (0,44 ml), palladium acetate (26 mg), 2-(di-tert-butylphosphino)biphenyl (70 mg) and TEA (0,65 ml) and the reaction is ionic solution was stirred at 120ºC for 3 hours. After the reaction solution was allowed to cool to room temperature, was added ethyl acetate and a saturated solution of ammonium chloride and the reaction solution was separated. After drying the organic layer over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 2:1) and received 491 mg (75%) of tert-butyl methyl ether (E)-3-(6-methoxy-5-nitropyridine-2-yl)acrylic acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1.55V (s, 9H), 4,16 (s, 3H), 6,93 (d, J=15.6 Hz, 1H), was 7.08 (d, J=8,8 Hz, 1H), 7,47 (d, J=15.6 Hz, 1H), 8,29 (d, J=8,8 Hz, 1H).

Synthesis of tert-butyl methyl ether (E)-3-(5-amino-6-methoxypyridine-2-yl)acrylic acid

Iron (780 mg) and ammonium chloride (1.5 g) was added to a suspension of tert-butyl methyl ether (E)-3-(5-amino-6-methoxypyridine-2-yl)acrylic acid (491 mg)obtained above in ethanol (40 ml) and water (8 ml) and heating the reaction solution at the boiling point under reflux was carried out for 7 hours. After the reaction solution was allowed to cool to room temperature, the precipitated substance was filtered through celite. To the filtrate was added ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was separated. After drying, the organization is a mini layer over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 2:1) and received 340 mg (78%) of tert-butyl methyl ether (E)-3-(5-amino-6-methoxypyridine-2-yl)acrylic acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): and 1.56 (s, 9H), to 4.01 (s, 3H), 4,03 (Sirs, 2H), 6,63 (d, J=15.6 Hz, 1H), 6,77 (d, J=8,8 Hz, 1H), for 6.81 (d, J=8,8 Hz, 1H), 7,40 (d, J=15.6 Hz, 1H).

Synthesis of tert-butyl methyl ether (E)-3-(5-formylamino-6-methoxypyridine-2-yl)acrylic acid

A solution of tert-butyl methyl ether (E)-3-(5-formylamino-6-methoxypyridine-2-yl)acrylic acid (136 mg)obtained above in methylene chloride (3 ml) was added dropwise to a mixed solution of acetic anhydride (0.2 ml) and formic acid (0.4 ml), stir at room temperature for 10 minutes. After stirring the reaction solution at room temperature for 20 minutes to the reaction solution were added ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was separated. After drying the organic layer over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 1:1) and received 151 mg (69%) tert-butyl ether (E)-3-(5-formylamino-6-methoxypyridine-2-yl)acrylic key is lots. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): and 1.54 (s, 9H), 4,06 (s, 3H), 6,76 (d, J=15.6 Hz, 1H), 6,99 (d, J=8,8 Hz, 1H), 7,45 (d, J=15.6 Hz, 1H), 7,79 (Sirs, 1H), and 8.50 (s, 1H), to 8.57 (d, J=8,8 Hz, 1H).

Synthesis of tert-butyl methyl ether (E)-3-{5-[formyl(2-oxopropyl)amino]-6-methoxypyridine-2-yl}acrylic acid

The cesium carbonate (490 mg), potassium iodide (13 mg) and chloroacetone (0,12 ml) was added to a solution of tert-butyl methyl ether (E)-3-{5-formyl(2-oxopropyl)amino]-6-methoxypyridine-2-yl}acrylic acid (104 mg)obtained above in DMF (2 ml) and the reaction solution was stirred at room temperature for 10 hours. Then to the reaction solution were added ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer was separated and after drying the organic layer over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate=1:1) and received 116 mg (93%) of tert-butyl methyl ether (E)-3-{5-[formyl(2-oxopropyl)amino]-6-methoxypyridine-2-yl}acrylic acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 1.53 (s, 9H), of 2.16 (s, 3H), of 4.00 (s, 3H), 4,50 (s, 2H), for 6.81 (d, J=15.6 Hz, 1H), 7,00 (d, J=8,8 Hz, 1H), 7,43 (d, J=15.6 Hz, 1H), 7,55 (d, J=8,8 Hz, 1H), 8,28 (s, 1H).

Synthesis of tert-butyl methyl ether (E)-3-[6-methoxy-5-(4-methyl-1H-imida the ol-1-yl)pyridin-2-yl]acrylic acid

Ammonium acetate (130 mg) was added to a solution of tert-butyl methyl ether (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid (116 mg), obtained above, in acetic acid (2 ml) and the reaction solution was stirred at 120ºC for 3 hours. Then after the reaction solution was allowed to cool to room temperature, the reaction solution was diluted with ethyl acetate and the resulting mixture was neutralized using a saturated aqueous solution of sodium bicarbonate. After separation and drying of the organic layer through anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: ethyl acetate) and received 40 mg (37%) tert-butyl ether (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1.55V (s, 9H), is 2.30 (s, 3H), 4,06 (s, 3H), 6,86 (d, J=15.6 Hz, 1H), 6,99 (s, 1H), 7,05 (d, J=8,8 Hz, 1H), of 7.48 (d, J=15.6 Hz, 1H), 7,52 (d, J=8,8 Hz, 1H), 7,82 (s, 1H).

Synthesis of (E)-N-indan-1-yl-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide

A solution of 4n. hydrochloric acid in ethyl acetate (3 ml) was added to (E)-N-indan-1-yl-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide (20 mg)obtained above, and the reaction solution was stirred at to matnog temperature for 3 hours. Then the reaction solution was concentrated under reduced pressure. 20 mg (69%) indicated in the title compound was obtained by condensation of the crude compound of acrylic acid with 1-aminoindane (of 0.015 ml) in the same manner as described in example 121. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,86-of 1.97 (m, 1H), 2,30 (s, 3H), 2,64-to 2.74 (m, 1H), 2,88-to 3.09 (m, 2H), Android 4.04 (s, 3H), 5,65 (kV, J=7,6 Hz, 1H), 5,95 (sird, J=7,6 Hz, 1H), 6,95 (d, J=15.6 Hz, 1H), 6,98 (Sirs, 1H), 7,06 (d, J=8,8 Hz, 1H), 7,20-7,39 (m, 4H), 7,56 (d, J=8,8 Hz, 1H), 7,60 (d, J=15.6 Hz, 1H), 7,81 (Sirs, 1H).

Example 24

Synthesis of (E)-N-indan-1-yl-3-[4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide

Formula 75

Synthesis of 5-bromo-4-methoxypyridine-2-carbaldehyde

Reagent dess-Martin (1,14 g) was added at 0ºC to a solution in methylene chloride (5 ml) (5-bromo-4-methoxypyridine-2-yl)methanol (450 mg)synthesized by a method described in Organic Process Research & Development 2000 4,473. The reaction solution was stirred at 0ºC for 1 hour and then stirred at room temperature for 1 hour. To the reaction solution was added 1N. the sodium hydroxide solution, the organic layer was separated and washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The floor is built the residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 1:1) and received 300 mg (67%) of 5-bromo-4-methoxypyridine-2-carbaldehyde. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): Android 4.04 (s, 3H), of 7.48 (s, 1H), up 8.75 (s, 1H), 10,1 (s, 1H).

Synthesis of tert-butyl methyl ether (E)-3-(5-bromo-4-methoxypyridine-2-yl)acrylic acid

tert-Butyl ether diethylphosphonate acid (0,26 ml) was added to a suspension of sodium hydride (45 mg) in THF (4 ml) and the reaction solution was stirred at room temperature for 1 hour. Then the reaction solution was cooled to 0ºC and added dropwise to the reaction solution a solution in THF (1 ml) of 5-bromo-4-methoxypyridine-2-carbaldehyde (200 mg)obtained above. The reaction solution was stirred for 1 HR at 0ºC and then was stirred for 12 hours at room temperature. After completion of the reaction to the reaction solution was added a saturated solution of ammonium chloride and the reaction solution was extracted with ethyl acetate to separate an organic layer. After drying the organic layer over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 2:1) and received 116 mg (40%) tert-butyl ether (E)-3-(5-bromo-4-methoxypyridine-2-yl)acrylic acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 1.53 (s, 9H), 3,98 (s, 3H), PC 6.82 (d, J=15.6 G is, 1H), 6,92 (s, 1H), 7,49 (d, J=15.6 Hz, 1H), 8,56 (s, 1H).

Synthesis of tert-butyl methyl ether (E)-3-(5-amino-4-methoxypyridine-2-yl)acrylic acid

Benzophenone (0.04 ml), tert-piperonyl sodium (26 mg) and DPPF (13 mg) and bis(1, 5cyclooctadiene) Nickel (0) was added to a solution in toluene (3 ml) tert-butyl ether (E)-3-(5-bromo-4-methoxypyridine-2-yl)acrylic acid (70 mg)obtained above, and heated at the boil under reflux of the solution was carried out for 14 hours. After the reaction solution was allowed to cool to room temperature, the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane-ethyl acetate 3:1) and received 45 mg (49%) iminovogo connection. Hydroxylamine hydrochloride (15 mg) and sodium acetate (30 mg) was added to the solution obtained iminovogo compounds in methanol (3 ml) and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction to the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. After drying of the organic layer through anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting will dissolve the l: heptane-ethyl acetate=1:2) and received 20 mg (73%) of tert-butyl methyl ether (E)-3-(5-amino-4-methoxypyridine-2-yl)acrylic acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 1.52 (s, 9H), 3,91 (s, 3H), 3,93 (Sirs, 2H), is 6.54 (d, J=15.6 Hz, 1H), to 6.88 (s, 1H), 7,49 (d, J=15.6 Hz, 1H), 8,00 (s, 1H).

Synthesis of tert-butyl methyl ether (E)-3-[4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid

In the same way as described in example 23, was sentenced to 15 mg (60%) of tert-butyl methyl ether (E)-3-(4-methoxy-5-(4-Mei-1-yl)pyridin-2-yl)acrylic acid from tert-butyl ether (E)-3-(5-amino-4-methoxypyridine-2-yl)acrylic acid (20 mg)obtained above. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ: and 1.54 (s, 9H), 2,31 (s, 3H), of 3.97 (s, 3H), 6,83 (d, J=15.6 Hz, 1H), 6,93 (s, 1H), 7,07 (s, 1H), 7,55 (d, J=15.6 Hz, 1H), 7,74 (s, 1H), 8,45 (s, 1H).

Synthesis of (E)-N-indan-1-yl-3-[4-methoxy-5-[4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide

In the same way as described in example 23, received 4 mg (27%) of (E)-N-indan-1-yl-3-[4-methoxy-5-(4-Mei-1-yl)pyridin-2-yl)acrylamide based on tert-butyl ether (E)-3-(4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)acrylic acid (15 mg)obtained above, and 1-aminoindane. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,84 is 1.96 (m, 1H), 2,30 (s, 3H), 2,65-to 2.74 (m, 1H), 2,88-is 3.08 (m, 2H), 3,98 (s, 3H), 5,65 (kV, J=7,6 Hz, 1H), 6,00 (sird, J=7,6 Hz, 1H), 6,93 (s, 1H), 7,01 (d, J=15.6 Hz, 1H), 7,05 (s, 1H), 7,21-7,37 (m, 4H), 7,66 (d, J=15.6 Hz, 1H), 7,72 (s, 1H), 8,43 (s, 1H).

Example 24-1

Synthesis of (E)-N-(9H-fluoren-9-yl)-3-(3-fluoro-4-(1H-imidazol-1-yl)phenyl]acrylamide

Formula 76

In the same way as described in example 12, received a 7.6 mg specified in the header connection on the basis of (E)-3-(3-fluoro-4-(1H-imidazol-1-yl)phenyl]acrylic acid (14 mg), and hydrochloride of 9-aminofluorene (20 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 396 [M++H]

In accordance with example 1 was changed to a combination of imidazole derivative and benzaldehyde derived and synthesized compounds are presented in table 2. Structural formulas and physical-chemical properties are presented in table 2, respectively.

Table 2-1
ExampleE1E2E3E4Data: MS m/z
25MeHHHM++H: 344 (ESI)
26F MeHHM++H: 362 (ESI)
27FHMeHM++H: 362 (ESI)
28FHHM++H: 424 (ESI)
29FHNO2HM++H: 393 (ESI)
30FHHOCH2-HM++H: 378 (ESI)
31MeOHHMeM++H: 374 (ESI)
32FHBrHM++H: 426 (ESI)
3 FHMeMeM++H: 376 (ESI)
34MeOHBrHM++H: 438 (ESI)
35MeOMeHHM++H: 374 (ESI)
36MeOHEtHM++H: 388 (ESI)
37MeOHCF3HM++H: 428 (ESI)
38MeOHNC-HM++H: 385 (ESI)
39HHH ++H: 436 (ESI)
40HHHM++H: 422 (ESI)

Table 2-2
ExampleE1E2E3E4Data: MS m/z
41HHHM++H: 450 (ESI)
42BrHHHM++H: 408 (ESI)
43ClHMeHM++H: 378 (ESI)
44Br HMeHM++H: 422 (ESI)
45MeOHHOCH2-HM++H: 390 (ESI)
46MeOHHM++H: 450 (ESI)
47MeOHFHM++H: 378 (ESI)
48MeOHHM++H:400 (ESI)
49MeOHi-PrHM++H: 402 (ESI)
50MeOHH ++H: 402 (ESI)
51HMeMeHM++H: 358 (ESI)
52HHMeHM++H: 344 (ESI)
53MeOHClHM++H: 394 (ESI)

Table 2-3
ExampleE1E2E3E4Data: MC m/z
54HHHM++H: 400 (ESI)
55SMeH HHM++H: 376 (ESI)
56SO2MeHHHM++H: 408 (ESI)
57HMeHM++H: 398 (ESI)
58HMeHM++H: 418 (ESI)
59HMeHM++H: 428 (ESI)
60HMeHM++H: 428 (ESI)
61HM eH M++H: 400 (ESI)
62HMeHM++H: 402 (ESI)
63MeOHHM++H: 416 (ESI)
64MeOHHM++H: 400 (ESI)
65MeOHHM++H: 486 (ESI)

Compounds shown in table 3, was synthesized as described in example 10. Their structural formulas and physical-chemical properties are presented in table 3, respectively.

Table 3
ExampleF 5Data: MS m/z
66M++H: 417 (ESI)
67M++H: 393 (ESI)
68M++H: 357 (ESI)
69M++H: 371 (ESI)
70M++H: 373 (ESI)
71M++H: 387 (ESI)
72M++H: 407 (ESI)
73M++H: 436 (ESI)
74M++H: 434 (ESI)

Example 75

Synthesis of amide N-(9H-fluoren-9-yl)-3-(3-methoxy-4-(4-meth is l-1H-imidazol-1-yl)phenyl)propionovoi acid

Formula 77

Synthesis of N-(4-bromo-2-methoxyphenyl)-2,2,2-trifurcated

Triperoxonane anhydride (24 ml) was added dropwise under ice cooling to a solution of 4-bromo-2-methoxyaniline (23,4 g) in pyridine (48 ml). The reaction solution was stirred for one hour and added to it the icy water. Precipitated crystals were isolated by filtration and dried in the air overnight. Received 32,4 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 3,93 (s, 3H), 7,07 (d, J=2.4 Hz, 1H), 7,16 (DD, J=8,8, 2.4 Hz, 1H), 8,21 (d, J=8,8 Hz, 1H), of 8.47 (Sirs, 1H).

Synthesis of 1-(4-bromo-2-methoxyphenyl)aminopropan-2-he

Chlorate (20 g) was added dropwise to a suspension of N-(4-bromo-2-methoxyphenyl)-2,2,2-trifurcated (32,4 g), cesium carbonate (71 g) and potassium iodide (1.8 g) in DMF (160 ml) and the reaction solution was stirred at room temperature for 2 hours. Then the reaction solution was stirred for 1 hour and added to it the icy water. Precipitated crystals were isolated by filtration. The obtained crystals suspended in methanol (360 ml) and 2n. the sodium hydroxide solution (55 ml) and the suspension was stirred for 30 minutes. To the suspension was added ice-cold water. Precipitated crystals were isolated by filtration and dried in the air overnight. Received 25,2 g specified in the connection header.

1H-NMR (CDCl 3) δ (ppm): of 2.25 (s, 3H), 3,85 (s, 3H), of 3.97 (d, J=5,2 Hz, 2H), of 5.05 (Sirs, 1H), 6,29 (d, J=8,4 Hz, 1H), 6,85 (d, J=2.0 Hz, 1H), 6,94 (DD, J=8,4, 2.0 Hz, 1H).

Synthesis of N-(4-bromo-2-methoxyphenyl)-N-(2-oxopropyl)ndimethylacetamide

A mixture of acetic anhydride (40 g) and formic acid (90 g) was stirred under ice cooling for 30 minutes. To the resulting solution was added dropwise a solution of 1-(4-bromo-2-methoxyphenyl)propan-2-it (25,2 g) in methylene chloride (65 ml) and the reaction solution was stirred for 30 minutes. After neutralization with sodium hydroxide solution, the reaction solution was extracted with simple ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was filtered off, washed with simple ether and dried in the air and got to 23.4 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 2,17 (s, 3H), of 3.84 (s, 3H), 4,43 (s, 2H), to 7.09 (d, J=2.0 Hz, 1H), 7,13 (DD, J=8,0, 2.0 Hz, 1H), 7,19 (d, J=8.0 Hz, 1H), 8,23 (s, 1H).

Synthesis of 1-(4-bromo-2-methoxyphenyl)-4-methyl-1H-imidazole

A mixture of N-(4-bromo-2-methoxyphenyl)-N-(2-oxopropyl)ndimethylacetamide (23,4 g), ammonium acetate (31,5 g) and acetic acid (49 g) was stirred while heating at 120ºC for 30 minutes. The reaction solution was neutralized with sodium hydroxide under ice cooling, then the reaction solution was extracted with ethyl acetate. the content of inorganic fillers layer was washed with saturated saline solution, was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent system hexane-ethyl acetate) and got to 19.4 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): to 2.29 (s, 3H), 3,85 (s, 3H), 6.87 in (s, 1H), 7,10-to 7.18 (m, 3H), of 7.65 (s, 1H).

Synthesis of 1-(4-iodine-2-methoxyphenyl)-4-methyl-1H-imidazole

Suspension in 1,4-dioxane (50 ml) of 1-(4-bromo-2-methoxyphenyl)-4-methyl-1H-imidazole (10.0 g) and copper iodide(I) (I) (7,13 g), sodium iodide (11.2 g) and N,N'-dimethylethylenediamine (6,59 g) was stirred at 110ºC for 9 hours. After cooling the reaction solution to room temperature, to the reaction solution were added ethyl acetate and a saturated solution of ammonium chloride and the reaction solution was stirred for 30 minutes. After filtration through celite the organic layer of the filtrate was washed with saturated saline solution and after drying over anhydrous magnesium sulfate, the reaction solution was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent system heptane-ethyl acetate) and received 4,07 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): to 2.29 (s, 3H), 3,86 (s, 3H), PC 6.82 (s, 1H), 6,97 (d, J=8.0 Hz, 1H), 7,34 (d, J=2.0 Hz, 1H), was 7.36 (DD, J=8,0, 2.0 Hz, 1H), 7,73 (s, 1H).

Synthesis of tert-butyl methyl ether (3-methoxy-4-4-methyl-1H-imidazol-1-yl)phenyl]propionovoi acid

Suspension in DMF (17 ml) of 1-(4-iodine-2-methoxyphenyl)-4-methyl-1H-imidazole (2.67 g) and tert-butylphosphonate (2.14 g), dichlorobis(triphenylphosphine)palladium(II) (300 mg), potassium carbonate (2.35 g) and copper Iodate (I) (162 mg) was stirred under heating at 100ºC for 20 minutes. After cooling the reaction solution to room temperature, to the reaction solution were added ethyl acetate and a saturated solution of ammonium chloride and the reaction solution was stirred for 30 minutes. After washing with saturated saline solution, the reaction solution was dried over anhydrous magnesium sulfate and the separated organic layer was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (system heptane-ethyl acetate) and received 2,45 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): and 1.56 (s, 9H), to 2.29 (s, 3H), a 3.87 (s, 3H), 6,93 (s, 1H), 7,21-7,24 (m, 3H), 7,78 (s, 1H).

Synthesis of [3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propionovoi acid

Triperoxonane acid (6.0 ml) was added under ice cooling to a solution in methylene chloride (30 ml) of tert-butyl methyl ether (3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)propionovoi acid (2,45 g) and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate. Precipitated crystals from the Yali by filtration and dried in the air overnight. Received 1.45 g specified in the connection header.

1H-NMR (DMSO-d6) δ (ppm): 2,32 (s, 3H), 3,92 (s, 3H), 7,44 (DD, J=8.0 a, and 1.6 Hz, 1H), to 7.61 (d, J=1.6 Hz, 1H), 7,66 (d, J=8.0 Hz, 1H), 7,71 (s, 1H), 9,18 (s, 1H).

Synthesis of amide N-(9H-fluoren-9-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propionovoi acid

Solution in DMF (2 ml) of [3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propionovoi acid (74 mg) and 9-aminofluorene (65 mg) and BOP (133 mg) and N,N'-IPEA (77 μl) was stirred at room temperature overnight. To the reaction solution were added water and chloroform, the organic layer was separated and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (Carrier: Chromatorex NH, eluting solvent system heptane-ethyl acetate) and received 45 mg specified in the connection header.

ESI-MS; m/z 420 [M++H].

1H-NMR (DMSO-d6) δ (ppm): 2,14 (s, 3H), 3,86 (s, 3H), 6,11 (d, J=8.0 Hz, 1H), 7,18 (s, 1H), 7,26 (d, J=6,4 Hz, 1H), 7,34-7,47 (m, 6H), 7,55 (d, J=7,6 Hz, 2H), to 7.84 (s, 1H), 7,88 (d, J=7,6 Hz, 2H), for 9.47 (d, J=8.0 Hz, 1H).

ESI-MS; m/z 420 [M++H].

Compounds shown in table 4, was synthesized as described in example 75. Structural formulas and physical-chemical properties are presented in table 4, respectively.

84
Table 4
ExampleD1Data: MS m/z
76M++H: 372 (ESI)
77M++H: 364 (ESI)
78M++H: 390 (ESI)
79M++H: 388 (ESI)
79-1M++H: 388 (ESI)
80M++H: 372 (ESI)
81M++H: 372 (ESI)
82M++H: 386 (ESI)
83M++H: 360 (ESI)
M++H: 381 (ESI)

Example 85

Synthesis of (E)-2-fluoro-N-[(1R)-hydroxymethyl-2-phenylethyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 78

Synthesis of ethyl ester of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

To a solution of sodium hydride (814 mg) in THF (15 ml) was added at 0ºC triethylphosphate acid (4,1 ml) and the reaction solution was stirred at 0°C for 30 minutes and at room temperature for 1 hour. After cooling the reaction solution at 0ºC to the reaction solution was added dropwise a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (4.0 g)synthesized in example 1, in THF (5 ml). The reaction solution is then stirred at 0ºC for 30 minutes and then at room temperature for 2 hours. To the reaction solution were added ethyl acetate and water and the organic layer was separated and washed with a saturated solution of ammonium chloride. After drying using anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. By recrystallization of the resulting solid substance, using a mixed solution of hexane and ethyl acetate were obtained 4,55 g (86%) specified in the connection header. Physical is waista this connection the following.

1H-NMR (CDCl3) δ (ppm): 1,71 (t, J=7.8 Hz, 3H), 2,60 (s, 3H), 3,79 (s, 3H), 4,58 (kV, J=7.8 Hz, 2H), 6,45 (d, J=16.2 Hz, 1H), 6,95 (m, 1H), 7,17 (d, J=1.6 Hz, 1H), 7,19 (DD, J=8,4, and 1.6 Hz, 1H), 7,28 (d, J=8,4 Hz、1H), to 7.68 (d, J=16.2 Hz, 1H), 7,72 (d, J=1.2 Hz, 1H).

Synthesis of ethyl ester of (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

Diethyl ether 2-formalnosci acid (670 ml) was added under ice cooling to a suspension of sodium hydride (170 mg) in THF (8 ml) and the reaction solution was stirred under ice cooling for 20 minutes and then stirred at room temperature for 1 hour. After adding dropwise the solution of the ethyl ester of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (1 g)obtained above in THF (2 ml) to the reaction solution for 10 minutes, the reaction solution was stirred at room temperature for 30 minutes and heated to boiling point under reflux for 8 hours. After the reaction solution was allowed to cool to room temperature, was added ethyl acetate and water and the organic layer was washed with a saturated solution of ammonium chloride. After drying the organic layer over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent hexane→hexane:ethyl acetate=1:1) and received 593 mg (56%) of ethyl ester of (E)-2-fluoro-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid. The physical properties of this compound are as follows.

ESI-MS; m/z 305 [M++H], 1H-NMR (CDCl3) δ (ppm): to 1.42 (t, J=7.8 Hz, 3H), 2,31 (s, 3H), with 3.89 (s, 3H), of 4.38 (q, J=7.8 Hz, 2H), 6,92 (d, J=36 Hz, 1H), 6,95 (m, 1H), 7,26 (d, J=8,4 Hz, 1H), 7,31 (DD, J=8,4, and 1.6 Hz, 1H), 7,37 (Sirs, 1H), 7,76 (d, J=1.6 Hz, 1H).

Synthesis of (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

To a solution of diethyl ether (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (593 mg) in THF (1 ml) and ethanol (4 ml) was added 2n. the sodium hydroxide solution (2 ml). The reaction solution was stirred at room temperature for 15 hours, neutralized using 2n. hydrochloric acid (2 ml). The solid precipitated from the reaction solution, and was isolated by filtration and washing the solid with ethanol received 512 mg (95%) of (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): of 2.15 (s, 3H), 3,85 (s, 3H), 7,06 (d, J=36,0 Hz, 1H), 7,18 (m, 1H), 7,38 (DD, J=8,4, and 1.6 Hz, 1H), 7,44 (DD, J=8,4, 1H), 7,51 (Sirs, 1H), to 7.84 (d, J=1.6 Hz, 1H).

Synthesis of (E)-2-fluoro-N-[(1R)-hydroxymethyl-2-phenylethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

71 mg (74%) indicated in the title compound was obtained from (E)-2-fluoro-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (65 mg) and D-phenylalaninol(43 mg), who received the same manner as described in example 121. The physical properties of this compound are as follows.

ESI-MS; m/z 410 [M++H], 1H-NMR (CDCl3) δ: 2,30 (s, 3H), 2,98 (d, J=7.2 Hz, 2H), 3,69 (DD, J=6,8, and 4.8 Hz, 1H), of 3.77 (DD, J=6,8, and 4.8 Hz, 1H), a 3.87 (s, 3H), 4,30-4,39 (m, 1H), 6,64 (shirt, 1H), make 6.90 (d, J=36,0 Hz, 1H), 6,94 (Sirs, 1H), 7,38 (DD, J=8,4, the 1.6 Hz, 1H), 7,25-7,38 (m, 8H), 7,74 (d, J=1.6 Hz, 1H).

Example 86

Synthesis of N-(9H-fluoren-9-yl)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 79

In the same way as described in Example 86, received 46 mg (36%) specified in the header connection on the basis of 2-fluoro-3-(3-methoxy-4-(4-methyl-imidazol-1-yl)phenyl)acrylic acid (80 mg)obtained in example 85, and 9-aminoglutethamide (64 mg). The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): of 2.15 (s, 3H), 3,85 (s, 3H), 6,17 (shirt, 1H), 7,10 (d, J=38,0 Hz, 1H), 7,18 (Sirs, 1H), 7,28-of 7.55 (m, 9H), 7,83 (d, J=1.6 Hz, 1H), 7,88 (d, J=7,6, 2H), of 9.30 (d, J=8,8 Hz, 1H).

Example 87

Synthesis of (E)-2-fluoro-N-(4-fluoro-3-morpholine-4-ylbenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 80

In the same way as described in Example 85, received 43,8 mg specified in the header connection on the basis of (E)-2-fluoro-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (40,0 mg) and 4-fluoro-3-morpholine-4-ivesiana (32,0 mg). Physical freedom is of this connection are as follows.

1H-NMR (CDCl3) δ (ppm): 7,74 (d, J=1.6 Hz, 1H), 7,27-7,29 (m, 3H), 7,00-7,05 (m, 2H), 6.89 in-to 6.95 (m, 3H), 6,61 is 6.67 (width, 1H), 4,54 (d, J=6.0 Hz, 2H), 3,88 (s, 3H), 3,86-to 3.89 (m, 4H), 3,09-3,11 (m, 4H), of 2.30 (s, 3H).

Example 88

Synthesis of (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methyl-N-(2-morpholine-4-yl-1-phenylethyl)acrylamide

Formula 81

In the same way as described in example 85, received 51,5 mg specified in the header connection on the basis of (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (45.0 mg) and methyl-(2-morpholine-4-ylphenidate)amine (1M solution in DMF, 245 μl). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,74 (s, 1H), 7,30-7,42 (m, 4H), 7,21-7,28 (m, 4H), 6,94 (s, 1H), 6,62 (d, J=38 Hz, 1H), 3,88 (s, 3H), 3,64-3,74 (m, 4H), 2,94-3,20 (m, 1H), 2,80-2,90 (m, 4H), 2,62-2,74 (width, 2H), 2,43-of 2.50 (m, 3H), of 2.30 (s, 3H)

Example 89

Synthesis of (E)-2-fluoro-N-[(1R,2S)-2-hydroxy-indan-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methylacrylamide

Formula 82

In the same way as described in example 85, received 76,0 mg specified in the header connection on the basis of (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (60,0 mg) and (1R,2S)1-methylamino-indan-2-ol (42,5 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,74 (s, 1H), 7.24 to 7,34 (m, 7H), to 6.95 (s, 1H), 6.73 x (d, J=37 Hz, 1H), 5,66-5,74 (m, 1H), 4,90-4,96 (m, 1H),with 3.89 (s, 3H), the 3.35 (DD, J=7,2, 17 Hz, 1H), 2,94-to 3.02 (m, 1H), 2,86-2,90 (m, 3H), of 2.30 (s, 3H).

Example 90

Synthesis of (E)-2-fluoro-N-[(1R,2S)-2-hydroxy-indan-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 83

In the same way as described in example 85, has been listed in the connection header (E)-2-fluoro-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (60,0 mg) and 76,0 mg of (1R,2S)1-amino-2-indanol (38,8 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,72 (s, 1H), 7,25-7,35 (m, 7H), 7,16 (d, J=8,4 Hz, 1H), 6,98 (d, J=38 Hz, 1H), 6,94 (s, 1H), 5,54 (DD, J=5,2, and 8.4 Hz, 1H), 4,77 (dt, J=2.0 a, 5,2 Hz, 1H), 3,86 (s, 3H), 3,26 (DD, J=5,2, 16 Hz, 1H), was 3.05 (DD, J=2.0 a, 16 Hz, 1H), to 2.29 (s, 3H).

Example 91

Synthesis of (E)-3-(4-imidazol-yl-3-methoxyphenyl)-N-indan-yl-2-methylacrylamide

Formula 84

Ester triethyl-2-phosphonopropionic acid (116 μl) and sodium hydride (43,0 mg) were added successively at 0 to a solution in DMF (5.0 ml) of 4-(1H-imidazol-1-yl)-3-methoxybenzaldehyde (100 mg)obtained in example 111. The reaction solution was heated to room temperature and was stirred overnight. Then to the reaction solution were added water and ethyl acetate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and received the by condensation under reduced pressure to 68.0 mg of the crude carboxylic acid. Then in the same way as described in example 324, got to 25.3 mg specified in the header connection on the basis of the obtained carboxylic acid (30,5 mg) and 1-aminoindane (24,0 µl). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 7.82 (s, 1H), 7,41 (s, 1H), 7,37 (d, J=6.0 Hz, 1H), 7,247,30 (m, 4H), of 7.23 (s, 1H), 7,18 (s, 1H), 7,02 (d, J=8,4 Hz, 1H), 7,01 (s, 1H), 6,14 (d, J=7,6 Hz, 1H), 5,64 (kV, J=7,6 Hz, 1H), 3,86 (s, 3H), 3,05 (DDD, J=4,0, 8,8, 16 Hz, 1H), 2,94 (TD, J=8.0 a, 16 Hz, 1H), 2,71 (DTD, J=4,0, 8,0, 12 Hz, 1H), 2,16 (s, 3H), 1,86 is 1.96 (m, 1H)

Example 92

Synthesis of (E)-2-cyano-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl)-N-indan-1-alacrimia

Formula 85

Cyanoethylated (76,0 ml) and piperidine were alternately added to the ethanol solution (5.0 ml) of 4-(1H-imidazol-1-yl-3-methoxybenzaldehyde (144 mg)obtained in example 111 (35,0 µl). The reaction solution was boiled under reflux for 3.5 hours, to the reaction solution were added water and ethyl acetate and the organic layer was separated. After the obtained organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to get crude product of ester. To a solution in THF (2 ml) of the obtained product of ester was added 2n. the sodium hydroxide solution (1.0 ml) and the reaction solution was stirred for 45 minutes the ri room temperature. Then the reaction solution was heated to 50ºC and stirred for 9 hours. The crude sodium salt of carboxylic acid was obtained by condensing the resulting reaction solution under reduced pressure. In the same way as described in example 324 on the basis of the obtained sodium salt of carboxylic acid and 1-aminoindane (41,0 ál) received 1.0 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,11 (s, 1H), 7,68 (s, 1H), 7.24 to 7,38 (m, 9H), 6,41 (d, J=7,6 Hz, 1H), 5,73 (kV, J=7,6 Hz, 1H), 3.96 points (s, 3H), is 3.08 (DDD, J=4,0, 8,8, 16 Hz, 1H), 2,88-3,00 (m, 1H), 2,75 (TDT, J=4,0, 8,0, 13 Hz, 1H), 1,93-2,02 (m, 1H).

Example 93

Synthesis of indan-1-ylamide (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]-2-buttonboy acid

Formula 86

Synthesis of 1-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]alanon

To a solution in DMF (15 ml) of 3,4-defloration (1.0 ml) was added imidazole (543 mg) and potassium carbonate (1.80 g). After stirring the reaction solution at 80ºC for 4 hours to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: hexane:ethyl is Etat=5:1→ethyl acetate) and received 1.40 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 7.95 (s, 1H), 7,86-a 7.92 (m, 2H), 7,52-to 7.59 (m, 1H), 7,39 (s, 1H), 7,25 (s, 1H), 2,65 (s, 3H).

Synthesis of indan-1-ylamide (E)-3-(3-fluoro-4-(1H-imidazol-1-yl)phenyl]crotonic acid

To a solution in THF (5.0 ml) of 1-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]ethanone (390 mg) was added methyl ether dimethyltitanocene acid (308 μl) and sodium hydride (to 44.0 mg) and the reaction solution was boiled under reflux for 2 hours. To the reaction solution was again added sodium hydride (40,0 mg) and the reaction solution was boiled under reflux for 5 hours. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 525 mg of the crude product of ester in the form of a mixture of isomers (E:Z=2,4:1). To a solution in THF (3.0 ml) of the obtained product of ester (260 mg) was added 2n. the sodium hydroxide solution (3.0 ml). The reaction solution was heated to 50ºC and was stirred for 1 hour and 40 minutes. By condensation of the reaction solution under reduced pressure received 235 mg of the crude sodium salt of carboxylic acid was obtained as a mixture of isomers. In the same way as described in note the re 324, got to 22.0 mg specified in the header connection on the basis of the obtained sodium salt of carboxylic acid and 1-aminoindane (234 μl). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,80 (s, 1H), 7,31-7,38 (m, 4H), 7,20-7,28 (m, 5H), 6,30 (d, J=7,6 Hz, 1H), 6,12-6,13 (m, 1H), 5,58 (kV, J=7,6 Hz, 1H), 3,01 (DDD, J=4,8, 8,8, 16 Hz, 1H), 2,93 (TD, J=8.0 a, 16 Hz, 1H), 2,60-2,69 (m, 1H), 2,60 (s, 3H), 1.85 to was 1.94 (m, 1H)

Example 94

Synthesis of (E)-N-[(1R,1S)-2-hydroxy-indan-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-methylacrylamide, salt triperoxonane acid

Formula 87

Synthesis of (E)-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-methylacrylate acid

Received 250 mg specified in the header connection on the basis of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (200 mg)obtained in example 1 and ethyl ether diethyl-2-phosphonopropionic acid (238 μl), in the same way as described in example 111. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 7,80 (d, J=1.2 Hz, 1H), to 7.61 (d, J=1.2 Hz, 1H), 7,41 (d, J=7,4 Hz, 1H), 7,29 (d, J=1.6 Hz, 1H), 7,16 (DD, J=1.6 Hz, 7.4 Hz, 1H), 7,14-to 7.15 (m, 1H), 3,85 (s, 3H), of 2.15 (s, 3H), 2,07 (s, 3H).

Synthesis of (E)-N-[(1R, 2S)-2-hydroxy-indan-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-methylacrylamide, salt triperoxonane acid

To a solution of (E)-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-methylacrylate acid (60,0 mg) in DMF is (3 ml) were successively added (1R,2S)-1-amino-2-indanol (39,4 mg), IPEA (0.05 ml), EDC (58 mg) and HOBT (41 mg) and the reaction solution was stirred at room temperature overnight. By purifying the resulting reaction solution by LC-MS was received of 55.5 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,66 (s, 1H), of 7.48 (s, 1H), 7.24 to 7,39 (m, 5H), 7,02-to 7.15 (m, 3H), of 6.68 (d, J=7,6 Hz, 1H), of 5.53-to 5.57 (m, 1H), 4,76 (Sirs, 1H), 3,90 (s, 3H), of 3.27 (DD, J=4,8, 16 Hz, 1H), to 3.02 (d, J=16 Hz, 1H), 2,48 (s, 3H), of 2.18 (s, 3H).

Example 95

Synthesis of (E)-N-[(1R,2S)-2-hydroxy-indan-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butylamide, salt triperoxonane acid

Formula 88

Synthesis of (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid

In the same way as described in example 111, (348 mg) was obtained 269 mg specified in the header connection on the basis of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (200 mg) and ethyl ester of 2-(diethoxyphosphoryl)butyric acid obtained in example 1. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 7,81 (d, J=1.2 Hz, 1H), to 7.59 (s, 1H), 7,43 (d, J=8.0 Hz, 1H), 7,25 (d, J=1.2 Hz, 1H), 7,16 (s, 1H), 7,11 (d, J=8.0 Hz, 1H), 3,86 (s, 3H), of 2.16 (s, 3H), 1,11-1,19 (m, 5H)

Synthesis of (E)-N-[(1R,2S)-2-hydroxy-indan-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butylamide, salt triperoxonane acid

Got to 26.0 mg indicated the data in the connection header in the same way, as described in example 111 from (E)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)butyl acid (20.0 mg) and (1R,2S)-1-amino-2-indanol (15.6 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,69 (d, J=1.6 Hz, 1H), 7,28 and 7.36 (m, 6H),? 7.04 baby mortality-7,06 (m, 3H), 6,68 (sird, J=7,6 Hz, 1H), 5.56mm (DD, J=4,8, and 7.6 Hz, 1H), amounts to 4.76 (dt, J=2.0 a, 4,8 Hz, 1H), 3,90 (s, 3H), of 3.28 (DD, J=4,8, 16 Hz, 1H), 3,01 (DD, J=2,0, 16 Hz, 1H), 2,56-to 2.65 (m, 2H), 2,48 (s, 3H), 1,21 (t, J=7,6 Hz, 3H).

Example 96

Synthesis of (E)-2-benzyl-N-[(1R,2S)-2-hydroxy-indan-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Formula 89

Synthesis of (E)-2-benzyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

Got 315 mg specified in the connection header in the same way as described in example 111 from 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (200 mg) and ethyl ester of 2-(diethoxyphosphoryl)-3-phenylpropionic acid (434 mg)obtained in example 1. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): a 7.92 (s, 1H), to 7.64 (s, 1H), 7,56 (d, J=7,6 Hz, 1H), 7,28-7,35 (m, 3H), 7,16-of 7.23 (m, 5H), to 3.92 (s, 2H), 3,69 (s, 3H), of 2.30 (s, 3H).

Synthesis of (E)-2-benzyl-N - [(1R,2S)-2-hydroxy-indan-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Got to 19.3 mg specified in the header connection on the basis of (E)-2-benzyl-3-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (25.0 mg) and (1R,2S)1-amino-2-indanol (16.1 mg), in the same way as described in example 94. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,64 (s, 1H), 7,76 (s, 1H), 7,22-7,37 (m, 8H), to 7.15 (TD, J=3,6, and 7.6 Hz, 1H), 7,10 (d, J=8,4 Hz, 1H), 7,02-7,06 (m, 2H), 6,93 (d, J=7.2 Hz, 1H), of 6.49 (sird, J=8.0 Hz, 1H), 5,44 (DD, J=5,2, 8.0 Hz, 1H), 4,59 (dt, J=1,6, and 5.2 Hz, 1H), 4.00 points (d, J=17 Hz, 1H), 3,99 (d, J=17 Hz, 1H), 3,71 (s, 3H), and 3.16 (DD, J=5,2, 16 Hz, 1H), 2,90 (DD, J=1,6, 16 Hz, 1H), 2,46 (s, 3H).

Example 97

Synthesis of (E)-2-cyclopropylmethyl-N-[(1R,2S)-2-hydroxy-indan-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Formula 90

Synthesis of (E)-2-cyclopropylmethyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

Received 102 mg specified in the connection header in the same way as described in example 111 from 3-methoxy-4-(4-Mei-1-yl)benzaldehyde (200 mg)obtained in example 1 and ethyl ester of 3-cyclopropyl-2-(diethoxyphosphoryl)propionic acid (384 mg). The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): of 7.82 (s, 1H), to 7.61 (s, 1H), 7,43 (d, J=8.0 Hz, 1H), 7,31 (s, 1H), 7,17-to 7.18 (m, 2H), 3,86 (s, 3H), of 2.15 (s, 3H), 2,45-of 2.50 (m, 2H), 0,90-0,98 (m, 1H), 0,39-0,43 (m, 2H), 0,12-0,16 (m, 2H).

Synthesis of (E)-2-cyclopropylmethyl-N-[(1R,2S)-2-hydroxyine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Got to 11.5 mg specified in the header Conn is in proceeding from (E)-2-cyclopropylmethyl-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (20.0 mg) and (1R,2S)1-amino-2-indanol in (11.5 mg), in the same way as described in example 94. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,72 (s, 1H), 7,28-7,40 (m, 6H), 7,07-7,10 (m, 3H), 6,79 (d, J=8,4 Hz, 1H), 5.56mm (DD, J=5,2, and 8.4 Hz, 1H), 4,77 (dt, J=2,4, and 5.2 Hz, 1H), 3,91 (s, 3H), of 3.28 (DD, J=5,2, 16 Hz, 1H), to 3.02 (DD, J=2,4, 16 Hz, 1H), 2,54 (d, J=6,4 Hz, 2H), 2,48 (s, 3H), from 0.88 to 0.96 (m, 1H), 0.50 to 0.60 (m, 2H), 0,18-0,26 (m, 2H).

Example 98

Synthesis of (E)-2-benzyl-N-(2-hydroxyethyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Formula 91

Received 15.3 mg specified in the header connection on the basis of (E)-2-benzyl-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (25.0 mg) and ethanolamine (8,8 mg)in the same way as described in example 94. The physical properties of this compound are as follows.

ESI-MS; m/z 392 [M++H].

Example 99

Synthesis of (E)-1-(4-indol-1-yl-piperidine-1-yl)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butane-1-it

Formula 92

Received of 76.8 mg specified in the header connection on the basis of (E)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)butyric acid (60,0 mg), and hydrochloride of 4-(1-indole)piperidine (74,6 mg)in the same way as described in example 111. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 7.69 (s, 1H), to 7.64 (d, J=8.0 Hz, 1H), 7,38 (d, J=8.0 Hz, 1H), 7.18 in-7,25 (m, 3H), 7,12 (t, J=7,6 Hz,1H), 6,92-of 6.96 (m, 3H), 6,53 (d, J=10 Hz, 2H), 4,65-4,95 (Sirs, 1H), 4,49-4,55 (m, 1H), 4,20-4,50 (width, 1H), 3,85 (s, 3H), 2,80-3,40 (width, 2H), 2,62-to 2.67 (m, 2H), 2,99 (s, 3H), 2,22 was 2.25 (m, 2H), 1,80-2,10 (width, 2H), of 1.18 (t, J=7.2 Hz, 3H).

Example 100

Synthesis of (E)-N-indan-1-yl-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl]benzylidene)butylamide, salt triperoxonane acid

Formula 93

Received 6,95 mg specified in the header connection on the basis of (E)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)butyric acid (13,8 mg) and 1-aminoindane (9.6 mg), in the same way as described in example 111. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,63 (s, 1H), 7,22-to 7.35 (m, 5H), 7,17 (s, 1H), 7,00-7,02 (m, 3H), between 6.08 (sird, J=7,6 Hz, 1H), 5,63 (kV, J=7,6 Hz, 1H), 3,48 (s, 3H), 3,05 (DDD, J=4,0, 8,8, 16 Hz, 1H), equal to 2.94 (dt, J=7,6, 16 Hz, 1H), 2,71 (DTD, J=4,0, 7,6, 16 Hz, 1H), of 2.51 at 2.59 (m, 2H), 2,47 (s, 3H), 1,86-of 1.95 (m, 1H), 1,20 (t, J=7,6 Hz, 3H).

Example 101

Synthesis of (E)-2-cyclopropylmethyl-N-indan-1-yl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Formula 94

Received 6,23 mg specified in the header connection on the basis of (E)-2-cyclopropylmethyl-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (15,0 mg) and 1-aminoindane (9.6 mg), in the same way as described in example 94. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,67 (s, 1H), 7,22 and 7.36 (who, 5H), 7,18 (s, 1H),? 7.04 baby mortality-7,05 (m, 3H), 6,24 (sird, J=7,6 Hz, 1H), 5,62 (kV, J=7,6 Hz, 1H), with 3.89 (s, 3H), 3,05 (DDD, J=4,0, 8,4, 16 Hz, 1H), 2,93 (dt, J=8.0 a, 16 Hz, 1H), 2,71 (DTD, J=4,0, 7,6, 16 Hz, 1H), 2,50 (d, J=6,4 Hz, 2H), 2,47 (s, 3H), 1,88-of 1.97 (m, 1H), 0,82-of 0.91 (m, 1H), 0,52-0,56 (m, 2H), 0,18-0,22 (m, 2H).

Example 102

Synthesis of (E)-2-benzyl-N-indan-1-yl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Formula 95

Received 6,76 mg specified in the header connection on the basis of (E)-2-benzyl-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (17,0 mg) and 1-aminoindane (9.6 mg), in the same way as described in example 94. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,61 (d, J=2.0 Hz, 1H), 7,71 (s, 1H), 7,20-7,37 (m, 7H), 7,05-7,13 (m, 3H), 6,99-7,01 (m, 2H), 6.87 in (d, J=7.2 Hz, 1H), 5,95 (sird, J=7,6 Hz, 1H), 5,50 (kV, J=7,6 Hz, 1H), 3,98 (d, J=16 Hz, 1H), 3,88 (d, J=16 Hz, 1H), 3,68 (s, 3H), 2,80-to 2.94 (m, 2H), 2,59 (DTD, J=4,0, 7,2, 13 Hz, 1H), 2,46 (s, 3H), 1,62-1,71 (m, 1H).

Compounds shown in table 5 were synthesized as described in example 85.

Structural formulas and physical-chemical properties are presented in table 5, respectively.

Table 5
ExampleD2 Data: MS m/z
103M++H: 406 (ESI)
104M++H: 410 (ESI)
105M++H: 436 (ESI)

Compounds shown in table 6, were synthesized as described in example 474. Structural formulas and physical-chemical properties are presented in table 6, respectively.

Table 6
ExampleD2Data: MS m/z
106M++H: 415 (ESI)
107M++H: 457 (ESI)
108M++H: 457 (ESI)
109M++H: 457 (ESI)
110M++N: 431 (ESI)

Example 111

Synthesis of (E)-N-(9H-fluoren-9-yl)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylamide

Formula 96

Synthesis of 4-(1H-imidazol-1-yl)-3-methoxybenzaldehyde

Potassium carbonate (6,70 g) and imidazole (2,60 g) were successively added to a solution of 4-fluoro-3-methoxybenzaldehyde (of 5.00 g) in DMF (30 ml) and the reaction solution was stirred at 130ºC during the night. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and by condensation under reduced pressure received value of 4.76 g of the crude aldehyde compounds. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 10.01 (s, 1H), 7,92 (s, 1H), EUR 7.57-of 7.60 (m, 2H), 7,49 (d, J=7,6 Hz, 1H), 7,29 (s, 1H), 7,21 (s, 1H), 3,98 (s, 3H).

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl)acrylic acid

Methyl ether dimethyltitanocene acid (3,80 ml) and the monohydrate of lithium hydroxide (1.20 g) in turn we use the and to a solution in THF (20 ml) of the crude aldehyde compounds (4,76 g), obtained above, and the reaction solution was stirred over night at room temperature. After confirming disappearance of the starting compounds to the reaction solution was added 2n. the sodium hydroxide solution (20 ml) and the reaction solution was stirred at 50ºC for 2 hours. The reaction solution was cooled to 0ºC, to the reaction solution was added 2n. hydrochloric acid solution (20 ml) and the precipitated substance was separated by filtration using a funnel of Kiriyama. The precipitate was washed with water and ethyl acetate and received 4,2 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): of 7.96 (s, 1H), 7,63 (d, J=16 Hz, 1H), 7,60 (d, J=1.6 Hz, 1H), of 7.48 (s, 1H), 7,45 (d, J=8.0 Hz, 1H), 7,39 (DD, J=1,6, 8.0 Hz, 1H), 7,06 (s, 1H), of 6.68 (d, J=16 Hz, 1H), 3,90 (s, 3H).

Amide (E)-N-(9H-fluoren-9-yl)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid

To a solution of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl)acrylic acid (3.50 g) in DMF (70 ml) were successively added 9-aminofluorene (2,40 g), IPEA (7.5 ml), EDC (3.00 g) and HOBT (2.10 g) and the reaction solution was stirred at room temperature overnight. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried to the anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: hexane:ethyl acetate=1:1→ethyl acetate→ethyl acetate:ethanol=10:1) and received 2.20 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,80 (s, 1H), 7,76 (d, J=16 Hz, 1H), 7,72 (d, J=7.2 Hz, 2H), 7,63 (d, J=7.2 Hz, 2H), 7,42 (t, J=7.2 Hz, 2H), 7,32 (dt, J=1.2 Hz, 7.2 Hz, 2H), 7,28 (d, J=8,4 Hz, 1H), 7,19-7,22 (m, 2H), 7,16-7,17 (m, 2H), 6,47 (d, J=16 Hz, 1H), to 6.39 (d, J=8,8 Hz, 1H), 6,00 (d, J=8,8 Hz, 1H), 3,88 (s, 3H).

Example 112

Synthesis of tert-butyl methyl ether (E)-{3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylamido}-(S)phenylacetic acid, salt triperoxonane acid

Formula 97

In the same way as described in example 94, received 14,0 mg specified in the header connection on the basis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid (20.0 mg) and tert-butyl methyl ether (S)-2-phenylglycine (25.0 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,19 (t, J=1.6 Hz, 1H), 7,79 (t, J=1.6 Hz, 1H), 7,63 (t, J=1.6 Hz, 1H), 7,52 (d, J=16 Hz, 1H), 7,50 (d, J=8,4 Hz, 1H), 7,40 (d, J=1.6 Hz, 1H), 7,26 and 7.36 (m, 6H), 7,32 (d, J=16 Hz, 1H), 5,38 (s, 1H), 3,88 (s, 3H), of 1.32 (s, 9H).

Example 113

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]-N-(3-iodobenzyl)acrylamide

Formula 98

In the same way as described in example 111, received 1.40 g is specified in the header is VCE connection from (E)-3-(4-1H-imidazol-1-yl-3-methoxyphenyl)acrylic acid (1,00 g) and 3-iodobenzylamine (550 μl). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,76 (s, 1H), 7,65 (s, 1H), to 7.64 (d, J=15.2 Hz, 1H), 7,58 (d, J=8.0 Hz, 1H), 7,28 (d, J=8.0 Hz, 1H), 7.23 percent (d, J=8.0 Hz, 1H), 7,20 (t, J=1.6 Hz, 1H), 7,11-7,16 (m, 3H),? 7.04 baby mortality (t, J=8.0 Hz, 1H), 6,94 (Sirs, 1H), is 6.54 (d, J=15.2 Hz, 1H), 4,51 (d, J=6.0 Hz, 2H), of 3.84 (s, 3H).

Example 114

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]-N-(3-fenetylline)acrylamide, salt triperoxonane acid

Formula 99

In the same way as described in example 94, received 2,30 mg specified in the header connection on the basis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid (10.0 mg) and hydrochloride 3-penicillamine (14,0 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,29 (t, J=1.6 Hz, 1H), 7,89 (t, J=1.6 Hz, 1H), 7,73 (t, J=1.6 Hz, 1H), 7.62mm (d, J=16 Hz, 1H), to 7.59 (d, J=8.0 Hz, 1H), 7,50 (d, J=1.6 Hz, 1H), 7,40 (DD, J=1,2, 8.0 Hz, 1H), 7,08-7,25 (m, 9H), is 6.78 (d, J=16 Hz, 1H), 4,48 (s, 2H), 3,98 (s, 3H), 2,90 (s, 4H).

Example 115

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)acrylamide, salt triperoxonane acid

Formula 100

In the same way as described in example 94, received 2.7 mg specified in the header connection on the basis of (E)-3-(4-1H-imidazol-1-yl-3-methoxyphenyl)acrylic acid (6,20 mg) and 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-she (6,00 mg). Physically the properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,31 (t, J=1.6 Hz, 1H), of 7.90 (t, J=1.6 Hz, 1H), 7,74 (t, J=1.6 Hz, 1H), 7,71 (d, J=8.0 Hz, 1H), to 7.67 (d, J=3,6, and 5.6 Hz, 1H), 7.62mm (d, J=8.0 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,55-7,58 (m, 3H), 7,40-to 7.50 (m, 5H), 7,20 (d, J=16 Hz, 1H), 5,46 (s, 1H), 4.00 points (s, 3H), 3,37 (s, 3H).

Example 116

Synthesis of (E)-N-(2-benzylbutyl)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylamide, salt triperoxonane acid

Formula 101

In the same way as described in Example 94, received 7.2 mg specified in the header connection on the basis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid (10.0 mg) and 2-benzylaniline (12.0 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,29 (t, J=1.6 Hz, 1H), 7,88 (t, J=1.6 Hz, 1H), 7,73 (t, J=1.6 Hz, 1H), 7,58 (d, J=8.0 Hz, 1H), 7,55 (d, J=16 Hz, 1H), 7,45 (d, J=1.6 Hz, 1H), was 7.36 (DD, J=1,6, 8.0 Hz, 1H), 7,32-7,34 (m, 1H), 7,19-7,27 (m, 5H), 7,12-to 7.15 (m, 3H), of 6.65 (d, J=16 Hz, 1H), 4,49 (s, 2H), 4,10 (s, 2H), of 3.97 (s, 3H).

Example 117

Synthesis of (E)-N-(9H-fluoren-1-yl)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylamide, salt triperoxonane acid

Formula 102

In the same way as described in example 94, received 14,0 mg specified in the header connection on the basis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid (20.0 mg) and 1-aminofluorene (22 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,29 (s, 1H), 7,98 (s, 1H), 7,89 (t, J=1,6 is C, 1H), 7,72-7,80 (m, 3H), 7,74 (t, J=1.6 Hz, 1H), 7,63 (d, J=8.0 Hz, 2H), 7,53-rate of 7.54 (m, 2H), 7,46 (d, J=8.0 Hz, 1H), 7,35 (t, J=7,6 Hz, 1H), 7,26 (dt, J=1,2, 7,6 Hz, 1H), of 6.96 (d, J=16 Hz, 1H), 4,01 (s, 3H), to 3.92 (s, 2H).

Example 118

Synthesis of (E)-N-(1H-benzoimidazol-2-ylmethyl)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylamide, salt nitrilotriacetic acid

Formula 103

In the same way as described in example 94, received 3,00 mg specified in the header connection on the basis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid (20.0 mg) and the dihydrochloride of 2-(aminomethyl)benzimidazole (26,0 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9.28 are (d, J=1.6 Hz, 1H), 7,89 (t, J=1.6 Hz, 1H), 7,55-to 7.61 (m, 2H), 7,74 (t, J=1.6 Hz, 1H), of 7.70 (d, J=16 Hz, 1H), 7,63 (d, J=8.0 Hz, 1H), 7,73 for 7.78 (m, 2H), 7,53 (d, J=1,6, 1H), 7,44 (DD, J=1,6, 8.0 Hz, 1H), make 6.90 (d, J=16 Hz, 1H), to 4.98 (s, 2H), 3,99 (s, 3H).

Example 119

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]-N-naphthalene-1-iletilerinde

Formula 104

In the same way as described in example 111, received 1,90 mg specified in the header connection on the basis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid (20.0 mg) and 1-naphthalenemethylamine (19,0 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 8.06 (d, J=8,4 Hz, 1H), 7,89 (d, J=7,6 Hz, 1H), 7,86 (d, J=12,4 Hz, 1H), 7,79 (s, 1H), 7,68 (d, J=15.6 Hz, 1H), 7,42-7,58 (m, 4H), 7,11-7,30 (m, 5H), 6,38 (d, J=15,6 is C, 1H), 5,86 (Sirs, 1H), of 5.05 (d, J=5,2 Hz, 2H), 3,85 (s, 3H).

Example 120

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]-N-(1H-imidazol-2-ylmethyl)acrylamide, salt nitrilotriacetic acid

Formula 105

Got a 15.7 mg specified in the header connection on the basis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid (15,0 mg) and dihydrochloride (1H-imidazol-2-yl)methylamine (15.3 mg), in the same way as described in example 94. The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,29 (t, J=1.6 Hz, 1H), 7,88 (t, J=1.6 Hz, 1H), 7,74 (t, J=1.6 Hz, 1H), 7,66 (d, J=16 Hz, 1H), to 7.61 (d, J=8.0 Hz, 1H), 7,51 (d, J=1.6 Hz, 1H), of 7.48 (s, 2H), 7,42 (DD, J=1,6, 8.0 Hz, 1H), at 6.84 (d, J=16 Hz, 1H), 4,78 (s, 2H), 3,99 (s, 3H)

Example 121

Synthesis of (E)-N-biphenyl-3-ylmethyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 106

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

To a solution in THF (40 ml) of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (of 4.00 g)obtained in example 1 were successively added ethyl ether diethylphosphonate acid (4,00 ml) and the monohydrate of lithium hydroxide (932 mg) and the reaction solution was stirred over night at room temperature. After confirming disappearance of the starting compounds to the reaction solution was added 2n. the solution of caustic soda is I (30 ml) and ethanol (5 ml) and the reaction solution was stirred at room temperature overnight. The reaction solution was cooled to 0ºC, to the reaction solution was added 2n. hydrochloric acid solution (30 ml) and the resulting thereafter, the precipitate was separated by filtration using a Kiriyama funnel. The precipitate was washed with water and ethyl acetate and received 4.61 in year specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 7,81 (s, 1H), 7,60 (d, J=16 Hz, 1H), 7,56 (s, 1H), 7,39 (d, J=8.0 Hz, 1H), 7,35 (d, J=8.0 Hz, 1H), 7,16 (s, 1H), 6,66 (d, J=16 Hz, 1H), 3,88 (s, 3H), of 2.15 (s, 3H).

Synthesis of (E)-N-biphenyl-3-ylmethyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

To a solution of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (2.20 g) in DMF (30 ml) were successively added hydrochloride 3-phenylendiamine (2.30 g), IPEA (4,57 ml), EDC (1,96 g) and HOBT (1,38 g) and the reaction solution was stirred at room temperature overnight. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:ethanol=10:1) and received 3,30 g specified in the connection header. Your physical is tion of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,71 (d, J=1.2 Hz, 1H), to 7.67 (d, J=16 Hz, 1H), 7,52-of 7.60 (m, 4H), 7,42-7,46 (m, 3H), 7,37 (TD, J=1,2, 7,6 Hz, 1H), 7,33 (sird, J=7,6 Hz, 1H), 7,24 (d, J=8.0 Hz, 1H), 7,17 (DD, J=1.6 Hz, 6.4 Hz, 1H), 7,13 (d, J=1.6 Hz, 1H), 6,93 (t, J=1.2 Hz, 1H), 6,45 (d, J=16 Hz, 1H), 6,09 (Sirs, 1H), 4,67 (d, J=5.6 Hz, 2H), a 3.87 (s, 3H), to 2.29 (s, 3H).

Example 122

Synthesis of (E)-N-[(1S)-indan-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Formula 107

To a solution of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (15,0 mg) in DMF (0.8 ml) were successively added (S)-(+)-1-aminoindan (12.0 mg), IPEA (30 μl), EDC (16,7 mg) and HOBT (11.8 mg) and the reaction solution was stirred at room temperature for 3 hours. After confirming disappearance of the starting compounds, the reaction solution was purified by LC-MS and received 6.6 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 9,15 (d, J=2.0 Hz, 1H), to 8.57 (d, J=8,4 Hz, 1H), 7,65 (d, J=16 Hz, 1H), to 7.59 (t, J=1.2 Hz, 1H), 7,56 (d, J=8.0 Hz, 1H), of 7.48 (d, J=1.6 Hz, 1H), 7,34 (DD, J=1,6, 6,8 Hz, 1H), 7.18 in-7,29 (m, 4H), 6,77 (d, J=16 Hz, 1H), 5,50-of 5.55 (m, 1H), of 3.97 (s, 3H), 3,05 (DDD, J=4,4, 8,8, 16 Hz, 1H), 2,90 (TD, J=7,6, 16 Hz, 1H), 2.57 m (DTD, J=4,4, 7,6, 16 Hz, 1H), 2,43 (s, 3H), 1,88-of 1.97 (m, 1H).

Example 123

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(2-foxitr)acrylamide, salt triperoxonane acid

Formula 108

In the same way as described in example 94, received 5.3 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15,0 mg) and 2-deoxyadenosine (13,0 µl). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,13 (d, J=1.6 Hz, 1H), and 8.50 (t, J=5.6 Hz, 1H), 7,54-to 7.61 (m, 3H), 7,47 (d, J=2.0 Hz, 1H), 7,37 (DD, J=2.0 a, and 8.4 Hz, 1H), 7,20-7,31 (m, 2H), 6.90 to-6,98 (m, 3H), 6,79 (d, J=15.6 Hz, 1H), 4,12 (t, J=5.6 Hz, 2H), of 3.97 (s, 3H), 3,69-3,74 (m, 2H), 2,43 (s, 3H).

Example 124

Synthesis of (E)-N-[(1R)-1-hydroxymethyl-2-phenylethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 109

In the same way as described in example 121, received 262 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (200 mg) and D-phenylalaninol (176 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 7.69 (d, J=1.6 Hz, 1H), 7,56 (d, J=15.6 Hz, 1H), 7,20-7,33 (m, 5H), 7,18 (d, J=8.0 Hz, 1H), 7,06-7,10 (m, 2H), 6,91 (t, J=1.2 Hz, 1H), 6,34 (d, J=15.6 Hz, 1H), 6,18 (d, J=7,6 Hz, 1H), or 4.31 is 4.36 (m, 1H), 3,84 (s, 3H), 3,79 (DD, J=3.2, and 11 Hz, 1H), 3,68 (DD, J=4,8, 11 Hz, 1H), 2,98 (d, J=7.2 Hz, 2H), to 2.29 (s, 3H).

Example 125

Synthesis of (E)-N-[2-(3-fluoro-foxi)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Formula 110

In the same way as described in note the re 94, received 2,10 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15,0 mg) and 2-(3-forpeace)ethylamine (13,0 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 8,89 (s, 1H), to 7.59 (d, J=16 Hz, 1H), 7,52 (d, J=8.0 Hz, 1H), 7,49 (m, 1H), 7,45 (d, J=1.6 Hz, 1H), was 7.36 (DD, J=1,6, and 8.4 Hz, 1H), 7,26 (dt, J=6,8, 8.0 Hz, 1H), 6,76-6,79 (m, 1H), 6,65 to 6.75 (m, 3H), of 4.12 (t, J=5,2 Hz, 2H), 3.96 points (s, 3H), and 3.72 (t, J=5,2 Hz, 2H), 2,39 (s, 3H).

Example 126

Synthesis of (E)-N-[(1S,2R)-2-hydroxy-indan-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Formula 111

In the same way as described in example 94, received 8,40 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (15,0 mg) and (1S,2R)-1-amino-2-indanol (13,0 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,14 (d, J=1.2 Hz, 1H), compared to 8.26 (d, J=8,8 Hz, 1H), to 7.67 (d, J=16 Hz, 1H), to 7.59 (m, 1H), 7,56 (d, J=8.0 Hz, 1H), 7,52 (d, J=1.6 Hz, 1H), 7,41 (DD, J=1,2, 8,8 Hz, 1H), 7,21-7,29 (m, 3H), 6,98 (d, J=16 Hz, 1H), 5,47 (kV, J=5.6 Hz, 1H), 4,63 (dt, J=2.0 a, and 5.6 Hz, 1H), 3,98 (s, 3H), 3,20 (DD, J=5,6, 16 Hz, 1H), 2,87 (DD, J=2.0 a, 16 Hz, 1H), 2,44 (s, 3H).

Example 127

Synthesis of (E)-N-[(1R)-1-hydroxymethyl-2-phenylethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(2-morpholine-4-retil)acrylamide

Formula 112

Synthesis of (2R)-2(2-morpholine-4-ylethylamine)-3-phenylpropane-1-ol

Iodide of sodium (84,5 mg) and sodium hydride (676 mg) and the hydrochloride of 4-(2-chloroethyl)of the research (2.1 g) was added to a solution of (R)-4-benzyl-2-oxazolidinone (1.0 g) in DMF (20 ml) at 0ºC and the reaction solution was heated to 60°C and was stirred for 3 hours. After stirring the reaction solution at room temperature over night to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent:heptane-ethyl acetate=2:1) and received 1,62 g oxazolidinones connection. Then to the solution obtained oxazolidinone in ethanol (14 ml) was added lithium hydroxide (1,61 g) and water (6.0 ml) and the reaction solution was boiled under reflux for 6 hours and 30 minutes. To the reaction solution were added water and ethyl acetate and the organic layer was separated. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and by condensation under reduced pressure received 549 mg of the crude amine compounds. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,14-7,32 (who, 5H), 3,67 is 3.76 (m, 1H), 3,64 (DD, J=4,8, 10 Hz, 1H), 3,51-3,62 (m, 3H), 3,39 (DD, J=5,6, 10 Hz, 1H), 2,86 of 2.92 (m, 1H), 2.70 height is 2.80 (m, 2H), 2,62 of 2.68 (m, 2H), 2,42-of 2.54 (m, 2H), 2,28-of 2.36 (m, 6H).

Synthesis of (E)-N-[(1R)-1-hydroxymethyl-2-phenylethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(2-morpholine-4-yl-ethyl) - acrylamide

Got to 18.1 mg specified in the connection header in the same way as described in Example 111 from (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15,0 mg) and (2R)-2-(2-morpholine-4-yl-ethylamino)-3-phenylpropane-1-ol (23,0 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,71 (d, J=1.2 Hz, 1H), 7,25-7,29 (m, 1H), 7,14-7,22 (m, 4H), 6,92-7,05 (m, 5H), 6.48 in (d, J=15 Hz, 1H), 4,27 is 4.36 (m, 1H), a 3.87 (s, 3H), 3,60-3,86 (m, 7H), 3,52-to 3.58 (m, 1H), 3,06-3,26 (m, 2H), 2,63 was 2.76 (m, 4H), 2,42-of 2.54 (m, 3H), of 2.30 (s, 3H).

Example 128

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[3-(morpholine-4-ylbenzyl)acrylamide

Formula 113

In the same way as described in example 121, got 12,0 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15,0 mg) and (3-morpholine-4-yl)benzylamine in (17.0 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 7.70 (d, J=1.2 Hz, 1H), 7,65 (d, J=16 Hz, 1H), 7.23 percent-7,27 (m, 2H), 7,16 (DD, J=1,6, and 8.4 Hz, 1H), 7,11 (d, J=1.6 Hz, 1H), 6,91 (t, J=1.2 Hz, 1H), 6,836,88 (m, 3H), 6,40 (d, J=16 Hz, 1H), 5,93 (Sirs, 1H), 4,54 (d, J=5.6 Hz, 2H), a 3.87 (s, 3H), 3,85 (t, J=4.8 Hz, 4H), and 3.16 (t, J=4.8 Hz, 4H), to 2.29 (s, 3H).

Example 129

Synthesis of (E)-N-(4-fluoro-3-morpholine-4-ylbenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt of oxalic acid

Formula 114

In the same way as described in example 121, received free connection specified in the connection header on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (200 mg) and 4-fluoro-3-morpholine-4-ivesiana (165 mg). By adding 1 equivalent of oxalic acid to the solution obtained free compound in methanol (2 ml) and removal of the reaction solvent was received 221 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 8,59 (t, J=6.0 Hz, 1H), 8,07 (Sirs, 1H), 7,50 (d, J=15.6 Hz, 1H), 7,427,44 (m, 2H), 7,27 (DD, J=1,6, and 8.4 Hz, 1H), 7,26-7,28 (m, 1H), to 7.09 (DD, J=8,4, to 12.8 Hz, 1H), 6,98 (DD, J=1,6, and 8.4 Hz, 1H), 6,88-6,91 (m, 1H), 6.75 in (d, J=15.6 Hz, 1H), 4,35 (d, J=5.6 Hz, 2H), a 3.87 (s, 3H), 3,74 (t, J=4.8 Hz, 4H), to 2.99 (t, J=4.8 Hz, 4H), to 2.18 (s, 3H).

Example 130

Synthesis of (E)-N-[2-(3-forfinal)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Formula 115

In the same way as described in Example 94, received 3.1 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15,0 mg) and 2-(3-Fortini is)ethylamine (12.0 ml). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,05 (s, 1H), 7,56 (d, J=15.6 Hz, 1H), 7,54 (DD, J=8,4 Hz, 1H), 7,45 (d, J=1.6 Hz, 1H), 7,35 (DD, J=1,6, and 8.4 Hz, 1H), 7,29 (DD, J=6,0, 8.0 Hz, 1H), 7,07 (d, J=8.0 Hz, 1H), 7,00 (d, J=10.0 Hz, 1H), 6,94 (dt, J=1,6, 8.0 Hz, 1H), of 6.68 (d, J=15.6 Hz, 1H), 3.96 points (s, 3H), of 3.56 (t, J=7.2 Hz, 2H), 2,89 (t, J=7.2 Hz, 2H), 2,41 (s, 3H).

Example 131

Synthesis of (E)-N-(benzo[B]thiophene-3-ylmethyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Formula 116

In the same way as described in example 94, received 1,40 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15,0 mg), and hydrochloride of 1-benzo[B]thiophene-3-ylmethylamino in (17.0 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,05 (s, 1H), 7,86-of 7.90 (m, 2H), to 7.64 (d, J=16 Hz, 1H), 7,51-rate of 7.54 (m, 3H), 7,46 (d, J=1.2 Hz, 1H), 7,35-7,42 (m, 3H), of 6.75 (d, J=16 Hz, 1H), 4,78 (s, 2H), 3.96 points (s, 3H), 2,41 (s, 3H).

Example 132

Synthesis of (E)-N-(biphenyl-3-ylmethyl)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, polyol oxalic acid (1/2)

Formula 117

In the same way as described in example 121, received 118 mg specified in the header connection on the basis of (E)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (60,0 mg) and hydrochloride 3-phenylendiamine (80.0 mg). Physical t the VA this connection the following.

1H-NMR (CD3OD) δ (ppm): 8,75 (t, J=4,8 Hz, 1H), 8,48 (s, 1H), 7,527,68 (m, 8H), 7,41-7,44 (m, 4H), 7,31-7,35 (m, 2H), 6,76 (d, J=16 Hz, 1H), a 4.86 (s, 3H), 4,58 (d, J=4,8 Hz, 2H).

Example 133

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methyl-N-(2-foxitr)acrylamide, salt triperoxonane acid

Formula 118

In the same way as described in example 94, received 41.0 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (70.0 mg) and methyl-(2-foxitr)amine (61,0 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,12 (s, 1H), 7,21-7,63 (m, 8H), 6.87 in-to 6.95 (m, 3H), 4,20-4,24 (m, 2H), was 4.02 (t, J=4,8 Hz, 1H), 3,98 (s, 1,5H), 3,95 (s, 1,5H), to 3.89 (t, J=5.6 Hz, 1H), 3,38 (s, 1,5H)and 3.15 (s, 1,5H), to 2.42 (s, 3H).

Example 134

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methyl-N-(2-morpholine-4-yl-1-phenylethyl)acrylamide, salt triperoxonane acid

Formula 119

In the same way as described in example 94, received 139 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (70.0 mg) and a solution of methyl-(2-morpholine-4-ylphenidate)amine (10 mm) in DMF (405 μl). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,16 (d, J=1.2 Hz, 1H), 7,74 (d, J=16 Hz, 1H), 7,56-to 7.59 (m, 3H), 7,35-7,47 (m, 6H), 7,2 (d, J=15 Hz, 1H), of 6.49 (DD, J=2,8, 12 Hz, 1H), 4,16 (t, J=12 Hz, 1H), 3,98 (s, 3H), 3,83 (DD, J=2,8, 12 Hz, 1H), 3,81-4,20 (m, 8H), to 2.94 (s, 3H), 2,43 (s, 3H).

Example 135

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methyl-N-(3-morpholine-4-yl-1-benzyl)acrylamide, polyol oxalic acid (1/2)

Formula 120

In the same way as described in example 121, received 132 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (68,0 mg) and N-methyl-N-[3-morpholine-4-yl)benzyl]amine (76,0 mg). The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 8,01 (Sirs, 1H), 7,55-of 7.60 (m, 2H), 7,40-7,44 (m, 2H), to 7.32 and 7.36 (m, 1H), 7.18 in-7,26 (m, 2H), 6,84-6,86 (m, 2H), 6,65-of 6.71 (m, 1H), 4,78 (s, 1H), 4,58 (s, 1H), 3,90 (s, 1,5H), a 3.87 (, 1,5H), 3,69-3,74 (m, 4H), 3,12 (s, 1,5H), 3,07-3,10 (m, 4H), of 2.93 (s, 1,5H), to 2.18 (s, 3H).

Example 136

Synthesis of (E)-N-[3-(2-hydroxyethoxy)benzyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methylacrylamide, salt triperoxonane acid

Formula 121

In the same way as described in example 94, received the 36.1 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (20.0 mg) and 2-(3-methylaminomethyl)ethanol (21,0 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,72 (s, 0,5H), 8,69 (s, 0,5H), of 7.75 (d, J=12 Hz, 0,5H), 7,72 (d, J=12 Hz, 0,5H), 7,28 and 7.36 (m, 2H), 7,20-7,21 (m, 1H), 6,977,12 (m, 2H), 6,79-6,91 (m, 4H), 4,71 (s, 1H), 4,69 (s, 1H), 4,07-4,12 (m, 2H), 3.96 points-of 4.00 (m, 2H), 3,95 (s, 1,5H), 3,90 (s, 1,5H), 3,13 (s, 1,5H), 3,12 (s, 1,5H), 2,48 (s, 1,5H), 2,47 (s, 1,5H).

Example 137

Synthesis of (E)-N-[1-(3-forfinal)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, salt triperoxonane acid

Formula 122

In the same way as described in example 94, received a 17.3 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (20.0 mg) and 1-(3-forfinal)ethylamine (16.2 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,68 (d, J=1.6 Hz, 1H), 7,63 (d, J=16 Hz, 1H), 7,30-7,35 (m, 2H), 7,22-7,26 (m, 1H), 7,19 (d, J=1.6 Hz, 1H), 7,15 (DD, J=1,2, and 8.4 Hz, 1H), 6,99-was 7.08 (m, 2H), 6,97 (dt, J=2,4, and 8.4 Hz, 1H), 6,55 (d, J=16 Hz, 1H), 6,02-between 6.08 (Sirs, 1H), 5,27 (kV, J=7.2 Hz, 1H), 3,99 (s, 3H), 2,47 (s, 3H), of 1.57 (d, J=7.2 Hz, 3H).

Example 139

Synthesis of amide (E)-N-[(1R)-vermeil-2-phenylethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

The formula 360

Synthesis of (R)-2-(1-vermeil-2-phenylethyl)isoindole-1,3-dione

(R)-2-(1-hydroxymethyl-2-phenylethyl)isoindole-1,3-dione (1.20 g) was added at-78ºC to a solution of DAST (825 mg) in methylene chloride (20 ml) and the reaction solution was stirred at room temperature. 2 hours to the reaction solution was added DAST (500 mg) and the reaction solution was stirred at 50ºC for 3 hours. P is, after cooling the reaction solution to room temperature, to the reaction solution was added saturated sodium bicarbonate solution and the organic layer was separated. The organic layer was concentrated under reduced pressure after drying over anhydrous magnesium sulfate. The residue was purified column chromatography on silica gel (system heptane-ethyl acetate) and obtained 52 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): and 3.16 (DD, J=14,0, 6.4 Hz, 1H), or 3.28 (DD, J=14,0, 9.6 Hz, 1H), 4,67 (DDD, J=40,8, of 8.8, 4.8 Hz, 1H), 4,82-4,94 (m, 1H), 4,98 (dt, J=47,2, 8,8 Hz, 1H), 7,13-of 7.24 (m, 5H), to 7.67-of 7.70 (m, 2H), to 7.77-7,79 (m, 2H).

Synthesis of (R)-1-vermeil-2-phenethylamine

A mixture of (R)-2-(1-vermeil-2-phenylethyl)isoindole-1,3-dione (52 mg) and hydrazine hydrate is added (two drops) and ethanol (1 ml) was heated to boiling point under reflux for 2 hours. The reaction solution was allowed to cool to room temperature and the precipitated crystals were isolated by filtration and concentrated under reduced pressure. The residue was purified by LC-MS and got 6.0 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 2,61 (DD, J=13,2, and 8.4 Hz, 1H), 2,82 (DD, J=13,2, and 5.6 Hz, 1H), 3,23-3,39 (m, 1H), 4,20-4,47 (m, 2H), 7,20-7,34 (m, 5H).

ESI-MS; m/z 154 [M++H].

Synthesis of amide (R)-(E)-[(1R)-vermeil-2-phenylethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

In the same way as described in example 121, got 1,38 mg specified in the header connection on the basis of 3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (10.0 mg) and (R)-1-vermeil-2-phenylethyl the ina (6.0 mg).

ESI-MS; m/z 394 [M++H].1H-NMR (CDCl3) δ (ppm): to 2.29 (s, 3H), 2,92-of 3.06 (m, 2H), with 3.89 (s, 3H), 4,34-4,56 (m, 3H), of 5.85 (d, J=8,2 Hz, 1H), 6,38 (d, J=15.2 Hz, 1H), 6,92 (s, 1H), 7,11-7,17 (m, 2H), 7.23 percent-7,27 (m, 4H), 7,31-7,35 (m, 2H), 7,60 (d, J=15.2 Hz, 1H), 7,71 (s, 1H).

Example 140

Synthesis of amide (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(6-vinylpyridin-2-ylmethyl)acrylic acid

Formula 124

In the same way as described in example 121, got mentioned in the title compound (83 mg) from (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (71 mg) and (6-vinylpyridin-2-ylmethyl)amine (61 mg).

ESI-MS; m/z 425 [M++H].1H-NMR (CDCl3) δ (ppm): 2,30 (s, 3H), 3,90 (s, 3H), 4,79 (d, J=4,8 Hz, 2H), to 6.57 (d, J=15.6 Hz, 1H), 6,94 (s, 1H), 7,10-7,29 (m, 5H), 7,43-7,56 (m, 3H), of 7.64-7,80 (m, 4H), 8,01 (d, J=15.6 Hz, 1H), 8,03 (s, 1H).

Example 141

Synthesis of amide (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methyl-N-(quinoline-4-ylmethyl)acrylic acid

Formula 125

In the same way as described in example 121, got mentioned in the title compound (18 mg) from (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (71 mg) and N-(medicinalis-4-yl)methylamine (57 mg).

ESI-MS; m/z 413 [M++H].1H-NMR (CDCl3) δ (ppm): 2.26 and (C, 0,9H), 2,30 (s, 2,1H), 3,17 (s, 2,1H), 3,24 (s, 0,9H), of 3.75 (s, 0,9H), 3,91 (s, 2,1H), 5,20 (s, 0,6H), of 5.24 (s, 1,4H), 6,60-7,29 (m, 6H), to 7.59-7,83 (m, 4H), 8,08-8,25 (m, 2H), 8,88-to 8.94 (m, 1H).

Example 1421 and Example 142-2

Synthesis of amide (E)-N-[(1R,2S) and (1S,2R)-(2-Florinda-1-yl)]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methylacrylate acid

Formula 126

Synthesis of methylamine(1R*,2S*)-(2-Florinda-1-yl)

To a solution in THF (1.0 ml) 2-Florinda-1-it (100 mg)synthesized in accordance with the method described in Tetrahedron Letters, vol.37, No. 20, p. 3591, 1996, was added with stirring under ice cooling a solution of 2M methylamine in THF (of 0.67 ml), acetic acid (400 mg) and triacetoxyborohydride sodium (282 mg) and after adding the reaction solution was stirred at room temperature. After 5 hours the reaction solution was added a solution of 2M methylamine in THF (of 0.67 ml) and the reaction solution was stirred over night. The organic layer was diluted with a saturated solution of sodium bicarbonate and ethyl acetate and separated. After drying the organic layer over anhydrous magnesium sulfate the organic layer was washed with a saturated solution of sodium chloride and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:methanol=20:1) and has been specified in the title compound (57 mg).

ESI-MS; m/z 166 [M++H].1H-NMR (CDCl3) δ (ppm): to 2.67 (s, 3H), to 3.09 (DDD, J=37,6, 17,2, and 4.4 Hz, 1H), up 3.22 (DD, J=23,2, and 17.2 Hz, 1H), 4,12 (DD, J=23,2, 4.0 Hz, 1H), 5,48 (dt, J=54,0, 4.0 Hz, 1H), 7.23 percent-7,27 (m, 3H), 7,1 was 7.45 (m, 1H).

Synthesis of (E)-N-[(1R*,2S*)-(2-Florinda-1-yl)]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methylacrylamide

In the same way as described in example 121, got mentioned in the title compound (81 mg) from (E)-3-(4-1H-imidazol-1-yl-3-methoxyphenyl)acrylic acid (74 mg) and (1R*,2S*)(2-Florinda-1-yl)methylamine (57 mg).

ESI-MS; m/z 406 [M++H],1H-NMR (CDCl3) δ (ppm): 2,31 (s, 3H), 3,10 (s, 3H), 3,18 of 3.28 (m, 2H), 3,92 (s, 3H), 5,46-5,63 (m, 1H), 6,29 (DD, J=27,2, 4.8 Hz, 1H), 6,95 (s, 1H),? 7.04 baby mortality (d, J=15.2 Hz, 1H), 7.18 in-7,24 (m, 2H), 7,25-7,38 (m, 5H) of 7.75 (s, 1H), 7,81 (d, J=15.2 Hz, 1H).

Synthesis of amide (E)-N-[(1R,2S) and (1S,2R)-(2-Florinda-1-yl]3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methylacrylate acid

Racemic compound amide N-[(1R*,2S*)-(2-Florinda-1-yl))-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methylacrylate acid (80 mg) were separated using a CHIRALCEL OD from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm : mobile phase; ethanol). Got mentioned in the title optically active substance with a retention time of 17 minutes (example 142-1: 35,8 mg; 99% of ei) and indicated in the title optically active substance with a retention time of 22 minutes (example 142-2: 30.9 mg; 99% of ei).

Example 143

Synthesis of amide (E)-N-[(1R*,2S*)-(2-Florinda-1-yl)]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

Formula 127

In the same way as described in example 121, received the specified reception in the e compound (6.2 mg) from (E)-3-(4-methyl-1H-imidazol-1-yl-3-methoxyphenyl)acrylic acid (24 mg) and (1R*,2S*)-(2-Florinda-1-yl)amine (17 mg).

ESI-MS; m/z 392 [M++H],1H-NMR (CDCl3) δ (ppm): 2,31 (s, 3H), 3,14-3,29 (m, 2H), 3,91 (s, 3H), 5,43 (dt, J=53,6, 4.0 Hz, 1H), 5,80 (DDD, J=25,6, and 9.2, 4.0 Hz, 1H), 6,21 (d, J=9,2 Hz, 1H), is 6.54 (d, J=15.6 Hz, 1H), 6,95 (s, 1H), 7.18 in-7,34 (m, 7H), 7,74 (s, 1H), of 7.75 (d, J=15.6 Hz, 1H).

Example 144

Synthesis of amide (E)-N-[(1R*,2S*)-(2-Florinda-1-yl)]-N-(4-methoxybenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

Formula 128

In the same way as described in example 121, got mentioned in the title compound (18.2 mg) from (E)-3-(4-methyl-1H-imidazol-1-yl-3-methoxyphenyl)acrylic acid (24 mg) and (1R*,2S*)-(2-Florinda-1-yl)-(4-methoxybenzyl)amine (15 mg).

ESI-MS; m/z 512 [M++H],1H-NMR (CDCl3) δ (ppm): 2,28 (s, 3H), 3,24 (d, J=28.4 Hz, 2H, in), 3.75 (s, 3H), 3,79 (s, 3H), 4,53 (d, J=18,0 Hz, 1H), and 4.68 (d, J=18,0 Hz, 1H), 5,59 (d, J=50.0 Hz, 1H), 6,40 (DD, J=25,6, 4.8 Hz, 1H), to 6.67 (d, J=15.6 Hz, 1H), PC 6.82 (s, 1H), 6.87 in-of 6.96 (m, 4H), 7,10-7,34 (m, 7H) to 7.67 (s, 1H), 7,73 (d, J=15.6 Hz, 1H).

Example 145-1 and Example 145-2

Synthesis of amide (E)-N-[(1R,2S) and (1S,2R)-(1-Florinda-2-yl)]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methylacrylate acid

Formula 129

In the same way as described in example 121, got mentioned in the title compound (228 mg) from (E)-3-(4-methyl-1H-imidazol-1-yl-3-methoxyphenyl)acrylic acid (190 mg) and (1R*,2S*)-(1-Florinda-2-yl)methylamine (146 mg).

ESI-MS; m/z 406 [M++H],1H-NMR (CDCl3) δ (ppm): 2,30 (s, H), 3,07-3,14 (m, 1H), 3.27 to (s, 3H), 3,36-of 3.46 (m, 1H), 3,91 (s, 3H), 5,52 (d, J=31,2 Hz, 1H), 5,90 (d, J=57.6 Hz, 1H), 6,94 (s, 1H), 6,98 (d, J=15.6 Hz, 1H), 7,17 (s, 1H), 7,19-7,46 (m, 5H) 7,50-of 7.55 (m, 1H), 7,73 (s, 1H), 7,74 (d, J=15.6 Hz, 1H).

Racemic compound amide N-[(1R*,2S*)-(1-Florinda-2-yl)]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methylacrylate acid (270 mg)obtained in example 145, were separated using a CHIRALPAKTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm : mobile phase; ethanol). Got mentioned in the title optically active substance with a retention time of 28 minutes (example 145-1: 105 mg; 99% of ei) and indicated in the title optically active substance with a retention time of 37 minutes (example 145-2: 124 mg; 86% of ei).

Example 146

Synthesis of amide (E)-N-[(1R*,2S*)-(1-Florinda-2-yl)]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

Formula 130

Specified in the header connection (9,05 mg) was obtained in the same manner as described in example 121 from (E)-3-(4-methyl-1H-imidazol-1-yl-3-methoxyphenyl)acrylic acid (14.3 mg) and (1R*,2S*)-(1-Florinda-2-yl)amine (10.1 mg).

ESI-MS; m/z 392 [M++H],1H-NMR (CDCl3) δ: 2,30 (s, 3H), 2,96-of 2.30 (m, 1H), 3,43 (DD, J=15,2, and 8.4 Hz, 1H), 3,91 (s, 3H), 4,90-free 5.01 (m, 1H), 5,77 (DD, J=58,4, and 4.4 Hz, 1H), 6,28 (d, J=8,8 Hz, 1H), 6,51 (d, J=15.6 Hz, 1H), 6,94 (s, 1H), 7,17-7,34 (m, 5H), 7,41-7,44 (m, 1H), 7,52-rate of 7.54 (m, 1H), 7,69 (d, J=15.6 Hz, 1H), 7,74 (s, 1H).

Example 147

Synthesis of amide (E)-N-[(2S)-(2-fluoro-2-phenylethyl)]-3-[3-methoxy-4-(4-methyl-1H-shall midazol-1-yl)phenyl]acrylic acid

Formula 131

To a solution in methylene chloride (1.0 ml) amide N-((2R)-(2-hydroxy-2-phenylethyl))-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (to 36.5 mg)obtained in example 195, was added at-78ºC DAST (23 mg) and the reaction solution was stirred for two hours at room temperature. After 2 hours the reaction solution was diluted with saturated sodium bicarbonate solution and chloroform and the organic layer was separated. After drying over anhydrous magnesium sulfate the organic layer was concentrated under reduced pressure. The residue was purified column chromatography (Carrier: ChromatorexTMNH, eluting solvent system heptane-ethyl acetate) and got to 5.7 mg specified in the connection header.

ESI-MS; m/z 380 [M++H],1H-NMR (CDCl3) δ (ppm): 2,30 (s, 3H), 3,50-3,61 (m, 1H), 3,90 (s, 3H), 4.04 the-4,19 (m, 1H), 5,63 (DDD, J=48,8, of 8.8 and 2.8 Hz, 1H), 6,12 (Sirs, 1H), 6,45 (d, J=15.6 Hz, 1H), 6,94 (s, 1H), 7,14-7,20 (m, 2H), 7,25-7,27 (m, 1H), was 7.36-7,46 (m, 5H), the 7.65 (d, J=15.6 Hz, 1H), 7,73 (s, 1H).

Example 148-1 and the Example 148-2

Synthesis of amide (E)-N-[(2R) and (2S)-fluoro-2-phenylethyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methylacrylate acid

Formula 132

In the same way as described in example 147, received 100 mg specified in the header of racemic compounds on the basis of the amide N-(2-hydroxy-2-phenylethyl)-3-(3-methoxy-4-(4-methyl-1H-they are the azole-1-yl)phenyl)-N-methylacrylate acid (310 mg), obtained in example 202.

ESI-MS; m/z 394 [M++H],1H-NMR (CDCl3) δ (ppm): 2,31 (s, 3H), 3,11 (s, 0,9H), of 3.32 (s, 2,1H), 3,38-of 3.48 (m, 1H), 3,90 (s, 3H), 4,24 (DDD, J=34,8, 14.4V, 2.4 Hz, 1H), of 5.81 (DDD, J=49,2, and 9.2, 2.4 Hz, 1H), of 6.68 (d, J=15.2 Hz, 0,3H), 6.90 to-to 6.95 (m, 1,7H), 7,05-of 7.48 (m, 8H), 7,58 (d, J=15.2 Hz, 0,3H), 7,69-7,74 (m, 1,7H).

The racemic amide compound (E)-N-(2-fluoro-2-phenylethyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-methylacrylate acid (100 mg), obtained above, were separated using a CHIRALPAKTMAD-H from the company Daicel Chemical Industries, Ltd. (cm: 2 cm×25 mobile phase; ethanol). Got mentioned in the title optically active substance with a retention time of 15 minutes (example 148-1: 49 mg; 99% of ei) and indicated in the title optically active substance with a retention time of 22 minutes (example 148-2: 35 mg; 99% of ei).

Example 149

Synthesis of amide N-[(1R, 2R)-(2-Florinda-1-yl)]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

Formula 133

In the same way as described in example 147, got 3,20 mg specified in the header connection on the basis of the amide N-[(1R,2S)-(2-hydroxyine-1-yl)]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (50 mg)obtained in example 198.

ESI-MS; m/z 392 [M++H].1H-NMR (CDCl3) δ (ppm): 2,30 (s, 3H), 3,13-3,24 (m, 1H), 3,36-to 3.49 (m, 1H), 3,88 (s, 3H), 5,28 (d, J=48,0 Hz, 1H), 5,65 (DDD, J=17,2, 7,2, 2.8 Hz, 1H), 5,77 (d, J=7.2 Hz, 1H), 6,41 (d, J=15.2 Hz, 1H), 6,93 (s, 1H), 7,12-7,20 (m, 2H), 7.24 to 7,38 (m, 5H), of 7.70 (d, J=15.2 in the C, 1H), 7,74 (s, 1H).

Compounds shown in table 7, were synthesized as described in example 121.

Structural formulas and physical-chemical properties are presented in table 7, respectively.

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Table 7-5

Table 7-6

Table 7-7

Table 7-8

Table 7-9

Table 7-10

Table 7-11

Table 7-12

Table 7-13

Table is CA 7-14

Table 7-15

Table 7-16

Table 7-17

Table 7-18

Example 320

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-nitrophenyl]-N-(indan-1-yl)acrylamide

Formula 134

Synthesis of 1-(4-bromo-2-nitrophenyl)-1H-imidazole

Potassium carbonate (1.80 g) and imidazole (667 mg) were successively added to a solution of 4-bromo-1-fluoro-2-nitrobenzene (1.0 ml) in DMF (10 ml) and the reaction solution was stirred at 80ºC for 3 hours and 30 minutes. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and 1.04 g of the crude prosteradlo compound was obtained by condensing under reduced pressure. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,15 (d, J=2.0 Hz, 1H), 7,86 (DD, J=2.0 a, and 8.4 Hz, 1H), 7.62mm (s, 1H), was 7.36 (d, J=8,4 Hz, 1H), 7,22-of 7.23 (m, 1H), 7,05 (m, 1H).

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-nitrophenyl]-N-(indan-1-yl)and is Alameda

Got to 21.0 mg specified in the header connection on the basis of 1-(4-bromo-2-nitrophenyl)-1H-imidazole (40,0 mg) and N-(indan-1-yl)acrylamide (42,0 mg)obtained in example 9. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,11 (d, J=2.0 Hz, 1H), 7,79 (DD, J=2,0, 8.0 Hz, 1H), 7,73 (d, J=16 Hz, 1H), 7,63 (s, 1H), 7,47 (d, J=8.0 Hz, 1H), 7,34 (d, J=7.2 Hz, 1H), 7,22-7,29 (m, 4H), 7,07 (s, 1H), 6,56 (d, J=16 Hz, 1H), 6,13 (sird, J=8.0 Hz, 1H), 5,64 (kV, J=8.0 Hz, 1H), 3.04 from (DDD, J=4,4, 8,8, 16 Hz, 1H), 2,93 (TD, J=8.0 a, 16 Hz, 1H), 2,68 (DTD, J=4,4, 8,0, 12 Hz, 1H), 1,87-of 1.36 (m, 1H).

Example 321

Synthesis of (E)-3-[3-cyano-4-(1H-imidazol-1-yl)phenyl]-N-(indan-1-yl)acrylamide

Formula 135

Synthesis of 5-bromo-2-(1H-imidazolyl)benzonitrile

Potassium carbonate (1.80 g) and imidazole (667 mg) were successively added to a solution of 5-bromo-2-perbenzoate (1.78 g) in DMF (10 ml) and the reaction solution was stirred at 80ºC for 3 hours and 30 minutes. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and received 1.07 g of the crude prosteradlo compounds by condensation under reduced pressure. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 7.95 (d, J=2.4 Hz, 1H), 7,84-7,88 (m, 2H), 7,34 and 7.36 (m, 2H), 7,29 (Sirs, 1H).

Synthesis of (E)-3-[3-cyano-4-(1H-shall midazol-1-yl)phenyl)-N-indan-1-alacrimia

In the same way as described in example 9, was received 5,20 mg specified in the header connection on the basis of 5-bromo-2-(1H-imidazol-1-yl)benzonitrile (38,0 mg) and N-indan-1-alacrimia (42,0 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to $ 7.91 (d, J=1.6 Hz, 1H), a 7.85 (s, 1H), 7,81 (DD, J=2.0 a, and 8.4 Hz, 1H), 7,66 (d, J=16 Hz, 1H), 7,45 (d, J=8,4 Hz, 1H), was 7.36 (s, 1H), 7,33 (d, J=4,8 Hz, 1H), 7,20-7,28 (m, 4H), is 6.54 (d, J=16 Hz, 1H), 6,33 (Sirs, 1H), 5,63 (kV, J=8,4 Hz, 1H), to 3.02 (DDD, J=4,8, 8,4, 16 Hz, 1H), 2,88-2,99 (m, 1H), 2,62-a 2.71 (m, 1H), 1,86 is 1.96 (m, 1H).

Example 322

Synthesis of (E)-3-[3-amino-4-(1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 136

Synthesis of 5-bromo-2-(1H-imidazol-1-yl)phenylamine

To a solution of 1-(4-bromo-2-nitro phenyl)-1H-imidazole (500 mg) in methylene chloride (10 ml) and methanol (10 ml) at 0ºC were alternately added to the uranyl Nickel (22,0 mg) and borohydride sodium (177 mg) and the reaction solution was stirred for 20 minutes. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH; eluting solvent: hexane:ethyl acetate=1:1→ethyl acetate) and received 431 mg specified in the header joint is. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 7.61 (s, 1H), 7,25 (s, 1H), to 7.09 (s, 1H), 6,99-6,70 (m, 1H), 6,97 (d, J=8,4 Hz, 1H), 6,94 (m, 1H), 3,78 (Sirs, 2H).

Synthesis of (E)-3-[3-amino-4-(1H-imidazol-1-yl)phenyl)-N-indan-1-alacrimia

In the same way as described in example 9, was received 249 mg specified in the header connection on the basis of 5-bromo-2-(1H-imidazol-1-yl)phenylamine (200 mg) and N-indan-1-alacrimia (236 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 7.64 (s, 1H), 7.62mm (d, J=16 Hz, 1H), 7,34 (d, J=6,8 Hz, 1H), 7,22-7,29 (m, 4H), 7,13 (s, 1H), 7,11 (d, J=7,6 Hz, 1H), 6,94-6,98 (m, 2H), to 6.39 (d, J=16 Hz, 1H), to 5.93 (d, J=8.0 Hz, 1H), 5,64 (kV, J=8.0 Hz, 1H), of 3.77 (Sirs, 2H), 3,03 (DDD, J=4,4, 8,8, 16 Hz, 1H), 2,93 (TD, J=8.0 a, 16 Hz, 1H), 2,67 (DTD, J=4,4, 8,0, 13 Hz, 1H), 1.85 to was 1.94 (m, 1H).

Example 323

Synthesis of (Z)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]-N-indan-1-alacrimia

Formula 137

To a solution in THF (7.0 ml) of 4-(1H-imidazol-1-yl)-3-methoxybenzaldehyde (300 mg)obtained in example 328, was added at-78ºC 18-crown-6 (2.0 g) and bis(trimethylsilyl)amide and potassium (0,5M solution in toluene, 4,4 ml) and ester (bis-(2,2,2,-triptoreline)phosphoryl)ethyl acetate (470 μl) and the reaction solution was stirred over night at room temperature. To the reaction solution was added a saturated solution of ammonium chloride and ethyl acetate and the organic layer was separated. After washing polucen the th organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH and an eluting solvent: hexane:ethyl acetate=1:1→ethyl acetate) and received 306 mg of the product of ester in the form of a mixture of isomers (E:Z=1:5,5). To a solution of the obtained product of ester in THF (5.0 ml) was added 2n. the sodium hydroxide solution (5.0 ml) and the reaction solution was stirred at room temperature overnight. Impurities isomeric compounds were separated by cooling the reaction solution at 0ºC, adding to the reaction solution 2n. hydrochloric acid and filtering off the resulting precipitate using a funnel of Kiriyama. The obtained filtrate was concentrated under reduced pressure and received 253 mg of the crude carboxylic acid. To a solution in DMF (5.0 ml) of the obtained carboxylic acid were successively added TEA (507 μl), 1-aminoindan (133 ml) and PYBOP (812 mg) and the reaction solution was stirred at room temperature for 1 hour. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: hexane:this is the acetate=1:1→ethyl acetate) and received 9.0 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,81 (s, 1H), 7,41 (s, 1H), 7,21-7,29 (m, 5H), 7,13-to 7.18 (m, 3H), 6,79 (d, J=12 Hz, 1H), 6,09 (d, J=12 Hz, 1H), of 5.83 (sird, J=7,6 Hz, 1H), 5,52 (kV, J=7,6 Hz, 1H), a 3.87 (s, 3H), 2,82-2,96 (m, 2H,), 2,59 (DTD, J=4,8, 7,6, 12 Hz, 1H), 1.70 to to 1.79 (m, 1H).

Example 324

Synthesis of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 138

Synthesis of 3-fluoro-4-(1H-imidazol-1-yl)benzaldehyde

Potassium carbonate (1,71 g) and imidazole (847 mg) was added to a solution of 3,4-diferentialglea (2.0 g) in DMF (20 ml). The reaction solution was stirred at 100ºC during the night, to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: hexane:ethyl acetate=1:1→ethyl acetate) and received 1,11 g specified in the connection header. The physical properties of this compound are as follows.

The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm)rating: 10.0 (s, 1H), of 7.96 (s, 1H), 7,82 (d, J=7.2 Hz, 2H), to 7.61 (t, J=7.2 Hz, 1H), was 7.36 (s, 1H), 7,27 (s, 1H).

Synthesis of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl)acrylic acid

In the same way as described in example 111, on which Uchali 1.66 g is specified in the header connection on the basis of 3-fluoro-4-(1H-imidazol-1-yl)benzaldehyde (1.40 g) and methyl ester dimethyltitanocene acid (1,40 ml). The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 8,10 (s, 1H), to 7.93 (d, J=13 Hz, 1H), 7,70-7,71 (m, 2H), 7,63 (s, 1H), 7.62mm (d, J=16 Hz, 1H), 7,15 (s, 1H), 6,69 (d, J=16 Hz, 1H).

Synthesis of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl)-N-(indan-1-yl)acrylamide

To a solution in DMF (4.0 ml) of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]acrylic acid (100 mg) were successively added TEA (167 μl), 1-aminoindan (83,0 ml) and PYBOP (448 mg) and the reaction solution was stirred at room temperature overnight. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: hexane:ethyl acetate=1:1→ethyl acetate) and received 95,0 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 7.82 (s, 1H), to 7.64 (d, J=16 Hz, 1H), 7,40 (s, 1H), 7,37-7,38 (m, 2H), 7,32 (d, J=7.2 Hz, 1H), 7,20-7,28 (m, 5H), to 6.43 (d, J=16 Hz, 1H), 6,02-6,14 (width, 1H), 5,62 (kV, J=7.2 Hz, 1H), to 3.02 (DDD, J=4,4, 8,8, 16 Hz, 1H), 2.91 in (TD, J=8.0 a, 16 Hz, 1H), 2,62-2,70 (m, 1H), 1.85 to was 1.94 (m, 1H)

Example 325

Synthesis of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl)-N-methylacrylamide

Formula 139

In the same way as described in example 324, got 17,5 mg specified in the header connection on the basis of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]acrylic acid (60,0 mg) and methylamine (650 µl). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,86 (s, 1H), to 7.61 (d, J=16 Hz, 1H), 7,42 (d, J=8,4 Hz, 1H), was 7.36-7,42 (m, 2H), 7.23 percent-7,29 (m, 2H), 6,40 (d, J=16 Hz, 1H), 5,66 (Sirs, 1H), 2,97 (d, J=4,8 Hz, 3H).

Example 326

Synthesis of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl)-N-phenylacetamide

Formula 140

In the same way as described in example 324, received 32 mg specified in the header connection on the basis of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]acrylic acid (50.0 mg) and aniline (29,0 µl). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,94 (Sirs, 1H), 7,88 (s, 1H), 7,72 (d, J=16 Hz, 1H), to 7.67 (d, J=7,6 Hz, 1H), 7,41 was 7.45 (m, 3H), 7,37 (t, J=8.0 Hz, 1H), 7,30 (d, J=1.2 Hz, 1H), 7.24 to 7,27 (m, 3H), 7,16 (t, J=8.0 Hz, 1H), 6,64 (d, J=16 Hz, 1H).

Example 327

Synthesis of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl)-N-(4-methoxybenzyl)acrylamide

Formula 141

In the same way as described in example 324, got 55,0 mg specified in the header connection on the basis of 3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]acrylic acid (50.0 mg) and 4-methoxybenzylamine (42,0 µl). The physical properties of this compound are as follows.

1H-NMR (CDCl3) is (ppm): 7,86 (s, 1H), 7,63 (d, J=16 Hz, 1H), 7,35-7,42 (m, 3H), 7.23 percent-7,28 (m, 4H), to 6.88 (TD, J=2.0 a, 8,8 Hz, 2H), to 6.43 (d, J=16 Hz, 1H), 6,05 (Sirs, 1H), to 4.52 (d, J=6.0 Hz, 2H), 3,80 (s, 3H).

Example 328

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]-N-indan-1-alacrimia

Formula 142

Synthesis of 4-(1H-imidazol-1-yl)-3-methoxybenzaldehyde

Potassium carbonate (2.0 g) and imidazole (662 mg) was added to a solution of 4-fluoro-3-methoxybenzaldehyde (1.50 g) in DMF (20 ml). The reaction solution was stirred at 80ºC overnight, to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: hexane:ethyl acetate=3:1→ethyl acetate→ethyl acetate:methanol=10:1) and received 960 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm)rating: 10.0 (s, 1H), 7,92 (s, 1H), 7,56-of 7.60 (m, 2H), of 7.48 (d, J=7,6 Hz, 1H), 7,30 (s, 1H), 7,21 (s, 1H), 3,98 (s, 3H).

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid

In the same way as described in example 111 was obtained 11.9 g is specified in the header connection on the basis of 4-(1H-imidazol-1-yl)-3-methoxybenzaldehyde (13,2 g). The physical properties of this connection is the following.

1H-NMR (DMSO-d6) δ (ppm): of 7.96 (t, J=1.2 Hz, 1H), 7,63 (d, J=16 Hz, 1H), to 7.59 (d, J=1.6 Hz, 1H), of 7.48 (t, J=1.2 Hz, 1H), 7,45 (d, J=8.0 Hz, 1H), 7,38 (DD, J=1.6 Hz, 8.0 Hz, 1H), 7,06 (t, J=1.2 Hz, 1H), of 6.68 (d, J=16 Hz, 1H), with 3.89 (s, 3H).

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]-N-indan-1-alacrimia

In the same way as described in example 111, received 142 mg specified in the header connection on the basis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid (100 mg) and 1-aminoindane (53,0 µl). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): a 7.85 (s, 1H), 7,69 (d, J=16 Hz, 1H), 7,35 (d, J=6,8 Hz, 1H), 7,16-7,29 (m, 8H), 6,44 (d, J=16 Hz, 1H), of 5.92 (d, J=8,4 Hz, 1H), 5,65 (kV, J=8,4 Hz, 1H), 3,88 (s, 3H), 3.04 from (DDD, J=4,0, 8,8, 16 Hz, 1H), 2.91 in-2,96 (m, 1H), 2,64-of 2.72 (m, 1H), 1,86-of 1.95 (m, 1H).

Example 329

Synthesis of (E)-N-{3-[1-(4-forfinal)-6-methylinden-1-yl]propyl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide, and (E)-N-{3-[1-(4-forfinal)-4-methylinden-1-yl]propyl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 143

Monohydrate p-toluensulfonate (95 mg) was added to a solution in toluene (10 ml) of 1-[4-(4-forfinal)-4-hydroxyether-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone (45 mg)obtained in example 350. Heating of the reaction solution by boiling under reflux was carried out for 3 hours. After completion of the reaction to the reaction solution was added to the control, the reaction solution was extracted with ethyl acetate and the organic layer was washed with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride. The organic layer was separated, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: ethanol:ethyl acetate=1:10) and received 10 mg (19%) specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1.50 in (m, 2H), 2,04 (m, 1H), 2,13 (m, 1H), 2,24 (m, 1H), a 2.36 (m, 1H), 2,30 (s, 3H), of 2.35 (s, 3H), and 2.83 (m, 2H), 3,36 (m, 2H), a 3.87 (s, 3H), 5,79 (Sirs, 1H), 6,36 (d, J=16.0 Hz, 1H), 6,92 (m, 1H), 6,925 (m, 1H), 6,93 (m, 1H),? 7.04 baby mortality (d, J=8.0 Hz, 1H), 7,11 (Sirs, 1H), 7,15 (d, J=8.0 Hz, 1H), 7,16 (d, J=8.0 Hz, 1H), 7,20 (m, 2H), 7.23 percent (d, J=8.0 Hz, 1H), to 7.59 (d, J=16.0 Hz, 1H), 7,71 (s, 1H).

ESI-MS; m/z 524 [M++H],1H-NMR (CDCl3) δ: 1.50 in (m, 2H), 2,04 (m, 1H), 2,13 (m, 1H), 2,24 (m, 1H), a 2.36 (m, 1H), and 2.26 (s, 3H), of 2.30 (s, 3H), 2,78 (m, 1H), 2,82 (m, 1H), 3,36 (m, 2H), a 3.87 (s, 3H), 5,79 (Sirs, 1H), 6.35mm (d, J=16.0 Hz, 1H), 6,925 (m, 1H), 6,93 (m, 2H), 6,98 (m, 1H), 7,03 (d, J=8.0 Hz, 1H), 7,11 (Sirs, 1H), 7,15 (d, J=8.0 Hz, 1H), 7,16 (d, J=8.0 Hz, 1H), 7,20 (m, 2H), 7.23 percent (d, J=8.0 Hz, 1H), to 7.59 (d, J=16.0 Hz, 1H), 7,71 (s, 1H).

Example 330

Synthesis of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl)-N-indan-1-yl-N-methylacrylamide

Formula 144

To a solution in DMF (1.0 ml) of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia (30.0 mg), n is obtained in example 324, was added at 0ºC sodium hydride (10.0 mg) and the reaction solution was allowed to warm to room temperature. To the reaction solution was added itmean (54,0 mm), the reaction solution was stirred at room temperature for 3 hours, to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: Chromatorex NH, eluting solvent of heptane-ethyl acetate=1:1) and received 8.5 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,86 (s, 0,5H), the 7.85 (s, 0,5H), 7,74 (d, J=16 Hz, 0,5H), to 7.68 (d, J=16 Hz, 0,5H), 7,38-7,47 (m, 3H), 7,13-7,28 (m, 6H), 7,06 (d, J=16 Hz, 0,5H), to 6.95 (d, J=16 Hz, 0.5 Hz), 6,41 (t, J=8.0 Hz, 0,5H), 5,67 (t, J=8.0 Hz, 0,5H), 3.00 and-of 3.12 (m, 1H), 2,94 (TD, J=8,4 Hz, 16 Hz, 1H), 2,80 (s, 1,5H), is 2.88 (s, 1,5H), 2,43 is 2.55 (m, 1H), 2,10-of 2.20 (m, 0,5H), 1,89-2,00 (m, 0,5H).

Example 331

Synthesis of (E)-N-((1R)-formyl-2-phenylethyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 145

Dimethyl sulfoxide (136 ml) was added at-78ºC to a solution of oxalicacid (100 μl) in methylene chloride (3 ml) and the reaction solution was stirred for 15 minutes. Then, to this reaction solution, EXT is ulali solution in methylene chloride (2.0 ml) (E)-N-[(1R)-1-hydroxymethyl-2-phenylethyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylamide (150 mg), obtained in example 124, and the reaction solution was stirred for 15 minutes. Then, to this reaction solution was added TEA (534 μl) for heating the reaction solution to 0ºC and the solution was stirred for 30 minutes. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:ethanol=10:1) and received 62,0 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 9,72 (s, 1H), 7,73 (s, 1H), to 7.64 (d, J=16 Hz, 1H), 7,25-7,34 (m, 4H), 7,16-7,20 (m, 3H), 7,14 (s, 1H), 6,93 (s, 1H), 6,45 (d, J=16 Hz, 1H), 6,33 (Sirs, 1H), 4.92 in (DD, J=5,6, 7.2 Hz, 1H), 3,89 (, 3H), of 3.32 (DD, J=5,6, 14 Hz, 1H), 3,25 (DD, J=7,2, 14 Hz, 1H), 2,30 (s, 3H).

Example 332

Synthesis of (E)-3-[3-methoxy-4-(4-(1H-Mei-1-yl)phenyl]-N-((1R)-morpholine-4-ylmethyl-2-phenylethyl)acrylamide

Formula 146

To a solution in methylene chloride (1.0 ml) of (E)-N-((1R)-formyl-2-phenylethyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (39,0 mg)obtained in example 331, were alternately added morpholine (13,0 μl), acetic acid (1.0 ml) and three-acetoxyvalerenic sodium (64,0 mg). After AC is shivani reaction solution at room temperature over night to the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent: ethyl acetate→ethyl acetate:ethanol=10:1) and received 13.9 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 7.70 (s, 1H), to 7.59 (d, J=16 Hz, 1H), 7,14-to 7.32 (m, 7H), 7,12 (s, 1H), 6,92 (s, 1H), 6,38 (d, J=16 Hz, 1H), 5,88 (d, J=7.2 Hz, 1H), 4,39-4,47 (m, 1H), 3,88 (s, 3H), 3,64-3,71 (m, 4H), 3,03 (DD, J=4,8, 14 Hz, 1H), 2,97 (DD, J=6,4, 14 Hz, 1H), 2,48 is 2.55 (m, 2H), 2,31-to 2.42 (m, 4H), of 2.30 (s, 3H).

Example 333

Synthesis of (E)-N-[(1R)-1-(CIS-2,6-dimethylmorpholine-4-ylmethyl)-2-phenylethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 147

In the same way as described in example 332, got 5.2 mg specified in the header connection on the basis of (E)-N-((1R)-formyl-2-phenylethyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (25.0 mg) and CIS-2 and 6-dimethylmorpholine (23,7 μl)obtained in example 331. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,72 (d, J=1.2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,29-7,33 (m, 2H), 7,17-7,26 (m, 5H), 7,13 (d, J=1.2 Hz, 1H), 6,93 (t, J=1.2 Hz, 1H), 6,38 (d, J=16 Hz, 1H), of 5.82 (d, J=6,8 Hz, 1H), to 4.38-4,46 (m, 1H), with 3.89 (s, 3H), to 3.58 at 3.69 (m, 2H), 3,05 (DD, J=4,8, 14 Hz, 1H), 2,97 (DD, J=6,4, 14 Hz, 1H), 2,67-a 2.71(m, 2H), 2,39 (DD, J=9,2, 13 Hz, 1H), 2,28 is 2.33 (m, 1H), 2,30 (s, 3H), of 1.85 (t, J=12 Hz, 1H), 1,67 (t, J=12 Hz, 1H), 1,13-of 1.16 (m, 6H).

Example 334

Synthesis of (E)-N-(1-benzyl-2-hydroxypropyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 148

To a solution in THF (3.0 ml) (E)-N-((1R)1-formyl-2-phenylethyl)-3-[(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (100 mg)obtained in example 331 was added at-78ºC chloride Metalmania (3M solution in THF, 0.17 ml). After heating the reaction solution to room temperature it was stirred for 3 hours and 30 minutes and the reaction solution was added chloride Metalmania (3M solution in THF, 0.51 ml). The reaction solution was stirred at room temperature overnight, to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:ethanol=10:1) and received 33,0 mg specified in the title compounds as a mixture of isomers. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 7.70 (m, 1H), to 7.59 (d, J=16H, 0,5H), 7,53 (d, J=16 Hz, 0,5H), 7,06-7,35 (m, 8H), 6,92-6,93 (m, 1H), 6.42 per (d, J=16 Hz, 0,5H), 6,32 (d, J=16 Hz, 0,5H), of 5.92-6,0 (width, 1H), 4,30-4,39 (m, 0,5H), 4,19-to 4.28 (m, 0,5H), 4,00-4,10 (m, 0,5H), 3,90-3,99 (m, 0,5H), 3,86 (s, 1,5H), 3,83 (s, 1,5H), 2,92-to 3.02 (m, 2H), to 2.29 (s, 3H), 1,10-1,30 (m, 3H).

Example 335

Synthesis of (E)-N-(1-benzyl-2-oxopropyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 149

To a solution in methylene chloride (2.0 ml) (E)-N-(1-benzyl-2-hydroxypropyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (29.0 mg) was added to the reagent des-Martin (60,7 mg). After stirring the reaction solution at room temperature for 4 hours and 30 minutes to the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:ethanol=10:1) and got to 15.4 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,73 (s, 1H), 7,60 (d, J=16 Hz, 1H), 7,27-7,33 (m, 3H), 7,25 (s, 1H), 7,14-to 7.18 (m, 4H), 6,93 (s, 1H), 6.42 per (d, J=16 Hz, 1H), 6,34 (d, J=6,8 Hz, 1H), 5,03 (TD, J=5,2, 6,8 Hz, 1H), with 3.89 (s, 3H)at 3.25 (DD, J=6,8, 14 Hz, 1H), and 3.16 (DD, J=5,2, 14 Hz, 1H), 2,30 (s, 3H), of 2.23 (s, 3H).

Example 336

Synthesis of (E)-N-(1-benzyl-2-hydroxy-2-methylpropyl)-3-[3-methoxy-4-(4-methyl-1H-shall midazol-1-yl)phenyl]acrylamide

Formula 150

To a solution in THF (1.0 ml) of (E)-N-(1-benzyl-2-oxopropyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (12.0 mg) was added at-78ºC chloride Metalmania (3M solution in THF, 198 μl), the reaction solution was allowed to warm to room temperature and stirred for 1 hour. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:ethanol=10:1) and got to 6.8 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 7.70 (s, 1H), of 7.48 (d, J=16 Hz, 1H), 7.18 in-7,30 (m, 6H), 7,10 (d, J=9.6 Hz, 1H), 7,07 (s, 1H), 6,92 (s, 1H), 6,29 (d, J=16 Hz, 1H), of 5.84 (d, J=8,8 Hz, 1H), 4,16-to 4.23 (m, 1H), 3,86 (s, 3H), 3,20 (DD, J=9,6, 14 Hz, 1H), 2,80 (DD, J=11, 14 Hz, 1H), to 2.29 (s, 3H), of 1.39 (s, 3H), of 1.34 (s, 3H).

Example 337

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1-(3-phenylpyrrolidine-1-yl)propenone

Formula 151

In the same way as described in example 121, received 65 mg (62%) specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic sour is s (70 mg) and 3-phenylpyrrolidine (40 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 388 [M++H],1H-NMR (DMSO-d6) δ: 1,99-2,22 (m, 1H), 2,28 (s, 1,5H), to 2.29 (s, 1,5H), 2,30 is 2.51 (m, 1H), 3,38-3,81 (m, 3H), 3,85 (s, 1,5H), a 3.87 (s, 1,5H), 3,88-4,20 (m, 2H), 6.73 x (d, J=15.6 Hz, 0,5H), 6,77 (d, J=15.6 Hz, 0,5H), 6,91 (Sirs, 0,5H), 6,93 (Sirs, 0,5H), 7,12-7,39 (m, 8H), 7.68 per-7,76 (m, 2H).

Example 338

Synthesis of (E)-1-{4-(1H-indol-2-yl)piperidine-1-yl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Formula 152

In the same way as described in example 121, received 47 mg (43%) specified in the header connection on the basis of (E)-3-[3-methoxy-4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (65 mg) and 2-piperidine-4-yl-1H-indole (50 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 441 [M++H],1H-NMR (DMSO-d6) δ (ppm): 1.70 to a 1.88 (m, 2H), 2,12-of 2.23 (m, 2H), 2,30 (s, 3H), 2,83-3,11 (m, 2H), 3.27 to of 3.43 (m, 1H), with 3.89 (s, 3H), 4,17-to 4.28 (m, 1H), 4,76-to 4.87 (m, 1H), 6,27 (s, 1H), 6,93 (Sirs, 1H), 6,94 (d, J=15.6 Hz, 1H), 7,05-7,28 (m, 5H), 7,33 (d, J=8.0 Hz, 1H), 7,55 (d, J=8.0 Hz, 1H), to 7.67 (d, J=15,6H, 1H), 7,74 (s, 1H), 8,25 (Sirs, 1H).

Example 339

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1-(4-feasibility-1-yl)propenone

Formula 153

In the same way as described in example 121, received 74 mg (91%) specified in the header connection on the basis of (E)-3-[3-methoxy-4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (50 mg), and hydrochloride of 4-deoxypyridoxine (42 mg). Coercion is their properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 1,70-2,10 (m, 4H), of 2.30 (s, 3H), 3,62-3,71 (m, 1H), 3,82-3,95 (m, 3H), 3,90 (s, 3H), 4,58 with 4.65 (m, 1H), 6,88-7,03 (m, 5H), 7,19 and 7.36 (m, 5H), 7,66 (d, J=15.2 Hz, 1H), 7,73 (s, 1H).

Example 340

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1-(6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)propenone

Formula 154

In the same way as described in example 121, received 112 mg (94%) specified in the header connection on the basis of (E)-3-[3-methoxy-4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (70 mg), 6-phenyl 1, 2, and 3 and 4 tetrahydropyrrolo [1,2-a] pyrazine (54 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,31 (s, 3H), 3,92 (s, 3H), 3.95 to 4,22 (m, 4H), 4,96-to 5.03 (m, 2H), 6,11 (d, J=3.2 Hz, 1H), 6,28 (d, J=3.2 Hz, 1H), 6,86-6,97 (m, 2H), 7,17 (Sirs, 1H), 7,21 was 7.45 (m, 7H), 7,73 (d, J=15.6 Hz, 1H), 7,74 (Sirs, 1H).

Example 341

Synthesis of (E)-3-[3-methoxy-4-methyl-1H-imidazol-1-yl)phenyl]-1-(1-fenilacetamidyo[3,2c]pyridine-5-yl)propenone

Formula 155

In the same way as described in example 121, received 46 mg (90%) specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (30 mg) and 1-fenilacetamidyo[3,2-c]pyridine (24 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 443 [M++H].1H-NMR (CDCl3) δ (ppm): 1,50 is 1.91 (m, 1H), 1,91 was 2.25 (m, 3H), of 2.30 (s, 3H), 2,49-of 2.64 (m, 1H), 3,01-3,12 (who, 0,5H), 3,24-3,55 (m, 3H), 3,65-of 3.77 (m, 0,5H), to 3.89 (s, 3H), 3,90-4,00 (m, 2H), 4,23 was 4.42 (m, 1H), 6,54-6,63 (m, 2H), of 6.68 (t, J=7.2 Hz, 1H), 6.87 in (d, J=15.2 Hz, 1H), 6,92 (Sirs, 1H), 7,12 (s, 1H), 7,17-7,28 (m, 4H), to 7.67 (d, J=15.2 Hz, 1H), 7,72 (s, 1H).

Example 342

Synthesis of (E)-1-(4-indol-1-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylpropane

Formula 156

In the same way as described in example 121, received 86 mg (82%) specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (50 mg) and 1-piperidine-4-yl-1H-indole (46 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 441 [M++H].1H-NMR (CDCl3) δ (ppm): 1.93 and is 2.10 (m, 2H), 2,19-to 2.29 (m,2H), 2,30 (s, 3H), 2,83-of 2.97 (m, 1H), 3,34-of 3.46 (m, 1H), 3,91 (s, 3H), 4.26 deaths-4,43 (m, 1H), 4,48-4,58 (m, 1H), 4,90-5,10 (m, 1H), 6,55 (d, J=3.2 Hz, 1H), 6,94 (s, 1H), of 6.96 (d, J=15.6 Hz, 1H), 7,11-7,19 (m, 3H), 7,21-7,29 (m, 3H), 7,40 (d, J=8.0 Hz, 1H), 7,65 (d, J=8.0 Hz, 1H), 7,71 (d, J=15.6 Hz, 1H), 7,73 (s, 1H).

Example 343

Synthesis of (E)-1-[4-(4-forfinal)piperazin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone, double salt triperoxonane acid

Formula 157

In the same way as described in example 94, received and 5.30 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15,0 mg) and 1-(4-forfinal)piperizine (16.0 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,16 (d, J=1.6 Hz, 1H), to 7.64 (d, J=15.6 Hz, 1H), 7,607,61 (m, 2H), 7,58 (d, J=8,4 Hz, 1H), 7,45 (DD, J=1,6 Hz and 8.4 Hz, 1H), 7,38 (d, J=15.6 Hz, 1H), 6,80-7,03 (m, 4H), of 4.00 (s, 3H), 3,95 (Sirs, 2H), 3,88 (Sirs, 2H), 3,17 (Sirs, 4H), 2,43 (s, 3H).

Example 344

Synthesis of (E)-1-[4-(2-forfinal)piperazin-1-yl]-3-[3-methoxy-4-(4-(1H-imidazol-1-yl)phenyl]propenone, double salt triperoxonane acid

Formula 158

In the same way as described in example 94, received 7.5 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15,0 mg) and monohydrochloride 1-(2-forfinal)piperizine (19,0 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,16 (d, J=1.6 Hz, 1H), to 7.64 (d, J=15.6 Hz, 1H), 7,60-to 7.61 (m, 2H), 7,58 (d, J=8,4 Hz, 1H), 7,45 (DD, J=1,6 Hz and 8.4 Hz, 1H), 7,38 (d, J=15.6 Hz, 1H), 6,80-7,03 (m, 4H), of 4.00 (s, 3H), 3,95 (Sirs, 2H), 3,88 (Sirs, 2H), 3,17 (Sirs, 4H), 2,43 (s, 3H).

Example 345

Synthesis of (E)-1-[4-(2,4-diferensial)piperazin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone, double salt triperoxonane acid

Formula 159

In the same way as described in example 94, received 4,00 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15,0 mg) dihydrochloride and 1-(2,4-diferensial)piperizine (25.0 mg). The physical properties of this compound are as follows.

1H is the Mr (CD 3OD) δ (ppm): 9,16 (d, J=1.6 Hz, 1H), 7,68 (d, J=16 Hz, 1H), to 7.59-to 7.67 (m, 3H), EUR 7.57 (d, J=8.0 Hz, 1H), 7,45 (DD, J=1,6 Hz and 8.4 Hz, 1H), 7,34 (d, J=16 Hz, 1H), 7,12-7,21 (m, 2H), of 4.44 (s, 2H), 3,80-4,20 (Sirs, 4H), to 3.99 (s, 3H), 3,40 (Sirs, 4H), 2,43 (s, 3H).

Example 346

Synthesis of (E)-1-(3,4-dihydro-1H-isoquinoline-2-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone, salt triperoxonane acid

Formula 160

In the same way as described in example 94, received 4,90 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15,0 mg) and 1,2,3,4-tetrahydroisoquinoline (12.0 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,16 (d, J=1.6 Hz, 1H), 7,65 (d, J=16 Hz, 1H), 7,60-7,63 (m, 2H), EUR 7.57 (d, J=8.0 Hz, 1H), 7,397,48 (m, 2H), 7,20 (Sirs, 4H), 4,96 (s, 1H), 4,82 (s, 1H), 4,01 (s, 3H), 4,01 (t, J=5.6 Hz, 1H), 3,91 (t, J=5.6 Hz, 1H), 3,00 (t, J=5.6 Hz, 1H), 2,93 (t, J=5.6 Hz, 1H), 2,43 (s, 3H).

Example 347

Synthesis of (E)-1-(3,4-dihydro-1H-isoquinoline-2-yl)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]propenone

Formula 161

In the same way as described in example 324, got 16,0 mg specified in the header connection on the basis of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]acrylic acid (20.0 mg) and 1,2,3,4-tetrahydroisoquinoline (22,0 µl). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to $ 7.91 (s, 1H), 7,63 (d, J=16 Hz, 1H), 7,38 was 7.45 (m, 3H), 7,27 (s, 1H), 7,14-724 (m, 4H), 7,13 (s, 1H), of 6.96-7,01 (m, 1H), 4,82 (s, 2H), 3,86-to 3.92 (m, 2H), 2,92-3,00 (m, 2H).

Example 348, Example 348-1 and Example 348-2

Synthesis of (E)-1-(3-benzyl-3-hydroxyethylpiperazine-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Formula 162

Synthesis of (±)-(E)-1-(3-benzyl-3-hydroxyethylpiperazine-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

To a solution in DMF (5 ml) of (E)-3-[4-methyl-1H-imidazol-1-yl]-3-methoxyphenyl)acrylic acid (250 mg)obtained in example 121, and (3-benzylpiperidine-3-yl)methanol (200 mg) was added isopropylaniline (0,34 ml), HOBT (158 mg) and EDC (230 mg) and the reaction solution was stirred at room temperature for 12 hours. After completion of the reaction to the reaction solution were added ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was separated. After drying the organic layer with anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:methanol=9:1) and obtained 310 mg (71%) of (±)-(E)-1-(3-benzyl-3-hydroxyethylpiperazine-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone. The physical properties of this compound are as follows.

ESI-MS; m/z 446 [M++H].

Synthesis of (+)-(E)-1-(3-benzyl-3-hydroxyethylpiperazine-1-yl)-3-[3-methodology the C-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone and (-)-(E)-1-(3-benzyl-3-hydroxyethylpiperazine-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

(±)-(E)-1-(3-benzyl-3-hydroxyethylpiperazine-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone (310 mg) were separated using a CHIRALPAKTMAD-H (25 cm×2 cm; mobile phase hexane:isopropanol 7:3) from the company Daicel Chemical Industries, Ltd. 30 mg (-)-(E)-1-(3-benzyl-3-hydroxyethylpiperazine-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone having a shorter retention time (retention time: 12.9 minutes), was obtained with 99% of ei, and 29 mg (+)-(E)-1-(3-benzyl-3-hydroxyethylpiperazine-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone having a longer retention time (retention time: 13.5 minutes), was obtained with 94% of ei.

Example 349, Example 349-1 and Example 349-2

Synthesis of (±)-(E)-1-[3-(4-forfinal)-3-hydroxypiperidine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl]phenyl]propenone

Formula 163

Synthesis of (±)-(E)-1-[3-(4-forfinal)-3-hydroxypiperidine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Isopropylaniline (0,07 ml), HOBT (45 mg) and EDC (64 mg) was added to a solution in DMF (3 ml) of (E)-3-[4-methyl-1H-imidazol-1-yl-3-methoxyphenyl)acrylic acid (71 mg)obtained in example 121, and 3-(4-forfinal)piperidine-3-ol (54 mg) and the reaction solution was stirred at room temperature for 12 hours. After completion of the reaction to the reaction solution were added ethyl acetate and a saturated aqueous solution of bicarbonate is the atrium and the organic layer was separated. After drying the organic layer with anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:methanol 9:1) and received 91 mg (75%) of (±)-(E)-1-[3-(4-forfinal)-3-hydroxypiperidine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone. The physical properties of this compound are as follows.

ESI-MS; m/z 436 [M++H].1H-NMR (CDCl3) δ (ppm): 1,55-of 2.20 (m, 3H), 2,32 (s, 3H), 2,68 was 2.76 (m, 1H), 3,12-to 3.50 (m, 2H), with 3.89 (s, 3H), 4,08-4,22 (m, 1H), 4,55-90 (m, 1H), 6,84? 7.04 baby mortality (m, 2H), 7,05-7,33 (m, 5H), 7,50-to 5.57 (m, 2H), of 7.64 for 7.78 (m, 2H).

Synthesis of (+)-(E)-1-[3-(4-forfinal)-3-hydroxypiperidine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone and (-)-(E)-1-[3-(4-forfinal)-3-hydroxypiperidine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazole-1-yl)phenyl]propenone

(±)-(E)-1-(3-(4-forfinal)-3-hydroxypiperidine-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone (80 mg), obtained above, were separated using CHIRALAKTMAD-H (25 cm×2 cm; mobile phase hexane: isopropanol 7:3) from the company Daicel Chemical Industries, Ltd. 14 mg of (-)-(E)-1-[3-(4-forfinal)-3-hydroxypiperidine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone having short retention time (retention time: 16.3 minutes), was obtained with 99% of ei, and 13 mg (+)-(E)-1-[3-(4-forfinal)-3-hydroxypiperidine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone having a longer retention time (retention time: 20.4 minutes) compared with(E)-1-(3-(4-forfinal)-3-hydroxypiperidine-1-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)propanone, received with 89% of ei.

Example 350

Synthesis of (E)-1-[4-(4-forfinal)-4-hydroxyether-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Formula 164

Synthesis of 1-{3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}azepin-4-it

For the synthesis of 1-{3-[3-methoxy-4-(4-Mei-1-yl)phenyl]acryloyl)azepin-4-she followed the method of example 121. The physical properties of this compound are as follows.

ESI-MS; m/z 354 [M++H]

Synthesis of (E)-1-[4-(4-forfinal)-4-hydroxyether-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Torbentorbeniscool (1,0M solution in THF, of 0.85 ml) was added under ice cooling to a solution of amide (100 mg)obtained above in THF (7 ml). The reaction solution was allowed to warm to room temperature and stirred for another 2 hours. After completion of the reaction was added to ice water, extracted with ethyl acetate and the organic layer was washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: ethanol:ethyl acetate=1:4) and received 63 mg (50%) specified in the connection header. The physical properties of this compound are as follows.

ESI-MS; m/z 450 [M++H], 1H-NMR (CDCl3) δ (ppm): to 1.87 (m, 1H), of 1.88 (m, 2H), 2,01 (m, 2H), 2,12 (m, 1H), of 2.23 (s, 3H), of 3.45 (m, 1H), 3,79 (m, 1H), 3,93 (s, 3H), 3,95 (m, 1H), 4,11 (m, 1H), 7,00 (DD, J=9,0, 9,0 Hz, 2H), 7,08 (sird, J=7,0 Hz, 1H), 7,19 (d, J=to 15.0 Hz, 1H), 7,32 (m, 1H), was 7.36 (m, 1H), 7,44 (m, 1H), 7,47 (m, 2H), to 7.61 (d, J=to 15.0 Hz, 1H), 7,81 (sird, J=7,0 Hz, 1H).

Example 351

Synthesis of (E)-1-[4-fluoro-4-(4-forfinal)azepin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Formula 165

To a solution in methylene chloride (4 ml) of (E)-1-[4-(4-forfinal)-4-hydroxyether-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone (50 mg)obtained in example 350, was added at-78ºC DAST (0,022 ml) and the reaction solution was allowed to warm to room temperature and the reaction solution was stirred for 7 hours. After completion of the reaction to the reaction solution was added ice water, extracted with ethyl acetate and the organic layer was washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: ethanol:ethyl acetate=1:10) and received 43 mg (86%) specified in the connection header. The physical properties of this compound are as follows.

ESI-MS; m/z 452 [M++H],1H-NMR (CDCl3) δ (ppm): 2,03 (m, 2H), 2,16 (m, 2H), 2,22 (s, 3H), of 2.72 (m, 1H), 2,85 (m, 1H), 3.46 in (sird, J=4,0, of 14.0 Hz, 1H), 3,55 (DDD, J=7,0, 7,0, of 14.0 Hz, 1H), 3,93 (s, 3H), 3,99 (m, 1H), 4,14 (DDD, J=7,0, 7,0, of 14.0 Hz, 1H), 7,06 (DD, J=7,0, 9,0 Hz, 2H), to 7.09 (d, J=7,0 Hz, 1H), 7,18 (d, J=to 15.0 Hz, 1H), 7,32 (m, 1H), 7,37 (m, 1H), 7,39 (m, 2H), 7,46 (Sirs, 1H), 7.62mm (d, J=to 15.0 Hz, 1H), 7,83 (d, J=7,0 Hz, 1H).

Example 352

Synthesis of (E)-1-[5-(4-forfinal)-2,3,4,7-tetrahydroazepine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone and (E)-1-[4-(4-forfinal)-2,3,6,7-tetrahydroazepine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Formula 166

Synthesis of tert-butyl ester 4-(4-forfinal)-4-hydroxyether-1-carboxylic acid

To a solution in THF (60 ml) tert-butyl ether 4-oxazepan-1-carboxylic acid (5 g) was added under ice cooling torbentorbeniscool (1,0M solution in THF, 82 ml) and the reaction solution was allowed to warm to room temperature and was stirred for 1 hour. After completion of the reaction to the reaction solution was added water under ice cooling, extracted with ethyl acetate and the organic layer was washed with a saturated solution of sodium chloride. The organic layer was separated, dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane:ethyl acetate=2:1) and got to 3.73 g (52%) of tert-butyl ester 4-(4-forfinal)-4-hydroxylase the n-1-carboxylic acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 1.47 (s, 9H), 1,62-of 2.26 (m, 6H), 3,22-3,44 (m, 2H), 3,37-to 3.89 (m, 3H), 6,95-7,07 (m, 2H), was 7.36-of 7.48 (m, 2H).

ESI-MS; m/z 332 [M++Na]

Synthesis of tert-butyl ester 4-(4-forfinal)-2,3,6,7-tetrahydroazepine-1-carboxylic acid and 5-(4-forfinal)-2,3,4,7-tetrahydroazepine-1-carboxylic acid tert-butyl ester 4-(4-forfinal)-4-hydroxyether-1-carboxylic acid

To a solution in methylene chloride (20 ml) of tert-butyl ester 4-(4-forfinal)-4-hydroxyether-1-carboxylic acid (500 mg)obtained above was added under cooling with ice TEA (1.13 ml) and methanesulfonamide (0.15 ml) and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction to the reaction solution were added water cooling liquid ice, extracted with ethyl acetate and the organic layer was washed with a saturated solution of sodium chloride. The organic layer was separated, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: heptane:ethyl acetate 2:1) and got to 3.73 g (52%) of olefinic compounds in the form of a mixture of isomers. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 1.46 (s, 9H), 1,90 (Sirs, 1H), 2,hirs, 1H), 2,60 is 2.80 (m, 2H), 3,463,70 (m, 3H), 3,92-to 4.14 (m, 1H), 5,95 (t, J=5.6 Hz, 1H), 6,97 (t, J=8,8 Hz, 2H), 7,20-to 7.32 (m, 2H).

ESI-MS; m/z 314 [M++Na],1H-NMR (CDCl3) δ: to 1.48 (s, 9H), 1,90 (Sirs, 1H), 2,hirs, 1H), 2,60 is 2.80 (m, 2H), 3.46 in-3,70 (m, 3H), 3,92-to 4.14 (m, 1H), 5,95 (t, J=5.6 Hz, 1H), 6,97 (t, J=8,8 Hz, 2H), 7,20-to 7.32 (m, 2H).

Synthesis of cleaners containing hydrochloride salt of 4-(4-forfinal)-2,3,6,7-tetrahydro-1H-azepin and cleaners containing hydrochloride salt of 5-(4-forfinal)-2,3,4,7-tetrahydro-1H-azepine

To an ethyl acetate (5 ml) solution of the olefin (250 mg)obtained above was added at room temperature for 4h. hydrochloric acid solution and the reaction solution was stirred for 2 hours. After the reaction solution was concentrated under reduced pressure and used for the next reaction as it was received, without any treatment.

Synthesis of (E)-1-[5-(4-forfinal)-2,3,4,7-tetrahydroazepine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone and (E)-1-[4-(4-forfinal)-2,3,6,7-tetrahydroazepine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

In the same way as described in example 121, received 157 mg (55%) specified in the header connection on the basis of the crude amine (150 mg)obtained above, and (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid. The physical properties of this compound are as follows.

ESI-MS; m/z 454 [M++Na],1H-NMR (CDCl3) δ (ppm): 2,00-2,12 (m, 2H), 2,30 (s, 3H), of 2.54 2.63 in (m, 1,5H), 2,66-2,77 (m, 1H), 2,80-2,90 (m, 1,5H), 3,80-3,98 (m, 3H), 3,90 (s, 3H), 4,33 (d, J=56 Hz, 1H), 5,95 (t, J=5.6 Hz, 0,5H), 6,09 (t, J=5.6 Hz, 0,5H), 6,82? 7.04 baby mortality (m, 2H), 7,08-to 7.18 (m, 1H), 7,19-7,34 (m, 4H), 7,62-to 7.77 (m, 2H).

1H-NMR (CDCl3) δ (ppm): 2,00-2,12 (m, 2H), 2,30 (s, 3H), of 2.54 2.63 in (m, 1,5H), 2,66-2,77 (m, 1H), 2,80-2,90 (m, 1,5H), 3,80-3,98 (m, 3H), 3,88 (s, 3H), 4.26 deaths (d, J=5,2 Hz, 1H), 5,98-the 6.06 (m, 1H), 6,82? 7.04 baby mortality (m, 2H), 7,08-to 7.18 (m, 1H), 7,19-7,34 (m, 4H), 7,62-to 7.77 (m, 2H).

Example 353

Synthesis of (E)-1-[4-(4-forfinal)azepin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Formula 167

Synthesis of tert-butyl ester 4-(4-forfinal)azepin-1-carboxylic acid

To a solution in methanol (10 ml), tert-butyl ester 4-(4-forfinal)-4-hydroxyether-1-carboxylic acid (100 mg)obtained in example 352, was added 10% Pd-C (100 mg) and the reaction solution was stirred in a stream of hydrogen at room temperature for 1 hour. After completion of the reaction was carried out by filtration with suction, the reaction solution using celite and the filtrate was concentrated under reduced pressure. The crude product tert-butyl ester 4-(4-forfinal)azepin-1-carboxylic acid used for the next reaction without further purification.

Synthesis of 4-(4-forfinal)azepane

In the same way as described in example 352, received 4-(4-forfinal)ASEAN based on tert-butyl ester 4-(4-forfinal)azepin-1-carboxylic acid (80 mg)obtained above. Received neojidanni the product was used for next reaction without further purification.

Synthesis of (E)-1-[4-(4-forfinal)azepin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

In the same way as described in example 121, received 75 mg (66%) specified in the header connection on the basis of 4-(4-forfinal)azepine (60 mg)obtained above, and (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid. The physical properties of this compound are as follows.

ESI-MS; m/z 456 [M++Na],1H-NMR (CDCl3) δ (ppm): 1,62-2,03 (m, 4H), 2,04-of 2.20 (m, 2H), to 2.29 (s, 1,5H), 2,30 (s, 1,5H), 2,62 was 2.76 (m, 1H), 3,44-and 3.72 (m, 2H), of 3.73-of 3.96 (m, 1,5H), 3,88 (s, 1,5H), 3,90 (s, 1,5H), 3,97-4,07 (m, 0,5H), 6,82-7,00 (m, 4H), 7,06-7,16 (m, 3H), 7,17-7,29 (m, 2H), 7.68 per-7,76 (m, 2H).

Example 354

Synthesis of (E)-1-[3-(4-forfinal)-4-hydroxyether-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Formula 168

Synthesis of tert-butyl methyl ether 3-(4-forfinal)-3-hydroxyacetone-1-carboxylic acid

In the same way as described in example 352, got 528 mg (72%) of tert-butyl methyl ether 3-(4-forfinal)-3-hydroxyacetone-1-carboxylic acid from tert-butyl ether 3-oxazepine-1-carboxylic acid (507 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 332 [M++Na],1H-NMR (CDCl3) δ (ppm): 1.50 in (s, 9H), 1.60-to around 1.74 (m, 2H), 1,80-2,10 (m, 4H), 2,90 is 3.40 (m, 2H), 3,80-4,10 (m, 1H), a 4.03 (d, J=15.2 Hz, 1H), 4,66 (s, 1H), 6,94-was 7.08 (m, 2H), 7,40-rate of 7.54 (m, 2H).

Synthesis of 3-(4-forfinal)azepin-3-ol

In the same way as opisanoj example 352, received 3-(4-forfinal)azepin-3-ol from tert-butyl ether 3-(4-forfinal)-3-hydroxyacetone-1-carboxylic acid (150 mg)obtained above. The crude product was used for next reaction without further purification.

Synthesis of (E)-1-[3-(4-forfinal)-4-hydroxyether-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

In the same way as described in example 121, received 160 mg (74%) specified in the header connection on the basis of 3-(4-forfinal)azepin-3-ol (119 mg)obtained above, and (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid. The physical properties of this compound are as follows.

ESI-MS; m/z 472 [M++Na].1H-NMR (CDCl3) δ: 1,64-of 2.26 (m, 6H), 2,24 (s, 3H), 3,50-with 3.79 (m, 2H), 3,93 (s, 3H), 3,98-4,32 (m, 2H), 7,00-to 7.15 (m, 3H), 7,20-7,31 (m, 2H), 7,32-7,44 (m, 2H), 7,46-7,73 (m, 3H), 7,87 (DD, J=1,0, 6,8 Hz, 1H).

Example 355

Synthesis of (E)-1-[3-fluoro-3-(4-forfinal)azepin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Formula 169

Synthesis of (E)-1-[3-fluoro-3-(4-forfinal)azepin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

To a solution in methylene chloride (5 ml) of (E)-1-[3-(4-forfinal)-4-hydroxyether-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone (50 mg)obtained in example 354, was added at-78ºC DAST (0,022 ml) and the reaction solution was allowed to warm to room temperature and paramesh the Wali for 13 hours. After completion of the reaction to the reaction solution was added ice water, extracted with ethyl acetate and the organic layer was washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: ethanol:ethyl acetate=1:5) and received 30 mg (60%) specified in the connection header. The physical properties of this compound are as follows.

ESI-MS; m/z 474 [M++Na].1H-NMR (CDCl3) δ (ppm): 1,68-to 2.40 (m, 5H), is 2.30 (s, 3H), 3,15-3,30 (m, 1H), 3,52-of 3.80 (m, 2H), 3,90 (s, 3H), 4,00 is 4.45 (m, 2H), 6,82-6,98 (m, 2H), 7,00-to 7.18 (m, 3H), 7,20-7,34 (m, 2H), was 7.36-rate of 7.54 (m, 2H), 7,66 (d, J=15.6 Hz, 1H), 7,74 (d, J=7,0 Hz, 1H).

Example 356

Synthesis of (E)-1-[6-(4-forfinal)-2,3,4,5-tetrahydroazepine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Formula 170

Synthesis of (E)-1-[6-(4-forfinal)-2,3,4,5-tetrahydroazepine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

In the same way as described in example 352, received 5 mg (6%) specified in the header connection on the basis of (E)-1-[3-(4-forfinal)-4-hydroxyether-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone (52 mg)obtained in example 354. The physical properties of this compound are as follows.

ESI-MS; m/z 432 [M++H].1H-NMR (CDCl3) δ: 1,80 (m, H), of 1.94 (m, 2H), 2,30 (s, 3H), 2,68 (m, 2H), with 3.89 (s, 3H), 3,91 (m, 2H), 6.75 in (s, 1H), 6.87 in (d, J=to 15.0 Hz, 1H), 6,92 (m, 1H), 7,06 (m, 2H), 7,11 (s, 1H), 7,24 (d, J=6.0 Hz, 1H), 7,27 (d, J=6.0 Hz, 1H), 7,34 (DDD, J=2,0, 5,0, 9,0 Hz, 2H), of 7.70 (d, J=to 15.0 Hz, 1H), 7,76 (m, 1H).

Example 357

Synthesis of (E)-1-(3-hydroxymethyl-4-phenylpyrrolidine-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Formula 171

In the same way as described in example 121, received 368 mg (76%) specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (290 mg) and TRANS-(4-phenylpyrrolidine-3-yl)methanol (200 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,28 (d, J=0.8 Hz, 1,5H), 2,30 (d, J 0.8 Hz, 1,5H), 2,55-by 2.73 (m, 1H), 3,17 (TD, J=10,0, 8.0 Hz, 0,5H), to 3.35 (TD, J=10,0, 8.0 Hz, 0,5H), 3,50-3,82 (m, 4H), a 3.87 (s, 1,5H), 3,91 (s, 1,5H), 4.09 to 4,22 (m, 2H), of 6.68 (d, J=15.2 Hz, 0,5H), is 6.78 (d, J=15.2 Hz, 0,5H), 6,91 (shirt, 0,5H), 6,93 (shirt, 0,5H), 7,11-7,40 (m, 8H), of 7.70 (d, J=0.8 Hz, 0,5H), 7,71 (d, J=15.2 Hz, 0,5H), 7,72 (d, J=15.2 Hz, 0,5H), 7,73 (d, J=0.8 Hz, 0,5H).

Example 358

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1-(TRANS-3-phenyl-4-piperidine-1-iletilenlerin-1-yl)propenone

Formula 172

To a solution in methylene chloride (3 ml) of (E)-1-(3-hydroxymethyl-4-phenylpyrrolidine-1-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)propanone (65 mg)obtained in example 357, was added at 0ºC reagent des-Martin (128 mg), the reaction RA the solution was stirred at the same temperature for 1 hour and then stirred at room temperature for 1 hour. The reaction solution was washed with saturated aqueous sodium bicarbonate solution and after drying the organic layer over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained aldehyde compound used for the next reaction without performing additional purification. To a solution in methylene chloride (2 ml) of the above aldehyde compound (17 mg) was added piperidine (5,9 ml) and acetic acid (4,5 ml). In addition, to the solution was added acetoxyvalerenic sodium (17 mg) and the reaction solution was stirred at room temperature for 12 hours. After completion of the reaction to the reaction solution were added ethyl acetate and the reaction solution was washed with saturated aqueous sodium bicarbonate solution. After drying, the separated organic layer with anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent: ethyl acetate→ethyl acetate:methanol 9:1) and got to 19.7 mg (76%) specified in the connection header. The physical properties of this compound are as follows.

ESI-MS; m/z 507 [M+Na+].1H-NMR (CDCl3) δ (ppm): 1,35-to 1.60 (m, 6H), 2,15-2,48 (m, 9H), 2,55-of 2.72 (m, 1H), 3,01 (kV, J=9.6 Hz, 0,5H), 3.15 in (kV, J=9.6 Hz, 0,5H), to 3.38 (DD, J=12,8, and 9.2 Hz, 0,5H), 3,52 (t, J=10.0 Hz, 0,5H), 3,61 (DD, J=12,8, 9,2 Hz, 0,5H), 3,67 t, J=10.0 Hz, 0,5H), a 3.87 (s, 1,5H), 3,93 (s, 1,5H), 4,06-is 4.21 (m, 2H), 6,70 (d, J=15.6 Hz, 0,5H), to 6.80 (d, J=15.6 Hz, 0,5H), 6,92 (shirt, 0,5H), 6,95 (shirt, 0,5H), 7,11 (d, J=1.6 Hz, 0,5H), 7,15-7,40 (m, 7,5H), of 7.70 (d, J=15.6 Hz, 0,5H), 7,72 (d, J=1.6 Hz, 0,5H), 7,73 (d, J=15.6 Hz, 0,5H), 7,74 (d, J=1.6 Hz, 0,5H).

Example 359

Synthesis of oxime (E)-1-{3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl]phenyl}acryloyl)-4-phenylpyrrolidine-3-carbaldehyde

Formula 173

To a solution in ethanol (2 ml) of (E)-1-{3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acryloyl}-4-phenylpyrrolidine-3-carbaldehyde (34 mg)obtained in example 358, was added hydroxylamine hydrochloride and sodium acetate and the reaction solution was stirred at room temperature for 12 hours. After condensation to the reaction solution under reduced pressure was added ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent: ethyl acetate:methanol=10:1) and received an increase of 16.2 mg (46%) indicated in the title compounds as a mixture oximes component of Z:E=1:2. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,28 (s, 1,5H), to 2.29 (s, 1,5H), 3,19-of 3.77 (m, 4H), a 3.87 (s, 1,5H), 3,90 (C ,5H), 4,08-4,37 (m, 2H), 6,67-6,79 (m, 1,3H), 6,92 (Sirs, 0,5H), 6,94 (Sirs, 0,5H), 7,11-7,42 (m, 8,7H), 7,71 (Sirs, 0,5H), 7,72 (Sirs, 0,5H), 7,75 (Sirs, 1H), 8,70 (Sirs, 0,35H), 9,01 (Sirs, 0,15H), 9,20 (Sirs, 0,35H), for 9.64 (Sirs, 0,15H).

Example 360

Synthesis of (E)-1-{3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}-4-phenylpyrrolidine-3-carbonitrile

Formula 174

To a solution in THF (3 ml) the reaction of (E)-1-{3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}-4-phenylpyrrolidine-3-carbaldehyde (17,8 mg)obtained in example 359, was added at room temperature CDI (32.4 mg) and was carried out for 3 hours heating at the boiling point under reflux. After the reaction solution was allowed to cool to room temperature, to the reaction solution were added ethyl acetate and saturated sodium bicarbonate solution and the organic layer was separated. After drying the organic layer through anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: ethyl acetate:methanol 10:1) and received by 14.6 mg (86%) specified in the connection header. The physical properties of this compound are as follows.

ESI-MS; m/z 413 [M++H],1H-NMR (CDCl3) δ (ppm): 2,30 (s, 1,8H), 2,31 (s, 1,2H), 3,18-to 3.34 (m, 1H), 3,65-a 3.87 (m, 2,6H), to 3.89 (s, 1,8H), to 3.92 (s, 1,2H), a 4.03 (t, J=9,2 Hz, 0,4H), 4,24 is 4.35 (m,2H), to 6.67 (d, J=15.6 Hz, 0,6H), of 6.68 (d, J=15.6 Hz, 0,4H), 6,93 (Sirs, 0,6H), 6,95 (Sirs, 0,4H), 7,13-7,46 (m, 8H), 7,73 (Sirs, 0,6H), 7,74 (Sirs, 0,4H), 7,75 (.J=15.6 Hz, 0,6H), 7,76 (d, J=15.6 Hz, 0,4H).

Example 361

Synthesis of(E)-TRANS-1-[4-(4-forpeace)-2-hydroxyethylpiperazine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Formula 175

In the same way as described in example 121, received 78 mg (68%) specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (63 mg) and TRANS-(4-(4-forpeace)piperidine-2-yl)methanol (55 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 466 [M++H].1H-NMR (CDCl3) δ (ppm): 1,76-to 1.86 (m, 1H), 2,16 to 2.35 (m, 5H), 2,82-2,99 (m, 1H), 3,41-to 3.58 (m, 1H), 3,76 is 4.13 (m, 5H), 4.75 V-is 5.06 (m, 3H), 6,85 (DD, J=9,2, 4,4 Hz, 2H), 6,93 (Sirs, 1H), 6,98 (t, J=9,2 Hz, 2H), 7,11 (Sirs, 1H), 7,14-7,28 (m, 3H), of 7.64 (d, J=15.2 Hz, 1H), 7,72 (Sirs, 1H).

Racemic mixtures or racemic compounds shown in table 8, were synthesized as described in examples 358, 359 and 360.

Structural formulas and physical-chemical properties are presented in table 8, respectively.

Table 8
ExampleXDan is haunted: MS m/z
363M++N: 461 (ESI)
363M++N: 493 (ESI)
364M++N: 533 (ESI)

Example 365

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1-[4-(1-methyl-1H-indol-2-yl)piperidine-1-yl]propenone

Formula 176

To a solution in THF (1 ml) of (E)-1-{4-(1H-indol-2-yl)piperidine-1-yl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone (20 mg)obtained in example 338, and iodomethane (0.04 ml) was added at room temperature sodium hydride (2.2 mg). The reaction solution was stirred at room temperature for 7 hours. After completion of the reaction to the reaction solution were added ethyl acetate and a saturated solution of ammonium chloride and the organic layer was separated. After drying the organic layer through anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent: ethyl acetate) and received 10 mg (49%) ukazannoj is in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,72-of 1.85 (m, 2H), 2,09-to 2.18 (m, 2H), 2,30 (s, 3H), 2,80-2,96 (m, 1H), 2,99-of 3.07 (m, 1H), 3,28-3,44 (m, 1H, in), 3.75 (s, 3H), 3,91 (s, 3H), 4,22 is 4.35 (m, 1H), 4,86-of 4.95 (m, 1H), 6,23 (s, 1H), 6,94 (, 1H), 6,95 (d, J=15.6 Hz, 1H), 7,07-to 7.32 (m, 6H), 7,55 (d, J=7,6 Hz, 1H), 7,68 (d, J=15.6 Hz, 1H), 7,73 (Sirs, 1H).

Example 366

Synthesis of (E)-1-{4-[1-(2-hydroxyethyl)-1H-indol-2-yl]piperidine-1-yl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone

Formula 177

In the same way as described in example 365, using (E)-1-{4-(1H-indol-2-yl)piperidine-1-yl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone (6 mg)obtained in example 338, and (2 bromoethoxy)tert-butyldimethylsilyl (0.04 ml), was obtained (E)-1-{4-[1-(2-tert-butyldimethylsiloxy)-1H-indol-2-yl]piperidine-1-yl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone. To a solution in THF (1 ml) obtained silyl-protected compound was added TBAF (1M solution in THF, 0,02 ml) and the reaction solution was stirred at room temperature for 3 hours. After completion of the reaction to the reaction solution were added ethyl acetate and a saturated solution of ammonium chloride and the organic layer was separated. After drying the organic layer through anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silicagel is e (eluting solvent: ethyl acetate:methanol=9:1) and received 0.9 mg (14%) specified in the connection header. The physical properties of this compound are as follows.

ESI-MS; m/z 485 [M++H].1H-NMR (CDCl3) δ (ppm): 1,75-to 1.83 (m, 2H), 2,09-to 2.18 (m, 2H), 2,280 (s, 3H), 2,79-to 2.94 (m, 1H), of 3.10-3.20 (m, 1H), 3,23 is 3.40 (m, 1H), 3,91 (s, 3H), 4.00 points (t, J=5.6 Hz, 2H), 4,22-to 4.33 (m, 1H), 4,34 (t, J=5,2 Hz, 2H), 4,84-of 4.95 (m, 1H), 6.30-in (s, 1H), 6,94 (t, J=1.2 Hz, 1H), 6,95 (d, J=15.6 Hz, 1H), 7,08-7,34 (m, 6H), 7,56 (d, J=7,6 Hz, 1H), 7,68 (d, J=15.6 Hz, 1H), 7,72 (d, J=1.2 Hz, 1H).

Compounds shown in table 9 were synthesized as described in example 121. Structural formulas and physical-chemical properties are presented in table 9, respectively.

Table 9-1

Table 9-2

Table 9-3

Example 397

Synthesis of (E)-1-(3-terbisil)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]pyrrolidin-2-it

Formula 178

Synthesis of tert-butyl ester 4-(tert-butyldimethylsilyloxy)-2-(diethoxyphosphoryl)butyric acid

To a solution in DMF (4.0 ml) of tert-butyl methyl ether dimethyltitanocene acid (1.0 ml) was added at 0ºC sodium hydride (256 mg), the reaction solution was allowed to warm up to 60ºC and was stirred for 2 hours. To the reaction solution was added (2-bromoethoxy)tert-butyldimethylsilyl (1,37 ml), the reaction solution was stirred at 80ºC overnight. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (heptane-ethyl acetate=1:1→ethyl acetate) and received 510 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 4.09 to 4,18 (m, 4H), 3,66-and 3.72 (m, 1H), 3,54 (dt, J=5,2, and 9.2 Hz, 1H), 3.15 in (DDD, J=3,6, 11, 22 Hz, 1H), 1,97-2,17 (m, 2H), 1,47 (s, 9H), 1,31-of 1.36 (m, 6H), to 0.89 (s, 9H), of 0.04 (s, 6H).

Synthesis of tert-butyl methyl ether (E)-4-(tert-butyldimethylsilyloxy)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid

To a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (295 mg)obtained in example 1 in THF (5.0 ml) and ethanol (5.0 ml) were successively added tert-butyl ester 4-(tert-butyldimethylsilyloxy)-2-(diethoxyphosphoryl)butyric acid (509 mg) and the monohydrate of lithium hydroxide (104 mg) and the reaction solution was stirred at room temperature overnight. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous sulfate is Agnes and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (heptane-ethyl acetate=2:1→1:1) and received 395 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,73 (s, 1H), 7,69 (s, 1H), 7,22-7,30 (m, 2H), 7,24 (s, 1H), 6,94 (s, 1H), 3,91 (t, J=6.4 Hz, 2H), a 3.87 (s, 3H), 2,77 (t, J=6.4 Hz, 2H), 2,30 (s, 3H), and 1.56 (s, 9H), of 0.87 (s, 9H), of 0.03 (s, 6H).

Synthesis of tert-butyl methyl ether (E)-4-hydroxy-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid

To a solution in THF (10 ml) of tert-butyl methyl ether (E)-4-(tert-butyldimethylsilyloxy)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)butyric acid (122 mg) was added TBAF (1M solution in THF, 318 μl) and the reaction solution was stirred at room temperature for 1 hour. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:ethanol=10:1) and received 49,7 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,72 (s, 1H), 7,69 (s, 1H), 7,20-7,25 (m, 3H), 7,07 (d, J=8.0 Hz, 1H), 6,93 (s, 1H), 3,88-of 3.94 (m, 2H), 3,86, 3H), was 2.76-2,84 (s, 2H), 2,30 (s, 3H), and 1.56 (s, 9H).

Synthesis of tert-butyl methyl ether (E)-4-(1,3-dioxo-1,3-dihydroindol-2-yl)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid

To a solution in anhydrous THF (3.0 ml) tert-butyl ether (E)-4-hydroxy-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid (100 mg) were successively added triphenylphosphine (87,8 mg), phthalimide (49,3 mg) and diisopropylcarbodiimide (77,0 µl). After stirring the reaction solution at room temperature for 1.5 hours the reaction solution, as it was obtained was concentrated under reduced pressure, the residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate) and received 119 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,72-7,76 (m, 2H), 7,63-to 7.68 (m, 4H), 7,13 (d, J=8.0 Hz, 1H), 6,99 (d, J=7.2 Hz, 1H), 6.90 to (s, 1H), 6,86 (s, 1H), 3,91 (t, J=6,8 Hz, 2H), of 3.77 (s, 3H), 2.95 points (t, J=6,8 Hz, 2H), 2,30 (s, 3H), to 1.60 (s, 9H).

Synthesis of tert-butyl methyl ether (E)-4-amino-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid

To a solution in ethanol (2.0 ml) tert-butyl ether (E)-4-(1,3-dioxo-1,3-dihydroindol-2-yl)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid (119 mg) was added hydrazine monohydrate (48,9 mg). After boiling under reflux the reaction solution during 30 minutes and confirm the disappearance of the original substances, the white precipitate was filtered. The obtained filtrate was concentrated under reduced pressure and got 86 mg of crude amino compounds. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,71 (d, J=1.2 Hz, 1H), 7,63 (s, 1H), 7,24 (d, J=8.0 Hz, 1H), 7,10 (d, J=1.2 Hz, 1H),? 7.04 baby mortality (DD, J=1,2, 8.0 Hz, 1H), 6,92 (t, J=1.2 Hz, 1H), 3,86 (s, 3H), of 2.92 (t, J=7,6 Hz, 2H), 2,68 (t, J=a 7.6 Hz, 2H), 2,30 (s, 3H), and 1.56 (s, 9H).

Synthesis of tert-butyl methyl ether (E)-4-(3-forbindelsen)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid

To a solution in methylene chloride (2.0 ml) tert-butyl ether (E)-4-amino-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid (71 mg) were successively added 3-forbindelse (21,1 μl), acetic acid (0.1 ml) and triacetoxyborohydride sodium (63,3 mg). After stirring the reaction solution at room temperature for 5.5 hours to the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on NH silica gel (eluting solvent: ethyl acetate→ethyl acetate:ethanol=20:1) and received 47,5 mg specified in the connection header. The physical properties of this compound are as follows.

1H-YAM who (CDCl 3) δ (ppm): 7,72 (s, 1H), 7.62mm (s, 1H), 7,22-7,28 (m, 2H), 7,10 (s, 1H), 7,00-7,06 (m, 3H), 6.90 to-of 6.96 (m, 2H), 3,82 (s, 3H), of 3.78 (s, 2H), 2,84 (t, J=6,8 Hz, 2H), 2,74 (t, J=6,8 Hz, 2H), 2,30 (s, 3H), 1,53 (s, 9H).

Synthesis of (E)-1-(3-terbisil)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]pyrrolidin-2-it

To a solution in methylene chloride (0.5 ml) of tert-butyl methyl ether (E)-4-(3-forbindelsen)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid (4,50 mg) was added triperoxonane acid (500 μl). After stirring the reaction solution at room temperature for 1.5 hours and confirm the disappearance of the starting substances of the reaction solution in the form as it was received, was concentrated under reduced pressure. The residue was dissolved in DMF (0.5 ml)to the reaction solution were added alternately IPEA (17,0 μl), EDC (5,58 mg) and HOBT (3,93 mg) and the reaction solution was stirred at room temperature for 1.5 hours. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:ethanol=20:1) and received 2,30 mg specified in the connection header. Physically the properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,74 (s, 1H), 7,42 (t, J=2,8 Hz, 1H), 7,28-7,35 (m, 1H), 7,28 (d, J=8.0 Hz, 1H), 7,15 (d, J=8.0 Hz, 1H), 7,13 (s, 1H), 7,07 (d, J=8.0 Hz, 1H), 6,70-7,30 (m, 2H), 6,94 (s, 1H), 4,69 (s, 2H), 3,88 (s, 3H), 3,44 (t, J=6,8 Hz, 2H), to 3.09 (dt, J=2,8, 6,8 Hz, 2H), 2,30 (s, 3H).

Example 398

Synthesis of (E)-1-(3-terbisil)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 179

Synthesis of ethyl ester of 2-(diethoxyphosphoryl)-4-[1,3]dioxolane-2-yl-butyric acid

To a solution in DMF (25 ml) diethylphosphonoacetate complex ether (10.0 ml) was added at 0ºC sodium hydride (3,02 g) and the reaction solution was heated to 70ºC and was stirred for 70 minutes. Then, after adding to the reaction solution of 2-(2-bromacil)-1,3-dioxolane (14,8 ml), the reaction solution was stirred at 80ºC for 15 hours and then the reaction solution was added sodium hydride (1.40 g) and 2-(2-bromo ethyl)-1,3-dioxolane (7,70 ml) and the reaction solution was stirred for 4 hours. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent; heptane-ethyl acetate=1:1→1:2→ethyl acetate) and received 3.58 g specified in C is the coupling head. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 4,87 (t, J=4.4 Hz, 1H), 4,10-of 4.25 (m, 6H), 3,93-to 3.99 (m, 2H), 3,81-3,88 (m, 2H), 3,03 (DDD, J=4,4, 11, 23 Hz, 1H), 1,94-of 2.16 (m, 2H), 1,64-of 1.84 (m, 2H), 1.30 and of 1.36 (m, 9H)

Synthesis of ethyl ester of (E)-4-[1,3]dioxolane-2-yl-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid

To a solution in THF (20 ml) (1.75 g) of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde obtained in Example 1 were successively added ethyl ester 2-(diethoxyphosphoryl)-4-[1,3]dioxolane-2-yl-butyric acid (2.50 g) and the monohydrate of lithium hydroxide (388 mg) and the reaction solution was stirred at room temperature overnight. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent; heptane-ethyl acetate=1:2→ethyl acetate) and received 1,05 g specified in the title compounds as a mixture of isomers (E:Z=4:1). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,74 (s, 1H), 7,66 (s, 1H), 7,27 (d, J=8,4 Hz, 1H), 7,13 (s, 1H), to 7.09 (d, J=8,4 Hz, 1H), 6,95 (s, 1H), 4.95 points (t, J=4,4, 1H), 4,29 (kV, J=7.2 Hz, 2H), 3,92-4,00 (m, 2H), 3,90 (s, 3H), 3,82-3,88 (m, 2H), 2.71 to a 2.75(m, 2H), 2,31 (s, 3H), 1,96 is 2.10 (m, 2H), of 1.37 (t, J=7.2 Hz, 3H).

Synthesis of (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-oxovalerate acid ethyl ester

To aqueous solution (243 mg) in ethyl ether (E)-4-[1,3]dioxolane-2-yl-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid were successively added acetic acid (2 ml) and triperoxonane acid (2.0 ml) and the reaction solution was stirred at room temperature for 4 hours. After confirming disappearance of the starting compounds to the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and by condensation under reduced pressure was obtained 110 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 9,81 (s, 1H), 7,72-7,74 (m, 2H), 7,27 (d, J=8.0 Hz, 1H), 6,94-7,01 (m, 3H), 4,30 (kV, J=7.2 Hz, 2H), a 3.87 (s, 3H), 2,89 (t, J=8.0 Hz, 2H), 2,74 (t, J=8.0 Hz, 2H), 2,30 (s, 3H), of 1.37 (t, J=7,2 Hz, 3H).

Synthesis of ethyl ester of (E)-5-(3-forbindelsen)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid

To a solution in methylene chloride (2.0 ml) ethyl ester of (E)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-5-oxovalerate acid (142 mg) were successively added-forbindelsen (141 μl), acetic acid (1.0 ml) and triacetoxyborohydride sodium (105 mg). After stirring the reaction solution at room temperature over night to the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent: ethyl acetate→ethyl acetate:ethanol=10:1) and received 81 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,72 (s, 1H), 7,66 (s, 1H), 7.23 percent (d, J=8,4 Hz, 1H), 6.89 in-7,07 (m, 7H), the 4.29 (q, J=7.2 Hz, 2H), 3,83 (s, 3H), of 3.78 (s, 2H), 2,69 (t, J=6,8 Hz, 2H), 2,62 (t, J=8.0 Hz, 2H), 2,30 (s, 3H), 1,74-to 1.83 (m, 2H), 1,36 (t, J=7.2 Hz, 3H).

Synthesis of (E)-1-(3-terbisil)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

The solution in acetic acid (3 ml), ethyl ether (E)-5-(3-forbindelsen)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (81 mg) was heated to boiling point under reflux overnight. After cooling the reaction solution to 0ºC it was neutralized using 1N. the sodium hydroxide solution and then the reaction solution was added to acadeny aqueous solution of sodium bicarbonate and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent: heptane-ethyl acetate=1:5→ethyl acetate) and received 21 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,88 (s, 1H), 7,73 (s, 1H), 7,25-7,34 (m, 3H), to 7.09 (d, J=7.2 Hz, 1H), 6,94-7,05 (m, 4H), to 4.73 (s, 2H), a 3.87 (s, 3H), 3,39 (t, J=6.0 Hz, 2H), 2,84 (dt, J=2,0, 6.4 Hz, 2H), 2,30 (s, 3H), 1,89 (m, 2H).

Example 399

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-[(1S)-1-phenylethyl]piperidine-2-it

Formula 180

To a solution in methylene chloride (2 ml), ethyl ether (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-oxovalerate acid (162 mg) were successively added (S)-(-)-alpha-methylbenzylamine (183 μl), acetic acid (1.0 ml) and triacetoxyborohydride sodium (120 mg). After stirring the reaction solution at room temperature over night to the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrate the Wali under reduced pressure. The obtained residue was dissolved in acetic acid (2 ml) and was carried out by heating the reaction solution to the boiling point under reflux overnight. After cooling the reaction solution to 0ºC its neutralized using a saturated aqueous solution of sodium bicarbonate to the reaction solution were added ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent: heptane-ethyl acetate=1:1→ethyl acetate:ethanol=10:1) and received 13,7 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 7.90 (s, 1H), 7,72 (d, J=1.2 Hz, 1H), 7.24 to 7,29 (m, 6H),? 7.04 baby mortality-7,06 (m, 2H), 6,94 (t, J=1.2 Hz, 1H), 6,26 (kV, J=7.2 Hz, 1H), 3,85 (s, 3H), of 3.25 (DDD, J=3,6, 8,4, 12 Hz, 1H), 2,96 (DDD, J=4,4, 6,8, 11 Hz, 1H), 2,72-to 2.85 (m, 2H), 2,30 (s, 3H), 1,79 of-1.83 (m, 1H), 1,68-of 1.74 (m, 1H), 1,58 (d, J=7.2 Hz, 3H).

Example 400

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-[1-(3-morpholine-4-ylphenyl)ethyl]piperidine-2-it

Formula 181

Synthesis of ethyl ester of (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-[1-(3-morpholine-4-ylphenyl)ethylamino]valerianic acid

To a solution in methylene chloride (10 ml), ethyl ether (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-oxovalerate acid (173 mg)obtained in example 398, were successively added 1-(3-morpholine-4-ylphenyl)ethylamine (157 mg) and acetic acid (0.1 ml) and triacetoxyborohydride sodium (214 mg). The reaction solution was stirred at room temperature for 1 hour, the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: Chromatorex NH, eluting solvent: heptane-ethyl acetate=1:2) and received 205 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,72 (s, 1H), 7.62mm (s, 1H), 7,19-of 7.23 (m, 2H), 7,02 (d, J=8,4 Hz, 1H), 6,98 (s, 1H), 6,93 (s, 1H), 6.87 in (s, 1H), 6,78-for 6.81 (m, 2H), 4,27 (kV, J=7.2 Hz, 2H), 3,82-3,86 (m, 4H), 3,81 (s, 3H), 3,70 (kV, J=6,8 Hz, 1H), 3,14 (t, J=4.8 Hz, 4H), 2,43-2,61 (m, 4H), of 2.30 (s, 3H), 1,62 and 1.80 (m, 2H), 1,35 (t, J=7.2 Hz, 3H), of 1.31 (d, J=6.8 Hz, 3H).

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-[1-(3-morpholine-4-ylphenyl)ethyl]piperidine-2-it

To a solution of ethyl ester of (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-[1-(3-morpholine-4-ylphenyl)e is ylamino] valerianic acid (55,0 mg) in THF (1.0 ml) and ethanol (1.0 ml) was added 2n. the sodium hydroxide solution (1.0 mg). The reaction solution was stirred at room temperature overnight, was added 2n. hydrochloric acid solution and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and received 50.0 mg of the crude compound carboxylic acid. To a solution in DMF (2.0 ml) of the obtained compound carboxylic acid were successively added IPEA (51,8 μl), EDC (38,0 mg) and HOBT (26,8 mg) and the reaction solution was stirred at room temperature for 1 hour. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: Chromatorex NH, eluting solvent: ethyl acetate=1:1→heptane-ethyl acetate) and received 6,00 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,89 (s, 1H), 7,72 (d, J=1.6 Hz, 1H), 7,22-7,28 (m, 2H), 7,05-7,07 (m, 2H), 6,93 (s, 1H), 6,83-of 6.90 (m, 3H), 6,21 (kV, J=7.2 Hz, 1H), 3,85-a 3.87 (m, 7H), 3,24 (DD, J=4,0, 8,4, 12 Hz, 1H), and 3.16 (t, J=4.8 Hz, 4H), 2.95 and-a 3.01 (m, 1H), was 2.76-2.82 from (m, 2H), 2,30 (s, 3H), 1,76-of 1.84 (m, 1H), ,67-1,73 (m, 1H), 1.55V (d, J=7.2 Hz, 3H).

Example 401

Synthesis of (E)-1-[(1R,2S)-2-hydroxyine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 182

Synthesis of ethyl ester of (E)-5-[(1R,2S)-2-hydroxyine-1 ylamino]-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid

To a solution in methylene chloride (2.0 ml) ethyl ester of (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-oxovalerate acid (110 mg) were successively added (1R,2S)-amino-2-indanol (to 63.2 mg), acetic acid (0.1 ml) and triacetoxyborohydride sodium (81,7 mg). After stirring the reaction solution at room temperature over night to the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent: ethyl acetate=1:1→heptane-ethyl acetate) and received 120 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,71 (d, J=1.6 Hz, 1H), 7,68 (s, 1H), 7,17-7,27 (m, 5H), 7,05 (DD, J=1.6 Hz, 1H), 7,01 (d, J=1.6 Hz, 1H), 6,93 (t, J=1.6 Hz, 1H), 4,39 (dt, J=2,8, and 5.2 Hz, 1H, 4,30 (kV, J=7.2 Hz, 2H), a 4.03 (d, J=5,2 Hz, 1H), 3,85 (s, 3H), 3.04 from (DD, J=5,2 Hz, 1H), 2,92-to 2.99 (m, 2H), 2,75-and 2.83 (m, 1H), 2,61-by 2.73 (m, 2H), 2,30 (s, 3H), 1,84 (kV, 7.2 Hz, 2H), of 1.37 (t, J=7.2 Hz, 3H).

Synthesis of (E)-1-[(1R,2S)-2-hydroxyine-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

To a solution in ethanol (2.0 ml) ethyl ester of (E)-5-[(1R,2S)-2-hydroxyine-1 ylamino]-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid (120 mg) was added 2n. the sodium hydroxide solution (1.0 ml). After heating the reaction solution to the boiling point under reflux for 30 minutes and confirm the disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent:heptane-ethyl acetate=1:1→ethyl acetate→ethyl acetate:ethanol=10:1) and received 78,9 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 7.82 (s, 1H), 7,71 (d, J=1.2 Hz, 1H), 7,22-7,30 (m, 5H), 7,02 (d, J=7.2 Hz, 1H), 7,01 (s, 1H), 6,92 (s, 1H), 6,01 (d, J=7.2 Hz, 1H), 4,91 (kV, J=7.2 Hz, 1H), 3,84 (s, 3H), 3,30 (DD, J=7,2, 16 Hz, 1H), 3,11-up 3.22 (m, 2H), 2,96 (DD, J=7,2, 16 Hz, 1H), 2,75-of 2.86 (m, 2H), 2,30 (s, 3H), 170-1,90 (m, 2H).

Example 402

Synthesis of (E)-1-(3-iodobenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it, salt montepertuso acid

Formula 183

In the same way as described in example 398, cooperated ethyl ester (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-oxovalerate acid (197 mg) and 3-iodobenzylamine (310 μl). By purification of the crude product by LC-MS received 7.8 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,72 (s, 1H), 7,88 (s, 1H), 7,63-7,66 (m, 2H), 7,34 (d, J=8.0 Hz, 1H), 7,29 (d, J=8.0 Hz, 1H), 7,07 for 7.12 (m, 4H), and 4.68 (s, 2H), 3,91 (s, 3H), 3,39 (t, J=5.6 Hz, 2H), 2,80-and 2.83 (m, 2H), 2,48 (, 3H), 1,86-of 1.92 (m, 2H).

Example 403

Synthesis of (E)-1-(2,6-dichloropyridine-4-ylmethyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 184

In the same way as described in example 398, got 7.4 mg specified in the header connection on the basis of the ethyl ester of (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-oxovalerate acid (130 mg) and C-(2,6-dichloropyridine-4-yl)methylamine (101 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,87 (s, 1H), 7,73 (s, 1H), 7,27 (d, J=8,4 Hz, 1H), 7,20 (s, 2H), 7,05 (d, J=8,4 Hz, 1H),? 7.04 baby mortality (s, 1H), 6,95 (s, 1H), 4,69 (s, 2H), a 3.87(s, 3H), 3,44 (t, J=5.6 Hz, 2H), 2,89 (t, J=5.6 Hz, 2H), 2.05 is (s, 3H), 1,92-to 1.98 (m, 2H).

Example 404

Synthesis of (E)-1-(3-terbisil)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]azepin-2-it

Formula 185

Synthesis of ethyl ester of 2-(diethoxyphosphoryl)-5-[1,3]dioxolane-2-Illarionova acid

To a solution in DMF (50 ml) diethylphosphonoacetate of ester (2.65 ml) were successively added at 0ºC sodium hydride (643 mg) and 2-(3-chloropropyl)-1,3-dioxolane (2.6 g) and the reaction solution was allowed to warm up to 60ºC and was stirred overnight. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and the organic layer was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (heptane-ethyl acetate=1:2 to 1:5→ethyl acetate) and received 1,62 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 4,84 (t, J=4,8 Hz, 1H), 4,10-of 4.25 (m, 6H), 3,93-of 3.97 (m, 2H), 3,80-of 3.85 (m, 2H), 2,88-2,90 (m, 1H), 1,97 is 2.10 (m, 1H), 1,82-of 1.94 (m, 1H), 1,64-1,71 (m, 2H), 1,40-of 1.57 (m, 2H), 1,21-of 1.35 (m, 9H).

Synthesis of ethyl ester of (E)-5-[1,3]dioxolane-2-yl-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid

To a solution of 3-methoxy-4-(4-methyl-1H-shall midazol-1-yl)benzaldehyde (580 mg), obtained in example 1, in THF (10 ml) and ethanol (10 ml) were successively added ethyl ester 2-(diethoxyphosphoryl)-5-[1,3]dioxolane-2-yl-valerianic acid (826 mg) and the monohydrate of lithium hydroxide (205 mg) and the reaction solution was stirred at room temperature overnight. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:ethanol=20:1) and received 485 mg specified in the title compounds as a mixture of isomers (E:Z=4:1). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,72 (s, 1H), to 7.64 (s, 1H), 7.24 to 7,26 (m, 1H), 7,01? 7.04 baby mortality (m, 2H), 6,93 (s, 1H), 4,89 (t, J=4.0 Hz, 1H), 4,28 (kV, J=7.2 Hz, 2H), 3,92-3,95 (m, 2H), a 3.87 (s, 3H), 3,81-of 3.85 (m, 2H), 2.57 m-2,61 (m, 2H), 2,30 (s, 3H), 1,66-of 1.78 (m, 4H), of 1.36 (t, J=7.2 Hz, 3H).

Synthesis of ethyl ester of (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-6-oxohexanoate acid

To aqueous solution (2.0 ml) ethyl ester of (E)-5-[1,3] dioxolane-2-yl-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene] valerianic acid (480 mg) were successively added acetic acid (1.0 ml) and triperoxonane acid (1.0 in the l) and the reaction solution was stirred at room temperature for 2.5 hours. After confirming disappearance of the starting compounds to the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:ethanol=10:1) and received 400 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 9,78 (s, 1H), 7,50-7,80 (Sirs, 1H), 7,69 (s, 1H), 7,28-7,31 (m, 1H), was 7.08 (d, J=8.0 Hz, 1H), 7,03 (s, 1H), 6.90 to-of 6.96 (m, 1H), 4,30 (kV, J=7.2 Hz, 2H), with 3.89 (s, 3H), 2,47-2,61 (m, 4H), 2,31 (s, 3H), 1,86-of 1.93 (s, 2H), of 1.37 (t, J=7.2 Hz, 3H).

Synthesis of ethyl ester of (E)-6-(3-forbindelsen)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexanoic acid

To a solution in methylene chloride (6 ml), ethyl ether (E)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-6-oxohexanoate acid (231 mg) were successively added 3-forbindelsen (88,7 μl), acetic acid (0.5 ml) and triacetoxyborohydride sodium (165 mg). After stirring the reaction solution at room temperature over night to the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. After about Yuki obtained organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: Chromatorex NH, eluting solvent: heptane-ethyl acetate=1:1→ethyl acetate→ethyl acetate:ethanol=10:1) and received 173 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,71 (s, 1H), 7.62mm (s, 1H), 7,20-7,25 (m, 2H), 6,98-was 7.08 (m, 4H), 6,86-6,93 (m, 2H), 4,27 (kV, J=7.2 Hz, 2H), of 3.84 (s, 3H), of 3.77 (s, 2H), 2,60-2,70 (m, 2H), 2,52-2,60 (m, 2H), 2,30 (s, 3H), 1,76-to 1.87 (m, 4H), of 1.35 (t, J=7.2 Hz, 3H).

Synthesis of (E)-1-(3-terbisil)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]azepin-2-it

To a solution in ethanol (2.0 ml) ethyl ester of (E)-6-(3-forbindelsen)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)hexanoic acid (173 mg) was added 2n. the sodium hydroxide solution (2.0 ml). After boiling under reflux the reaction solution for 1 hour and confirm the disappearance of the original substances 2n. hydrochloric acid solution and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution in DMF (5.0 ml) obtained carbonbearing compound (112 mg) were successively added IPEA (134 μl), EDC (of 98.2 mg) and HOBT (69,2 mg) and the reaction solution was stirred at room temperature overnight. After confirmation of ischeznut the I initial substances to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate) and received 70,3 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 7,72 (d, J=1.2 Hz, 1H), 7,28-7,34 (m, 1H), 7.23 percent (d, J=26 Hz, 1H), 6,95-to 7.15 (m, 6H), 6,94 (t, J=1.2 Hz, 1H), 4,67 (s, 2H), 3,86 (s, 3H), 3,36 (t, J=5,2 Hz, 2H), 2,62 (t, J=5,2 Hz, 2H), 2,30 (s, 3H), 1,82-of 1.88 (m, 2H), 1,61 by 1.68 (m, 2H).

Example 405

Synthesis of 3-[4-(1H-imidazol-1-yl)-3-methoxybenzylidene]-1-naphthalene-1-iletilerini-2-it, salt triperoxonane acid

Formula 186

Synthesis of 1-naphthalene-1-iletilerini-2-it

To a solution in DMF (20 ml) δ-valerolactam (1.0 g) were successively added at 0ºC sodium hydride (404 mg), 1-(chloromethyl)naphthalene (1.78 g) and sodium iodide (151 mg) and the reaction solution was allowed to warm up to 60ºC and was stirred for 6 hours. To the reaction solution was added 2n. a solution of hydrochloric acid and THF and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eptan: eluting solvent; the ethyl acetate=1:2→ethyl acetate) and received 2,42 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 8,08-8,11 (m, 1H), 7,83-a 7.85 (m, 1H), 7,78 (d, J=8,4 Hz, 1H), 7,45-7,53 (m, 2H), 7,40 (DD, J=6,8, 8.0 Hz, 1H), 7,31 (d, J=6,8 Hz, 1H), to 5.08 (s, 2H), to 3.09 (t, J=6.0 Hz, 2H), 2,50 (t, J=6.0 Hz, 2H,), 1,67-to 1.79 (m, 4H).

Synthesis of 3-[4-(1H-imidazol-1-yl)-3-methoxybenzylidene]-1-naphthalene-1-iletilerini-2-it, salt triperoxonane acid

To a solution in THF (7.0 ml) 1-naphthalene-1-iletilerini-2-she (800 mg) was added at 0ºC bis(trimethylsilyl)amide lithium (concentration of 1,5M in THF, of 6.68 ml) and the reaction solution was stirred for 20 minutes. To the reaction solution was added dropwise a solution in THF (2 ml) of 4-(1H-imidazol-1-yl)-3-methoxybenzaldehyde (676 mg)obtained in example 1 and the reaction solution was stirred at room temperature overnight. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane: eluting solvent:ethyl acetate=one→ethyl acetate→ethyl acetate:ethanol 10:1) and obtained 330 mg of alcohol compounds. Then to the solution in methylene chloride (1.0 ml) obtained alcohol compounds the Oia at 0ºC (113 μl) was added methanesulfonamide (31 μl) and TEA and the reaction solution was stirred for 3 hours and 30 minutes. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in methylene chloride (1.0 ml) was added DBU (24,7 mg) and the reaction solution was stirred at room temperature overnight. The reaction solution, as it was obtained, was purified by LC-MS and received 3.1 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,24 (s, 1H), 8,10-to 8.12 (m, 1H), 7,89-a 7.92 (m, 1H), 7,83-a 7.85 (m, 2H), 7,72 (s, 1H), 7,51-of 7.55 (m, 2H), 7,44-7,47 (m, 2H), was 7.36 (d, J=6,4 Hz, 1H), 7,25 (s, 1H), was 7.08 (d, J=8.0 Hz, 1H), 5,19 (d, J=15 Hz, 1H), 5,07 (d, J=15 Hz, 1H), with 3.89 (s, 3H), 3;,41 (DD, J=4,0, 13 Hz, 1H), 3,14-3,24 (m, 2H), 2,95 (DD, J=9,2, 14 Hz, 1H), 2,78-2,84 (m, 1H), 1,78-of 1.88 (m, 2H), from 1.66 to 1.76 (m, 1H), 1,51-1,60 m, 1H).

Example 406

Synthesis of 3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-naphthalene-1-iletilenlerin-2-it, salt triperoxonane acid

Formula 187

Synthesis of 1-naphthalene-1-iletilenlerin-2-it

In the same way as described in example 405, received 2,32 g is specified in the header compounds based on 2-pyrrolidone (767 μl) and 1-(chloromethyl)naphthalene (1.78 g). The physical properties of this compound are as follows.

1H-I Is R (CDCl 3) δ (ppm): 9,41 (s, 1H), 8,15-8,17 (m, 1H), 8,00 (s, 1H), 7,94-of 7.97 (m, 1H), 7,87 (d, J=8.0 Hz, 1H), a 7.85 (s, 1H), 7,78 (s, 1H), to 7.64 (d, J=8.0 Hz, 1H), 7,47-EUR 7.57 (m, 3H), 7,40-7,42 (m, 2H), 7.23 percent (d, J=and 8.4 Hz, 1H), 5,14 (s, 2H), with 3.89 (s, 3H), 3,32 (t, J=5.6 Hz, 2H), of 2.81 (t, J=5.6 Hz, 2H), 1,78 (t, J=5.6 Hz, 2H).

Synthesis of 3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-naphthalene-1-iletilenlerin-2-it, monosol triperoxonane acid

In the same way as described in example 405, using 1-naphthalene-1-iletilenlerin-2-er (300 mg)obtained in example 1 was obtained 3.4 mg specified in the header connection on the basis of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (431 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 9,14 (t, J=1.2 Hz, 1H), 8,16-8,18 (m, 1H), 7,88-to 7.93 (m, 2H), 7,46-7,58 (m, 7H), 7,38-7,41 (m, 1H), 7,32 (d, J=7,6 Hz, 1H), 5,11 (s, 2H), 3,95 (s, 3H), 3,37 (t, J=6,8 Hz, 2H), 3,05-3,10 (m, 2H,), 2,42 (s, 3H).

Example 407

Synthesis of 3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-naphthalene-1-ilmatieteen-2-it, salt triperoxonane acid

Formula 188

Synthesis of 1-naphthalene-1-ilmatieteen-2-he

In the same way as described in example 405, received 2,53 g is specified in the header connection on the basis of ε-caprolactam (1,14 g) and 1-(chloromethyl)naphthalene (1.78 g). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 8.12 (d, J=8,4 Hz, 1H), 7,85-7,87 (m, 1H), 7,80 (d, J=8,4 Hz, 1H), of 7.48-7,56 (m, 2H), 7,42 (t, J=8,4 Hz,1H), to 7.35 (d, J=6,4 Hz, 1H), is 5.06 (s, 2H), 3,26-3,29 (m, 2H), 2,62-to 2.65 (m, 2H), 1,58 is 1.70 (m, 4H), 1,21-of 1.26 (m, 2H).

Synthesis of 3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-naphthalene-1-ilmatieteen-2-he, salt triperoxonane acid

In the same way as described in example 405, received 1.0 mg specified in the header connection on the basis of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (383 mg)obtained in example 1 and 1-naphthalene-1-ilmatieteen-2-she (300 mg). The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): remaining 9.08 (d, J=1.2 Hz, 1H), 8,18 (d, J=9,2 Hz, 1H), 7,92 (DD, J=2.0 a, 7,6 Hz, 1H), 7,88 (d, J=7,6 Hz, 1H), 7,44-EUR 7.57 (m, 6H), 7,31 (d, J=1.2 Hz, 1H), 7.23 percent (DD, J=1,6, and 8.4 Hz, 1H),? 7.04 baby mortality (s, 1H), 5,16 (s, 2H), of 3.94 (s, 3H), 3,44 (t, J=5.6 Hz, 2H), 2,59 (t, J=5.6 Hz, 2H), 2,43 (s, 3H), 1,63 was 1.69 (m, 2H), 1,22-1,25 (m, 2H).

Example 408

Synthesis of (Z)-3-benzyl-5-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]imidazolidin-2,4-dione

Formula 189

Synthesis of methyl ester of (Z)-2-benzyloxycarbonylamino-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

To the suspension in methylene chloride (10 ml) of tert-butoxide potassium (290 mg) was added dropwise at-70ºC solution in methylene chloride (3 ml) methyl ester benzyloxycarbonylamino(diethoxypropane)acetic acid (850 mg). After stirring the reaction solution at-70ºC for 2 hours was added dropwise a solution of methylene chloride (7 ml) of 3-methoxy-4-(-methyl-1H-imidazol-1-yl)benzaldehyde (500 mg), obtained in example 1. The reaction solution was stirred at-70ºC for 1 hour and then stirred at room temperature for 4 hours. After completion of the reaction to the reaction solution were added ethyl acetate and a saturated solution of ammonium chloride and the organic layer was separated. After drying the organic layer through anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (ethyl acetate 4:1→eluting solvent: hexane:ethyl acetate) and received 433 mg (45%) of the methyl ester of (Z)-2-benzyloxycarbonylamino-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): is 2.37 (s, 3H), 3,68 (s, 3H), 3,86 (s, 3H), 5,11 (s, 2H), 6,50 (Sirs, 1H), 6,91 (s, 1H), 7,11-7,35 (m, 9H), of 7.70 (s, 1H).

Synthesis of benzyl ester of (Z)-(1-benzylcarbamoyl-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl)carbamino acid

To a solution of methyl ester (Z)-2-benzyloxycarbonylamino-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (433 mg)obtained in the previous phase, in THF (1 ml) and methanol (2 ml) was added 2n. the sodium hydroxide solution (1.5 ml) and the reaction solution was stirred at room temperature for 12 hours. After completion of the reaction to reactionauditory was added 2n. hydrochloric acid solution (1.5 ml) to neutralize the solution and the reaction solution was extracted with ethyl acetate. Then the organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. By adding a simple ether to the resulting residue was obtained 363 mg (87%) of compound carboxylic acid in the form of solids. To a solution in DMF (3 ml) of the obtained carboxylic acid (66 mg) and benzylamine (0,018 ml) was added diethylethanolamine (0.05 ml), HOBT (30 mg) and EDC (40 mg) and the reaction solution was stirred at room temperature for 12 hours. After completion of the reaction to the reaction solution were added ethyl acetate and saturated aqueous sodium bicarbonate solution and after separation of the organic layer and drying the resulting organic layer by using anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: hexane:ethyl acetate=4:1→ethyl acetate) and received 448 mg (60%) of benzyl ester of (Z)-(1-benzylcarbamoyl-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl)carbamino acid. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,30 (s, 3H), 3,68 (s, 3H), 4,55 (d, J=7.2 Hz, 2H), further 5.15 (s, 2H), 6.22 per 6,38 (m, 1H), 6,55 (shirt, J=2 Hz, 1H), 6,91 (s, 1H), 7.03 is-7,39 (m, 14H), 7,68 (s, 1H).

Synthesis of (Z)-3-benzyl-5-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]imidazolidin-2,4-dione

To a solution in THF (3 ml) benzyl ester (Z)-{1-benzylcarbamoyl-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}carbamino acid (48 mg)obtained above, was added TBAF (1M solution in THF, 0.01 ml) and was carried out by heating the reaction solution to the boiling point under reflux for 3 hours. After the reaction solution was allowed to cool to room temperature, was added ethyl acetate and washed with a saturated solution of ammonium chloride. After drying the organic layer over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluting solvent: hexane:ethyl acetate 1:1→ethyl acetate) and obtained 28 mg (75%) of (Z)-3-benzyl-5-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]imidazolidin-2,4-dione. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,31 (s, 3H), of 3.78 (s, 3H), 4,79 (s, 2H), 6,72 (s, 1H), 6,88 (Sirs, 1H), 7.03 is was 7.45 (m, 9H), for 9.95 (s, 1H), 12.7mm (Sirs, 1H).

Example 409

Synthesis of (Z)-5-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-3-(4-methoxyphenyl)-2-dioxoimidazolidin-4-it

Formula 190

Synthesis of (Z)-5-[3-methoxy-4-(4-methyl-1H-imidazol-yl)benzylidene]-3-(4-methoxyphenyl)-2-dioxoimidazolidin-4-it

To a solution in ethanol (2 ml) of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (20 mg)obtained in example 1 and 3-(4-methoxyphenyl)-2-dioxoimidazolidin-4-it (21 mg) was added piperidine (0,019 ml) and was carried out by heating the reaction solution to the boiling point under reflux for 12 hours. The reaction solution was allowed to cool to room temperature and the precipitated solid was isolated by filtration and, after washing with ethanol and simple broadcast received 18 mg (47%) specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): of 2.15 (s, 3H), 3,81 (s, 3H), 3,93 (s, 3H), 6,69 (s, 1H), 7,22 (d, J=9,2 Hz, 2H), 7,20 (s, 1H), 7,38 (d, J=9,2 Hz, 2H), 7,44 (d, J=8.0 Hz, 1H), 7,54 (Sirs, 1H), 7,56 (sird, J=8.0 Hz, 1H), 7,85 (Sirs, 1H).

Compounds shown in table 9 were synthesized as described in example 409. Structural formulas and physical-chemical properties are presented in table 9, respectively.

Table 10
ExampleXYData: MS m/z
410 NM++H: 435 (ESI)
411NM++N: 405 (ESI)
412IUM++H: 435 (ESI)

Example 413 and the Example 414

Synthesis of (E)-N-[(4R) and (4S)-chroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 191

To a solution in DMF (4 ml) of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (70 mg)obtained in example 121, in an atmosphere of nitrogen was added at room temperature chroman-4-ylamine (CAS#53981-38-7) (49 mg), EDC (62 mg) and HOBT (44 mg) and the reaction solution was stirred at room temperature for 17 hours. To the reaction solution were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate the organic layer was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (eluting solvent system methanol-ethyl acetate) was obtained (E)-N-(chroman-4-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)FeNi is]acrylamide, the racemic compound (90 mg). This compound (50 mg) were separated using a CHIRALPAKTMAD-H (2 cm×25 cm : mobile phase; hexane-ethanol 20%) of the company Daicel Chemical Industries, Ltd. and has been mentioned in the title optically active substance with a retention time of 22 minutes (16 mg,>99% of ei) and indicated in the title optically active substance with a retention time of 28 minutes (19 mg, >98% of ei). The physical properties specified in the title optically active substance with a retention time of 22 minutes (example 413) following.

1H-NMR (CDCl3) δ (ppm): 2,11-of 2.21 (m, 1H), 2.26 and-a 2.36 (m, 1H), to 2.29 (s, 3H), 3,88 (s, 3H), 4,15-to 4.23 (m, 1H), 4,27 is 4.35 (m, 1H), 5.25-in, 5,32 (m, 1H), 5,88 (d, J=7.2 Hz, 1H), to 6.39 (d, J=15.6 Hz, 1H), 6,83-to 6.95 (m, 3H), 7,11-7,28 (m, 5H), to 7.67 (d, J=15.2 Hz, 1H), 7,71 (d, J=1.2 Hz, 1H).

The physical properties specified in the title optically active substance with a retention time of 22 minutes (Example 414) following.

1H-NMR (CDCl3) δ (ppm): 2,11-of 2.21 (m, 1H), 2.26 and-a 2.36 (m, 1H), to 2.29 (s, 3H), 3,88 (s, 3H), 4,15-to 4.23 (m, 1H), 4,27 is 4.35 (m, 1H), 5.25-in, 5,32 (m, 1H), 5,88 (d, J=7.2 Hz, 1H), to 6.39 (d, J=15.6 Hz, 1H), 6,83-to 6.95 (m, 3H), 7,11-7,28 (m, 5H), to 7.67 (d, J=15.2 Hz, 1H), 7,71 (d, J=1.2 Hz, 1H).

Example 415

Synthesis of (E)-N-[1-(4-forfinal)-1-methylethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

Formula 192

To a solution in DMF (5 ml) of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (60 mg)obtained in example 121 was added at room themes is the temperature value in nitrogen atmosphere 1-(4-forfinal)-1-methylethylamine (CAS#17797-10-3) (43 mg), EDC (53 mg) and HOBT (38 mg) and the reaction solution was stirred at room temperature for 12 hours. To the reaction solution were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate the organic layer was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (eluting solvent system methanol-ethyl acetate) and got mentioned in the title compound (60 mg).

1H-NMR (CDCl3) δ (ppm): 1.77 in (s, 6H), to 2.29 (d, J=0.8 Hz, 3H), a 3.87 (s, 3H), 5,90 (Sirs, 1H), 6,41 (d, J=15.2 Hz, 1H), 6.90 to-6,94 (m, 1H), 6,97-7,05 (m, 2H), to 7.09 (d, J=2.0 Hz, 1H), 7,14 (DD, J=2,0, 8.0 Hz, 1H), 7,20-7,28 (m, 1H), 7,35-the 7.43 (m, 2H), 7,54 (d, J=15.2 Hz, 1H), 7,71 (d, J=1.2 Hz, 1H).

Example 416

Synthesis of (E)-1-(3,4-diferensial)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-he

Formula 193

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

To a suspension of sodium hydride (mineral oil 40%, 2,77 g) in THF (50 ml) and DMF (200 ml) was added dropwise within 20 minutes at 5ºC solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (10 g)obtained in example 1 and 1-acetylpiperidine-2-it (7,17 g) in THF (50 ml) and DMF (200 ml). This reaction solution was stirred at 0ºC for 2 hours. Reaction the second solution was added to ice water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated solution of sodium chloride and concentrated under reduced pressure after drying over anhydrous magnesium sulfate. Precipitated solids were separated by filtration and, after washing with diethyl ether there was obtained 5.0 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,86 is 1.96 (m, 2H), 2,30 (s, 3H), 2,81-2,87 (m, 2H), 3,42-to 3.50 (m, 2H), 3,86 (s, 3H), 5,97 (Sirs, 1H), 6,93 (s, 1H), 7,00-was 7.08 (m, 2H), 7,22-7,28 (m, 1H), 7,71 (d, J=1.2 Hz, 1H), 7,79 (s, 1H).

Synthesis of (E)-1-(3,4-diferensial)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

To a solution in DMF (6.0 ml) (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it (100 mg)obtained above was added dropwise at 0ºC bis(trimethylsilyl)amide lithium (1M solution in hexane, to 0.60 ml) and the reaction solution was stirred at 0ºC for 30 minutes. To this solution at 0ºC was added 3,4-differenziale (0.06 ml) and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was added ice water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate then concentrated under reduced pressure. The obtained residue was column purified chromium is cografya on silica gel (eluting solvent system heptane-ethyl acetate) and received 110 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,83-of 1.92 (m, 2H), 2,30 (s, 3H), 2,80-2,87 (m, 2H), 3,34-to 3.41 (m, 2H), 3,86 (s, 3H), of 4.66 (s, 2H), 6,91-to 6.95 (m, 1H), 7,00-7,07 (m, 3H), 7,07-to 7.18 (m, 2H), 7,22-7,28 (m, 1H), 7,71 (d, J=1.6 Hz, 1H), 7,86 (s, 1H).

Example 417

Synthesis of (E)-1-[1-(3,4-diferensial)-(3S)-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 194

Synthesis of ethyl ester of 5-chloro-2-(diethoxyphosphoryl)valerianic acid

Sodium hydride (mineral oil 40%, and 9.8 g) was washed with hexane (50 ml) 3 times to remove oily substances. To a suspension in THF (400 ml) of sodium hydride at 0ºC for 30 minutes was added dropwise a solution of triethylphosphate acid (50 g) in THF (100 ml). Then the reaction solution was allowed to warm to room temperature and stirred for 1 hour. To this reaction solution for 30 minutes was added dropwise 1-bromo-3-chloropropane (70,2 g). After completion of adding dropwise for 15 hours was carried out by heating the reaction solution while boiling under reflux. This reaction solution was allowed to cool to room temperature, was added ethyl acetate (1 l) and saturated aqueous solution of ammonium chloride (1 l) and the organic layer was separated. By drying with anhydrous magnesium sulfate condensate obtained organic layer under reduced pressure got to 61.2 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,26-to 1.38 (m, 9H), 1,55-of 2.36 (m, 4H), 2,89-a 3.01 (m, 1H), 3,54 (t, J=6.4 Hz, 2H), 4,23-4,58 (m, 6H).

Synthesis of ethyl ester of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid

To a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (5 g)obtained in example 1 in THF (60 ml) and ethanol (20 ml) were successively added ethyl ester 5-chloro-2-(diethoxyphosphoryl)valerianic acid (7.6 g) and the monohydrate of lithium hydroxide (2.9 g) and the reaction solution was stirred at room temperature overnight. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Received 3,76 g specified in the connection header by purification of the residue by chromatography on silica gel (eluting solvent: heptane:ethyl acetate=1:1) and recrystallization of the resulting solid substance from a mixture of solvents consisting of ethyl acetate and hexane. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 1.37 (t, J=7,6 Hz, 3H), 2,02-of 2.09 (m, 2H), 2,30 (s, 3H), 2,70 was 2.76 (m, 2H), 3,60 (t, J=6.4 Hz, 2H), 3,88 (s, 3H), 4,29 (kV, J=7,6 Hz, 2H), 6,94 (m, 1H), 7,02 d, J=1.2 Hz, 1H), 7,06 (DD, J=8,4, 1.2 Hz, 1H), 7,26 (d, J=8,4 Hz, 1H), 7,68 (s, 1H), 7,72 (d, J=1.2 Hz, 1H).

Synthesis of tert-butyl ester [(3S)-1-(3,4-diferensial)pyrrolidin-3-yl]carbamino acid

To a solution of (3S)-3-(tert-butoxycarbonylamino)pyrrolidine (916 mg) in methylene chloride (10 ml) were successively added 3,4-differenziale (0.7 ml) and IPEA (2.2 ml) and the reaction solution was stirred at room temperature for 20 hours. After completion of the reaction to the reaction solution was added saturated aqueous sodium bicarbonate solution and the organic layer was separated. It was dried over anhydrous magnesium sulfate and the organic layer was concentrated under reduced pressure. Received 1.55 g specified in the connection header by purification of the residue by chromatography on silica gel (eluting solvent: heptane:ethyl acetate=1:1). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): the 1.44 (s, 9H), 1,55-of 1.64 (m, 1H), 2,18-2,22 (m, 2H), 2,46-of 2.81 (m, 3H), 3,52 (d, J=13,6 Hz, 1H), 3,55 (d, J=13,6 Hz, 1H), 4,11-to 4.23 (m, 1H), 4,82 (Sirs, 1H), 6,97-7,19 (m, 3H).

Synthesis dihydrochloride [(3S)-1-(3,4-diferensial)pyrrolidin-3-yl]amine

To a solution of tert-butyl methyl ether (3S)-(1-(3,4-diferensial)pyrrolidin-3-yl)carbamino acid (1.55 g) in ethyl acetate (5 ml) was added 4n. a solution of hydrochloric acid in ethyl acetate (5 ml) and the reaction solution was stirred at room temperaturesare 10 hours the precipitated substance was isolated from the reaction solution by filtration, and thus making a simple washing with ether, received 904 mg specified in the connection header. The physical properties of this compound are as follows.

ESI-MS; m/z 213 [M++H].

Synthesis of (E)-1-[1-(3,4-diferensial)-(3S)-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

To a solution of ethyl ester of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (200 mg) and dihydrochloride ((3S)-1-(3,4-diferensial)pyrrolidin-3-yl)amine (315 mg) in acetonitrile (8 ml) and water (2 ml) was added potassium carbonate (228 mg) and sodium iodide (831 mg). After heating the reaction solution to the boiling point under reflux for 12 hours, the reaction solution was allowed to cool to room temperature and concentrated under reduced pressure. To the obtained residue was added 2n. the sodium hydroxide solution (1 ml) in ethanol (5 ml). After stirring the reaction mixture at room temperature for 12 hours it was neutralized using 5N. hydrochloric acid and the reaction solution was extracted with ethyl acetate. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Received 200 mg specified in the connection header by purification of the residue of chromium is ografia on silica gel (Carrier: Chromatorex TMNH; eluting solvent: ethyl acetate). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,75-of 1.93 (m, 3H), 2,22 is 2.33 (m, 2H), to 2.29 (s, 3H), 2,50 (DD, J=10,4, and 8.4 Hz, 1H), 2,70 (DD, J=10,4, 3.6 Hz, 1H), 2.77-to 2,95 (m, 3H), 3,45-3,62 (m, 4H), of 3.84 (s, 3H), 5,17-of 5.45 (m, 1H), 6,92 (s, 1H), 6,98-7,27 (m, 6H), of 7.70 (d, J=1.2 Hz, 1H), 7,78 (s, 1H).

Example 418

Synthesis of (E)-1-indan-2-yl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 195

Synthesis of tert-butyl ester 5-chloro-2-(diethoxyphosphoryl)valerianic acid

Sodium hydride (mineral oil 40%, 17,4 g) was washed 3 times with hexane (100 ml) to remove oily substances. To a suspension of sodium hydride in THF (500 ml) at 0ºC for 30 minutes was added dropwise a solution in THF (100 ml) of tert-butyl methyl ether diethylphosphonate acid (100 g). Then the reaction solution was allowed to warm to room temperature and stirred for 1 hour. To this reaction solution for 30 minutes was added dropwise a solution of 1-bromo-3-chloropropane (125 g) in THF (100 ml). After completion of adding dropwise for 15 hours was carried out by heating the reaction solution while boiling under reflux. This reaction solution was allowed to cool to room temperature, was added ethyl acetate (1 l) and saturated aqueous solution x is orida of ammonia (1 l) and the organic layer was separated. By drying with anhydrous magnesium sulfate and condensation of the organic layer under reduced pressure got to 113.4 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,31 is 1.48 (m, 6H), to 1.48 (s, 9H), 1,79 with 2.14 (m, 4H), 2,73-only 2.91 (m, 1H), 3,55 (t, J=6.4 Hz, 2H), 4,10-4,19 (m, 4H).

Synthesis of tert-butyl methyl ether (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid

To a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (50 g) in THF (600 ml) and ethanol (200 ml)were added alternately tert-butyl ester 5-chloro-2-(diethoxyphosphoryl)valerianic acid (83,5 g) and the monohydrate of lithium hydroxide (29,1 g) and the reaction solution was stirred at room temperature overnight. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Received 54,9 g specified in the connection header by purification of the residue by chromatography on silica gel (eluting solvent: heptane:ethyl acetate=1:1) and recrystallization of the resulting solid substance from a mixed solution of ethyl acetate and hexane. Physical properties of this with the following organisations.

1H-NMR (CDCl3) δ (ppm): 1.55V (s, 9H), 1,99-of 2.08 (m, 2H), 2,30 (s, 3H), 2.63 in-a 2.71 (m, 2H)and 3.59 (t, J=6.4 Hz, 2H), a 3.87 (s, 3H), 6,93 (m, 1H), 7,00 (d, J=1.2 Hz, 1H), to 7.09 (DD, J=8,4, 1.2 Hz, 1H), 7,27 (d, J=8,4 Hz, 1H), 7,58 (s, 1H), 7,72 (m, 1H).

Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid, salt triperoxonane acid

To a solution of tert-butyl methyl ether (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (5 g) in methylene chloride (20 ml) was added triperoxonane acid (10 ml) and the reaction solution was stirred at room temperature for 2 hours. After confirming disappearance of the starting compounds, the reaction solution was concentrated under reduced pressure. The resulting solids were isolated by filtration and, after washing the ethyl acetate was obtained 5.7 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 1,93-2,03 (m, 2H), 2,35 (s, 3H), 2,58-of 2.66 (m, 2H), 3,70 (t, J=6.4 Hz, 2H), 3,91 (s, 3H), 7,24 (DD, J=8,4, 1.2 Hz, 1H), 7,37 (d, J=1.2 Hz, 1H), to 7.64 (d, J=8,4, 1H), 7,66 (m, 1H), 7,76 (s, 1H), 9,36 (m, 1H).

Synthesis of indan-2-ylamide (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid

To a solution in DMF (200 ml) of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (13 g), and hydrochloride of 2-aminoindane (7,8 g) poach the Reden added IPEA (24,1 ml), HOBT (9.4 g) and EDC (13.3 g) and the reaction solution was stirred at room temperature. After 15 hours to the reaction solution were added ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was separated. After washing the organic layer with a saturated solution of sodium chloride, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Received 6,93 g specified in the connection header by purification of the residue by chromatography on silica gel (eluting solvent: ethyl acetate). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,93-2,04 (m, 2H), 2,28 (s, 3H), 2,67-by 2.73 (m, 2H), 2,90 (DD, J=16,0, 4,4 Hz, 2H), 3,40 (DD, J=16,0, 7.2 Hz, 2H), of 3.56 (t, J=5.6 Hz, 2H), of 3.84 (s, 3H), 4,81-of 4.95 (m, 1H), 6,29 (d, J=7.2 Hz, 1H), 6.90 to-6,94 (m, 3H), 7,10 (s, 1H), 7.18 in-7,27 (m, 5H), to 7.68 (d, J=1.6 Hz, 1H).

Synthesis of (E)-1-indan-2-yl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

To a solution in DMF (50 ml) indan-2-ylamide (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (6.9 g) was added at room temperature sodium hydride (mineral oil 40%, 740 mg) and the reaction solution was stirred at room temperature for 1 hour and 30 minutes. The reaction solution was poured into ice-cold water after completion of the reaction, and the precipitated solids were isolated by filtration. By Perek is stallization obtained solid substance from a mixture of solvents, consisting of ethyl acetate, ethanol and hexane were obtained 4.9 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,81-of 1.88 (m, 2H), 2,30 (s, 3H), 2.77-to 2,84 (m, 2H), 3,00 (DD, J=16,4, 6,0 Hz, 2H), 3,24-of 3.32 (m, 4H), 3,86 (s, 3H), 5,75-of 5.83 (m, 1H), 6,93 (d, J=1.2 Hz, 1H), 7,02-7,07 (m, 2H), 7,17-7,28 (m, 5H), 7,71 (d, J=1.2 Hz, 1H), a 7.85 (s, 1H).

Example 419 and Example 420

Synthesis of (E)-1-[(4R) and (4S)-chroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 196

To a solution of ethyl ester of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (50 mg)obtained in example 417, in acetonitrile (2 ml) and water (0.2 ml) was added at room temperature chroman-4-ylamine (CAS#53981-38-7) (31 mg) and cesium carbonate (90 mg) and the interaction of the mixture was carried out in the reaction mixture in the microwave for synthesis (80 watts; About 150ºc) for 1 hour. The reaction solution was allowed to cool to room temperature, to the reaction solution were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate the organic layer was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent: the system heptane-ethyl acetate) and was obtained ethyl ester (E)-5-(chroman-4-ylamino)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid (25 mg). To a solution in ethanol (3 ml), ethyl ether (E)-5-(chroman-4-ylamino)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid (59 mg), obtained by repeating the above operations, at room temperature was added 2n. the sodium hydroxide solution (1 ml), the reaction solution was stirred at room temperature for 12 hours and within 1 hour was carried out by heating to the boiling temperature under reflux. The reaction solution was allowed to cool to room temperature, the reaction solution was added with ice cooling 2n. hydrochloric acid solution (1 ml) and the reaction solution was concentrated under reduced pressure. To a suspension in DMF (3 ml) of the obtained residue was added EDC (50 mg) and HOBT (36 mg) and the reaction solution was stirred at room temperature for 16 hours. To the reaction solution were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate the organic layer was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent system heptane-ethyl acetate) was obtained (E)-1-(chroman-4-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it looks like a rat the chemical compound (21 mg). This compound (21 mg) were separated using a CHIRALPAKTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm:mobile phase; ethanol) and got mentioned in the title optically active substance with a retention time of 45 minutes (7 mg, >99% of ei) and indicated in the title optically active substance with a retention time of 61 minutes (6 mg, >99% of ei). The physical properties specified in the title optically active substance with a retention time of 45 minutes (example 419) following.

1H-NMR (CDCl3) δ (ppm): 1.70 to 1,95 (m, 2H), 2.00 in 2,28 (m, 2H), 2,30 (s, 3H), 2,74-to 2.85 (m, 1H), 2,87 are 2.98 (m, 1H), 3,05-3,14 (m, 1H), 3,15-3,26 (m, 1H), a 3.87 (s, 3H), 4,20-4,30 (m, 1H), or 4.31-and 4.40 (m, 1H), 6,23 (DD, J=6,4, 9.6 Hz, 1H), at 6.84 (d, J=8.0 Hz, 1H), 6.89 in (DD, J=7,2, 7,6 Hz, 1H), 6,94 (s, 1H), 7,02-7,10 (m, 3H), 7,12-to 7.18 (m, 1H), 7.23 percent-7,29 (m, 1H), 7,72 (s, 1H), to $ 7.91 (s, 1H).

The physical properties specified in the title optically active substance with a retention time of 61 minutes (example 420) following.

1H-NMR (CDCl3) δ (ppm): 1.70 to 1,95 (m, 2H), 2.00 in 2,28 (m, 2H), 2,30 (s, 3H), 2,74-to 2.85 (m, 1H), 2,87 are 2.98 (m, 1H), 3,05-3,14 (m, 1H), 3,15-3,26 (m, 1H), a 3.87 (s, 3H), 4,20-4,30 (m, 1H), or 4.31-and 4.40 (m, 1H), 6,23 (DD, J=6,4, 9.6 Hz, 1H), at 6.84 (d, J=8.0 Hz, 1H), 6.89 in (DD, J=7,2, 7,6 Hz, 1H), 6,94 (s, 1H), 7,02-7,10 (m, 3H), 7,12-to 7.18 (m, 1H), 7.23 percent-7,29 (m, 1H), 7,72 (s, 1H), to $ 7.91 (s, 1H).

Example 421 and the Example 422

Synthesis of (E)-1-[(R) and (S)-6-methoxyindol-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 197

To a suspension in DMF (2 ml) of (E)-5-chloro-2-[3-methoxy-4-(methyl-1H-imidazol-1-yl)benzylidene]valerianic acid in salt form triperoxonane acid (50 mg), obtained in example 418, and 6-methoxyindol-1-ylamine (CAS#103028-81-5) (27 mg) was added at room temperature IPEA (0.06 ml), EDC (64 mg) and HOBT (45 mg) and the reaction solution was stirred at room temperature for 12 hours. To the reaction solution was added saturated sodium bicarbonate solution and ethyl acetate and the organic layer was separated. The organic layer was washed successively with a saturated solution of ammonium chloride and water, and saturated sodium chloride solution and after drying over anhydrous magnesium sulfate the organic layer was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (eluting solvent system methanol-ethyl acetate) and received (6-methoxyindol-1-yl)amide (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid (29 mg). To a solution in DMF (2 ml) were obtained (6-methoxyindol-1-yl)amide (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (29 mg) was added at room temperature sodium hydride (mineral oil 40%, 20 mg) and the reaction solution was stirred for 10 minutes at room temperature. To the reaction solution was added saturated sodium bicarbonate solution and ethyl acetate and the organic layer was separated. The organic layer was washed successively with a saturated solution of ammonium chloride and water and a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate the organic layer was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (eluting solvent system methanol-ethyl acetate) was obtained (E)-1-(6-methoxyindol-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it is in the form of a racemic compound (17 mg). This compound (17 mg) were separated using a CHIRALCELTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm:mobile phase; ethanol) and got mentioned in the title optically active substance with a retention time of 36 minutes (6 mg, >99% of ei) and indicated in the title optically active substance with a retention time of 43 minutes (6 mg, >95% of ei). The physical properties specified in the title optically active substance with a retention time of 36 minutes (example 421) following.

1H-NMR (CDCl3) δ (ppm): 1,73-1,90 (m, 2H), 1,94-2,03 (m, 1H), 2,30 (s, 3H), 2,45-of 2.56 (m, 1H), 2,74-to 3.02 (m, 4H), 3.04 from 3.21-in (m, 2H), of 3.77 (s, 3H), 3,86 (s, 3H), 6,47 (DD, J=7,6, and 8.4 Hz, 1H), 6,70 (d, J=2.4 Hz, 1H), 6,80 (DD, J=2,4, and 8.4 Hz, 1H), 6,94 (s, 1H), 7.03 is-7,10 (m, 2H), 7,15 (d, J=8,4 Hz, 1H), 7,22-7,28 (m, 1H), 7,72 (s, 1H), of 7.90 (s, 1H).

The physical properties specified in the title optically active substance with a retention time of 43 minutes (example 422) following.

1H-NMR (CDCl3) δ (ppm): 1,73-1,90 (m, 2H), 1,94-2,03 (m, 1H), 2,30 (s, 3H), 2,45-of 2.56 (m, 1H), 2,74-to 3.02 (m, 4H), 3.04 from 3.21-in (m, 2H), of 3.77 (s, 3H), 3,86 (s, 3H), 6,47 (DD, J=7,6, and 8.4 Hz, 1H), 6,70 (d, J=2.4 Hz, 1H), 6,80 (DD, J=2,4, and 8.4 Hz, 1H), 6,94 (s, 1H), 7.03 is-7,10 (m, 2H), 7,15 (d, J=8,4 Hz, 1H), 7,22-7,28 (m, 1H), 7,72 (s, 1H), of 7.90 (s, 1H).

Example 423 and the Example 424/p>

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-[(R) and (S)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]piperidine-2-it

Formula 198

To a solution of ethyl ester of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid (50 mg)obtained in example 417, in acetonitrile (3 ml) and water (0.3 ml)was added at room temperature 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylamine (CAS#50399-51-4) (25 mg), potassium carbonate (57 mg) and sodium iodide (21 mg) and was carried out by heating the reaction solution at the boiling point under reflux for two days. The reaction solution was allowed to cool to room temperature, to the reaction solution were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent system heptane-ethyl acetate) and was obtained ethyl ester (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1 ylamino)valerianic acid (24 mg). To a solution in ethanol (1 ml) obtained ethyl ester (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-(7-methoxy-1,2,34-tetrahydronaphthalen-1 ylamino)valerianic acid (24 mg) was added at room temperature for 2H. a solution of sodium hydroxide (0.3 ml) and the reaction solution was stirred at room temperature for 16 hours. To the reaction solution was added with ice cooling 2n. hydrochloric acid solution (0.3 ml) and the reaction solution was concentrated under reduced pressure. To a suspension of the obtained residue in DMF (2 ml) was added EDC (25 mg) and HOBT (18 mg) and the reaction solution was stirred at room temperature for 24 hours. To the reaction solution were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent system heptane-ethyl acetate) was obtained (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-2-it is in the form of a racemic compound (19 mg). This compound (19 mg) were separated using a CHIRALCELTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm:mobile phase; ethanol) and got mentioned in the title optically active substance with a retention time of 17 minutes (7 mg, >99% of ei) and indicated in the title optically active substance with a retention time of 25 minutes (6 mg, >99% of ei). The physical properties of the criminal code is mentioned in the title optically active substance with a retention time of 17 minutes (example 423) following.

1H-NMR (CDCl3) δ (ppm): 1,72-to 1.82 (m, 4H), 1,96 with 2.14 (m, 2H), 2,31 (s, 3H), 2,68-2,84 (m, 3H), 2,88 are 2.98 (m, 1H), 3,05-3,13 (m, 1H), 3,18-3,26 (m, 1H, in), 3.75 (s, 3H), a 3.87 (s, 3H), 6,07-x 6.15 (m, 1H), 6,66 (d, J=2,8 Hz, 1H), to 6.75 (DD, J=2,8, and 8.4 Hz, 1H), 6,95 (s, 1H), 7,02-7,11 (m, 3H), 7.24 to 7,30 (m, 1H), 7,73 (d, J=1.2 Hz, 1H), 7,92 (s, 1H).

The physical properties specified in the title optically-active substance (example 424) with a retention time of 25 minutes following.

1H-NMR (CDCl3) δ (ppm): 1,72-to 1.82 (m, 4H), 1,96 with 2.14 (m, 2H), 2,31 (s, 3H), 2,68-2,84 (m, 3H), 2,88 are 2.98 (m, 1H), 3,05-3,13 (m, 1H), 3,18-3,26 (m, 1H, in), 3.75 (s, 3H), a 3.87 (s, 3H), 6,07-x 6.15 (m, 1H), 6,66 (d, J=2,8 Hz, 1H), to 6.75 (DD, J=2,8, and 8.4 Hz, 1H), 6,95 (s, 1H), 7,02-7,11 (m, 3H), 7.24 to 7,30 (m, 1H), 7,73 (d, J=1.2 Hz, 1H), 7,92 (s, 1H).

Example 425

Synthesis of (E)-1-[(1S)-1-(4-forfinal)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 199

Synthesis of ((1S)-1-(4-forfinal)ethyl)amide (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid

To a solution in DMF (50 ml) of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (8.00 g) and (S)-1-(4-forfinal)ethylamine (2,60 g) were successively added IPEA (12,4 ml), EDC (6,82 g) and HOBT (to 4.81 g) and the reaction solution was stirred at room temperature overnight. After confirming disappearance of the starting substances, the solvent was concentrated under reduced pressure, to the residue was added water and utilized the t and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (eluting solvent: heptane-ethyl acetate=2:3→1:1→ethyl acetate) and received 3,90 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,56 (d, J=6.8 Hz, 3H), 1,95-2,02 (m, 2H), 2,30 (s, 3H), 2,70-to 2.74 (m, 2H), to 3.58 (t, J=6.0 Hz, 2H), 3,85 (s, 3H), 5,17-5,24 (m, 1H), x 6.15 (d, J=6,8 Hz, 1H), 6,92-of 6.96 (m, 3H), 7,02-7,07 (m, 2H), 7,17 (s, 1H), 7.23 percent-of 7.25 (m, 1H), 7,32 and 7.36 (m, 2H), 7,70-7,71 (s, 1H).

Synthesis of (E)-1-[(1S)-1-(4-forfinal)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

To a solution in DMF (30 ml) ((S)-1-(4-forfinal)ethyl)amide (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl]benzylidenemalonate acid (3,90 g) was added at 0ºC sodium hydride (mineral oil 40%, 410 mg), the reaction solution was allowed to warm to room temperature and was stirred overnight. After confirming disappearance of the starting compounds, the reaction solution was cooled to 0ºC and to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. OST the current was purified by chromatography on silica gel (eluting solvent; the ethyl acetate→ethyl acetate:ethanol 10:1). The obtained solid is washed with diethyl ether and the subsequent recrystallization with ethyl acetate received 2,60 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,50 (d, J=7.2 Hz, 3H), 1,65-of 1.74 (m, 1H), 1,78-to 1.87 (m, 1H), 2,30 (s, 3H), 2.71 to to 2.85 (m, 2H), 2.91 in-of 2.97 (m, 1H), 3,24 (DDD, J=3,6, 8,8, 12.0 Hz, 1H), 3,86 (s, 3H), 6,23 (kV, J=7.2 Hz, 1H), 6,93 (t, J=1.2 Hz, 1H), 7,00-7,06 (m, 4H), 7.24 to 7,26 (m, 1H), 7,31-7,34 (m, 2H), 7,72 (d, J=1.2 Hz, 1H), 7,89 (s, 1H).

Example 426

Synthesis of (E)-1-[3-fluoro-4-(morpholine-4-yl)benzyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 200

Synthesis of 3-fluoro-4-(morpholine-4-yl)benzonitrile

To a solution in DMF (20 ml) of 3,4-difterential (3.00 g) was added morpholine (2,82 g) and potassium carbonate (5,97 g) and the reaction solution was allowed to warm up to 100ºC and was stirred for 5.5 hours. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and by condensation under reduced pressure got to 4.41 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) is (ppm): 3,19-up 3.22 (m, 4H), 3,86-3,88 (m, 4H), 6,92 (t, J=8,4 Hz, 1H), 7,29 (DD, J=2.0 a, 13,0 Hz, 1H), 7,37-7,40 (m, 1H).

Synthesis of 3-fluoro-4-(morpholine-4-yl)benzylamine

To a suspension in THF (30 ml) sociallyengaged (975 mg) was added dropwise at-78ºC a solution of 3-fluoro-4-(morpholine-4-yl)benzonitrile (to 4.41 g) in THF (10 ml). Then the reaction solution was allowed to warm to room temperature and was stirred overnight. After confirming disappearance of the starting compounds, the reaction solution was cooled to 0ºC, to the reaction solution were successively added water and 5N. the sodium hydroxide solution and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent: ethyl acetate=1:1→heptane-ethyl acetate) and was received of 3.60 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 3,06-is 3.08 (m, 4H), 3,81 (s, 2H), a 3.87-to 3.89 (m, 4H), 6,91 (t, J=8,8 Hz, 1H), 7,01-7,05 (m, 2H).

Synthesis of [3-fluoro-4-(morpholine-4-yl)benzyl]amide (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid

To a solution in DMF (4.0 ml) of 5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid in the form of the Oli triperoxonane acid (200 mg), obtained in example 418, and 3-fluoro-4-(morpholine-4-yl)benzylamine (112 mg) were successively added IPEA (231 mg), EDC (171 mg) and HOBT (120 mg) and the reaction solution was stirred at room temperature overnight. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Received 135 mg specified in the connection header by purifying the obtained residue by chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:methanol=90:10). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,99-to 2.06 (m, 2H), to 2.29 (s, 3H), 2,72 was 2.76 (m, 2H), 3,06-to 3.09 (m, 4H), to 3.58 (t, J=6.0 Hz, 2H), 3,85 (s, 3H), 3,84-3,88 (m, 4H), of 4.49 (d, J=5.6 Hz, 2H), 6,28-6,38 (m, 1H), 6,88-6,98 (m, 4H), 7,01-7,06 (m, 2H), 7,17 (s, 1H), 7,22-7,25 (m, 1H), of 7.70 (s, 1H).

Synthesis of (E)-1-[3-fluoro-4-(morpholine-4-yl)benzyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

To a solution in DMF (4 ml) of [3-fluoro-4-(morpholine-4-yl)benzyl]amide (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl]benzylidene)valerianic acid (135 mg) was added at 0ºC sodium hydride (mineral oil 40%, 35.6 mg) and the reaction solution was allowed to warm to room temperature and stirred is for 45 minutes. After confirming disappearance of the starting compounds, the reaction solution was cooled to 0ºC, to the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By purifying the obtained residue by chromatography on silica gel (eluting solvent; ethyl acetate→ethyl acetate:ethanol 90:10) was received 113 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,82-1,90 (m, 2H), 2,30 (s, 3H), and 2.83 (t, J=5.6 Hz, 2H), 3,07-to 3.09 (m, 4H), 3,37 (t, J=5.6 Hz, 2H), 3,86 (s, 3H), 3,86-3,88 (m, 4H), of 4.66 (s, 2H), 6.90 to (t, J=8.0 Hz, 1H), 6,94 (s, 1H), 7,02-7,05 (m, 4H), 7,25-7,27 (m, 1H), 7,72 (s, 1H), 7,82 (s, 1H).

Example 427

Synthesis of (E)-1-[(6-chloropyridin-2-yl)methyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 201

To a suspension of ethyl ester of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl]benzylidene)valerianic acid (200 mg)obtained in example 417, and 2-(aminomethyl)-6-chloropyridin (CA 188637-75-4) hydrochloride (100 mg) in ethanol (3 ml) and DMF (3 ml) was added anhydrous potassium carbonate (100 mg) and the reaction mixture was stirred at 100ºC for 8 hours. After the reaction mixture was allowed to cool to room temperature, Rea is operating and the mixture was poured into ice water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate then concentrated under reduced pressure. To the residue was added ethanol (10 ml) and aqueous solution (5 ml) of sodium hydroxide (1.0 g) and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was added ice water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate then concentrated under reduced pressure. By purification of the residue by chromatography on silica gel (eluting solvent system heptane-ethyl acetate) received 23 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,88 is 1.96 (m, 2H), 2,30 (s, 3H), 2,82-2,89 (m, 2H), 3,54-3,62 (m, 2H), 3,85 (s, 3H), 4,78 (s, 2H), 6,92 (s, 1H), 6,99-7,05 (m, 2H), 7,20-7,28 (m, 2H), 7,31 (d, J=7,6 Hz, 1H), 7,63 (t, J=7,6 Hz, 1H), of 7.70 (d, J=1.2 Hz, 1H), 7,83 (s, 1H).

Example 428

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-[(6-(morpholine-4-yl)pyridine-3-yl)methyl]piperidine-2-it

Formula 202

Synthesis of 2-[6-(morpholine-4-yl)pyridine-3-yl]metalsound-1,3-dione

To a solution in THF (200 ml) (6-(morpholine-4-yl)pyridine-3-yl)methanol (CA 388088-73-1) (3.2 g), phthalimide (of 3.64 g) and triphenylphosphine (of 6.49 g) was added at 0ºC for 5 the minutes of diisopropylcarbodiimide (5,43 ml). After 12 hours stirring at room temperature the reaction solution was concentrated under reduced pressure. By purification of the residue by chromatography on silica gel (system heptane-ethyl acetate) was obtained 3.8 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 3,42-to 3.50 (m, 4H), 3,74-3,82 (m, 4H), to 4.73 (s, 2H), 6,56 (d, J=8,4 Hz, 1H), 7,42-7,72 (m, 1H), of 7.64-7,72 (m, 2H), 7,78-to 7.84 (m, 2H), 8,29 (d, J=2.0 Hz, 1H).

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl]benzylidene)-1-[(6-(morpholine-4-yl)pyridine-3-yl]methyl)piperidine-2-it

To a solution in ethanol (50 ml) of 2-[6-(morpholine-4-yl)pyridine-3-yl]methylisoborneol-1,3-dione (3.8 g)obtained above, was added hydrazine monohydrate (2,95 ml) and within 2 hours was carried out by heating the reaction solution to the boiling temperature under reflux. The reaction solution was allowed to cool to room temperature, the reaction solution was added diethyl ether (100 ml) and the reaction solution was stirred for 30 minutes at room temperature. C-[6-(morpholine-4-yl)pyridine-3-yl]methylamine (3.0 g) was obtained by filtration of the reaction solution is insoluble solids and condensation of the obtained filtrate under reduced pressure. To a solution in DMF (30 ml) of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (0.20 g)obtained the example 418, and C-[6-(morpholine-4-yl)pyridine-3-yl]methylamine (0,30 g) was added at room temperature, HOBT (0,181 g), IPEA (0,388 ml) and EDC (0,257 g) and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was added water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline solution and after drying over anhydrous magnesium sulfate then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent: from the system heptane-ethyl acetate system methanol-ethyl acetate) and was obtained 0.21 g of [6-(morpholine-4-yl)pyridine-3-yl]methylamide (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid.

To a solution in DMF (30 ml) of [6-(morpholine-4-yl)pyridine-3-yl]methylamide (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid (0.21 g)obtained above was added at room temperature hydric sodium content of mineral oil 40%, and 29.7 mg) and the reaction solution was stirred for 30 minutes at the same temperature. The reaction solution was added water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline solution and after drying over anhydrous magnesium sulfate then concentrated under reduced pressure. By PTS is tough residue by chromatography on silica gel (eluting solvent: from the system heptane-ethyl acetate system methanol-ethyl acetate) received 0.125 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,78-of 1.88 (m, 2H), 2,30 (s, 3H), 2,75-and 2.83 (m, 2H), 3,32-3,39 (m, 2H), 3,44-of 3.54 (m, 4H), 3,76-3,88 (m, 4H), 3,85 (s, 3H), 4,59 (s, 2H), 6,62 (d, J=8,8 Hz, 1H), 6,92 (s, 1H), 6,98? 7.04 baby mortality (m, 2H), 7,20-7,28 (m, 1H), EUR 7.57 (DD, J=2.0 a, 8,8 Hz, 1H), of 7.70 (s, 1H), to 7.84 (s, 1H), 8,12 (d, J=2.0 Hz, 1H).

Example 429

Synthesis of (E)-1-[(5-chloro-2-methylpyridin-3-yl)methyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 203

Synthesis of (5-chloro-2-methylpyridin-3-yl)methanol

To a solution in THF (30 ml) of methyl ester of 5-chloro-2-methylnicotinic acid (CAS# 350597-49-8) (1.0 g) was added at 0ºC lithium borohydride (0,153 g). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was added ice water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline solution and after drying over anhydrous magnesium sulfate then concentrated under reduced pressure. By purification of the residue by chromatography on silica gel (eluting solvent system heptane-ethyl acetate) was obtained 0.26 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 2,47 (s, 3H), 4,70 (s, 2H), 7,74 (d, J=2.4 Hz, 1H), with 8.33 (d, J=2.4 Hz, 1H).

Synthesis of 2-[(5-chloro-2-methylpyridin-3-yl]methyl)isoindole-1,3-dione

To a solution in THF (10 ml) of (5-chloro-2-methylpyridin-3-yl)methanol (0.26 g)obtained above, phthalimide (0,364 g) and t is Ivanilova (0,649 g) was added at 0ºC for 5 minutes diisopropylsalicylic (0,585 ml). The reaction solution was stirred for three days at room temperature and then concentrated under reduced pressure. By purification of the residue by chromatography on silica gel (eluting solvent system heptane-ethyl acetate) was obtained 0.20 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): of 2.68 (s, 3H), of 4.83 (s, 2H), 7,55 (s, 1H), 7,70-7,80 (m, 2H), 7,80-to 7.95 (m, 2H), 8,35 (s, 1H).

Synthesis of (E)-1-[(5-chloro-2-methylpyridin-3-yl)methyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

To a solution of 2-((5-chloro-2-methylpyridin-3-yl)methyl)isoindole-1,3-dione (0.20 g) in ethanol (10 ml) was added hydrazine monohydrate (0,50 ml) and within 2 hours was carried out by heating the reaction solution to the boiling temperature under reflux. The reaction solution was allowed to cool to room temperature, the reaction solution was added diethyl ether (50 ml) and the reaction solution was stirred for 30 minutes at room temperature. C-(5-chloro-2-methylpyridin-3-yl)methylamine (0,13 g) was obtained by filtering off insoluble substances from the reaction solution and condensing the obtained filtrate under reduced pressure.

To a solution in DMF (20 ml) of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid in salt form triperoxonane acid (0.20 g)obtained in example 418, and C-(5-chlorine is-2-methylpyridin-3-yl)methylamine (0,13 g) was added HOBT (0,301 g), IPEA (0,397 ml) and EDC (0,428 g) and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was added water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline solution and after drying over anhydrous magnesium sulfate then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent system heptane-ethyl acetate) and was obtained 0.14 g (5-chloro-2-methylpyridin-3-yl)methylamide (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid.

To a solution in DMF (10 ml) of (5-chloro-2-methylpyridin-3-yl)methylamide (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (0.14 g)obtained above was added at room temperature sodium hydride (mineral oil 40%, with 47.4 mg) and the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was added water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate then concentrated under reduced pressure. By purification of the residue by chromatography on silica gel (eluting solvent system heptane-ethyl acetate) received 0,027 g specified in the connection.

1H-NMR (CDCl3) δ (ppm): 1,90-2,00 (m, 2H), 2,30 (s, 3H), of 2.54 (s, 3H), 2,85 of 2.92 (m, 2H), 3,34-to 3.41 (m, 2H), a 3.87 (s, 3H), 4.72 in (s, 2H), 6,92-to 6.95 (m, 1H), 7,02-was 7.08 (m, 2H), 7.24 to 7,30 (m, 1H), 7,41 (d, J=2.4 Hz, 1H), 7,72 (d, J=1.2 Hz, 1H), 7,87 (s, 1H), of 8.37 (d, J=2.4 Hz, 1H).

Example 430

Synthesis of (E)-1-(4-tert-butylbenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 204

To a solution in DMF (2 ml) of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-she (70 mg)obtained in example 416, was added dropwise under ice cooling bis(trimethylsilyl)amide lithium (1M solution in THF, of 0.47 ml) and the reaction solution was stirred for 30 minutes under ice cooling. Then to the reaction solution was added 1-tert-butyl-4-chloromethylbenzene (0,073 ml) and the reaction solution was stirred for 30 minutes under ice cooling. To the reaction solution were added water and ethyl acetate and the organic layer was separated. The obtained organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent system heptane-ethyl acetate) and was received of 37.8 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): is 1.31 (s, 9H), to 1.86 (m, 2H), 2,30 (s, 3H), 2,82 (m, 2H), 3,38 (m, 2H), 3,85 (s, 3H), 4,70 (s, 2H), 6,92 (t, J=1.2 Hz, 1H), 7,01 (s, 1H), 7,02 (d, J=84 Hz, 1H), 7,22-7,26 (m, 3H), 7,34 (d, J=8,4 Hz, 2H), of 7.70 (d, J=1.2 Hz, 1H), 7,86 (s, 1H).

Example 431

Synthesis of (E)-3-[4-(4-vermeil-1H-imidazol-1-yl)-3-methoxyphenyl]-N-indan-1-alacrimia

Formula 205

In the same way as described in example 147, received 11 mg specified in the header connection on the basis of (E)-3-[4-(4-hydroxymethyl-1H-imidazol-1-yl)-3-methoxyphenyl]-N-indan-1-alacrimia (20 mg)obtained in example 45.

1H-NMR (CDCl3) δ (ppm): 1,87 is 1.96 (m, 1H), 2,65-by 2.73 (m, 1H), 2,90 are 2.98 (m, 1H), 3,01-is 3.08 (m, 1H), 3,90 (s, 3H), of 5.40 (d, J=49.2 Hz, 2H), 5,66 (kV, J=7,6 Hz, 1H), of 5.99 (d, J=8 Hz, 1H), 6,46 (d, J=15.6 Hz, 1H), 7,17-7,37 (m, 8H), of 7.70 (d, J=15.6 Hz, 1H), 7,79 (s, 1H).

Example 432

Synthesis of (E)-3-[4-(4-formyl-1H-imidazol-1-yl)3-methoxyphenyl]-N-indan-1-alacrimia

Formula 206

To a solution in chloroform (5 ml) of (E)-3-(4-(4-hydroxymethyl-1H-imidazol-1-yl)-3-methoxyphenyl)-N-indan-1-alacrimia (15 mg)obtained in example 45 was added activated manganese dioxide (280 mg) and the reaction mixture was stirred at room temperature overnight. The reaction solution was filtered through filter paper and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent: ethyl acetate) and received 30 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,86 is 1.96 (m,1H), 2,63-by 2.73 (m, 1H), 2,89-of 2.97 (m, 1H), 3.00 and-of 3.07 (m, 1H), 3,91 (s, 3H), 5,65 (kV, J=7,6 Hz, 1H), 5,94 (d, J=8,8 Hz, 1H), 6,47 (d, J=15.6 Hz, 1H), 7,19 and 7.36 (m, 6H), of 7.70 (d, J=15.6 Hz, 1H), to 7.84 (d, J=1 Hz, 1H), 7,92 (d, J=1 Hz, 1H), 9,96 (s, 1H).

Example 433

Synthesis of (E)-3-[4-(4-deformity-1H-imidazol-1-yl)-3-methoxyphenyl]-N-indan-1-alacrimia

Formula 207

Received 6 mg specified in the header connection on the basis of the above (E)-3-(4-(4-formyl-1H-imidazol-1-yl)3-methoxyphenyl)-N-indan-1-alacrimia (9 mg) and DAST (0,012 ml) in a manner analogous to the synthesis method of example 147.

1H-NMR (CDCl3) δ (ppm): 1,86 is 1.96 (m, 1H), 2,65-by 2.73 (m, 1H), 2,89-of 2.97 (m, 1H), 3,01-is 3.08 (m, 1H), 3,90 (s, 3H), 5,65 (kV, J=7,6 Hz, 1H), 5,85 (d, J=8,8 Hz, 1H), 6,44 (d, J=15.6 Hz, 1H), 6,74 (t, J=56 Hz, 1H), 7,17 and 7.36 (m, 6H), 7,46 (s, 1H), of 7.70 (d, J=15.6 Hz, 1H), 7,80 (s, 1H).

Example 434

Synthesis of (E)-N-indan-1-yl-3-[3-methoxy-4-(4-methoxymethyl-1H-imidazol-1-yl]phenyl)acrylamide

Formula 208

A solution of thionyl chloride (0.4 ml) (E)-3-[4-(4-hydroxymethyl-1H-imidazol-1-yl)-3-methoxyphenyl]-N-indan-1-alacrimia (15 mg)obtained in example 45, was stirred for 40 minutes at 50ºC and then the reaction solution was concentrated under reduced pressure. To the obtained residue was added a solution of sodium methoxide (40% solution in methanol, 2 ml) and the reaction solution was stirred for 90 minutes at room temperature. After the reaction solution conc who was narrowly under reduced pressure, to the residue were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent system hexane-ethyl acetate) and received 4 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,86-of 1.95 (m, 1H), 2,64-by 2.73 (m, 1H), 2,89-of 2.97 (m, 1H), 3.00 and-of 3.07 (m, 1H), 3,47 (s, 3H), 3,88 (s, 3H), 4,48 (s, 2H), 5,65 (kV, J=7,6 Hz, 1H), 5,85 (d, J=8,4 Hz, 1H), 6.42 per (d, J=15.6 Hz, 1H), 7,15-7,29 (m, 7H), 7,35 (d, J=7,6 Hz, 1H), 7,69 (d, J=15.6 Hz, 1H), 7,78 (s, 1H).

Example 435

Synthesis of (biphenyl-3-ylmethyl)amide (E)-5-hydroxy-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid

Formula 209

Synthesis of ethyl ester of (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]5-(tetrahydropyran-2-yloxy)valerianic acid

To a suspension of sodium hydride (mineral oil 40%, to 1.25 g) in DMF (30 ml) was added dropwise at room temperature triethylphosphate acid (4,89 ml). After stirring the reaction solution at room temperature for 3 hours the solution was added dropwise a solution of 2-(3-bromopropane)tetrahydro-2H-Piran in DMF (10 ml). The reaction solution was stirred at 60ºC for 6 the aces. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and a saturated solution of ammonium chloride and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: hexane:ethyl acetate=2:1→ethyl acetate) and was obtained 2.9 g of ethyl ester of 2-(diethoxyphosphoryl)-5-(tetrahydropyran-2-yloxy) valerianic acid.

To a solution in THF (5 ml) of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (283 mg)obtained in example 1 and ethyl ester of 2-(diethoxyphosphoryl)-5-(tetrahydropyran-2-yloxy)valerianic acid (480 mg) was added monohydrate of lithium hydroxide (110 mg) and the reaction solution was stirred at room temperature for 19 hours. To the reaction solution were added ethyl acetate and a saturated solution of ammonium chloride and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Carrier: ChromatorexTMNH and an eluting solvent: hexane:ethyl acetate=1:1→ethyl is Etat) and received 186 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,36 (t, J=7.2 Hz, 3H), 1,47-of 1.93 (m, 10H), 2,31 (s, 3H), 2,62 was 2.76 (m, 2H), 3,39-of 3.53 (m, 2H), 3,76-a 3.87 (m, 2H), 3,88 (s, 3H), 4,29 (kV, J=7.2 Hz, 2H), 4,54 (Sirs, 1H), 6,94 (Sirs, 1H), 7,05 (Sirs, 1H), 7,13 (sird, J=7,6 Hz, 1H), 7,25 (d, J=7,6 Hz, 1H), 7,66 (Sirs, 1H), 7,72 (Sirs, 1H).

Synthesis of (biphenyl-3-ylmethyl)amide (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-(tetrahydropyran-2-yloxy)valerianic acid

To a solution of ethyl ester of (E)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)5-(tetrahydropyran-2-yloxy)valerianic acid (186 mg)in methanol (3 ml) was added 2n. an aqueous solution of sodium hydroxide (0.5 ml) and the reaction solution was stirred at room temperature for 19 hours. To the reaction solution was added 2n. hydrochloric acid solution (0.5 ml) and the solution was concentrated under reduced pressure. To a solution of the obtained residue in DMF (5 ml) were successively added 3-phenylendiamin (87 mg), HOBT (86 mg), EDC (108 mg) and IPEA (0.15 ml) and the reaction solution was stirred at room temperature for 12 hours. To the reaction solution were added ethyl acetate and a saturated solution of ammonium chloride and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue behaviour is whether chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:methanol=9:1) and received 168 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1.32 to 1,71 (m, 6H), 1,84-of 1.95 (m, 2H), 2,30 (s, 3H), 2,64-2,77 (m, 2H), 3,40-3,47 (m, 2H), 3,70-a-3.84 (m, 2H), 3,85 (s, 3H), 4,48 (Sirs, 1H), 4,63 (DD, J=10,4, 5.6 Hz, 1H), 4,70 (DD, J=10,4, 4.5 Hz, 1H), of 6.71 (t, J=5.6 Hz, 1H), 6,92 (Sirs, 1H), 6,98 (Sirs, 1H), 7,02 (sird, J=8.0 Hz, 1H), 7.23 percent (d, J=8.0 Hz, 1H), 7,33 to 7.62 (m, 10H), 7,71 (Sirs, 1H).

Synthesis of (biphenyl-3-ylmethyl)amide (E)-5-hydroxy-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid

To a solution in methanol (5 ml) (biphenyl-3-ylmethyl)amide (E)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-5-(tetrahydropyran-2-yloxy) valerianic acid (168 mg) was added to the Dow - XTM50W X-8 (300 mg) and the reaction solution was stirred at 45ºC for 5 hours. The resin was filtered and to the filtrate was added an aqueous solution of ammonia (1 ml) and the solution was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent: ethyl acetate→ethyl acetate:methanol=9:1) and received 120 mg specified in the connection header. The physical properties of this compound are as follows.

ESI-MS; m/z 482 [M++H],1H-NMR (CDCl3) δ (ppm): is 1.81 (quintet, J=6.8 Hz, 2H), 2,30 (s, 3H), by 2.73 (t, J=6,8 Hz, 2H), to 3.67 (t, J=6,8 Hz, 2H), 3,85 (s, 3H)and 4.65 (d, J=5.6 Hz, 2H), 6,63 (t, J=5.6 Hz, 1H), 6,92 (Sirs, 1H), 6,98-7,02 (m, 2H), 7,25 (d, J=8,8 Hz, 1H), 7,33 to 7.62 (m, 10H), 7,71 (Sirs, 1H).

Example 436

Synthesis of (E)-3-[4-(4-ethyl-1H-imidazol-1-yl)-3-methoxyphenyl]-N-((1S)-1-hydroxym the Teal-2-phenylethyl)acrylamide

Formula 210

Synthesis of (E)-3-[4-(4-ethyl-1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid

In the same way as described in example 121, got 3,05 g is specified in the header connection on the basis of 4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzaldehyde (2,72 g)obtained in example 637, and diethylphosphonoacetate of ester (3,17 g). The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 0,46 (t, J=7,6 Hz, 3H)and 1.83 (q, J=7,6 Hz, 2H), 3,13 (s, 3H), USD 5.76 (d, J=16 Hz, 1H), 6.35mm (s, 1H), 6,50 (DD, J=2 Hz and 8.4 Hz, 1H), is 6.61 (d, J=8,4 Hz, 1H), 6,62 (d, J=1.6 Hz, 1H), is 6.61 (d, J=8,4 Hz, 1H), 6,86 (d, J=16 Hz, 1H), 7,18 (s, 1H).

Synthesis of (E)-3-[4-(4-ethyl-1H-imidazol-1-yl)-3-methoxyphenyl]-N-((1S)-1-hydroxymethyl-2-phenylethyl)acrylamide

In the same way as described in example 121, received 58 mg specified in the header connection on the basis of (E)-3-(4-(4-ethyl-1H-imidazol-1-yl)-3-methoxyphenyl)acrylic acid (116 mg) and D-phenylalaninol (78 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 1.28 (t, J=7,6 Hz, 3H), 2,66 (kV, J=7,6 Hz, 2H), 3,68 (DD, J=4.4 Hz, 11.2 Hz, 1H), 3,79 (DD, J=3,6 Hz, 11.2 Hz, 1H), 3,83 (s, 3H), 4,33-4,37 (m, 2H), of 6.31 (d, J=7,6 Hz, 1H), 6,38 (d, J=16 Hz, 1H), 6,92 (s, 1H), 7,06 (s, 1H), was 7.08 (DD, J=1.6 Hz, 8 Hz, 1H), 7.18 in-7,33 (m, 6H), EUR 7.57 (d, J=16 Hz, 1H), 7,72 (d, J=1.2 Hz, 1H).

Example 437

Synthesis of (E)-3-[3-formyl-4-(1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 211

Synthesis of 5-bromo-2-(1H-imidazol-1-yl)benzaldehyde

In the same way as described in example 11, was obtained 2.8 g specified in the header connection on the basis of 5-bromo-2-forventelige (5 g) and imidazole (2 g).

1H-NMR (CDCl3) δ (ppm): 7,21 (t, J=1.2 Hz, 1H), 7,28-7,29 (m, 1H), 7,34 (d, J=8,4 Hz, 1H), 7,71 (t, J=1.2 Hz, 1H), 7,86 (DD, J=2,8 Hz and 8.4 Hz, 1H), 8,17 (d, J=2,8 Hz, 1H), 9,75 (s, 1H).

Synthesis of (E)-3-[3-formyl-4-(1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

In the same way as described in example 9, was received 44 mg specified in the header connection on the basis of 5-bromo-2-(1H-imidazol-1-yl)benzaldehyde (50 mg) and N-indan-1-alacrimia (45 mg).

1H-NMR (CDCl3) δ (ppm): 1,87 is 1.96 (m, 1H), 2,64-of 2.72 (m, 1H), 2,90-of 3.07 (m, 2H), 5,64 (kV, J=7,6 Hz, 1H), to 6.19 (d, J=8,4 Hz, 1H), 6,60 (d, J=15.6 Hz, 1H), 7,21-to 7.35 (m, 5H), 7,44 (d, J=8,4 Hz, 1H), 7,72 (s, 1H), 7,75 (d, J=15.6 Hz, 1H), 7,81 (DD, J=2 Hz, 15.6 Hz, 1H), 8,18 (d, J=2 Hz, 1H), 9,82 (s, 1H).

Example 438

Synthesis of (E)-3-[5-bromo-2-(1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 212

In the same way as described in example 1 was received 49 mg specified in the header connection on the basis of 5-bromo-2-(1H-imidazol-1-yl)benzaldehyde (30 mg) and diethyl ether indan-1-ylcarbonylglycine acid (37 mg).

1H-NMR (CDCl3) δ (ppm): 1,80-1,89 (m, 1H), 2,58-of 2.66 (m, 1H), 2,85-of 2.93 (m, 1H), 2,96-3,03 (m, 1H), 5,55 (kV, J=7,6 Hz, 1H), of 5.99 (d, J=8,4 Hz, 1H), 6,20 (d, J=15.6 Hz, 1H), 7,06 (t, J=1.2 Hz, 1H), 7,16-7,28 (m, 5H), 7,38 (d, J=15,GC, 1H), 7,55-7,58 (m, 2H), 7,79 (d, J=2 Hz, 1H).

Example 439

Synthesis of (E)-3-[3-hydroxymethyl-4-(1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 213

Borohydride sodium (2 mg) was added to a solution in ethanol (1 ml) of (E)-3-(3-formyl-4-(1H-imidazol-1-yl)phenyl)-N-indan-1-alacrimia (17 mg)obtained in example 437, and the reaction mixture was stirred for 30 minutes at room temperature. After the reaction solution was concentrated under reduced pressure, to the residue were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent system methanol-ethyl acetate) and received 1.8 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,86-of 1.95 (m, 1H), 2,63-of 2.72 (m, 1H), 2,89-of 2.97 (m, 1H), 3.00 and-of 3.07 (m, 1H), 4,55 (s, 2H), 5,65 (kV, J=7,6 Hz, 1H), of 5.89 (d, J=8,4 Hz, 1H), 6.48 in (d, J=15.6 Hz, 1H), 7.18 in-7,35 (m, 7H), 7,54 (DD, J=the 2.4 Hz, 8 Hz, 1H), 7,71 (d, J=1.2 Hz, 1H), 7,79 (d, J=2 Hz, 1H).

Example 440

Synthesis of (E)-3-[3-(1-hydroxyethyl)-4-(1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 214

To a solution in THF (0.5 ml) of (E)-3-(3-formyl-4-(1H-imidazol-1-yl)phenyl)-N-indan-1-alacrimia (23 mg) obtained in example 437, was added in nitrogen atmosphere while cooling with ice methylanisole (3M solution in a simple ether of 0.04 ml) and the reaction mixture was stirred for 1 hour. To the reaction solution was added saturated aqueous solution of ammonium chloride and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent system methanol-ethyl acetate) and received 10 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,40 (d, J=6.4 Hz, 3H), 1,86-of 1.95 (m, 1H), 2,66-by 2.73 (m, 1H), 2,89-of 2.97 (m, 1H), 3.00 and-of 3.07 (m, 1H), 4,79 (kV, J=6,4 Hz, 1H), 5,65 (kV, J=7,6 Hz, 1H), 5,90 (d, J=8,4 Hz, 1H), 6,50 (d, J=15.6 Hz, 1H), to 7.09 (t, J=1.2 Hz, 1H), 7,20-to 7.35 (m, 5H), 7,49 (DD, J=1.6 Hz, 8 Hz, 1H), to 7.61 (s, 1H), 7,73 (d, J=15.6 Hz, 1H), 7,89 (d, J=2 Hz, 1H).

Example 441

Synthesis of (E)-3-[3-acetyl-4-(1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 215

To a solution in chloroform (0.5 ml) of (E)-3-(3-(1-hydroxyethyl)-4-(1H-imidazol-1-yl)phenyl)-N-indan-1-alacrimia (3 mg)obtained in example 440, was added activated manganese dioxide (14 mg) and the reaction mixture was stirred at room temperature overnight. The reaction solution was filtered through filter paper and the filtrate is has koncentrirebuli under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent: ethyl acetate) and received 3.8 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,86 is 1.96 (m, 1H), 2,02 (s, 3H), 2,65-by 2.73 (m, 1H), 2,89-of 2.97 (m, 1H), 3.00 and-is 3.08 (m, 1H), 5,64 (kV, J=7,6 Hz, 1H), 5,88 (d, J=8,4 Hz, 1H), of 6.49 (d, J=15.6 Hz, 1H), 7,12 (t, J=1.2 Hz, 1H), 7,22-7,39 (m, 6H), to 7.64 (t, J=1.2 Hz, 1H), of 7.70 (DD, J=1.6 Hz, 8 Hz, 1H), 7,78 (d, J=1.6 Hz, 1H).

Example 442

Synthesis of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxymethyl]-N-indan-1-alacrimia

Formula 216

Borohydride sodium (127 mg) was added to a solution in ethanol (10 ml) of 5-bromo-2-(1H-imidazol-1-yl)benzaldehyde (420 mg)obtained in example 437, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, to the residue were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution in methanol (2 ml) of the crude alcohol compounds were added sodium methoxide (40% solution in methanol, 10 ml) and the reaction mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, to the residue was added water and tracecut and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and obtained crude compound methoxymethyl (211 mg). In the same way as described in example 9, were given 15 mg specified in the header connection on the basis of this crude methoxymethyl compound (23 mg) and N-indan-1-alacrimia (16 mg).

1H-NMR (CDCl3) δ (ppm): 1,86-of 1.97 (m, 1H), 2,63-of 2.72 (m, 1H), 2,90-2,96 (m, 1H), 3.00 and-of 3.07 (m, 1H), 3,39 (s, 3H), 4,23 (s, 2H), 5,65 (kV, J=7,6 Hz, 1H), of 5.89 (d, J=8,4 Hz, 1H), 6,47 (d, J=15.6 Hz, 1H), 7,17 (t, J=1.2 Hz, 1H), 7,22-7,35 (m, 7H), 7,54 (DD, J=2 Hz and 8.4 Hz, 1H), 7,70 to 7.75 (m, 2H).

Example 443

Synthesis of (E)-3-[3-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 217

In the same way as described in example 9, was received 32 mg specified in the header connection on the basis of 1-(4-bromo-2-fluoro-6-methoxyphenyl)-4-methyl-1H-imidazole (30 mg) and N-indan-1-alacrimia (24 mg)synthesized in the same manner as described in example 16. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,85-of 1.94 (m, 1H), to 2.29 (s, 3H), 2,62-2,70 (m, 1H), 2,87-2,95 (m, 1H), 2,98-of 3.06 (m, 1H), 3.96 points (s, 3H), 5,62 (kV, J=7,6 Hz, 1H), 6,02 (d, J=8,4 Hz, 1H), to 6.39 (d, J=15.6 Hz, 1H), of 6.96 (d, J=0.8 Hz, 1H),? 7.04 baby mortality-was 7.08 (m, 2H), 7,20-7,34 (m, 4H), to 7.61 (d, J=15.6 Hz, 1H), of 7.70 (t, J=1.6 Hz, 1H).

Example 444

Synthesis of (E)-3-[2,5-dimethoxy-4-(4-methyl-1H-imidazol-1-ylphenyl]-N-indan-1-alacrimia

Formula 218

Received 35 mg specified in the header connection on the basis of 1-(4-bromo-2,5-acid)-4-methyl-1H-imidazole (58 mg)obtained in a manner analogous to that described in example 18, and N-indan-1-alacrimia (44 mg)in the same way as described in example 9. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,86-of 1.95 (m, 1H), 2,30 (s, 3H), 2,63-of 2.72 (m, 1H), 2,88-2,96 (m, 1H), 2,99 was 3.05 (m, 1H), 3,81 (s, 3H), 3,86 (s, 3H), 5,65 (kV, J=7,6 Hz, 1H), of 5.92 (d, J=8,4 Hz, 1H), 6,59 (d, J=15.6 Hz, 1H), for 6.81 (s, 1H), 6,94-to 6.95 (m, 1H), 7,13 (s, 1H), 7,21-7,29 (m, 3H), of 7.36 (d, J=6,8 Hz, 1H), 7,74 (d, J=1.2 Hz, 1H), 7,86 (d, J=15.6 Hz, 1H).

Example 445

Synthesis of (E)-3-[2-chloro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-indan-1-alacrimia

Formula 219

Received 19 mg specified in the connection header in the same way as described in example 9 from 1-(4-bromo-5-chloro-2-methoxyphenyl)-4-methyl-1H-imidazole (72 mg) in a manner analogous to that described in example 18, and N-indan-1-alacrimia (49 mg).

The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,87 is 1.96 (m, 1H), to 2.29 (s, 3H), 2,64-by 2.73 (m, 1H), 2,89-of 2.97 (m, 1H), 3.00 and-of 3.07 (m, 1H), 3,88 (s, 3H), 5,65 (kV, J=7,6 Hz, 1H), 5,96 (d, J=8,4 Hz, 1H), 6,45 (d, J=15.6 Hz, 1H), 6,92 (t, J=1.2 Hz, 1H), 7,17 (s, 1H), 7,22-7,29 (m, 3H), 7,33 (s, 1H), was 7.36 (d, J=6,8 Hz, 1H), 7,73 (d, J=1.6 Hz, 1H), 7,98 (d, J=15.6 Hz, 1H).

Example 446

Synthesis of (E)-3-[3-cyano-4-(5-methyl-1H-they are the azole-1-yl)phenyl]-N-indan-1-alacrimia

The formula 220

In the same way as described in example 9, was sentenced to 9 mg specified in the header connection on the basis of 5-bromo-2-(5-methyl-1H-imidazol-1-yl)benzonitrile (30 mg).

1H-NMR (CDCl3) δ (ppm): 1,87-of 1.97 (m, 1H), 2,18 (s, 3H), 2,65-to 2.74 (m, 1H), 2,90 are 2.98 (m, 1H), 3,01-is 3.08 (m, 1H), 5,65 (kV, J=7,6 Hz, 1H), 5,91 (d, J=8,4 Hz, 1H), 6,50 (d, J=16 Hz, 1H), 6,98 (t, J=1.2 Hz, 1H), 7,22-7,30 (m, 3H), 7,34 (d, J=7,6 Hz, 1H), 7,41 (d, J=8,4 Hz, 1H), 7,58 (d, J=1.2 Hz, 1H) 7,73 (d, J=16 Hz, 1H), 7,83 (DD, J=2,4 Hz and 8.4 Hz, 1H), 7,94 (d, J=2 Hz, 1H).

Were synthesized compounds are presented in table 11, where the example 447 for example 450 followed the method of example 434, with an example 451 for example 455 followed the method of example 20 and example 456 and example 457 followed the method of example 1, changing the group of substituents in the imidazole ring and the benzene ring. Structural formulas and physical properties are presented in table 11, respectively.

Table 11

Compounds shown in table 12 were synthesized as described in example 85. Structural formulas and physical properties are presented in table 12, respectively.

Table 12-1

Table 12-2

Example 474

Synthesis of amide (Z)-2-fluoro-3-[-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(6-vinylpyridin-2-ylmethyl)acrylic acid

Formula 221

Synthesis of (Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid

In the same way as described in example 111 was given to 4.52 g is specified in the header connection on the basis of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (4.0 g)synthesized in example 1, teeterboro ester 2-fluoro-2-phosphonooxy acid (of 5.82 g) and monohydrate of lithium hydroxide (0,664 g). The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): of 2.16 (s, 3H), 3,82 (s, 3H), 7,02 (d, J=24 Hz, 1H), 7,20 (s, 1H), 7,25 (d, J=8.0 Hz, 1H), was 7.36 (d, J=8.0 Hz, 1H), to 7.59 (s, 1H), to 7.93 (s, 1H).

Synthesis of amide (Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(6-vinylpyridin-2-ylmethyl)acrylic acid

In the same way as described in example 111, received 12,1 mg specified in the header connection on the basis of (Z)-2-fluoro-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (10 mg) and (6-vinylpyridin-2-yl)methylamine (10 mg). The physical properties of this compound are as follows.

ESI-MS; m/z 443 [M++H].

The following compounds shown in table 13 were synthesized as described in example 474. Structural formulas and physical-chemical properties are presented in table 13, respectively.

Table 13

The following connections, as the e in table 14. were synthesized as described in example 23. Structural formulas and physical-chemical properties are presented in table 14, respectively.

Table 14

The following compounds shown in table 15, were synthesized as described in example 121. Structural formulas and physical-chemical properties are presented in table 15, respectively.

Table 15-1

Table 15-2

Table 15-3

Table 15-4

Table 15-5

Table 15-6

Example 538

Synthesis of (E)-1-(3,4-diferensial)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]pyrrolidin-2-it

Formula 222

Synthesis of (E)-1-acetyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]pyrrolidin-2-it

The triethylamine (45 ml) was added to a solution in ethanol (80 ml) of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (3.0 g) and (1-acetyl-2-ocsober ridin-3-yl)triphenylphosphorane (8,4 g), synthesized by the method described in Journal of Medicinal Chemistry, vol.30, No. 11, p.1995, 1987. The reaction solution was subjected to interaction at 60ºC for 2 hours. The reaction solution was cooled to room temperature and added to a mixed solution of ethyl acetate and ice water. The precipitated solids were isolated by filtration, then dried under reduced pressure and got 3.3 grams specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): of 2.15 (s, 3H), 2,46-of 3.54 (m, 3H), is 3.08-and 3.16 (m, 2H), 3,74-of 3.80 (m, 2H), with 3.89 (s, 3H), 7,18 (t, J=1.2 Hz, 1H), 7,28-7,34 (m, 1H), 7,42-to 7.50 (m, 3H), to 7.84 (d, J=1.2 Hz, 1H).

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene] pyrrolidin-2-it

(E)-1-acetyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]pyrrolidin-2-he (7.5 g) and potassium carbonate (1.6 g) in a mixed solution of ethanol (100 ml) and methanol (100 ml) was stirred at room temperature for 2 hours. After condensing the reaction solution up to 1/3 of the solution was added to ice water and ethyl acetate and the precipitated solids were isolated by filtration to obtain 4.7 g specified in the connection header. In addition, the filtrate was extracted with ethyl acetate and, after washing with saturated salt solution and the organic layer was dried over anhydrous magnesium sulfate. This solution was concentrated and precipitated solids were obtained is filtered to obtain 2.7 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,30 (s, 3H), 3.15 and is 3.25 (m, 2H), 3,55-3,63 (m, 2H), 3,88 (s, 3H), 5,97 (Sirs, 1H), 6,94 (d, J=1.2 Hz, 1H), 7,11 (d, J=1.6 Hz, 1H), 7,15 (DD, J=1,6、8.0 Hz, 1H), 7,28 (d, J=8.0 Hz, 1H), 7,35 (t, J=2,8 Hz, 1H), 7,72 (d, J=1.6 Hz, 1H).

Synthesis of (E)-1-(3,4-diferensial)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]pyrrolidin-2-it

To a solution in DMF (6.0 ml) (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)pyrrolidin-2-it (100 mg) was added at 0ºC bis(trimethylsilyl)amide lithium (1M solution in hexane, of 0.53 ml) and the reaction solution was stirred for 30 minutes at 0ºC. To this solution at 0ºC was added 3,4-differenziale (to 0.060 ml), the reaction solution was stirred at room temperature for 1 hour. The reaction solution was added ice water and ethyl acetate and the organic layer was separated. The obtained organic layer was washed with saturated saline solution and after drying over anhydrous magnesium sulfate then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent system heptane-ethyl acetate) and received 80 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,30 (s, 3H), 3,05-3,13 (m, 2H), 3,38 is-3.45 (m, 2H), 3,88 (s, 3H), 4,58 (s, 2H), 6,91-to 6.95 (m, 1H), 6,99-7,05 (m, 1H), 7,08-7,17 (m, 4H), 7,27 (d, J=8.0 Hz, 1H), 7,40 (t, J=2,8 Hz, 1H), 7,72 (d, J=1,2 is C, 1H).

The following compounds shown in table 16, were synthesized as described in example 538. Structural formulas and physical-chemical properties are presented in table 16, respectively.

Table 16-1

Table 16-2

Example 554, Example 555 and Example 556

Synthesis of (E)-1-[1-(3,4-diferensial)-(4R)-hydroxy-(3R)-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it (E)-1-[1-(3,4-diferensial)-(4S)-hydroxy-(3S)-pyrrolidin-3-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 223

Synthesis of tert-butyl methyl ether (E)-TRANS-3-hydroxy-4-(3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-2-oxopiperidin-1-yl)pyrrolidin-1-carboxylic acid

In the same way as described in example 418, got 2,61 g is specified in the header connection on the basis of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (3,66 g) and tert-butyl ether TRANS-3-amino-4-hydroxypyrrolidine-1-carbamino acid (1.5 g)synthesized in accordance with the method described in The Journal of Organic Chemistry, vol. 62, No. 12, p.4197, 1997. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 1.47 (s, 9H), 1,83-2,02 (m, 2H), 2,30 (s, 3H), 2,70-is 2.88 (m, 2H), 3.25 to 3,63 (m, 4H), 3,79-a 3.83 (m, 2H), 3,85 (s, 3H), 4,33-4,43 (m, 1H), 4,87-of 4.95 (m, 1H), 6,92 (Sirs, 1H), 7,00 (Sirs, 1H), 7,01 (DD, J=to 9.6, 1.2 Hz, 1H), 7,24 (d, J=9.6 Hz, 1H), 7,71 (d, J=1.2 Hz, 1H), 7,80 (Sirs, 1H).

Synthesis of (E)-1-[1-(3,4-diferensial)-TRANS-4-hydroxy-3-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Triperoxonane acid (1 ml) was added to a solution in methylene chloride (1 ml) of tert-butyl ester (100 mg) (E)-TRANS-3-hydroxy-4(3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-2-oxopiperidin-1-yl)pyrrolidin-1-carboxylic acid and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved with methylene chloride (3 ml) was added to a solution of 3,4-differentally (0,046 ml) and triacetoxyborohydride sodium (132 mg). After stirring the reaction solution at room temperature for 6 hours to the reaction solution were added ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Received 100 mg specified in the connection header by purification of the residue chromatographie the on silica gel (Carrier: Chromatorex TMNH and an eluting solvent: heptane:ethyl acetate =1:1→ethyl acetate). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,79-1,89 (m, 1H), 1.93 and-2,02 (m, 1H), 2,30 (s, 3H), 2,39 at 2.45 (m, 1H), 2,63-of 2.97 (m, 4H), is 3.08-3,13 (m, 1H), 3,34-of 3.42 (m, 1H), 3,49 (d, J=13,2 Hz, 1H), 3,50-to 3.58 (m, 1H), 3,63 (d, J=13,2 Hz, 1H), 3,72 (Sirs, 1H), 3,85 (s, 3H), 4,18-4,24 (m, 1H), 4,55-br4.61 (m, 1H), 6,92 (Sirs, 1H), 7,00 (Sirs, 1H), 7,01 (sird, J=8.0 Hz, 1H), 7,05-7,19 (m, 3H), from 7.24 (d, J=8.0 Hz, 1H), 7,71 (d, J=0.8 Hz, 1H), to 7.77 (Sirs, 1H).

Synthesis of (E)-1-[1-(3,4-diferensial)-(4R)-hydroxy-(3R)-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it (E)-1-[1-(3,4-diferensial)-(4S)-hydroxy-(3S)-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

The above racemic compound (10 mg) were separated using a CHIRALPAKTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase; hexane:isopropanol=30:70). Got mentioned in the title optically active substance with a retention time of 13 minutes (4 mg, >99% of ei) and indicated in the title optically active substance with a retention time of 16 minutes (4 mg, >99% of ei). The physical properties specified in the title optically active substance with a retention time of 13 minutes (example 555) following.

1H-NMR (CDCl3) δ (ppm): 1,79-1,89 (m, 1H), 1.93 and-2,02 (m, 1H), 2,30 (s, 3H), 2,39 at 2.45 (m, 1H), 2,63-of 2.97 (m, 4H), is 3.08-3,13 (m, 1H), 3,34-of 3.42 (m, 1H), 3,49 (d, J=13,2 Hz, 1H), 3,50-to 3.58 (m, 1H), 3,63 (d, J=13,2 Hz, 1H), 3,72 (Sirs, 1H), 3,85, 3H), 4,18-4,24 (m, 1H), 4,55-br4.61 (m, 1H), 6,92 (Sirs, 1H), 7,00 (Sirs, 1H), 7,01 (sird, J=8.0 Hz, 1H), 7,05-7,19 (m, 3H), from 7.24 (d, J=8.0 Hz, 1H), 7,71 (d, J=0.8 Hz, 1H), to 7.77 (Sirs, 1H).

The physical properties specified in the title optically active substance with a retention time of 16 minutes (example 556) following.

1H-NMR (CDCl3) δ (ppm): 1,79-1,89 (m, 1H), 1.93 and-2,02 (m, 1H), 2,30 (s, 3H), 2,39 at 2.45 (m, 1H), 2,63-of 2.97 (m, 4H), is 3.08-3,13 (m, 1H), 3,34-of 3.42 (m, 1H), 3,49 (d, J=13,2 Hz, 1H), 3,50-to 3.58 (m, 1H), 3,63 (d, J=13,2 Hz, 1H), 3,72 (Sirs, 1H), 3,85 (s, 3H), 4,18-4,24 (m, 1H), 4,55-br4.61 (m, 1H), 6,92 (Sirs, 1H), 7,00 (Sirs, 1H), 7,01 (sird, J=8.0 Hz, 1H), 7,05-7,19 (m, 3H), from 7.24 (d, J=8.0 Hz, 1H), 7,71 (d, J=0.8 Hz, 1H), to 7.77 (Sirs, 1H).

The following compounds shown in table 17, were synthesized as described in example 554, example 555 and example 556. Structural formulas and physical-chemical properties are presented in table 17, respectively.

Table 17-1

Table 17-2

Table 17-3

Example 576

Synthesis of tert-butyl methyl ether (E)-CIS-3-hydroxy-4-{3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-2-oxopiperidin-1-yl}pyrrolidin-1-carboxylic acid

Formula 224

To a solution in THF (5 ml) of tert-butyl methyl ether (E)-TRANS-3-hydroxy-4-(3-(3-methoxy-4-(4-METI what-1H-imidazol-1-yl)benzylidene)-2-oxopiperidin-1-yl)pyrrolidin-1-carboxylic acid (30 mg), obtained in example 554, was added diisopropylethylamine (0,024 ml), triphenylphosphine (33 mg) and acetic acid (0,007 ml) and the reaction solution was stirred at room temperature for 3 hours. To the reaction solution were added ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Received 10 mg specified in the connection header by purification of the residue by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent:ethyl acetate). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): for 1.49 (s, 9H), 1,91 of 1.99 (m, 2H), 2,31 (s, 3H), of 2,75 2,90 (m, 2H), 3,20-a-3.84 (m, 6H), 3,86 (s, 3H), br4.61-4,71 (m, 1H), 4,73-4,80 (m, 1H), 6,93 (Sirs, 1H), 7,01 (Sirs, 1H), 7,03 (DD, J=10,0、1.2 Hz, 1H), of 7.25 (d, J=10.0 Hz, 1H), 7,72 (d, J=1.6 Hz, 1H), 7,80 (Sirs, 1H).

Example 577

Synthesis of (E)-1-benzoyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-[1,4'] bipyridinyl-2-it, salt triperoxonane acid

Formula 225

To a solution in methylene chloride (1 ml) of tert-butyl methyl ether (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-2-oxo-[1,4']bipyridinyl-1'-carboxylic acid (20 mg)obtained in example 716, added triperoxonane (1 ml) and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and a solution of the obtained residue in methylene chloride (2 ml) was added IPEA (0,022 ml) and benzoyl chloride (0.01 ml). The reaction solution was stirred at room temperature for 12 hours, the reaction solution was added saturated aqueous sodium bicarbonate solution and the organic layer was separated. Got to 9.4 mg specified in the header of the compounds obtained by condensation of the organic layer and purification by LC-MS. The physical properties of this compound are as follows.

ESI-MS; m/z 485 [M++H].

Example 578

Synthesis of (E)-1-TRIFLUOROACETYL-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-[1,4'] bipyridinyl-2-it, salt triperoxonane acid

The formula is 226

In the same way as described in example 577, received 11 mg specified in the title compound from tert-butyl ether (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-2-oxo-[1,4']bipyridinyl-1'-carboxylic acid (20 mg) and anhydride triperoxonane acid (0,02 ml). The physical properties of this compound are as follows.

ESI-MS; m/z 477 [M++H].

Example 579

Synthesis of (E)-3-[4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzylidene]-1-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-2-it

Formula 227

Synthesis of 4-(4-ethyl-1H-imidazo the-1-yl)-3-methoxybenzaldehyde

7,3 g specified in the title compounds were obtained through a series of stages based on the methyl ester of 4-formylamino-3-methoxybenzoic acid (24.8 g) in a similar way, including the path from the methyl ester of 4-formylamino-3-methoxybenzoic acid to 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde as described in example 1, except that chlorate was replaced with 1-bromo-2-butanone.

1H-NMR (CDCl3) δ: of 1.30 (t, J=7,6 Hz, 3H), 2,69 (kV, J=7,6 Hz, 2H), of 3.97 (s, 3H), 7,00 (kV, J=1.2 Hz, 1H), 7,46 (d, J=7,6 Hz, 1H), 7,55 (DD, J=1.6 Hz and 7.6 Hz, 1H), 7,58 (d, J=1.6 Hz, 1H), 7,86 (d, J=1.6 Hz, 1H), 10,01 (with, 1H).

Synthesis of tert-butyl methyl ether (E)-5-chloro-2-[4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzylidene]valerianic acid

In the same way as described in example 418, received 3.2 g specified in the header connection on the basis of 4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzaldehyde (7,3 g) and tert-butyl ester 5-chloro-2-(diethoxyphosphoryl)valerianic acid (12.5 g). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 1.29 (t, J=7,6 Hz, 3H), 1,60 (s, 9H), 2.00 in 2,07 (m, 2H), 2,65-a 2.71 (m, 4H), of 3.60 (t, J=6.4 Hz, 2H), 3,88 (s, 3H), 6,94 (s, 1H), 7,01 (s, 1H), 7,03 (d, J=8 Hz, 1H), 7,28 (d, J=8 Hz, 1H), of 7.60 (s, 1H), 7,76 (d, J=0.8 Hz, 1H).

Synthesis of (E)-5-chloro-2-[4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzylidene]valerianic acid, salt triperoxonane acid

In the same way as described in example 418, and following the method of synthesis of (E)-5-chloro-2(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid, received 3.5 g specified in the title compound from tert-butyl ether (E)-5-chloro-2-(4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzylidene)valerianic acid (3.2 g). The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 1,25 (t, J=7,6 Hz, 3H), 1,94 is 2.01 (m, 2H), 2,60-of 2.64 (m, 2H), 2,71 (kV, J=7,6 Hz, 2H), 3,70 (t, J=6 Hz, 2H), 3,91 (s, 3H), 7,24 (DD, J=8, 1.6 Hz, 1H), 7,37 (d, J=1.6 Hz, 1H), to 7.64 (d, J=8 Hz, 1H), 7,69 (s, 1H), of 7.75 (d, J=1.2 Hz, 1H), 9,27 (s, 1H).

Synthesis of (E)-3-[4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzylidene]-1-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-2-it

In the same way as described in example 418, received 159 mg specified in the header connection on the basis of (E)-5-chloro-2-(4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzylidene)valerianic acid in salt form triperoxonane acid (200 mg) and (S)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylamine (144 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 1.30 (t, J=7.0 Hz, 3H), 1,58-1,89 (m, 4H), 1,98-2,05 (m, 1H), 2,08-2,12 (m, 1H), 2,66-2,82 (m, 5H), 2,90-2,96 (m, 1H), 3,07-of 3.12 (m, 1H), 3,18-of 3.25 (m, 1H, in), 3.75 (s, 3H), 3,88 (s, 3H), between 6.08-6,12 (m, 1H), 6,65 (s, 1H), 6.75 in (d, J=4.4 Hz, 1H), 6,94 (s, 1H), 7.03 is-7,10 (m, 3H), 7,26-7,29 (m, 1H), of 7.75 (s, 1H), 7,92 (s, 1H).

The following compounds shown in table 18, were synthesized as described in example 579. Structural formulas and physical-chemical properties are presented in table 18, respectively.

Table 18-1

Table 18-2

Example 596

Synthesis of (E)-3-[4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzylidene]-1-(indan-2-yl)piperidine-2-he

Formula 228

Synthesis of 1-(4-[1,3]dioxolane-2-yl-2-methoxyphenyl)-1H-imidazol

To a solution in toluene (70 ml) of 4-(1H-imidazol-1-yl-3-methoxybenzaldehyde (4.3 g) and ethylene glycol (6.5 g) was added monohydrate para-toluensulfonate acid (4.8 g), used the device, Dean-stark and has been heated to the boiling temperature under reflux for 4 hours. After the reaction mixture was allowed to cool to room temperature, was added a saturated aqueous solution of sodium bicarbonate and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline solution and after drying over anhydrous magnesium sulfate then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent system hexane-ethyl acetate) and received 3,15 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 3,88 (s, 3H), 4,06-4,18 (m, 4H), to 5.85 (s, 1H), 7,15-7,17 (m, 2H), 7,19-7,20 (m, 2H), 7,29 (d, J=7,6 Hz, 1H), 7,78 (t, J=1 Hz, 1H).

Synthesis of 2-chloro-1-(4-[1,3]dioxolane-2-IL2-methoxyphenyl)-1H-imidazole

To a solution in THF (50 ml) of 1-(4-[1,3]dioxolane-2-yl-2-methoxyphenyl)-1H-imidazole (of 3.85 g) was added dropwise n-utility (1,6M solution in hexane, 12 ml) in a nitrogen atmosphere at-78ºC and the reaction solution was stirred for 30 minutes. To the reaction solution was added a solution of hexachloroethane (6,1 g) in THF (10 ml) and after stirring for 30 minutes at-78ºC the reaction solution was stirred at room temperature for 1 hour. To the reaction mixture were added water and ethyl acetate and the organic layer was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent system hexane-ethyl acetate) and received 3,19 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 3.84 (s, 3H), 4,07-4,19 (m, 4H), to 5.85 (s, 1H), 6,98 (d, J=1.6 Hz, 1H), 7,06 (d, J=1.6 Hz, 1H), 7,17 (DD, J=1.6 Hz, 8.0 Hz, 1H), 7,19 (d, J=1.6 Hz, 1H), 7,27 (d, J=8 Hz, 1H).

Synthesis of 4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde

To a solution in THF (40 ml) of 2-chloro-1-(4-[1,3]dioxolane-2-yl-2-methoxyphenyl)-1H-imidazole (3,19 g) was added 5N. hydrochloric acid solution (15 ml) and the reaction solution was stirred for 2 hours. The reaction mixture was podslushivaet using 5N. water rest the RA of sodium hydroxide, added ethyl acetate and the organic layer was separated. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to get 2,69 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 3,91 (s, 3H),? 7.04 baby mortality (d, J=1.6 Hz, 1H), 7,10 (d, J=1.6 Hz, 1H), of 7.48 (d, J=8.0 Hz, 1H), EUR 7.57-to 7.59 (m, 2H), 10,06 (s, 1H).

Synthesis of tert-butyl methyl ether (E)-5-chloro-2-[4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzylidene]valerianic acid

Received 4,55 g is specified in the header connection on the basis of 4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde (3,19 g) and tert-butyl ester 5-chloro-2-(diethoxyphosphoryl)valerianic acid (5.32 g) in a manner analogous to the method of synthesis of tert-butyl methyl ether (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid in Example 418. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,60 (s, 9H), 2.00 in 2,07 (m, 2H), 2,67-a 2.71 (m, 2H), 3,60 (t, J=6.4 Hz, 2H), of 3.84 (s, 3H), 6,70-was 7.08 (m, 4H), 7,26-7,29 (m, 1H), 7,27 (s, 1H).

Synthesis of (E)-5-chloro-2-[4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzylidene]valerianic acid

A solution of tert-butyl ester 5-chloro-2-(4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzylidene)valerianic acid (1.35 g) in triperoxonane acid (15 ml) was stirred under ice cooling. Ceres hours the reaction solution was concentrated under reduced pressure. After purification of the residue by LC-MS received 0,99 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 1,96-2,00 (m, 2H), 2,60-of 2.64 (m, 2H), 3,70 (t, J=6.4 Hz, 2H), 3,83 (s, 3H),? 7.04 baby mortality (s, 1H), 7,17 (d, J=8.0 Hz, 1H), 7,28 (s, 1H), 7,40 (s, 1H), 7,43 (d, J=8.0 Hz, 1H), 7,68 (s, 1H).

Synthesis of indan-2-ylamide (E)-5-chloro-2-[4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzylidene]valerianic acid

In the same way as described in example 418, received 11 mg specified in the header connection on the basis of (E)-5-chloro-2-(4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzylidene)valerianic acid (50 mg) and cleaners containing hydrochloride salt of 2-aminoindane (36 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ: 1,83-to 1.87 (m, 2H), 2,79-and 2.83 (m, 2H), 2,98 totaling 3.04 (m, 2H), 3.25 to of 3.32 (m, 4H), 3,82 (s, 3H), 5,76-of 5.81 (m, 1H), 7,01-7,02 (m, 2H),? 7.04 baby mortality-7,07 (m, 2H), 7,16-7,26 (m, 5H), 7,87 (s, 1H).

Compounds shown in table 19, were synthesized as described in example 596. Structural formulas and physical-chemical properties are presented in table 19, respectively.

Table 19-1

Table 19-2

Example 611

Synthesis of (E)-1-(3,4-diferensial)-3-{[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-yl]methylene}piperidine-2-it

Formula 229

Synthesis of 5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-carbaldehyde

In solution in methanol (5 ml), ethyl ether (E)-3-(6-chloro-5-methoxypyridine-3-yl)acrylic acid (123 mg)synthesized by the method of example 22, under stirring at-78ºC was barbotirovany ozone. After 10 minutes, the introduction of ozone was stopped, the reaction solution was added dimethyl sulfide (1 ml) and the reaction mixture was allowed to warm to room temperature over 1 hour and 30 minutes under stirring. The reaction solution was concentrated under reduced pressure and a solution of the obtained residue in DMF (1 ml) was added 4-Mei (125 mg). The reaction solution was stirred at 120ºC for 3 hours. After the reaction solution was allowed to cool to room temperature, to the reaction solution were added ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was separated. After washing the organic layer with saturated aqueous sodium bicarbonate solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Received 50 mg specified in the connection header by purification of the residue by chromatography on silica gel (eluting solvent heptane:ethyl acetate=9:1 - ethyl acetate). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,31 (s, 3H), 4,05 (who, 3H), the 7.65 (s, 1H), 7,78 (s, 1H), charged 8.52 (s, 2H), 10,07 (s, 1H).

Synthesis of tert-butyl methyl ether (E)-5-chloro-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-ylmethylene]valerianic acid

In the same way as described in example 418, received 35 mg specified in the header connection on the basis of 5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-carbaldehyde (50 mg) and tert-butyl ester 5-chloro-2-(diethoxyphosphoryl)valerianic acid (83 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): and 1.56 (s, 9H), of 1.78-1.90 (m, 2H), 2,30 (s, 3H), 2,66-by 2.73 (m, 2H), to 3.58-to 3.64 (m, 2H), 3,98 (s, 3H), 7,35 (s, 1H), 7,54 (s, 2H), of 8.06 (s, 1H), of 8.37 (s, 1H).

Synthesis of (E)-1-(3,4-diferensial)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-ylmethylene]piperidine-2-it

In the same way as described in example 418, received 15 mg specified in the title compound from tert-butyl ether (E)-5-chloro-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridine-3-ylmethylene] valerianic acid (35 mg) and 3,4-differentiatin (0,02 ml). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,76 of-1.83 (m, 2H), 2,30 (s, 3H), 2,81-2,87 (m, 2H), 3,36-to 3.41 (m, 2H), of 3.97 (s, 3H), of 4.66 (s, 2H), 7,02-to 7.18 (m, 3H), 7,31 (d, J=1.2 Hz, 1H), 7,54 (Sirs, 1H), 7,82 (Sirs, 1H), of 8.09 (d, J=1.2 Hz, 1H), at 8.36 (d, J=1.2 Hz, 1H).

Compounds shown in table 20, were synthesized as described in example 611. Structural formulas and physical-chemical properties are presented in t the blitz 20 respectively.

Table 20

Example 616 and the Example 617

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]he-[(R) and (S)-(5-morpholine-4-yl-indan-1-yl))piperidine-2-it

Formula 230

Synthesis of 5-morpholine-4-yl-indan-1-it

1-Methyl-2-pyrrolidone (10 ml) of 5-florenzano (1.97 g) and morpholine (1,71 g) was stirred at 100ºC for 26 hours and 30 minutes. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent system heptane-ethyl acetate) and received 2.20 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,64-to 2.67 (m, 2H), 3,03-of 3.07 (m, 2H), 3,34 (t, J=4.8 Hz, 4H), 3,86 (t, J=4.8 Hz, 4H), PC 6.82 (s, 1H), to 6.88 (DD, J=2.0 a, 8,8 Hz, 1H), 7,65 (d, J=8,8 Hz, 1H).

Synthesis of 5-morpholine-4-yl-indan-1-he-oxime

A solution in ethanol (5.0 ml) 5-morpholine-4-yl-indan-1-it (2.20 g), hydroxylaminopurine (1,05 g) and triethylamine (4,22 ml) was boiled under reflux for 3 hours. To the reaction solution were added water and ethyl acetate and the organic layer was separated. Polycentricity layer was washed with a saturated solution of sodium chloride and, after drying over anhydrous magnesium sulfate by condensation under reduced pressure received 2.28 g specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,92-2,96 (m, 2H), 2,98 totaling 3.04 (m, 2H), 3,20-3,26 (m, 4H), 3,85 (t, J=4.8 Hz, 4H), 6,78-6,85 (m, 2H), 7,53 (d, J=8,8 Hz, 1H).

Synthesis of 5-morpholine-4-yl-indan-1-ylamine

A suspension of 5-morpholine-4-Ilinden-1-he-oxime (2.76 g) and 10% palladium on carbon (water content 48%, 1.0 g) in ethanol (20 ml) was stirred at room temperature in a hydrogen atmosphere at a pressure of 0.4 MPa for 6 hours. After filtration of the reaction solution and condensation of the filtrate under reduced pressure received 1.64 g specified in the connection header by purifying the obtained residue by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent system heptane-ethyl acetate→system ethyl acetate : methanol). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,65-1,70 (m, 1H), 2,47 of $ 2.53 (m, 1H), 2,78 (TD, J=8,4, 16 Hz, 1H), 2,92 (DDD, J=3,6, 8,8, 16 Hz, 1H), 3,13 (t, J=4.8 Hz, 4H), 3,85 (t, J=4.8 Hz, 4H), or 4.31 (t, J=7.2 Hz, 1H), 6,79-for 6.81 (m, 2H), 7,21 (d, J=8,8 Hz, 1H).

Synthesis of (5-morpholine-4-yl-indan-1-yl)amide (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid

To a solution in DMF (5.0 ml) of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (3.0 g)obtained in example 418, and 5-morpholine-4-Ilinden-1-ylamine (1.80 g) were successively added IPEA (5,18 mg), EC (3,84 g) and HOBT (2,71 g) and the reaction solution was stirred at room temperature for 1 hour. After confirming disappearance of the starting substances, the solvent was concentrated under reduced pressure, to the residue were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Received 2,80 g specified in the connection header by purifying the obtained residue by chromatography on silica gel (eluting solvent system heptane-ethyl acetate). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,88-of 1.97 (m, 1H), 2.00 in of 2.08 (m, 2H), 2,30 (s, 3H), 2,63-of 2.72 (m, 1H), 2,74 (t, J=7.2 Hz, 2H), 2,82-to 2.94 (m, 1H), 2,87 was 3.05 (m, 1H), 3,10-3,18 (m, 4H)and 3.59 (t, J=6.0 Hz, 2H), 3,82-a-3.84 (m, 4H), of 3.85 (s, 3H), 5,52 (kV, J=7,6 Hz, 1H), 6,10 (d, J=7,6 Hz, 1H), 6,80-6,83 (m, 2H), 6,92-of 6.96 (m, 3H), 7,14 (s, 1H), 7.23 percent-of 7.25 (m, 2H), of 7.70 (s, 1H).

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-[(R) and (S)-(5-morpholine-4-yl-indan-1-yl)]piperidine-2-it

To a solution of (5-morpholine-4-yl-indan-1-yl)amide ((E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (2,80 g) in DMF (5.0 ml) was added at 0ºC sodium hydride (mineral oil 40%, 267 mg) and the reaction solution was stirred for 15 minutes. After confirming disappearance of the starting compounds to the reaction solution were added water and ethyl acetate and the organic layer was separated. After the organic layer was washed with saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By purifying the obtained residue by chromatography on silica gel (eluting solvent system heptane-ethyl acetate system ethyl acetate-ethanol) received 2,12 g (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-1-(5-morpholine-4-yl-indan-1-yl)piperidine-2-it is in the form of racemic compounds. Then this compound (140 mg) were separated using CHRIALPAKTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase; ethanol) and got mentioned in the title optically active substance with a retention time of 14 minutes (64 mg, >99% of ei) and indicated in the title optically active substance with a retention time of 16 minutes (58 mg, >97% of ei). The physical properties specified in the title optically active substance with a retention time of 14 minutes following.

1H-NMR (CDCl3) δ (ppm): 1,72-to 1.86 (m, 2H), 1,90-2,00 (m, 1H), 2,30 (s, 3H), 2,44-of 2.56 (m, 1H), 2,78-of 2.86 (m, 2H), 2,86-3,00 (m, 2H), 3,02-3,14 (m, 2H), 3,14-3,17 (m, 4H), 3,85-3,86 (m, 4H), 3,86 (s, 3H), 6,41 (t, J=6,8 Hz, 1H), 6,78-to 6.80 (m, 2H), 6,93 (s, 1H),? 7.04 baby mortality-was 7.08 (m, 3H), 7.24 to 7,25 (m, 1H), 7,71 (s, 1H), 7,88 (s, 1H).

The physical properties specified in the title optically active substance with a retention time of 16 minutes following.

1H-NMR (CDCl3) δ (ppm): 1,72-to 1.86 (m, 2H), 1,90-2,00 (m, 1H), 2,30 (s, 3H), 2,44-of 2.56 (m, 1H), 2,78-of 2.86 (m, 2H), 2,86-3,00 (m, 2H), 3,02-3,14 (m, 2H), 3,14-3,17 (m, 4H), 3,85-3,86 (m, 4H), 3,86 (s, 3H), 6,41 (t, J=6,8 Hz, 1H), 6,78-to 6.80 (m, 2H), ,93 (s, 1H),? 7.04 baby mortality-was 7.08 (m, 3H), 7.24 to 7,25 (m, 1H), 7,71 (s, 1H), 7,88 (s, 1H).

Example 618 and the Example 619

Synthesis of (E)-1-[(R) and (S)-1-(4-fluoro-2-morpholine-4-ylphenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 231

Synthesis of 1-(4-fluoro-2-morpholine-4-ylphenyl)ethanone

Solution in DMF (5.0 ml) of 2,4-defloration (1.0 g) and research (558 mg) was stirred at 110ºC for 6 hours and 30 minutes. To the reaction solution were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent system heptane-ethyl acetate) and received 642 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 2.64 (s, 3H), 2,98-3,00 (m, 4H), 3,84-a 3.87 (m, 4H), of 6.71-6,77 (m, 2H), 7,44-of 7.48 (m, 1H).

Synthesis of 1-(4-fluoro-2-morpholine-4-ylphenyl)Ataraxia

A solution in ethanol (5.0 ml) of 1-(4-fluoro-2-morpholine-4-ylphenyl)ethanone (630 mg), hydroxylaminopurine (294 mg) and triethylamine (1,18 ml) was boiled under reflux for 5 hours. To the reaction solution were added water and the resulting thereafter, the precipitate was filtered and dried in the air with getting 642 mg ukazannoj is in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,24 (s, 0,75H), and 2.27 (s, 2,25H), 2,96-to 2.99 (t, J=4.8 Hz, 4H), 3,81 (t, J=4.8 Hz, 4H), 6,70-6,79 (m, 2H), 7,14 (t, J=6,8 Hz, 0,25H), 7,22 (t, J=6,8 Hz, 0,75H), 7,97 (Sirs, 0,25H), 8,24 (Sirs, 0,75H).

Synthesis of 1-(4-fluoro-2-morpholine-4-ylphenyl)ethylamine

Suspension in ethanol (5.0 ml) of 1-(4-fluoro-2-morpholine-4-ylphenyl)Ataraxia (548 mg) and 10% palladium on carbon (water content 48%, 548 mg) was stirred for 32 hours and 30 minutes at room temperature in a hydrogen atmosphere at a pressure of 0.4 MPa. After filtration of the reaction solution and condensation of the filtrate under reduced pressure received 155 mg specified in the connection header by purifying the obtained residue by chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent system heptane-ethyl acetate→system ethyl acetate : methanol). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 1.38 (d, J=6.4 Hz, 3H), 1,68 (Sirs, 2H), 2,88 (t, J=4.4 Hz, 4H), 3,85 (t, J=4.4 Hz, 4H), 4,54 (kV, J=6,4 Hz, 1H), for 6.81-6,85 (m, 2H), 7,35-7,39 (m, 1H).

Synthesis of [1-(4-fluoro-2-morpholine-4-ylphenyl]ethyl)amide (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid

To a solution in DMF (3.0 ml) (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (280 mg)obtained in example 418, and 1-(4-fluoro-2-Mohali the-4-ylphenyl)ethylamine (155 mg) were successively added IPEA (484 mg) and EDC (359 mg) and HOBT (253 mg) and the reaction the solution was stirred at room temperature for 1 hour and 20 minutes. After confirming disappearance of the starting substances, the solvent was concentrated under reduced pressure, to the residue were added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (eluting solvent system heptane:ethyl acetate→system ethyl acetate : methanol) was obtained 270 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,49 (d, J=6.8 Hz, 3H), 1,95 for 2.01 (m, 2H), to 2.29 (s, 3H), 2,70-to 2.74 (m, 2H), 2,78-2,82 (m, 2H), 3,13-3,17 (m, 2H), to 3.58 (t, J=6.0 Hz, 2H), 3,85 (s, 3H), 3,82-3,93 (m, 4H), of 5.53-the ceiling of 5.60 (m, 1H), 6,68-6,74 (m, 1H), 6,83-to 6.95 (m, 4H), to 7.15 (s, 1H), 7.23 percent-7,30 (m, 3H), of 7.70 (s, 1H).

Synthesis of (E)-1-[(R) and (S)-1-(4-fluoro-2-morpholine-4-ylphenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

To a solution in DMF (3.0 ml) (1-(4-fluoro-2-morpholine-4-ylphenyl)-ethyl)amide (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (270 mg) was added at 0ºC sodium hydride (mineral oil 40%, 50 mg), the reaction solution was allowed to warm to room temperature and was stirred for 5 hours and 20 minutes. After confirming disappearance of the starting compounds, the reaction solution was cooled to 0ºC, reactio the resultant solution was added water and ethyl acetate and the organic layer was separated. After washing the organic layer with saturated saline, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting solvent system heptane-ethyl acetate→system ethyl acetate : methanol) and received 223 mg (E)-1-(1-(4-fluoro-2-morpholine-4-ylphenyl)ethyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it is in the form of racemic compounds. Then this compound (150 mg) were separated using a CHIRALPAKTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase; ethanol) and got mentioned in the title optically active substance with a retention time of 6 minutes (63,6 mg, >99% of ei) and indicated in the title optically active substance with a retention time of 7 minutes (54,0 mg, >98% of ei). The physical properties specified in the title optically active substance with a retention time of 6 minutes following.

1H-NMR (CDCl3) δ (ppm): of 1.52 (d, J=7.2 Hz, 3H), 1,74-to 1.82 (m, 2H), 2,30 (s, 3H), 2,59-of 2.72 (m, 1H), 2,79-to 2.94 (m, 6H), 3,21 (TD, J=5,6, 12 Hz, 1H), of 3.77-3,88 (m, 4H), 3,86 (s, 3H), 6,27 (kV, J=7.2 Hz, 1H), 6,83-6,93 (m, 3H), 7,01-7,03 (m, 2H), 7,22-7,25 (m, 1H), 7,31 (t, J=7,6 Hz, 1H), of 7.70 (s, 1H), to 7.84 (s, 1H).

The physical properties specified in the title optically active substance with a retention time of 7 minutes following :

1H-NMR (CDCl3) δ (ppm): of 1.52 (d, J=7.2 Hz, 3H), 1,74-to 1.82 (m, 2H), 2,30 (s, 3H), 2,59-of 2.72 (m, 1H), 2,79-to 2.94 (m, 6H), 3,21 (TD, J=5,6, 12 Hz, 1H), of 3.77-3,88 (m, 4H), 3,86 (s, 3H), 6,27 (kV, J=7.2 Hz, 1H), 6,83-6,93 (m, 3H), 7,01-7,03 (m, 2H), 7,22-7,25 (m, 1H), 7,31 (t, J=7,6 Hz, 1H), of 7.70 (s, 1H), to 7.84 (s, 1H).

Example 620 and the Example 621

Synthesis of (E)-1-[(1R) and (1S)-1-(2,4-differenl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 232

To a solution in DMF (5 ml) of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (250 mg)obtained in example 418, and 1-(2,4-differenl)ethylamine (CAS#603951-43-5,141 mg) were successively added IPEA (0.5 ml), EDC (430 mg) and HOBT (303 mg) and the reaction solution was stirred at room temperature within 1 hour. To the reaction solution were added water and ethyl acetate and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluting solvent system heptane-ethyl acetate). Received [1-(2,4-differenl)ethyl]amide (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid. To a solution of this compound in DMF (5 ml) was added sodium hydride (mineral oil 40%, 20 mg) and the reaction solution was stirred at room temperature for 5 minutes. To the reaction solution were added water and ethyl acetate and the organic is a mini layer was separated. The obtained organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel (eluting solvent system heptane-ethyl acetate), was obtained 151 mg (E)-1-(1-(2,4-differenl)ethyl)-3-(3-methoxy-4-(methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it is in the form of racemic compounds. This compound (25 mg) were separated using a CHIRALPAKTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase; hexane:ethanol=7:3) and has been specified in the title optically active substance with a retention time of 25 minutes (example 620: 11,8 mg, >99% of ei) and indicated in the title optically active substance with a retention time of 45 minutes (example 621: 11,2 mg, >99% of ei). The physical properties specified in the title optically active compound with a retention time of 25 minutes following.

1H-NMR (CDCl3) δ (ppm): 1,59 (d, J=7.2 Hz, 3H), 1.77 in-of 1.84 (m, 2H), 2,30 (s, 3H), 2.71 to and 2.83 (m, 2H), 2,99 was 3.05 (m, 1H), 3.27 to to 3.33 (m, 1H), 3,85 (s, 3H), 6,18 (kV, J=7.2 Hz, 1H), 6,79-6,85 (m, 1H), 6,86-6,92 (m, 1H), 6,93 (t, J=1.6 Hz, 1H), 7,02 (s, 1H), 7,02 (d, J=8.0 Hz, 1H), 7,24 (d, J=8.0 Hz, 1H), 7,33-7,39 (m, 1H), 7,71 (d, J=1.2 Hz, 1H), 7,86 (s, 1H).

The physical properties specified in the title optically active compound with a retention time of 45 minutes following.

1H-NMR (CDCl3) δ (ppm): 1,59 (d, J=7.2 Hz, 3H), 1.77 in-of 1.84 (m, 2H), 2,30 (s, 3H), 2.71 to and 2.83 (m, 2H), 2,99 was 3.05 (m, 1H), 3.27 to to 3.33 (m, 1H), 3,85 (s, 3H), 6,18 (kV, J=7.2 Hz, 1H), 6,79-6,85 m, 1H), 6,86-6,92 (m, 1H), 6,93 (t, J=1.6 Hz, 1H), 7,02 (s, 1H), 7,02 (d, J=8.0 Hz, 1H), 7,24 (d, J=8.0 Hz, 1H), 7,33-7,39 (m, 1H), 7,71 (d, J=1.2 Hz, 1H), 7,86 (s, 1H).

Example 622

Synthesis of (E)-1-[1-(4-forfinal)-TRANS-4-hydroxypyrrolidine-3-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 233

Synthesis of 3-(4-forfinal)-6-oxa-3-azabicyclo[3,1,0]hexane

To a solution in methanol (5 ml) of 1-(4-forfinal)-2,5-dihydro-1H-pyrrole (300 mg)synthesized in accordance with the method described in The Journal of Organic Chemistry vol. 25, p.2230, 1960, were alternately added acetonitrile (0.8 ml), potassium bicarbonate (221 mg) and 20% hydrogen peroxide (0.8 ml) and the reaction solution was stirred at room temperature for 10 hours. To the reaction solution were added ethyl acetate and a saturated sodium thiosulfate solution and the organic layer was separated. After washing the organic layer with saturated aqueous sodium bicarbonate solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Received 75 mg specified in the connection header by purification of the residue by chromatography on silica gel (heptane:eluting solvent; ethyl acetate=3:1). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 3,25 (d, J=8.1 Hz, 2H), 3,69 (d, J=8.1 Hz, 2H), a 3.87 (Sirs, 2H), 6,37-to 6.43 (m, 2H), 6,88-of 6.96 (m, 2H).

Synthesis of TRANS-4-amine is-1-(4-forfinal)pyrrolidin-3-ol

To a solution of 3-(4-forfinal)-6-oxa-3-azabicyclo[3,1,0]hexane (75 mg) in 1,4-dioxane (3 ml) was added an aqueous solution (1 ml) of sodium azide (82 mg) and the reaction solution was stirred at 100ºC for 7 hours. After the reaction solution was allowed to cool to room temperature, to the reaction solution were added ethyl acetate and a saturated solution of sodium chloride and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in ethanol (5 ml) was added 10% palladium on carbon (water content 48%, 10 mg) and the reaction solution was stirred at room temperature in a hydrogen atmosphere for 3 hours. By filtration of the reaction solution through celite and condensation of the filtrate under reduced pressure was obtained 61 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CD3OD3) δ (ppm): 3,05-3,17 (m, 2H), 3,38-3,44 (m, 1H), 3,57-to 3.67 (m, 2H), 4,10-to 4.14 (m, 1H), 6,44-of 6.49 (m, 2H), 6.87 in-6,94 (m, 2H).

Synthesis of (E)-1-[1-(4-forfinal)-TRANS-4-hydroxypyrrolidine-3-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

In the same way as described in example 418, received 70 mg specified in the header connection on the basis of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)WAHLER is anovas acid in salt form triperoxonane acid (175 mg) and TRANS-4-amino-1-(4-forfinal)pyrrolidin-3-ol (61 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,83-2,00 (m, 2H), 2,30 (s, 3H), 2,72-2,96 (m, 2H), up 3.22 (DD, J=10,0, 5.6 Hz, 1H), 3,41-of 3.48 (m, 3H), 3,62 (DD, J=10,0, 8.0 Hz, 1H), 3,70 (DD, J=10,0, 6,8 Hz, 1H), 3,86 (s, 3H), 4,50-4,56 (m, 1H), 5,03-5,10 (m, 1H), 6,50-6,55 (m, 2H), 6,92-7,05 (m, 5H), 7,25 (d, J=8.6 Hz, 1H), 7,71 (d, J=1.2 Hz, 1H), 7,82 (Sirs, 1H).

Example 623, Example 624 and the Example 625

Synthesis of (E)-1-[1-(4-forfinal)-(3S) and (3R)-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

The formula 234

Synthesis of 1-(4-forfinal)-3-pyrrolidinone 1-(4-forfinal)pyrrolidin-3-ylamine

Sodium azide (722 mg) was added to a solution of methane sulfonate (CAS#618068-72-7, 289 mg) in DMSO (10 ml). The reaction solution was stirred at 50ºC for 15 hours. The reaction solution was allowed to cool to room temperature, the reaction solution was added a simple ether and saturated aqueous sodium bicarbonate solution and the organic layer was separated. After washing the organic layer with saturated aqueous sodium bicarbonate solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in ethanol (5 ml) was added 10% palladium on carbon (48% water, 10 mg) and the reaction solution was stirred at room temperature in a hydrogen atmosphere for 20 hours. By filtration of the reaction is about the solution through celite and condensation of the filtrate under reduced pressure received 187 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,75-of 1.85 (m, 1H), 2,18-of 2.28 (m, 1H), 2,96-a 3.01 (m, 1H), 3.25 to of 3.32 (m, 1H), 3,38-to 3.50 (m, 2H), 3,68 of 3.75 (m, 1H), to 6.43-of 6.49 (m, 2H), 6.90 to-6,97 (m, 2H).

Synthesis of (E)-1-(1-(4-forfinal)pyrrolidin-3-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it (example 623)

In the same way as described in example 418, received 82 mg specified in the header connection on the basis of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (278 mg) and 1-(4-forfinal)pyrrolidin-3-ylamine (142 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,83-of 1.97 (m, 2H), 2,11-of 2.21 (m, 1H), 2,30 (s, 3H), 2,31-2,39 (m, 1H), 2,75-2,90 (m, 2H), 3,23-3,30 (m, 2H), 3,39-3,55 (m, 4H), 3,86 (s, 3H), of 5.53-5,61 (m, 1H), 6.48 in-6,54 (m, 2H), 6,91-7,05 (m, 5H), from 7.24 (DD, J=8,0, 2.0 Hz, 1H), 7,71 (s, 1H), 7,83 (Sirs, 1H).

Synthesis of (E)-1-[1-(4-forfinal)-(3S) and (3R)-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

The above racemic compound (14 mg) were separated using a CHIRALPAKTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase; hexane:ethanol=70:30). Got mentioned in the title optically active substance with a retention time of 36 minutes (4,6 mg, >99% of ei) and indicated in the title optically active substance with a retention time of 39 minutes (4.3 mg; >88% of ei). The physical properties specified in the title optically active substance with a retention time of 36 minutes (example 624) following.

1H-NMR (CDCl3) δ (ppm): 1,83-of 1.97 (m, 2H), 2,11-of 2.21 (m, 1H), 2,30 (s, 3H), 2,31-2,39 (m, 1H), 2,75-2,90 (m, 2H), 3,23-3,30 (m, 2H), 3,39-3,55 (m, 4H), 3,86 (s, 3H), of 5.53-5,61 (m, 1H), 6.48 in-6,54 (m, 2H), 6,91-7,05 (m, 5H), from 7.24 (DD, J=8,0, 2.0 Hz, 1H), 7,71 (s, 1H), 7,83 (Sirs, 1H).

The physical properties specified in the title optically active substance with a retention time of 39 minutes (example 625) following.

1H-NMR (CDCl3) δ (ppm): 1,83-of 1.97 (m, 2H), 2,11-of 2.21 (m, 1H), 2,30 (s, 3H), 2,31-2,39 (m, 1H), 2,75-2,90 (m, 2H), 3,23-3,30 (m, 2H), 3,39-3,55 (m, 4H), 3,86 (s, 3H), of 5.53-5,61 (m, 1H), 6.48 in-6,54 (m, 2H), 6,91-7,05 (m, 5H), from 7.24 (DD, J=8,0, 2.0 Hz, 1H), 7,71 (s, 1H), 7,83 (Sirs, 1H).

Example 626 and Example 627

Synthesis of (E)-1-[(R) and (S)-cyclopropyl-(4-forfinal)methyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 235

In the same way as described in example 418, received 133 mg (E)-1-cyclopropyl-(4-forfinal)methyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it is in the form of racemic compounds on the basis of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in the form salt triperoxonane acid (250 mg) and cyclopropyl-(4-forfinal)methylamine (CAS#705-14-6, 187 mg). Then this compound (8.0 mg) were separated using a CHIRALCELTMOJ from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase; hexane:ethanol=80:20)were specified in the title optically active substance with a retention time of 9 minutes (0.9 mg; >87% of the s) and indicated in the title optically active substance with a retention time of 12 minutes (0.8 mg; >88% of ei).

The physical properties specified in the title optically active substance with a retention time of 9 minutes following.

1H-NMR (CDCl3) δ (ppm): from 0.50 to 0.68 (m, 3H), 0,86 to 0.92 (m, 1H), 1,29-to 1.38 (m, 1H), 1,68-of 1.78 (m, 1H), 1,86-of 1.94 (m, 1H), 2,30 (s, 3H), 2,75-2,82 (m, 1H), 2.91 in (TD, J=4,8, 16 Hz, 1H), 3,10 -, and 3.16 (m, 1H), 3,51 (DDD, J=3,6, 10, 12 Hz, 1H), 3,86 (s, 3H), 5,22 (d, J=10 Hz, 1H), 6,94 (s, 1H), 7,00-7,07 (m, 4H), 7,25-7,27 (m, 1H), 7,44 (DD, J=5,6, 6,8 Hz, 2H), 7,73 (s, 1H), 7,89 (s, 1H).

The physical properties specified in the title optically active substance with a retention time of 12 minutes following.

1H-NMR (CDCl3) δ (ppm): from 0.50 to 0.68 (m, 3H), 0,86 to 0.92 (m, 1H), 1,29-to 1.38 (m, 1H), 1,68-of 1.78 (m, 1H), 1,86-of 1.94 (m, 1H), 2,30 (s, 3H), 2,75-2,82 (m, 1H), 2.91 in (TD, J=4,8, 16 Hz, 1H), 3,10 -, and 3.16 (m, 1H), 3,51 (DDD, J=3,6, 10, 12 Hz, 1H), 3,86 (s, 3H), 5,22 (d, J=10 Hz, 1H), 6,94 (s, 1H), 7,00-7,07 (m, 4H), 7,25-7,27 (m, 1H), 7,44 (DD, J=5,6, 6,8 Hz, 2H), 7,73 (s, 1H), 7,89 (s, 1H).

Example 628

Synthesis of (E)-1-[2-fluoro-4-morpholine-4-ylbenzyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 236

Synthesis of 2-fluoro-4-morpholine-4-eventelement

In the same way as described in example 426, got 740 mg specified in the title compound using 2-fluoro-4-morpholine-4-Evansville (CAS#554448-62-3, 1.0 g). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1.55V (Sirs, 2H), 3,13 (t, J=4.8 Hz, 4H), 3,80 (s, 2H), 3,84 (t, J=4.8 Hz, 4H), 6,56 (DD, J=2,4, 13 Hz, 1H), 6,63 (DD, J=2,4, and 8.4 Hz, 1H), 7,17 (t, J=8,8 Hz,1H).

Synthesis of (E)-1-[2-fluoro-4-morpholine-4-ylbenzyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

In the same way as described in example 418, received 126 mg specified in the header connection on the basis of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (200 mg) and 2-fluoro-4-morpholine-4-ivesiana (141 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,82-of 1.88 (m, 2H), 2,30 (s, 3H), 2,78-of 2.81 (m, 2H), 3.15 in (t, J=3,6 Hz, 4H), to 3.41 (t, J=5.6 Hz, 2H), 3,83-3,86 (m, 4H), of 3.84 (s, 3H), 4,69 (s, 2H), 6,56 (DD, J=2,4, 13 Hz, 1H), only 6.64 (DD, J=2,4, 8,8 Hz, 1H), 6,92 (s, 1H), 7,00-7,02 (m, 2H), 7.23 percent (d, J=8,4, 1H), 7,32 (t, J=8,8 Hz, 1H), of 7.70 (s, 1H), 7,83 (s, 1H).

Example 629

Synthesis of (E)-1-[(1R)-(4-forfinal)-2-hydroxyethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 237

Synthesis of (2R)-amino-2-(4-forfinal)ethanol

Solution in THF (5.0 ml) of D-(-)-4-florfenicol (500 mg) was cooled to 0ºC. To the reaction solution was added borohydride sodium (246 mg) and iodine (751 mg). After boiling the reaction solution under reflux during the night to the reaction solution was added methanol and the reaction solution was concentrated under reduced pressure. Then to the reaction solution was added 5N. the sodium hydroxide solution and ethyl acetate and the organic layer was separated. P is after washing the organic layer with a saturated solution of sodium chloride by drying with anhydrous magnesium sulfate and condensed under reduced pressure received 389 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 2,24 (Sirs, 3H), 3,52 (DD, J=8.0 a, 11 Hz, 1H), 3,70 (DD, J=4,0, 11 Hz, 1H), Android 4.04 (DD, J=4,0, 8.0 Hz, 1H), 7,00? 7.04 baby mortality (m, 2H), 7,27-7,31 (m, 2H).

Synthesis of (E)-1-[(1R)-(4-forfinal)-2-hydroxyethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

In the same way as described in example 418, received 25 mg specified in the header connection on the basis of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (250 mg) and (2R)-amino-2-(4-forfinal)ethanol (104 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,72-1,90 (m, 2H), 2,30 (s, 3H), 2,79-2,84 (m, 2H), 3,09 (DDD, J=4,4, 7,6, 12 Hz, 1H), 3.33 and (DDD, J=4,4, 8,0, 12 Hz, 1H), 3,85 (s, 3H), 4,17-of 4.25 (m, 2H), 5,86 (DD, J=6,0, 8.0 Hz, 1H), 6,92-6,93 (m, 1H), 7,02-was 7.08 (m, 4H), 7,20-to 7.32 (m, 3H), 7,71 (d, J=1.2 Hz, 1H), 7,87 (s, 1H).

Example 630 and the Example 631

Synthesis of (E)-1-[(1R) and (1S)-(3,4-differenl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 238

Synthesis of (E)-1-((1R) and (1S)-(3,4-differenl)ethyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it

In the same way as described in example 418, received 150 mg of (E)-1-(1-(3,4-differenl)ethyl-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it is in the form of racemic compounds on the basis of (E)-5-chloro-2-(3-methoxy-4-(4-IU the Il-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (250 mg) and 1-(3,4-differenl)ethylamine (CAS#276875-21-9, 140 mg). Then this compound (150 mg) were separated using a CHIRALPAKTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: ethanol) and got mentioned in the title optically active substance with a retention time of 6 minutes (to 68.0 mg, >99% of ei) and indicated in the title optically active substance with a retention time of 7 minutes (66,2 mg; >91% of ei). The physical properties specified in the title optically active substance with a retention time of 6 minutes following.

1H-NMR (CDCl3) δ (ppm): and 1.54 (d, J=7.2 Hz, 3H), 1,62 to 1.76 (m, 1H), 1,80-1,90 (m, 1H), 2,30 (s, 3H), 2,72 is 2.80 (m, 1H), 2,83-2,90 (m, 1H), 2,92 are 2.98 (m, 1H), 3,26 (DDD, J=3,6, 8,8, 12 Hz, 1H), 3,86 (s, 3H), to 6.19 (kV, J=7,2 Hz, 1H), 6,92 (s, 1H), 7.03 is-to 7.18 (m, 5H), 7.24 to 7,25 (m, 1H), 7,71 (s, 1H), 7,88 (s, 1H).

The physical properties specified in the title optically active substance with a retention time of 7 minutes following :

1H-NMR (CDCl3) δ (ppm): and 1.54 (d, J=7.2 Hz, 3H), 1,62 to 1.76 (m, 1H), 1,80-1,90 (m, 1H), 2,30 (s, 3H), 2,72 is 2.80 (m, 1H), 2,83-2,90 (m, 1H), 2,92 are 2.98 (m, 1H), 3,26 (DDD, J=3,6, 8,8, 12 Hz, 1H), 3,86 (s, 3H), to 6.19 (kV, J=7,2 Hz, 1H), 6,92 (s, 1H), 7.03 is-to 7.18 (m, 5H), 7.24 to 7,25 (m, 1H), 7,71 (s, 1H), 7,88 (s, 1H).

Example 632 and an Example 633

Synthesis of (E)-1-[(1R) and (1S)-(4-forfinal)propyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 239

Synthesis of (E)-1-[(1R) and (1S)-(4-forfinal)propyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

In the same way as opisanoj example 418, got to 21.9 mg (E)-1-(1-(4-forfinal)propyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-it is in the form of racemic compounds on the basis of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (150 mg) and 1-(4-forfinal)Propylamine (CAS#74877-10-4, with 76.8 mg). Then this compound (20.0 mg) were separated using a CHIRALPAKTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: ethanol) and got mentioned in the title optically active substance with a retention time of 6 minutes (6,10 mg, >99% of ei) and indicated in the title optically active substance with a retention time of 7 minutes (5,10 mg; >92% of ei). The physical properties specified in the title optically active substance with a retention time of 6 minutes following.

1H-NMR (CDCl3) δ (ppm): 1,02 (t, J=7.2 Hz, 3H), 1,57 is 1.70 (m, 1H), 1,76-of 1.88 (m, 1H), 1,89-of 1.97 (m, 1H), 1,99-2,07 (m, 1H), 2,30 (s, 3H), 2.71 to 2,84 (m, 2H), 2,92-of 2.97 (m, 1H), 3,21 (DDD, J=3,6, 8,4, 12 Hz, 1H), 3,85 (s, 3H), 6,01 (DD, J=6,0, 10 Hz, 1H), 6,92 (s, 1H), 6,99? 7.04 baby mortality (m, 4H), 7.23 percent-of 7.25 (m, 1H), 7,31-7,35 (m, 2H), 7,71 (s, 1H), 7,87 (s, 1H).

The physical properties specified in the title optically active substance with a retention time of 7 minutes following :

1H-NMR (CDCl3) δ (ppm): 1,02 (t, J=7.2 Hz, 3H), 1,57 is 1.70 (m, 1H), 1,76-of 1.88 (m, 1H), 1,89-of 1.97 (m, 1H), 1,99-2,07 (m, 1H), 2,30 (s, 3H), 2.71 to 2,84 (m, 2H), 2,92-of 2.97 (m, 1H), 3,21 (DDD, J=3,6, 8,4, 12 Hz, 1H), 3,85 (s, 3H), 6,01 (DD, J=6,0, 10 Hz, 1H), 6,92 (s, 1H), 6,99? 7.04 baby mortality (m, 4H), 7.23 percent-of 7.25 (m, 1H), 7,31-7,35 (who, 2H), 7,71 (s, 1H), 7,87 (s, 1H).

Example 634

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-(2-piperidine-1-ylbenzyl)piperidine-2-it

Formula 240

In the same way as described in example 641, got to 8.40 mg specified in the title compound from tert-butyl ether (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (50 mg) and 2-piperidine-1-ivesiana (1M DMF solution, 256 μl). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,52-of 1.74 (m, 6H), 1,82-of 1.88 (m, 2H), 2,30 (d, J=1.2 Hz, 3H), 2,82-of 2.86 (m, 6H), 3,28-of 3.31 (m, 2H), 3,86 (s, 3H), a 4.86 (s, 2H), 6,93 (m, 1H), 7,02-7,06 (m, 3H), to 7.09 (DD, J=1,2, and 8.4 Hz, 1H), 7,20-7,26 (m, 3H), 7,79 (d, J=1.2 Hz, 1H), 7,88 (s, 1H).

Example 635

Synthesis of (E)-1-[(1S)-(4-chlorophenyl)ethyl]-3-[3-methoxy-4-(4-Mei-2-yl)benzylidene]piperidine-2-it

Formula 241

In the same way as described in example 641, got 10.5 mg specified in the title compound from tert-butyl ether (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (50 mg) and (S)-1-(4-chlorophenyl)ethylamine (32,0 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1.55V (d, J=6.8 Hz, 3H), 1,64-of 1.73 (m, 1H), 1,76-of 1.88 (m, 1H), 2,30 (s, 3H), 2.71 to to 2.85 (m, 2H), 2.91 in-2,96 (m, 1H), 3,24 (DTD, J=4,0, 8,8, 12 Hz, 1H), 3,85 (s, 3H), 6,21 (kV, J=6,8 Hz, 1H), 6,92-6,93 (m, 1H), 7.03 is-7,05 (m, 2H),7,22-to 7.32 (m, 5H), of 7.70 (d, J=1.6 Hz, 1H), 7,88 (s, 1H).

Example 636

Synthesis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-(4-trifloromethyl)piperidine-2-it, salt triperoxonane acid

Formula 242

In the same way as described in example 416, received 12.5 mg specified in the title compound from tert-butyl ether (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (50 mg) and 4-(trifluoromethyl)benzylamine (36,0 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,87-of 1.93 (m, 2H), 2,48 (s, 3H), 2,82 (t, J=5.6 Hz, 2H), 3,41 (t, J=6.0 Hz, 2H), 3,90 (s, 3H), 4,78 (s, 2H), 7,06 (d, J=6,4 Hz, 2H), to 7.09 (d, J=8.0 Hz, 1H), 7,33 (d, J=8.0 Hz, 1H), 7,42 (d, J=8.0 Hz, 1H), 7,60 (d, J=8.0 Hz, 2H), 7,87 (s, 2H), 8,71 (d, J=1.2 Hz, 1H).

Example 637

Synthesis of (E)-3-[4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzylidene]-1-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-2-it

Formula 243

Synthesis of (E)-5-chloro-2-[4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzylidene]valerianic acid, salt triperoxonane acid

In the same way as described in example 418, received 3.5 g specified in the title compound from tert-butyl ether (E)-5-chloro-2-(4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzylidene)valerianic acid (3.2 g)obtained above. The physical properties of this compound are as follows.

1 6) δ (ppm): 1,25 (t, J=7,6 Hz, 3H), 1,94 is 2.01 (m, 2H), 2,60-of 2.64 (m, 2H), 2,71 (kV, J=7,6 Hz, 2H), 3,70 (t, J=6 Hz, 2H), 3,91 (s, 3H), 7,24 (DD, J=1.6 Hz, 8 Hz, 1H), 7,37 (d, J=1.6 Hz, 1H), to 7.64 (d, J=8 Hz, 1H), 7,69 (s, 1H), of 7.75 (d, J=1.2 Hz, 1H), 9,27 (s, 1H).

Synthesis of (E)-3-[4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzylidene]-1-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-2-it

In the same way as described in example 641, received 159 mg specified in the header connection on the basis of (E)-5-chloro-2-(4-(4-ethyl-1H-imidazol-1-yl)-3-methoxybenzylidene)valerianic acid in salt form triperoxonane acid (200 mg) and (S)-7-methoxy-1,2,3,4-tetrahydronaphthalen-ylamine (144 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 1.30 (t, J=7.0 Hz, 3H), 1,58-1,89 (m, 4H), 1,98-2,05 (m, 1H), 2,08-2,12 (m, 1H), 2,66-2,82 (m, 5H), 2,90-2,96 (m, 1H), 3,07-of 3.12 (m, 1H), 3,18-of 3.25 (m, 1H, in), 3.75 (s, 3H), 3,88 (s, 3H), between 6.08-6,12 (m, 1H), 6,65 (s, 1H), 6.75 in (d, J=4.4 Hz, 1H), 6,94 (s, 1H), 7.03 is-7,10 (m, 3H), 7,26-7,29 (m, 1H), of 7.75 (s, 1H), 7,92 (s, 1H).

Example 638

Synthesis of (E)-1-[(1R)-(4-forfinal)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 244

In the same way as described in example 418, received 1.0 g specified in the header connection on the basis of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (1.6 g) and (R)-1-(4-forfinal)ethylamine (495 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,50 (d, J=7.2 Hz, 3H), 1,65-of 1.74 (m, 1H), 1,78-to 1.87 (m, 1H), 2,30 (s, 3H), 2.71 to to 2.85 (m, 2H), 2.91 in-of 2.97 (m, 1H), 3,24 (DDD, J=3,6, 8,8, 12.0 Hz, 1H), 3,86 (s, 3H), 6,23 (kV, J=7.2 Hz, 1H), 6,93 (t, J=1.2 Hz, 1H), 7,00-7,06 (m, 4H), 7.24 to 7,26 (m, 1H), 7,31-7,34 (m, 2H), 7,72 (d, J=1.2 Hz, 1H), 7,89 (s, 1H).

Example 639

Synthesis of (E)-1-[4-(4-forfinal)tetrahydropyran-4-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 245

In the same way as described in example 418, got 1,15 g is specified in the header connection on the basis of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (2.1 g) and 4-(4-forfinal)tetrahydropyran-4-ylamine (833 mg)synthesized in accordance with the method described in Journal of Medicinal Chemistry, vol.10, No. 1 p.128 1967. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,75-of 1.84 (m, 2H), 2,30 (s, 3H), 2,32-of 2.38 (m, 2H), 2,74-is 2.88 (m, 4H), 3,34-3,39 (m, 2H), 3,71-of 3.78 (m, 2H), 3,80-3,88 (m, 5H), 6,92 (Sirs, 1H), 6,99-7,07 (m, 4H), of 7.23 (d, J=8.0 Hz, 1H), 7,44-7,50 (m, 2H), 7,68 (Sirs, 1H), 7,72 (s, 1H).

Example 640

Synthesis of (E)-1-[1-(3,4-diferensial)-(3R)-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 246

In the same way as described in example 417, received 12 mg specified in the header connection on the basis of the ethyl ester of (E)-5-chloro-2-(3-methoxy--(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (50 mg) and dihydrochloride (3R)-1-(3,4-diferensial)pyrrolidin-3-ylamine (40 mg)

The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,75-of 1.93 (m, 3H), 2,22 is 2.33 (m, 2H), to 2.29 (s, 3H), 2,50 (DD, J=10,4, and 8.4 Hz, 1H), 2,70 (DD, J=10,4, 3.6 Hz, 1H), 2.77-to 2,95 (m, 3H), 3,45-3,62 (m, 4H), of 3.84 (s, 3H), 5,17-of 5.45 (m, 1H), 6,92 (s, 1H), 6,98-7,27 (m, 6H), of 7.70 (d, J=1.2 Hz, 1H), 7,78 (s, 1H).

Example 641

Synthesis of (E)-4-{(3S)-(3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-2-oxopiperidin-1-yl)pyrrolidin-1-yl}benzonitrile

Formula 247

Synthesis of tert-butyl methyl ether [(1S)-(4-cyanophenyl)pyrrolidin-3-yl]carbamino acid

Suspension in DMF (10 ml) of (3S)-3-(tert-butoxycarbonylamino)pyrrolidine (837 mg) and 4-perbenzoate (544 mg) and potassium carbonate (1.24 g) was stirred at 120ºC for 22 hours. After the reaction solution was allowed to cool to room temperature, to the reaction solution were added ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By recrystallization of the residue from a mixed solution of ethyl acetate and hexane was 320 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,45 (s, 9H), 1,94-2,05 (m, 1H), 2,25-is 2.37 (m, 1H), 3,16-to 3.67 (m, 4H), 4,36 (Sirs, 1H), 4,67 (Sirs, 1H), of 6.49 (d, J=6,8 Hz, 2H), 7,45 (d, J=6,8 Hz, 2H).

Synthesis of 4-[(3S)-aminopyrrolidine-1-yl]benzonitrile, double salt triperoxonane acid

Triperoxonane acid (1 ml) was added to a solution of tert-butyl methyl ether ((1S)-(4-cyanophenyl)pyrrolidin-3-yl)carbamino acid (100 mg) in methylene chloride (3 ml) and the reaction solution was stirred at room temperature for 15 hours. By condensation of the reaction solution under reduced pressure received 144 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CD3OD) δ (ppm): 2,18-of 2.28 (m, 1H), 2,45-of 2.56 (m, 1H), 3.43 points of 3.75 (m, 4H), 3,99-4,07 (m, 1H), to 6.67 (d, J=6,8 Hz, 2H), 7,53 (d, J=6,8 Hz, 2H).

Synthesis of (E)-4-{(3S)-{(3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-2-oxopiperidin-1-yl}pyrrolidin-1-yl}benzonitrile

To a mixed solution of 4-((3S)-aminopyrrolidine-1-yl)benzonitrile, double salt triperoxonane acid (144 mg)and tert-butyl methyl ether (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (136 mg) in acetonitrile (5 ml) and water (0.5 ml) was added potassium carbonate (239 mg) and sodium iodide (52 mg) and was carried out by heating the reaction the mixture up to the boiling temperature under reflux for 34 hours. After the reaction solution was allowed to cool to room temperature, to the reaction solution were added ethyl acetate and water and the organic layer was separated. Recip is to cancel the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in methylene chloride (3 ml) was added triperoxonane acid (1 ml) and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and a solution of the obtained residue in DMF (3 ml) was added HOBT (188 mg), EDC (266 mg) and IPEA (0,36 ml). The reaction mixture was stirred at room temperature for 6 hours. To the reaction solution were added ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By purification of the residue by chromatography on silica gel (Carrier: ChromatorexTMNH and an eluting solvent: heptane:ethyl acetate=1:1→ethyl acetate) received 47 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,86-2,00 (m, 2H), 2,19-of 2.38 (m, 5H), 2,75 of 2.92 (m, 2H), 3,29-3,4 (m, 4H), 3,53-to 3.67 (m, 2H), 3,86 (s, 3H), 5,48-to 5.57 (m, 1H), 6,53 (d, J=6,8 Hz, 2H), 6,93 (Sirs, 1H), 7,01 (Sirs, 1H),? 7.04 baby mortality (sird, J=7,0 Hz, 1H), 7,25 (d, J=7,0 Hz, 1H), 7,47 (d, J=6,8 Hz, 2H), of 7.70 (s, 1H), 7,83 (Sirs, 1H).

Example 642

Synthesis of (E)-4-{3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-2-oxopiperidin-1-yl}piperidine-1-yl)benzonitrile

Formula 248

In the same way as described in note the re 641, received 72 mg specified in the header connection on the basis of 4-(4-aminopiperidin-1-yl)benzonitrile (142 mg) and tert-butyl methyl ether (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (129 mg). The physical properties of this compound are as follows.

1H-NMR (DMSO-d6) δ (ppm): 1.60-to is 1.81 (m, 6H), and 2.14 (s, 3H), 2,73-2,78 (m, 2H), 2,92-to 3.02 (m, 2H), 3,24-3,30 (m, 2H), of 3.84 (s, 3H), 4,01-4,10 (m, 2H), 4,60-4,71 (m, 1H),? 7.04 baby mortality (d, J=9,2 Hz, 2H), was 7.08 (DD, J=9,2, and 1.6 Hz, 1H), 7,14 (s, 1H), 7.23 percent (d, J=1.6 Hz, 1H), 7,38 (d, J=9,2 Hz, 1H), 7,55 (d, J=9,2 Hz, 2H), 7.62mm (Sirs, 1H), to 7.77 (DD, J=1.2 Hz, 1H).

Example 643

Synthesis of (E)-1-[4-(1-methoxy-1-methylethyl)benzyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-he

Formula 249

In the same way as described in example 418, received 100 mg specified in the header connection on the basis of (E)-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (250 mg) and 4-(1-methoxy-1-methylethyl)benzylamine (174 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): of 1.52 (s, 6H), 1,84 is 1.91 (m, 2H), 2,30 (s, 3H), 2,82-to 2.85 (m, 2H), of 3.07 (s, 3H), 3,38-to 3.41 (m, 2H), 3,86 (s, 3H), to 4.73 (s, 2H), 6,94 (t, J=1.2 Hz, 1H), 7,03 (s, 1H), 7.03 is-7,05 (m, 1H), 7,25-7,30 (m, 3H), 7,38 (d, J=8.0 Hz, 2H), 7,72 (d, J=1.2 Hz, 1H), 7,89 (s, 1H).

Example 644

Synthesis of (E)-1-[3-fluoro-4-(1-methoxy-1-methylethyl)benzyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it/p>

Formula 250

In the same way as described in example 418, received 57 mg specified in the header connection on the basis of (E)-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (250 mg) and 3-fluoro 4-(1-methoxy-1-methylethyl)benzylamine (132 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): to 1.59 (s, 6H), 1,86-of 1.92 (m, 2H), 2,30 (s, 3H), 2,81-of 2.86 (m, 2H), 3,18 (s, 3H), 3,38-of 3.42 (m, 2H), 3,86 (s, 3H), 4,70 (s, 2H), 6,92 (s, 1H), 6,97 (d, J=12 Hz, 1H), 7,02 (s, 1H), 7,03 (d, J=8.0 Hz, 1H),? 7.04 baby mortality (t, J=8.0 Hz, 1H), 7,24 (m, 1H), 7,37 (t, J=8.0 Hz, 1H), 7,71 (1H, s, 1H), 7,86 (1H, s, 1H).

Example 645

Synthesis of (E)-1-[2-fluoro-4-(1-methoxy-1-methylethyl)benzyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 251

In the same way as described in example 418, received 110 mg specified in the header connection on the basis of (E)-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid in salt form triperoxonane acid (250 mg) and 3-fluoro 4-(1-methoxy-1-methylethyl)benzylamine (154 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1.50 in (s, 6H), 1,86-of 1.92 (m, 2H), 2,30 (s, 3H), 2,81-to 2.85 (m, 2H), is 3.08 (s, 3H), 3.45 points-of 3.48 (m, 2H), 3,85 (s, 3H), amounts to 4.76 (s, 2H), 6,92 (t, J=1.2 Hz, 1H), 7,00 (s, 1H), 7,00-7,03 (m, 1H), 7,09-7,15 (m, 2H), 7,22-7,24 (m, 1H), was 7.36 (t, J=8.0 Hz, 1H), of 7.70 (d, J=1.2 Hz, 1H), a 7.85 (s, 1H).

Example 646

Synthesis of (E)-1-(4-chloro-3-terbisil)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 252

In the same way as described in example 416, received 100 mg specified in the header connection on the basis of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-she (80 mg) and 4-chloro-3-ftorangidridy (0,070 ml). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,84-of 1.92 (m, 2H), 2,30 (s, 3H), 2,80-is 2.88 (m, 2H), 3,34-of 3.42 (m, 2H), 3,86 (s, 3H), and 4.68 (s, 2H), 6,93 (s, 1H), 7,00-was 7.08 (m, 3H), 7,11 (d, J=8,8 Hz, 1H), 7,22-7,30 (m, 1H), 7,35 (t, J=8,4 Hz, 1H), 7,71 (s, 1H), 7,86 (s, 1H).

Example 647

Synthesis of (E)-1-[4-methyl-2-(4-triptoreline)-1,3-thiazol-5-ylmethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 253

In the same way as described in example 416, received 24 mg specified in the header connection on the basis of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidine-2-she (80 mg) and 5-(chloromethyl)-4-methyl-2-(4-triptoreline)-1,3-thiazol cases (94.2 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,85-of 1.95 (m, 2H), 2,30 (s, 3H), by 2.55 (s, 3H), 2,80-to 2.85 (m, 2H), 3.45 points-of 3.54 (m, 2H), 3,85 (s, 3H), of 4.83 (s, 2H), 6,91-6,93 (m, 1H), 6,98-7,05 (m, 2H), 7,22-7,27 (m, 1H), 7,65 (d, J=8,4 Hz, 2H), of 7.70 (d, J=1.2 Hz, 1H), 7,86 (s, 1H), 8,00 (d, J=8,4 Hz, 2H).

Example 648

Synthesis of (E)-1-(3,4,5-triptorelin)-3-[3-methoxy-4-(4-METI what-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 254

In the same way as described in example 416, received 55 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it (50 mg) and 3,4,5-triterpenoid (0,027 ml). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,86-of 1.94 (m, 2H), 2,30 (s, 3H), 2,80-is 2.88 (m, 2H), 3,35-of 3.42 (m, 2H), 3,86 (s, 3H), with 4.64 (s, 2H), 6.90 to-6,98 (m, 3H), 7,00-7,05 (m, 2H), 7,22-7,28 (m, 1H), 7,69-7,73 (m, 1H), a 7.85 (s, 1H).

Example 649

Synthesis of (E)-1-(3,4-dichlorobenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 255

In the same way as described in example 416, received 30 mg specified in the header connection on the basis of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it (30 mg) and 3,4-dichlorobenzaldehyde (0,020 ml). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,84-of 1.92 (m, 2H), 2,30 (s, 3H), 2,80-is 2.88 (m, 2H), 3,34-to 3.41 (m, 2H), 3,86 (s, 3H), of 4.67 (s, 2H), 6.90 to-to 6.95 (m, 1H), 7,00-7,06 (m, 2H), 7,17 (DD, J=2.0 a, and 8.4 Hz, 1H), 7.23 percent-7,27 (m, 1H), 7,40 (d, J=2.0 Hz, 1H), 7,40 (d, J=8,4 Hz, 1H), 7,71 (d, J=1.2 Hz, 1H), 7,86 (s, 1H).

Example 650

Synthesis of (E)-1-[6-chloro-2-(morpholine-4-yl)pyridine-3-ylmethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 256

In the same way as described in example 418, received 2 mg specified in the header connection on the basis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid in salt form triperoxonane acid (200 mg) and (6-chloro-2-(morpholine-4-yl)pyridine-3-yl)methylamine (250 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,82-of 1.92 (m, 2H), 2,31 (s, 3H), 2,82-2,90 (m, 2H), 3,12-3,20 (m, 4H), 3,22-3,30 (m, 2H), 3,80-3,90 (m, 4H), a 3.87 (s, 3H), 4,71 (s, 2H), 6.90 to-7,00 (m, 1H), 6,97 (d, J=8.0 Hz, 1H),? 7.04 baby mortality (s, 1H), 7,05 (d, J=8,4 Hz, 1H), 7,20-7,30 (m, 1H), 7,43 (d, J=8.0 Hz, 1H), 7,74 (Sirs, 1H), 7,88 (s, 1H).

Example 651

Synthesis of (E)-(2,2-debtorrent[1,3] dioxol-5-ylmethyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 257

In the same way as described in example 427, received 44 mg specified in the header connection on the basis of ethyl (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid (100 mg) and (2,2-debtorrent[1,3]dioxol-5-ylmethyl)methylamine (77,5 mg). The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,83-of 1.92 (m, 2H), 2,30 (s, 3H), 2,80-of 2.86 (m, 2H), 3,35-to 3.41 (m, 2H), 3,86 (s, 3H), and 4.68 (s, 2H), 6,91-6,94 (m, 1H), 6,98-7,05 (m, 4H), 7,07-7,10 (m, 1H), 7,22-7,27 (m, 1H), 7,71 (d, J=1.2 Hz, 1H), 7,86 (s, 1H).

Example 652

Synthesis of (E)-1-(3-chloro-4-terbisil)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 258

In the same way as described in example 427, received 27 mg specified in the header connection on the basis of ethyl(E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valerianic acid (100 mg) and 3-chloro-4-forbindelsen (100 mg). Physical properties this is about connection the following.

1H-NMR (CDCl3) δ (ppm): 1,84-of 1.92 (m, 2H), 2,30 (s, 3H), 2,80-2,87 (m, 2H), 3,34-to 3.41 (m, 2H), 3,88 (s, 3H), of 4.66 (s, 2H), 6,91-6,94 (m, 1H), 7,00-7,05 (m, 2H), 7,10 (t, J=8,8 Hz, 1H), 7,17-of 7.23 (m, 1H), 7.23 percent-7,28 (m, 1H), was 7.36 (DD, J=2.0 a, 6,8 Hz, 1H), 7,71 (d, J=1.6 Hz, 1H), 7,86 (s, 1H).

Compounds shown in table 21, were synthesized as described in example 418.

Structural formulas and physical properties are presented in table 21, respectively.

The separation conditions specified in the column “remarks” in table 21, the following:

Conditions division A: CHIRALPAKTMAD-H (2 cm×25 cm: mobile phase:system hexane-ethanol)

Conditions division B: CHIRALPAKTMOJ-H (2 cm×25 cm: mobile phase:system hexane-ethanol)

Table 21-1

Table 21-2

Table 21-3

Table 21-4

Table 21-5

Table 21-6

Table 21-7

Table 21-8

Table 21-9

Table 21-10

Table 21-11

Table 21-12

Table 21-13

Table 21-14

Table 21-15

Table 21-16

Table 21-17

Table 21-18

Table 21-19

Compounds shown in table 22, were synthesized as described in example 85. Structural formulas and physical properties are presented in table 22, respectively. The separation conditions specified in the column “remarks” the following table:

Conditions division E: CHIRALCELKTMOD from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase:hexane-ethanol)

Table 22
ExampleE1Data: MS m/zNotes
839M++N: 408 (ESI)Optically-active compound (separation conditions E: retention time: 8.7 minutes; absolute configuration: unknown)
840M++N: 408 (ESI)Optically-active compound (separation conditions E: retention time: 13,6 minutes; absolute configuration: unknown)

Compounds shown in table 23, were synthesized as described in example 121. Structural formulas and physical properties are presented in table 23, respectively.

Table 23

The connection presented in table 24 was synthesized as described in example 1. Structural formulas and physical properties are presented in table 24, respectively.

Table 24
ExampleR11E1Data: MS m/zNotes
851IUM++N: 404 (ESI)Optically-active substance
852EtM++N: 408 (ESI)Optically-active substance

Compounds shown in table 25, were synthesized as described in example 121. Structural formulas and physical properties are presented in table 25, respectively.

Table 25-1
ExampleE1Data: MS m/z
853 M++H: 447 (ESI)
854M++H: 445 (ESI)

Table 25-2

Compounds shown in table 26, were synthesized as described in example 418. Structural formulas and physical properties are presented in table 26, respectively. The separation conditions specified in the column “notes” table, the following:

Conditions division A: CHIRALPAKTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase:system hexane-ethanol)

Table 26-1

Table 26-2

Compounds shown in table 27, were synthesized as described in example 418. Structural formulas and physical properties are presented in table 27, respectively. The separation conditions specified in the column “notes” table, the following:

Conditions division A: CHIRALPAKTMAD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase:system hexane-ethanol)

Conditions division B: CHIRALCELTMOJ-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase:system hexane-ethanol)

Conditions of division C CHIRALCEL TMOD-H from the company Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase:system hexane-ethanol)

Table 27-1

Table 27-2

Table 27-3

Table 27-4

Table up 27-5

Table 27-6
ExampleG8Data: MS m/zNotes
924M++N: 464 (ESI)The racemate
925M++N: 420 (ESI)Optically-active substance
926 M++N: 464 (ESI)Optically-active substance

Example 927 and 928 Example

Synthesis of (E)-1-{(R)-(4-forfinal)-[(S)-tetrahydrofuran-2-yl]methyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it (E)-1-{(S)-(4-forfinal)-[(R)-tetrahydrofuran-2-yl]methyl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 259

Synthesis of Erythro-(4-forfinal)-(tetrahydrofuran-2-yl)methyl azide

Diethylazodicarboxylate (120 mg), threo-(4-forfinal)-(tetrahydrofuran-2-yl)methanol (90 mg)synthesized in accordance with the method described in Chem. Comm., 1999, p. 1745, and diphenylphosphoryl (0,099 ml) was sequentially added to a solution of triphenylphosphine (180 mg) in THF (5 ml) at 0ºC and the reaction solution was stirred for 1 hour. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (Carrier: ChromatorexTMNH, eluting solvent: heptane→heptane:ethyl acetate=4:1) to give 28 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,79-of 1.94 (m, 4H), 3,76-3,82 (who, 1H), 3,85-3,93 (m, 1H), 4,08-to 4.14 (m, 1H), 4,63 (d, J=4,8 Hz, 1H), 7,01-was 7.08 (m, 2H), 7,26-7,33 (m, 2H).

Synthesis of Erythro-(4-forfinal)-(tetrahydrofuran-2-yl)methylamine

10% palladium on carbon (water content: 50%, 5 mg) was added to a solution of Erythro-(4-forfinal)-(tetrahydrofuran-2-yl)methylated (28 mg) in ethanol and the reaction solution was stirred in a stream of hydrogen at room temperature for 10 hours. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to obtain 25 mg specified in the connection header. The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,55 of 1.99 (m, 4H), 3,66-a 3.83 (m, 2H), 4,25-and 4.40 (m, 2H), 6,97-7,06 (m, 2H), 7,44-of 7.55 (m, 2H), 8,78-9,02 (Sirs, 2H).

Synthesis of (E)-1-{(R)-(4-forfinal)-[(S)-tetrahydrofuran-2-yl]methyl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it (E)-1-{(S)-(4-forfinal)-[(R)-tetrahydrofuran-2-yl]methyl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Received 41 mg of racemic compounds on the basis of triptoreline (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerianic acid (63 mg) and Erythro-(4-forfinal)-(tetrahydrofuran-2-yl)methylamine (25 mg) in the same manner as described in example 418.

The racemic compound (41 mg) was fractionally using CHIRALPAKTMAD-H, manufacturer Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: g is Xan:ethanol=3:7) to obtain specified in the title optically active substance with a retention time of 43 minutes (13.5 mg; >99% of ei) and indicated in the title optically active substance with a retention time of 64 minutes (10.5 mg; >99% of ei).

Physical properties of the optically active substance with a retention time of 43 minutes (example 927) following.

1H-NMR (CDCl3) δ (ppm): 1,61-1,72 (m, 1H), 1.77 in-2,12 (m, 5H), is 2.30 (s, 3H), 2,74 is 2.80 (m, 2H), 3,06-3,14 (m, 1H), 3.27 to the 3.35 (m, 1H), 3,82-of 3.96 (m, 5H), to 4.52-4,59 (m, 1H), of 5.92 (d,J=8,8 Hz, 1H), 6,93 (Sirs, 1H), 6,99-7,05 (m, 4H), from 7.24 (d, J=8.0 Hz, 1H), 7,46 is 7.50 (m, 2H), 7,72 (d, J=1.2 Hz, 1H), 7,87 (Sirs, 1H).

Physical properties of the optically active substance with a retention time of 64 minutes (example 928) following.

1H-NMR (CDCl3) δ (ppm): 1,61-1,72 (m, 1H), 1.77 in-2,12 (m, 5H), is 2.30 (s, 3H), 2,74 is 2.80 (m, 2H), 3,06-3,14 (m, 1H), 3.27 to the 3.35 (m, 1H), 3,82-of 3.96 (m, 5H), to 4.52-4,59 (m, 1H), of 5.92 (d, J=8,8 Hz, 1H), 6,93 (Sirs, 1H), 6,99-7,05 (m, 4H), from 7.24 (d, J=8.0 Hz, 1H), 7,46 is 7.50 (m, 2H), 7,72 (d, J=1.2 Hz, 1H), 7,87 (Sirs, 1H).

Example 929 and Example 930

Synthesis of (E)-1-{(R)-(4-forfinal)-[(R)-tetrahydrofuran-2-yl]methyl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it (E)-1-{(S)-(4-forfinal)-[(S)-tetrahydrofuran-2-yl]methyl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidine-2-it

Formula 260

Synthesis of Erythro-(4-forfinal)-(tetrahydrofuran-2-yl)methanol

Diethylazodicarboxylate (491 mg), threo-(4-forfinal)-(tetrahydrofuran-2-yl)methanol (368 mg) and benzoic acid (251 mg) was sequentially added to a solution of triphenylphosphine (736 mg) in THF (20 m is) at 0ºC. The reaction solution was stirred at 0ºC for 1 hour and then stirred at room temperature for 12 hours. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluting solvent: heptane→heptane:ethyl acetate=3:1) to give 187 mg (4-forfinal)-(tetrahydrofuran-2-yl)methylbenzoate. To the solution obtained (4-forfinal)-(tetrahydrofuran-2-yl)methylbenzoate (187 mg) in methanol (5 ml) was added 1 n aqueous sodium hydroxide solution (3 ml) and the reaction solution was stirred at room temperature for 4 hours. To the reaction solution was added a saturated brine and ethyl acetate and the organic layer was separated. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 120 mg specified in the connection header.

The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,54-1,90 (m, 4H), of 3.77-of 3.85 (m, 1H), 3,89-of 3.96 (m, 1H), was 4.02-4,08 (m, 1H), 4,90 (d, J=4.0 Hz, 1H), 6,99-7,05 (m, 2H), 7,31 and 7.36 (m, 2H).

Synthesis of threo-(4-forfinal)-(tetrahydrofuran-2-yl)methylamine

In the same way as described in example 927 received 8 mg Treo-(4-forfinal)-(tetrahydrofuran-2-yl)methylamine on the basis of Erythro-(4-forfinal)-(tetrahydrofuran-2-yl)methanol (120 mg).

The physical properties of this compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1,49 w