Indole derivative and its use in therapeutic purposes

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

 

The technical field to which the invention relates

The present invention relates to the derivatives of azaindole used as medicines.

More specifically the present invention relates to the derivatives of azaindole possessing inhibitory activity against xanthine oxidase and used as agents for preventing or treating diseases associated with abnormal levels of uric acid in serum, their prodrugs or pharmaceutically acceptable salts.

The level of technology

Uric acid is the end product of purine metabolism in humans. Many mammals in contrast to the human uric acid then decomposes under the action of urotoxicity (uricase) in the liver to allantoin that is excreted through the kidneys. A person by the main output of uric acid are the kidneys, through which about two-thirds of uric acid excreted in the urine. The remaining amount is excreted in the feces. Excessive production or reduced output of uric acid hyperuricemia occurs. There are three types of hyperuricemia with excessive production of uric acid, with insufficient excretion of uric acid and mixed type. This classification hyperuricemia is clinically important. In order to reduce the IC undesirable actions of therapeutic agents, they are chosen in accordance with each class (for example, see the reference to non-patent document 1).

When hyperuricemia with excessive production of uric acid increases the elimination of uric acid with urine, and when the elimination of uric acid with urine is additionally increased by the use of tools that promote uric acid excretion may develop as complications of kidney stones. Therefore, basically, the excessive production of uric acid used allopurinol, an inhibitor of production of uric acid (or sometimes referred to as inhibitor of the synthesis of uric acid in the text of the application called "inhibitor of the production of uric acid").

Uric acid is formed from purine bodies, which are formed from food intake and, in the end, endogenously synthesized through the oxidation of xanthine by xanthine oxidase. Allopurinol developed as an inhibitor of xanthine oxidase and is used in medical practice as the sole inhibitor of the production of uric acid. Although, it is reported that allopurinol is effective in hyperuricemia and various diseases caused by hyperuricemia, however, it was also reported severe negative effects such as the syndrome poisoning (allergic shall acculite), the syndrome of Stevens-Johnson, exfoliative dermatitis, anaplastic anemia, liver dysfunction and other complications (for example, see the reference to non-patent document 2). As one of the reasons it was noted that allopurinol has a similar structure to the nucleic acid, and inhibits the path of pyrimidine metabolism (for example, see the reference to non-patent document 3).

On the other hand, when hyperuricemia with insufficient excretion of uric acid, the output of uric acid decreases. It was reported that the application of allopurinol, which becomes in the process of metabolism in oxypurinol, which is excreted through the kidneys by the same mechanism as in the case of uric acid, the output oxipurinol also decreases, which increases the incidence of liver disease (for example, see the reference to non-patent document 4). Therefore, when an insufficient output of uric acid, mainly used in tools that promote the excretion of uric acid, such as probenecid, benzbromarone and other similar medicines. However, these funds contribute to the elimination of uric acid, have also negative effects, such as gastrointestinal disease, renal disease and other similar diseases. In particular, it is known that in the case of suffering at the Giya patients benzbromarone can cause fulminant hepatitis (e.g., see the reference to non-patent document 5).

Thus, it is noted that as the existing inhibitor of the production of uric acid, and a means of facilitating the excretion of uric acid, have limitations in patients or severe negative effects. Therefore, it is desirable to develop easy to use tools for the treatment of hyperuricemia.

Uric acid is excreted mainly by the kidneys, and to present series of experiments investigated the dynamics of urate in the kidney using membrane vesicles brush edges (BBMV)prepared from cortical substance of the kidney (see, for example, a reference to non-patent documents 6 and 7). It is known that in humans, uric acid passes freely through the renal glomeruli, and there are mechanisms of reabsorption and excretion of uric acid in the proximal tubule (see, for example, a reference to non-patent document 8).

In recent years there has been identified a gene (SLC22A12), encoding a Transporter of urate in human kidney (see, for example, a reference to non-patent document 9). The vector encoded by this gene (vector urates 1, denoted in the text of the application as URAT1"), is a 12-transmembrane molecule that belongs to the family of OAT. URAT1 mRNA specifically expressed in the kidney, and observed the localization of URAT1 the upper wall of the proximal tubules in the tissue section of human kidney. In the experiment using the system for the expression of xenopus oocytes was shown to capture uric acid via URAT1. In addition, it was shown that the captured uric acid is transported by sharing with organic anions, such as lactic acid, perintalmanna acid (PZA), nicotinic acid and other similar acids, and the capture of uric acid via URAT1 inhibited the means for facilitating the excretion of uric acid, probenecid and benzbromarone. Thus, as expected, on the basis of the experiment using membrane vesicles was put forward convincing assumption that URAT1 exchanges lithate/anion. Namely, it was shown that URAT1 is a Transporter that plays an important role in the reabsorption of uric acid in the kidneys (see, for example, a reference to non-patent document 9).

In addition, it became apparent link between URAT1 and diseases. Idiopathic renal hypouricemia is a disease, which increases the excretion of uric acid due to disturbed dynamics of urate in the kidney and the level of uric acid in the serum becomes low. It is known that the disease is often associated with kidney stone disease or acute renal failure after exercise. URAT1 identified as a gene that causes kidney g is morikami (for example, see the reference to non-patent document 9). These facts also allow to put forward a convincing assumption that URAT1 is responsible for the regulation of uric acid levels in the blood.

Therefore, a substance having inhibitory action on URAT1, can be used as a means for the treatment and prevention of diseases associated with high levels of uric acid in the blood, that is, hyperuricemia, gouty nodes, gouty arthritis, renal diseases associated with hyperuricemia, kidney stones or other similar diseases.

It was reported that in the treatment of hyperuricemia combination of allopurinol, an inhibitor of the production of uric acid and tools, with activity on the excretion of uric acid, lowers the level of uric acid in the serum more strongly than using only one of allopurinol (for example, see the reference to non-patent documents 10 and 11). Therefore, when the treatment using only one of the available remedies may not provide sufficient steps, a higher therapeutic effect can be expected due to the use of a combination of an inhibitor of the production of uric acid and tools that promote the excretion of uric acid. Also, consider that since the excretion of uric acid in the urine can be lowered to put the m reducing uric acid levels in the blood, when hyperuricemia with insufficient excretion of uric acid can be reduced the risk of kidney stones caused by monotherapy using tools that promote the excretion of uric acid. In addition, it is expected a high therapeutic effect in hyperuricemia mixed type. Thus, it can be expected that the tool, as having inhibitory activity against the production of uric acid, and activity in relation to the excretion of uric acid, is an extremely effective tool for the prevention and treatment of hyperuricemia or other similar diseases.

As compounds with both inhibitory action against xanthine oxidase, and inhibitory action on URAT1, a known natural product Maureen (see the reference to non-patent document 12). Furthermore, as compounds with activity on the excretion of uric acid, known burilnye or dianiline ether compound (see patent document 1).

It was reported that derivatives of 1-phenylindole possess inhibitory activity during differentiation of stem cells (see references in patent documents 2-4). In addition, it was reported that the derived 1-pyrimidinyl has inhibitory activity against sodium channel (Smotritsky to patent document 5). However, the derived azaindole the present invention has a different structure from the compounds described in the above publications, and nothing is described, and nothing is assumed about the fact that they possess inhibitory activity against xanthine oxidase, or that they can be used to prevent or treat diseases associated with abnormal levels of uric acid in serum, such as gout, hyperuricemia or other similar diseases.

Patent document 1: Tokkai 2000-001431 (JPA2000-001431)

Patent document 2: WO 2005/007838 description

Patent document 3: Tokkai 2006-180763 (JPA2006-180763)

Patent document 4: Tokkai 2006-204292 (JPA2006-204292)

Patent document 5: WO 2005/003099 description

Non-patent document 1: Atsuo Taniguchi and 1 person,Modern Physician, 2004, Vol.24, No.8, pp.1309-1312

Non-patent document 2: Kazuhide Ogino and 2 persons,Nihon Rinsho(Japan Clinical), 2003, Vol.61, Extra edition 1, pp.197-201

Non-patent document 3: Hideki Horiuchi and 6 persons,Life Science, 2000, Vol.66, No.21, pp.2051-2070

Non-patent document 4: Hisashi Yamanaka and 2 persons,Konyosankessyo to Tsufu(Hyperuricemia and gout), issued by Medical Review Co., 1994, Vol.2, No.1, pp.103-111

Non-patent document 5: edited byKonyosankessyo, tsufu no Chiryo guideline sakuseiiinkaiThe Committee establishing a guideline for the treatment of hyperuricemia and gout), The guideline for the treatment of hyperuricemia and gout, Edition 1, issued by Nihontsuhu kakusan taisya gakkai(Japanese society of gout and nucleic acid metabolism), 2002, pp.32-33

Repatent the second document 6: Francoise Roch-Ramel and 2 persons, Am. J. Physiol., 1994, Vol.266 (Renal Fluid Electrolyte Physiol., Vol.35), F797-F805

Non-patent document 7: Francoise Roch-Ramel and 2 persons, J. Pharmacol. Exp. Ther., 1997, Vol.280, pp.839-845

Non-patent document 8: Hiroaki Kimura and 3 persons,Nihon rinsyo(Japan Clinical), 2003, Vol.61, Extra Edition 1, pp.119-123

Non-patent document 9: Atsushi Enomoto and 18 persons, Nature, 2002, Vol.417, pp.447-452

Non-patent document 10: Takahashi S and 5 persons, Ann. Rheum. Dis., 2003, Vol.62, pp.572-575

Non-patent document 11: M. D. Feher and 4 persons, Rheumatology, 2003, Vol.42, pp.321-325

Non-patent document 12: Zhifeng Yu and 2 persons, J. Pharmacol. Exp. Ther., 2006, Vol.316, pp.169-175

Description of the invention

The problem solved by the invention

The present invention provides a means for preventing or treating diseases associated with abnormal levels of uric acid in the blood serum, which has inhibitory activity against the production of uric acid.

Ways of solving the problem

The authors of the present invention has set itself the task to solve the above problem. In the result it was found that derivatives of azaindole represented by the following General formula (I), exhibit a strong inhibitory activity against xanthine oxidase and extremely reduce the levels of uric acid in serum, and therefore they can be used as a means to prevent or treat diseases associated with abnormal UB is high uric acid in blood serum, thus was established the present invention.

Namely, the present invention relates to:

[1] derived azaindole represented by the General formula:

where T represents nitro, cyano or trifluoromethyl;

ring J represents an aryl ring or heteroaryl ring;

Q represents carboxy, lower alkoxycarbonyl, carbarnoyl, mono(di)(lower alkyl)carbarnoyl, sulfo, sulfamoyl or 5-tetrazolyl;

Y represents a hydrogen atom, hydroxyl, amino, halogen atom, nitro, optionally substituted lower alkyl or optionally substituted lower alkoxy, provided that two or more Y optionally exist on ring J and these Y are optionally the same or different from each other;

X1X2and X3independently represent CR2or N, provided that all X1X2and X3are not simultaneously N; and when there are two or more R2these R2are not necessarily the same or different from each other; and

R1and R2independently represent a halogen atom, cyano, PERFLUORO(lower alkyl), -AA, -A-D-E-G or-N(-D-E-G)2provided that two (-D-E-G) do not necessarily differ from each other;

in the formula AArepresents a hydrogen atom, hydroxy, thiol, -CHO, carboxy, -CONHR3 -The other3, -N(R3)CHO, -N(R3)CONHR4or-SO2Other3;

A represents A single bond, -O-, -S-, -CO-, -COO-, -CON(R3)-, -SO2-, -SO2N(R3)-, -N(R3)-, -N(R3)CO-, -N(R3)COO-, -N(R3)SO2- or-N(R3)CONR4-where R3and R4independently represent a hydrogen atom or lower alkyl;

D represents optionally substituted lower alkylene, optionally substituted lower albaniles, optionally substituted lower akinyan, optionally substituted cycloalkyl, optionally substituted heterocyclochain, optionally substituted, Allen or optionally substituted, heteroaryl provided that D is optionally additionally substituted-E-G;

E represents a single bond, -O-, -N(R5)-, -S-, -CO-, -COO-, -CON(R5)-, -SO2-, -SO2N(R5)-, -N(R5)CO-, -N(R5)COO-, -N(R5)SO2- or-N(R5)CON(R6)- provided that R5and R6independently represent a hydrogen atom or lower alkyl; and

G represents a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower quinil, optionally substituted cycloalkyl, optionally substituted heteroseksualci, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C is cloaker(lower alkyl), optionally substituted heteroseksualci(lower alkyl), optionally substituted aryl(lower alkyl) or optionally substituted heteroaryl(lower alkyl), provided that when G is a hydrogen atom, E is a single bond, -O-, -N(R5)-, -S-, -COO-, -CON(R5)-, -N(R5)CO-, -N(R5)CON(R6)- or-SO2N(R5)-, or G is not necessarily connected with R5and R6with the formation of rings, or provided that when there are R1and R2or two R2associated with the neighboring atoms, these R1and R2or two R2optionally linked together to form a ring;

or its prodrug, or pharmaceutically acceptable salt;

[2] derived azaindole described in the above item [1], where X1X2and X3independently represent CR2provided that when there are two or more R2these R2are not necessarily the same or different from each other; or its prodrug, or pharmaceutically acceptable salt;

[3] derived azaindole described in the above [1] or [2], where T represents cyano; or its prodrug, or pharmaceutically acceptable salt;

[4] derived azaindole described in any of the above paragraphs [1]-[3], where Q represents a Carbo is si; or its prodrug, or pharmaceutically acceptable salt;

[5] derived azaindole described in any of the above paragraphs [1]-[4], where Y represents a hydrogen atom, hydroxy or a halogen atom; or its prodrug, or pharmaceutically acceptable salt;

[6] derived azaindole described in the above item [5], where Y is hydroxy; or its prodrug, or pharmaceutically acceptable salt;

[7] derived azaindole described in any of the above paragraphs [1]-[6], where the ring J represents a benzene ring; or its prodrug, or pharmaceutically acceptable salt;

[8] derived azaindole described in the above item [4], where the group represented by the General formula:

is a group represented by the following General formula (IIa):

where in the formula

Z1, Z2and Z3independently represent CR7or N; and

Y1and R7independently represent a hydrogen atom, hydroxy, amino, halogen atom, lower alkyl or lower alkoxy, provided that when there are two or more R7these R7are not necessarily the same or different from each other; or its prodrug, or pharmaceutically acceptable salt;

[9] p is izvozna of azaindole, described in the above item [8], where

Z1and Z3represent CH, and Z2is CR8or N; and

Y1and R8independently represent a hydrogen atom, hydroxy or a halogen atom; or its prodrug, or pharmaceutically acceptable salt;

[10] derived azaindole described in any of the above items [4]-[6], where the ring J represents a 5-membered heteroaryl ring having 1 to 3 identical or different heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom, provided that an oxygen atom and a sulfur atom are not next to each other; and Y represents a hydrogen atom, hydroxy, amino, halogen atom, optionally substituted lower alkyl or optionally substituted lower alkoxy, provided that at ring J optional there are two or more Y, and these J are not necessarily the same or different from each other; or its prodrug, or pharmaceutically acceptable salt;

[11] derived azaindole described in the above item [10], where the group represented by the General formula:

is a group represented by the following General formula (IIb):

where in the formula:

Z4, Z5and Z7represent the atom sour the ode, the nitrogen atom, a sulfur atom, provided that Z4and Z5at the same time are not atoms selected from oxygen atom and sulfur atom, or CR9in which R9represents a hydrogen atom, hydroxy, amino, halogen atom, lower alkyl or lower alkoxy, provided that when there are two or more R9these R9are not necessarily the same or different from each other; Z6represents a carbon atom; and Z4, Z5, Z6and Z7tied together with the carbon atom associated with a carboxyl group, with the formation of 5-membered heteroaryl ring; or its prodrug, or pharmaceutically acceptable salt;

[12] derived azaindole described in the above item [4], where the group represented by the General formula:

is a group represented by the following General formula (IId):

R1represents a hydrogen atom; X1is CR10where R10is lower alkyl or-O-(lower alkyl)-; X2is CR11where R11represents a halogen atom or a lower alkyl; and X3represents CH; or its prodrug, or pharmaceutically acceptable salt;

[13] derived azaindole described in the above item [12], where R10predstavljaet methyl or methoxy; and R11represents a fluorine atom, a chlorine atom or methyl; or its prodrug, or pharmaceutically acceptable salt;

[14] the inhibitor of xanthine oxidase, comprising as an active ingredient derived azaindole described in any of the above paragraphs [1]-[13], or its prodrug, or pharmaceutically acceptable salt;

[15] a pharmaceutical composition comprising as an active ingredient derived azaindole described in any of the above paragraphs [1]-[13], or its prodrug, or pharmaceutically acceptable salt;

[16] the pharmaceutical composition described in the above item [15], which is a tool for prevention or treatment of a disease selected from the group consisting of hyperuricemia, gouty site, gouty arthritis, renal diseases associated with hyperuricemia and kidney stones;

[17] the pharmaceutical composition described in the above item [16], which is a tool for prevention or treatment of hyperuricemia;

[18] the pharmaceutical composition described in the above item [15], which is a medicine to lower uric acid levels in the serum;

[19] the pharmaceutical composition described in the above item [15], which is an inhibitor of products is tiravanija uric acid;

[20] the pharmaceutical composition described in any of the above paragraphs [15]-[19], which includes additional combination with at least one drug selected from the group consisting of colchicine, non-steroidal anti-inflammatory drugs, steroid and podslushivaet urine as the active ingredient; and other similar tools.

In derivative azaindole represented by the above General formula (I) of the present invention, each term has the following meaning.

The term "halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.

The term "lower" means a linear or branched hydrocarbon group having 6 or less carbon atoms. Examples of the lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,Deut-butyl,tert-butyl, pentyl, isopentyl, neopentyl,tertpentyl, hexyl and other similar alkali, an example of the lowest alkenyl is vinyl, allyl, 1-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 2-methylallyl and other such alkenyl, and an example of the lower quinil is ethinyl, 2-PROPYNYL and other similar alkinyl. An example of the lower alkylene is methylene, METROTILE, dimethylmethylene, ethylene, 1-methylation, 2-mutilation, propane-1,3-diyl, 1-methylpropan-1,3-diyl, 1,1-dimethyl shall ropan-1,3-diyl, 2-methylpropan-1,3-diyl, 2,2-DIMETHYLPROPANE-1,3-diyl, 3-methylpropan-1,3-diyl, 3,3-DIMETHYLPROPANE-1,3-diyl, butane-1,4-diyl, 1-methylbutane-1,4-diyl, 1,1-Dimethylbutane-1,4-diyl, 2,2-Dimethylbutane-1,4-diyl, 3,3-dimethylbutan-1,4-diyl, 4-methylbutane-1,4-diyl, 4,4-Dimethylbutane-1,4-diyl, pentane-1,5-diyl, 1-methylpentan-1,5-diyl, 2-methylpentan-1,5-diyl, 3-methylpentan-1,5-diyl, 4-methylpentan-1,5-diyl, 5-methylpentan-1,5-diyl, hexane-1,5-diyl and other similar alkylene, for example lower Alcanena is vinile, propene-1,3-diyl, 1-butene-1,4-diyl, 2-butene-1,4-diyl, 1,3-butadiene-1,4-diyl, 1-penten-1,5-diyl, 2-penten-1,5-diyl, 1,3-pentadiene-1,5-diyl, 1-hexene-1,6-diyl, 2-hexene-1,6-diyl, 3-hexene-1,6-diyl, 1,3-hexadiene-1,6-diyl, 1,3,5-hexatriene-1,6-diyl and other similar Alcanena, and an example of the lower akinlana is ethynylene, 2-propylen and other similar Alcanena. Examples of the lower alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,Deut-butoxy,tert-butoxy, pentyloxy, isopentylamine, neopentylene,tert-pentyloxy, hexyloxy and other similar alkoxy, and an example of the lower alkoxycarbonyl is methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide,Deut-butoxycarbonyl,tert-butoxycarbonyl, pentyloxybenzoyl, isopentylamine, neopentylglycol,tert-pantoloc carbonyl, hexyloxybenzoyl and other similar alkoxycarbonyl.

The term "PERFLUORO(lower alkyl)" means the above lower alkyl, which is substituted by fluorine atoms, and the preferred are methyl, substituted by 1-3 fluorine atoms, or ethyl, substituted by 1-5 fluorine atoms.

The term "cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and the term "cycloalkyl" denotes a divalent group derived from the above cycloalkyl.

The term "heteroseksualci" denotes a 3-8-membered aliphatic monocyclic hydrocarbon group having any 1 or 2 heteroatoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, in the ring, and optionally having 1 or 2 carbonyl group, such as aziridine, azetidine, morpholine, 2-morpholinyl, thiomorpholine, 1-pyrrolidinyl, piperidino, 4-piperidinyl, 1-piperazinil, 1-pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl and other similar groups defined above or a 5-6-membered aliphatic monocyclic hydrocarbon group which is condensed with benzene ring, for example, 1,3-doxasozin-2-yl, and other similar groups, and the term "heterocyclochain" denotes a divalent group derived from the above geterotsiklicheskie.

The term "aryl" denotes phenyl or nafta is, the term "Allen" denotes a divalent group derived from the above aryl.

The term "cycloalkyl(lower alkyl)" means the above lower alkyl substituted by the above cycloalkyl, the term "heteroseksualci(lower alkyl)" means the above lower alkyl substituted by the above heterocyclization, the term "aryl(lower alkyl)" means the above lower alkyl substituted by the above aryl, the term "heteroaryl(lower alkyl)" means the above lower alkyl substituted by the above heteroaryl. Deputy optionally substituted cycloalkyl(lower alkyl) can be located either on cycloalkyl, or lower alkyl. The same applies to the optional substituted heteroseksualci(lower alkyl), optionally substituted, the aryl(lower alkyl), and optionally substituted by heteroaryl(lower alkyl).

The term "heteroaryl" denotes a 5 - or 6-membered aromatic heterocyclic group having any of the 1-4 heteroatoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, in the ring, which is derived from thiazole, oxazole, isothiazole, isoxazol, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, furazan and the and other similar groups, or 5 - or 6-membered aromatic heterocyclic group condensed with a 6-membered ring, having any of the 1 to 4 heteroatoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, which is derived from indole, isoindole, benzofuran, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzisoxazole, benzisothiazole, indazole, benzimidazole, quinoline, isoquinoline, phthalazine, cinoxacin, heatline, sinolink, indolizine, naphthiridine, pteridine or other similar groups, and the term "heteroaryl" denotes a divalent group derived from the above above heteroaryl.

The term "optionally substituted" means that may be present from 1 to 3 identical or different substituents.

Examples of the substituent in the optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower quinil, optionally substituted cycloalkyl or optionally substituted heteroseksualci is a fluorine atom, PERFLUORO(lower alkyl), -OW1, SW1, carboxy, sulfo, lower alkyl, lower alkylsulfonyl, lower alkoxycarbonyl, -OCOW2, -N(W2)COW3, -OCOOW4, -N(W2)COOW4, -NHC(=NH)-NW2W3, NW2W3, -CONW2W3, -N(W5)CONW6W7, -N(W2)SO2W5, -SOsub> 2NW2W3, -SO2W4; aryl, which may have any 1 to 3 groups selected from the group consisting of halogen atom, hydroxy, lower alkyl, lower alkoxy and trifloromethyl; and heteroaryl, which may have any 1 to 3 groups selected from the group consisting of halogen atom, hydroxy, lower alkyl, lower alkoxy and trifloromethyl. A preferred example of the substituent in the optionally substituted lower alkyl and Y is a fluorine atom, PERFLUORO(lower alkyl), lower alkyl, hydroxyl group and lower alkoxy.

A preferred example of the substituent in the optionally substituted lower alkoxy is a fluorine atom, PERFLUORO(lower alkyl), lower alkyl, hydroxyl group and lower alkoxy.

Examples of the substituent in the optionally substituted aryl and optionally substituted heteroaryl is a halogen atom, PERFLUORO(lower alkyl), cyano, nitro, -OW8, SW8, carboxy, lower alkyl, lower alkylsulfonyl, lower alkoxycarbonyl, -OCOW2, -N(W2)COW3, -OCOOW4, -N(W2)COOW4, -NHC(=NH)-W2W3, NW2W3, -CONW2W3, -N(W5)CONW6W7, -N(W2)SO2W5, -SO2NW2W3, -SO2W4, aryl which may have any of 1-3 groups selected from the group consisting of halogen atom, hydroxy, nor the higher of alkyl, lower alkoxy and trifloromethyl; and heteroaryl, which can have any of 1-3 groups selected from the group consisting of halogen atom, hydroxy, lower alkyl, lower alkoxy and trifloromethyl.

Above W1represents a hydrogen atom, lower alkyl, PERFLUORO(lower alkyl); aryl, which may have any 1 to 3 groups selected from the group consisting of halogen atom, hydroxy, alkyl, lower alkoxy and trifloromethyl; aryl(lower alkyl); or lower alkyl having from 2 to 6 carbon atoms, which has a group selected from the group consisting of amino, mono(di)(lower alkyl)amino and lower alkylsulfonamides, provided that an oxygen atom or a sulfur atom associated with W1and the nitrogen atom in W1linked to different carbon atoms;

W2, W3, W5, W6and W7independently represent a hydrogen atom, lower alkyl, aryl(lower alkyl), or W2and W3and W5and W6or W6and W7can form the alicyclic amino group with the linking nitrogen atom;

W4represents lower alkyl, or W2and W4can form the alicyclic amino group with the linking nitrogen atom;

and W8represents a hydrogen atom, lower alkyl, PERFLUORO(lower alkyl); aryl, which may have any 1 to 3 groups selected from the groups who, consisting of halogen atom, hydroxy, alkyl, lower alkoxy and trifloromethyl; aryl(lower alkyl); or lower alkyl having from 2 to 6 carbon atoms, which has a group selected from the group consisting of amino, mono(di)(lower alkyl)amino and lower alkylsulfonamides, provided that an oxygen atom or a sulfur atom associated with W8and the nitrogen atom in W8linked to different carbon atoms, and when two-OW8are on adjacent carbon atoms in the aryl ring, these W8can be linked together with the formation of a methylene chain which may be substituted by 1 or 2 fluorine atoms, or ethylene chain which may be substituted by 1 to 4 fluorine atoms, respectively.

The term "mono(di)(lower alkyl)amino" means an amino group mono - or disubstituted by the above lower alkyl, and the term "mono(di)(lower alkyl)carbarnoyl" means carbarnoyl, mono - or disubstituted by the above lower alkyl. Two groups of lower alkyl disubstituted in the group may differ from each other.

The term "alicyclic amino" denotes a 3-8-membered cyclic amino group, optionally having a heteroatom selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, but not the nitrogen atom at the binding position in the ring, such as aziridine, azetidine, morpholine, tio is morpholino, 1-pyrrolidinyl, piperidino, 1-piperazinil, 1-pyrrolyl and other similar groups optionally having 1 or 2 carbonyl group and optionally having 1 or 2 double bonds in the ring, for example, 2-oxo-1-pyrrolidinyl and other similar groups.

The ring G and either R5and R6or R1and R2or two R2optionally linked together to form a ring, is optionally substituted cycloalkyl or optionally substituted heteroseksualci, each of which may have from 1 to 3 oxoprop on the ring and 1 or 2 double bonds in the ring, respectively.

Preferably, in the formula (I) R1was a halogen atom, cyano, a hydrogen atom, hydroxy, -O-(optionally substituted lower alkyl), optionally substituted lower alkyl, optionally substituted aryl, or other similar groups, more preferably, R1was a halogen atom, a hydrogen atom, hydroxy, lower alkoxy, lower alkyl or other groups. In the X1or X2it is preferable that CR2was a halogen atom, cyano, trifluoromethyl, hydrogen atom, hydroxy, carboxy, mono(di)(lower alkyl)amino, optionally substituted lower alkyl, optionally substituted lower alkenyl, cycloalkyl, cycloalkyl(lower alkoxy), optionally substituted aryl, obazatelno replaced by heteroaryl, -O-(optionally substituted lower alkyl), -CO-(optionally substituted by heterocyclization), -CON(R3)-(optionally substituted lower alkyl), -N(R3)SO2-(lower alkyl), -O-(lower alkylene)-N(R5)COO-(optionally substituted lower alkyl), where R3and R5have the same meanings as defined in the above item [1], or other similar groups, more preferably CR2was a halogen atom, a hydrogen atom, hydroxy, lower alkyl, lower alkoxy or other groups; and X3preferred is a halogen atom, a hydrogen atom, lower alkyl or other groups, and more preferred is a halogen atom or a hydrogen atom.

In derivative azaindole represented by the General formula (I), in the case where the group represented by the above formula (II)is a group represented by the following formula (IIc), where QCis carboxy or 5-tetrazolyl; X1and X2independently represent CR2; and among R1and two R2any two of them represent a hydrogen atom and the other represents a hydrogen atom, lower alkyl, PERFLUORO(lower alkyl), halogen atom, cyano or lower alkoxy, preferably Y was hydroxy, amino, halogen atom, nitro, optionally substituted dissimulation or optionally substituted lower alkoxy, provided that two or more Y optionally exist on ring J and these Y are optionally different from each other, and more preferably, Y was the hydroxy or amino.

The preferred compound among the derivatives of azaindole represented by the above General formula (I) of the present invention, also has an inhibitory action on URAT1. Accordingly, such a connection may have an effect that promotes the excretion of uric acid, in addition to the inhibitory action on the synthesis of uric acid, and characterized by exceptional lowering effect on the level of uric acid in serum. As a compound that has inhibitory action on URAT1, can be cast-derived indole represented, for example, the following General formula (IA).

In the formula, R1has the same meaning as defined above.

In another aspect of the preferred compounds, which also has an inhibitory action on URAT1 and is characterized by excellent pharmacokinetics, can be cast-derived indole represented, for example, the following General formula (IB).

In the formula, R2bpredstavlyayuschij alkyl or lower alkoxy, and the preferred are methyl or methoxy. R2crepresents a halogen atom or lower alkyl, and preferred are a fluorine atom, a chlorine atom or methyl.

Derivatives azaindole of the present invention represented by the above General formula (I)can be obtained, for example, by the method described below, or an equivalent method, or a method described in the literature, or an equivalent method, or other similar methods. In addition, when necessary, the protective group can be carried out according to the conventional methods of operation for the introduction of the protect and unprotect, not necessarily in combination.

[Method for the synthesis of 1]

In the formula, L represents a halogen atom, and T, ring J, Q, Y, X1-X3and R1have the same meanings as defined above.

Method 1

Derived azaindole of the present invention represented by the above General formula (I)may be obtained by reaction of a combination of compound (2) with compound (3) in an inert solvent or without using any solvent, in the presence of a base and optionally removing a protective group. As the inert solvent can be usedN,N-dimethylformamide, tetrahydrofuran,N-methylpyrrolidone, 1,2-dimethoxyethan, d is methylsulfoxide, 1,2-diethoxyethane, 1,4-dioxane, a mixture of these solvents, and other similar solvents. As the base can be used sodium hydride, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methylate and other similar reasons. The reaction temperature is usually from room temperature to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days, depending on the initial reagents, solvent and reaction temperature or other parameters. In addition, in the present method, the reaction can be optionally carried out in the reactor at high pressure.

Derived azaindole of the present invention represented by the above General formula (I)can be obtained by the reaction of a combination of compounds (2) and compound (3) in an inert solvent in the presence of a base, a catalytic amount of copper iodide and ligand, optionally with removal of the protective group. As the inert solvent can be usedN,N-dimethylformamide, tetrahydrofuran,N-methylpyrrolidone, 1,2-dimethoxyethane, dimethylsulfoxide, a mixture of these solvents, and other similar solvents. As the base can be used potassium phosphate, potassium carbonate, cesium carbonate and other similar reasons. In the operation of the ligand can be used N,N-dimethylethylenediamine, (1R,2R)-(-)-N,N'dimethylcyclohexane-1,2-diamine, (1S,2S)-(+)-N,N'dimethylcyclohexane-1,2-diamine, Proline,N,N-dimethylaminophenyl and other similar ligands. The reaction temperature is usually from room temperature to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days, depending on the initial reagents, solvent and reaction temperature or other parameters. In addition, in the present method, the reaction can be optionally carried out in the reactor at high pressure.

The above reaction can also be carried out using the method described in the following literature (a).

a) Hui Zhang,; Qian Cai,; and Dawei Ma, J. Org. Chem, Vol. 70, No. 13, 2005, 5173.

In the formula, Rarepresents a hydrogen atom or lower alkyl, provided that two Racan be different and both Racan connect together to form a ring, and T, ring J, Q, Y, X1-X3and R1have the same meanings as defined above.

Method 2

Derived azaindole of the present invention represented by the above General formula (I)can be obtained by the reaction of a combination of compounds (2) and compound (4) in an inert solvent in the presence of the basis of the project and catalytic amounts of copper acetate, and optionally removing a protective group. As the inert solvent can be used dichloromethane, 1,2-dichloroethane,N,N-dimethylformamide, tetrahydrofuran,N-methylpyrrolidone, 1,2-dimethoxyethan, a mixture of these solvents, and other similar solvents. As the base can be used triethylamine,N,N-diisopropylethylamine, pyridine, 2,6-lutidine, and other similar reasons. The reaction temperature is usually from room temperature to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days, depending on the initial reagents, solvent and reaction temperature or other parameters. In addition, in the present method, the reaction can be optionally carried out in the reactor at high pressure.

Among the derivatives of azaindole represented by the above General formula (I) of the present invention can also be obtained compound (Ia), where Q represents carboxy, for example, by the method of synthesis of 2.

[Method of synthesis of 2]

In the formula, T, ring J, Y, X1-X3and R1have the same meanings as defined above.

Method 3

Derived azaindole (Ia) of the present invention can be also obtained by reacting the aldehyde (5) with an oxidant in an inert solvent in the presence or absence of a base. As the inert solvent can be used dichloromethane, 1,4-dioxane, acetonitrile, acetone, hexane, cyclohexane,tert-butanol, water, a mixture of these solvents, and other similar solvents. As the base can be used sodium hydroxide, potassium hydroxide, lithium hydroxide and other similar reasons. As the oxidizing agent can be used permanganate potassium permanganate barium, silver oxide, and other similar oxidizing agents. The reaction temperature is usually from room temperature to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days, depending on the initial reagents, solvent and reaction temperature or other parameters. In addition, in the present method, the reaction can be optionally carried out in the reactor at high pressure.

Among the derivatives of azaindole represented by the above General formula (I) of the present invention can also be obtained compound (Ib), where T represents cyano, for example, by the method of synthesis of 3.

[Method for the synthesis of 3]

In the formula, ring J, Q, Y, X1-X3and R1have the same meanings as defined above.

Method 4

The aldehyde (7) can be obtained by formirovaniya connection (6) in an inert R is storytale in the presence of N,N-dimethylformamide and chloride of fostoria. As the inert solvent can be usedN,N-dimethylformamide, acetonitrile, benzene, toluene, chlorobenzene, dichloromethane, 1,2-dichloroethane, chloroform, a mixture of these solvents, and other similar solvents. The reaction temperature is usually from 0°C to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days depending on the initial reagents, solvent and reaction temperature or other parameters.

Method 5

Derived azaindole (Ib) of the present invention can also be obtained by cyanation of the aldehyde (7) using hydroxylamine or cleaners containing hydrochloride salt in an inert solvent in the presence or absence of a base, in the presence or in the absence of a condensing agent. As the inert solvent can be usedN,N-dimethylformamide, acetonitrile, benzene, toluene, chlorobenzene, dichloromethane, 1,2-dichloroethane, chloroform,N-methylpyrrolidone, a mixture of these solvents, and other similar solvents. As the base can be used triethylamine,N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diazabicyclo[5,4,0]-7-undecene, potassium carbonate, sodium carbonate and other similar reasons. As condensing Agay is that can be used acetic anhydride, thionyl chloride, Piatigorsky phosphorus,N,N'dicyclohexylcarbodiimide,N,N'carbonyldiimidazole and other such condensing agents. The reaction temperature is usually from 0°C. to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days depending on the initial reagents, solvent and reaction temperature or other parameters.

The above cyanation reaction can also be carried out by reacting the aldehyde (7) and hydroxylamine or its hydrochloride with sodium formate in formic acid used as solvent. The reaction temperature is usually from 0°C. to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days depending on the initial reagents, solvent and reaction temperature or other parameters.

Among the derivatives of azaindole of the present invention represented by the above General formula (I)can also be obtained from compound (Ic), for example, by the method of synthesis of 4, where R1or R2represent A-D-E-G, provided that A represents-O-, -S - or-N(R3)-, or-N(-D-E-G)2provided that D represents the lowest alkylene, and E, G, and R3have the same meanings as defined above. In the method of synthesis of 4 described the example where R1 A-E-G, where DArepresents the lowest alkylene; X1-X3represent CH.

[Method for the synthesis of 4]

In the formula L2represents a halogen atom, methanesulfonate, p-toluensulfonate or triptorelin-sulfonyloxy, and DA, E, G, T, ring J, Q and Y have the same meanings as defined above.

The way 6-1

Derived azaindole (Ic) of the present invention can also be obtained by alkylation of hydroxyindole (8) with compound (9) in an inert solvent in the presence of a base and optionally in the presence of a phase transfer catalyst. As the inert solvent can be used diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,N,N-dimethylformamide, dimethylsulfoxide,N-methylpyrrolidone, benzene, toluene, dichloromethane, a mixture of these solvents, and other similar solvents. As the base can be used inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, and other such inorganic bases and organic bases such as triethylamine,N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diazabicyclo[5,4,0]-7-undecene and other such organic bases. As the phase transfer catalyst could the t to be used Tetra- n-butylammonium, Tetra-n-butylammonium, 18-crown-6 and other similar catalysts phase transfer. The reaction temperature is usually from room temperature to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days depending on the initial reagents, solvent and reaction temperature or other parameters. In addition, in the present method, the reaction can be optionally carried out in the reactor at high pressure.

In the formula DA, E, G, T, ring J, Q and Y have the same meanings as defined above.

How 6-2

Derived azaindole (Ic) of the present invention can also be obtained by alkylation of compound (10) using hydroxycodone (11) in an inert solvent in the presence of a condensing agent and phosphorus compounds. As the inert solvent can be used diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,N,N-dimethylformamide, dimethylsulfoxide,N-methylpyrrolidone, benzene, toluene, dichloromethane, a mixture of these solvents, and other similar solvents. As the condensing agent can be used ethyl azodicarboxylate, isopropyl azodicarboxylate, 1,1'-(azodicarbon)dipiperidino and others like undesirous agents. As the phosphorus compounds can be used triphenylphosphine and other phosphorus compounds. The reaction temperature is usually from room temperature to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days depending on the initial reagents, solvent and reaction temperature or other parameters. In addition, in the present method, the reaction can be optionally carried out in the reactor at high pressure.

Among the derivatives of azaindole of the present invention represented by the above General formula (I)can also be obtained compound (Id), for example, by the method of synthesis of 5, where R1or R2are-A-D-E-G, provided that A represents A single bond and D represents optionally substituted albaniles, provided that a double bond exists near A, optionally substituted, Allen or optionally substituted, heteroaryl, and E and G have the same meanings as defined above. In the method of synthesis 5 describes an example where R1is-AB-DB-E-G, where ABrepresents a single bond, DBare optionally substituted albaniles, optionally substituted, Allen or optionally substituted, heteroaryl; and X1-X3represent CH.

[Method Sint is 5]

In the formula, L4represents a halogen atom or trifloromethyl, DBrepresents optionally substituted lower albaniles, optionally substituted, Allen or optionally substituted, heteroaryl, and E, G, T, ring J, Q and Y have the same meanings as defined above.

Method 7 [Method 1]

Derived azaindole (Id) of the present invention can be also obtained by the reaction of a combination of the Suzuki-Miyaura connection (12) using the corresponding arylboronic acid or heteroarylboronic acid in an inert solvent in the presence of a base and a palladium catalyst. As the inert solvent can be used benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethanol, 2-propanol, butanol,N,N-dimethylformamide,N-methylpyrrolidone, dimethylsulfoxide, water, a mixture of these solvents, and other similar solvents. As the base can be used sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, sodium methylate, potassium fluoride, cesium fluoride, triethylamine,N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diazabicyclo[5,4,0]-7-undecene and other similar basis for the Oia. As the palladium catalyst can be used tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and other such palladium catalysts. The reaction temperature is usually from 0°C. to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days depending on the initial reagents, solvent and reaction temperature or other parameters. In addition, in the present method, the reaction can be optionally carried out in the reactor at high pressure.

Method 7 [Method 2]

Derived azaindole (Id) of the present invention can also be obtained by carrying out for compound (12) reaction Mizoroki-Hake using the corresponding alkene in an inert solvent in the presence of a base and a palladium catalyst. As the inert solvent can be used benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethanol, 2-propanol, butanol,N,N-dimethylformamide,N-methylpyrrolidone, dimethylsulfoxide, water, a mixture of these solvents, and other similar solvents. As the base can be used triethylamine,N,N-diisopropylethylamine, is iridin, 2,6-lutidine, 1,8-diaza-bicyclo[5,4,0]-7-undecene and other similar reasons. As the palladium catalyst can be used palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and other such palladium catalysts. In addition, depending on the type palladium catalyst this reaction can also be carried out with ligand, and the ligand can be used triphenylphosphine, tri-o-tolylphosphino, threetert-butylphosphine tetrafluoroborate and other similar ligands. The reaction temperature is usually from 0°C. to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days depending on the initial reagents, solvent and reaction temperature or other parameters. In addition, in the present method, the reaction can be optionally carried out in the reactor at high pressure.

The reaction arilirovaniya or heteroarylboronic in method 7 (method 1) can also be carried out using the method described, for example, in the following literature (b)-(f).

(b) Anderson, K. W.; Buchwald, S. L. Angew Chem, Int Ed. 2005, 44 (38), 6173-6177.

(c) Appukkuttan, P.; Van Der Eycken, E. et al. Synlett 2005, (1), 127-133.

(d) Wang, W.; Xiong, C et al. Tetrahedron Lett. 2001, 42 (44), 7717-7719.

(e) Yang, Y.; Martin, A. R. Synth Commun 1992, 22 (12, 1757-1762.

(f) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew Chem, Int Ed 2006, 45 (21), 3484-3488.

The reaction alkenylamine in method 7 (method 2) can also be carried out using the method described, for example, in the following literature (g)-(i).

(g) Hassner, A.; Loew, D. et al. J Org Chem. 1984, 49 (14), 2546.

(h) Leclerc, J.-P.; Andre, M. et al. J Org Chem. 2006, 71 (4), 1711-1714.

(i) Harrison, C.-A.; Jackson, P. M. et al. J Chem Soc, Perkin Trans 1, 1995, (9), 1131-1136.

Among the initial reagents (2)used in the above methods, the compound (2a), where T represents cyano, produced in industry or can be obtained by a known method or an equivalent method, or other similar methods. In addition, it can be obtained by the following method, an equivalent method, or other similar methods.

In the formula L5represents a halogen atom, X1-X3and R1have the same meanings as defined above.

Method 8

Amide (15) can be obtained by amidation reaction between the carboxylic acid (14) and ammonia with an optional additive such as 1-hydroxybenzotriazole or other such additives, in an inert solvent in the presence or in the absence of a condensing agent, in the presence or in the absence of base. As the inert solvent can be used tetrahydrofuran, 1,4-dioxane, 12-dimethoxyethan, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, a mixture of these solvents, and other similar solvents. As the condensing agent can be used acetic anhydride, thionyl chloride, oxalicacid,N,N'carbonyldiimidazole,N,N'dicyclohexylcarbodiimide, diisopropylcarbodiimide,N-ethyl-N'-3-dimethylaminopropylamine and its hydrochloride, diphenylphosphoryl and other such condensing agents. As the base can be used triethylamine,N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diazabicyclo[5,4,0]-7-undecene and other similar reasons. The reaction temperature is usually from 0°C. to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days depending on the initial reagents, solvent and reaction temperature or other parameters.

Method 9

Nitrile (2a) can be obtained by dehydration of the amide (15) in an inert solvent in the presence of dehydrating. As the inert solvent can be used tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,N,N-dimethylformamide, acetonitrile, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, a mixture of these solvents, and other similar solvents. As dehydrating cf is DSTV can be used acetic anhydride, thionyl chloride, the chloride phosphoryl, methanesulfonamido,p-toluensulfonate,N,N'dicyclohexylcarbodiimide, phosphorus pentoxide, triphosgene and other similar dehydrating. The reaction temperature is usually from 0°C. to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days, depending on the initial reagents, solvent and reaction temperature or other parameters.

Method 10

The aldehyde (17) can also be obtained by formirovanie connection (16) using a method similar to the method described in the above method 4.

Method 11

Nitrile (2a) can also be obtained by cyanidation of the aldehyde (17) using a method similar to the method described in the above method 5.

Way 12

Halogenated compound (18) can be obtained by halogenoalkanes connection (16) in an inert solvent in the presence of a halogenation agent. As the inert solvent can be used tetrahydrofuran, 1,4-dioxane, acetic acid, dichloromethane, 1,2-dichloroethane, chloroform, a mixture of these solvents, and other similar solvents. As the halogenation agent can be used bromine,N-bromosuccinimide, perbromic of pyridinylamino, iodine and other similar halo is anerousis agents. The reaction temperature is usually from 0°C. to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days depending on the initial reagents, solvent and reaction temperature or other parameters.

Way 13

Nitrile (2a) can also be obtained by cyanidation halogenated compounds (18) in an inert solvent in the presence of tianyoude reagent, base and palladium catalyst. As the inert solvent can be used benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethanol, 2-propanol, butanol,N,N-dimethylformamide,N-methylpyrrolidone, dimethylsulfoxide, water, a mixture of these solvents, and other similar solvents. As tianyoude reagent can be used sodium cyanide, potassium cyanide, copper cyanide, cyanide zinc, trimethylsilyl cyanide, and other similar tianyoude reagents. As the base can be used sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, sodium methylate, potassium fluoride, cesium fluoride, triethylamine,N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diazabicyclo[5,4,0]-7-undecene and other similar reasons. As the palladium catalyst may be used tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and other such palladium catalysts. The reaction temperature is usually from 0°C. to the boiling temperature, and the reaction time is usually from 30 minutes to 7 days depending on the initial reagents, solvent and reaction temperature or other parameters. In addition, in the present method, the reaction can be optionally carried out in the reactor at high pressure.

The reaction of the cyanide method 13 may also be carried out using the method described, for example, in the following literature (j) an equivalent method or other similar methods.

(j) Sakamoto, T.; Ohsawa, K.; J Chem Soc, Perkin Trans 1 1999, (16), 2323-2326.

Source reagents (16)used in the above methods, can be produced by the industry or can be obtained using the method described, for example, in the following literature (k)-(n) an equivalent method or other similar methods.

(k) Rege Pankaj D.; Tian, Yuan; Corey, E. J. Organic Letters, 2006, 8 (14), 3117-3120.

(l) Wang Jianji; Soundarajan Nachimuthu et al. Tetrahedron Letters, 2005, 46 (6), 907-910.

(m) Sandro Cacchi; Giancarlo Fabrizi; Luca Parisi M. Organic Letters, 2003, 5 (21), 3843-3846.

(n) Bosco Marcella; Dalpozzo Renato; by Bartoli et al. Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry, 1991, (5), 657-63.

In addition, they can also be obtained by the method shown in the following met the de synthesis of 6, an equivalent method or other similar methods.

[Method for the synthesis of 6]

In the formula, X1-X3and R1have the same meanings as defined above.

Way 14

Indole (16) can also be obtained by conversion of nitrobenzene derivative (19) or (20) using a metal catalyst under normal pressure or under pressure in an atmosphere of hydrogen in an inert solvent. As the inert solvent can be used methanol, ethanol,n-butanol, acetic acid, ethyl acetate, tetrahydrofuran,N,N-dimethylformamide, acetonitrile, water, a mixture of these solvents, and other similar solvents. As the metal catalyst can be used palladium on charcoal, rhodium on charcoal, platinum oxide(IV) and other such metal catalysts. The reaction temperature is usually from 0°C. to the boiling temperature, and the reaction time is usually from 1 hour to 7 days depending on the initial reagents, solvent and reaction temperature or other parameters.

As the protective groups used in the present invention can be applied to various protective groups commonly used when carrying out organic reactions. For example, as a protective gr the PP for the hydroxyl group can be used in addition to p-methoxybenzyloxy group, benzyl group, methoxymethyl group, acetyl group, pivellina group, benzoline group,tert-butyldimethylsilyl group,tert-butyldiphenylsilyl group, allyl group, and other such protective groups, when two hydroxyl groups are close by, as the protective groups can be used isopropylidene group, cyclopentadecanone group, cyclohexylidene group and other such protective groups. As protective groups for Tilney groups can be usedp-methoxybenzylidene group, benzyl group, acetyl group, pivellina group, benzoline group, benzyloxycarbonyl group and other such protective groups. As protective groups for the amino group can be used benzyloxycarbonyl group,tert-butoxycarbonyl group, benzyl group, p-methoxybenzyl group, trifluoracetyl group, acetyl group, calolina group and other such protective groups. As protective groups for a carboxyl group may be used by the group of lower alkyl, benzyl group,tert-butyldimethylsilyl group, allyl group and other similar protective group.

The connection represented by the above General formula (I) present is about invention, may be isolated or purified by conventional separation methods such as fractional recrystallization, purification using chromatography, liquid-liquid extraction, solid-phase extraction and other similar methods.

Derivatives azaindole of the present invention represented by the above General formula (I)can be converted into their pharmaceutically acceptable salts in the usual way. As such salts can be used in salt accession inorganic acid, such as chloromethane acid, Hydrobromic acid, iodomethane acid, sulfuric acid, nitric acid, phosphoric acid and other similar acids, salt accession of organic acids, such as formic acid, acetic acid, methanesulfonate acid, benzolsulfonat acid,p-toluensulfonate acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, aspartic acid and other similar acids, inorganic salt such as sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, lithium salt, an aluminium salt and other salt, salt with organic the definition amine, such asN-methyl-D-glucamine,N,N'dibenziletilendiaminom, 2-aminoethanol, Tris(hydroxymethyl)aminomethane, arginine, lysine, piperidine, choline, diethylamine, 4-phenylcyclohexane and other similar amines.

Derived azaindole of the present invention represented by the above General formula (I), the compound having the unsaturated bond, there are two geometric isomer, the compound CIS - (Zshape and connection of the TRANS (E) form. In the present invention can be applied one of these compounds, and can also apply a mixture.

Derived azaindole of the present invention represented by the above General formula (I), the compound having a chiral carbon atom, there are connectionRform and joinSforms for each chiral carbon. In the present invention can be applied to one of the optical isomers of the compounds, and can also be used a mixture of optical isomers.

Derived azaindole of the present invention represented by the above General formula (I), there can be multiple tautomers, and compounds of the present invention also include these tautomers.

In the present invention, the term "prodrug" denotes a compound that is modified from the original connection using commonly used in prolac is rste pharmaceutically acceptable group, which attaches to such property, such as improved stability, substantively, the ability to oral absorption and other properties, and you can expect it to turn into original connection inside the body (in the liver, intestines and other organs) to the provision of appropriate action. The prodrug compounds of the present invention represented by the above General formula (I)can be obtained by introducing a corresponding forming a prodrug group in any one or more groups selected from hydroxyl group, amino group, carboxyl group and other similar groups that can form a prodrug of the compound represented by the above General formula (I), using the appropriate reagent to obtain prodrugs, such as a halide compound or other similar reagent, in the usual way, and then through the appropriate allocation and, if necessary, purification in the usual way.Gekkan-Yakuji iyakuhin tekiseisiyou no tameno rinsyou yakubutudoutai(monthly pharmaceutical, clinical pharmacokinetics for the proper use of pharmaceutical products), 2003.3. extra number Vol.42, No.4, p.669-707,New drug Drug delivery systemPublished by CMC Co., Ltd., 2000.1.31., page 67-173. As a group forming a prodrug used in the case of hydroxyl groups or amino groups, can be used, for example, (lower alkyl)-CO-, such as and ITIL, propionyl, butisol, isobutyryl, pivaloyl and other similar groups; aryl-CO-, such as benzoyl; (lower alkyl)-O-(lower alkylene)-CO-; (lower alkyl)-OCO-(lower alkylene)-CO-; (lower alkyl)-OCO-, such as methyloxycarbonyl, ethoxycarbonyl, propylenecarbonate, isopropoxycarbonyl, tert-butyloxycarbonyl and other similar groups; (lower alkyl)-O-(lower alkylene)-OCO-; (lower alkyl)-COO-(lowest alkylen), such as acetoacetyl, pivaloyloxymethyl, 1-(atomic charges)ethyl, 1-(pivaloyloxy)ethyl and other similar groups; (lower alkyl)-OCOO-(lower alkylene), such as methoxycarbonylmethyl, 1-(methoxycarbonylamino)ethyl, ethoxycarbonylmethyl, 1-(ethoxycarbonyl)ethyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyl)ethyl,tert-butyloxycarbonyl, 1-(tert-butyloxycarbonyl)ethyl and other similar groups; cycloalkyl-OCOO-(lower alkylene), such as cyclohexyloxycarbonyloxy, 1-(cyclohexyloxycarbonyl)ethyl and other similar groups; ester or amide amino acids such as glycine and other similar groups.

As a group forming a prodrug used in the case of a carboxyl group, can be used, for example, lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl,tert-butyl and other similar groups; (lower alkyl)-COO-(lower alkylene), such as Beers is lilacsigil, acetoacetyl, 1-(pivaloyloxy)ethyl, 1-(atomic charges)ethyl and other similar groups; (lower alkyl)-OCOO-(lower alkylene), such as ethoxycarbonylmethyl, 1-(ethoxycarbonyl)ethyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyl)ethyl,tert-butyloxycarbonyl, 1-(tert-butyloxycarbonyl)ethyl and other similar groups; cycloalkyl-OCOO-(lower alkylene), such as cyclohexyloxycarbonyl, 1-(cyclohexyloxycarbonyl)ethyl and other similar groups.

Derived azaindole represented by the General formula (I), or its prodrug, or pharmaceutically acceptable salt can sometimes be obtained in the form of its hydrate or MES in the way of cleaning or get its salts. Derived azaindole represented by the General formula (I), or its prodrug, or pharmaceutically acceptable salt includes its hydrate or its MES with a pharmaceutically acceptable solvent. As pharmaceutically acceptable solvents may be used ethanol and other solvents.

The pharmaceutical composition of the present invention is used as a means for prevention or treatment of diseases associated with high levels of uric acid in the blood, such as hyperuricemia, gouty site, gouty arthritis, kidney disease, SV is related to hyperuricemia, kidney stone disease or other similar diseases, in particular hyperuricemia.

In current practice when applying the pharmaceutical composition of the present invention for the prevention or treatment of diseases, determine the appropriate dose of the compound represented by the above General formula (I), or its prodrug, or pharmaceutically acceptable salt as an active ingredient, depending on age, sex, body weight and intensity of the symptoms and treatment of each patient, for example, which lies in the approximate range from 1 to 2000 mg per day per adult human in the case of oral administration, the daily dose can be divided into several input doses per day.

In practice, when applying the pharmaceutical composition of the present invention to prevent or treat diseases, use a variety of oral or parenteral dosage forms. Depending on their application, the preferred dosage forms for oral administration are, for example, such forms as powders, fine granules, granules, tablets, capsules, dry syrups, or other similar forms.

These pharmaceutical compositions can be obtained optionally by mixing using an appropriate pharmaceutical additive such as nab, nicely, the disintegrators, binders, flowing agents, and other similar substances, and by forming a mixture of traditional methods.

For example, the powders can be formed, if necessary, by carefully mixing the active ingredient with appropriate fillers, slip agents and other similar components. For example, tablets can be formed by tabletting traditional methods of active ingredient with appropriate fillers, disintegrators, binders, slip agents and other similar components. In addition, if necessary, they can be respectively coated with obtaining film-coated tablets, tablets, sugar coated tablets with intersolubility coating and other similar tablets. For example, capsules can be formed by traditional methods by carefully mixing the active ingredient with appropriate fillers, slip agents and other such components, or by forming small pellets, granules, and by filling in the appropriate capsule. In addition, in the case of such drugs for oral administration, it may also be prepared in the form of dosage forms quick release or slow release of the active ingredient depending on ways of preventing or treating diseases.

The compound of the present invention represented by the above General formula (I), or its prodrug, or pharmaceutically acceptable salt, can be used in combination with any other drug for the treatment of hyperuricemia, or drug for the treatment of gout. As a drug for the treatment of hyperuricemia, which can be used in the present invention can be applied, for example, podslushivaet urine, such as sodium bicarbonate, potassium citrate and sodium citrate, and other similar medicines. In addition, as a drug for the treatment of gout can be used colchicine or nonsteroidal anti-inflammatory drugs such as indomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, Ketoprofen, etoricoxib, tenoxicam and other similar drugs, and steroids and other drugs. In addition, in the present invention, the active ingredient of the present invention can also be used in combination, at least one of these drugs. And a pharmaceutical composition comprising a combination of at least one of these drugs include any drug form is not the only drug incoming VM the CTE with the active ingredient of the present invention, but also a combination consisting of a pharmaceutical composition comprising the active ingredient of the present invention, and separately prepared pharmaceutical composition for simultaneous administration or administration at different intervals between the administration of medicines. In addition, when used in combination with any drug, other than the active ingredient of the present invention, the dose of a compound of the present invention may be reduced depending on the dose of the other drug used in combination, and depending on circumstances may be obtained positive effect, greater than additive effect in the prevention or treatment of the above diseases, or may be eliminated or reduced negative effect of another drug used in combination.

The implementation of the invention

Derivatives azaindole of the present invention represented by the above General formula (I), exhibit a strong inhibitory activity against xanthine oxidase and inhibit the production of uric acid. In addition, the preferred compound of the present invention can also exhibit strong inhibitory action on URAT1 and increase the excretion of uric acid. The poet is derived azaindole of the present invention, represented by the General formula (I), or its prodrug, or their pharmaceutically acceptable salts, can very effectively suppress the increase of the level of uric acid in serum and they are used as a means to prevent or treat diseases associated with inappropriate normal level of uric acid in serum, such as hyperuricemia, or other similar diseases.

The best option of carrying out the invention

The present invention is hereinafter illustrated in more detail by the following reference examples, examples, and sample tests. However, they are not limiting for the present invention.

Reference example 1

Ethyl ester of 4-fluoro-2-hydroxybenzoic acid

To a solution of 4-fluoro-2-hydroxybenzoic acid (3.0 g) in ethanol (40 ml) was added thionyl chloride (5,61 ml) at 0°C., and the mixture is boiled under reflux for 24 hours. The reaction mixture was concentrated under reduced pressure. This residue was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the above compound (3.5 g).

Reference example 2

Ethyl ester of 4-fluoro-2-methoxyethoxymethyl the th acid

To a solution of ethyl ester of 4-fluoro-2-hydroxybenzoic acid (3.5 g) in dichloromethane (30 ml) was addedN,N-diisopropylethylamine (5.0 g) and (chloromethyl)methyl ether (2.3 g) at 0°C, and the reaction mixture was stirred at room temperature overnight. This reaction mixture was poured into water, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate) to give the titled compound (2.8 g).

Reference example 3

Methyl ester of 4-fluoro-2-methoxyethoxymethyl acid

To a solution of 4-fluoro-2-hydroxybenzoic acid (3.0 g) inN,N-dimethylformamide (5 ml) was added sodium hydride (60% 1.0 g) and (chloromethyl)methyl ether (2.1 g) at room temperature, and the mixture was stirred for 48 hours at the same temperature. This reaction mixture was poured into chloroethanol acid with a concentration of 2 mol/l, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:n-hexa is/ethyl acetate) to give the titled compound (0,22 g).

Reference example 4

5,6-Debtor-1H-indole-3-carbaldehyde

To a solution of 5,6-debtor-1H-indole (1.0 g) inN,N-dimethylformamide (10 ml) was added to the chloride phosphoryl (1.2 g) at 0°C., and the mixture was stirred at room temperature for 4 hours. To this mixture was added aqueous sodium hydroxide with a concentration of 2 mol/l (5 ml)and the resulting mixture was stirred at 70°C for 0.5 hour. After cooling to ambient temperature the mixture was poured into chloroethanol acid with a concentration of 1 mol/l, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the above compound (1.1 g).

Reference example 5

5,6-Debtor-1H-indol-3-carbonitril

To a solution of 5,6-debtor-1H-indole-3-carbaldehyde (1.0 g) in tetrahydrofuran (15 ml) was added hydroxylamine hydrochloride (0,81 g) and pyridine (1.9 g), and the mixture was stirred at 80°C for 8 hours. To the reaction mixture was added acetic anhydride, and the mixture was stirred at 80°C for 8 hours. After cooling to ambient temperature, this mixture was added aqueous sodium hydroxide with a concentration of 2 mol/l, and the resulting mixture was stirred for 30 minutes. This mixture was poured into chloroethanol acid the concentration of 2 mol/l, and the precipitated solid was filtered and washed with water and n-hexane. The solid was dissolved in ethyl acetate, and the residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate) to give the titled compound (0.95 g).

Reference example 6

6-Fluoro-1H-indol-3-carbonitril

To a solution of 6-fluoro-1H-indole-3-carbaldehyde (0.97 g) in 90% formic acid (25 ml) was added hydroxylamine (0.65 g) and sodium formate (0,81 g), and the mixture was stirred at 100°C for 3 hours. After cooling to ambient temperature, this reaction mixture was added water, and the precipitated solid was filtered, washed with water and dried to obtain the above compound (0,57 g).

Reference example 7

5-Phenyl-1H-endocervical

The named compound was obtained as described in reference example 5 using the corresponding source reagents.

Reference example 8

Benzyl ether of 3-formyl-1H-indole-5-carboxylic acid

To a solution of benzyl ester 1H-indole-5-carboxylic acid (3.5 g) inN,N-dimethylformamide (30 ml) was added to the chloride phosphoryl (2.6 g) under ice cooling, and the mixture was stirred at room temperature for 2 hours. To this reaction mixture was added aqueous sodium hydroxide with a concentration is of 2 mol/l until while the pH value was not equal to 6, and the mixture was stirred at 70°C for 30 minutes. After cooling to ambient temperature the precipitated solid was filtered, washed with water and methanol, dried to obtain the above compound (3.9 g).

Reference example 9

Benzyl ether of 3-cyano-1H-indole-5-carboxylic acid

To a solution of benzyl ester 3-formyl-1H-indole-5-carboxylic acid (4.3 g) and pyridine (4.8 g) in tetrahydrofuran (60 ml) was added hydroxylamine hydrochloride (1.6 g) at room temperature, and the mixture was stirred at 80°C during the night. Was added to the reaction mixture at the same temperature acetic anhydride, and the mixture was stirred for 8 hours. After cooling to ambient temperature was added to the mixture of sodium hydroxide with a concentration of 1 mol/l (20 ml)and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate) to give the titled compound (2.8 g).

Reference example 10

Benzyl ether of 3-benzyloxy-4-methylbenzoic acid

To a solution of 3-hydroxy-4-methylbenzoic acid (5.0 g) inN ,N-dimethylformamide (100 ml) was added cesium carbonate (32 g) and benzyl bromide (12 g) at the same temperature, and the mixture was stirred at room temperature for 2 days. To this reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate) to give the titled compound (7.5 g).

Reference example 11

(3-Benzyloxy-4-were)methanol

To a suspension of lithium aluminum hydride in diethyl ether (50 ml) was added dropwise a solution of benzyl ester of 3-benzyloxy-4-methylbenzoic acid (7.5 g) in diethyl ether (11 ml) in an argon atmosphere at 0°C., and the mixture was stirred at room temperature for 6 hours. To this reaction mixture was added dropwise water (3.2 ml), and then to this mixture was added celite, and perform the filtering. The filtrate was concentrated to obtain the above mentioned compounds in the form of a mixture of benzyl alcohol (7.0 g).

Reference example 12

3-Benzyloxy-4-methylbenzaldehyde

To a solution of (3-benzyloxy-4-were)methanol (1.0 g) in dichloromethane (50 ml) was added dioxide the margana is a (2.5 g), and the mixture was stirred at room temperature for 2 days. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. This residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate) to give the titled compound (0.39 g)

Reference example 13

5-Benzyloxy-2-bromo-4-methylbenzaldehyde

To a solution of 3-benzyloxy-4-methylbenzaldehyde (0.39 g) in a mixture of dichloromethane (1 ml) and methanol (1 ml) was added a solution of bromine (0,410 g) in dichloromethane (0.2 ml) at 0°C., and the mixture was stirred at room temperature for 2 hours. This mixture was poured into water, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate) to give the titled compound (0.39 g).

Reference example 14

Methyl ester (Z)-3-(5-benzyloxy-2-bromo-4-were)-2-benzyloxycarbonylamino acid

To a solution of 5-benzyloxy-2-bromo-4-methylbenzaldehyde (0.39 g) and trimethylboron etherN(benzyloxycarbonyl)-alpha-phosphonoglycine (0,38 g) in dichloromethane (2 ml) was added 1,1,3,3-tetramethylguanidine (0.18 g) at room is temperature, and the mixture was stirred at room temperature for 2 days. To this reaction mixture was added chloroethanol acid with a concentration of 1 mol/l, and the precipitated solid was filtered, washed with water, dried under reduced pressure to obtain the above compound (0.34 g).

Reference example 15

Methyl ester of 5-benzyloxy-6-methyl-1H-indole-2-carboxylic acid

To a solution of methyl ester (Z)-3-(5-benzyloxy-2-bromo-4-were)-2-benzyloxycarbonylamino acid (0.2 g) and copper iodide(I) (0.075 g) in dimethyl sulfoxide (8 ml) was added cesium acetate (0,38 g) at room temperature, and the mixture was stirred in argon atmosphere at 90°C for 5 hours. To this reaction mixture was added aqueous ammonia (28%), and the precipitated solid was filtered, washed with water, dried under reduced pressure to obtain the above compound (0,073 g).

Reference example 16

5-Benzyloxy-6-methyl-1H-indole-2-carboxylic acid

To a solution of methyl ester of 5-benzyloxy-6-methyl-1H-indole-2-carboxylic acid (1.3 g) in a mixture of 1,4-dioxane (40 ml) and water (20 ml) was added monohydrate of lithium hydroxide (1.8 g) at room temperature, and the mixture was stirred at 50°C for 1 hour. After this the reaction mixture was cooled to room temperature, was added khorovod the native acid with a concentration of 1 mol/L. The precipitated solid was filtered, washed with water, dried under reduced pressure to obtain the above compound (1.0 g).

Reference example 17

5-Benzyloxy-6-methyl-1H-indol

To a solution of 5-benzyloxy-6-methyl-1H-indole-2-carboxylic acid (0.6 g) in quinoline (6 ml) was added copper powder (0.15 g), and the mixture was stirred at 220°C for 20 minutes. This reaction mixture was poured into chloroethanol acid with a concentration of 1 mol/l, and the resulting mixture was extracted with ethyl acetate. This organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate) to give the titled compound (0.21 g).

Reference example 18

5-Benzyloxy-6-methyl-1H-indole-3-carbaldehyde

A named connection (0,48 g) was obtained as described in reference example 4 using the appropriate source reagents.

Reference example 19

5-Benzyloxy-6-methyl-1H-indol-3-carbonitril

The named compound (0.10 g) was obtained as described in reference example 5 using the corresponding source reagents.

Reference example 20

Ethyl ester of 4-(6-nitroindole-1-yl)benzoic acid

To a solution of 6-NITR what-1H-indole (0.5 g) in N,N-dimethylformamide (10 ml) was added cesium carbonate (1.2 g) and ethyl ester of 4-fluoro-benzoic acid (0,62 g), and the mixture was stirred at 75°C during the night. This reaction mixture was poured into water and the precipitated solid was filtered, washed with water andn-hexane, dried under reduced pressure to obtain the above compound (0.64 g).

Reference example 21

1-(5-Formylfuran-2-yl)-1H-indol-3-carbonitril

A suspension of 3-cyanoindole (0.14 g), 5-bromo-2-furaldehyde (0.18 g) and cesium carbonate (0.39 g) inN,N-dimethylformamide (3 ml) was stirred at room temperature for 3 hours. This reaction mixture was heated at 50°C. was stirred for 2 hours. After cooling to ambient temperature, this reaction mixture was added water. This mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate=2/1) to obtain the titled compound (0,086 g).

Reference example 22

Ethyl ester of 4-(6-formylindole-1-yl)benzoic acid

The named compound was obtained as described in reference example 20, using an appropriate source reagents.

Ethyl ester of 4-(6-acetoxymethyl-indol-1-yl)benzoic acid

To a solution of ethyl ester of 4-(6-formylindole-1-yl)benzoic acid in a mixture of tetrahydrofuran (3 ml) and methanol (10 ml) was added sodium borohydride (0.075 g) at 0°C., and the mixture was stirred at room temperature for 0.5 hours. This reaction mixture was poured into a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain ethyl ester 4-(6-hydroxymethylene-1-yl)benzoic acid (0,38 g). To a solution of ethyl ester of 4-(6-hydroxymethylene-1-yl)benzoic acid (0.09 g) in dichloromethane (1 ml) was added acetic anhydride (0,093 g) and pyridine (0,024 g), and the mixture was stirred at room temperature for 2 days. The mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the titled compound (0,068 g).

Reference example 24

Methyl 4-fluoro-2-methylcarbonate

To a solution of 4-fluoro-2-METHYLPHENOL (2.0 g) in 1,4-dioxane (20 ml) was added methylchloroform (3.0 g) and PI is one (2.5 g) under ice cooling, and the mixture was stirred at room temperature overnight. Insoluble material was removed by filtration and the filtrate was added chloroethanol acid with a concentration of 1 mol/L. This mixture was extracted with ethyl acetate, and the organic layer was twice washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure obtaining these compounds.

Reference example 25

4-fluoro-2-methyl-5-NITROPHENOL

To a solution of methyl 4-fluoro-2-methylcarbonate (2.9 g) in concentrated sulfuric acid (11 ml) was added dropwise fuming nitric acid (1.1 ml) for 10 minutes under ice cooling, and the mixture was stirred at the same temperature for 1 hour. This reaction mixture was poured into ice water and was extracted with ethyl acetate. The organic layer was twice washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in methanol, to this solution was added sodium bicarbonate (2.6 g) and potassium carbonate (2.2 g) at room temperature, and the mixture was stirred for 2 hours. To the reaction mixture were added chloroethanol acid with a concentration of 1 mol/l up until the pH value was not equal to 1, and removing the organic solvent under reduced pressure. This residue extragere the Ali ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:nhexane/ethyl acetate) to give the titled compound (1.5 g).

Reference example 26

1-Fluoro-4-methoxy-5-methyl-2-nitrobenzene

To a solution of 4-fluoro-2-methyl-5-NITROPHENOL (0.5 g) inN,N-dimethylformamide (5 ml) was added potassium carbonate (0,44 g) and jodean (0,46 g), and the mixture was stirred at room temperature overnight. To this reaction mixture was added water, and the precipitated solid was filtered and washed with water andnhexane to obtain the above compound (0,44 g).

Reference example 27

Methyl ester of cyano-(4-methoxy-5-methyl-2-nitrophenyl)acetic acid

To a suspension of sodium hydride (0,86 g)N,N-dimethylformamide (5 ml) was added dropwise a solution of methyl ester tsianuksusnogo acid (0.35 g) inN,N-dimethylformamide (3 ml) under ice cooling, and the mixture was stirred for 15 minutes. To this reaction mixture was added dropwise a solution of 1-fluoro-4-methoxy-5-methyl-2-nitrobenzene (0,44 g) under ice cooling, and the mixture was stirred at room temperature for 30 minutes and then stirred at 70°C during the night. After the OHL is being introduced to the ambient temperature of this reaction mixture was added chloroethanol acid with a concentration of 1 mol/l (5 ml). This resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:nhexane/ethyl acetate) to give the titled compound (0.45 g).

Reference example 28

(4-Methoxy-5-methyl-2-nitrophenyl)acetonitrile

To a solution of methyl ester of cyano-(4-methoxy-5-methyl-2-nitrophenyl)acetic acid in methanol (1.7 ml) was added chloroethanol acid with a concentration of 6 mol/l (1.7 ml), and the mixture is boiled under reflux for 9 hours. After cooling to ambient temperature the organic solvent was removed under reduced pressure, and the resulting mixture was extracted with ethyl acetate. The residue was purified by column chromatography on silica gel (eluent:nhexane/ethyl acetate) to give the titled compound (0.25 g).

Reference example 29

6-Methoxy-5-methylindol

To a solution of (4-methoxy-5-methyl-2-nitrophenyl)acetonitrile (0.24 g) in a mixture of tetrahydrofuran (2 ml) andn-butanol (2 ml) was added a powder of palladium on coal (0,043 g) in an argon atmosphere, and the mixture was stirred at 60°C in an atmosphere of hydrogen for 36 hours. Insoluble material was removed by filtration, and the filtrate to what has centriole under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:nhexane/ethyl acetate) to give the titled compound (0,13 g).

Reference example 30

3-Cyano-6-methoxy-5-methylindol

A named connection (0,070 g) was obtained as described in reference example 4 and reference example 5 using the corresponding source reagents.

Reference example 31

1-Methoxy-2-methyl-4-nitrobenzene

To a solution of 1-hydroxy-2-methyl-4-nitrobenzene (1.0 g) inN,N-dimethylformamide (10 ml) was added potassium carbonate (1.8 g) and jodean (1.3 g) at room temperature, and the mixture was stirred at the same temperature for 24 hours. This reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the above compound (0.95 g).

Reference example 32

(5-Methoxy-4-methyl-2-nitrophenyl)acetonitrile

To a solution of 1-methoxy-2-methyl-4-nitrobenzene (0.4 g), and (4 chlorophenoxy)acetonitrile (0.4 g) inN,N-dimethylformamide (10 ml) was added tert-butyl potassium (0.3 g) under ice cooling, and the mixture was stirred at the same temperature for 1 hours. This mixture was poured into water, and the resulting mixture extras is listed with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:nhexane/ethyl acetate) to give the titled compound (0.2 g).

Reference example 33

5-Methoxy-6-methyl-1H-indol

A named connection (0,065 g) was obtained as described in reference example 29, using an appropriate source reagents.

Reference example 34

5-Methoxy-6-methyl-1H-indol-3-carbonitril

The named compound (0.05 g) was obtained as described in reference example 4, and 5, using the appropriate source reagents.

Reference example 35

5-Benzyloxy-6-chloro-1H-indole

To a solution of (5-benzyloxy-4-chloro-2-nitrophenyl)acetonitrile (4,170 g) in ethanol (70 ml) was added platinum oxide(IV) (0,344 g) at room temperature, and the mixture was stirred in hydrogen atmosphere (30-35 psi) for 12 hours. To this reaction mixture was added acetic acid (7 ml) and water (7 ml), and the mixture was stirred under the same conditions for 24 hours. After the reaction mixture was placed in an atmosphere of argon, insoluble material was removed by filtration. To this filtrate was added water, and the resulting mixture was extracted with diethyl ether. The body is ical layer was washed with brine, was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/nhexane=75/25) to give the titled compound (0,629 g).

Reference example 36

5-Benzyloxy-6-chloro-1H-indole-3-carbaldehyde

A named connection (0,270 g) was obtained as described in reference example 4 using the appropriate source reagents.

Reference example 37

5-Benzyloxy-6-chloro-1H-indol-3-carbonitril

A named connection (0,267 g) was obtained as described in reference example 5 using the corresponding source reagents.

Reference example 38

Benzyl ester of cyano(4-fluoro-5-methyl-2-nitrophenyl)acetic acid

A suspension of 1,4-debtor-2-methyl-5-nitrobenzene (1,00 g), benzyl ether tsianuksusnogo acid (1.01 g) and potassium carbonate (1,76 g)N,N-dimethylformamide (20,0 ml) was stirred at 60°C for 1 day. To this reaction mixture was added chloroethanol acid with a concentration of 1 mol/l (25,4 ml), and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure. The residue was washed with ethanol to obtain the above compounds is of (1.54 g).

Reference example 39

6-Fluoro-5-methyl-1H-indol

To a solution of benzyl ester cyano(4-fluoro-5-methyl-2-nitrophenyl)acetic acid (1.54 g), acetic acid (7 ml) and water (7 ml) in ethanol (15 ml) was added 10% palladium on coal (0,154 g) in an argon atmosphere. This reaction mixture was stirred at room temperature for 60 hours in an atmosphere of hydrogen. After this reaction mixture was added water, the hydrogen was replaced by argon. Insoluble material was removed by filtration, and the filtrate was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/nhexane=75/25) to give the titled compound (0,536 g).

Reference example 40

6-Fluoro-5-methyl-1H-indole-3-carbaldehyde

A named connection (0.577 g) was obtained as described in reference example 4 using the appropriate source reagents.

Reference example 41

6-Fluoro-5-methyl-1H-indol-3-carbonitril

A named connection (0,544 g) was obtained as described in reference example 5 using the corresponding source reagents.

Reference example 42

6-Benzyloxy-5-methoxy-1H-indol

4-Benzyloxy the-3-methoxybenzaldehyde (4,85 g) was added dropwise to nitric acid (d=1,42, 20 ml) for 1 hour at room temperature, and the mixture was stirred for 1 hour. This reaction mixture was poured into ice water, and the precipitated solid was filtered. This solid is washed with water, dried under reduced pressure at 50°C To produce 4-benzyloxy-5-methoxy-2-nitrobenzaldehyde (4,99 g). To this product was added acetic acid (50 ml), then was added nitromethane (3,19 g) and ammonium acetate (are 5.36 g), and the mixture was stirred for 5 hours at 100°C. This reaction mixture was concentrated under reduced pressure. To the residue was added water, and the precipitated solid was filtered, and this solid was washed with methanol, dried to obtain 1-benzyloxy-2-methoxy-5-nitro-4-(2-nitrovinyl)benzene (a 4.03 g). To this compound was added benzene (96 ml), acetic acid (72 ml) and cyclohexane (24 ml), then was added silica gel (18 g) and iron powder (10.2 g), and the mixture was stirred at 100°C for 1 hour. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/nhexane=75/25) to give the titled compound (1.06 g).

Reference example 43

6-Benzyloxy-5-methoxy-1H-indole-3-carbaldehyde

The named compound was obtained in the same way as it is written in reference example 4, using the appropriate source reagents.

Reference example 44

6-Benzyloxy-5-methoxy-1H-indol-3-carbonitril

The named compound was obtained as described in reference example 5 using the corresponding source reagents.

Reference examples 45-47

These compounds were obtained as described in reference example 29, using an appropriate source reagents.

Reference example 48

Detil(4-nitro-2-triptoreline)Amin

To a solution of 1-fluoro-4-nitro-2-triptoreline (2.0 g) in tetrahydrofuran (20 ml) was added dimethylamine (0.64 g) and sodium hydride (0.34 g) at room temperature, and the mixture was stirred at 50°C for 16 hours. This reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:nhexane/ethyl acetate) to give the titled compound (0,94 g).

Reference example 49

(5-Dimethylamino-2-nitro-4-triptoreline)acetonitrile

To a solution of dimethyl-(4-nitro-2-triptoreline)amine (0.95 g) inN,N-dimethylformamide (20 ml) was added (4-chlorophenoxy)acetonitrile (0.75 g) and of potassium tert-butylate to what concentrations of 1 mol/l (4.5 ml, solution in tetrahydrofuran) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. This reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:nhexane/ethyl acetate) to give the titled compound (0.11 g).

Reference example 50

Dimethyl(6-trifluoromethyl-1H-indol-5-yl)Amin

To a solution of (5-dimethylamino-2-nitro-4-triptoreline)acetonitrile (0,058 g) in ethanol (1 ml), acetic acid (0.1 ml) and water (0.1 ml) was added a powder of palladium on coal (0,0058 g), and the mixture was stirred at 35°C for 16 hours. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the above compound (0,058 g).

Reference example 51

Ethyl ester of 4-(5-dimethylamino-6-cryptomaterial-1-yl)-benzoic acid

The named compound was obtained as described in reference example 20, using an appropriate source reagents.

Reference example 52

Ethyl ester of 4-(3-formyl-5-methylamino-6-cryptomaterial-1-yl)benzoic acid

To a solution of ethyl ester of 4-(5-dimetil the Ino-6-trifluoromethyl-indol-1-yl)benzoic acid (0,054 g) N,N-dimethylformamide (2 ml) was added to the chloride phosphoryl (0,026 g) under ice cooling, and the mixture was stirred at room temperature for 16 hours. To this mixture was added aqueous sodium hydroxide with a concentration of 2 mol/l (5 ml)and the resulting mixture was stirred at 50°C for 30 minutes. After cooling to ambient temperature, this mixture was added chloroethanol acid with a concentration of 1 mol/l (10 ml), and precipitated solid was filtered. This solid is washed with water andnhexane and dried under reduced pressure at 50°C To produce these compounds (0,026 g).

Reference example 53

The named compound was obtained as described in reference example 29, using (3-benzyloxy-2,4-dimethyl-6-nitrophenyl)acetonitrile instead of (4-methoxy-5-methyl-2-nitrophenyl)acetonitrile.

Reference examples 54-55

These compounds were obtained as described in reference example 5, using indole, obtained as described in reference example 31, using reference example 53 and the corresponding source reagents.

Reference examples 56-63

These compounds were obtained as described in reference example 5 using the corresponding source reagents.

Example 1

Ethyl ester of 4-(3-cyano-5,6-differental-yl)-2-methoxyethoxymethyl acid

To a solution of 3-cyano-5,6-difterinaya (0.25 g) inN,N-dimethylformamide (10 ml) was added cesium carbonate (0,91 g), ethyl ester of 4-fluoro-2-methoxyethoxymethyl acid (0.32 g), and the mixture was stirred at 75°C during the night. This reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/nhexane=10/90-75/25) to give the titled compound (0.12 g).

Example 2

Ethyl ester of 4-(3-cyano-5,6-differental-1-yl)-2-hydroxybenzoic acid

To a solution of ethyl ester of 4-(3-cyano-5,6-differental-1-yl)-2-methoxyethoxymethyl acid (0.12 g) in a mixture of tetrahydrofuran (1.5 ml) and ethanol (3 ml) was added chloroethanol acid with a concentration of 2 mol/l (1.0 ml), and the mixture was stirred at 70°C during the night. After cooling to ambient temperature the precipitated solid was filtered and washed with water andnhexane and dried under reduced pressure at 40°C To produce these compounds (0,074 g).

Example 3

4-(3-Cyano-5,6-differental-1-yl)-2-hydroxybenzoic acid

To a solution of ethyl ester of 4-(3-cyano-5,6-differental-1-yl)-2-Ki is oxybenzoic acid (0,074 g) in a mixture of tetrahydrofuran (3.0 ml) and ethanol (0.75 ml) was added 0.1 g/ml aqueous solution of lithium hydroxide (0,62 ml) and water (1.0 ml), and the mixture was stirred at room temperature for 26 hours. To this reaction mixture was added chloroethanol acid with a concentration of 2 mol/l (5 ml), the organic solvent was removed under reduced pressure. The resulting mixture was extracted with ethyl acetate, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain the above compound (0.06 g).

Example 4

Ethyl ester of 4-(6-benzyloxy-3-cyanoindole-1-yl)-2-methoxyethoxymethyl acid

The named compound (3.4 g) was obtained as described in example 1, using the corresponding source reagents.

Example 5

4-(6-Benzyloxy-3-cyanoindole-1-yl)-2-hydroxybenzoic acid

The named compound was obtained as described in example 2 and example 3, using the corresponding source reagents.

Example 6

Ethyl ester of 4-(3-cyano-6-hydroxyindole-1-yl)-2-methoxyethoxymethyl acid

To a solution of ethyl ester of 4-(6-benzyloxy-3-cyanoindole-1-yl)-2-methoxyethoxymethyl acid in a mixture of ethyl acetate (60 ml) and methanol (60 ml) was added a powder of palladium on coal (and 0.61 g) in an argon atmosphere at 0°C., and the mixture was stirred at 40°C in an atmosphere of hydrogen for 3 hours. Insoluble material was removed by filtration,and the filtrate was concentrated under reduced pressure to obtain the above compound (2.5 g).

Example 7

Ethyl ester of 4-[6-(2-benzyloxycarbonylamino)-3-cyanoindole-1-yl]-2-methoxyethoxymethyl acid

To a solution of ethyl ester of 4-(3-cyano-6-hydroxyindole-1-yl)-2-methoxyethoxymethyl acid (0,37 g)N,N-dimethyl-formamide (10 ml) was added benzyl ether (2-bromacil)carbamino acid (0.39 g) and potassium carbonate (0.28 g), and the mixture was stirred at 50°C during the night. This reaction mixture was poured into water and the precipitated solid was filtered. This solid was washed with methanol and dried to obtain the above compound (0.40 g).

Example 8

4-[6-(2-Benzyloxycarbonylamino)-3-cyanoindole-1-yl]-2-hydroxybenzoic acid

To a solution of ethyl ester 4-[6-(2-benzyloxycarbonylamino)-3-cyanoindole-1-yl]-2-methoxyethoxymethyl acid (0.14 g) in ethanol (2.5 ml), tetrahydrofuran (5 ml) and water (2.5 ml) was added monohydrate of lithium hydroxide (0.03 g), and the mixture was stirred at room temperature for 3 hours. To this reaction mixture was added chloroethanol acid with a concentration of 2 mol/l (0.75 ml), and the mixture was stirred at 50°C for 5 hours. This reaction mixture was treated chloroethanol acid with a concentration of 1 mol/l (5 ml) and concentrated under reduced pressure until such time as the volume of solvent nasolabial one-third the original volume. The precipitated solid was filtered and washed with water, methanol and ether to obtain these compounds (0,097 g).

Example 9

4-[6-(2-Aminoethoxy)-3-cyanoindole-1-yl]-2-hydroxybenzoic acid

To a solution of 4-[6-(2-benzyloxycarbonylamino)-3-cyanoindole-1-yl]-2-hydroxybenzoic acid (0,087 g) in a mixture of ethyl acetate (2 ml) and methanol (2 ml) was added a powder of palladium on coal (0,016 g) in an argon atmosphere at 0°C., and the mixture was stirred at 40°C in an atmosphere of hydrogen for 3 hours. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained light yellow solid was washed with diethyl ether, dried with obtaining these compounds (0,058 g).

Example 10

Ethyl ester of 4-[6-(2-aminoethoxy)-3-cyanoindole-1-yl]-2-methoxyethoxymethyl acid

To a solution of ethyl ester 4-[6-(2-benzyloxycarbonylamino)-3-cyanoindole-1-yl]-2-methoxyethoxymethyl acid (0.27 g) in a mixture of ethyl acetate (5 ml) and methanol (5 ml) was added a powder of palladium on coal (0.05 g) in an argon atmosphere at 0°C., and the mixture was stirred at 40°C in an atmosphere of hydrogen for 3 hours. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained light yellow solid was washed diethyl shall FYROM, dried to obtain the above compound (0.20 g).

Example 11

Ethyl ester of 4-[6-(2-acetamidoacrylate)-3-cyanoindole-1-yl]-2-methoxyethoxymethyl acid

To a solution of ethyl ester 4-[6-(2-aminoethoxy)-3-cyanoindole-1-yl]-2-methoxyethoxymethyl acid (0.10 g) and triethylamine (0,076 g) in dichloromethane (5 ml) was added acetylchloride (0,049 g) at room temperature, and the mixture was stirred at room temperature for 12 hours. This reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane:methanol=10:1) to give the titled compound (0.083 g).

Example 12

4-[6-(2-Acetamidoacrylate)-3-cyanoindole-1-yl]-2-hydroxybenzoic acid

A named connection (0,039 g) was obtained as described in example 8 using the appropriate source reagents.

Example 13

Ethyl ester of 4-(5-bromo-3-cyanoindole-1-yl)benzoic acid

To a solution of 5-bromo-3-cyanoindole (2.0 g) inN,N-dimethyl-formamide (50 ml) was added cesium carbonate (7.4 g) and ethyl ester of 4-fermenting acid (3.0 g), and the mixture was stirred at 80°C for 48 hours. This reaction mixture was poured into water and the precipitated solid was filtered. This solid substance was washed with water and dried under reduced d is the pressure at 50°C To produce the above compound (1.8 g).

Example 14

Ethyl ester of 4-[3-cyano-5-(4-methoxyphenyl)indol-1-yl]benzoic acid

A mixture of ethyl ester of 4-(5-bromo-3-cyanoindole-1-yl)benzoic acid (0.1 g), 4-methoxyphenylacetic acid (of 0.066 g), potassium carbonate (0.09 g) in a mixture of 1,2-dimethoxyethane (3 ml), ethanol (0.5 ml) and water (0.5 ml) was stirred in the presence of a catalyst tetrakis(triphenylphosphine)palladium at 90°C for 18 hours. This reaction mixture was poured into water and the precipitated solid was filtered. This solid is washed with water, dried under reduced pressure at 50°C To produce these compounds (0,098 g).

Example 15

4-[3-Cyano-5-(4-methoxyphenyl)indol-1-yl]benzoic acid

A named connection (of 0.081 g) was obtained as described in example 3 using the corresponding source reagents.

Example 16

4-{5-[(E)-2-Ethoxycarbonylphenyl]-3-cyanoindole-1-yl}benzoic acid

A solution of ethyl ester of 4-(5-bromo-3-cyanoindole-1-yl)benzoic acid (0.1 g), ethyl ester of acrylic acid (0.11 g) and triethylamine (0,082 g)N,N-dimethylformamide (2 ml) was stirred in the presence of palladium(II) acetate (0,0061 g) and triphenylphosphine (0,014 g) at 100°C for 30 hours. This reaction mixture was poured into water, and the resulting mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and sushiland anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/nhexane=10/90-75/25) to give the titled compound (0.035 g).

Example 17

4-[5-((E)-2-Carboxyvinyl)-3-cyanoindole-1-yl]benzoic acid

The named compound was obtained as described in example 3 using the corresponding source reagents.

Example 18

Ethyl ester of 4-(4-benzyloxy-3-cyanoindole-1-yl)benzoic acid

The named compound (0.16 g) was obtained as described in example 13 using the appropriate source reagents.

Example 19

4-(4-Benzyloxy-3-cyanoindole-1-yl)benzoic acid

To a solution of ethyl ester of 4-(4-benzyloxy-3-cyanoindole-1-yl)-benzoic acid (0.16 g) in ethanol (2 ml) was added aqueous sodium hydroxide with a concentration of 2 mol/l (0.4 ml), and the mixture was stirred at 50°C during the night. The ethanol was removed under reduced pressure, and to this reaction mixture was added chloroethanol acid with a concentration of 2 mol/l (3 ml). The precipitated solid was filtered, and the solid is washed with water andnhexane to obtain the above compound (0.11 g).

Example 20

Ethyl ester of 4-(3-cyano-6-nitroindole-1-yl)benzoic acid

To a solution of ethyl ester of 4-(6-Nitron the ol-1-yl)benzoic acid (0,53 g) N,N-dimethylformamide (6 ml) was added to the chloride phosphoryl (0.31 g) under ice cooling, and the mixture was stirred at 70°C during the night. After cooling to ambient temperature, this reaction mixture was added aqueous sodium hydroxide with a concentration of 2 mol/l, and the mixture was stirred for 30 minutes. This reaction mixture was poured into chloroethanol acid with a concentration of 1 mol/l, and the precipitated solid was filtered, washed with water andnhexane and dried under reduced pressure at 40°C with obtaining the ethyl ester of 4-(3-formyl-6-nitroindole-1-yl)benzoic acid (0,46 g). To a solution of this aldehyde (0,46 g) in tetrahydrofuran (10 ml) was added hydroxylamine hydrochloride (0,19 g) and pyridine (0,43 g) at room temperature, and the mixture was stirred at 80°C for 8 hours. To this reaction mixture was added acetic anhydride (0,42 g) at 80°C, and the mixture was stirred at the same temperature throughout the night. After cooling to ambient temperature, this reaction mixture was added chloroethanol acid with a concentration of 1 mol/l, and the precipitated solid was filtered. The solid is washed with water,nhexane and diethyl ether to obtain the above compound (0,13 g).

Example 21

Ethyl ester of 4-(6-amino-3-cyanoindole-1-yl)benzoic acid

is the solution of the ethyl ester of 4-(3-cyano-6-nitroindole-1-yl)-benzoic acid (0.11 g) in a mixture of tetrahydrofuran (2 ml) and methanol (2 ml) was added a powder of palladium on coal (0.04 g) in an argon atmosphere, and the mixture was stirred at room temperature in a hydrogen atmosphere for 7 hours. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the above compound (0,070 g).

Example 22

Ethyl ester of 4-(3-cyano-6-methanesulfonylaminoethyl-1-yl)benzoic acid

To a solution of ethyl ester of 4-(5-amino-3-cyanoindole-1-yl)benzoic acid (0,070 g) in dichloromethane (2 ml) was added methanesulfonamide (0.035 g) and pyridine (0.036 g) at room temperature, and the mixture was stirred at room temperature overnight. This reaction mixture was poured into chloroethanol acid with a concentration of 1 mol/l, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/nhexane=10/90-75/25) to give the titled compound (0,046 g).

Example 23

4-(3-Cyano-6-methanesulfonylaminoethyl-1-yl)benzoic acid

A named connection (0,040 g) was obtained as described in example 3 using the corresponding source reagents.

Example 24

Ethyl ester of 4-(5-benzyloxy-3-cyanoindole-1-yl)benzoic acid

Named link who received the same as described in example 13 using the appropriate source reagents.

Example 25

Ethyl ester of 4-(5-hydroxy-3-cyanoindole-1-yl)benzoic acid

The named compound was obtained as described in example 6, using the appropriate source reagents.

Example 26

Ethyl ester of 4-[3-cyano-5-(thiophene-2-ylmethylene)indol-1-yl]benzoic acid

To a solution of ethyl ester of 4-(5-hydroxy-3-cyanoindole-1-yl)-benzoic acid and thiophene-2-methanol (0,057 g) and triphenylphosphine (0,012 g) in tetrahydrofuran (2.5 ml) was added diisopropylcarbodiimide (40% toluene solution of 0.18 ml) at room temperature, and the mixture was stirred for 3 hours. This reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/nhexane=1/3) to give the titled compound (0.10 g).

Example 27

4-[3-Cyano-5-(thiophene-2-ylmethylene)indol-1-yl]benzoic acid

The named compound (0.01 g) was obtained as described in example 3 using the corresponding source reagents.

Example 28

Ethyl ester of 4-(3-cyano-5-benzyloxycarbonylamino-1-yl)benzoic acid

The named compound (0.24 g) was obtained as described in example 13 using the appropriate source reagents.

<> Example 29

4-(5-Carboxy-3-cyanoindole-1-yl)benzoic acid

A named connection (0,050 g) was obtained as described in example 3 using the corresponding source reagents.

Example 30

Ethyl ester of 4-(5-carboxy-3-cyanoindole-1-yl)benzoic acid

To a solution of ethyl ester of 4-(3-cyano-5-benzyloxycarbonylamino-1-yl)benzoic acid (0.16 g) in a mixture of methanol (5 ml) and tetrahydrofuran (5 ml) was added a powder of palladium on coal (0.03 g) at 0°C in an argon atmosphere, and the mixture was stirred at room temperature in a hydrogen atmosphere for 3 hours. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the above compound (0,057 g).

Example 31

Ethyl ester of 4-(3-cyano-5-hydroxymethylene-1-yl)benzoic acid

To a solution of ethyl ester of 4-(5-carboxy-3-cyanoindole-1-yl)benzoic acid (0,057 g) in tetrahydrofuran (2 ml) was added to the complex of borane-tetrahydrofuran (0.2 ml of a solution in tetrahydrofuran of 1.2 mol/l) at 0°C., and the mixture was stirred at room temperature for 2 hours. To this reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent in which alali under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/nhexane=1/1) to give the titled compound (0,032 g).

Example 32

4-(3-Cyano-5-hydroxymethylene-1-yl)benzoic acid

A named connection (0,029 g) was obtained as described in example 3 using the corresponding source reagents.

Example 33

Ethyl ester of 4-(3-cyano-5-dimethylaminocarbonylmethyl-1-yl)benzoic acid

To a solution of ethyl ester of 4-(5-carboxy-3-cyanoindole-1-yl)benzoic acid (0,084 g), dimethylamine hydrochloride (0,061 g), triethylamine (0,13 g) and 4-dimethylaminopyridine (0,006 g) in dichloromethane (2.5 ml) was addedN-ethyl-N'-3-dimethylaminopropylamine (0,058 g) at room temperature, and the mixture was stirred at room temperature overnight. This reaction mixture was poured into chloroethanol acid with a concentration of 1 mol/l and were extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/nhexane=1/2) to obtain the titled compound (0,020 g).

Example 34

4-(3-Cyano-5-dimethylaminocarbonylmethyl-1-yl)benzoin the I acid

A named connection (0.0025 g) was obtained as described in example 3 using the corresponding source reagents.

Example 35

5-(3-Cyanoindole-1-yl)furan-2-carboxylic acid

To a suspension of 1-(5-formylfuran-2-yl)-1H-indol-3-carbonitrile (of 0.085 g) in methanol (4 ml) and tetrahydrofuran (4 ml) was added silver oxide (0.1 g) and aqueous sodium hydroxide with a concentration of 2 mol/l (0,27 ml), the mixture was stirred at room temperature for 6 hours. Insoluble material from the reaction mixture were removed by filtration, and the filtrate was concentrated under reduced pressure. To this residue was added water (15 ml) and chloroethanol acid with a concentration of 2 mol/l (2 ml)and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to obtain the titled compound (0,023 g).

Example 36

Ethyl ester of 3-(3-cyanoindole-1-yl)benzoic acid

To a solution of 1H-indole-3-carbonitrile (0.28 g) in dimethyl sulfoxide (3 ml) was added ethyl ester 3-identies acid (0,61 g), cesium carbonate (0.65 g), copper iodide (0,038 g) andN,N-dimethylglycine (0,041 g), and the mixture was stirred at 75°C for 3 days. To this reactio the Noah mixture was added ethyl acetate, insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added water, the precipitated solid was filtered and washed with water andnhexane and dried under reduced pressure at 40°C To produce these compounds (0,38 g).

Example 37

3-(3-Cyanoindole-1-yl)benzoic acid

A named connection (0,30 g) was obtained as described in example 3 using the corresponding source reagents.

Example 38

Ethyl ester of 2-(3-cyanoindole-1-yl)isonicotinic acid

A mixture of 1H-indole-3-carbonitrile (0.1 g), ethyl ester 2-bromoisonicotinic acid (0.16 g), potassium phosphate (0.27 g), (1R,2R)-(-)-N,N'dimethylcyclohexane-1,2-diamine (0,017 g), copper iodide (0,006 g) and toluene (0.7 ml) was stirred at 110°C for 38 hours. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/nhexane=10/90-66/34) to give the titled compound (0,061 g).

Example 39

2-(3-Cyanoindole-1-yl)isonicotinate acid

A named connection (0,038 g) was obtained as described in example 8 using the appropriate source reagents.

Example 40

Methyl ester of 4-(3-cyanoindole-1-yl)-2-NITR the benzoic acid

The named compound was obtained as described in example 1, using the corresponding source reagents.

Example 41

4-(3-Cyanoindole-1-yl)-2-nitrobenzoic acid

The named compound was obtained as described in example 3 using the corresponding source reagents.

Example 42

2-Amino-4-(3-cyanoindole-1-yl)benzoic acid

To a solution of 4-(3-cyanoindole-1-yl)-2-nitrobenzoic acid (0,012 g) in ethanol (1 ml), water (0.5 ml) and tetrahydrofuran (0.5 ml) was added powdered zinc level (0.041 g) and ammonium chloride (0.004 g) at room temperature, and the mixture was stirred at 80°C for 2.5 hours. After cooling to ambient temperature, this reaction mixture was added ethyl acetate. Insoluble material was removed by filtration, and the filtrate was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the above compound (0.003 g).

Example 43

2-Acetoxy-(3-cyanoindole-1-yl)benzoic acid

To a suspension of 4-(3-cyanoindole-1-yl)-2-hydroxybenzoic acid in pyridine (0.5 ml) was added acetic anhydride (0.1 ml) at 0°C., and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured into chloroethanol acid with a concentration of 1 mol/l and were extracted ethylacetate is. The organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the above compound (0,047 g).

Example 44

Ethyl ester of 2-(3-cyanoindole-1-yl)nicotinic acid

The named compound was obtained as described in reference example 13, using the ethyl ester of 6-chloronicotinic acid instead of the ethyl ester of 4-fermenting acid.

Example 45

2-(3-Cyanoindole-1-yl)nicotinic acid

The named compound was obtained as described in example 3 using the corresponding source reagents.

Example 46

Ethyl ester of 2-(3-cyanoindole-1-yl)-4-methylthiazole-5-carboxylic acid

The named compound was obtained as described in reference example 13, using the ethyl ester of 2-chloro-4-methylthiazole-5-carboxylic acid instead of the ethyl ester of 4-fermenting acid.

Example 47

2-(3-Cyanoindole-1-yl)-4-methylthiazole-5-carboxylic acid

The named compound was obtained as described in example 3 using the corresponding source reagents.

Examples 48-55

Connection examples 48-55 was obtained as described in example 13 using the appropriate source reagents.

Examples 56-65

Connection examples 56-65 got like about it is isano in example 7, using the appropriate source reagents.

Examples 66-76

Connection examples 66-76 was obtained as described in example 14, using the appropriate source reagents.

Examples 77-81

Connection examples 77-81 was obtained as described in example 33, using an appropriate source reagents.

Examples 82-84

Connection examples 82-84 was obtained as described in example 26, using an appropriate source reagents.

Examples 85-86

Connection examples 85-56 was obtained as described in example 44, using an appropriate source reagents.

Example 87

The compound of example 87 was obtained as described in example 13 using the appropriate source reagents.

Example 88

The compound of example 88 was obtained as described in example 20, using an appropriate source reagents.

Examples 89-107

Connection examples 89-107 was obtained in the same way as described in example 1 using the corresponding source reagents.

Examples 108-109

Connection examples 108-109 was obtained as described in example 6, using the appropriate source reagents.

Examples 110-134

Connection examples 110-134 was obtained as described in example 7 using the appropriate source reagents.

An example is 135-136

Connection examples 135-136 was obtained as described in example 26, using an appropriate source reagents.

Example 137

The compound of example 137 was obtained as described in example 10, using the appropriate source reagents.

Examples 138-140

Connection examples 138-140 was obtained as described in example 11, using an appropriate source reagents.

Examples 141-187

Connection examples 141-187 was obtained in the same way as described in example 3 using the corresponding source reagents.

Examples 188-225

Connection examples 188-225 was obtained in the same way as described in example 2 and example 3, using the corresponding source reagents.

Examples 226-227 of

Connection 226-227 of the examples were obtained as described in example 8 using the appropriate source reagents.

Examples 228-234

Connection examples 228-234 was obtained in the same way as described in example 2 and example 3, using the corresponding source reagents.

Example 235

The compound of example 235 was obtained as described in example 8 using the appropriate source reagents.

Examples 236-237

Connection examples 236-237 was obtained in the same way as described in example 2 and example 3, using the corresponding source reagents.

Examples 238-240

Join the reamers 238-240 received as well as described in example 8 using the appropriate source reagents.

Example 241

The compound of example 235 was obtained in the same way as described in example 3 using the corresponding source reagents.

Example 242

Ethyl ester of 4-(3-cyano-5-methoxy-6-methylindol-1-yl)benzoic acid

The named compound was obtained as described in example 13 using the appropriate source reagents.

Example 243

Ethyl ester of 4-(5-benzyloxy-6-chloro-3-cyanoindole-1-yl)benzoic acid

The named compound (0.31 g) was obtained as described in example 13 using the appropriate source reagents.

Example 244

Ethyl ester of 4-(6-chloro-3-cyano-5-hydroxyindole-1-yl)benzoic acid

To a solution of ethyl ester of 4-(5-benzyloxy-6-chloro-3-cyanoindole-1-yl)benzoic acid (0,310 g) in dichloromethane (7 ml) was added trichromacy boron (dichloromethane, concentration 1 mol/l) (0,860 ml) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. To this reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was removed under reduced pressure. The residue was washed with diethyl ether obtaining these compounds (0,181 g).

Note the R 245

Ethyl ester of 4-(6-chloro-3-cyano-5-methoxyindol-1-yl)benzoic acid

The named compound was obtained as described in example 31, using an appropriate source reagents.

Example 246

Ethyl ester of 4-(6-chloro-3-cyano-5-triftoratsetilatsetonom-1-yl)benzoic acid

To a solution of ethyl ester of 4-(6-chloro-3-cyano-5-hydroxyindole-1-yl)benzoic acid (0.079 in g) and pyridine (0,056 ml) in dichloromethane (2.3 ml) was added triftormetilfullerenov anhydride (0,058 ml) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. To this reaction mixture was added chloroethanol acid with a concentration of 1 mol/l (0,370 ml) and water. After separation of organic layer, the organic solvent was removed under reduced pressure to obtain the above compound (0,103 g).

Example 247

Ethyl ester of 4-(6-chloro-3-cyano-5-methylindol-1-yl)benzoic acid

To a solution of ethyl ester of 4-(6-chloro-3-cyano-5-triftoratsetilatsetonom-1-yl)benzoic acid (0,103 g), trimethylboroxine (0,033 g) and potassium triphosphate (0,070 g) in dioxane (2.0 ml) was added the catalyst tetrakis(triphenylphosphine)palladium (0,038 g), and the mixture was stirred at 80°C for 1 day. The reaction mixture was purified by column chromatography on silica gel (eluent: ethyl acetate/nhexane=75/25) with what rucenim these compounds (0,0568 g).

Example 248

Ethyl ester of 4-(3-cyano-6-fluoro-5-methylindol-1-yl)benzoic acid

A named connection (0,117 g) was obtained as described in example 13 using the appropriate source reagents.

Example 249

Ethyl ester of 6-(3-cyano-6-fluoro-5-methylindol-1-yl)nicotinic acid

The named compound (0.152 g) was obtained as described in example 44, using an appropriate source reagents.

Example 250

Ethyl ester of 4-(3-cyano-6-fluoro-5-methylindol-1-yl)-2-methoxyethoxymethyl acid

A named connection (0,116 g) was obtained as described in example 1, using the corresponding source reagents.

Example 251

Ethyl ester of 4-(6-benzyloxy-3-cyano-5-methoxyindol-1-yl)-benzoic acid

The named compound was obtained as described in example 13 using the appropriate source reagents.

Example 252

Ethyl ester of 4-(3-cyano-6-hydroxy-5-methoxyindol-1-yl)benzoic acid

The named compound was obtained as described in example 6, using the appropriate source reagents.

Example 253

Ethyl ester of 4-(3-cyano-6-cyclopropyl-5-methoxyindol-1-yl)benzoic acid

To a solution of ethyl ester of 4-(3-cyano-6-hydroxy-5-methoxyindol-1-yl)benzoic acid (of € 0.195 g) and pyridine (was 0.138 g) in Dich armetale (2.3 ml) was added triftormetilfullerenov anhydride (0,246 g) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. To this reaction mixture was added chloroethanol acid with a concentration of 1 mol/l (0,370 ml) and water and the organic layer was separated. The organic solvent was concentrated under reduced pressure to obtain ethyl ester 4-(3-cyano-5-methoxy-6-triftoratsetilatsetonom-1-yl)benzoic acid (0,238 g). Then to this product (0,070 g) was added toluene (1.5 ml), to this mixture was added cyclopropylboronic acid (0,016 g), potassium carbonate (0,031 g) and tetrakis(triphenylphosphine)palladium (0) (0,026 g), and the mixture was stirred at 80°C for 1 day. The reaction mixture was purified by column chromatography on silica gel (eluent: ethyl acetate/nhexane=75/25) to give the titled compound (0.037 g).

Example 254

Ethyl ester of 4-(cyano-5-hydroxy-6-methylindol-1-yl)benzoic acid

The named compound was obtained as described in example 244, using the ethyl ester of 4-(3-cyano-5-methoxy-6-methylindol-1-yl)benzoic acid.

Example 255

Ethyl ester of 4-(3-cyano-5,6-dimethylindole-1-yl)benzoic acid

The named compound was obtained as described in example 246 and example 247, using the ethyl ester of 4-(cyano-5-hydroxy-6-methylindol-1-yl)benzoic acid.

Example 256

The named compound was obtained as well as the, as described in example 13 using the appropriate source reagents.

Example 257

4-(3-cyano-6-fluoro-5-hydroxyindole-1-yl)benzoic acid

To a solution of ethyl ester of 4-(3-cyano-6-fluoro-5-methoxyindol-1-yl)benzoic acid (1.2 g) in dichloromethane (20 ml) was added dropwise trichromacy boron (dichloromethane, concentration 1 mol/l) (10 ml) under ice cooling, and the mixture was stirred at room temperature for 12 hours. This reaction mixture was poured into ice water, extracted with ethyl acetate and concentrated under reduced pressure to obtain the above compound (0,44 g).

Example 258

2-Methoxyethoxy ester 4-[3-cyano-6-fluoro-5-(2-methoxyethoxy)indol-1-yl]benzoic acid

To a solution of 4-(3-cyano-6-fluoro-5-hydroxyindole-1-yl)benzoic acid (0.06 g) inN,N-dimethylformamide (2 ml) was added 1-bromo-2-methoxyethane (0.14 g) and potassium carbonate (0,13 g) at room temperature, the mixture was stirred at the same temperature for 16 hours. This reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give the titled compound (0.79 in).

Examples 259-264

These compounds were obtained as described in example 13 using the appropriate source reagents.

Example 265

The named compound was obtained as described in example 245, using an appropriate source reagents.

Example 266

The named compound was obtained as described in example 252, using the appropriate source reagents.

Examples 267-270

These compounds were obtained as described in example 1, using the corresponding source reagents.

Example 271

The named compound was obtained as described in example 244, using an appropriate source reagents.

Examples 272-277

These compounds were obtained as described in example 1, using the corresponding source reagents.

Example 278

The named compound was obtained as described in example 252, using the appropriate source reagents.

Example 279

The named compound was obtained as described in example 1, using the corresponding source reagents and ethyl ester of 2,4-debtor-6-methoxyethoxymethyl acid instead of the ethyl ester of 4-fluoro-2-methoxyethoxymethyl acid.

Examples 280-282

These compounds were obtained as described in example 258, use the Zuya corresponding source reagents.

Example 283

Ethyl ester of 4-(3-cyano-5-dimethylamino-6-cryptomaterial-1-yl)benzoic acid

To a solution of ethyl ester of 4-(3-formyl-5-methylamino-6-cryptomaterial-1-yl)benzoic acid (0,026 g) in tetrahydrofuran (1 ml) was added hydroxylamine hydrochloride (0,0067 g) and pyridine (0.02 g), and the mixture was stirred at 60°C for 4 hours. After cooling to ambient temperature to the reaction mixture was added acetic anhydride (0,013 g), and the mixture was stirred at 60°C for 12 hours. This reaction mixture was poured into water and the precipitated solid was filtered. The solid is washed with water andnhexane and dried under reduced pressure at 50°C To produce these compounds (0,026 g).

Examples 284-291

These compounds were obtained as described in example 3 using the corresponding source reagents.

Example 292

The named compound was obtained as described in example 257 using the appropriate source reagents.

Examples 293-308

These compounds were obtained as described in example 3 using the corresponding source reagents.

Example 309

After getting the appropriate carboxylic acid in the same way as described in example 3, this product was added chloroethanol acid with Koh and what entrala 2 mol/l until while the pH value was not equal to 1, and the mixture was stirred over night. The precipitated solid was filtered to obtain these compounds.

Examples 310-321

These compounds were obtained as described in example 309, using the appropriate source reagents.

Example 322

The named compound was obtained as described in example 2 and example 3, using the corresponding source reagents.

Example 323

The named compound was obtained as described in example 6, using the appropriate source reagents.

Example 324

The named compound was obtained as described in example 309, using the appropriate source reagents, and then spent alkylation, as described in example 7.

Example 325

The named compound was obtained as described in example 309, using the appropriate source reagents.

Example 326

The named compound was obtained as described in example 324, using the appropriate source reagents.

Example 327

The named compound was obtained as described in example 309, using the appropriate source reagents.

Example 328

The named compound was obtained as described in example 41 and example 21, using appropriate is eastwoodiae source reagents.

In tables 1-3 and 42-45 chemical structure and data1H-NMR for the above compounds of reference examples 1-23 and 24-53, table 46 describes the chemical structure of the compounds of reference examples 54-63, in tables 4-41, 47-49 and 53-59 chemical structure and data1H-NMR for the above compounds of examples 1-241, 242-258 and 284-328, in tables 50-52 shows the chemical structure of the compounds of examples 259-283, respectively.

Used abbreviations in these tables: "Ref. approx. No.", "approx. No.", "structure" and "Rest.” represent the number of the reference example, example, the chemical structure and the solvent in which to conduct measurement1H-NMR, respectively.

[Table 1]
Ref. approx. No.Struct.(Rest.)1H-NMRδppm:
1(CDCl3) of 1.41 (3H, t, J=7.2 Hz), to 4.41 (2H, q, J=7.2 Hz), 6,55-of 6.65 (1H, m), to 6.67 (1H, DD, J=10.4 Hz, 2.6 Hz), 7,86 (1H, DD, J=9,0 Hz, 6.6 Hz), 11,08 (1H, d, J=2.5 Hz)
2(CDCl3) to 1.37 (3H, t, J=7.0 Hz), 3,52 (3H, s), 4,35 (2H, q, J=7.0 Hz), a 5.25 (2H, is), 6,07-of 6.78 (1H, m)6,94 (1H, DD, J=2,4, and 10.8 Hz), 7,83 (1H, d, J=7,0, 8,9 Hz)
3(CDCl3) to 3.52 (3H, s), 3,88 (3H, in), 5.25 (2H, s)6,70-to 6.80 (1H, m), 6.90 to-7,00 (1H, m), 7,75-of 7.95 (1H, m).
4(DMSO-d6) 7,58 (1H, DD, J=10,9 Hz, 7.0 Hz), 7,94 (1H, DD, J=10,9 Hz, 8.0 Hz), of 8.37 (1H, s) 9,92 (1H, s)to 12.28 (1H, users)
5(DMSO-d6) to 7.61 (1H, DD, J=10,7 Hz, 7.0 Hz), 7,69 (1H, DD, J=10,6 Hz, 7.7 Hz), 8,32 (1H, s), 12,34 (1H, users)
6(DMSO-d6) 7,05-7,20 (2H, m), the 7.65 to 7.75 (2H, m), to 8.62 (1H, s)
7(DMSO-d6) 7,30-8,35 (9H, m), and 12.2 (1H, users)
8(DMSO-d6) 5,38 (2H, s), 7,25-of 7.55 (5H, m), a 7.62 (1H, d, J=8.7 Hz), the 7.85-of 7.95 (1H, m), 8,44 (1H, s), 8,80 (1H, s), 9,98 (1H, s), and 12.4 (1H, s)
9(CDCl3) 5,42 (2H, d), 7,30-of 7.55 (6H, m), 7,80 (1H, d, J=2,9 Hz), 8,08 (1H, DD, J=8.7 Hz, 1.5 Hz), 8,50-8,65 (1H, m), and 8.3 (1H, users)
10(DMSO-d6) 2,32 (3H, s), 5,11 (2H, s), of 5.34 (2H, s), 7,15-of 7.70 (13H, m)

[Table 2]
Ref. Approx. No.Struct.(Rest.)1H-NMRδppm:
11(CDCl3) of 2.28 (3H, s), 4,70 (2H, s), 5,10 (2H, s), 6,80-7,20 (3H, m), 7,25 is 7.50 (5H, m)
12(CDCl3) a 2.36 (3H, s), of 5.15 (2H, s), 7,30 is 7.50 (8H, m), 9,92 (1H, s)
13(DMSO-d6) of 2.28 (3H, s), with 5.22 (2H, s), 7,25 is 7.50 (6H, m), of 7.64 (1H, s), 10,13 (1H, s)
14(CDCl3) of 2.24 (3H, s), 3,85 (3H, s), 4,82 (2H, s), is 5.06 (2H, s), 6,34 (1H, users), 7,07 (1H, s), 7,20 was 7.45 (12H, m)
15(CDCl3) 2,35 at 2.45 (3H, m)to 3.92 (3H, s), 5,11 (2H, s), was 7.08 (1H, s), 7,10 (1H, DD, J=2.0 Hz, 0.8 Hz), 7,20 (1H, s), 7,30 is 7.50 (5H, what), 8,65 (1H, users)
16(DMSO-d6) of 2.30 (3H, s), 5,11 (2H, s), 7,02 (1H, s), 7,16 (1H, s), 7.23 percent (1H, s), 7,33 (1H, t, J=7,3 Hz), 7,41 (2H, t, J=7,3 Hz), of 7.48 (2H, d, J=7,3 Hz), 11,67 (1H, s)
17(CDCl3) 2,39 (3H, s), 5,12 (2H, s), 6,40-6,50 (1H, m), 7,05-to 7.15 (2H, m), 7,18 (1H, s), 7,25-to 7.35 (1H, m), 7,35-7,45 (2H, m), 7,45-of 7.55 (2H, m), 7,94 (1H, users)
18(DMSO-d6) 2,31 (3H, s), 5,14 (2H, s), 7,31 (1H, s), 7,33 (1H, d, J=7,3 Hz), 7,40 (2H, t, J=7,3 Hz), 7,51 (2H, d, J=7,6 Hz), 7,66 (1H, s), 8,13 (1H, d, J=2,9 Hz), 9,87 (1H, s), 11,92 (1H, s)
19(DMSO-d6) of 2.34 (3H, s), of 5.15 (2H, s), 7,21 (1H, s), 7,24 (1H, s), 7,34 (1H, d, J=7,4 Hz), 7,40 (2H, t, J=7,7 Hz), 7,49 (2H, d, J=7,4 Hz), 7,60 (1H, d, J=2,9 Hz), to 8.41 (1H, users)

[Table 3]
Ref. Approx. No.Struct.(Rest.)1H-NMRδppm:
20(DMSO-d6) of 1.37 (3H, t, J=7,1 Hz), to 4.38 (2H, q, J=7,1 Hz), 695-7,05 (1H, m), 7,80-of 7.95 (3H, m), of 8.06 (1H, DD, J=8.0 Hz, 2.0 Hz), 8,15-of 8.25 (3H, m), 8,40-and 8.50 (1H, m)
21(CDCl3) 6,56 (1H, d, J=3,7 Hz), 7,40-of 7.55 (3H, m), 7,80-of 7.95 (2H, m), with 8.05 (1H, s), 9,65 (1H, s)
22(DMSO-d6) of 1.36 (3H, t, J=7,1 Hz), to 4.38 (2H, q, J=7,1 Hz), 6.90 to-6,95 (1H, m), 7,65-of 7.90 (4H, m), 8,08 (1H, d, J=3,4 Hz), 8,15-8,30 (3H, m), and 10.0 (1H, s)
23(DMSO-d6) 1,30-1,40 (3H, m), 2,03 (3H, s), 4,30-4,45 (2H, m), 5,16 (2H, s)6,70-to 6.80 (1H, m), 7,10-of 7.25 (1H, m), 7,60 is 7.85 (5H, m), 8,15 (2H, d, J=8.6 Hz)

[Table 4]
Approx. No.Struct.(Rest.)1H-NMRδppm:
1(CDCl3) of 1.33 (1H, t, J=7,1 Hz), 3,44 (3H, s), 4,32 (2H, q, J=7,1 Hz), of 5.39 (2H, s), 7,30-of 7.55 (2H, m), 7,70-of 7.95 (3H, m), is 8.75 (1H, s)
2(DMSO-d6) of 1.37 (3H, t, J=7,1 Hz)to 4.41 (2H, q, J=7,1 Hz), 7,20-to 7.35 (2H, m), 7,70-with 8.05 (3H, m), is 8.75 (1H, s)
3 (DMSO-d6) 7,15-to 7.35 (2H, m), 7,75-of 7.95 (2H, m), of 8.00 (1H, d, J=8,2 Hz), the rate of 8.75 (1H, s)
4(CDCl3) to 1.42 (3H, t, J=7,1 Hz), of 3.54 (3H, s), 4,42 (2H, q, J=7,1 Hz), 5,07 (2H, s), from 5.29 (2H, s), 7,00-7,20 (3H, m), 7,25-of 7.55 (6H, m), of 7.70 (1H, d, J=8,8 Hz), 7,73 (1H, s), of 7.97 (1H, d, J=8,2 Hz)
5(DMSO-d6) of 5.17 (2H, s), 7,11 (1H, DD, J=8,7 Hz, 2.0 Hz), 7,15-of 7.55 (8H, m), of 7.64 (1H, d, J=8.7 Hz), to 7.99 (1H, d, J=8,4 Hz), charged 8.52 (1H, s)
6(DMSO-d6) of 1.42 (3H, t, J=7.2 Hz), of 3.45 (3H, s), or 4.31 (2H, q, J=7.2 Hz), lower than the 5.37 (2H, s), to 6.88 (1H, DD, J=8.7 Hz, 1.7 Hz), 7,05 (1H, d, J=1.7 Hz), 7,34 (1H, DD, J=8,4 Hz, 1.8 Hz), 7,44 (1H, d, J=1,8 Hz), 7,53 (1H, d, J=8,4 Hz), 7,86(1H, d, J=8,4 Hz), 8,44 (1H, s)9,68 (1H, users)
7(CDCl3) to 1.42 (3H, t, J=7.2 Hz), of 3.54 (3H, s),3,62 (2H, m), Android 4.04 (2H, t, J=4,9 Hz)to 4.41 (2H, q, J=7.2 Hz), 5,10 (2H, s), with 5.22 (1H, user. C)5,31 (2H, s), 6.90 to-7,10 (2H, m), 7,14 (1H, DD, J=8,5, 1.9 Hz), 7,20-7,40 (6H, m), 7,68 (1H, d, J=8.5 Hz), 7,73 (1H, s), to 7.99 (1H, d, J=8,5 Hz)

[Table 5]
Approx. No.(Rest.)1H-NMRδppm:
8(DMSO-d6) 3,30-3,50 (2H, m), 3.95 to a 4.1 (2H, m), free 5.01 (2H, s), 6,95-of 7.55 (10H, m), of 7.64 (1H, d, J=8.6 Hz), 8,01 (1H, d, J=8.5 Hz), 8,53 (1H, s)
9(DMSO-d6) 3,10-3,50 (2H, m), 4,10-4,30 (2H, m), 7,05-to 7.35 (4H, m), of 7.70 (1H, d, J=8.6 Hz), 7.95 is is 8.25 (3H, m), to 8.57 (1H, s)
10(CDCl3) to 1.42 (3H, t, J=7,1 Hz), 3,10 (2H, t, J=5,1 Hz)to 3.99 (2H, t, J=5,1 Hz), 4,42 (2H, q, J=7,1 Hz), 5,32 (2H, s), 7,02 (1H, DD, J=8,7 Hz, 2.2 Hz), 7,05 (1H, d, J=2.2 Hz), 7,16 (1H, DD, J=8,3 Hz, 1.9 Hz), was 7.36 (1H, d, J=1.9 Hz), 7,69 (1H, d, J=8.7 Hz), 7,73 (1H, s), 7,98 (1H, d, J=8,3 Hz)
11(CDCl3) to 1.42 (3H, t, J=7,1 Hz), a 2.01 (3H, s), 3,55 (3H, s), 3,60 of 3.75 (2H, m), 3,68 (2H, q, J=5.8 Hz), a 4.03 (2H, t, J=5.0 Hz), 4,42 (2H, q, J=7,1 Hz), 5,32 (2H, s), of 5.92 (1H, users), 7,00 (1H, DD, J=8,5 and 2.2 Hz), 7,03 (1H, d, J=2.2 Hz), to 7.15 (1H, DD, J=8,3, 2,1 Hz), 7,35 (1H, d, J=2.1 Hz), of 7.70 (1H, d, J=8.5 Hz), 7,74 (1H, s), to 7.99 (1H, d, J=8,3 Hz)
12(DMSO-d6) of 1.81 (3H, s), 3,30-3,50 (2H, m), 3.95 to-4,10 (2H, m), 6,95-to 7.35 (4H, m), 7,60 to 7.7 (1H, m), 7.95 is to 8.2 (2H, m), 8,53 (1H, s)
13(DMSO-d6) of 1.36 (3H, t, J=7,1 Hz), 4,37 (2H, q, J=7,1 Hz), 7,55 (1H, DD, J=8,9 Hz, 1.8 Hz), 7,66 (1H, d, J=8,9 Hz), 7,80-of 7.90 (2H, m), of 7.96 (1H, d, J=1,8 Hz), 8,15-of 8.25 (2H, m), 8,77 (1H, s)

[Table 6]
Approx. No.Struct.(Rest.)1H-NMRδppm:
14(DMSO-d6) of 1.35 (3H, t, J=7.0 Hz), 3,82 (3H, s), 4,37 (2H, q, J=7.0 Hz), 7,05 (2H, d, J=8.5 Hz), to 7.68 (1H, DD, J=9,3 Hz, 1.6 Hz), 7,71 (2H, d, J=8.5 Hz), 7,76 (1H, d, J=8.5 Hz), 7,87 (2H, d, J=8.5 Hz), 7,92 (1H, d, J=1.6 Hz), 8,19 (2H, d, J=8.5 Hz), a total of 8.74 (1H, s)
15(DMSO-d6) 3,82 (3H, s), 7,05 (2H, d, J=8,9 Hz), to 7.67-7,72 (3H, m), of 7.75 (1H, d, J=8,9 Hz), to 7.84 (2H, d, J=8,4 Hz), to $ 7.91 (1H, d, J=1.5 Hz), 8,17 (2H, d, J=8,9 Hz), 8,73 (1H, s), and 13.3 (1H, users)
16(DMSO-d6) of 1.26 (3H, t, J=7.2 Hz), of 1.35 (3H, t, J=7.2 Hz), 4,20 (2H, q, J=7.2 Hz), 4,37 (2H, q, J=7.2 Hz), 6,74 (1H, d, J=16.2 Hz), of 7.70 (1H, d, J=8.5 Hz), 7,80-of 7.90 (4H, m), 8,15-of 8.25 (3H, m), 8,77 (1H,),
17 (DMSO-d6) of 6.61 (1H, d, J=16.1 Hz), 7,69 (1H, d, J=8,9 Hz), 7,76-of 7.82 (5H, m), 8,10 (1H, s), 8,16 (2H, d, J=8.5 Hz), a total of 8.74 (1H, s)
18(DMSO-d6) of 1.36 (3H, t, J=7,1 Hz), 4,37 (2H, q, J=7,1 Hz), are 5.36 (2H, s), 7,00 (1H, d, J=7.9 Hz), 7,20 is 7.50 (5H, m), 7,55-the 7.65 (2H, m), 7,75-of 7.90 (2H, m), 8,10-of 8.25 (2H, m), at 8.60 (1H, s)
19(DMSO-d6) lower than the 5.37 (2H, s), 6,95-7,10 (1H, m), 7,20 is 7.5 (5H, m), 7,55-of 7.70 (2H, m), 7,80 (2H, d, J=8.1 Hz), 8,16 (2H, d, J=8.1 Hz), 8,61 (1H, s), 13,10-13,40 (1H, users)
20(DMSO-d6) of 1.37 (3H, t, J=7,1 Hz), 4,39 (2H, q, J=7,1H), of 7.90-of 8.00 (2H, m), 8,03 (1H, m), 8,20-8,30 (3H, m), 8,43 (1H, d, J=2.0 Hz), the remaining 9.08 (1H, s)

[Table 7]
Approx. No.Struct.(Rest.)1H-NMRδppm:
21(DMSO-d6) of 1.36 (3H, t, J=7,1 Hz), 4,37 (2H, q, J=7,1 Hz), 5,32 (2H, users), 6,72 (1H, DD, J=8,5 Hz, 1.8 Hz), PC 6.82 (1H, d, J=1,8 Hz), 7,39 (1H, d, J=8.5 Hz), 7,76 (2H, d, J=8.6 Hz), 8,16 (2H, d, J=8.6 Hz), 8,29 (1H, s)
22 (DMSO-d6) of 1.36 (3H, t, J=7,1 Hz), of 2.97 (3H, s), to 4.38 (2H, q, J=7,1 Hz), 7,28 (1H, DD, J=8.6 Hz, 1.9 Hz), 7,56 (1H, d, J=1.9 Hz), of 7.75 (1H, d, J=8.6 Hz), 7,80-of 7.90 (2H, m), 8,15-of 8.25 (2H, m), 9,82 (1H, s)
23(DMSO-d6) of 2.97 (3H, s), 7,00-a 7.85 (5H, m), 8,00 is 8.25 (2H, m), 9,00 to-10.0 (1H, s), 8,65 (1H, s), 13,0-13,5 (1H, users)
24(CDCl3) of 1.44 (3H, t, J=7,1 Hz), of 4.44 (2H, q, J=7,1 Hz), 5,16 (2H, s), was 7.08 (1H, DD, J=9.1 Hz, 2.5 Hz), 7,30-the 7.65 (9H, m), 7,79 (1H, s), 8,20 to 8.3 (2H, m)
25(DMSO-d6) of 1.35 (3H, t, J=7,1 Hz), 4,37 (2H, q, J=7,1 Hz), make 6.90 (1H, DD, J=8,9 Hz, 2.3 Hz), 7,01 (1H, d, J=2.3 Hz), 7,54 (1H, d, J=8,9 Hz), 7,75-a 7.85 (2H, m), 8,10-of 8.25 (2H, m), 8,56 (1H, s), of 9.55 (1H, users)
26(CDCl3) was 1.43 (3H, t, J=7.2 Hz), of 4.44 (2H, q, J=7.2 Hz), 5,32 (2H, s), 6.90 to-7,40 (6H, m), 7,46 (1H, d, J=8,9 Hz), 7,56 (2H, d, J=8.5 Hz), 7,79 (1H, s), 8,24 (2H, d, J=8,5 Hz)
27(DMSO-d6) 5,42 (2H, s), 6,95 was 7.45 (4H, m), 7,50-a 7.85 (4H, m), 8,10-to 8.20 (2H, m)8,64 (1H, s), and 13.2 (1H, s)

[Table 8]
Approx. No.Struct.(Rest.)1H-NMRδppm:
28(CDCl3) of 1.44 (3H, t, J=7.2 Hz), of 4.45 (2H, q, J=7.2 Hz), 5,43 (2H, s), 7,30-the 7.65 (8H, m), to $ 7.91 (1H, s), 8,11 (1H, d, J=8,8 Hz), of 8.28 (2H, d, J=8.5 Hz), 8,61 (1H, s)
29(DMSO-d6) 7,65-8,50 (7H, m), 8,82 (1H, s), 13,1 (2H, m)
30(DMSO-d6) of 1.36 (3H, t, J=7,1 Hz), to 4.38 (2H, t, J=7,1 Hz), of 7.75 (1H, d, J=8,8 Hz), 7,87 (2H, d, J=8,4 Hz), 7.95 is-with 8.05 (1H, m), to 8.20 (2H, d, J=8,4 Hz), 8,25-8,35 (1H, m), 8,81 (1H, s)
31(CDCl3) of 1.44 (3H, t, J=7.2 Hz), 1.77 in (1H, t, J=5.5 Hz), of 4.44 (2H, q, J=7.2 Hz), a 4.86 (2H, d, J=5.5 Hz), 7,41 (1H, DD, J=8,5, 1.3 Hz), 7,50-the 7.65 (3H, m), 7,80-of 7.90 (2H, m), compared to 8.26 (2H, d, J=8,5 Hz)
32(DMSO-d6) with 4.65 (2H, s), 5,20-of 5.40 (1H, m), 7,30-of 7.90 (5H, m), 8,00 to 8.3 (2H, m), 8,66 (1H, s), and 13.2 (1H, users)
33(DMSO-d6) of 1.36 (3H, t, J=7.2 Hz), 2,8 -3,15 (6H, m)to 4.38 (2H, q, J=7.2 Hz), 7,46 (1H, DD, J=8,5, and 1.6 Hz), 7,70-a 7.85 (2H, m), 7,87 (2H, d, J=8,8 Hz), to 8.20 (2H, d, J=8,8 Hz), 8,80 (1H, s)
34(DMSO-d6) of 3.00 (6H, users), was 7.45 (1H, DD, J=8.7 Hz, 1.5 Hz), 7,73 (1H, d, J=8.7 Hz), 7,75-a 7.85 (2H, d, J=8.5 Hz), 8,77 (1H, s)

[Table 9]
Approx. No.Struct.(Rest.)1H-NMRδppm:
35(DMSO-d6) 6,72 (1H, d, J=3.1 Hz), 6,97 (1H, users), 7,40 was 7.45 (1H, m), 7,46-7,52 (1H, m), to 7.77 (1H, d, J=8.1 Hz), to 7.84 (1H, d, J=8.1 Hz), 8,69 (1H, s)
36(DMSO-d6) of 1.34 (3H, t, J=7,1 Hz), 4,37 (2H, q, J=7,1 Hz), 7,30-the 7.65 (3H, m), 7,70-a 7.85 (2H, m), of 7.90-to 8.20 (3H, m), 8,69 (1H, s)
37(DMSO-d6) 7,35 is 7.50 (2H, m), 7,55-the 7.65 (1H, m), 7,70-a 7.85 (2H, m), of 7.90-8,00 (1H, m), 8,05-of 8.15 (2H, m), 8,69 (1H, s)
38(DMSO-d6) of 1.38 (3H, t, J=7,1 Hz), 4,43 (2H, q, J=7,1 Hz), 7,30-of 7.55 (2H, m), 7,70-7,80 (1H, m), 7,89 (1H, DD, J=5,1 Hz, 1.3 Hz, of 8.25 (1H, s), 8,43 (1H, d, J=8.5 Hz), 8,80-of 8.90 (1H, m), 9,10 (1H, s)
39(DMSO-d6) 7,30-of 7.95 (4H, m), 8,23 (1H, s), to 8.41 (1H, d, J=8.1 Hz), 8,83 (1H, d, J=5,1 Hz), the remaining 9.08 (1H, s)of 13.5-14.5 (1H, users)
40(DMSO-d6) 3,91 (3H, s), 7,42 (2H, m), 7,79-7,80 (2H, m), 8,12-8,19 (2H, m), 8,43 (1H, d, J=1.9 Hz), the rate of 8.75 (1H, s)
41(DMSO-d6) 7,42-7,46 (2H, m), 7,76 (2H, m), 8,10-to 8.12 (2H, m), at 8.36 (1H, d, J=1.4 Hz), the rate of 8.75 (1H, s)
42(DMSO-d6) 6,70 (1H, DD, J=6,5, and 2.3 Hz), 7,00 (1H, d, J=2.0 Hz), 7,40-7,47 (2H, m), 7,72 (1H, d, J=7.8 Hz), 7,76 (1H, d, J=6.8 Hz), 7,95 (1H, d, J=8.6 Hz), 8,48 (1H, s)

[Table 10]
Approx. No.Struct.(Rest.)1H-NMRδppm:
43(DMSO-d6) to 2.29 (3H, s), 7,30-a 7.85 (6H, m)to 8.14 (1H, d, 8.0 Hz), 8,69 (1H, s)
44 (DMSO-d6) of 1.37 (3H, t, J=7,1 Hz), and 4.40 (2H, q, J=7,1 Hz), 7,40-of 7.55 (2H, m), 7,70-7,80 (1H, m), 8,03 (1H, d, J=8,8 Hz), 8,45 at 8.60 (2H, m), 9,07 (1H, s), 9,10-to 9.15 (1H, m)
45(DMSO-d6) 7,35-of 7.60 (2H, m), 7,70-7,80 (1H, m), to 7.99 (1H, d, J=8.6 Hz), 8,48 (1H, DD, J=8.6 Hz, 2.3 Hz), 8,53 (1H, d, J=8,4 Hz), 9,03 (1H, s), 9,10-to 9.15 (1H, m)
46(DMSO-d6) of 1.33 (3H, t, J=7,1 Hz), 2,71 (3H, s)to 4.33 (2H, q, J=7,1 Hz), 7,40-the 7.65 (2H, m), 7,78 (1H, d, J=7.9 Hz), and 8.50 (1H, d, J=8.5 Hz), 8,97 (1H, s)
47(DMSO-d6) 2,69 (3H, s), 7,40-the 7.65 (2H, s), 7,78 (1H, d, J=8.0 Hz), 8,49 (1H, d, J=8,4 Hz), 8,96 (1H, s)13,59 (1H, users)
48(DMSO-d6) of 1.35 (3H, t, J=7,3 Hz), to 4.38 (2H, q, J=7,3 Hz), 7,38 (1H, t, J=7.4 Hz), 7,49 (2H, t, J=7,6 Hz), 7,72-7,80 (4H, m), 7,88 (2H, d, J=8.1 Hz), 7,98 (1H, d, J=1.2 Hz), to 8.20 (2H, d, J=8.1 Hz), 8,75 (1H, s)
49(DMSO-d6) of 1.35 (3H, t, J=7,1 Hz), 4,37 (2H, q, J=7,1 Hz), 7,38 (1H, t, J=6.8 Hz), 7,46 (2H, t, J=7.4 Hz), 7,70-7,73 (3H, m), 7,86 (2H, d, J=8,2 Hz), 7,92 (2H, d, J=8,2 Hz), to 8.20 (2H, d, J=8,2 Hz), a total of 8.74 (1H, s)

[Table 11]
Approx. No.Struct.(Rest.)1H-NMRδppm:
50(DMSO-d6) to 3.92 (3H, s), 7,35 is 7.50 (2H, m), 7,65-of 7.90 (3H, s), to 7.99 (1H, d, J=2.1 Hz), of 8.06 (1H, d, J=8,4 Hz), 8,73 (1H, s)
51(DMSO-d6) of 2.10 (3H, s)to 3.92 (3H, s), 7,14-7,16 (1H, m), 7,34-7,40 (2H, m), to 7.61 (1H, d, J=8.1 Hz), to 7.77-7,79 (1H, m), to 7.99 (1H, DD, J=8,1 Hz, 1.8 Hz), 8,11 (1H, d, J=1,8 Hz), 8,55 (1H, s)
52(DMSO-d6) of 3.94 (3H, s), 7,14-7,42 (3H, m), 7,78 (1H, m), to $ 7.91 (1H, t, J=8.1 Hz), 8,02-8,08 (2H, m), 8,65 (1H, s)
53(DMSO-d6) of 3.33 (3H, s), 7,40-7,47 (2H, m), 7,71 (1H, DD, J=8,5 Hz, 2.0 Hz), to 7.77-7,79 (2H, m), 7,81 (1H, DD, J=8,5 Hz, 2.0 Hz), 8,11 (1H, t, J=8,2 Hz), 8,73 (1H, s)
54(DMSO-d6) a 3.83 (3H, s), 3,93 (3H, s), 7,33 (1H, DD, J=8,5 Hz, 1.6 Hz), 7,39-7,44 (3H, m), 7,76 for 7.78 (2H, m), 7,88 (1H, d, J=8.1 Hz), 8,71 (1H, s)
55(DMSO-d6) of 1.34 (3H, t, J=7,1 G is), of 2.33 (3H, s), 4,36 (2H, q, J=7,1 Hz), of 5.26 (2H, s), 7,29 (1H, s), 7,34 (1H, t, J=7,3 Hz), 7,42 (2H, t, J=7,3 Hz), 7,51 (2H, d, J=7,3 Hz), 7,55 (1H, s), 7,81 (2H, d, J=8,3 Hz), 8,17 (2H, d, J=8,3 Hz), 8,55 (1H, s)
56(CDCl3) of 1.44 (3H, t, J=7,1 Hz), 3,48 (3H, s), 3.75 to of 3.85 (2H, m), 4,15-of 4.25 (2H, m), of 4.44 (2H, q, J=7,1 Hz), 7,06 (1H, DD, J=9,0 Hz, 2.4 Hz), 7,24 (1H, d, J=2.4 Hz), was 7.45 (1H, d, J=9.0 Hz), 7,50-the 7.65 (2H, m), 7,78 (1H, s), 8,20 to 8.3 (2H, m)

[Table 12]
Approx. No.Struct.(Rest.)1H-NMRδppm:
57(CDCl3) of 1.44 (3H, t, J=7,1 Hz), 4,35-4,50 (6H, m), 6,95-7,05 (4H, m), 7,25 to 7.4 (3H, m), 7,46 (1H, d, J=9.0 Hz), 7,05-of 7.60 (2H, m), 7,79 (1H, s), 8,20-8,30 (2H, m)
58(CDCl3) of 1.44 (3H, t, J=7,1 Hz), 3,85 (3H, s), of 4.44 (2H, q, J=7,1 Hz), and 4.75 (2H, s), 7,10 (1H, d, J=9,1, 2,5 Hz), 7,18 (1H, d, J=2.5 Hz), of 7.48 (1H, d, J=9.1 Hz), 7,56 (2H, d, J=8.5 Hz), 7,81 (1H, s), of 8.25 (2H, d, J=8,5 Hz)
59(CDCl3) of 1.44 (3H, t, J=7.2 Hz), to 2.13 (3H, s), 4,20-4,55 (6H, m),? 7.04 baby mortality (1H, DD, J=9,1, 2.4 Hz), 7,24 (1H, d, J=2,4 Hz), 47 (1H, d, J=9.1 Hz), 7,56 (2H, d, J=8.5 Hz), 7,80 (1H, s), of 8.25 (2H, d, J=8,5 Hz)
60(CDCl3) of 1.44 (3H, t, J=7.0 Hz), of 2.08 (3H, s), 2,15 was 2.25 (2H, m), is 4.15 (2H, t, J=6,1 Hz), 4,30 (2H, t, J=6,1 Hz), of 4.44 (2H, q, J=7.0 Hz), of 6.99 (1H, DD, J=8,9, and 2.4 Hz), 7,15-7,30 (1H, m), 7,45 (1H, d, J=8,9 Hz), 7,56 (2H, d, J=8,2 Hz), 7,79 (1H, s), of 8.25 (2H, d, J=8,2 Hz)
61(DMSO-d6) of 1.15 (3H, t, J=7.0 Hz), of 1.36 (3H, t, J=7,1 Hz), 3,53 (2H, q, J=7.0 Hz), 3,60-,90 (2H, m), 4,10-4,30 (2H, m), 4,37 (2H, q, J=7,1 Hz), 6,95-to 7.15 (1H, m), 7.23 percent (1H, s), 7,50-of 7.70 (1H, m), 7,70-7,95 (2H, m), 8,05-8,30 (2H, m), 8,63 (1H, s)
62(DMSO-d6) of 1.36 (3H, t, J=7.0 Hz), 3,70-are 3.90 (2H, m), 4,20 is 4.35 (2H, m), 4,37 (2H, q, J=7.0 Hz), 4,58 (2H, s), 7,05 (1H, DD, J=9,1, 2.3 Hz), 7,15 was 7.45 (6H, m), a 7.62 (1H, d, J=9.1 Hz), 7,82 (2H, d, J=8,5 Hz), 8,17 (2H, d, J=8.5 Hz), 8,63 (1H, s)

[Table 13]
Approx. No.Struct.(Rest.)1H-NMRδppm:
63(DMSO-d6) of 1.36 (3H, t, J=7,1 Hz), 3,30 (3H, s), 3,60-3,70 (2H, m), 4,10-4,20 (2H, m), to 4.38 (2H, q, J=7,1 Hz),? 7.04 baby mortality (1H, DD, J=8,7 Hz, 2.0 Hz, 7,16 (1H, d, J=2.0 Hz), to 7.64 (1H, d, J=8.7 Hz), to 7.84 (2H, d, J=7.8 Hz), 8,17 (2H, d, J=7.8 Hz), 8,56 (1H, s)
64(DMSO-d6) of 1.34 (3H, t, J=7,1 Hz), 2,02 (3H, s), 4,20-of 4.25 (2H, m), 4,30-and 4.40 (4H, m), 7,05 (1H, DD, J=8.7 Hz and 2.1 Hz), 7,16 (1H, d, J=2.1 Hz), the 7.65 (1H, d, J=8.7 Hz), 7,80-of 7.90 (2H, m), 8,15-to 8.20 (2H, m), to 8.57 (1H, s)
65(CDCl3) of 1.44 (3H, t, J=7,1 Hz), is 3.08 (3H, s), of 4.44 (2H, q, J=7,1 Hz), at 5.27 (2H, s), 7,10 (1H, DD, J=8,9, and 2.3 Hz), 7,29 (1H, d, J=2.3 Hz), 7,49 (1H, d, J=8,9 Hz), 7,56 (2H, d, J=8.5 Hz), of 7.70 (2H, d, J=8.0 Hz), 7,81 (1H, s), to 7.99 (2H, d, J=8.0 Hz), compared to 8.26 (2H, d, J=8,5 Hz)
66(DMSO-d6) of 1.37 (3H, t, J=7,1 Hz), 3,86 (3H, s), 4,37 (2H, q, J=7,1 Hz), of 6.96 (1H, d, J=7,2 Hz), 7,29-the 7.43 (3H, m), 7,72-7,79 (2H, m), 7,88 (2H, d, J=8,2 Hz), 8,00 (1H, s), to 8.20 (2H, d, J=7.9 Hz), 8,75-8,77 (1H, m)
67(DMSO-d6) of 1.38 (3H, t, J=7.2 Hz), with 3.79 (3H, s), to 4.38 (2H, q, J=7.2 Hz), was 7.08 (1H, t, J=7.5 Hz), to 7.15 (1H, d, J=8,8 Hz), 7,37-rate of 7.54 (3H, m), 7,73 (1H, d, J=8,8 Hz), to 7.77 (1H, d, J=1.3 Hz), 7,88 (2H, d, J=8,4 Hz), 8,19 (2H, d, J=8,4 Hz), a total of 8.74 (1H, s)
68(DMSO-d6) of 1.35 (3H, t, J=7.0 Hz), 4,37 (2H, q, J=7.0 Hz), 7,15-7,29 (1H, m), EUR 7.57 (1H, d, J=5.0 Hz), 7,63 (1H, d, J3,5 Hz), 7,70 to 7.75 (2H, m), 7,86 (2H, d, J=8,3 Hz), 7.95 is-8,00 (1H, m), 8,19 (2H, d, J=8,3 Hz), a total of 8.74 (1H, s)

[Table 14]
Approx. No.Struct.(Rest.)1H-NMRδppm:
69(DMSO-d6) of 1.37 (3H, t, J=7,3 Hz), to 4.38 (2H, q, J=7,3 Hz), 7,80-of 7.95 (6H, m), 8,15-of 8.25 (3H, m), 8,60-to 8.70 (2H, m), 8,80 (1H, s)
70(DMSO-d6) of 1.35 (3H, t, J=7,1 Hz), 2,95 (6H, s), 4,37 (2H, q, J=7,1 Hz), 6,83 (2H, d, J=8.6 Hz), 7,55 to 7.75 (3H, m), 7,72 (1H, d, J=8,8 Hz), 7,80-of 7.90 (3H, m), 8,19 (2H, d, J=8,2 Hz), to 8.70 (1H, s)
71(DMSO-d6) of 1.35 (3H, t, J=7,1 Hz), 2.63 in (3H, s), to 4.38 (2H, q, J=7,1 Hz), 7,80-a 7.85 (2H, m), a 7.85-of 8.00 (4H, m), 8,00-8,15 (3H, m), 8,15-of 8.25 (2H, m), 8,78 (1H, s)
72(DMSO-d6) of 1.35 (3H, t, J=7.2 Hz), with 3.27 (3H, s), to 4.38 (2H, q, J=7.2 Hz), 7,80-a 7.85 (2H, m), 7,88 (2H, d, J=8.6 Hz), 8,02 (2H, d, J=8.6 Hz), 8,08 (2H, d, J=8.6 Hz), 8,10-of 8.15 (1H, m), to 8.20 (2H, d, J=8.6 Hz), 8,80 (1H, s)
73
74(DMSO-d6) of 1.35 (3H, t, J=7.2 Hz), 4,37 (2H, q, J=7.2 Hz), is 5.18 (2H, s), 7,14 (2H, d, J=8,3 Hz), 7,35-of 7.55 (5H, m), 7,65-7,80 (4H, m), a 7.85-of 7.95 (3H, m), 8,19 (2H, d, J=7,7 Hz), a total of 8.74 (1H, s)

[Table 15]
Approx. No.Struct.(Rest.)1H-NMRδppm:
75(DMSO-d6) of 1.37 (3H, t, J=7.2 Hz), 4,37 (2H, q, J=7.2 Hz), 6,85-of 6.90 (2H, m), 7,60-of 7.70 (1H, m), 7,70-7,80 (2H, m), a 7.85-of 7.95 (3H, m), 8,19 (2H, d, J=8,3 Hz), 8,72 (1H, s)
76(DMSO-d6) of 1.35 (3H, t, J=7.2 Hz), 3,01 (3H, s), 4,37 (2H, q, J=7.2 Hz), 7,30 (2H, d, J=8.0 Hz), 7,65-7,80 (4H, m), a 7.85-of 7.90 (2H, m), 7,95 (1H, d, J=1,8 Hz), 8,15-of 8.25 (2H, m), a total of 8.74 (1H, s)
77(CDCl3) of 1.44 (3H, t, J=7.0 Hz), of 4.45 (2H, q, J=7.0 Hz), 4,71 (2H, d, J=5.7 Hz), 6,53 (1H, users), 7,25-of 7.70 (8H, m), a 7.85-of 8.00 (2H, m), 8,21 (1H, s), of 8.28 (2H, d, J=8,5 Hz)
78 (CDCl3) of 1.44 (3H, t, J=7.2 Hz), 2,80-3,20 (3H, m), of 4.44 (2H, q, J=7.2 Hz), 4,50-of 4.90 (2H, m), 7,10-of 7.70 (9H, m), 7,80-8,10 (2H, m), of 8.27 (2H, d, J=8,2 Hz)
79(CDCl3) of 1.44 (3H, t, J=7.2 Hz), 3.43 points (3H, s), 3,62 (2H, t, J=5.0 Hz), 3,65 of 3.75 (2H, m), of 4.45 (2H, q, J=7.2 Hz), 6,62 (1H, users), 7,50-the 7.65 (3H, m), a 7.85-of 7.95 (2H, m), 8,20 is 8.25 (1H, m), of 8.28 (2H, d, J=8,5 Hz)

[Table 16]
Approx. No.Struct.(Rest.)1H-NMRδppm:
80(CDCl3) of 1.44 (3H, t, J=7,1 Hz), 3.00 and-3,90 (10H, m), of 4.45 (2H, q, J=7,1 Hz), of 7.48 (1H, DD, J=8,5, and 1.6 Hz), 7,50-the 7.65 (3H, m), 7,80-with 8.05 (2H, m), of 8.27 (2H, d, J=8,5 Hz)
81(CDCl3) of 1.44 (3H, t, J=7.2 Hz), 3,20-4,15 (8H, m), of 4.45 (2H, q, J=7.2 Hz), 7,47 (1H, DD, J=8,5, and 1.6 Hz), 7,50-the 7.65 (3H, m), a 7.85-of 7.95 (2H, m), of 8.28 (2H, d, J=8,8 Hz)
82(CDCl3) of 1.44 (3H, t, J=7,1 Hz), of 4.44 (2H, q, J=7,1 Hz)to 5.17 (2H, s), 7,07 (1, DD, J=9,0, 2,5 Hz), 7,20 (1H, DD, J=47, 1.3 Hz), 7,25 was 7.45 (3H, m), 7,46 (1H, d, J=9.0 Hz), 7,56 (2H, d, J=8.7 Hz), 7,79 (1H, s), of 8.25 (2H, d, J=8.7 Hz)
83(CDCl3) of 1.44 (3H, t, J=7,1 Hz), 1,95 is 2.10 (2H, m), of 2.28 (6H, s), 2.49 USD (2H, t, J=7,3 Hz), 4,05-4,20 (2H, m), of 4.44 (2H, q, J=7,1 Hz), 7,00 (1H, DD, J=9,1, 2.3 Hz), 7,24 (1H, d, J=2.3 Hz), 7,44 (1H, d, J=9.1 Hz), 7,56 (2H, d, J=8.7 Hz), 7,78 (1H, s), 8,24 (2H, d, J=8.7 Hz)
84(CDCl3) of 1.40-1.50 (12H, m), 1,95 is 2.10 (2H, m), 3,30 is-3.45 (2H, m), 4,05-4,00 (2H, m), of 4.44 (2H, q, J=7.2 Hz), of 4.77 (1H, users), 7,00 (1H, DD, J=8,9, and 2.3 Hz), 7,22 (1H, d, J=2.3 Hz), was 7.45 (1H, d, J=8,9 Hz), 7,56 (2H, d, J=8.5 Hz), 7,79 (1H, s), of 8.25 (2H, d, J=8,5 Hz)
85(DMSO-d6) of 1.37 (3H, t, J=7,1 Hz), 4,39 (2H, q, J=7,1 Hz), are 5.36 (2H, s), 7,05 (1H, d, J=8.0 Hz), 7,25 was 7.45 (4H, m), 7,50-the 7.65 (2H, m), 8,02 (1H, d, J=8.6 Hz), and 8.1 (1H, d, J=8.6 Hz), 8,5 (1H, DD, J=8.6 Hz that 2.4 Hz), of 8.95 (1H, s), 9,12 (1H, m)

[Table 17]
Note no.Struct.(Rest.)1H-NMRδppm:
86(DMSO-d) 1,30-1,45 (3H, m), 2,47 (3H, s), 4,30-4,45 (2H, m), and 7.3 (1H, d, J=8.7 Hz), 7,53 (1H, s), of 8.00 (1H, d, J=8.7 Hz), 8,44 (1H, d, J=8.6 Hz), 8,45-8,55 (1H, m), and 9.0 (1H, s), 9,05 is 9.15 (1H, m)
87(DMSO-d6) of 1.36 (3H, t, J=7,1 Hz), of 2.97 (3H, s), 4,37 (2H, q, J=7,1 Hz), 7,20-7,40 (1H, m), to 7.59 (1H, d, J=2.0 Hz), of 7.70 (1H, d, J=9.0 Hz), 7,75-of 7.90 (2H, m), 8,10-of 8.25 (2H, m), to 8.70 (1H, s), 9,79 (1H, users)
88(DMSO-d6) of 1.35 (3H, t, J=7,1 Hz)to 2.94 (3H, s), 4,37 (2H, q, J=7,1 Hz), 5,19 (2H, s), 7,05-8,25 (7H, m), 8,73 (1H, s)
89(DMSO-d6) of 1.42 (3H, t, J=7,1 Hz), 3,55 (3H, s), and 4.40 (2H, q, J=7,1 Hz), 5,31 (2H, s), 7,19 (1H, DD, J=8,3 Hz, 2 Hz), 7,25-the 7.65 (4H, m), 7,80-with 8.05 (3H, m)
90(DMSO-d6) 2,47 (3H, s), 3,44 (3H, s), 3,86 (3H, s)5,38 (2H, s), 7,20-7,30 (1H, m), 7,35-of 7.70 (4H, m), of 7.90 (1H, d, J=8,4 Hz), to 8.62 (1H, s)
91(DMSO-d6) of 2.44 (3H, s), 3,44 (3H, s), 3,86 (3H, s), of 5.39 (2H, s), 7,20-7,30 (1H, m), 7,39 (1H, DD, J=8,3 Hz, 2.0 Hz), to 7.50 (1H, d, J=2.0 Hz), 7,52 (1H, s), the 7.65 (1H, d, J=8,2 Hz), of 7.90 (1H, d, J=8,4 Hz), 8,59 (1H, s)
92 (DMSO-d6) of 1.33 (3H, t, J=7,1 Hz), 3,44 (3H, s), 4,32 (2H, q, J=7,1 Hz), 5,38 (2H, s), 7,20-the 7.65 (4H, m), 7,73 (1H, DD, J=9,0 Hz, 4,1 Hz), 7,88 (1H, d, J=8,3 Hz), a total of 8.74 (1H, s)

[Table 18]
Approx. No.Struct.(Rest.)1H-NMRδppm:
93(DMSO-d6) of 1.33 (3H, t, J=7,1 Hz), 3,44 (3H, s), 4,32 (2H, q, J=7,1 Hz), of 5.39 (2H, s), 7,20-the 7.65 (4H, m), 7,75-a 7.85 (1H, m), 7,88 (1H, d, J=8,4 Hz), and 8.7 (1H, s)
94(DMSO-d6) of 1.33 (3H, t, J=7,1 Hz), 3,44 (3H, s), 4,32 (2H, q, J=7,1 Hz), 5,38 (2H, s), 7,41 (1H, DD, J=8,3 Hz, 2 Hz), to 7.50 (1H, d, J=2.0 Hz), 7,80-of 7.95 (3H, m), 8,79 (1H, s)
95(DMSO-d6) of 3.43 (3H, s), 3,85 (3H, s), of 5.39 (2H, s), 6,10 (2H, s), 7,21 (1H, s), 7.23 percent (1H, s), 7,30 is 7.50 (2H, m), a 7.85-of 7.95 (1H, m), to 8.45 (1H, s)
96(DMSO-d6) of 1.33 (3H, t, J=7,1 Hz), 3,44 (3H, s)to 4.33 (2H, q, J=7,1 Hz), lower than the 5.37 (2H, s), 7,40-7,50 (1H, m), 7,55-of 7.60 (1H, m), 7,65-7,80 (1H, m), to $ 7.91 (1H, d, J=8,3 Hz), 7.95 is to 8.1 (2H, m), of 8.92 (1H, s)
97 (DMSO-d6) of 1.32 (3H, t, J=7,1 Hz), 3,44 (3H, s), 3,86 (3H, s), 4,32 (2H, q, J=7,1 Hz), 5,38 (2H, s), 7,03 (1H, DD, J=9.1 Hz, 2.4 Hz), 7,21 (1H, d, J=2.4 Hz), 7,30-of 7.55 (2H, m), 7,63 (1H, d, J=9.1 Hz), 7,87 (1H, d, J=8,2 Hz), to 8.62 (1H, s)
98(DMSO-d6) of 1.32 (3H, t, J=7,1 Hz), 3,44 (3H, s), 4,32 (2H, q, J=7,1 Hz), 5,38 (2H, s), and 7.4 (1H, DD, J=8,3 Hz, 2.1 Hz), 7,44 (1H, DD, J=8,9 Hz, 2.0 Hz), and 7.5 (1H, d, J=2.1 Hz), 7,73 (1H, d, J=8,9 Hz), 7,83 (1H, d, J=2 Hz), 7,88 (1H, d, J=8,3 Hz), 8,76 (1H, s)

[Table 19]
Approx. No.Struct.(Rest.)1H-NMRδppm:
99(DMSO-d6) of 1.32 (3H, t, J=7,1 Hz), of 3.46 (3H, s), 4,32 (2H, q, J=7,1 Hz), of 5.40 (2H, s), 7,35-of 7.55 (5H, m), 7,70-a 7.85 (4H, m), of 7.90 (1H, d, J=8,3 Hz), 7,98 (1H, s), 8,72 (1H, s)
100(DMSO-d6) of 1.32 (3H, t, J=7,1 Hz), of 3.45 (3H, s), 4,32 (2H, q, J=7,1 Hz), of 5.40 (2H, s), 7,35 is 7.50 (4H, m), a 7.62 (1H, d, J=2.0 Hz), 7,70 to 7.75 (3H, m), a 7.85 (1H, d, J=8,4 Hz), of 7.90-of 7.95 (2H, m), 8,72 (1H, s)
101(DMSO-d6) of 1.41 (3H, t, J=7.2 Hz), 3,55 (3H, s)to 4.41 (2H, the, J=7,2 Hz), further 5.15 (2H, s), 5,31 (2H, s), was 7.08 (1H, DD, J=9.1 Hz, 2.4 Hz), 7,16 (1H, DD, J=8,3 Hz, 2.0 Hz), 7,30-of 7.55 (8H, m), 7,78 (1H, s), of 7.97 (1H, d, J=8,3 Hz)
102(DMSO-d6) of 1.34 (3H, t, J=7,1 Hz), 3,44 (3H, s), or 4.31 (2H, q, J=7,1 Hz), and 5.30-of 5.40 (4H, m), of 6.99 (1H, d, J=7.5 Hz), 7,25 is 7.50 (7H, m), to 7.59 (2H, d, J=7,6 Hz), 7,86 (1H, d, J=8,4 Hz), 8,58 (1H, s)
103(DMSO-d6) of 1.33 (3H, t, J=7,1 Hz), 3,44 (3H, s)to 4.33 (2H, q, J=7,1 Hz), lower than the 5.37 (2H, s), 7,41 (1H, DD, J=8,3 Hz, 2.0 Hz), 7,52 (1H, d, J=2.0 Hz), 7,79 (1H, DD, J=8.7 Hz, 1.6 Hz), 7,80-7,87 (1H, m), 7,89 (1H, d, J=8,3 Hz), 8,35 an 8.4 (1H, m), 8,88 (1H, s)
104(DMSO-d6) of 1.33 (3H, t, J=7,1 Hz), 3,44 (3H, s)to 4.33 (2H, q, J=7,1 Hz), of 5.39 (2H, s), 7,40-of 7.60 (2H, m), 7,70-8,1 (3H, m), 8,24 (1H, s), to 8.94 (1H, s)

[Table 20]
Approx. No.Struct.(Rest.)1H-NMRδppm:
105(DMSO-d6) of 1.33 (3H, t, J=7,1 Hz), 3,44 (3H, s)to 4.33 (2H, q, J=7,1 Hz), lower than the 5.37 (2H, s), 7,41 (1H, DD, J=8,3 Hz, 2.0 Hz), 7,50-of 7.60 (2H, m), a 7.85-of 7.95 (2H, m), 8,0-with 8.05 (1H, m), to 8.94 (1H, s)
106(DMSO-d6) of 1.33 (3H, t, J=7,1 Hz), 3,44 (3H, s), 4,32 (2H, q, J=7,1 Hz), 5,38 (2H, s), 7,15-of 7.60 (5H, m), 7,88 (1H, d, J=8,3 Hz), 8,73 (1H, s)
107(DMSO-d6) of 1.20 and 1.35 (9H, m), 3.00 and-3,10 (1H, m), of 3.45 (3H, s), 4,32 (2H, q, J=7,1 Hz), of 5.39 (2H, s), 6,80-of 7.95 (6H, m), to 8.62 (1H, s)
108(DMSO-d6) of 1.32 (3H, t, J=7,1 Hz), 3,44 (3H, s), or 4.31 (2H, q, J=7,1 Hz), 6.89 in (1H, DD, J=9,0 Hz, 2.4 Hz), 7,01 (1H, d, J=2.4 Hz),
of 7.36 (1H, DD, J=8,3 Hz, 2.0 Hz), was 7.45 (1H, d, J=2.0 Hz), 7,55 (1H, d, J=9.0 Hz), 7,86 (1H, d, J=8,3 Hz), 8,53 (1H, s), 9,54 (1H, users)
109(DMSO-d6) of 1.32 (3H, t, J=7,1 Hz), of 3.45 (3H, s), 4,32 (2H, q, J=7,1 Hz), 5,38 (2H, s)6,70 (1H, d, J=8.0 Hz), 7,07 (1H, d, J=8.0 Hz), 7.23 percent (1H, t, J=8.0 Hz), 7,40 (1H, DD, J=8,3 Hz, 2.0 Hz), 7,52 (1H, d, J=2.0 Hz), 7,89 (1H, d, J=8,3 Hz), 8,72 (1H, s), 9,82
(1H, s)
110(DMSO-d6) of 1.09 (6H, d, J=6,4 Hz)of 1.34 (3H, t, J=7,1 Hz), 2.00 in of 2.20 (1H, m), 3,44 (3H, s), 3,95 (2H, d, J=5.5 Hz), or 4.31 (2H, q, J=7,1 Hz), lower than the 5.37 (2H, s), 6,83 (1H, d,
J=7.4 Hz), 7,20-7,40 (3H, m), 7,46 (1H, s), 7,86 (1H, d, J=8,2 Hz), 8,53 (1H, s)

Table 21]
Approx. No.Struct.(Rest.)1H-NMRδppm:
111(DMSO-d6) of 1.01 (6H, d, J=6.6 Hz), 1,32 (3H, t, J=7,1 Hz), 2.00 in to 2.15 (1H, m), 3,44 (3H, s), 3,85 (2H, d, J=6.6 Hz), 4,32 (2H, q, J=7,1 Hz), 5,38 (2H, s), 7,30 (1H, DD, J=9.1 Hz, 2.4 Hz), 7,19 (1H, d, J=2,4 Hz), 7,37 (1H, DD, J=8,3 Hz, 2.0 Hz), 7,47 (1H, d, J=2.0 Hz), a 7.62 (1H, d, J=9.1 Hz), 7,87 (1H, d, J=8,3 Hz), 8,59 (1H, s)
112(DMSO-d6) 1,25-1,40 (9H, m), 3,44 (3H, s), 4,32 (2H, q, J=7,1 Hz), 4,65-4,80 (1H, m), 5,38 (2H, s), 7,00 (1H, DD, J=9,0 Hz, 2.3 Hz), 7,19 (1H, d, J=2.3 Hz), 7,37 (1H, DD, J=8,3 Hz, 2.0 Hz), 7,47 (1H, d, J=2,0 Hz), to 7.61 (1H, d, J=9.0 Hz), 7,87 (1H, d, J=8,3 Hz), 8,59 (1H, s)
113(DMSO-d6) of 1.32 (3H, t, J=7,1 Hz)to 2.06 (3H, s), 3,44 (3H, s), 4,25 is 4.45 (6H, m), 5,38 (2H, s), 7,05 (1H, DD, J=9.1 Hz, 2.4 Hz), 7,25 (1H, d, J=2.4 Hz), 7,38 (1H, DD, J=8,4 Hz, 2.0 Hz), 7,47 (1H, d, J=2.0 Hz), to 7.64 (1H, d, J=9.1 Hz), 7,87 (1H, d, J=8,4 Hz), 8,61 (1H, s)
114(DMSO-d6) of 1.32 (3H, t, J=7,1 Hz)to 3.33 (3H, s), 3,44 (3H, s), 3,65-3,8 (2H, m), 4,15-of 4.25 (2H, m), 4,32 (2H, q, J=7,1 Hz), 5,38 (2H, s), 6,95-7,10 (1H, m), 7,15-of 7.25 (1H, m), 7,30 is 7.5 (2H, m), 7,63 (1H, d, J=9.1 Hz), 7,87 (1H, d, J=8,2 Hz), at 8.60 (1H, s)
(CDCl3) of 1.41 (3H, t, J=7,1 Hz), 3,55 (3H, s), of 3.84 (3H, s)to 4.41 (2H, q, J=7,1 Hz), 4,74 (2H, s), and 5.30 (2H, s), 7,05-of 7.25 (3H, m), 7,33 (1H, d, J=1.9 Hz), 7,49 (1H, d, J=8,9 Hz), 7,79 (1H, s), of 7.97 (1H, d, J=8,2 Hz)
116(CDCl3) of 1.41 (3H, t, J=7,3 Hz)of 1.47 (3H, t, J=6.9 Hz), 3,55 (3H, s), of 4.13 (2H, q, J=6.9 Hz), to 4.41 (2H, q, J=7,3 Hz), 5,31 (2H, s), 7,00 (1H, DD, J=9,0, 2,5 Hz), 7,16 (1H, DD, J=8,4, and 2.1 Hz), 7,21 (1H, d, J=2,5 Hz), 7,34 (1H, d, J=2.1 Hz), 7,46 (1H, d, J=9.0 Hz), to 7.77 (1H, s), of 7.97 (1H, d, J=8,4 Hz)

[Table 22]
Approx. No.Struct.(Rest.)1H-NMRδppm:
117(CDCl3) to 1.42 (3H, t, J=7.2 Hz), of 3.45 (3H, s), 3,55 (3H, s), 3,70-of 3.85 (2H, m), 4,05-4,20 (2H, m)to 4.41 (2H, q, J=7.2 Hz), 5,31 (2H, s), 7,05 (1H, DD, J=8,8, 1.9 Hz), was 7.08 (1H, d, J=1.9 Hz), to 7.15 (1H, DD, J=8,3, 1,8 Hz), 7,35 (1H, d, J=1,8 Hz), to 7.68 (1H, d, J=8,8 Hz), 7,73 (1H, s), 7,98 (1H, d, J=8,3 Hz)
118(CDCl3) to 1.42 (3H, t, J=7,1 Hz), of 3.56 (3H, s), of 3.80 (3H, s), 4,42 (2H, q, J=7,1 Hz), of 4.66 (2H, s), 5,33 (2H, s), 7,06 (1H, DD, J=8,8, 2.2 Hz), was 7.08 (1H, d, J=2.2 Hz), 7,13 (1H, is d, J=8,3, 1.8 Hz), 7,35 (1H, d, J=1,8 Hz), 7,72 (1H, d, J=8,8 Hz), of 7.75 (1H, s), 7,98 (1H, d, J=8,3 Hz)
119(CDCl3) to 1.42 (3H, t, J=7,1 Hz), is 2.09 (3H, s), 3,55 (3H, s)to 4.17 (2H, t, J=4,7 Hz), 4,35-4,50 (4 H, m), 5,32 (2H, s), 6,95-7,10 (2H, m), to 7.15 (1H, DD, J=8,2, 1.3 Hz), 7,35 (1H, d, J=1.3 Hz), of 7.70 (1H, d, J=8,5 Hz), 7,74 (1H, s), 7,98 (1H, d, J=8,2 Hz)
120(CDCl3) of 1.23 (3H, t, J=7,0 Hz)of 1.42 (3H, t, J=7.2 Hz), of 3.56 (3H, s), of 3.60 (2H, q, J=7.0 Hz), 3.75 to of 3.85 (2H, m), 4,05-4,20 (2H, m)to 4.41 (2H, q, J=7.2 Hz), 5,31 (2H, s),? 7.04 baby mortality (1H, DD, J=8,8, 2,1 Hz), was 7.08 (1H, d, J=2.1 Hz), to 7.15 (1H, DD, J=8,3, 2.2 Hz), 7,35 (1H, d, J=2.2 Hz), to 7.68 (1H, d, J=8,8 Hz), 7,72 (1H, s), of 7.97 (1H, d, J=8,3 Hz)
121(CDCl3) was 1.04 (3H, t, J=7.4 Hz), of 1.42 (3H, t, J=7.0 Hz), 1.70 to 1,95 (2H, m), 3,55 (3H, s), 3,91 (2H, t, J=6.6 Hz), to 4.41 (2H, q, J=7.0 Hz), 5,31 (2H, s), 7,01 (1H, DD, J=8,5, 1.9 Hz), 7,03 (1H, d, J=1.9 Hz), 7,16 (1H, DD, J=8,4, 1.8 Hz), 7,37 (1H, d, J=1,8 Hz), to 7.67 (1H, d, J=8.5 Hz), 7,71 (1H, s), 7,98 (1H, d, J=8,4 Hz)

[Table 23]
Approx. No.Struct.(Rest.)1H-NMRδppm:
122 (CDCl3) and 0.98 (3H, t, J=7.4 Hz), of 1.42 (3H, t, J=7,1 Hz), 1,45-to 1.60 (2H, m), 1.70 to of 1.85 (2H, m), 3,55 (3H, s), of 3.95 (2H, t, J=6.5 Hz), to 4.41 (2H, q, J=7,1 Hz), 5,31 (2H, s) 6,95-7,10 (2H, m), 7,16 (1H, DD, J=8,1, 1,5 Hz), 7,37 (1H, d, J=1.5 Hz), to 7.67 (1H, d, J=8,8 Hz), 7,71 (1H, s), 7,98 (1H, d, J=8.1 Hz)
123(CDCl3) to 1.42 (3H, t, J=7.2 Hz), of 3.54 (3H, s), 4,25-and 4.40 (4H, m)to 4.41 (2H, q, J=7.2 Hz), 5,31 (2H, s), 6,85-7,05 (3H, m), 7,06 (1H, DD, J=8,8, 2,1 Hz), 7,12 (1H, d, J=2.1 Hz), to 7.15 (1H, DD, J=8,4, 1.9 Hz), 7,29 (2H,, t, J=8.0 Hz), 7,37 (1H, d, J=1.9 Hz), of 7.70 (1H, d, J=8,8 Hz), 7,74 (1H, s), 7,98 (1H, d, J=8,4 Hz)
124(DMSO-d6) 1,25-1,40 (6H, m), 3,44 (3H, s)4,06 (2H, q, J=7.0 Hz), 4,32 (2H, q, J=7,1 Hz), of 5.39 (2H, s), 7,00 (1H, DD, J=8,8 Hz, 2.1 Hz), 7,16 (1H, d, J=2.1 Hz), 7,39 (1H, DD, J=8,4 Hz, 2.0 Hz), 7,52 (1H, d, J=2.0 Hz), 7,63 (1H, d, J=8,8 Hz), 7,88 (1H, d,J=8,4 Hz), 8,53 (1H, s)
125(DMSO-d6) of 1.27 (6H, d, J=6.0 Hz), of 1.33 (3H, t, J=7,1 Hz), 3,44 (3H, s), 4,32 (2H, q, J=7,1 Hz), 4,55-of 4.75 (1H, m), 5,38 (2H, s), 6,95-7,05 (1H, m), 7,10-7,20 (1H, m), 7,30-7,40 (1H, m), 7,45-of 7.55 (1H, m), a 7.62 (1H, d, J=8,8 Hz), 7,89 (1H, d, J=8,3 Hz), charged 8.52 (1H, s)
126(DMSO-d6) of 1.31 (3H, t, J=7,1 Hz), 1,95-2,10 (5H, m), 3,44 (3H, s), 4,05-4,20 (4H, m), or 4.31 (2H, q, J=7,1 Hz), of 5.39 (2H, s), 7,01 (1H, DD, J=8.6 G is, and 2.1 Hz), 7,17 (1H, d, J=2.1 Hz), 7,38 (1H, DD, J=8.6 Hz, 1.9 Hz), 7,52 (1H, d, J=1.9 Hz), 7,63 (1H, d, J=8.6 Hz), 7,87 (1H, d, J=8.6 Hz), 8,53 (1H, s)

[Table 24]
Approx. No.Struct.(Rest.)1H-NMRδppm:
127(DMSO-d6) of 1.34 (3H, t, J=7.2 Hz), 1.60-to of 1.85 (4H, m), from 2.00 (3H, s), 3,44 (3H, s), 4,00-4,10 (4H, m), or 4.31 (2H, q, J=7.2 Hz), of 5.39 (2H, s), 7,00 (1H, DD, J=8.6 Hz, 1.8 Hz), 7,16 (1H, d, J=1,8 Hz), 7,38 (1H, DD, J=8.6 Hz, 1.8 Hz), 7,51 (1H, d, J=1,8 Hz), a 7.62 (1H, d, J=8.6 Hz), 7,87 (1H, d, J=8.6 Hz), charged 8.52 (1H, s)
128(DMSO-d6) of 1.34 (3H, t, J=7,1 Hz), 3.43 points (3H, s), or 4.31 (2H, q, J=7,1 Hz), to 5.21 (2H, s)5,38 (2H, s), 7,05-to 7.15 (1H, m), 7,25-of 7.70 (8H, m), 7,87 (1H, d, J=8.6 Hz), 8,55 (1H, s)
129(DMSO-d6) of 1.31 (3H, t, J=7,1 Hz), 3,44 (3H, s), 4,32 (2H, q, J=7,1 Hz), is 5.18 (2H, s)5,38 (2H, s), 7,11 (1H, DD, J=8.6 Hz, 1.8 Hz), 7,28 (1H, d, J=1,8 Hz), 7,33 (1H, DD, J=8.6 Hz, 1.8 Hz), 7,35-7,45 (3H, m), 7,49 (1H, d, J=1,8 Hz), 7,50-of 7.55 (1H, m), 7,66 (1H, d, J=8.6 Hz), 7,87 (1H, d, J=8.6 Hz), 8,54 (1H, s)
130(DMSO-d6) of 1.32 (3H, t,J=7,1 Hz), 3,44 (3H, s), 4,32 (2H, q, J=7,1 Hz), further 5.15 (2H, s)5,38 (2H, s), to 7.09 (1H, DD, J=8,7 Hz, 2.2 Hz), 7,28 (1H, d, J=2.2 Hz), 7,35 (1H, DD, J=8,3 Hz, 1.9 Hz), 7,40-to 7.50 (5H, m), the 7.65 (1H, d, J=8.7 Hz), 7,87 (1H, d, J=8,3 Hz), 8,54 (1H,s)
131(DMSO-d6) to 0.25-0.35 (2H, m), 0.50 to 0.60 (2H, m), 1,10-1,30 (1H, m)is 1.31 (3H, t, J=7,1 Hz), 3,44 (3H, s), a-3.84 (2H, d, J=7,6 Hz), or 4.31 (2H, q, J=7,1 Hz), 5,38 (2H, s), 7,01 (1H, DD, J=8,8 Hz, 1.8 Hz), 7,14 (1H, d, J=1,8 Hz), 7,37 (1H, DD, J=8.6 Hz, 1.8 Hz), 7,51 (1H, d, J=1,8 Hz), to 7.61 (1H, d, J=8.6 Hz), 7,87 (1H, d, J=8.6 Hz), 8,51 (1H, s)

[Table 25]
Approx. No.Struct.(Rest.)1H-NMRδppm:
132(DMSO-d6) of 1.31 (3H, t, J=7,1 Hz), 1,75-of 1.95 (4H, m), 2.00 in to 2.15 (2H, m), 2,65 is 2.80 (1H, m), of 3.45 (3H, s), of 3.97 (2H, d, J=6.8 Hz), or 4.31 (2H, d, J=6.8 Hz), of 5.40 (2H, s), 7,00 (1H, DD, J=8,3 Hz, 2.0 Hz), 7,17 (1H, d, J=2.0 Hz), 7,38 (1H, d, J=8,3 Hz), 7,53 (1H, d, J=2.0 Hz), to 7.61 (1H, d, J=8.6 Hz), 7,87 (1H, d, J=8.6 Hz), charged 8.52 (1H, s)
133(CDCl3) to 1.42 (3H, t, J=7,1 Hz), was 2.34 (6H, s), is 2.74 (2H, t, J=5.6 Hz), 3,55 (3H, s), of 4.05 (2H, t, J=5.6 Hz), 4,42 (2H, q, J=7,1 Hz), 5,32 (2H, s), 7,00-7,10 (2H, m), 7,16 (1H, DD, J=8,3, 2.0 Hz), was 7.36 (1H, d, J=2.0 Hz), to 7.68 (1H, d, J=8.7 Hz), 7,72 (1H,s), 7,98 (1H, d, J=8,3 Hz)
134(DMSO-d6) of 0.92 (6H, d, J=6.8 Hz), is 1.31 (3H, t, J=7.0 Hz), of 1.62 (2H, q, J=6.8 Hz), 1.70 to of 1.85 (1H, m), 3,44 (3H, s)to 4.01 (2H, t, J=6.6 Hz), or 4.31 (2H, q, J=7.0 Hz), of 5.39 (2H, s), 7,00 (1H, d, J=8,7 Hz, 2.2 Hz), 7,18 (1H, d, J=2.2 Hz), 7,38 (1H, DD, J=8,3 Hz, 1.9 Hz), 7,53 (1H, d, J=1.9 Hz), a 7.62 (1H, d, J=8.7 Hz), 7,87 (1H, d, J=8,3 Hz), 8,53 (1H, s)
135(CDCl3) to 1.42 (3H, t, J=7.2 Hz), 1,90-of 2.05 (2H, m), of 2.23 (6H, s), is 2.44 (2H, t, J=7,3 Hz), 3,55 (3H, s)to 4.01 (2H, t, J=6.5 Hz), to 4.41 (2H, q, J=7.2 Hz), 5,31 (2H, s), 7,00 (1H, DD, J=8,8, 2,1 Hz),? 7.04 baby mortality (1H, d, J=2.1 Hz), to 7.15 (1H, DD, J=8,4, and 2.1 Hz), was 7.36 (1H, d, J=2.1 Hz), to 7.67 (1H, d, J=8,8 Hz), 7,71 (1H, s), 7,98 (1H, d, J=8,4 Hz)
136(DMSO-d6) 1,35 of 1.50 (12H, m), 1,90-of 2.05 (2H, m), 3.25 to 3.40 in (2H, m), 3,55 (3H, s)to 4.01 (2H, t, J=6.0 Hz), to 4.41 (2H, q, J=7.2 Hz), to 4.73 (1H, users), 5,32 (2H, s), 7,00 (1H, DD, J=8,7, 2,1 Hz)? 7.04 baby mortality (1H, d, J=2.1 Hz) to 7.15 (1H, DD, J=8,3, 2.0 Hz) of 7.36 (1H, d, J=2.0 Hz) to 7.68 (1H, d, J=8.7 Hz) 7,72 (1H, s) 7,98 (1H, d, J=8,3 Hz)

[Table 26]
Approx. No.Struct.(Rest.)1H-NMRδppm:
137 (CDCl3) 1,30-of 1.55 (3H, m), 1,80-of 2.05 (2H, m), 2,80 was 3.05 (2H, m), 3,55 (3H, s), 3.95 to to 4.15 (2H, m), 4,30-4,50 (2H, m), 5,32 (2H, s), 6.90 to-to 7.25 (3H, m), 7,30 was 7.45 (1H, m), 7,60-7,80 (2H, m), of 7.90-8,10 (1H, m)
138(CDCl3) to 1.42 (3H, t, J=7,1 Hz), to 3.02 (3H, s), 3,50-the 3.65 (5H, m), 4,11 (2H, t, J=4.9 Hz), 4,42 (2H, q, J=7,1 Hz), of 4.77 (1H, users), 5,32 (2H, s), of 6.99 (1H, DD, J=8,7, and 2.1 Hz),? 7.04 baby mortality (1H, d, J=2.1 Hz), to 7.15 (1H, DD, J=to 8.3 and 2.1 Hz), 7,35 (1H, d, J=2.1 Hz), 7,71 (1H, d, J=8.7 Hz), of 7.75 (1H, s), to 7.99 (1H, d, J=8,3 Hz)
139(CDCl3) to 1.42 (3H, t, J=7.2 Hz), to 1.98 (3H, s), 2,00-2,10 (2H, m), of 3.46 (2H, q, J=6.6 Hz), 3,55 (3H, s), a 4.03 (2H, t, J=5.8 Hz), 4,42 (2H, q, J=7.2 Hz), 5,32 (2H, s), 5,74 (1H, users), of 6.99 (1H, DD, J=8,6, 2.0 Hz), 7,03 (1H, d, J=2.0 Hz), to 7.15 (1H, DD, J=8,2, 1.9 Hz), was 7.36 (1H, d, J=1.9 Hz), 7,69 (1H, d, J=8.6 Hz), 7,73 (1H, s), to 7.99 (1H, d, J=8,2 Hz)
140(CDCl3) to 1.42 (3H, t, J=7,1 Hz), 2,00 -2,15 (2H, m), 2,96 (3H, s), 3,39 (2H, q, J=6.3 Hz), 3,55 (3H, s), 4.09 to (2H, t, J=5.8 Hz), to 4.41 (2H, q, J=7,1 Hz)to 4.52 (1H, users), 5,32 (2H, s), of 6.99 (1H, DD, J=8,6, and 2.1 Hz),? 7.04 baby mortality (1H, d, J=2.1 Hz), 7,16 (1H, DD, J=8,2, 2,1 Hz), was 7.36 (1H, d, J=2.1 Hz), 7,69 (1H, d, J=8.6 Hz), 7,74 (1H, s), to 7.99 (1H, d, J=8,2 Hz)
141(DMSO-d6) lower than the 5.37 (2H, s), 7,05 (1H, d, J=7.9 Hz), 7,30 is 7.50 (5H,m), 8,45-8,55 (1H, m), 8,93 (1H, s), 9,05 is 9.15 (1H, m)

[Table 27]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
1427,35 is 7.50 (2H, m), 7,54 cent to 8.85 (3H, m), 7,94 (1H, d, J=2.2 Hz), of 8.04 (1H, d, J=8,3 Hz), 8,72 (1H, s), 13,50-14 (1H, users)
1432,47 (3H, s), 7,25-to 7.35 (1H, m), 7,54 (1H, s), to 8.45 (1H, d, J=8.6 Hz), 8,48 (1H, DD, J=8,6 Hz, 2.2 Hz), 9,01 (1H, s), which is 9.09 (1H, d, J=2.2 Hz), 13,00-14,00 (1H, users)
144of 3.33 (3H, s), 7,10-8,15 (8H, m), 13,30 (1H, users)
1457,35-7,45 (3H, m), 7,75-with 8.05 (4H, m), 8,55-8,65 (1H, m), 13,62(1H, users)
1467,40-7,46 (2H, m), 7,66-to 7.67 (1H, m), 7,76 for 7.78 (3H, m), 8,10 (1H, t, J=8,2 Hz), 8,72 (1H, s)
1472,47 (3H, s), 3,44 (3H, s), lower than the 5.37 (2H, s), 7,20-7,45 3H, m), 7,56 (1H, m), 7,60-the 7.65 (1H, m), 7,88 (1H, d, J=8,3 Hz)
148to 3.92 (3H, s), 7,25 is 7.50 (4H, m), 7,70-of 7.90 (3H, m), to 8.70 (1H, s), and 12.4 (1H, users)
149of 2.33 (3H, s), of 5.26 (2H, s), 7,25-of 7.60 (7H, m), 7,70-a 7.85 (2H, m), 8,10-of 8.25 (2H, m), 8,54 (1H,s), 13,25 (1H, users)

[Table 28]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
1507,30-7,95 (10H, m), 8,10-of 8.25 (2H, m), a total of 8.74 (1H, s), of 13.27 (1H, users)
1515,23 (2H, s), 7,11 (1H, DD, J=9.1 Hz, 2.4 Hz), 7,25-of 7.55 (5H, m), 7,63 (1H, d, 9.1 Hz), 7,75-of 7.90 (2H, m), 8,10 to 8.2 (2H, m), 8,63 (1H, s)
1526,85-7,10 (2H, m), 7,45-of 7.90 (3H, m), 8,10-of 8.25 (2H, m), 8,55 (1H, s), 9,45-to 9.70 (1H, users)
1533,65 of 3.75 (2H, m), 4,15-of 4.25 (2H, m),? 7.04 baby mortality (1H, DD, J=9.1 Hz, the 2.4 Hz), 7,22 (1H, d, J=2.3 Hz), a 7.62 (1H, d, J=9.1 Hz), 7,75-a 7.85 (2H, m), 8,10-to 8.20 (2H, m)8,64 (1H, s), 13,00-13,50 (1H, users)
1544,30-4,55 (4H, m), 6.90 to-7,05 (3H, m), 7,07 (1H, DD, J=9.1 Hz, 2.4 Hz), 7,25-7,40 (3H, m), 7,63 (1H, d, J=9.1 Hz), 7,75-a 7.85 (2H, m), 8,10-to 8.20 (2H, m), 8,65 (1H, s), 13,10-13,40 (1H, users)
1557,30-7,95 (10H, m), 8,10-of 8.25 (2H, m), a total of 8.74 (1H, s), 13,32 (1H, users)
1563,86 (3H, s), 6,85-8,25 (11H, m), a total of 8.74 (1H, s)

[Table 29]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
157with 3.79 (3H, s), 6.90 to-of 7.90 (9H, m), 8,10-of 8.25 (2H, m), 8,73 (1H, s)
1587,10-of 7.25 (1H, m), 7,50-8,25 (9H, m), 8,73 (1H, s), 13,24 (1H, users)
1597,75-8,45 (10H, m), 8,75-8,90 (3H, what), 13,34 (1H, users)
1604,45-4,6 (2H, m), 7,70-to 7.5 (5H, m), 7,65-with 8.05 (4H, m), 8,10-of 8.25 (2H, m), 8,35 to 8.5 (1H, m), 8,79 (1H, s), 9,15-9,3 (1H, m), and 13.3 (1H, users)
161only 2.91 (3H, users), 4,40-4,85 (2H, m), 7,00 and 7.6 (6H, m), 7,65 to 8.0 (4H, m), 8,05 to 8.3 (2H, m), 8,78 (1H, users), and 13.2 (1H, users)
1623,40 of 3.6 (4H, m), 7,70 to 8.0 (4H, m), 8,10-of 8.25 (2H, m), 8,30-to 8.45 (1H, m), 8,65 cent to 8.85 (2H, m), and 13.3 (1H, users)
163of 3.00 (3H, s), 7,40-of 8.00 (5H, m), 8,17 (2H, d, J=8,4 Hz), 8,77 (1H, s), and 13.2 (1H, users)

[Table 30]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
1643,00-4,0 (8H, m), 7,40-of 7.55 (1H, m), 7,60 to 8.0 (4H, m), 8,05-8,30 (2H, m), 8,70 cent to 8.85 (1H, m), and 13.3 (1H, users)
1652,96 (6H), 6,83 (2H, d, J=8.1 Hz), and 7.6 (2H, d, J=8.1 Hz), the 7.65 (1H, d, J=8.1 Hz), 7,73 (1H, d, J=8.1 Hz), 7,80-a 7.85 (3H, m), 8,17 (2H, d, J=8.1 Hz), to 8.70 (1H, s), and 13.2 (1H, users)
1662,63 (3H, s), 7,80-of 7.90 (4H, m), 7,95 (2H, d, J=8.5 Hz), of 8.06 (2H, d, J=8.5 Hz), 8,11 (1H, s), 8,18 (2H, d, J=8.5 Hz), 8,78 (1H, s)
167of 3.28 (3H, s), 7,80-a 7.85 (4H, m), 8,02 (2H, d, J=8.5 Hz), 8,08 (2H, d, J=8.5 Hz), 8,13 (1H, s), 8,17 (2H, d, J=8.7 Hz), 8,79 (1H, s)
168of 1.23 (3H, t, J=7,6 Hz)to 2.66 (2H, q, a 7.6 Hz), 7,25-7,40 (2H, m), the 7.65 to 8.25 (9H, m), 8,73 (1H, s), to 13.29 (1H, users)
169of 1.36 (3H, t, J=6.5 Hz), 4,08 (2H, q, J=6.5 Hz), 7,05-a 7.85 (8H, m), of 7.90-8,70 (4H, m), and 13.2 (1H, users)
170of 4.77 (2H, s), 6,95-of 7.25 (2H, m), 7,50-of 7.90 (3H, m), 8,00 is 8.25 (2H, m), 8,63 (1H, users), 12,50-14,0 (2H, m)

[Table 31]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
1713,70-3,8 (2H, m), 4.09 to (2H, t, J=4.9 Hz), 4.80 to of 4.95 (1H, m),? 7.04 baby mortality (1H, DD, J=9.1 Hz, 2.5 Hz), 7,21 (1H, d, J=2.5 Hz), to 7.61 (1H, d, J=9.1 Hz), 7,78 (2H, d, J=8,3 Hz), 8,15 (2H, d, J=8,3 Hz), to 8.62 (1H, s), 13,2 (1H, users)
1721,80-2,00 (2H, m), 3,50-3,70 (2H, m), 4,00-of 4.25 (2H, m), 4,40-4,7 (1H, m), 6,95-7,10 (1H, m), 7,15-of 7.25 (1H, m), 7,50-the 7.65 (1H, m), 7,70-a 7.85 (2H, m), 8,05 is 8.25 (2H, m), 8,61 (1H, s), 13,30 (1H, users)
173by 5.18 (2H, s), 7,00-7,95 (14H, m), 8,10-of 8.25 (2H, m), 8,71 (1H, s)
1741,05-1,25 (3H, m), 3.45 points-of 3.85 (4H, m), 4,10-of 4.25 (2H, m), 6,95-to 7.35 (2H, m), 7,50-of 7.95 (3H, m), 8,00-8,30 (2H, m), 8,50 is 8.75 (1H, m), and 13.2 (1H, users)
1753,70-of 3.95 (2H, m), 4,15-and 4.40 (2H, m), 4,58 (2H, s), 6,95 was 7.45 (7H, m), 7,50-of 7.90 (3H, m), 8,05 is 8.25 (2H, m), to 8.62 (1H, s), and 13.2 (1H, users)
176to 5.21 (2H, s), to 7.09 (1H, DD, J=8,8 Hz, 1.6 Hz), 7,22 (1H, d, J=4,8 Hz), 7,32 (1H, d, J=1.6 Hz), 7,50-of 7.70 (5H, m), 7,79 (1H, d, J=8,2 Hz), 8,15 (1H, d, J=8,2 Hz), 8,64 (1H, s), and 13.2 (1H, users)
177 2,10-of 2.25 (2H, m), of 2.81 (6H, s), 3.15 and is 3.40 (2H, m), 4,17 (2H, t, J=6,1 Hz),? 7.04 baby mortality (1H, DD, J=9.1 Hz, 2.4 Hz), 7,24 (1H, d, J=2.4 Hz), to 7.64 (1H, d, J=9.1 Hz), 7,75-a 7.85 (2H, m), 8,10-to 8.20 (2H, m), 8,65 (1H, s), 9,88 (1H, users), and 13.2 (1H, users)

[Table 32]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
178of 3.23 (3H, s)5,38 (2H, s), 7,00 was 7.45 (2H, m), 7,50 was 7.45 (2H, m), 7,50-8,40 (9H, m), 8,65 (1H, s), 13,20 (1H, users)
1797,00-to 7.15 (1H, m), 7,55-of 8.00 (7H, m), 8,10-of 8.25 (2H, m), 8,73 (1H, s), 10,32 (1H, s), to 13.29 (1H, users)
180to 1.38 (9H, s), 1,80-of 1.95 (2H, m), 3,05-3,20 (2H, m), 4,00-to 4.15 (2H, m), 6,85-7,10 (2H, m), 7,15-of 7.25 (1H, m), to 7.61 (1H, d, J=9,2 Hz), 7,79 (2H, d, J=8.0 Hz), 8,15 (2H, d, J=8.0 Hz), to 8.62 (1H, s), and 13.2 (1H, users)
1811,95-2,15 (2H, m), 2,90-3,10 (2H, m), 4,10-of 4.25 (2H, m), 6,95-7,10 (1H, m), 7,15-7,30 (1H, m), 7,63 (1H, d, J=9,2 Hz), 7,79 (2H, d, J=8.0 Hz), to 7.84 (2H, users), 8,16 (2H, d, J=8.0 Hz), 8,64 (1H, s), and 13.2 (1H, users)
1822,98 (3H, s), 7,03 (1H, DD, J=9,0 Hz, 1.9 Hz), to 7.59 (1H, d, J=1.9 Hz), of 7.70 (1H, d, J=9.0 Hz), 7,75-a 7.85 (2H, m), 8,10-to 8.20 (2H, m), 8,69 (1H, s), 9,78 (1H, s), 13,0-13,5 (1H, users)
1833,03 (3H, s), 7,32 (2H, d, J=8.1 Hz), 7,69 (1H, DD, J=7,3, 1.5 Hz), of 7.75 (2H, d, J=8.1 Hz), 7,78 (1H, s), 7,83 (2H, d, J=8.5 Hz), 7,95 (1H, d, J=2.0 Hz), 8,17 (2H, d, J=8,9 Hz), 8,72 (1H, s), and 13.2 (1H, users)
184to 4.62 (2H, d, J=5.3 Hz), 5,26 (1H, t, J=5.3 Hz), 7,25-a 7.85 (5H, m), 8,10-of 8.25 (2H, m)8,64 (1H, s), 13,25 (1H, users)

[Table 33]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
1853,30 (3H, s), 3,60-3,70 (2H, m), 4,10-4,20 (2H, m), 7,03 (1H, DD, J=8,7, 1.7 Hz), to 7.15 (1H, d, J=1.7 Hz), to 7.64 (1H, d, J=8.7 Hz), 7,80 (2H, d, J=8.7 Hz), 8,15 (2H, d, J=8.7 Hz), 8,55 (1H, s)
186the 3.65-of 3.80 (2H, m), a 4.03 (2H, t, J=5.0 Hz), 4.80 to of 4.95 (1H, m), 6,95-7,20 (2H, m), 7,60-of 7.90 (3H, m), 8,10-8,5 (2H, m), 8,55 (1H, s), 13,28 (1H, users)
1872,47 (3H, s), 2,68 (3H, s), 7,30 was 7.45 (2H, m), 7,55 (1H, s), with 8.33 (1H, d, J=8.6 Hz), 8,89 (1H, s), 13,62 (1H, users)
1887,20 is 7.50 (4H, m), 7,70-7,80 (2H, m), 8,01 (1H, d, J=8.5 Hz), 8,69 (1H, s)
189the 2.46 (3H, S), 7,15-to 7.35 (3H, m), 7,55 (1H, s), 7,63 (1H, d, J=8,4 Hz), of 7.90-8,10 (1H, m), 8,55-to 8.70 (1H, m)
1907,15 is 7.50 (3H, m), 7,35 is 7.50 (1H, m), 7,65 is 7.85 (2H, m), 8,01 (1H, d, J=8,3 Hz), 8,72 (1H, s)
1917,15-to 7.35 (3H, m), 7,58 (1H, DD, J=8,8 Hz, 2.5 Hz), 7,74 (1H, DD, J=8,8 Hz, 4.4 Hz), 8,01 (1H, d, J=8,4 Hz), a total of 8.74 (1H, s)

[Table 34]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
1927,20-to 7.35 (3H, m), 7,54 (1H, DD, J=9.9 Hz, 2.2 Hz), 7,79 1H, DD, J=8,8 Hz, 5.2 Hz), 8,01 (1H, d, J=8.7 Hz), to 8.70 (1H, s)
1937,20-to 7.35 (2H, m), 7,86 (1H, d, J=9.1 Hz), of 7.90 (1H, d, J=9.1 Hz), 8,01 (1H, d, J=8.7 Hz), 8,79 (1H, s)
1946,10 (2H, s), 7,15-of 7.25 (4H, m), of 7.90-with 8.05 (1H, m), to 8.45 (1H, s)
1957,10-to 7.35 (2H, m), the 7.65 to 7.75 (1H, m), 7,92 (1H, s), 7,95-8,10 (2H, m), 8,89 (1H, s)
1963,86 (3H, s), 7,03 (1H, DD, J=9,0 Hz, 2.5 Hz), 7,15-7,30 (3H, m), of 7.64 (1H, d, J=9.0 Hz), 8,00 (1H, d, J=8,3 Hz), at 8.60 (1H, s)
1977,15-to 7.35 (3H, m), 7,44 (1H, DD, J=9,0 Hz, 2.2 Hz), 7,73 (1H, d, J=9.0 Hz), 7,81 (1H, d, J=2.2 Hz), 8,01 (1H, d, J=8,4 Hz), the rate of 8.75 (1H, s)
1987,25-7,40 (3H, m), 7,50 (2H, t, J=7,6 Hz), 7,70-a 7.85 (4H, m), of 7.97 (1H, s), 8,01 (1H, d, J=9.8 Hz), 8,73 (1H, s)

[Table 35]
Approx. No.Struct. 1H-NMRδppm (DMSO-d6):
1997,25-of 7.55 (5H, m), 7,65-8,05 (6H, m), 8,72 (1H, s)
200with 5.22 (2H, s), 7,00-of 7.60 (9H, m), 7,63 (1H, d, J=9.0 Hz), of 7.96 (1H, 8,4 Hz), 8,59 (1H, s)
201make 6.90 (1H, DD, J=9,0 Hz, 2.3 Hz), 7,00 (1H, d, J=2.1 Hz), 7,15-7,30 (2H, m), 7,56 (1H, d, 9.0 Hz), 7,98 (1H, d, J=8.5 Hz), 8,55 (1H, s), 9,58 (1H, users)
202to 5.35 (2H, s)6,70-6,85 (2H, m)6,94 (1H, d, J=8,3 Hz), 7,20 (1H, d, J=8,8 Hz), 7,26-7,34 (2H, m), 7,35-7,45 (2H, m), to 7.59 (2H, d, J=8,3 Hz), 7,81 (1H, d, J=7.9 Hz), of 8.47 (1H, s)
2036,69 (1H, d, J=7,6 Hz), 7,11 (1H, d, J=8,8 Hz), 7,15-of 7.25 (3H, m), 7,98 (1H, d, J=8,8 Hz), 8,49 (1H, s), and 10.3 (1H, s)
204of 1.09 (6H, d, J=6.3 Hz), 2,10-to 2.15 (1H, m), 3,90 (2H, d, J=5.8 Hz), 6,83 (1H, d, J=8.1 Hz), 7,19-7,29 (4H, m), 7,98 (1H, d, J=8.5 Hz), 8,53 (1H, s)
205a 1.01 (6H, d, J=6.6 Hz), a 2.0 to 2.15 (1H, m), 3,85 (2H, d, J=6.4 Hz), 7,03 (1H, DD, J=9.1 Hz, 2.4 Hz), 7,15-7,30 (3H, m), 7,63 (1H, d, J=9.1 Hz), to 7.99 (1H, d, J=8,3 Hz), 8,59 (1H, s)

[Table 36]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
2067,20-to 7.35 (2H, m), 7,75-of 7.90 (2H, m), 8,02 (1H, d, J=8,4 Hz), at 8.36 (1H, s), 8,88 (1H, s)
2077,25-7,40 (2H, m), 7,70-7,80 (1H, m), of 7.96 (1H, d, J=8,3 Hz), 8,02 (1H, d, J=8,3 Hz), of 8.25 (1H, s), to 8.94 (1H, s)
208of 7.25 (1H, DD, J=8,5 Hz, 2.1 Hz), 7,31 (1H, d, J=2.1 Hz), 7,50-of 7.60 (1H, m), a 7.85-8,00 (1H, m), 7,95-8,10 (2H, m), to 8.94 (1H, s)
209of 1.30 (6H, d, J=6.0 Hz), 4,65-4,80 (1H, m), 7,00 (1H, DD, J=9.1 Hz, 2.3 Hz), 7,10-7,30 (3H, m), to 7.61 (1H, d, J=9.1 Hz), to 7.99 (1H, d, J=8,2 Hz), 8,59 (1H, s)
210of 3.75 (2H, t, J=4,8 Hz), 4.09 to (2H, d, J=4,8 Hz), 4,50-a 5.25 (1H, usher.), ? 7.04 baby mortality (1H, DD, J=9.1 Hz and 2.2 Hz), 7,15-7,30 (3H, m), 7,63 (1H, d, J=9.1 Hz), to 7.99 (1H, d, J=8,2 Hz), at 8.60(1H, C)
211to 3.34 (3H, s), 3,65 of 3.75 (2H, m), 4,15-of 4.25 (2H, m),? 7.04 baby mortality (1H, DD, J=9,2 Hz, 2.5 Hz), 7,15-7,30 (3H, m), 7,63 (1H, d, J=9,2 Hz), to 7.99 (1H, d, J=8,2 Hz), at 8.60 (1H, s)
2126,87 (1H, DD, J=6,8, and 2.1 Hz), 7,05 (1H, d, J=2.1 Hz), 7.18 in-7,21 (2H, m), 7,52 (1H, d, J=8,4 Hz), 7,98 (1H, d, J=8.1 Hz), 8,44 (1H, s), 9,67 (1H, s)

[Table 37]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
2134,80 (2H, s), 6.90 to was 7.45 (4H, m), 7,50 to 7.75 (1H, m), 7,80-8,10 (1H, m), to 8.62 (1H, s)13,0 (1H, users)
2141,20-of 1.55 (3H, m), 4,00-of 4.25 (2H, m), 6,80-7,40 (4H, m), 7,50-of 7.70 (1H, m), 7,80-8,10 (1H, m), 8,40-to 8.70 (1H, m)
2153,30 (3H, s), 3,60 of 3.75 (2H, m), 4,00-of 4.25 (2H, m), 6.90 to to 7.4 (4H, m), 7,50 to 7.7 (1H, m), of 7.90-8,10 (1H, m), charged 8.52 (1H, s)
216 of 4.75 (2H, s), 6,95-7,40 (4H, m), the 7.65 (1H, d, J=8,3 Hz), of 7.90-with 8.05 (1H, m), 8,54 (1H, s)13,0 (1H, users)
2173,81 (3H, s), 7,03 (1H, DD, J=8,8 Hz, 2.1 Hz), 7,05-to 7.35 (3H, m), of 7.64 (1H, d, J=8,8 Hz), 8,01 (1H, d, J=8,9 Hz), charged 8.52 (1H, s)
218the 3.65-of 3.80 (2H, m), 3.95 to to 4.15 (2H, m), 6,95-7,40 (4H, m), 7,63 (1H, d, J=8,2 Hz), of 7.90-8,10 (1H, m), charged 8.52 (1H, s)

[Table 38]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
219a 1.11 (3H, t, J=7.0 Hz), 3,5 (2H, q, J=7.0 Hz), 3,60-3,8 (2H, m), 4,05-4,20 (2H, m), 6,95-to 7.35 (4H, m), 7,63 (1H, d, J=8.7 Hz), of 7.90-8,10 (1H, m), charged 8.52 (1H, s)
220and 0.98 (3H, t, J=7,3 Hz), 1,65-of 1.85 (2H, m), of 3.96 (2H, t, J=6.5 Hz), 7,03 (1H, DD, J=8,7 Hz, 2.0 Hz), 7,10-to 7.15 (1H, m), 7,20-to 7.35 (2H, m), a 7.62 (1H, d, J=8.7 Hz), of 7.90-8,10 (1H, m), 8,51 (1H, s)
221of 0.93 (3H, t, J=7.4 Hz), 1,35-of 1.55 (2H, m), 1,60-1,8 (2H, m), 4,0 (2H, t, J=6.4 Hz), 7,02 (1H, DD, J=8,8 Hz to 2.0 Hz), 7,13 (1H, d, J=2.0 Hz), 7,15-7,30 (2H, m), a 7.62 (1H, d, J=8,8 Hz), 7.95 is-with 8.05 (1H, m), 8,51 (1H, s)
2224,25 is 4.45 (4H, m), 6,80-7,05 (3H, m), was 7.08 (1H, DD, J=8,8 Hz, 2.0 Hz), 7,15 was 7.45 (5H, m), the 7.65 (1H, d, J=8,8 Hz), and 8.0 (1H, d, J=9.1 Hz), 8,53 (1H, s)
223of 1.34 (3H, t, J=7.0 Hz), 4,06 (2H, q, J=7.0 Hz), 7,02 (1H, DD, J=8.7 Hz and 2.1 Hz), 7,13 (1H, d, J=2.1 Hz), 7,20-7,30 (2H, m), a 7.62 (1H, d, J=8.7 Hz), 8,00 (1H, d, J=9.0 Hz), 8,51 (1H, s)
224of 1.30 (6H, d, J=6.0 Hz), 4,55-4,70 (1H, m), 7,02 (1H, DD, J=8.7 Hz and 2.1 Hz), 7,12 (1H, d, J=2.1 Hz), 7,20-7,30 (2H, m), a 7.62 (1H, d, J=8.7 Hz), 7.95 is-with 8.05 (1H, m), 8,51 (1H, s)

[Table 39]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
2257,10 and 7.5 (4H, m), 7,54 (1H, d, J=8,4 Hz), 8,01 (1H, d, J=8,4 Hz), a total of 8.74 (1H, s)
2262,05-of 2.20 (2H, m), and 2.79 (3H, s), 2,80 (3H, s), 3.00 and-3,5 (2H, m), 4,10 (2H, t, J=6.0 Hz), 7,05 (1H, DD, J=8.7 Hz, 20 Hz), 7,16 (1H, d, J=2.0 Hz), 7,20-7,30 (2H, m), to 7.67 (1H, d, J=8.7 Hz), and 8.0 (1H, d, J=8,3 Hz), 8,53 (1H, s), 9,67 (1H, users)
2272,00-2,10 (2H, m), 2,90 was 3.05 (2H, m), of 4.12 (2H, t, J=6,1 Hz), 7,06 (1H, DD, J=8.7 Hz and 2.1 Hz), 7,17 (1H, d, J=2.1 Hz), 7,20-7,30 (2H, m), 7,66 (1H, d, J=8.7 Hz), of 7.90-8,10 (4H, m), 8,54 (1H, s)
2281,85-of 1.88 (2H, m), 3,54 is 3.57 (2H, m), 4,05-4,08 (2H, m), 7,02 (1H, DD, J=6,2, 1.9 Hz), 7,14 (1H, s), 7.23 percent-of 7.25 (2H, m), a 7.62 (1H, d, J=8.6 Hz), 8,00 (1H, d, J=8.6 Hz), 8,51 (1H, s)
2291.55V is 1.58 (2H, m), 1,74 is 1.75 (2H, m), 3.43 points-of 3.46 (2H, m), 4,01-was 4.02 (2H, m), 7,01 (1H, d, J=8,9 Hz), 7,13 (1H, s), 7,25-7,27 (2H, m), to 7.61 (1H, d, J=8,9 Hz), to 7.99 (1H, d, J=8.6 Hz), 8,51 (1H, s)
2305,23 (2H, s), 7,11 (1H, DD, J=6,2, 2.3 Hz), 7,21-of 7.23 (2H, m), 7,27 (1H, d, J=2.1 Hz), 7,38-7,40 (2H, m), 7,51-7,52 (1H, m), to 7.61-7,63 (1H, m), 7,66 (1H, d, J=8,4 Hz), to 7.99 (1H, d, J=8.1 Hz), 8,55 (1H, s)

[Table 40]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
231 5,19 (2H, s), 7,11 (1H, DD, J=6,6 and 2.2 Hz), 7,17 (1H, DD, J=6,1, 2,1 Hz), 7,22 (1H, d, J=1.9 Hz), 7,25 (1H, d, J=1.9 Hz), 7,39-7,44 (3H, m), 7,54 (1H, s), the 7.65 (1H, d, J=8.7 Hz), to 7.99 (1H, d, J=8.7 Hz), 8,54 (1H, s)
232of 5.17 (2H, s), 7,01 (1H, DD, J=6,7, and 2.1 Hz), 7,19-7,22 (2H, m), 7,25 (1H, d, J=2.1 Hz), 7,45-7,51 (m, 4H), to 7.64 (1H, d, J=8,8 Hz), to 7.99 (1H, d, J=8,3 Hz), 8,54 (1H, s)
2330,32 is 0.33 (2H, m), 0.56 to 0,57 (2H, m), 1,19-of 1.26 (1H, m), 3,85 (2H, d, J=6.3 Hz), 7,02 (1H, DD, J=6,6, and 2.1 Hz), 7,11 (1H, d, J=1.9 Hz), 7.23 percent-of 7.25 (2H, m), to 7.61 (1H, d, J=8.7 Hz), to 7.99 (1H, d, J=8,9 Hz), 8,51 (1H, s)
2341,83-1,90 (4H, m), 2.05 is-2,07 (2H, m), 2,69 is 2.75 (1H, m), 3,98 (2H, d, J=6.2 Hz), 7,01 (1H, DD, J=6,5, 2.2 Hz), 7,12 (1H, d, J=2.2 Hz), 7,21-7,22 (2H, m), to 7.61 (1H, d, J=8.7 Hz), to 7.99 (1H, d, J=9.0 Hz), 8,51 (1H, s)
235of 2,75 2,95 (6H, m), 3,40-of 3.60 (2H, m), 4,30-4,45 (2H, m), 7,05-to 7.35 (4H, m), and 7.7 (1H, d, J=8.7 Hz), 8,01 (1H, d, J=8,3 Hz), 8,58 (1H, s), 9,86 (1H, users)
236to 0.92 (6H, d, J=6.6 Hz), 1,55-1,70 (2H, m), 1,75-of 1.81 (1H, m), a 4.03 (2H, t, J=6.6 Hz), 7,02 (1H, DD, J=6,4, 2.0 Hz), 7,14 (1H, d, J=2.0 Hz), 7.23 percent-of 7.25 (2H, m), to 7.61 (1H, d, J=8,8 Hz), to 7.99 (1H, is, J=8,8 Hz), 8,51 (1H, s)
237to 1.24 (6H, d, J=7,2 Hz), 3,02-of 3.07 (1H, m), 7,22-7,24 (2H, m), 7,31 (1H, d, J=8,3 Hz), 7,52 (1H, s), to 7.67 (1H, d, J=7,6 Hz), 8,00 (1H, d, J=8,3 Hz), at 8.60 (1H, s)

[Table 41]
Approx. No.Struct.1H-NMRδppm (DMSO-d6):
238to 2.94 (3H, s), 3,20-3,50 (2H, m), 4,00-to 4.15 (2H, m), 6.90 to-7,40 (5H, m), the 7.65 (1H, d, J=8.5 Hz), 8,00 (1H, d, J=7.8 Hz), 8,53 (1H, s)
239of 1.78 (3H, s), 1,80-of 1.95 (2H, m), 3,05-3,30 (2H, m), 3.95 to to 4.15 (2H, m), 6,95-to 7.35 (4H, m), 7,60-of 7.70 (1H, m), 7,80-8,10 (2H, m), charged 8.52 (1H, s)
2401,85 is 2.00 (2H, m)to 2.29 (3H, s), 3,05-3,20 (2H, m), 4,07 (2H, t, J=6.0 Hz), 7,00-7,10 (2H, m), to 7.15 (1H, DD, J=1.9 Hz), 7,20-to 7.35 (2H, m), of 7.64 (1H, d, J=8,8 Hz), 8,01 (1H, d, J=9.1 Hz), 8,53 (1H, s)
2415,43 (2H, s), 7,16 (1H, s), 7,25-of 7.55 (5H, m), 7,80-to 8.20 (4H, m), 8,71 (1H, s), 8,88 (1H, s)

[Table 42]
Ref. Approx. No.Struct.(Rest.)1H-NMRδppm:
24(CDCl3) 2,22 (3H, s), 3,91 (3H, s), 6,85-to 7.15 (3H, m)
25(CDCl3) of 2.33 (3H, s), 5,15 (1H, s), 7,06 (1H, d, J=11.3 Hz), 7,49 (1H, d, J=6.2 Hz)
26(CDCl3) of 2.28 (3H, s)to 3.89 (3H, s), 7,00-7,10 (1H, m), 7,46 (1H, d, J=6.3 Hz)
27(CDCl3) 2,30-to 2.40 (3H, m), 3,86 (3H, s), of 3.95 (3H, s), to 5.58 (1H, s), 7,45 (1H, s), of 7.69 (1H, s)
28(CDCl3) 2,32 (3H, s), 3,93 (3H, s), of 4.13 (2H, s), 7,40 was 7.45 (1H, m), 7,66 (1H, s)
29(DMSO-d6) 2,19 (3H, s), of 3.78 (3H, s), 6,20-6,30 (1H, m), 6,85 (1H, s), 7,05-to 7.15 (1H, m), 7,24 (1H, s), and 10.8 (1H, users)
30 (DMSO-d6) 2,20-of 2.30 (3H, m), 3,82 (3H, s), 6,98 (1H, s), 7,37 (1H, s), of 8.04 (1H, d, J=2,8 Hz), 11,9 (1H, users)
31(DMSO-d6) 2,98 (3H, s), 3,93 (3H, s), to 7.15 (1H, d, J=8,9 Hz), 8,05-to 8.20 (2H, m)
32(DMSO-d6) 2,22 (3H, s), of 3.95 (3H, s), 4,30 (2H, s), 7,27 (1H, s), of 8.09 (1H, s)
33(DMSO-d6) 2,22 (3H, s), 3,76 (3H, s), 6,20-6,40 (1H, m), 6.90 to-to 7.25 (3H, m), is 10.75 (1H, users)

[Table 43]
Ref. Approx. No.Struct.(Rest.)1H-NMRδppm:
34(DMSO-d6) of 2.24 (3H, s), of 3.84 (3H, s), 7,03 (1H, s), 7,30 (1H, s), of 8.06 (1H, s), 11,92 (1H, users)
35(CDCl3) to 5.17 (2H, s), 6,35-6,55 (1H, m), 7,05-the 7.65 (8H, m), of 8.04 (1H, users)
36 (CDCl3) of 5.24 (2H, s), 7,25-the 7.65 (6H, m), 7,70-a 7.85 (1H, m), of 7.90-with 8.05 (1H, m), 8,59 (1H, users), 10,02 (1H, s)
37(CDCl3) to 5.21 (2H, s), 7,20 to 7.75 (8H, m), and 8.50 (1H, users)
38(CDCl3) 2,25-2,60 (3H, m), 5,10-of 5.45 (2H, m), of 5.68 (1H, s), 7,20-of 7.70 (6H, m), 7,80-8,10 (1H, m)
39(CDCl3) 2,20-to 2.55 (3H, m), 6,35-6,55 (1H, m), 6.90 to-7,50 (3H, m), of 8.04 (1H, users)
40(CDCl3) 2,30-of 2.50 (3H, m), 7,00-7,20 (1H, m), 7,70-of 7.90 (1H, m), 8,05 is 8.25 (1H, m)8,64 (1H, users), 10,02 (1H, s)
41(CDCl3) 2,30-of 2.50 (3H, m), 7,00-7,20 (1H, m), 7,45-7,80 (2H, m), 8,51 (1H, users)
42(CDCl3) of 3.94 (3H, s), 5,19 (2H, s), 6,35-6,50 (1H, m), 6,80-to 6.95 (1H, m), 7,00-7,20 (2H, m), 7,25-of 7.55 (5H, m), 7,92 (1H, users)

[Table 44]
Ref. Approx. No. Struct.(Rest.)1H-NMRδppm:
43(CDCl3) 3,74 (3H, s), 5,02 (2H, s), 7,15-the 7.65 (6H, m), 7,79 (1H, s), 8,25-and 8.50 (1H, m), 9,86 (1H, s)
44(CDCl3) of 3.84 (3H, s), 5,12 (2H, s), 7,00-7,20 (2H, m), 7,25-of 7.55 (5H, m), of 7.90-of 8.15 (1H, m)
45(DMSO-d6) 3,81 (3H, s), 6.30-in-6,45 (1H, m), 7,10-to 7.35 (3H, m), 10,96 (1H, users)
46(DMSO-d6) to 2.29 (3H, s)to 2.35 (3H, s), 3,62 (3H, s), 6,20-6,40 (1H, m), 6.90 to-7,30 (2H, m), 10,80 (1H, users)
47(DMSO-d6) of 3.85 (3H, s), 6,40-6,60 (1H, m), 7,25-of 7.70 (3H, m), 11,30 (1H, users)
48(DMSO-d6) 2,95 was 3.05 (6H, m), 7,26 (1H, d, J=9.5 Hz), 8,20-to 8.40 (2H, m)
49(DMSO-d6) of 3.00-3.15 in (6H, m), 4,36 (2H, s), 7,32 (1H, s), 8,39 (1H, s)
50 (DMSO-d6) 2,63 (6H, s), 6,40-6,60 (1H, m), 7,50-7,80 (3H, m), is 11.39 (1H, users)
51(DMS0-d6) 1,25-1,45 (3H, m)to 2.67 (6H, s), 4,20 is 4.45 (2H, m), 6.75 in-6,90 (1H, m), 7,25-8,25 (7H, m)

[Table 45]
Ref. Approx. No.Struct.(Rest.)1H-NMRδppm:
52(DMSO-d6) of 1.35 (3H, t, J=7,1 Hz), 2,70 (6H, s), 4,37 (2H, q, J=7,1 Hz), 7,79 (1H, s), a 7.85-8,30 (4H, m), at 8.36 (1H, s)8,89 (1H, s), of 10.09 (1H, s)
53(DMSO-d6) of 2.24 (3H, s)to 2.29 (3H, s), 6,15-7,20 (3H, m), 7,40 (1H, s), of 10.58 (1H, users)

[Table 46]
Ref. Approx. No.Struct.Ref. Approx. No.Struct.
5455
5657
5859
6061
6263

[Table 47]
Approx. No.Struct.(Rest.)1H-NMRδppm:
242(DMSO-d6) of 1.36 (3H, t, J=7,1 Hz), and 2.27 (3H, s), 3,90 (3H, s), 4,36 (2H, q, J=7,1 Hz), 7,17 (1H, s), 7,52 (1H, s), 7,75 is 8.25 (4H, m), 8,55 (1H, s)
243(CDCl3) of 1.44 (3H, t, J=7,1 Hz), of 4.44 (2H, the, J=7,1 Hz), a 5.25 (2H, s), 7,25-a 7.85 (10H, m), 8,15-8,35 (2H, m)
244(CDCl3) of 1.44 (3H, t, J=7,1 Hz), of 4.45 (2H, d, J= 7,1 Hz), of 5.55 (1H, s), the 7.43 (1H, s), 7,45-7,65
(3H, m), 7,80 (1H, s), 8,15-8,35 (2H, m)
245(CDCl3) of 1.44 (3H, t, J=7.2 Hz), to 4.01 (3H, s), of 4.44 (2H, q, J=7.2 Hz), 7,20-to 7.35 (1H, m), 7,45-the 7.65 (3H, m), 7,79 (1H, s), 8,20-8,35 (2H, m)
246(CDCl3) a 1.45 (3H, t, J=7,1 Hz), to 4.46 (2H, d, J=7,1 Hz), 7,45-the 7.65 (2H, m), to 7.67 (1H, s), 7,81
(1H, s), to 7.93 (1H, s), 8,20-to 8.40 (2H, m)
247(CDCl3) of 1.44 (3H, t, J=7,1 Hz), 2,52 (3H, s), of 4.45 (2H, q, J=7,1 Hz), 7,45-the 7.65 (3H, m), 7,68 (1H, s), 7,79 (1H, s), 8,20-8,35 (2H, m)
248(CDCl3) 1,30-1,60 (3H, m), 2,42 (3H, s), 4,30-4,55 (2H, m), 7,10-to 7.35 (1H, m), 7,45-of 7.70 (3H, m), 7,78 (1H, s), 8,15-8,35 (2H, m)

249
[Table 48]
Approx. No.Struct.(Rest.)1H-NMRδppm:
(CDCl3) a 1.45 (3H, t, J=7.2 Hz), 2,35-of 2.50 (3H, m), to 4.46 (2H, q, J=7.2 Hz), 7,45-the 7.65 (2H, m), 8,00-of 8.15 (1H, m), to 8.20 (1H, s), 8,40 at 8.60 (1H, m), 9,10-of 9.30 (1H, m)
250(CDCl3) to 1.42 (3H, t, J=7,1 Hz), 2,35 at 2.45 (3H, m), 3,55 (3H, s)to 4.41 (2H, q, J=7,1 Hz), 5,31 (2H, s), 7,05-7,40 (3H, m), 7,50-the 7.65 (1H, m), to 7.77 (1H, s), of 7.90-with 8.05 (1H, m)
251(CDCl3) a 1.45 (3H, t, J=7,1 Hz), of 4.00 (3H, s), of 4.45 (2H, q, J=7,1 Hz), further 5.15 (2H, s), 6,98 (1H, s), 7,22 (1H, s), 7,25 is 7.50 (7H, m), 7,66 (1H, s), 8,10-8,30 (2H, m)
252(CDCl3) of 1.44 (3H, t, J=7.2 Hz), was 4.02 (3H, s), of 4.44 (2H, q, J=7.2 Hz), 7,12 (1H, s), 7,19 (1H, s), 7,45-the 7.65 (2H, m), 7,68 (1H, s), 8,15-8,35 (2H, m)
253(CDCl3) 0,50-0,70 (2H, m), 0,85-1,05 (2H, m)of 1.44 (3H, t, J=7.2 Hz), 2,10-of 2.34 (1H, m), of 3.97 (3H, s), of 4.44 (2H, q, J=7.2 Hz), 7,03 (1H, s), 7,17 (1H, s), 7,40-the 7.65 (2H, m), 7,71 (1H, s), 8,10-to 8.40 (2H, m)
254(CDCl3) of 1.44 (3H, t, J=7,1 Hz), a 2.36 (3H, s), of 4.44 (2H, q, J=7,1 Hz), 7,17 (1H, s), 7,31 (1H, s), 7,45-the 7.65 (2H, m), 7,72 (1H, s), 8,15-8,35 (2H, m)

[Table 49]
Approx. No.Struct.(Rest.)1H-NMRδppm:
255(CDCl3) of 1.44 (3H, t, J=7,1 Hz), is 2.37 (3H, s)to 2.41 (3H, s), of 4.44 (2H, q, J=7,1 Hz), 7,33 (1H, s), 7,45-the 7.65 (3H, m), 7,72 (1H, s), 8,15-8,35 (2H, m)
256(DMSO-d6) of 1.36 (3H, t, J=7,1 Hz), of 3.96 (3H, s), 4,36 (2H, q, J=7,1 Hz), 7,35 (4H, m), 8,66 (1H, s)
257(DMSO-d6) 7,10-to 8.20 (6H, m), 8,59 (1H, s), of 10.05 (1H, s), 13,22 (1H, users)
258(DMSO-d6) 3,20-3,40 (6H, m), 3,60-of 3.80 (4H, m), 4,20-4,60 (4H, m), 7,35-8,25 (6H, m), 8,66 (1H, s)

260
[Table 50]
Approx. No.Struct.Approx. No.Struct.
259
261262
263264
265266
267268
269270

[Table 51]
Approx. No.Struct.Approx. No.Struct.
271272
273274
275276
277278
279280
281282

[Table 52]
Approx. No.Struct.
283

[Table 53]
When the. No.Struct.1H-NMRδppm:DMSO-d6
284of 2.28 (3H, s), 3,82 (3H, s), 7,05-to 7.15 (1H, s), 7,45-of 7.55 (1H, s), 7,75-of 7.90 (2H, m), 8,10-of 8.25 (2H, m), of 8.47 (1H, s), 13,19 (1H, users)
285of 2.27 (3H, s), 3,90 (3H, s), 7,10-8,25 (6H, m), 8,53 (1H, s)
2867,25-to 7.35 (1H, m), 7,40-of 7.60 (7H, m), 7,80-of 7.90 (2H, m), 8,10-of 8.25 (2H, m), is 8.75 (1H, s), and 13.3 (1H, users)
287of 3.96 (3H, s), 7,35-to 8.20 (6H, m)8,64 (1H, s), 13,26 (1H, users)
288of 2.33 (3H, s), 2,62 (3H, s), of 3.69 (3H, s), 7,35 (1H, s), 7,65-to 8.20 (4H, m), 8,58 (1H, s), 13,28 (1H, users)
289of 2.56 (3H, s), of 3.84 (3H, s), 7,14 (1H, d, J=9,2 Hz), 7,45-of 7.55 (1H, m), 7,75-a 7.85 (2H, m), 8,10-to 8.20 (2H, m), 8,65 (1H, s), 13,24 (1H, users)
2900,55-0,75 (2H, m), 0,80-1,00 (2H, m), 2.05 is-is 2.30 (1H, m), 3,93 (3H, s), to 7.09 (1H, s), 7,18 (1H, s), to 7.64 (2H, m), 8,05 is 8.25 (2H, m), charged 8.52 (1H, s), of 13.18 (1H, users),

[Table 54]
Approx. No.Struct.1H-NMRδppm:DMSO-d6
291of 2.33 (3H, s), 2,62 (3H, s)to 3.36 (3H, s), 3,60-of 3.95 (4H, m), 7,74 (1H, s), 7,76 is 8.25 (4H, m), to 8.57 (1H, s)
292of 2.27 (3H, s), of 2.56 (3H, s), 6,50-8,50 (7H, m)
293of 3.97 (3H, s), 7,40 (1H, s), 7,65-of 7.95 (3H, m), 8,05 is 8.25 (2H, m), 8,68 (1H, s), 13,22 (1H, users)
2943,20-of 3.45 (3H, m), 3,60-3,90, (2H, m), 4,15-of 4.45 (2H, m)to 4.23 (1H, s), 7,65-of 7.95 (3H, m), 8,05-8,30 (2H, m), 8,68 (1H, s), 13,23 (1H, users)
2952,35-2,60 (3H, m), 7,65-of 7.95 (4H, m), 8,05 is 8.25 (2H, m), to 8.70 (1H, s), 13,24 (1H, users)
296of 2.24 (3H, s), 7,03 (1H, s), and 7.4 (1H, C), 7,60-of 7.90 (2H, m), 7,95-8,30 (2H, m), 8,46 (1H, s), of 9.56 (1H, users), 13,20 (1H, users)
297of 2.34 (3H, s), is 2.37 (3H, s), 7,40-of 7.60 (2H, m), 7,70-a 7.85 (2H, m), 8,05 is 8.25 (2H, m), 8,53 (1H, s)

[Table 55]
Approx. No.Struct.1H-NMRδppm:DMSO-d6
298of 2.38 (3H, s), 7,30-8,40 (6H, m), 8,66 (1H, s), 13,22 (1H, users)
2997,10-the 7.65 (3H, m), 7,70-of 7.90 (3H, m), 8,10-of 8.25 (2H, m), 8,79 (1H, s), to 13.29 (1H, users)
300of 2.72 (6H, s), 7,75-of 7.90 (3H, m), 7,98 (1H, s), 8,10-of 8.25 (2H, m), 8,87 (1H, s)
301of 1.32 (6H, d, J=6.0 Hz), 4.80 to 5,10 (1H, m), 7,55 (1H, s), 7,70-8,30 (5H, m), 8,83 (1H, s), 13,33 (1H, users)
302of 1.40 (3H, t, J=7,1 Hz), is 4.21 (2H, q, J=7,1 Hz), 7,30-8,25 (6H, m), 8,65 (1H, s) 13,25 (1H, users)
303of 1.32 (6H, d, J=6,1 Hz), 4,60-of 4.90 (1H, m), 7,30-8,30 (6H, m), 8,66 (1H, s), of 13.27 (1H, users)
304of 0.96 (6H, d, J=6,7 Hz), 1,50-2,00 (3H, m), 4,10-4,30 (2H, m), 7,30-8,30 (6H, m), 8,65 (1H, s), to 13.29 (1H, users)

[Table 56]
Approx. No.Struct.1H-NMRδppm:DMSO-d6
305of 3.33 (3H, s), 3,65-of 3.80 (2H, m), 4,20-and 4.40 (2H, m), 7,35-8,25 (6H, m), 8,66 (1H, s), to 13.29 (1H, users)
306the 3.89 (3H, s), 7,14 (1H, s), 7,80-of 8.15 (2H, m), 8,35-8,55 (1H, m), 8,79 (1H, s), 8,95 is 9.15 (1H, m), 9,37 (1H, users), 13,48 (1H, users)
3072,39 (3H, s), 7,55-7,80 (1H, m), of 7.90-8,10 (1H, m), 8,30 at 8.60 (2H, m), 8,90-a 9.25 (2H, m), 13,52 (1H, users)
3083,44 (3H, s)5,38 (2H, s), 7,26-of 7.55 (4H, m), 7,65-8,00 (H, m), 8,68 (1H, s), 12,99 (1H, users)
3097,20-7,30 (2H, m), 7,35 is 7.50 (2H, m), to 7.67 (1H, DD, J=8.0 Hz, 1.0 Hz), 8,01 (1H, d, J=8.7 Hz), 8,81 (1H, s)
310of 2.72 (3H, s), 7,14 (1H, d, J=7,2 Hz), 7,20-to 7.35 (3H, m), 7,52 (1H, d, J=8.5 Hz), 8,00 (1H, d, J=8.1 Hz), 8,66 (1H, s)
311of 3.95 (3H, s), 7,15-with 8.05 (5H, m), 8,63 (1H, s)

[Table 57]
Approx. No.Struct.1H-NMRδppm:DMSO-d6
3127,10-7,30 (3H, m), 7,50-with 8.05 (2H, m), to 8.57 (1H, s)10,06 (1H, s)
313to 2.55 (3H, s), of 3.84 (3H, s), 7,14 (1H, d, J=9.0 Hz), 7.18 in-7,30 (2H, m), 7,45-of 7.55 (1H, m), 7.95 is-with 8.05 (1H, m), 8,63 (1H, s)
314of 2.27 (3H, s), 3,90 (3H, s), 7,10-of 7.25 (3H, m), 7,52 (1H, s), of 7.90-with 8.05 (1H, m), and 8.50 (1H, s)
3157,20-7,40 (2H, m), 7,65-7,80 (1H, m), a 7.85-of 7.95 (1H, m), 8,03 (1H, d, J=8.6 Hz), 8,05-to 8.20 (1H, m), 8,88 (1H, s)
316of 2.38 (3H, s), 7,10-to 7.35 (2H, m), 7,40 to 7.75 (2H, m), of 7.90-to 8.20 (1H, m)8,64 (1H, s)
317a 3.87 (3H, s), 6,95-to 7.35 (4H, m), of 7.90-8,10 (1H, m), 8,39 (1H, s), 9,38 (1H, users)
3187,10 was 7.45 (4H, m), to 7.59 (1H, d, J=7.8 Hz), 7,95 (1H, d, J=8,2 Hz), 8,63 (1H, s)

[Table 58]
Approx. No.Struct.1H-NMRδppm:DMSO-d6
319of 4.00 (3H, s), 7,10-8,10 (5H, m), 8,81 (1H, s)
3207,10-the 7.65 (5H, m), to 7.77 (1H, d, J=9.0 Hz), 8,01 (1H, d, J=8,4 Hz), 8,76 (1H, s)
321322of 2.45 (3H, s), 7,20-7,30 (3H, m), 7,52 (1H, s), to 7.64 (1H, d, J=8.0 Hz), 8,01 (1H, d, J=8.0 Hz), to 8.57 (1H, s)
323of 1.32 (3H, t, J=7,3 Hz), 2,24 (3H, s), 3,44 (3H, s), or 4.31 (2H, q, J=7,3 Hz), 5,38 (2H, s), 7,03 (1H, s), 7,30 is 7.50 (3H, m), 7,86 (1H, d, J=8,4 Hz), 8,44 (1H, s), of 9.56 (1H, s)
324of 2.28 (3H, s), 3,70-of 3.80 (2H, m), 4,15-4,30 (2H, m), 7,10-7,30 (3H, m), 7,53 (1H, s), 7.95 is-with 8.05 (1H, m), and 8.50(1H, s)
325of 2.24 (3H, s) 7,02 (1H, s), 7,15-of 7.25 (2H, m), 7,46 (1H, s), 7,98 (1H, d, J=9.0 Hz), 8,44 (1H, s), of 9.56 (1H, s)

[Table 59]
Approx. No.Struct.1H-NMRδppm:DMSO-d6
326of 1.32 (6H, d, J=5,9 Hz), of 2.25 (3H, s), 4,65-4,80 (1H, m), 7,10-8,10 (5H, m), 8,49 (1H, s)
327 of 1.25 (3H, t, J=7.5 Hz), 2,78 (2H, q, J=7.5 Hz), 7,10-7,40 (3H, m), 7,50 to 7.75 (2H, m), of 7.90-8,10 (1H, m), 8,63 (1H, s)
328of 2.38 (3H, s)6,70-to 6.80 (1H, m), 7,01 (1H, d, J=2.3 Hz), 7,49 (1H, d, J=a 10.6 Hz), 7,60-7,80 (1H, m), 7,89 (1H, d, J=8.5 Hz), 8,58 (1H, s)

The test example 1

The inhibitory activity against xanthine oxidase

(1) preparation of test compounds

Compound was dissolved in DMSO (Wako) with a concentration of 40 mm and then diluted to the desired concentration with saline phosphate buffer (PBC).

(2) measurement Method

Preparing the xanthine oxidase (from bovine milk, Sigma) with saline phosphate buffer (PBC) with a concentration of 0.02 units/ml, and then the solution was added to 96-well tablets 50 ál/well. Also added test compounds diluted in PBS, 50 μl/well. Added xanthine (Wako) in the amount of 200 μm, prepared with PBS, 100 μl/well, and reaction was performed for 10 minutes at room temperature. Measured the absorbance at 290 nm using a reader SpectraMax Plus 384 (Molecular device). The absorption in the absence of xanthine is 0%, and the absorption of the control sample in the absence of the test compound is 100%. Vicis the Yali concentration of the test compounds at a fifty percent inhibitory activity (IC 50) (Table 60). The Abbreviation "CA. # "in the table means "Example".

The test example 2

Inhibitory effect on the transport of uric acid membrane vesicles brush edges (BBMV)

The inhibitory activity of the tested compounds on the transport of uric acid was investigated using a partially modified method described in the publication Am. J. Physiol. 266 (Renal Fluid Electrolyte Physiol, 35): F797-F805, 1994.

(1) Preparation of BBMV from the cortical substance of the kidney of man

BBMV from the cortical substances of human kidney were supplied by the firm KAC. Renal cortical substance was dissected from human kidney and cut into small pieces. Then the cortical substance homogenized in 5 volumes of chilled using ice isotonic buffer (300 mm mannitol, 5 mm ethylene glycol-bis-(β-aminoethylamino)-N,N,N',N'-tetraoxane acid (EGTA), 12 mm Tris(hydroxymethyl)aminomethan (Tric)∙HCl, pH 7,4). After adding 1 M of magnesium chloride to a final concentration of 12 mm, the suspension was stirred and left to stand on ice for 15 minutes. Homogenized solution was centrifuged at 2500×g for 15 minutes at 4°C, then further centrifuged supernatant fluid at 30,000×g for 30 minutes at 4°C. the Precipitate resuspendable cooled in ice buffer 1 (150 m is mannitol, 2.5 mm EGTA, 6 mm Tris∙HCl, pH 7,4). After adding 1 M of magnesium chloride to a final concentration of 12 mm, the suspension was stirred and left to stand on ice for 15 minutes. After another centrifugation at 2500×g for 15 minutes at 4°C, then further centrifuged supernatant fluid at 30,000×g for 30 minutes at 4°C. the Precipitate resuspendable cooled in ice buffer 2 (100 mm mannitol, 100 mm potassium gluconate, 20 mm 2-[4-(2-hydroxyethyl)-1-piperazinil]econsultancy acid (Hepes)-Tris, pH 7,4). After centrifugation at 30,000×g for 30 minutes at 4°C the precipitate resuspendable in the buffer 2 and then determined the protein concentration.

(2) Preparation of the test compounds

Test compounds were dissolved in DMSO (Wako) with a concentration of 40 mm and then diluted to a concentration of 2 times higher than necessary, with the help of Clˉ gradient buffer (100 mm mannitol, 100 mm potassium gluconate, 20 mm Hepes-Tris, pH 7,4). For control used Clˉ gradient buffer without test compounds. In addition, an equal volume of Clˉ gradient buffer containing14C-labeled uric acid (Moravek) and probenecid (Wako)was added to test compounds and the control sample, and, finally, to prepare the buffer for analysis, including 40 μm uric acid and 5 μm probenecid. To measure absorption14C-labeled machevo the acid using an independent method with Clˉ gradient buffer for analysis were prepared with Clˉ equilibrium buffer (100 mm mannitol, 60 mm potassium gluconate, 40 mm potassium chloride, 20 mm Hepes-Tris, pH 7,4) instead of Clˉ gradient buffer.

(3) measurement Method

BBMV were thawed on ice. After adding 8 ml intravesical buffer (100 mm mannitol, 60 mm potassium gluconate, 40 mm Chloe potassium, 20 mM Hepes-Tris, pH 7,4) to 200 ál of prepared BBMV (protein concentration: 16 mg/ml), BBMV suspended with a needle 25 gauge and brought to equilibrium at room temperature for 60 minutes. After centrifugation at 30,000×g for 30 minutes at 4°C the precipitate resuspendable 1.2 ml intravesical buffer. The suspension was kept on ice until the start of the measurement. The absorption of uric acid in BBMV was measured using methods emergency filtration. The required number of BBMV (20 μl/1 response) was heated for 20 minutes at room temperature. The absorption of uric acid initiated by mixing with 100 μl of buffer for analysis. After incubation for 20 seconds at room temperature was added 3 ml of a cooled ice stop reagent (300 mm mannitol, 60 mm sodium sulfate, 100 mm probenecid (Wako), 5 mm Tris-H2SO4, pH 7,4) and then the solution was quickly filtered through nitrocellulose filters (pore size of 0.65 μm, Sartoriuc)under vacuum. In addition, the filters were twice washed in 3 ml of stop reagent was dissolved in 10 ml of Filter-Count (PerkinElmer), and radioactivity was counted in a liquid of scintillation the m counter (PerkinElmer). The radioactivity associated with the filters in the absence of BBMV, used as a corrective amendments. Then calculate the percentage of inhibition for the test compounds at 10 μm according to the following formula (table 61). The Abbreviations "CA. No.", "conc." and "inhibition %" in the table means "Example", "the concentration of the test compounds (μm)and the percentage of inhibition (%)", respectively.

The percentage of inhibition (%)=[1-(B-C)/(A-C)]×100

A: Radioactivity control sample

B: Radioactivity in the case of adding the test compounds

C: Radioactivity Clˉ equilibrium buffer

[Table 61]
Approx. No.Conc. (µm)Inhibition %
2371064

The test example 3

Inhibitory effect on the transport of uric acid by human cells expressing URAT1

(1) Preparation of human cells, quickly expressing URAT1

Full URAT1 human cDNA (NCBI Accession No. NM_144585) subcloned in expressing vector, pcDNA3.1 (Invitrogen). Expressing URAT1 vector man was transferrable in COS7 cells (RIKEN CELL BANK RCB0539)using a set of reagents Lipofectamine 2000. COS7 cells were cultured on coated collagen 24-hole plates (Asahi Techno Glasc), with 2× 105/well in D-MEM culture medium (Invitrogen)containing 10% fetal bovine serum (Sanko Junyaku), for 2 hours at 37°C in an atmosphere of 5% CO2. For 1 wells 2 μl of Lipofectamine 2000 was diluted in 50 ál of OPTI-MEM (Invitrogen) and kept at room temperature for 7 minutes (hereinafter referred to as Lipo2000-OPTI). For 1 wells 0.8 µg expressing URAT1 vector man was diluted in 50 ál of OPTI-MEM (Invitrogen), and gently mixed with Lipo2000-OPTI. After keeping at room temperature for 25 minutes, the mixture was added to COS7 cells at 100 μl/well. Then COS7 cells were cultured for 2 days at 37°C in an atmosphere of 5% CO2and used to measure the inhibitory effect on the absorption of uric acid.

(2) Preparation of the test compounds

Test compounds were dissolved in DMSO (Wako) to obtain concentrations of 10 mm and then diluted to a concentration of 2 times higher than necessary, using a buffer for pre-treatment (125 mm sodium gluconate, 4.8 mm potassium gluconate, 1.2 mm potassium dihydrophosphate, 1.2 mm magnesium sulfate, 1.3 mm calcium gluconate, 5.6 mm glucose, 25 mm Hepes, pH 7,4). Buffer for pre-treatment without the test compounds used for control. In addition, to test compounds and the control sample is obavljale equal volume of buffer for pre-treatment, contains14C-labeled uric acid (Moravek), and finally received buffer for analysis, including 20 μm uric acid.

(3) measurement Method

All the tests were carried out on the heater at 37°C. the Buffer for pre-treatment and buffer for analysis were incubated at 37°C and then used for analysis. The medium was removed from the tablets and add 700 ál of buffer for pre-treatment, and the cells were pre-incubated for 10 minutes. After repeating the same stage buffer for pre-treatment was removed and added to the buffer for analysis in 400 μl/well. The absorption reaction was carried out for 5 minutes. After termination of the reaction buffer for analysis were rapidly removed, and cells washed twice by adding a cooled ice buffer for pre-treatment of 1.2 ml/well. Then the cells were literally by the addition of 0.2 n sodium hydroxide solution in the amount of 300 μl/well. Lysed solution was transferred into a Picoplate (PerkinElmer) was added Microscinti 40 (PerkinElmer) in the amount of 600 μl/well. After mixing were counting the radioactivity in a liquid scintillation counter (PerkinElmer). As a control under similar conditions was also calculated radioactivity in COS7 cells that were not subjected to transferowy with URAT1 expressing vector. In addition, in kislali the percentage of inhibition for the test compounds at 10 μm according to the following formula (table 62). The Abbreviations "CA. No.", "conc." and "inhibition %" in the table means "Example", "the concentration of the test compounds (μm)and the percentage of inhibition (%)", respectively.

The percentage of inhibition (%)=[1-(B-C)/(A-C)]×100

A: Radioactivity control sample

B: Radioactivity in the case of adding the test compounds

C: Radioactivity COS7 cells that were not subjected to transferowy with URAT1 expressing vector

[Table 62]
Approx. No.Conc. (µm)Inhibition %
1931047
1941064

The test example 4

Impact on reducing the level of uric acid in serum

(1) measurement Method

The test compounds at a dose of 3 mg/kg, suspended in 0.5% solution of methylcellulose was administered orally during the night the hungry male rats CD (SD) IGS (5 weeks of age, Charls River Japan). After 2 hours the introduction of the collected blood under ether anesthesia from the abdominal aorta and separated serum usual method. Determined the levels m the U.S. acid in serum using the kit for determination of uric acid (Uric acid C-Test Wako: Wako) and calculated the percentage reduction in the concentration of uric acid according to the following formula.

The percentage reduction in the concentration of uric acid (%)=(amount of uric acid levels in the serum of control animals - Magnitude levels of uric acid in the blood serum of animals that were administered the test compounds)×100/Value levels of uric acid in the serum of control animals.

(2) Results

The compounds of examples 3, 188, 191 and 192 provide a lower level of uric acid in serum by more than 60% within 2 hours after oral administration. The above results confirm that the compounds of the present invention have a powerful impact on reducing the level of uric acid in serum.

Industrial applicability

Derivatives azaindole of the present invention represented by the above General formula (I), or its prodrug, or their pharmaceutically acceptable salts possess high inhibitory activity against xanthine oxidase and, therefore, may have an inhibitory effect on the production of uric acid and reduce the level of uric acid in the blood. Thus, the present invention provides a means for the prevention or treatment of hyperuricemia, gouty site, gouty arthritis, renal diseases associated with hyperuricemia, renal disease or other diseases is s.

1. Derived (Aza)indole represented by the General formula:

where T represents cyano;
ring J represents a phenyl ring or a 5 - or 6-membered heteroaryl ring containing one or two heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom;
Q represents carboxy or lower alkoxycarbonyl;
Y represents a hydrogen atom, hydroxy, amino, halogen atom, nitro, lower alkyl or lower alkoxy, optionally substituted lower alkoxy, provided that two or more Y optionally exist on ring J and these Y are optionally the same or different from each other;
X1X2and X3independently represent CR2or N, provided that all X1X2and X3are not simultaneously N; and when there are two or more R2these R2are not necessarily the same or different from each other; and
R1and R2independently represent a halogen atom, cyano, PERFLUORO(lower alkyl), -AA, -A-D-E-G or-N(-D-E-G)2provided that two (-D-E-G) do not necessarily differ from each other;
AArepresents a hydrogen atom, hydroxy, carboxy, -other3or-SO2Other3;
A represents a single bond, -O-, -CO-, -COO-, -CON(R3)- -SO2N(R3)-, -N(R 3)CO -, or-N(R3)SO2-where R3represents a hydrogen atom or lower alkyl;
D is the lowest alkylene, optionally substituted by halogen atom, lower albaniles,3-8cycloalkyl, 6-membered heterocyclochain with two heteroatoms, one of which is a nitrogen atom and the other atom of oxygen, phenylene, optionally substituted by halogen atom, or a 5 - or 6-membered, heteroaryl with one heteroatom selected from a nitrogen atom and sulfur atom;
E represents a single bond, -O-, -N(R5)-, -CO-, -COO-, -CON(R5)-, -SO2-, -SO2N(R5)-, -N(R5)CO-, -N(R5)COO -, or-N(R5)SO2-, provided that R5independently represents a hydrogen atom or lower alkyl; and
G represents a hydrogen atom, lower alkyl, C3-8cycloalkyl, phenyl, optionally substituted by a halogen atom or a lower alkylsulfonyl, 5-membered heteroaryl with one heteroatom, represents a sulfur atom or phenyl(lower alkyl), provided that when G is a hydrogen atom, E is a single bond, -O-, -N(R5)-, -COO-, -CON(R5)-, -N(R5)CO - or-SO2N(R5), or provided that when there are two R2associated with the neighboring atoms, these two R2optionally linked together to form a ring,
or, respectively, its prodrug, or its pharmaceutical is Eski acceptable salt,
where "prodrug" means a compound, where one or more groups selected from hydroxyl group and carboxyl group in the compound of the above formula (I) substituted by a group forming a prodrug, and a group forming a prodrug is (lower alkyl)-CO - for a hydroxyl group or lower alkyl for carboxyl group.

2. Derived (Aza)indole according to claim 1, where X1X2and X3independently represent CR2provided that when there are two or more R2these R2are not necessarily the same or different from each other, or its prodrug, or pharmaceutically acceptable salt.

3. Derived (Aza)indole according to claim 1, where Q represents carboxy, or its prodrug, or pharmaceutically acceptable salt.

4. Derived (Aza)indole according to claim 1, where Y represents a hydrogen atom, hydroxy or halogen atom, or its prodrug, or pharmaceutically acceptable salt.

5. Derived (Aza)indole according to claim 4, where Y is hydroxy, or its prodrug, or pharmaceutically acceptable salt.

6. Derived (Aza)indole according to claim 1, where the ring J represents a benzene ring, or its prodrug, or pharmaceutically acceptable salt.

7. Derived (Aza)indole according to claim 4, where the group represented by the General formula:

is a group represented by the following General formula (IIa):

where in the formula
Z1, Z2and Z3independently represent CR7or N; and
Y1and R7independently represent a hydrogen atom, hydroxy, amino, halogen atom, lower alkyl or lower alkoxy, provided that when there are two or more R7these R7are not necessarily the same or different from each other, or its prodrug, or pharmaceutically acceptable salt.

8. Derived (Aza)indole according to claim 7, where
Z1and Z3represent CH, and Z2is CR8or N; and
Y1and R8independently represent a hydrogen atom, hydroxy or halogen atom, or its prodrug, or pharmaceutically acceptable salt.

9. Derived (Aza)indole of claim 8, where Z2represents CH; or its prodrug, or pharmaceutically acceptable salt.

10. Derived (Aza)indole according to claim 9, where Y1represents hydroxy; or its prodrug, or pharmaceutically acceptable salt.

11. Derived (Aza)indole according to claim 4, where the ring J represents a 5-membered heteroaryl ring having 1 to 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom, provided that an oxygen atom and a sulfur atom nah not the are next to each other; and Y represents a hydrogen atom, hydroxy, amino, halogen atom, lower alkyl or lower alkoxy, optionally substituted lower alkoxy, provided that the ring J is optional there are two or more Y, and these Y are optionally the same or different from each other, or its prodrug, or pharmaceutically acceptable salt.

12. Derived (Aza)indole according to claim 11, where the group represented by the General formula:

is a group represented by the following General formula (IIb):

where in the formula
one or two of the Z4, Z5and Z7represent an oxygen atom, nitrogen atom or sulfur atom and the others represent CR9provided that Z4and Z5at the same time are not atoms selected from oxygen atom and sulfur atom, R9represents a hydrogen atom, hydroxy, amino, halogen atom, lower alkyl or lower alkoxy, provided that when there are two or more R9these R9are not necessarily the same or different from each other;
Z6represents a carbon atom; and Z4, Z5, Z6and Z7tied together with the carbon atom associated with a carboxyl group, with the formation of 5-membered heteroaryl ring, or its prodrug, or pharmaceutically when mlama salt.

13. Derived indole according to claim 1, selected from the group consisting of:
4-(3-cyano-5,6-differental-1-yl)-2-hydroxy-benzoic acid,
4-(3-cyanoindole-1-yl)-2-hydroxy-benzoic acid,
4-(3-cyano-5-methylindol-1-yl)-2-hydroxy-benzoic acid,
4-(3-cyano-6-Clorinda-1-yl)-2-hydroxy-benzoic acid,
4-(3-cyano-5-Florinda-1-yl)-2-hydroxy-benzoic acid,
4-(3-cyano-6-Florinda-1-yl)-2-hydroxy-benzoic acid,
4-(6-chloro-3-cyano-5-Florinda-1-yl)-2-hydroxy-benzoic acid,
4-(7-cyano-1,3-dioxolo[4,5-f]indol-5-yl)-2-hydroxy-benzoic acid,
4-(3-cyano-6-cryptomaterial-1-yl)-2-hydroxy-benzoic acid,
4-(3-cyano-5-methoxyindol-1-yl)-2-hydroxy-benzoic acid,
4-(5-chloro-3-cyanoindole-1-yl)-2-hydroxy-benzoic acid,
4-(3-cyano-5-hydroxyindole-1-yl)-2-hydroxy-benzoic acid,
4-(3-cyano-4-hydroxyindole-1-yl)-2-hydroxy-benzoic acid,
4-(3-cyano-6-hydroxyindole-1-yl)-2-hydroxy-benzoic acid,
4-(3-cyano-6-methoxyindol-1-yl)-2-hydroxy-benzoic acid,
4-(3-cyano-4-Florinda-1-yl)-2-hydroxy-benzoic acid,
4-(3-cyano-6-isopropylindole-1-yl)-2-hydroxy-benzoic acid and
4-(3-cyano-6-fluoro-5-methyl-indol-1-yl)-2-hydroxy-benzoic acid,
or its prodrug, or pharmaceutically acceptable salt.

14. Inhibitor of xanthine oxidase, comprising as an active ingredient derived (Aza)ind the La according to any one of claims 1 to 13, or its prodrug, or pharmaceutically acceptable salt.

15. Pharmaceutical composition having inhibitory activity against xanthine oxidase, comprising as an active ingredient derived (Aza)indole according to any one of claims 1 to 13, or its prodrug, or pharmaceutically acceptable salt.

16. The pharmaceutical composition according to item 15, which is a tool for prevention or treatment of a disease selected from the group consisting of hyperuricemia, gouty site, gouty arthritis, renal diseases associated with hyperuricemia and renal stone disease.

17. The pharmaceutical composition according to item 16, which is a tool for prevention or treatment of hyperuricemia.

18. The pharmaceutical composition according to item 15, which is a medicine to lower uric acid levels in the serum.

19. The pharmaceutical composition according to item 15, which is an inhibitor of the production of uric acid.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to particular compounds, which demonstrate inhibiting activity with respect to ERK, whose structure formula is given in description, to their pharmaceutically acceptable salts, based on them pharmaceutical composition and their application for treatment of cancer, mediated by ERK activity.

EFFECT: obtaining compounds, which demonstrate inhibiting activity with respect to ERK.

5 cl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof: (I) where R1, R2 and R3, which are identical or different, denote H, lower alkyl; R4, R5, R6, R7 and R8, which are identical or different, denote H, lower alkyl, halogen, nitro, -X-OR0, -X-NR10R11, -X-NR0C(O)R10, -X-O-halogen lower alkyl, -X-O-X-phenyl; or R6 and R7 are combined to form -O-lower alkylene-O-; R, which is identical or different, denotes H, lower alkyl; R10, R11, which are identical or different, denote H, lower alkyl; X, which is identical or different, denotes a bond, lower alkylene.

EFFECT: compounds exhibit type 5 17βHSD inhibiting activity, which enables their use in producing a pharmaceutical composition and in a method of inhibiting type 5 17βHSD.

15 cl, 11 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted pyrazolopyrimidines derivatives of formula , wherein Y1, Y2, Y3, Y4 represent N or C-, wherein at least, two groups of Y1-Y4 represent carbon atom, R1 represents chlorine or bromine, R2-R7 represent, e.g. hydrogen, methyl or ethyl; and R10 and R11 independently represent, e.g. hydrogen or C1-C6alkyl, their optical isomers and pharmaceutically acceptable salts. Also, the invention refers to using said compounds for treating and preventing a number of acute and chronic mGluR5 related neurological disorders, such as, e.g. pains of various character, dyskinesia, Parkinson's disease, anxiety disorder, Alzheimer's disease and others, a pharmaceutical composition containing specified compounds and methods for preparing them.

EFFECT: compounds are strong mGluR5 modulators.

21 cl, 2 tbl, 274 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclohexylamine derivatives of formula (I), having inhibiting properties towards at least one monoamine transporter, such as serotonin transporter, dopamine transporter or norepinephrine transporter, or a combination of two or more transporters. The compounds can be used to treat and/or prevent central nervous system disorders such as pain, depression, anxiety, schizophrenia, sleep disorder etc. In formula (I) , n equals 0 or 1; s equals 1, 2 or 3, m equals a whole number from 0 to 12; Ar is

or where Y and Z are (i) both halogen; or (ii) one of Y and Z is CF3 or OCF3 and the other is hydrogen; Y1, Z1, Y2 and Z2 each independently denotes H or a halogen; each X independently denotes H, halogen, CF3, OR5, (C1-C4)alkyl, optionally substituted with halogen or OH, or NR6R7; each R1 and R2 independently denotes H or (C1-C6)alkyl; and each R3 and R4 independently denotes H or (C1-C9)alkyl optionally substituted with OH; where each R5 independently denotes H, (C1-C4)alkyl or phenyl; and each R6 and R7 independently denotes H or (C1-C4)alkyl; where at least two of R1, R2, R3, R4 and X together with atoms to which they are bonded are optionally bonded to form a 5-6-member ring, where the 5-6-member ring is selected from: a) R3 and R4 together with a nitrogen atom to which they are bonded optionally form a pyrrolidine, piperidine, piperazine or morpholine ring, which is optionally substituted with (C1-C4)alkyl; b) when R3 is H or lower alkyl, X and R4 together with atoms to which they are bonded optionally form a 1,3-oxazine ring; c) two X substitutes together with a carbon atom to which they are bonded optionally form a 1,3-dioxolane ring; and d) when R1 and R3 denote hydrogen, R2 and R4 together with atoms to which they are bonded optionally form a 5- or 6-member saturated heterocyclic ring containing one nitrogen atom.

EFFECT: high efficiency of using the compounds.

29 cl, 36 dwg, 11 tbl, 6 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to novel compounds - tetrahydronaphthyridine derivatives of formula (I) or their pharmaceutically acceptable salts, where R1 represents C1-6alkoxycarbonyl group optionally substituted with 1-5 substituents, etc; R2 represents C1-6alkyl group; R3 represents hydrogen or and all; R4 represents C1-4alkylene group; R5 represents optionally substituted unsaturated 5-8-member heterocyclic group containing 1-4 heteroatoms independently selected from oxygen and nitrogen atoms; R6, R7 and R8 represent independently hydrogen atom, hydroxygroup, cyanogroup, C1-6alkyl group, C1-6alkoxygroup, mono- or di- C1-6alkylcarbamoyl group or mono- or di- C1-6alkylaminogroup, optionally substituted with 1-6 substituents independently selected from halogen atom, C1-6alkoxygroup and aminogroup; R10 represents optionally substituted with 1-2 substituents phenyl group; which possess inhibiting activity with respect to cholesteryl ester transfer protein (CETP).

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzodiazine of the formula (1), which possess properties of inhibiting proliferative action and can be used during treatment of hyper-proliferative diseases like cancer. In formula (I) G1 and G2 each independently representing a halogen; X1 -R1 selected C1-C6-alkoxy, X2 represents a simple bond; Q1 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, where Q1 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different , selected from cyano, carbamoyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkyl-sulfinyl C1-C6-alkyl-sulfonyl, N-C1-C6-alkyl-carbamoyl N,N-di-[C1-C6-alkyl]carbamoyl, C1-C6-alkanoyl, sulfamoyl, N-C1-C6-alkyl-sulfamoyl, N,N-di-[C1-C6-alkyl-]sulfamoyl, carbamoyl C1-C6-alkyl, N-C1-C6-alkyl-carbamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]carbamoylC1-C6-alkyl, sulfamoylC1-C6-alkyl, N-C1-C6-alkyl-sulfamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]sulfamoylC1-C6-alkyl, C1-C6-alkanoylC1-C6-alkyl, or from the group with the formula: Q2 -X3-, where X3 represents CO and Q2 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular nitrogen heteroatom and not necessarily 1 or 2 heteroatoms, selected from nitrogen and sulphur, and where. Q2 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different, selected from halogens, C1-C4-alkyl, and where any C1-C6-alkyl and C2-C6-alkaloid groups within the limits of Q1 does not necessarily have one or more substitute groups, which can be similar or different, selected from hydroxy and C1-C6-alkyl and/or not necessarily a substitute selected from cyano, C1-C6-alkoxy, C2-C6-alkanoxy and NRaRb, where Ra represents hydrogen or C1-C4-alkyl and Rb represents hydrogen or C1-C4-alkyl, or Ra and Rb together with a nitrogen atom, to which they are attached, they form a 4-, 5- or 6- member non-aromatic saturated monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, which not necessarily have 1 or 2 substitutes, which can be similar or different, on the available carbon atom, and selected from halogens and C1-C3-alkilenedioxy.

EFFECT: obtaining new derivatives benzodiazine, which possess properties of inhibiting proliferative action and can be used during the treatment of hyper-proliferative diseases such as cancer

27 cl, 73 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

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

SUBSTANCE: invention relates to novel substituted derivatives of noscapine of the general formula (1) or its racemates, optical isomers, or their pharmaceutically acceptable salts and/or hydrates possessing anticarcinogenic activity, and to a pharmaceutical composition as tablets, capsules or injection formulations placed into pharmaceutically acceptable package, ant to methods for their synthesis, and to a method for inhibition of proliferation by their using. In compounds of the formula (1) R1 represents a substitute of amino-group chosen from alkyl; R2 represents a substitute of cyclic system chosen from possibly substituted alkyl wherein substitutes are chosen from possibly substituted amino-group or azaheterocycle comprising possibly oxygen (O), sulfur (S) or nitrogen (N) atoms as an additional heteroatom, and added to alkyl group by nitrogen atom, possibly substituted aryl possibly substituted and possibly condensed heteroaryl comprising at least one heteroatom chosen from nitrogen, sulfur and oxygen atoms, possibly substituted sulfamoyl. Except for, invention relates to 3-(9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 3-(9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 5-(4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-9-carbaldehyde (or -9-carbonitrile, or -9-sulfonyl chloride, or -9-carboxylic acid) and 3-(9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, and method for their synthesis. Also, invention relates to combinatory and focused libraries.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 5 tbl, 9 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

32 cl, 1 tbl, 132 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of imidazo[4,5-c]chinoline of general formula or to its pharmaceutically acceptable salts, where R1 represents straight-chained C1-C6alkyl, possibly substituted with one substituent, selected from C1-C3alkoxy; Z1 represents C2-C6alkylene; X1 represents NR5 or >NCOR5; Y1 represents C1-C6alkylene; R3 represents C1-C6alkyl, possibly substituted with C1-C6alkoxy; R5 represents hydrogen, piperidinyl, possibly substituted by piperidinyl nitrogen with group R10, group C1-C6alkyl, where the last group is possibly substituted with one substituent, independently selected from NR7R8 or R9; or R5 represents C1-C6alkylene, which can be bound with carbon atom in C2-C6alkylene group Z1 with formation of piperidine ring; each of R7 and R8 independently represents tetrahydropyranyl, piperidinyl, possibly substituted by piperidinyl nitrogen atom with group R10a, C1-C6alkyl, where the last group is possibly substituted with one group, independently selected from OR12; or R7 and R8 together with nitrogen atom, to which they are bound, form 4-7-membered saturated heterocyclic ring, selected from asetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4-oxazepanyl and 1,4-diazepanyl, where heterocyclic ring is possibly substituted with one or two substituents, independently selected from S(O)qR15, OR15, CO2R15, COR15, CONR15R16, NR15CO2R16, pyrimidinyl and C1-C6alkyl, where the last group is possibly substituted with one group, independently selected from OR18 and CO2R18; R9 represents S(O)qR20; R10 and R10a independently represent COR2 or group C1-C6alkyl; each of R12, R15, R16, R18, R20 and R24 independently represents hydrogen or C1-C6alkyl; q equals 2; m and n both equal 0; and A represents phenyl. Invention also relates to method of obtaining formula (I) compound, based on it pharmaceutical composition, and to method of treating said pathological conditions.

EFFECT: obtained are novel derivatives of imidazo[4,5-c]chinoline, useful modulation of TLR7 activity.

17 cl, 18 dwg, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heterocyclic amide compound of formula I: or a pharmaceutically acceptable salt thereof. Described also is a pharmaceutical composition containing said compound, having protein kinase inhibitor, regulator or modulator properties, which is acceptable in treating or preventing a proliferative disease, an anti-proliferative disorder, inflammation, arthritis, neurologic or neurodegenerative disease, cardiovascular disease, hair loss, neural disease, ischemic disorder, viral disease or fungal disease.

EFFECT: high efficiency of using the compounds.

2 cl, 20 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrole nitrogen-containing heterocyclic derivatives of formula (I) or their pharmaceutically acceptable salts:

,

wherein: X means C, N; each R1,R2 means H; R3 means C1-10alkyl; R4 means -[CH2CH(OH)]rCH2NR9R10, -(CH2)nNR9R10; provided X means N, R5 is absent, each R6, R7, R8 means H, halogen; provided X means C, each R5, R6, R7, R8 means H, halogen, hydroxyC1-10alkyl, C1-10alkyl, phenyl, 6-member heteroaryl with one N, -OH, -OR9, -NR9R10, -(CH2)nCONR9R10, -NR9COR10, -SO2R9 and -NHCO2R10, wherein said phenyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, C1-10alkoxyl, halogen; each R9, R10 means H, C1-10alkyl wherein C1-10alkyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, phenyl, halogenophenyl, -OH, C1-10alkoxy, OH- C1-10alkyl; or R9 and R10 together with an attached atom form a 5-6-member heteroring which may contain one O; n is equal to 2- 6; z is equal to 1-2; r is equal to 1-6;.

EFFECT: compounds may be used as protein kinase inhibitors.

14 cl, 2 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2-heteroaryl-substituted benzothiophene and benzofuran, precursors thereof and therapeutic use of said compounds, having structural formula (1a) where R1, R2, X9 and Q assume values given in the description, and pharmaceutically acceptable salts thereof, which are suitable for imaging amyloid deposits in living patients. The invention also relates to pharmaceutical compositions based on compounds of formula 1a, use and methods of producing said compounds. More specifically, the present invention relates to a method of imaging brain amyloid deposits in vivo for intravital diagnosis of Alzheimer's disease, and measuring clinical efficiency of therapeutic agents against Alzheimer's disease.

EFFECT: high efficiency of using said compounds.

15 cl, 1 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel tricyclic derivative of chemical formula 1 or pharmaceutically acceptable salts thereof: formula 1, where Y1, Y2 and Y3 independently denote H, C1-C10 alkyl with a straight or branched chain, hydroxy, C1-C10 alkoxy, -CCOR1, -NR2R3 or -A-B; A denotes -O-, -CH2-, -CH(CH3)-, -CH-N- or -CONH-; B denotes -(CH2)n1-Z, -(CH2)n2-NR2R3 or -(CH2)n3-OR1; Z denotes C5-C20 aryl, unsubstituted or substituted with R5 and selectively R6, C3-C10 cycloalkyl, unsubstituted or substituted with R5 and selectively R6, C1-C20 heterocyclic compound, unsubstituted or substituted with R5 and selectively R6; R1 denotes H or C1-C10 alkyl with a straight or branched chain; R2 and R3 independently denote H, C1-C10 alkyl with a straight or branched chain or -(CH2)n4R7; R5 denotes H, C1-C10 alkyl with a straight or branched chain, C5-C20 aryl or C1-C20 heterocyclic compound; R6 denotes H or C1-C10 alkyl with a straight or branched chain; R7 denotes -NR8R9, -COOR1, -OR1, -CF3, -CN, halogen or Z; R8 and R9 independently denote H or C1-C10 alkyl with a straight or branched chain; n1-n4 respectively denote an integer from 0 to 15; Y denotes H or C1-C10 alkyl with a straight or branched chain. The invention also relates to methods of producing a compound of formula 1, compositions containing the described compound and with effective inhibiting activity on poly(ADP-ribose)polymerase (PARP).

EFFECT: obtaining and describing novel compounds which can be suitable for preventing or treating diseases caused by excess PARP activity, especially neuropathic pain, neurodegenerative diseases, cardiovascular diseases, diabetic neuropathy, inflammatory diseases, osteoporosis and cancer.

23 cl, 123 ex, 7 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, method for production thereof, use thereof to produce a medicinal agent which inhibits MR activity.

EFFECT: improved method.

11 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) where values of substituents are given in description, possessing inhibiting activity with respect to cathepsin K as well as to pharmaceutical compositions for treating diseases, associated with cysteine protease activity and to methods of inhibiting cathepsin K in mammals, requiring such treatment by introduction of efficient amount of compound to mammal.

EFFECT: claimed is application of formula (I) compound or its pharmaceutically acceptable salt in manufacturing medication for application in cathepsin K inhibition in a warm-blooded animal.

10 cl, 45 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 7-substituted indoles of formula I:

or their pharmaceutically acceptable salts wherein the values A1, B1, C1, D1, E1, F1, G1, L are presented in cl. 1 of the patent claim.

EFFECT: compounds inhibit activity of anti-apoptotic protein Mc1-1 that enables using them in pharmaceutical compositions.

5 cl, 7 dwg, 2 tbl, 609 ex

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