WO2006054912A1 - Aryl(hetaryl)-3-aminomethyl-quinilone-2 derivatives in the form of no-synthetase i and cyclooxygenase-2 nhibitors, methods for the production thereof and compositions based thereon - Google Patents

Abstract

The invention relates to compounds of formula (1), to methods for the production thereof, to biologically active compounds inhibiting NO-synthetase and cyclooxygenase-2 and to pharmaceutical compositions which are bases thereon and can be used for treating cardio-vascular diseases, gastrointestinal disturbances, different organ functional disorders, inflammatory processes in an organism, cerebral accidents, Alzheimer's and Parkinson's diseases, for controlling a pain filling, a sleep time, gastric secretion, blood pressure, trombocyte aggregation, etc.

Description

 Derivatives of apyl (hetaryl) -3-aminomethylquinolinone-2 as inhibitors of NO synthetase and cyclooxygenase-2, methods for their preparation, biologically active compounds and pharmaceutical compositions based on them

FIELD OF THE INVENTION

The invention relates to the field of organic chemistry and medicine, in particular to biologically active compounds that inhibit NO synthetase and cyclooxygenase-2, and pharmaceutical compositions based on them, which can be used in the treatment of cardiovascular, gastrointestinal diseases; various disorders of the functioning of organs; inflammatory processes in the body; strokes, Alzheimer's and Parkinson's disease; regulation of pain, duration of sleep, secretion of gastric juice, blood pressure, platelet aggregation, etc.

The current level of technology

NO synthetase is an enzyme that catalyzes the conversion of L-arginine to nitric oxide (II) (NO). This process was first discovered in the late 80s, and since then until now have been discovered more and more NO functions in the body. Accordingly, the importance of NO synthetase for regulating various body functions is constantly increasing, and therefore, the importance of various inhibitors and modulators of this enzyme for the treatment of diseases associated with impaired functions is also increasing. In the general case, we can say that nitric oxide (II) is involved:

1. In the regulation of smooth muscle tone, which leads to relaxation / contraction and, therefore, to the expansion / contraction of blood vessels (cardiovascular diseases, as well as various disorders of the functioning of the genital organs) and intestines (gastrointestinal diseases).

2. In the functioning of all phagocytic cells of the body, which are necessary for the body to fight microbes and foreign bodies. NO mediates inflammatory processes and is necessary in the formation of all related responses.

3. In neurotransmission (when transmitting a signal between neurons, including some structures of the brain). Exposure to this process leads to the possibility of alleviating the course of epileptic seizures and the consequences of strokes, Alzheimer's and Parkinson's disease, regulating the sensation of pain, duration of sleep, etc.

Cyclooxygenase is an enzyme that takes part in one of the main directions of arachidonic acid metabolism. It catalyzes the conversion of the latter to prostaglandins G ₂ and H ₂ , from which the remaining prostaglandins subsequently form.

Two main forms of cyclooxygenase (souslohepase, COX) are known: COX-I and COX-2. The first of them is a constitutive enzyme, constantly contained in the gastric mucosa, platelets, endothelium of blood vessels and in the kidneys. The second is inducible and is expressed in activated macrophages and monocytes, as well as in smooth muscle cells, epithelial and endothelial cells and neurons.

The products of the cyclooxygenase reaction - prostaglandins - take part in a large number of physiological and pathological processes in the body. The literature mentions the role of these compounds in regulating the secretion of gastric juice, blood pressure, platelet aggregation, and reproductive function. Finally, prostaglandins mediate the development of processes such as inflammation and pain. It is known that only the inducible form of cyclooxygenase — COX-2 — is involved in the latter, and therefore the search for selective inhibitors of this particular enzyme is of particular interest.

The literature describes structural analogues of the proposed compounds, which are biologically active compounds and are used in biology and medicine. In world practice, there are drugs used for these diseases, including those based on the action of NO synthetase inhibitors. Anti-inflammatory drugs are also known whose effect is caused by the inhibition of cyclooxygenase.

U.S. Pat. No. 5,874,472 discloses NO synthetase inhibitors in which the arginine side chain is modified to include five or six membered aromatic or heteroaromatic rings (thiophene, benzene, pyridine, etc.). The data on activity against NO synthetase isolated from various sources show activity at the level of Ki of 0.5-50 and higher nM. No toxicity information is provided for the compounds presented in this patent. Among other patented compounds exhibiting activity with respect to NO synthetase without specifying its specific values, it is necessary to mention JP N ° 10-120654, which describes 4-methyl-3,4-dehydro-2-imino-sherpidine derivatives.

Among the structural analogues of the proposed substances in the prior art there are also several compounds that inhibit MOR. So, for example, in the application EP JCHsZ 85662 describes heterocyclic compounds that manifest themselves as COX-2 inhibitors, but do not show activity against COX-I.

Application EP N ° 439265 discloses heterocyclic compounds which are cyclooxygenase and lipoxygenase inhibitors, which are used as antiallergenic and antimicrobial agents.

From US Pat. No. 5,064,837, compounds are known which are 3-substituted l-apyl-2 (H) -quinolones, effectively affecting 5-lipoxygenase and cyclooxygenase and, therefore, used as anti-inflammatory drugs with reduced side effects. JP 03-220160 discloses heterocyclic compounds, which are COX and lipoxygenase inhibitors, used to treat allergic and inflammatory diseases.

The described COX inhibitors have the structural formulas shown below:

A common disadvantage of these compounds is that they have an anti-inflammatory effect, vivo, but the observed activity with respect to COX-2 and vitro is approximately 200-500 times less, and selectivity with respect to COX-I is also not observed. In addition, in these sources there is no information about the detection of the activity of these compounds against inducible NO-synatase.

Derivatives of quinolone-2 are also described in the prior art for the treatment of various diseases.

Thus, for example, USNa6509352 describes quinolone-2 derivatives used as immunosuppressants, anti-inflammatory and anti-allergic drugs.

Derivatives of quinolone-2 are known from the patent RU N ° 2167874 for the treatment of hypertension, ischemia, myocardial infarction, angina pectoris, etc.

Application JP N ° 58-225065 describes anti-allergic and anti-asthmatic substances based on quinolone-2 and its derivatives.

US Pat. No. 5,646,132 discloses quinolone-2 derivatives useful for treating various forms of epilepsy, Alzheimer's disease, schizophrenia and sclerosis.

The quinolone-2 derivatives known from the application RU N ° 95-l 09098 are used as anticonvulsants. US Pat. No. 6,605,616 describes quinoline derivatives which are amides of 4-oxo-quinol-2-one-3-carboxylic acids on aromatic amines, which necessarily contain a methyl substituent at the nitrogen atom. These compounds were tested as inhibitors of acute experimental autoimmune encephalomyelitis, however, there is no mention of their activity against NO synthetase or MOR.

Thus, from the analysis of the data available in the above sources of information, we can draw the following conclusions.

one). Most currently known inhibitors are characterized by insufficient selectivity, which leads to the development of a variety of side effects when using drugs based on them.

2) To date, it has not been possible to find a COX-2 inhibitor that inhibits the inflammatory process, but does not have an ulcerogenic effect on the gastric mucosa characteristic of COX-I inhibitors. 3) Derivatives of quinolone-2, which are simultaneously inhibitors of NO synthetase and COX-2, are not known from the prior art.

4) The vast majority of existing inhibitors of both enzymes at the same time are characterized by insufficient selectivity with respect to their various isoforms, which leads to the development of various side effects when using drugs based on them.

5) It is extremely important to note that not one of the known sources reports on the synergism of the action of substances as inhibitors of inducible NO synthetase and inducible cyclooxygenase as the basis of the significant anti-inflammatory effect they show.

SUMMARY OF THE INVENTION

The problem to which the present invention is directed, is to obtain amino and hydroxy derivatives of phenyl-3-amino-methyl-quinolone-2, as well as derivatives of get-3-amino-methyl-quinolone-2, which have significantly higher activity (IC ₅₀ 1 -10 nM), as well as higher selectivity with respect to the corresponding enzyme isoforms (inducible and neuronal NO synthetase and inducible cyclooxygenase compared to endothelial NO synthetase and constitutive cyclooxygenase) with simultaneous pronounced synergism of action, little toxic to the human body with no identified side effects.

Another objective of the present invention is to develop methods for the synthesis of these compounds, as well as pharmaceutical compositions containing a therapeutically effective amount thereof in combination with a pharmaceutically acceptable carrier.

The present invention proposes new compounds, which are inhibitors of the arginine site of inducible and neuronal NO synthetases, do not affect its endothelial form in the physiologically acceptable concentration range, and while they are inhibitors of the inducible form of cyclooxygenase, which are highly active and do not affect the constitutive form in same range. The description of the present application provides a method for inhibiting the conversion of arginine to nitric oxide by the inducible and neuronal forms of NO synthetase and a method for inhibiting cyclooxygenases of the first and second types, i.e., the concentrations of the inhibitors described below that are sufficient for effective inhibition of enzymes under physiological conditions, the conditions for their administration, as well as the method of their inhibition in conditions such as rheumatoid arthritis, pathologically low blood pressure, septic shock, colitis or autoimm nnye disorders, conditions and methods of administration and dosing of these inhibitors, sufficient to achieve a therapeutic effect. The effectiveness of the proposed methods is due to the synergism of the actions of patented compounds as inhibitors of COX and inducible NO synthetase. The proposed substances are new derivatives of quinolone-2, namely the amino and hydroxy derivatives of phenyl-3-aminomethyl-quinolone-2, as well as get -yl-3-aminomethyl-quinolone-2, and are positioned as inhibitors of the so-called inducible N and neuronal -synthetases responsible for the generation of NO, mainly in phagocytic cells and neurons, as well as cyclooxygenase, primarily of the second type, which ensures the generation of prostaglandins in them. Medicines created on the basis of these substances can be used to treat a number of diseases, such as rheumatoid arthritis, asthma, colitis and the like. The compounds claimed in the present invention are mainly secondary amines, in contrast to the known analogues, which are tertiary amides. This important difference causes a difference in the methods of synthesis and physicochemical properties of the obtained compounds. In addition, in the claimed compounds, the substituent at position 4 of the quinoline ring is H or AIk, unlike the acloxy substituent (-OR) at the same position in the known compounds described in the above patents.

Thus, we can conclude that both the claimed derivatives of 3-aminomethyl-quinolone-2 and their inhibitory properties with respect to NO synthetase and COX-2 are not known from the achieved scientific and technical level.

Detailed disclosure of the invention.

The following notation is used in the description and claims:

“OAlk” means an alkoxy group, i.e. an alkyl group attached to a fragment of the parent molecule through an oxygen atom. Non-limiting examples of alkoxy groups are methoxy, ethoxy, propoxy, butoxy, etc. "Alk" means alkyl, i.e. straight or branched chain saturated hydrocarbon containing from 1 to 10 carbon atoms. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, etc.

"SAlk" means thioalkyl, i.e. an alkyl group attached to a fragment of the parent molecule through a sulfur atom. Examples of thioalkyls, without limiting the scope of the present invention, include, for example, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, etc.

“SO ₂ Alk” means alkylsulfonyl, i.e. an alkyl group attached to a fragment of the parent molecule through a sulfonyl group — SO ₂ . Examples of alkylsulfonyls are. Without limiting the scope of this invention, methylsulfonyl, ethylsulfonyl, etc.

“Ar” means aryl, i.e. monocyclic aromatic system, for example, without limiting the scope of the invention, benzyl, phenyl, etc.

“H” means hydrogen. "NO ₂ " refers to a nitro group.

"NH ₂ " refers to an amino group.

“Hal” means halogen: F, Cl or Br.

“Het” means a heterocycle and includes a mono- or bicyclic system. The monocyclic system may contain a 3- or 4-membered ring containing a heteroatom independently selected from oxygen, nitrogen or sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur. 5-membered ring contains

0-2 double bonds, and the 6- and 7-membered ring contains 0-3 double bonds. Non-limiting examples of monocyclic heterocycles are furyl, imidazolyl, morpholinyl, scherazinyl, piperidinyl, pyranyl, etc. Bicyclic systems are represented by any of the above monocyclic heterocycles attached to any aromatic group described above. Examples of such systems, not limiting the scope of this invention, are: indazolyl, quinolinyl, etc.

“OH” refers to a hydroxy group.

“CO” means a carbonyl group.

“COOAlk” means alkoxycarbonyl, i.e. alkoxygroup attached to the fragment of the original molecule through a carbonyl group.

Non-limiting examples of alkoxycarbonyls are: methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.

“CN” means a cyano group. “COOH” means a carboxy group.

“Bz” means a monocyclic aromatic radical benzyl.

In accordance with one aspect of the invention, amino derivatives of phenyl-3-aminomethyl-quinolone-2 are provided having the general formula (1):

Where:

Rl, R2, R3, R4 are H; or

Rl, R2, R3, R4 are independently the same or different, and at least one of Rl, R2, R3, R4 is selected from the group consisting of:

AIk, OAIk, Ar, OAr, CH ₂ C ₆ H ₅ , SAIk, F, Cl, Br, OCF ₃ , NO ₂ , NH ₂ , NHAIk, N (AIk) ₂ ; wherein the other or the other of Rl, R2, R3, R4 are H; or

R 2 and R 3 are taken together and selected from - (CH ₂ ) s -, - (CH ₂ ) ₄ -, -OCH ₂ O-, - OCH ₂ CH ₂ O-, with Rl and R4 being the same or different and independently selected from H, AIk, OAIk, HaI;

R5 is independently selected from H or AIk;

R6 is independently selected from H, AIk, CH ₂ NO ₂ ;

R7, R8, RlO, RIl are independently the same or different, and at least one of R7, R8, RlO, RIl is selected from AIk, OAIk, CH ₂ OH, SAIk,

Ar, OAr, F, Cl, Br, CF ₃ , OCF ₃ , COORi ₄ , COONR ₁₅ Ri ₆ , NRI ₇ RJ ₈ , NHCOR ₁₉ , SO ₂ NR ₂₀ R _2I , NO ₂ ; where R14, R15, R16, R17, R18, R19, R20, R21 are the same or different and are independently selected from H or AIk; wherein the other or other of R7, R8, RlO, RIl are H;

R9 is independently selected from H or from the following substituents:

where (*) corresponds to the point of attachment of the bond of the substituent R9 to the phenyl moiety in the formula (I); n is 1, 2, 3 or 4;

X is independently selected from OH or AIk;

Y is independently selected from AIk, OAIk, Ar, or He;

R22, R23 are independently selected from H, AIk, OAIk, SAIk, HaI, COOH, COOAIk, SO ₂ AIk ₅ NO ₂ , CN;

R24, R25 are the same or different and are independently selected from H, AIk;

R26 is independently selected from H or AIk;

R27, R28 are independently selected from H, AIk, OAIk, HaI, NO ₂ , CN; or and

R8 and R9 are taken together and selected from - (CH ₂ ) s-, - (CH ₂ V? -OCH ₂ O-, - OCH ₂ CH ₂ -, while R7, RIl are independently the same or different and are selected from H, HaI, NO ₂ ; and RlO is H; Rl 2, Rl 3 are independently the same or different and are selected from the group consisting of H, AIk, Bz.

Specific compounds corresponding to the general formula (1) include, for example, the following, but not limited to: 3 - [(4-dimethylamino-phenylamino) methyl] -5,6,7-trimethoxy-S-quinolin-2 ~ one ;

3 - [(4-dimethylamino-phenylamino) methyl] b-ethyl- 1 H-quinoline-2-one;

6-ethoxy-3 - [(4-pyppolidin-1-yl-phenylamino) methyl] - 1 H-quinoline-2-one;

7-methoxy-3 - [(4-piperidin-l-yl-phenylamino) methyl] -Sh-quinolin-2-one;

7-ethoxy-3 - [(4-piperidin-l-yl-phenylamino) -methylj-lH-quinolin-2-one; 7-methyl-3 - [(4-morpholin-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one;

6-ethoxy-3 - [(4-morpholin-l-yl-phenylamino) -methyl-lH-quinolin-2-one;

6-isopropyl-3 - [(4-morpholin-l-yl-phenylamino) methyl] -Sh-quinolin-2-one;

7 - [(4-morpholin-l-yl-phenylamino) -m-ethyl] -5H- [l, 3] dioxol [4.5] quinolin-6-one;

6-methyl-3 {[4- (4-methyl-piperidin-l-yl) phenylamino] methyl} -Sh-quinolin-2-one; 7-methoxy-3 {[4- (4-methyl-sherpidin-1-yl) -phenylamino] -methyl} - 1 H-quinolin-2-

it ;

3 - [(4-dimethylamino-phenylamino) methyl] -5,6,7-trimethoxy-III-quinolin-2-one;

3 - [(4-dimethylamino-phenylamino) methyl] -6-ethyl-lH-quinolin-2-one;

6-ethoxy-3 - [(4-shrppolidin-1-yl-phenylamino) methyl] ~ 1 H-quinolin-2-one;

7-methoxy-3 - [(4-piperidin-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one;

7-ethoxy-3 - [(4-piperidin-l-yl-phenylamino) methyl] -Sh-quinolin-2-one;

7-methyl-3 - [(4-morpho-ling-1-yl-phenylamino) -methyl] - 1 H-quinolin-2-one;

6-ethoxy-3 - [(4-morpholin-l-yl-phenylamino) methyl] -Sh-quinolin-2-one; 6-isopropyl-3 - [(4-morpholin-l-yl-phenylamino) methyl] -Sh-quinolin-2-one;

7 - [(4-morpholin-l-yl-phenylamino) -m-ethyl] -5H- [l, 3] dioxol [4.5] quinolin-6-one;

6-methyl-3 {[4- (4-methyl-piperidin-l-yl) phenylamino] methyl} -Sh-quinolin-2-one;

7-mexoxy-3 {[4- (4-methyl-piperidin-1-yl) phenylamino] methyl] -1 H-quinolin-2-one;

7 - {[4- (3-hydroxy-piperidin-l-yl) phenylamino] methyl] -5H- [l, 3] dioxolo [4,5-g] quinolin-6-one;

8 - {[4- (3-hydroxy-piperidin-l-yl) -phenylamino] -methyl} -2,3-dihydro-6H-

[l, 4] dioxo [2,3-g] quinolin-7-one; 3 - {[4- (4-carboethoxy-piperidin-l-yl) phenylamino] methyl] -7-methyl-III-quinolin-2-one;

3 - {[4- (4-carboethoxy-piper din-1-l) phenylamino] methyl} - 8-methyl-1 H-quinolin-2-one;

3 - {[4- (3-carboethoxy-piperidin-l-yl) phenylamino] methyl] -6-methoxy-Sh-quinolin-2-one;

3- {[4- (3-carboethoxy-piperidin-1-yl) phenylamino] methyl] -7-methoxy-1 H-quinolin-2-one;

3 - {[4- (cyclohexyl-methyl-amino) -phenylamino] -methyl} -5,8-dimethyl-Ш-quinolin-

2-one; 7 - {[4- (cyclohexyl-methyl-amino) phenylamino] methyl} -5H- [l, 3] dioxole [4,5-g] quinolin-6-one; b-methyl-3- {[4- (4-methyl-piperazin-1-yl) phenylamino] methyl] -1 H-quinolin-2-one;

3 - {[4- (3-carboethoxy-piperidin-l-yl) phenylamino] methyl] -7-methoxy-lH-quinolin-2-one; 3 - {[4- (cyclorexyl-methyl-amshϊθ) -phenylamino] -methyl} -5,8-dimethyl-lH-quinoline-

2-one; 7 - {[4- (cyclohexyl-methyl-amino) phenylamino] methyl} -5H- [l, 3] dioxole [4,5-g] quinolin-6-one; b-methyl-3 - {[4- (4-methyl-piperazin-1-yl) phenylamino] methyl] -1 H-quinolin-2-one;

5,8-dimethyl-3 - {[4- (4-methyl-piperazin-l-yl) phenylamino] methyl] -H-quinolin-2-one;

3 - {[4- (4-acetyl-piperazin-l-yl) phenylamino] methyl] -7-ethoxy-W-quinolin-2-one;

7 - {[4- (4-acetyl-piperazin-l-yl) phenylamino] methyl} -5H- [l, 3] dioxolo [4,5-g] quinolin-6-one; 3 - ({4- [4- (fyran-2-carbonyl) -piperazin-l-yl] phenylamino} methyl) -5,7-dimethyl-

1 H-quinolin-2-one;

3 - ({4- [4- (pyran-2-carbonyl) -piperazine-1-yl] phenylamino} -methyl) -5, 8-dimethyl-

1 H-quinolin-2-one;

7-methyl-3 - {[4- (4-benzyl-piperazin-1-yl) phenylamino] methyl] - 1 H-quinolin-2-one; 5,6,7-trimethoxy-3 {[4- (4-phenyl-piperazin-l-yl) -phenylamino] methyl] -H- quinolin-2-one;

3- {[4- (3,4-dihydro-1 H-isoxinolin-2-yl) phenylamino] methyl] -7-methyl-1 H-quinolin-2-one;

6,7-dimethoxy-3 - {[4- (4-pyrimid-2-yl-piperazin-l-yl) -phenylamino] methyl] -H- quinolin-2-one;

6-methoxy-3 - {[4- (4-irapid-2-yl-piperazin-1-yl) -phenylamino] -methyl} - 1 H-quinolin-2-one;

6,7-dimethoxy-3 - [(2-methyl-l-yl-phenylamino) methyl] -H-quinolin-2-one;

1-ethyl-7-methoxy-3 - [(4-morpholin-4-yl-phenylamino) -methyl] - 1 H-quinolin-2-one; 3- ({[4- (4-hydroxy-piperidin-1-yl) phenyl] methyl-amino} -6-methoxy-l H-quinolin-2-one; 7-methoxy-1-methyl-3- {[methyl- (4-morpholin-4-yl-phenyl) -amino] -methyl} - 1 H-quinolin-2-one;

3 - [(4-ethoxy-phenylamino) methyl] -1-ethyl-7-methoxy-1 H-quinolin-2-one;

3 - {[(2,4-dimethoxy-phenyl) methyl-amino] methyl} -l, 6-dimethyl-III-quinolin-2-one;

3 - [(3,4-dimethoxy-phenylamino) methyl] -7-methoxy-III-quinolin-2-one;

3 - [(benzene [l, 3] dioxol-5-yl-methyl-amino) -methyl] -6,7-dimethyl-Ш-quinolin-2-one;

7-methoxy-3- {4- [4- (2-methoxy-ethyl) piperazin-l-yl] phenylamino} methyl) - 1 H-quinolin-2-one;

3- {[4- (3-hydroxy-piperidin-1-yl) phenylamino] methyl] -1, 6,7-trimethyl-1 H-quinolin-2-one;

In accordance with another aspect of the invention, hydroxy derivatives of phenyl-3-aminomethyl-quinolone-2 are provided having the general formula (2):

Where:

Rl, R2, R3, R4 are H; or

Rl, R2, RZ, R4 are independently the same or different, and at least one of Rl, R2, RZ, R4 is selected from the group consisting of: AIk, OAIk, Ar, OAr, CH ₂ C ₆ H ₅ , SAIk, F, Cl, Br, OCF ₃ , NO ₂ , NH ₂ , NHAIk, N (AIk) ₂ ; wherein the other or the other of Rl, R2, R3, R4 are H; or

R 2 and R 3 are taken together and selected from - (CH ₂ ) s -, - (CH ₂ ) ₄ -, -OCH ₂ O-, - OCH ₂ CH ₂ O-, with Rl and R4 being the same or different and independently selected from H, AIk, OAIk, HaI; R5 is independently selected from H or AIk;

R6 is independently selected from H, AIk, CH ₂ NO ₂ ; at least one of R7, R8, R9, RlO, RIl is OH, and the other or the other of R7, R8, R9, RlO, RIl are independently the same or different and are selected from H, AIk, OAIk, Ar, OAr, SAIk;

Rl 2, Rl 3 are independently the same or different and are selected from the group consisting of H, AIk, Bz.

Particular compounds corresponding to general formula (2) include, for example, the following, but not limited to: 3 - [(3,4-dihydroxy-phenylamino) methyl] -5,7-dimethyl-III-quinolin-2-one ;

3 - [(2,4-dihydroxy-phenylamino) methyl] b, 7-dimethyl-lH-quinolin-2-one; 3 - [(3,5-dihydroxy-phenylamino) methyl] -6-methyl-III-quinolin-2-one; 3 - [(2-hydroxy-phenylamino) methyl] -6-ethyl-1 H-quinolin-2-one;

In accordance with a third aspect of the invention, there are provided derivatives of hetapyl-3-aminomethylquinolinone-2 having the general formula (3):

Where:

Rl, R2, R3, R4 are H; or

Rl, R2, RZ, R4 are independently the same or different, and at least one of Rl, R2, RZ, R4 is selected from the group consisting of: AIk, OAIk, Ar, OAr, CH ₂ C ₆ H ₅ , SAIk, F, Cl, Br, OCF ₃ , NO ₂ , NH ₂ , NHAIk,

N (AIk) ₂ ; wherein the other or the other of Rl, R2, R3, R4 are H;

or

R2 and R3 are taken together and selected from - (CH ₂ ) s- _? - (CH ₂ ). = -, -OCH ₂ O-, - OCH ₂ CH ₂ O-, with Rl and R4 being the same or different and

independently selected from H, AIk, OAIk, HaI; R5 is independently selected from H or AIk;

R6 is independently selected from H, AIk, CH ₂ NO ₂ ;

Rl 2, Rl 3 are independently the same or different and are selected from the group consisting of H, AIk, Bz.

R9 is independently selected from the following substituents:

where (*) corresponds to the attachment site of the heterocyclic bond

a substituent, R29 to a nitrogen atom in the formula (3);

RZO, R31 are the same or different and independently selected

from H, AIk, OAIk, SAIk, OH, HaI, COOH, CONH ₂ , COOAIk, COR34;

where R34 is independently selected from the following substituents:

where (*) corresponds to the site of attachment of the heterocyclic substituent R34 to the oxygen atom of the carbonyl group; R32, RZZ are independently selected from H, AIk, OAIk;

Specific compounds corresponding to the general formula (3) include, for example, the following, but are not limited to:

3 - [(9,9-dioxo-9,10-dihydro-9λ ^* 6 ^* -thia-10-aza-phenanthen-3-ylamino) -methyl] -7-methyl-Ш-quinolin-2-one; 3 - [(2,6-dimethoxy-pyridin-3-ylamino) methyl] -l, 6,7,8-tetrahydrocyclopenta [g] quinolin-2-one;

3 - [(W, 1 H [2,5] bisbenzimidazolyl-5-ylamino) methyl] -6,7-dimethoxy-Sh-quinolin-2-one;

3- [(1 H-indazol-5-ylamino) methyl] b-methyl-1 H-quinolin-2-one; 7-ethoxy-3 - [(3-hydroxy-6-methyl-pyridin-2-ylamino) methyl] - 1 H-quinolin-2-one;

7-methyl-3 - [(3-methyl-4-tetrazol-l-yl-phenylamino) methyl] -lH-quinolin-2-one;

8-methyl-3 - [(2-pyridin-3-yl-Ш-benzoimidazole-5-ylamino) -methyl] -Sh-quinolin-

2-one;

6-ethyl-3 - [(5-methoxy-quinolin-8-ylamino) -methyl] -S-quinolin-2-one; 7-ethoxy-3- (quinolin-5-ylaminomethyl) - 1 H-quinolin-2-one; b-methoxy-3 - [(3-methoxy-4-tetrazol-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one;

3 - [(2-Hydroxy-5-methyl-pyridin-3-ylamino) methyl] -7-methoxy-W-quinolin-2-one;

3 - [(b-ethoxy-pyridin-3-ylamino) methyl] -6-methoxy-lH-quinolin-2-one;

3 - [(4, b-dimethyl-pyridin-2-ylamino) methyl] -5,7-dimethyl-Ш-quinolin-2-one; b, 7-dimethoxy-3 - [(2-methyl-5-pyrpol-1-yl-phenylamino) -methyl] - 1 H-quinolin-2-one; 6-methyl-3- (pyridin-3-ylamino-methyl) -Sh-quinolin-2-one;

3 - [(2-hydroxy-pyridin-3-ylamino) methyl] - 1 H-quinolin-2-one;

3 - [(10, ll-dihydro-5H-dibenzo [b, f] azepin-3-ylamino) methyl] -7-methoxy-Sh-quinolin-2-one;

3 - [(3-quinoxcalil-2-yl-phenylamino) methyl] -H-quinolin-2-one;

7 - ({4- [2- (l-methyl-SH-benzimidazol-2-yl) ethyl] phenylamino} methyl) -5H-

[l, 3] dioxol [4,5-g] quinolin-6-one;

N- {5 - [(7-ethoxy-2-oxo-l, 2-dihydro-quinolin-3-ylmethyl) -amino] -benzothiazol-2-yl} -acetamide;

3 - [(2-ethoxy-pyridin-3-ylamino) methyl] -8-methyl-III-quinolin-2-one;

3 - [(2,4-di-piperidin-l-yl-phenylaminaminamino) methyl] -5,7-dimethyl-III-quinoline-

2-one;

7-ethyl-3 {[4- (5-oxo- [l, 4] diazepan-1-yl) phenylamino] methyl] - 1 H-quinolin-2-one;

3- {4- [4- (2-methoxy-ethyl) -piperazin-1-yl] phenylamino} -methyl) -6-methyl-1 H-quinolin-2-one;

The problem is also solved by the methods of obtaining the proposed amino and hydroxy derivatives of phenyl-3-aminomethyl-quinolone-2, as well as getapyl-3-aminomethyl-quinolone-2, having the above general formulas (1-3), and biologically active compounds and a pharmaceutical composition based on them.

The synthesis of the proposed compounds having the general formula (1) is carried out by reacting the corresponding substituted 2-quinolone-3-carbaldehyde with the corresponding phenylenediamine derivatives. Further, the obtained azomethines or the so-called Piff compounds are reduced. The synthesis of the proposed compounds having the general formula (2) is carried out by reacting the corresponding substituted 2-quinolone-3-carbaldehyde with various anisidines, then the resulting Schiff bases are reduced, after which the alkyl esters are cleaved with Lewis acids. The synthesis of the proposed compounds having the General formula (3) is carried out by the interaction of the corresponding substituted 2-quinolone-3-carbaldehyde with various heterocyclic compounds containing an amino group, followed by reduction of the resulting Schiff bases.

The preparation of the corresponding starting 2-quinolone-3-carbidederivers is carried out in several stages and the synthesis sequence is described in more detail in Scheme 1:

Scheme 1.

In the first step, substituted acetanilides are synthesized from anilines with substituents Rl, R2, R3, R4, such as described above. Next, the synthesized acetanilide is added to the Vilsmeier formative mixture obtained by dropping POCl ₃ to dimethylformamide. At this stage, two options for its implementation are possible: with cooling the reaction mixture (example 1) or with its heating to 50 ° C (example 3). It should be noted that the choice of starting acetanilides for the reaction under consideration is determined by the nature of the substituents in the benzene fragment. Most preferred is the presence of electron-donating substituents in the benzene ring, while the presence of weak electron-withdrawing substituents leads to a significant decrease in the yield of the target reaction products. In the case of metasubstituted acetanilides, the direction of the reaction is regioselective with the formation of almost one isomer, namely, 7-substituted quinolines. After adding the selected acetanilide to the formative mixture, the reaction mixture is maintained, then the temperature is gradually raised to 90-100 ° C. The reaction time ranges from 8 to 24 hours. Isolation of 2-chlorop-quinolin-3-carbide synthesized at this stage is carried out by hydrolysis the reaction mixture in a large excess of finely divided ice (it was experimentally found that at least 1 kg of ice is required per 100 ml of the reaction mixture). The desired reaction products isolated after hydrolysis are solids and are used, as a rule, without additional purification. However, if necessary, they can be recrystallized from a suitable solvent, for example acetone, chloroform or ethyl acetate.

The final stage in the synthesis of substituted 2-quinolone-3-carbaldehydes is the hydrolysis of the corresponding 2-chloropinquinoline-3-carbaldehydes by boiling them in aqueous acetic acid (the concentration of acetic acid is about 80-90%) (example 2). The reaction time ranges from 4 to 12 hours. The reaction product, as a rule, is isolated in the form of a crystalline substance as the reaction proceeds, or after completion of the process by cooling the reaction mixture. The resulting substituted 2-quinolone-3-carbaldehydes were usually used in further transformations without further purification. If necessary, the synthesized substances were brought to the required degree of purity by recrystallization from acetic acid or dimethylformamide.

Some substituted p-phenylenediamine necessary for the synthesis of the target products are obtained in two stages according to scheme 2:

Scheme 2.

As one of the starting compounds, 4-chloronitrobenzene can be used in which the substituents R7, R8, RlO, RI l are as described above. In the first stage, the corresponding N, N-disubstituted p-nitrobenzene at 80-100 ° C is obtained as a result of nucleophilic substitution reaction (Example 43). Substituent R9 is selected from the above groups. The reaction is usually carried out with an excess of the corresponding amine or the environment of the secondary amine itself. In some cases, the interaction is carried out in a medium of dimethylformamide (example 61) or another solvent (acetonitrile, dioxane, etc.) in the presence of an inorganic base (potash, soda, etc.). Purification of the obtained nitro compounds is carried out by recrystallization from a suitable solvent or separation using silica gel column chromatography.

In the second stage, the obtained nitro derivatives are reduced to the corresponding amines using any reducing reagents available and suitable for this type of reaction (catalytic hydrogenolysis (example 44), reduction with hydrazine hydrate in the presence of Raney nickel (example 72), iron in hydrochloric acid, tin chloride and other). The synthesized amines are purified by recrystallization or silica gel column chromatography is used. Often, the amines obtained are not stable substances and are rapidly oxidized by atmospheric oxygen, as a result of which there is a need to use these compounds in further syntheses immediately after their preparation.

The final target products - amino derivatives of phenyl-3-aminomethyl-quinolone-2 receive according to scheme 3:

Scheme 3.

At this stage, the corresponding substituted 2-quinolone-3-carbaldehydes and p-phenylenediamine obtained according to the above schemes I and 2 are used.

Schiff bases and the corresponding hydroxyenamines, as one of the possible intermediates that may be formed as a result of the reaction, are reduced to give the final desired products. As one of the options, an intermediate allocation of Schiff bases is possible. In this case, the reaction is most often carried out in dioxane or in dimethylformamide with temperature of about 100 ⁰ C. The resulting Schiff bases are reduced without further purification with sodium borohydride in alcohol (methanol, ethanol).

In the case of a synthesis variant without intermediate isolation of Schiff bases, the reaction is carried out in an inert solvent (acetonitrile, dichloroethane, etc.). Initially, for some time (about 1 hour), the reaction between the corresponding aldehyde and the primary amine is carried out with gentle heating. Subsequently, sodium triacetoxyborohydride or sodium cyanoborohydride is added in portions with effective stirring in the reaction mass (example 73). If necessary, a small amount of acetic acid is added. At the end of the process, the reaction mixture is diluted with an aqueous solution of soda or potash. The organic layer was separated, dried. The resulting desired products are recrystallized from a suitable solvent or purified by silica gel column chromatography.

Conducting synthesis with an intermediate isolation of Schiff bases or without their isolation is determined only by convenience and expediency. For example, if the Schiff bases formed are unstable, then, obviously, their selection is impractical, and in some cases simply impossible. On the other hand, if further synthesis requires additional purification of Schiff bases, their isolation is desirable.

The final target products - hydroxy derivatives of phenyl-3-aminomethyl-quinolone-2, corresponding to the general formula (2), are obtained according to scheme 4:

Scheme 4.

In this scheme, pre-synthesized substituted 2-quinolin-3-carbaldehydes obtained according to the above scheme 1, and anisidines are used. The reduction of Schiff bases gives the corresponding alkyl esters, which are further cleaved by acids Lewis to obtain the target products containing a free hydroxyl group in the compounds of General formula (2). Depending on the selected starting anisidine, it is possible to obtain the desired final compounds with one or more hadroxyl groups in the phenyl moiety. For the synthesis, anisidines synthesized both by methods known from the literature and commercially available can be used. As the Lewis acid, boron tribromide is used (Example 128). The reaction is carried out at very low temperatures (up to -50 ⁰ C) in inert solvents such as methylene chloride. At the end of the reaction, the mixture is decomposed with absolute methanol. Purification of the resulting substances is carried out by recrystallization from a suitable solvent.

The desired target products - derivatives of heteryl-3-aminomethyl-quinolone-2 are obtained according to scheme 5:

Scheme 5.

The starting compounds used are the corresponding substituted 2-quinolone-3-carbaldehyde synthesized according to Scheme I ₅ and the corresponding heterocyclic compounds in which there are amino groups. Next, Schiff bases are obtained, which are then reduced. As noted above, the reaction is possible both with an intermediate isolation of Schiff bases, and without it. In the latter case, the synthesis is carried out under the conditions of a reductive amination reaction.

Replacement of R6, Rl 2 and Rl 3 with other substituents other than H mentioned above can be carried out by reacting the compounds obtained in accordance with the above schemes 1-5 with reagents containing these groups by carrying out the corresponding reactions. The compounds described in this invention may exist in the form of therapeutically acceptable salts. This means that the salts of these * compounds are soluble or dispersible in water or oils, toxic and acceptable for the treatment of diseases without side effects, do not cause allergies. Salts can be prepared by finishing the desired product or separately by reaction with a suitable acid. Such salts may be alginates, aspartates, acetates, benzoates, benzosulfonates, bigluconates, bromides, butyrates, glycerophosphates, gluconates, camphorites, camphorsulfonates, lactates, maleates, nicotinates, oxalates, pectinates, persulfates, propionates, subcinates, tincinates, subcinate, citrates, sulfides, phosphates, etc.

Basic salts can be prepared in the process of final cleaning of the target product or separately by interaction with a base containing lithium, sodium, potassium, calcium, magnesium or aluminum ions.

The compounds described in this invention may exist as prodrugs.

This means that prodrugs that are acceptable for contacting patients with diseases are non-toxic, do not cause side effects and allergies. This term refers to compounds that are rapidly transformed ip vivo into compounds of formulas (1), (2) or (3), for example, by hydrolysis in blood.

Pharmaceutical compositions of the subject compounds include effective amounts thereof with one or more pharmaceutically acceptable excipients. This term refers to non-toxic, solid, semi-solid and liquid fillers, solvents, encapsulating materials. Examples of such excipients are sugars, cellulose or its derivatives, oils, glycols, solutions; buffering, coloring, coating, softening, flavoring perfumes, etc. The pharmaceutical compositions may be administered parenterally, intracisternally, orally, rectally or intraperitoneally. Liquid forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups H elixirs. In this case, in addition to the claimed compounds, they contain solvents and / or emulsifiers. In addition to inert solvents, oral compositions may include wetting, emulsifying, flavoring and perfuming agents. These drugs must be sterilized by filtration through filters that trap bacteria, or contain sterilizing agents.

Solid forms for oral administration are capsules, tablets, pills, powders or granules. In this case, the claimed compound is mixed with at least one inert, therapeutically acceptable excipient, such as a carrier, diluent, adsorbent, wetting or lubricating material. These compositions may also optionally include buffering agents. Suppositories for rectal administration can be prepared by mixing the claimed compounds with excipients that are solid at ordinary temperature, but liquid when ingested.

The claimed compounds can be encapsulated or microencapsulated with one or more inert excipients described above. Tablets, dragees, capsules, pills or granules may be coated. To this end, the claimed compounds can be mixed with at least one inert solvent and a tabletting lubricant or additive.

Preferred Embodiments

Example 1

Synthesis of 2-chlorop-6-methylquinolin-3-carbaldehyde (I).

To the Vilsmeier formulating mixture obtained by dropping with simultaneous cooling of 170 ml (1.75 mol) of POCl ₃ to 60 ml (0.75 mol) of dimethylformamide, 37.3 g (0.25 mol) of N-para-tolyl acetanilide are added with simultaneous vigorous stirring and cooling. The reaction mixture is kept at room temperature for 1 hour, then the temperature is raised to 90-100 C and maintained at this temperature. Next, the reaction mixture is cooled and poured onto 1.5 kg of finely divided ice. After hydrolysis, the resulting suspension is filtered, the precipitate is washed with water until slightly acidic or neutral (pH> 5). 38 g (75%) of product (I) are obtained. An analytically pure sample is isolated by recrystallization from acetone or chloroform. T. pl. 127- 128 ⁰ C. According to published data, 124-125 ⁰ C, ethyl acetate (see Мeth-Сhп, Отоо; Narіpe, Вrаmha; Таmowski, Врап; JCPRB4; J.Сhem.Sos.Реrkiп Trans. 1; EN; 1981 ; 1520-1530).

H-NMR spectrum (δ, DMSO-d ₆ ): 2.4 (ЗН, s), 7.8 (IH, d, J = 8.5 Hz), 7.9 (IH, d, J = 8.5 Hz), 8.0 (IH, d, J = 3.5 Hz), 8.8 (IH, s), 10.4 (IH, s).

Example 2

Synthesis of 6-methyl-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (II).

2-Chlorop-6-methylquinolin-3-carbaldehyde (38 g, 0.185 mol) is dissolved in 250 ml of a mixture of acetic acid - water (10: 1 ratio) and boiled for 3-4 hours. At the end of the reaction, product (II) begins to precipitate from the boiling solution. The reaction mixture is cooled, the precipitate is filtered, washed with a mixture of alcohol-water, then with water to remove residual acetic acid. 22 g (65%) of product (II) are isolated. An analytically pure sample is obtained by recrystallization from dimethylformamide. T. pl. 310-312 ⁰ C. According to published data - 275 ⁰ C, acetic acid (see Tilakraj, T .; Ambekar, Sarvottam Y .; JICSAH; J.Ipdiap Chem.Soc; EN; 62; 3; 1985; 251-253 )

H-NMR spectrum (δ, DMSO-d _b ): 2.2 (3H, s), 7.2 (IH, d, J = 8.5 Hz), 7.5 (IH, d, J = 8.5 Hz), 7.6 (IH, d, J = 3.5 Hz), 8.5 (IH, s), 10.1 (IH, s), 12.0 (IH, broad peak).

Example 3

Synthesis of 2-chlorop-8-methylquinolin-3-carbaldehyde (III).

The formulating mixture is prepared according to Example 1 and 37.3 g (0.25 mol) of N-ortho-tolyl acetanilide are added at a temperature of about 50 ^° C. The resulting reaction mixture is maintained at the indicated temperature for 1 hour, then the temperature of the reaction mixture is raised to 90-100 ⁰ C and withstand. Next, the reaction mixture is cooled and poured onto 1.5 kg of finely divided ice. After hydrolysis, the resulting suspension is filtered off, washed with water until slightly acidic or neutral (pH> 5). 28 g (54%) of product (III) are isolated. An analytically pure sample is obtained by recrystallization from acetone or chloroform. T. pl. 134-136 ⁰ C. According to published data, 137-138 ⁰ C, ethyl acetate (see Меt-Сhп, Оttо; Narіpe, Вrmkhа; Тamоwski, Врап; JCPRB4; J. Сhem. Сос.Реркип Trans. 1; EN; 1981 ; 1520-1530).

Ni-NMR spectrum (δ, DMSO-d _b ): 2.6 (3H, s), 7.6 (IH, t, J = 8.5 Hz), 7.9 (IH, d, J = 8.5 Hz), 8.0 (IH, d, J = 8.5 Hz), 8.9 (IH, s), 10.2 (IH, s).

Example 4

Synthesis of 8-methyl-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (IV).

Conducted according to the methodology described in example 2. Obtain 26.5 g (74%) of product (IV). Mp 299-300 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.4 (ЗН, s); 7.1 (IH, t, J = 8.5 Hz); 7.5 (IH, d,

J = 8.5 Hz); 7.7 (IH, d, J = 8.5 Hz); 8.5 (IH, s); 10.1 (IH, s); 11.0 (IH ₃ broad peak).

Example 5

Synthesis of 2-chlorop-7-methylquinolin-3-carbaldehyde (V).

Conducted according to the methodology described in example 1. Receive 42 g (82%) of product (V). T. pl. 143-144 ⁰ C (lit. 144-145 ⁰ C, ethyl acetate, [18]).

H _r NMR spectrum (δ, DMSO-d _b ): 2.4 (ЗН, s), 7.6 (IH, d, J = 8.5 Hz), 7.7 (IH, d, J = 3.5 Hz), 8.2 (IH, d, J = 8.5 Hz), 8.9 (IH, s), 10.4 (IH, s).

Example 6

Synthesis of 7-methyl-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (VI).

Conducted according to the methodology described in example 2. Receive 24.5 g (78%) of product (VI). Mp 296-297 ⁰ C. H-NMR spectrum (δ, DMSO-d _b ): 2.2 (3H, s); 6.9 (IH, d, J = 8.5 Hz); 7.1 (IH, s);

7.7 (IH, d, J = 8.5 Hz); 8.2 (IH, s); 10.1 (IH, s); 12.0 (IH, broad peak).

Example 7

Synthesis of 2-chlorop-6-ethoxyquinolin-3-carbaldehyde (VII).

Conducted according to the methodology described in example 3. Receive 36 g (60%) of the product (VII). Mp 168-170 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d _b ): 1.3 (3H, t, J = 7.5 Hz), 4.2 (2H, q, J = 7.5 Hz), 7.6 (3H, m), 7.9 (IH, d, J = 8.5 Hz), 8.8 (IH, s), 10.4 (IH, s).

Example 8

Synthesis of 6-ethoxy-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (VIII).

Conducted according to the methodology described in example 2. Receive 25g (73%) of the product (VIII). Mp 298-300 ⁰ C (decomp.).

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.1 (3H, t, J = 7.5 Hz); 4.0 (2H, q, J = 7.5 Hz); 7.2 (2H, m); 7.4 (IH, s); 8.4 (IH, s); 10.1 (IH, s); 12.0 (IH, broad peak).

Example 9

Synthesis of 2-chlorop-5,8-dimethylquinolin-3-carbaldehyde (IX).

Conducted according to the methodology described in example 3. Obtain 30 g (55%) of product (IX). T. pl. 184-185 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d _b ): 2.6 (ЗН, s), 2.7 (ЗН, s), 7.4 (IH, d, J = 8.5 Hz), 7.7 (IH, d, J = 8.5 Hz) 8.8 (IH, s); 10.4 (IH, s).

Example 10

Synthesis of 5,8-dimethyl-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (X).

Conducted according to the methodology described in example 2. Obtain 26.5 g (74%) of product (X). Mp 297-298 ⁰ C. Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.2 (S, s); 2.5 (3H ₃ s); 6.9 (IH, d, J = 8.5 Hz);

7.2 (IH, d, J = 8.5 Hz); 8.5 (IH, s); 10.1 (IH, s); 11.1 (IH, broad peak).

Example 11

Synthesis of 2-chlorop-7-methoxyquiniline-3-carbaldehyde (XI).

Conducted according to the methodology described in example 1. Yield 45 g (81%). Mp

187-189 ⁰ C (lit. 197-198 ⁰ C, ethyl acetate, [16]).

Ni-NMR spectrum (δ, DMSO-d ₆ ): 3.8 (3H, s), 7.3 (3H, m), 8.1 (IH, d, J = 8.5 Hz), 8.8 (IH, s), 10.4 (IH ₅ from).

Example 12

Synthesis of 7-methoxy-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (XII).

Conducted according to the methodology described in example 2. Receive 22 g (64%). T. pl. 286-288 ⁰ C.

Ni-NMR spectrum (δ, DMCO-d ₆ ): 3.8 (S, s), 6.7 (IH, d, J = 3.5 Hz), 6.8 (IH ₅ d / d, J = 8.5 Hz / 3.5 Hz), 7.8 (IH, d, J = 8.5 Hz), 8.4 (IH, s), 10.2 (IH, s), 12.0 (IH, broad peak).

Example 13

Synthesis of 2-chlorop-6-ethylquinolin-3-carbaldehyde (XIII).

Conducted according to the methodology described in example 1. Receive 40 g (78%) of the product (XIII). T. pl. 95-97 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d _b ): 1.2 (3H, t, J = 7.5 Hz); 2.9 (2H, q, J = 7.5 Hz);

7.85 (IH, d \ d, J = 8.5 Hz \ J = 3.5 Hz); 7.95 (IH, d, J = 8.5 Hz); 8.05 (IH, d, J = 3.5 Hz); 8.9 (IH, s); 10.2 (IH, s).

Example 14

Synthesis of 6-ethyl-2-oxo-l, 2-dihydroxinolin-3-carbaledera (XIV). Conducted according to the methodology described in example 2. Receive 24.5 g

(78%) of product (XIV). Mp 240-241 ⁰ C.

H-NMR spectrum (δ, DMSO-d ₆ ): 1.2 (3H ₃ t, J = 7.5 Hz); 2.65 (2H, q, J = 7.5 Hz); 7.3 (IH, d, J = 8.5 Hz); 7.5 (IH, d \ d, J = 8.5 Hz \ J = 3.5 Hz); 7.7 (IH, d, J = 3.5 Hz); 8.3 (IH, s); 10.2 (IH, s); 12.0 (IH, broad peak).

Example 15

Synthesis of 2-chlorop-7,8-dimethylquinoline-3-carbaldehyde (XV).

Conducted according to the methodology described in example 1. Receive 40 g (75%) of product (XIV). T. pl. 124-126 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d _b ): 2.4 (ЗН, s), 2.6 (ЗН, s), 7.5 (IH, d, J = 8.5 Hz),

8.0 (IH, d, J = 8.5 Hz), 8.8 (IH, s), 10.4 (IH, s).

Example 16

Synthesis of 7,8-dimethyl-2-oxo-l, 2-dihydroxinolin-3-carbbaldehyde (XVI).

Conducted according to the methodology described in example 2. Obtain 26.5 g (74%) of product (XVI). Mp > 330 ° C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.4 (ЗН, s); 2.6 (ZN, s); 7.2 (IH, d, ¹ J = 8.5 Hz); 7.6 (IH, d, J = 8.5 Hz); 8.3 (IH, s); 10.3 (IH, s); 11.6 (IH, broad peak).

Example 17

Synthesis of 2-chlorop-6,7-dimethylquinolin-3-carbaldehyde (XVI).

Conducted according to the methodology described in example 1. Receive 39 g (70%) of the product (XVI). T. pl. 164-166 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.3 (3H, s), 2.4 (3H, s), 7.6 (IH, s), 7.9 (IH, s), 8.7 (IH, s), 10.4 ( W, c).

Example 18 Synthesis of 6,7-dimethyl-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (XVII).

Conducted according to the methodology described in example 2. Obtain 26.5 g (74%) of product (XVIII). Mp 236-238 ⁰ C.

H-NMR spectrum (δ, DMSO-d ₆ ): 2.3 (3H, s), 2.4 (3H, s), 7.1 (IH, s), 7.5 (IH, s), 8.2 (IH, s), 10.2 ( IH ₅ s), 12.0 (IH, broad peak).

Example 19

Synthesis of 6-chlorop- [l ₅ 3] dioxol [4,5-g] quinolin-7-carbaldehyde (XIX).

Conducted according to the methodology described in example 1. Receive 40 g (72%) of the product (XIX). Mp 188-190 ⁰ C.

H-NMR spectrum (δ, DMSO-d ₆ ): 6.3 (2H, s), 7.4 (IH, s), 7.6 (IH, s), 8.7 (IH, s), 10.4 (IH, s).

Example 20

Synthesis of 6-oxo-5,6-dihydro- [l, 3] dioxole [4,5-g] quinolin-7-carbaldehyde (XX).

Conducted according to the methodology described in example 2. Receive 28 g (80%) of the product (XX). Mp > 300 ° C.

Ni-NMR spectrum (δ, DMCO-d _b ): 6.1 (2H, s), 6.6 (IH, s), 7.6 (IH, s), 8.6 (IH, s), 10.2 (IH, s), 12.0 ( IH, broadened peak).

Example 21

Synthesis of 7-chlorop-2,3-dihydro- [l, 4] dioxino [2,3-g] quinolin-8-carbaldehyde

(Xxi).

Conducted according to the methodology described in example 1. Receive 42 g (73%) of the product (XXI). Mp 226-228 ° C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 4.1 (4H, s), 7.5 (IH, s), 8.0 (IH, s), 8.5 (IH, s), 10.5 (W, s). Example 22

Synthesis of 7-oxo-6,7-dihydro- [l, 4] dioxo [2,3-g] quinolin-8-carbaldehyde (XXII).

Conducted according to the methodology described in example 2. Receive 28 g (80%) of the product (XXII). Mp > 300 ° C.

Ni-NMR spectrum (δ, DMSO-d _b ): 6.1 (2H, s), 6.6 (IH, s), 7.6 (IH, s), 8.6 (IH, s), 10.2 (IH, s), 12.0 ( IH, broadened peak).

Example 23

Synthesis of 2-chlorop-6,8-dimethylquinolin-3-carbaldehyde (XXIII).

Conducted according to the methodology described in example 3. Receive 35 g (65%) of the product (XXIII). Mp 107-108 ⁰ C. According to published data, it is 110-111 ⁰ C (see Мeth-Сhп et al .; TELEAY; Tetrahedred Lett; 1979; 3111.3112, 3113).

Н-NMR spectrum (δ, ДМCO-d ₆ ): 2.4 (ЗН, s), 2.6 (ЗН, s), 7.6 (IH, s), 7.7 (IH, s), 8.7 (IH, s), 10.4 (IH, from).

Example 24

Synthesis of 6,8-dimethyl-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (XXIV).

Conducted according to the methodology described in example 2. Receive 24.5 g (78%) of product (XXIV). Mp 299-301 ⁰ C.

H-NMR spectrum (δ, DMSO-d ₆ ): 2.2 (3H, s); 2.4 (ZN, s); 7.2 (IH, s); 7.5 (IH, s); 8.4 (IH, s); 10.1 (IH, s); 11.2 (IH, broad peak).

Example 25

Synthesis of 2-chlorop-7-ethoxyquinolin-3-carbaldehyde (XXV).

Conducted according to the methodology described in example 3. Receive 36 g (60%) of the product (XXV). Mp 166-167 ⁰ C. Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.4 (3H, t, J = 7.5 Hz); 4.25 (2H, q, J = 7.5 Hz);

7.2 (IH, d \ d, J = 8.5 \ 3.5 Hz); 7.4 (IH, d, J = 3.5 Hz); 8.1 (IH, d, J = 8.5 Hz); 8.9 (IH, s); 10.1 (IH ₅ s).

Example 26

Synthesis of 7-ethoxy-2-oxo-1, 2-dihydroxinolin-3-carbaldehyde (XXVI).

Conducted according to the methodology described in example 2. Receive 22 g (64%). T. pl. 288-290 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.35 (ZN, t, J = 7.5 Hz); 4.1 (2H, q, J = 7.5 Hz); 6.8 (IH, d, J = 3.5 Hz); 6.9 (IH, d \ d, J = 8.5 \ 3.5 Hz); 7.8 (IH, d, J = 8.5 Hz); 8.2 (IH, s); 10.1 (IH, s); 12.0 (IH, broad peak).

Example 27

Synthesis of 2-chlorop-5,7-dimethylquinolin-3-carbaldehyde (XXVII).

Conducted according to the methodology described in example 1. Receive 44 g (78%) of the product (XXVII). T. pl. 96-98 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.5 (S, s), 2.7 (S, s), 7.4 (IH, s), 7.6 (IH, s), 8.8 (IH, s), 10.4 ( IH, s).

Example 28

Synthesis of 5,7-dimethyl-2-oxo-1, 2-dihydroxinolin-3-carbaldehyde

(Xxviii).

Conducted according to the methodology described in example 2. Receive 24.5 g (78%) of product (XXVIII). Mp 253-254 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.3 (S, s), 6.9 (IH, s), 7.0 (IH, s), 8.45 (IH, s), 10.2 (IH, s), 12.0 ( IH, broadened peak).

Example 29

Synthesis of 2-chlorop-quinoline-3-carbaldehyde (XXIX). Conducted according to the methodology described in example 1. Receive 37 g (78%) of the product (XXIX). T. pl. 178-180 ⁰ C.

H-NMR spectrum (δ, DMSO-d ₆ ): 7.4 (IH, t, J = 8.5 Hz); 7.6 (IH, d, J = 8.5 Hz); 7.8 (IH, t, J = 8.5 Hz); 8.9 (IH, s); 10.2 (IH, s).

Example 30

Synthesis of 2-oxo-l, 2-dihydroxinolin-3-carbalderide (XXX).

Conducted according to the methodology described in example 2. Receive 24.5 g (78%) of the product (XXX). Mp 307-310 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 7.1 (IH, t, J = 8.5 Hz); 7.3 (IH, d, J = 8.5 Hz); 7.6 (IH, t, J = 8.5 Hz); 8.5 (IH, s); 10.0 (IH, s); 12.0 (IH, broad peak).

Example 31

Synthesis of 2-chlorop-6-isopropylquinolin-3-carbaldehyde (XXXI).

Conducted according to the methodology described in example 1. Receive 40 g (68%) of the product (XXXI). T. pl. 125-126 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d _b ): 1.35 (6H, d, J = 7.5Hz), 3.06 (IH, m), 7.77 (IH, d, J = 8.5Hz), 7.89 (IH, d, J = 8.5 Hz), 8.02 (IH, d, J = 3.5 Hz), 8.76 (IH ₅ s), 10.55 (IH, s).

Example 32

Synthesis of 6-isopropyl-2-oxo-1, 2-dihydroxinolin-3-carbaldehyde (XXXII).

Conducted according to the methodology described in example 2. Receive 24.5 g (78%) of the product (XXXII). Mp 221-222 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.2 (6H, d, J = 8.5 Hz); 2.95 (IH ₅ sep, J = 7.5 Hz); 7.2 (IH, d, J = 8.5 Hz); 7.5 (IH, d \ d, J = 8.5 \ 3.5 Hz); 7.9 (IH, d, J = 3.5 Hz); 8.4 (IH, s); 10.2 (IH, s); 12.0 (IH, broad peak).

Example 33 Synthesis of 2- ^χ lop-5,6,7-thimethoxyxyquinoline-3-carbaldehyde (XXXIII).

Conducted according to the methodology described in example 1. Receive 44 g (78%) of the product (XXXII). T. pl. 114-116 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d _b ): 3.9 (ZN, s); 4.0 (ZN, s); 4.1 (ZN, s); 7.3 (IH, s); 8.75 (IH, s); 1 O. Z (1H, s).

Example 34

Synthesis of 5,6,7-trimethoxy-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (XXXIV).

Conducted according to the methodology described in example 2. Receive 24.5 g (78%) of the product (XXXIV). Mp 268-270 ⁰ C (decomp.).

Ni-NMR spectrum (δ, DMSO-d ₆ ): 3.7 (S, s); 3.8 (ZN, s); 3.9 (ZN, s); 6.7 (IH, s); 8.4 (IH, s); 1O.2 (1H, s); 12.0 (IH ₅ broad peak).

Example 35

Synthesis of 2-chlorop-6-tert-butylquinolin-3-carbaldehyde (XXXV).

Conducted according to the methodology described in example 1. Receive 38 g (62%) of the product (XXXV). T. pl. 101-102 ⁰ C.

Ni-NMR spectrum (δ, DMCO-d ₆ ): 1.36 (9H, s), 7.59 (IH, d, J = 8.5 Hz), 7.92 (IH, d, J = 8.5 Hz), 8.13 (IH, d, J = 3.5 Hz), 8.95 (IH, s), 10.55 (IH, s).

Example 36

Synthesis of 6-tert-butyl-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde

(XXXVI).

Conducted according to the methodology described in example 2. Receive 26.5 g (67%) of the product (XXXVI). Mp 228-230 ⁰ C. Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.25 (9H, s); 7.2 (W, d, J = 8.5 Hz); 7.5 (IH, d,

J = 8.5 Hz); 7.95 (IH, d, J = 3.5 Hz); 8.5 (IH, s); 10.2 (IH, s); 12.0 (IH, broad peak).

Example 37

Synthesis of 2-chlorop-6-propylquinolin-3-carbaldehyde (XXXVII).

Conducted according to the methodology described in example 1. Receive 40 g (68%) of the product (XXXVII). T. pl. 105-106 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 0.9 (ZN, t, J = 7.5 Hz); 1.6 (2H, q, J = 7.5 Hz); 2.6 (2H, t, J = 7.5 Hz); 7.4 (IH, d, J = 8.5 Hz); 7.8 (IH, d, J = 8.5 Hz); 8.2 (IH, s); 8.8 (IH, s); 10.3 (IH, s).

Example 38

Synthesis of 6-propyl-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (XXXVIII).

Conducted according to the methodology described in example 2. Receive 25 g (68%) of the product (XXXVIII). Mp 213-215 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d _b ): 0.9 (ZN, t, J = 7.5 Hz); 1.6 (2H, q, J = 7.5 Hz);

2.5 (2H, t, J = 7.5 Hz); 7.1 (IH, d, J = 8.5 Hz); 7.5 (IH, d, J = 8.5 Hz); 7.8 (IH, s); 8.4 (IH, s); 10.1 (IH, s); 12.0 (IH, broad peak).

Example 39

Synthesis of 2-chlorop-7,8-dihydro-6H-cyclopenta [g] quinolin-3-carbaldehyde (IXL).

Conducted according to the methodology described in example 1. Receive 40 g (68%) of the product (IXL). T. pl. 138-140 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.1 (2H, m, J = 7.5 Hz); 3.05 (2H, m, J = 7.5 Hz); 3.15 (2H, m, J = 7.5 Hz); 7.8 (IH, s); 8.05 (IH, s); 8.8 (IH, s); 10.4 (IH, s).

Example 40 Synthesis of 2-oxo-2,6,7,8-tetrahydro-III-cyclopent [g] quinolin-3-carbaldehyde (XL).

Conducted according to the methodology described in example 1. Receive 40 g (68%) of the product (XL). T. pl. > 310 ⁰ C.

H-NMR spectrum (δ, DMSO-d ₆ ): 2.0 (2H, m, J = 7.5 Hz); 2.9 (2H, m, J = 7.5 Hz);

3.0 (2H, m, 3 = 7.5 Hz); 7.1 (IH, s); 7.6 (IH ₅ s); 8.2 (IH, s); 10.1 (IH, s); 12.0 (IH, broad peak).

Example 41

Synthesis of 2-chlorop-6-methoxy-3-carbaldehyde (XLI).

Conducted according to the methodology described in example 3. Receive 40 g (68%) of the product (XLI). T. pl. 158-159 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 3.8 (S, s); 7.9 (IH, d \ d, J = 8.5 Hz \ 3.5 Hz); 8.1 (IH ₅ d, J = 8.5 Hz); 8.2 (IH, d, J = 3.5 Hz); 9.0 (IH, s); 10.2 (IH, s).

Example 42

Synthesis of 6-methoxy-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (XLII).

Conducted according to the methodology described in example 2. Receive 25 g (68%) of the product (XLII). Mp 282-284 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 3.7 (S, s); 7.5 (IH, d \ d, J = 8.5 Hz \ 3.5 Hz); 7.9 (IH, d, J = 8.5 Hz); 8.0 (IH, d, J = 3.5 Hz); 8.6 (IH, s); 10.0 (IH, s); 12.0 (IH, broad peak).

Example 43

Synthesis of l- (4-nitrophenyl) -pippolidine (XLIII).

A mixture of 4-nitrochlorobenzene (16 g, 0.1 mol) and 30 ml of pyrrolidine (25.5 g,

0.36 mol) is heated with stirring under reflux to a temperature of 80-85 ⁰ C. Upon completion of the reaction, the mixture is diluted with water (200-300 ml). The resulting product in the form of a thick oil is separated by filtration.

The resulting product is purified by passing through a layer of silica gel (KCK, 60/100 μm) in a hexane-ether system. 13.6 g (71%) of product (XLIII) are obtained.

LС-Mass (M + H) ⁺ : 193

Example 44

Synthesis of 4-pyppolidin-l-yl-aniline (XLIV).

The previously obtained according to example 44 l- (4-nitrophenyl) -pyprolidine (13.6 g, 0.07 mol) was dissolved in 100 ml of pure methanol and hydrogenated in the presence of palladium on activated carbon (10% mass, 1.5 g, 1.4 mmol) at 2-2.5 atm. and a temperature of not more than 20 ⁰ C at the installation of Parr Instruments (USA). At the end of the recovery process, the reaction mixture is filtered and concentrated. 8.1 g (70%) of product (XLIV) are obtained.

LС-Mass (M + H) ⁺ : 163

Example 45

Synthesis of l- (4-nitrophenyl) piperidine (XLV).

Conducted according to the methodology described in example 43, using piperidine instead of pyrrolidine. 17.6 g (85%) of XLV product are obtained.

LС-Mass (M + H) ⁺ : 207

Example 46

Synthesis of 4-piperidin-l-yl-aniline (XLVI).

Conducted according to the procedure described in example 44 using l- (4-nitrophenyl) -piperidine. 12 g (80%) of the product (XLVI) are obtained. LС-Mass (M + H) ⁺ : 177.

Example 47

Synthesis of 4-methyl-l- (4-nitrophenyl) piperidine (XLVII). Conducted according to the methodology described in example 43, using 4-methylpiperidine instead of pyrrolidine. 17.1 g (77%) of product (XLVII) are obtained.

LС-Mass (M + H) ⁺ : 221.

Example 48

Synthesis of 4- (4-methylpiperidine-1-yl) -aniline (XL VIII).

Conducted according to the procedure described in example 44 using 4-methyl-l- (4-nitrophenyl) -piperidine. 12 g (80%) of product (XLVIII) are obtained.

LС-Mass (M + H) ⁺ : 191

Example 49

Synthesis of 3-methyl-l- (4-nitrophenyl) piperidine (IL).

Carried out according to the procedure described in example 43, using 3-methylpiperidine instead of pyrrolidine. 16.2 g (73%) of IL product are obtained.

LС-Mass (M + H) ⁺ : 221.

Example 50

Synthesis of 4- (3-methylpiperidin-l-yl) -aniline (L).

Conducted according to the procedure described in example 44, using 3-methyl- 1- (4-nitrophenyl) -piperidine. Obtain 10.5 g (77%) of product L.

LС-Mass (M + H) ⁺ : 191

Example 51

Synthesis of 3,5-dimethyl-l- (4-nitrophenyl) piperidine (LI).

Conducted according to the procedure described in example 43, using instead of pyrrolidine 3,5-dimethylpiperidine. 17.8 g (76%) of LI product are obtained.

LС-Mass (M + H) ⁺ : 235. Example 52

Synthesis of 4- (3,5-dimethylpiperidin-l-yl) -aniline (LII).

Conducted according to the procedure described in example 44 using 3,5-dimethyl-l- (4-nitrophenyl) -piperidine. Obtain 11.2 g (72%) of product LII.

LC-Mass (MH-H) ⁺ : 205.

Example 53

Synthesis of 4-hydroxy-l- (4-nitrophenyl) piperidine (LIII).

Conducted according to the methodology described in example 43, using 4-hydroxypiperidine instead of pyrrolidine. 16.7 g (75%) of product LIII are obtained.

LС-Mass (MH-H) ⁺ : 223.

Example 54

Synthesis of 4- (4-hydroxypiperidin-l-yl) -aniline (LIV).

Conducted according to the procedure described in example 44 using 4-hydroxy-l- (4-nitrophenyl) -piperidine. 12.1 g (84%) of LIV product are obtained.

LС-Mass (MH-H) ⁺ : 193.

Example 55

Synthesis of 3-hydroxy-l- (4-nitrophenyl) piperidine (LV).

Conducted according to the methodology described in example 43, using 3-hydroxypiperidine instead of pyrrolidine. 15.2 g (69%) of the product LV are obtained.

LС-Mass (M + H) ⁺ : 223.

Example 56

Synthesis of 4- (3-hydroxypiperidin-l-yl) -aniline (LVI). Conducted according to the procedure described in example 44 using 3-hydroxy-l- (4-nitrophenyl) -piperidine. 11.2 g (79%) of the LVI product are obtained.

LС-Mass (M + H) ⁺ : 193.

Example 57

Synthesis of l- (4-nitrophenyl) -piperidine-4-ethylcarboxylates (LVII).

Conducted according to the methodology described in example 43, using instead of pyrrolidine, ethyl isonipecotate. 20.7 g (74%) of product LVII are obtained.

LС-Mass (M + H) ⁺ : 279.

Example 58

Synthesis of 4- (4-carboethoxysherpidine-1-l) -aniline (LVIII).

Conducted according to the methodology described in example 44 using l- (4-nitrophenyl) -piperidine-4-ethylcarboxylate. 15.2 g (83%) of product LVIII are obtained.

LС-Mass (M + H) ⁺ : 249.

Example 59

Synthesis of l- (4-nitrophenyl) -piperidine-3-ethylcarboxylates (LIX).

Conducted according to the methodology described in example 43, using ethylnipecotate instead of pyrrolidine. 18.6 g (67%) of LIX product are obtained.

LС-Mass (M + H) ⁺ : 279.

Example 60

Synthesis of 4- (3-carboethoxypiperidin-l-yl) -aniline (LX).

Conducted according to the procedure described in example 44 using l- (4-nitrophenyl) -piperidine-3-ethylcarboxylate. 13.1 g (79%) of LX product are obtained. LС-Mass (M + H) ⁺ : 249.

Example 61

Synthesis of l- (4-nitrophenyl) -piperidine-4-carbamide (LXI).

A mixture of 4-nitrochlorobenzene (16 g, 0.1 mol) and isonipecotamide (27.5 g, 0.22 mol) in 50 ml of dimethylformamide is heated under stirring under reflux to a temperature of about 100 ⁰ C. After the reaction is completed, the mixture is diluted with water (200-300 ml). The resulting product in the form of a precipitate was separated by filtration. The resulting product was purified by passing through a layer of silica gel (KCK, 60/100 μm) in a hexane-ethyl acetate system. The fractions containing the product are concentrated. 15.8 g (63%) of LXI product are obtained.

LС-Mass (M + H) ⁺ : 250.

Example 62

Synthesis of 4- (4-carbamidosherpidin-l-yl) -aniline (LXII).

Conducted according to the methodology described in example 44 using l- (4-nitrophenyl) -piperidine-4-carbamide. 10.1 g (76%) of LXIL product are obtained.

LС-Mass (M + H) ⁺ : 220.

Example 63

Synthesis of Cyclohexyl-methyl- (4-nitrophenyl) -amine (LXIII).

Conducted according to the methodology described in example 43, using N-methylcyclohexylamine instead of pyrrolidine. Obtain 14.2 g (60%) of product LXIII.

LС-Mass (M + H) ⁺ : 235.

Example 64

Synthesis of N-cyclohexyl-N-methyl-para-phenylenediamine (LXIV). Conducted according to the methodology described in example 44 using cyclohexyl-methyl- (4-nitrophenyl) -amine. 8.7 g (71%) of LXIV product are obtained.

LС-Mass (M + H) ⁺ : 205.

Example 65

Synthesis of l-methyl-4- (4-nitrophenyl) rasherazine (LXV).

Conducted according to the methodology described in example 43, using N-methylgosherazine instead of pyrrolidine. 15.3 g (69%) of LXV product are obtained.

LС-Mass (M + H) ⁺ : 222.

Example 66

Synthesis of 4- (4-methyl-piperisin-1-yl) -aniline (LXVI).

Conducted according to the procedure described in example 44 using l-methyl-4- (4-nitrophenyl) piperazyl. 9.6 g (72%) of LXVI product are obtained.

LС-Mass (M + H) ⁺ : 192.

Example 67

Synthesis of l- [4- (4-nitrophenyl) -piperazin-l-yl] -acetamide (LXVII).

Conducted according to the methodology described in example 61, using N-acetylpiperazine instead of isonipecotamide. 19.1 g (77%) of product LXVII are obtained.

LС-Mass (M + H) ⁺ : 250.

Example 68

Synthesis of l- [4- (4-aminophenyl) piperazin-l-yl] -acetamide (LXVIII).

Conducted according to the procedure described in example 44, using l- [4- (4-nitrophenyl) -piperazin-l-yl] -acetamide. 11.6 g (79%) of product LXVIII are obtained.

LС-Mass (M + H) ⁺ : 220. Example 69

Synthesis of fyran-2-yl- [4- (4-nitrophenyl) piperazin-l-yl] -amide (LXIX).

Conducted according to the methodology described in example 61, using instead of isonipecotamide N-furoylpshierazine. 19.8 g (66%) of LXIX product are obtained.

LС-Mass (M + H) ⁺ : 302.

Example 70

Synthesis of fyran-2-yl- [4- (4-aminophenyl) piperazin-l-yl] -amide (LXX).

Conducted according to the methodology described in example 44 using fyran-2-yl- [4- (4-nitrophenyl) piperazin-l-yl] -amide. 15.3 g (86%) of LXX product are obtained.

LС-Mass (M + H) ⁺ : 272.

Example 71

Synthesis of l-benzyl-4 (4-nitrophenyl) -silverine (LXXI).

Carried out according to the procedure described in example 43, using N-benzylpiperazine instead of pyrrolidine. 17.3 g (58%) of LXXI product are obtained.

LС-Mass (M + H) ⁺ : 298.

Example 72

Synthesis of 4- (4-benzyl-sherizin-l-yl) -aniline (LXXII).

Obtained in the previous example, l-benzyl-4 (4-nitrophenyl) piperazine (17.3 g, 0.06 mol) is the product of LXXI, dissolved in 150 ml of methanol, the temperature of the reaction mixture is brought to 40-45 ⁰ C and then hydrazine hydrate is added ( 80%, 10 ml, 0.15 mol) and then Raney nickel is added in portions. At the end of the reaction, the reaction mixture was filtered and concentrated. The resulting product is purified by passing through a layer of silica gel (KCK, 60/100 μm) in a chloroform-methanol system. The fractions containing the product are concentrated. 9.1 g (58%) of product LXXII are obtained. LС-Mass (M + H) ⁺ : 268.

Example 73

Synthesis of l- (4-nitrophenyl) -4-phenyl-sherpasin (LXXIII).

Conducted according to the methodology described in example 43 using instead of pyrrolidine N-phenylsherazine. 16.3 g (58%) of product LXXIII are obtained.

LС-Mass (M + H) ⁺ : 284.

Example 74

Synthesis of 4- (4-phenyl-piperazin-l-yl) -aniline (LXXIV).

Conducted according to the methodology described in example 44 using l- (4-nitrophenyl) -4-phenyl-sherpasin. 10.3 g (70%) of product (LXXIV) are obtained.

LС-Mass (M + H) ⁺ : 254.

Example 75

Synthesis of 2- (4-nitrophenyl) -l, 2,3,4-tetrahydroisoxinoline (LXXV).

Carried out according to the methodology described in example 43, using tetrahydroisoquinoline instead of pyrrolidine. 16.3 g (65%) of LXXV product are obtained.

LС-Mass (M + H) ⁺ : 255.

Example 76

Synthesis of 4- (3,4-dihydro-III-isoxinolin-2-yl) -aniline (LXXVI).

Conducted according to the procedure described in example 44 using 2- (4-nitrophenyl) -l, 2,3,4-tetrahydroisoxinoline. 9.5 g (66%) of LXXVI product are obtained.

LС-Mass (M + H) ⁺ : 225. Example 77

Synthesis of l- (4-nitrophenyl) -4-pyrid-2-yl-piperazine (LXXVII).

Conducted according to the methodology described in example 61 using instead of isonipecotamide 2-pyridylpiperazine. 15.6 g (55%) of product LXXVII are obtained.

LС-Mass (M + H) ⁺ : 285.

Example 78

Synthesis of 4- (4-Pyrid-2-yl-piperazin-l-yl) -aniline (LXXVIII).

Conducted according to the methodology described in example 44 using l- (4-nitrophenyl) -4-pyrid-2-yl-piperazine. 9.8 g (70%) of product LXXVIII are obtained.

LС-Mass (M + H) ⁺ : 255.

Example 79

Synthesis of 2- [4- (4-nitrophenyl) piperazin-l-yl] pyrimidine (LXXIX).

Conducted according to the methodology described in example 61 using instead of isonipecotamide 2-pyrimidylsherpazine. 16.8 g (59%) of LXXIX product are obtained.

LС-Mass (M + H) ⁺ : 286.

Example 80

Synthesis of 4- (4-pyrimid-2-yl-piperazin-l-yl) -aniline (LXXX).

Conducted according to the methodology described in example 44, using 2- [4- (4-nitrophenyl) -sherpasin-l-yl] pyrimidine. 10.7 g (71%) of LXXX product are obtained.

LС-Mass (MH-H) ⁺ : 256. Example 81

Synthesis of 2- [Benzyl- (4-nitrophenyl) amino] ethanol (LXXXI).

Conducted according to the methodology described in example 43, using N-benzylethanolamine instead of pyrrolidine. Obtain 14.8 g (54%) of the product LXXXI.

LС-Mass (M + H) ⁺ : 273.

Example 82

Synthesis of 2- [benzyl- (4-aminophenyl) amino] ethanol (LXXXII).

Conducted according to the procedure described in example 72 using 2- [benzyl- (4-nitrophenyl) amino] ethanol. 9.2 g (70%) of product LXXXII are obtained.

LС-Mass (M + H) ⁺ : 243.

Example 83

Synthesis of 3 - [(4-Dimethylamino-phenylamino) methyl] -5,6,7-trimethoxy-S-quinolin-2-one (LXXXIII).

A mixture of substance XXXIV (2.63 g, 10 mmol) and N, N-dimethylpaphenyl enamine diamine (1.5 g, 11 mmol) was dissolved in 50 ml of dichloroethane.

The reaction mixture was stirred with heating at a temperature of ~ 70 ° C for 1 hour and sodium triacetoxyborohydride (3.5 g, 16.5 mmol) was added portionwise with vigorous stirring. At the end of the reaction, the mixture is cooled, diluted with an aqueous solution of soda, the layers are separated, the organic layer is dried and concentrated. The isolated product is recrystallized from ethyl acetate. Obtain 1.87 g (49%) of product LXXXIII. Mp 193-194.

LС-Mass (M + H) ⁺ : 384.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.8 (S, s); 3.6 (ZN, s); 3.7 (ZN, s); 3.75 (ZN, s); 4.0 (2H, D, J = 5 Hz); 5.2 (IH, t, J = 5 Hz); 6.5 (2H ₅ d, J = 8.5 Hz); 6.6 (2H, d, J = 8.5 Hz); 6.7 (IH, s); 7.6 (IH, s); 11.6 (IH, broad). Example 84

Synthesis of 3 - [(4-Dimethylamino-phenylamino) methyl] -6-ethyl-1 H-quinolin-2-one (LXXXIV).

Conducted according to the methodology described in example 83, using XIV instead

Xxxiv. Obtain 1.44 g (45%) of product LXXXIV. Mp 228-229 ⁰ C.

LС-Mass (M + H) ⁺ : 322.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.2 (3H, t, J = 7.3 Hz); 2.6 (2H, q, J = 7.3 Hz); 2.7 (6H, s); 4.0 (2H, d, J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.65 (2H, d, J = 8.5 Hz); 7.2 (IH, d, J = 8.5 Hz); 7.3 (IH, d, J = 8.5 Hz); 7.4 (IH, d, J = 3.0 Hz); 7.7 (IH, s); 11.6 (IH, broad peak).

Example 85

Synthesis of 6-ethoxy-3 [(4-pyppolidin-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one. (LXXXV).

Conducted according to the methodology described in example 83, using the connection

VIII and XLIV as starting reagents. Obtain 1.58 g (43%) of product LXXXV. Mp 248-250 ⁰ C.

LС-Mass (M + H) ⁺ : 364.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.2 (3H, t, J = 7.5 Hz); 1.8 (4H, m); 3.0 (4H, m); 4.0 (4H, superposition of a quadruplet with J = 7.5 Hz and a doublet with J = 5 Hz); 5.2 (IH, t, J = 5 Hz); 6.4 (2H, d, J = 8.5 Hz); 6.6 (2H, d, J = 8.5 Hz); 6.7 (IH, d \ d, J = 8.5 \ 3.25 Hz); 6.8 (IH ₃ d, J = 3.25 Hz); 7.4 (IH, d, J = 8.5 Hz); 7.6 (IH, s); 11.4 (IH, broad peak).

Example 86

Synthesis of 7-methoxy-3 [(4-sherpidin-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one (LXXXVI). Conducted according to the methodology described in example 83, using compounds

XII and XLVI as starting reagents. Obtain 1.98 g (55%) of product LXXXVI. Mp 240-242 ⁰ C.

LС-Mass (M + H) ⁺ : 364.

H _! NMR spectrum (δ, DMSO-d ₆ ): 1.4 (2H, m); 1.6 (4H, m); 2.8 (4H, m); 3.7 (ZN, s); 4.0 (2H, d, J = 5 Hz); 5.6 (IH, t, J = 5 Hz); 6.4 (2H, d, J = 8.5 Hz); 6.6 (ZN, m); 6.8 (IH, s); 7.4 (IH ₃ d, J = 8.5 Hz); 7.6 (IH, s); 11.6 (IH, broad peak).

Example 87

Synthesis of 7-ethoxy-3 [(4-piperidin-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one (LXXXVII).

Conducted according to the methodology described in example 83, using compounds XXVI and XLVI as starting reagents. Obtain 1.92 g (51%) of product LXXXVII. Mp 258-260 ⁰ C.

LС-Mass (M + H) ⁺ : 378.

H _r NMR spectrum (δ, DMSO-d ₆ ): 1.3 (ЗН, t, J = 7.5 Hz); 1.5 (2H, m); 1.6 (4H, m);

2.9 (4H, m); 4.1 (4H, superposition of a quadruplet with J = 7.3 Hz and a doublet with J = 5 Hz); 5.4 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (ZN, superposition 2H - d with J = 8.5 Hz and IH - d with J = 8.5 Hz); 6.8 (IH, d, J = 3 Hz); 7.4 (IH, d, J = 8.5 Hz); 7.65 (IH, s); 11.4 (IH, broad peak).

Example 88

Synthesis of 7-methyl-3 [(4-morpholin-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one (LXXXVIII).

Conducted according to the methodology described in example 83, using compound VI and 4-morpholin-4-yl-aniline as starting reagents. Obtain 1.77 g (51%) of product LXXXVIII. Mp 263-265 ⁰ C.

LС-Mass (M + H) ⁺ : 350. H _r NMR spectrum (δ, DMSO-d ₆ ): 2.39 (S, s); 2.8 (4H, m); 3.6 (4H, m); 4.0 (2H, d, J = 5 Hz); 5.6 (W, t, J = 5 Hz); 6.4 (2H, d, J = 8.5 Hz); 6.8 (2H, d, J = 8.5 Hz); 7.0 (IH, d, J = 8.5 Hz); 7.1 (IH, s); 7.4 (IH, d, J = 8.5 Hz); 7.6 (IH, s); 11.6 (IH ₃ broad peak).

Example 89

Synthesis of 6-ethoxy-3 [(4-morpholin-l-yl-phenylamino) methyl] - 1 H-quinolin-2-one (LXXXIX).

Conducted according to the methodology described in example 83, using the connection of VPI and 4-morpholin-4-yl-aniline as starting reagents. Obtain 1.94 g (51%) of the product LXXXlX. Mp 228-229 ⁰ C.

LС-Mass (M + H) ⁺ : 380.

Ni-NMR spectrum (δ, DMSO-d _b ): 1.2 (3H, t, J = 7.5 Hz); 2.8 (4H, m); 3.6 (4H ₅ m); 3.9 (2H, q, J = 7.5 Hz); 4.0 (2H, d, J = 5 Hz); 5.6 (IH, t, J = 5 Hz); 6.4 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.0 (ZN, m); 7.2 (IH, d, J = 8.5 Hz); 7.6 (IH, s); 11.6 (IH, broad peak).

Example 90

Synthesis of 6-isopropyl-3 [(4-morpholin-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one (XC).

Conducted according to the methodology described in example 83, using the compound XXXII and 4-morpholin-4-yl-aniline as starting reagents. Obtain 1.52 g (40%) of product XC. Mp 258-259 ⁰ C.

LС-Mass (M + H) ⁺ : 378.

Ni-NMR spectrum (δ, DMSO-d _b ): 1.2 (6H, d, J = 7.3 Hz); 2.9 (4H, m); 3.6 (4H, m); 4.1 (2H, d, J = 5 Hz); 5.4 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.6 (2H, d, J = 8.5 Hz); 7.2 (IH, d, J = 8.5 Hz); 7.3 (IH, d, J = 8.5 Hz); 7.4 (IH, d, J = 3.0 Hz); 7.7 (IH, s); 11.6 (IH, broad peak). Example 91

Synthesis of 7 [(4-morpholin-1-yl-phenylamino) -m-ethyl-5H-

[1, 3] dioxol o [4.5g] quinoline-6-one (XIC).

Conducted according to the methodology described in example 83, using the compound XX and 4-morpholin-4-yl-aniline as starting reagents. Obtain 1.45 g (38%) of XIC product. Mp 270-274 ° C (razl).

LС-Mass (M + H) ⁺ : 380.

Ni-NMR spectrum (δ, DMSO-d _b ): 2.9 (4H, m); 3.7 (4H, m); 4.0 (2H ₅ d, J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.0 (2H, s); 6.5 (2H, d, J = 8.5 Hz); 6.8 (2H, d, J = 8.5 Hz); 6.9 (IH, s); 7.1 (IH, s); 7.6 (IH ₅ s); 11.6 (IH, broad peak).

Example 92

Synthesis of 6-methyl-3 {[4- (4-methyl-piperidin-l-yl) phenylamino] methyl} -H-quinolin-2-one (XIIC).

Conducted according to the methodology described in example 83, using compounds II and XLVIII as starting reagents. Obtain 1.76 g (49%) of product XIIC. Mp 256-258 ⁰ C.

LС-Mass (M + H) ⁺ : 362.

H _r NMR spectrum (δ, DMSO-d ₆ ): 1.0 (S, d, J = 7.5 Hz); 1.3 (ZN, m); 1.7 (2H, m); 2.2 (ZN, s); 2.5 (2H, m); 3.2 (2H, m); 4.0 (2H, d, J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.2 (2H, m); 7.4 (IH, s); 11.5 (IH, broad peak).

Example 93

Synthesis of 7-Methoxy-3 {[4- (4-methyl-piperidin-l-yl) phenylamino] methyl] - W-quinolin-2-one (XIIIC).

Conducted according to the methodology described in example 83, using compounds XII and XLVIII as starting reagents. Obtain 1.88 g (50%) of product XIIIC. Mp 242-243 ⁰ C. LС-Mass (M + H) ⁺ : 378.

H-NMR spectrum (δ, DMSO-d ₆ ): 0.9 (S, d, J = 7.5 Hz); 1.2 (2H, m); 1.4 (IH, m); 1.6 (2H, m); 2.5 (2H, m); 3.3 (2H, m); 3.9 (3H, s); 4.1 (2H, d, J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (ZN, m); 6.8 (IH, s); 7.5 (IH, d, J = 8.5 Hz); 7.7 (IH, s); 11.5 (IH, broad peak).

Example 94

Synthesis of 7-methyl-3 {[4- (4-methyl-piperidin-1-yl) phenylamino] methyl] - 1 H-quinolin-2-one (XIVC).

Conducted according to the methodology described in example 83, using compounds VI and XLVIII as starting reagents. Obtain 1.91 g (53%) of product XIVC. Mp 254-255 ⁰ C.

LС-Mass (M + H) ⁺ : 362.

Hj-NMR spectrum (δ, DMSO-d ₆ ): 1.09 (ZN, d, J = 7.5 Hz); 1.3 (3H ₅ m); 1.6 (2H, m); 2.4 (ZN, s); 2.5 (2H, m); 3.4 (2H, m); 4.0 (2H, d, J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 6.9 (IH, d, J = 8.5 Hz); 7.0 (IH, d, J = 3 Hz); 7.45 (W, d, J = 8.5 Hz); 7.7 (IH, s); 11.5 (IH, broad peak).

Example 95

Synthesis of 6-methyl-3 {[4- (3-methyl-piperidin-1-yl) phenylamino] methyl] - 1 H-quinolin-2-one (XVC).

Conducted according to the methodology described in example 83, using the connection

II and XLV as starting reagents. Obtain 1.56 g (43%) of product XVC. Mp 233-234 ⁰ C.

LС-Mass (M + H) ⁺ : 362.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 0.8 (4H, m); 1.6 (4H, m); 2.0 (IH, m); 2.3 (ZN, s); 2.4 (IH, m); 3.2 (2H, m, overlapped with a H ₂ O signal); 4.0 (2H, d, J = 5 Hz); 5.4 (IH, t, J = 5 Hz); 6.4 (2H, d, J = 8.5 Hz); 6.8 (2H ₅ d, J = 8.5 Hz); 7.2 (2H, m); 7.3 (IH, s); 7.6 (IH, s); 11.6 (IH, broad peak). Example 96

Synthesis of 5,6,7-trimethoxy-3 {[4- (3-methyl-piperidin-l-yl) -phenylamino] -methyl} -S-quinolin-2-one (XVIC).

Conducted according to the methodology described in example 83, using compounds XXXIV and XLV as starting reagents. Obtain 1.94 g (44%) of product XVIC. Mp 179-180 ⁰ C.

LС-Mass (M + H) ⁺ : 438.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 0.9 (4H ₅ m); 1.7 (4H, m); 2.1 (IH, m); 2.4 (IH, m); 3.7 (ZN, s); 3.8 (ZN, s); 3.84 (ZN, s); 4.1 (2H, d, J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (IH, s); 6.75 (2H, d, J = 8.5 Hz); 7.8 (IH, s); 11.5 (IH, broad peak).

Example 97

Synthesis of 6-ethoxy-3 {[4- (3, 5-dimethyl-piperidin-1-yl) -phenylamino] -methyl} - Ш-quinolin-2-one (XVIIC).

Conducted according to the methodology described in example 83, using compounds VIII and LIII as starting reagents. Obtain 1.88 g (46%) of product XVIIC. Mp 179-180 ⁰ C.

LC-Mass (M + H) ⁺ : 406.

Ni-NMR spectrum (δ, DMSO-d _b ): 0.8-1.0 (S, d, J = 7.5 Hz); 1.3 (ZN, t, J = 7.5 Hz); 1.6 (2H, m); 2.0 (2H, m); 3.0-3.4 (2H, m); 3.9 (2H, q, J = 7.5 Hz); 4.1 (2H, D, J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.1 (ZN, m); 7.2 (IH, d, J = 8.5 Hz); 7.7 (IH, s); 11.5 (IH, broad peak).

Example 98

Synthesis of 3 - {[4- (4-hydroxy-piperidin-1-yl) -phenylamino] methyl] - 1 H-quinolin-2-one (XVIIIC). Conducted according to the methodology described in example 83, using the connection

XXX and LIV as starting reagents. Obtain 1.88 g (46%) of product XVIIIC. Mp 226-227 ⁰ C.

LС-Mass (M + H) ⁺ : 350.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.5 (2H, m); 1.8 (2H, m); 2.5 (2H, m); 3.2 (2H, m); 3.6 (IH, m); 4.1 (2H, d, J = 5 Hz); 4.4 (IH, d, J = 4.0 Hz); 5.6 (IH, t, J = 5 Hz); 6.4 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.1 (IH, t, J = 8.5 Hz); 7.3 (IH, d, J-8.5 Hz); 7.45 (IH, t, J = 8.5 Hz); 7.6 (IH, d, J = 8.5 Hz); 7.8 (IH, s); 12.0 (IH, broad peak).

Example 99

Synthesis of 3 - {[4- (4-Hydroxy-sherpidin-1-yl) -phenylamino] -methyl} -8-methyl-

W-quinolin-2-one (IC).

Conducted according to the methodology described in example 83, using compounds XXX and LIV as starting reagents. Obtain 1.49 g (41%) of product IC. Mp 208-209 ⁰ C.

LС-Mass (M + H) ⁺ : 364.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.5 (2H, m); 1.65 (2H, m); 2.3 (ZN, s); 2.6 (2H, m); 3.19 (2H, m); 3.60 (IH, m); 4.1 (2H, d, J = 5 Hz); 4.4 (IH, d, J = 4.5 Hz); 5.6 (IH, t, J = 5 Hz); 6.4 (2H ₅ d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.0 (IH, t, J = 8.5 Hz); 7.25 (IH, d, J = 8.5 Hz); 7.4 (IH, d, J = 8.5 Hz); 7.7 (IH, s); 10.8 (IH, broad peak).

Example 100

Synthesis of 3 - {[4- (4-Hydroxy-piperidin-l-yl) phenylamino] methyl] -7,8-dimethyl-III-quinolin-2-one (C).

Conducted according to the methodology described in example 83, using compounds XVI and LG as initial reagents. Obtain 1.67 g (44%) of product C. T.pl. 208-209 ⁰ C.

LС-Mass (M + H) ⁺ : 378. Ni-NMR spectrum (δ, DMSO-de): 1.55 (2H, m); 1.65 (2H, m); 2.3 (6H, s); 2.45 (2H, m);

3.20 (2H, m); 3.50 (IH, m); 4.0 (2H, d, J = 5 Hz); 4.4 (IH, d, J = 4.5 Hz); 5.6 (IH, t, J = 5 Hz); 6.4 (2H, d, J = 8.5 Hz); 6.6 (2H, d, J = 8.5 Hz); 6.95 (IH, d, J = 8.5 Hz); 7.20 (IH, d, J = 8.5 Hz); 7.65 (IH, s); 10.8 (IH, broad peak).

Example 101

Synthesis of 8- {[4- (4-hydroxypiperidin-l-yl) -phenylamino] methyl] -2,3 ~ dihydro-6H- [l, 4] dioxino [2,3-g] -quinoline-7-one (CI).

Conducted according to the methodology described in example 83, using compounds XXII and LIV as starting reagents. Obtain 1.95 g (48%) of product CI. Mp 257-259 ⁰ C.

LC-Mass (MH-H) ⁺ : 408.

H-NMR spectrum (δ, DMSO-d ₆ ): 1.3 (2H, m); 1.6 (2H, m); 2.45 (2H, s); 3.15 (2H, m); 3.4 (W, m); 4.0 (2H, d, J = 5 Hz); 4.3 (4H, m); 4.4 (IH, d, J = 4.5 Hz); 5.5 (IH, t, J = 5 Hz); 6.4 (2H, d, J = 8.5 Hz); 6.8 (2H, d, J = 8.5 Hz); 6.85 (IH, s); 7.0 (IH, s); 7.5 (IH, s); 11.6 (IH, broad peak).

Example 102

Synthesis of 7- {[4- (4-hydroxypiperidin-l-yl) phenylamino] methyl] -5H-

[1, 3] [4,5-g] -quinolin-6-one dioxol (SP).

Conducted according to the methodology described in example 83, using compounds XXII and LIV as starting reagents. Obtain 1.79 g (46%) of product SP. Mp 234-235 ° C (razl).

LC-Mass (M + H) ⁺ : 394.

H _r NMR spectrum (δ, DMSO-d ₆ ): 1.4 (2H, m); 1.7 (2H, m); 2.5 (2H, m); 3.0 (2H, m); 3.5 (IH, m); 4.0 (2H, d, J = 5 Hz); 4.5 (IH, broad); 5.5 (IH, t, J = 5 Hz); 6.0 (2H, s); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 6.8 (IH, s); 7.0 (IH, s); 7.5 (IH, s); 11.0 (IH, broad peak). Example 103

Synthesis of 3- {[4- (3-hydroxy-piperidin-1-yl) -phenylamino] methyl] -7-methyl-W-quinolin-2-one (CIII).

Conducted according to the methodology described in example 83, using compounds VI and LVI as starting reagents. Obtain 1.97 g (54%) of product CIII. T.pl. 214-216 ⁰ C.

LС-Mass (M + H) ⁺ : 364.

H-NMR spectrum (δ, DMSO-d ₆ ): 1.1 (IH, m); 1.4 (IH, m); 1.6 (IH, m); 1.9 (IH, m); 2.2 (3H ₅ s); 2.49 (2H, m); 3.3 (2H, m); 4.0 (2H, d, J = 5 Hz); 4.5 (IH, d, J = 4.5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.6 (2H, d, J = 8.5 Hz); 6.9 (IH, d, J = 8.5 Hz); 7.0 (IH, d, J = 3.0 Hz); 7.45 (IH, d, J = 8.5 Hz); 7.6 (IH, s); 11.6 (IH, broad peak).

Example 104

Synthesis of 3 - {[4- (3-Droxy-piperidin-1-l) phenylamino] methyl} -6-ethyl-Ш-quinolin-2-one (CGV).

Conducted according to the methodology described in example 83, using the connection

XIV and LVI as starting reagents. Obtain 1.65 g (44%) of product CIV. Mp 213-214 ⁰ C.

LС-Mass (M + H) ⁺ : 378.

Ni-NMR spectrum (δ, DMSO-d _b ): 1.1 (4H ₅ m); 1.4 (IH, m); 1.6 (IH, m); 1.9 (IH, m); 2.2 (2H, m); 2.49 (2H, m); 3.3 (2H ₅ m); 4.0 (2H, d, J = 5 Hz); 4.5 (IH ₅ d, J = 4.5 Hz); 5.5 (IH, t, J = 5 Hz); 6.4 (2H, d, J = 8.5 Hz); 6.7 (2H ₅ d, J = 8.5 Hz); 7.2 (2H, m); 7.4 (IH, s); 7.6 (IH, s); 11.5 (IH, broad peak).

Example 105

Synthesis of 3 - {[4- (3-Hydroxy-piperidin-l-yl) phenylamino] methyl] -6-propyl-W-quinolin-2-one (CV). Conducted according to the methodology described in example 83, using the connection

XXXVIII and LVI as starting reagents. Obtain 1.27 g (32%) of the product CV. Mp 217-218 ⁰ C.

LС-Mass (M + H) ⁺ : 392.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 0.9 (ZN, t, J = 7.5 Hz); 1.0-1.9 (6H, m); 2.4 (IH, m); 2.5 (IH, m); 2.65 (2H, t, J = 7.5 Hz); 3.0 (4H, m); 3.5 (IH, m); 4.0 (2H, d, J = 5 Hz); 4.5 (IH, d, J = 4.5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.25 (2H, m); 7.4 (IH, s); 7.70 (IH, s); 11.5 (IH, broad peak).

Example 106

Synthesis of 3 - {[4- (3-Hydroxy-piperidin-l-yl) phenylamino] methyl] -6-isopropyl-1 H-quinolin-2-one (CVI).

Conducted according to the methodology described in example 83, using compounds XXXII and LVI as starting reagents. Obtain 1.43 g (37%) of the product CVI. Mp 219-220 ⁰ C.

LС-Mass (M + H) ⁺ : 392.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.0 (7H, m); 1.4 (IH, m); 1.7 (IH, m); 1.9 (IH, m); 2.2 (IH, m); 2.9 (IH, m); 3.1 (IH, m); 3.5 (IH, m); 4.0 (2H, d, J = 5 Hz); 4.5 (IH, d, J = 4.5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.8 (2H, d, J = 8.5 Hz); 7.1 (2H, d, JM8.5 Hz); 7.3 (2H, d, J = 8.5 Hz); 7.4 (IH, s); 7.6 (IH, s); 11.5 (IH, broad peak).

Example 107

Synthesis of 3 - {[4- (3-Hydroxy-piperidin-l-yl) phenylamino] methyl] -6-tert-butyl-1 H-quinolin-2-one (CVII).

Conducted according to the methodology described in example 83, using compounds XXXVI and LVI as starting reagents. Obtain 1.75 g (43%) of product CVII. Mp 243-245 ⁰ C.

LC-Mass (M + H) ⁺ : 406. Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.2 (UN, m); 1.5 (IH, m); 1.7 (IH, m); 1.9 (IH, m); 2.3

(IH, m); 2.5 (IH, m); 3.2 (IH, m); 3.6 (IH, m); 4.1 (2H, d, J = 5 Hz); 4.5 (IH, d, J = 4.5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.2 (2H, d, J = 8.5 Hz); 7.5 (2H, m); 7.7 (IH, s); 11.5 (IH, broad peak).

Example 108

Synthesis of 3 - {[4- (3-Hydroxy-piperidin-l-yl) phenylamino] methyl] -6,7-dimethyl-1 H-quinoline-2-one (CVIII).

Conducted according to the methodology described in example 83, using compounds XVIII and LVI as starting reagents. Obtain 2.05 g (54%) of product CVIII. Mp 260-262 ° C (razl.).

LС-Mass (M + H) ⁺ : 378.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.2 (IH, m); 1.5 (IH, m); 1.7 (IH ₅ m); 1.9 (IH, m); 2.2 (ZN, s); 2.25 (ZN, s); 2.45 (2H, m); 3.1 (IH, m); 3.2 (IH, m); 3.5 (IH, m); 4.0 (2H, d, J = 5 Hz); 4.5 (IH, d, J = 4.5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.0 (IH, s); 7.35 (IH, m); 7.6 (IH, s); 11.5 (IH, broad peak).

Example 109

Synthesis of 3 - {[4- (3-Hydroxy-piperidin-l-yl) phenylamino] methyl] -7-methoxy-III-quinolin-2-one (CIX).

Conducted according to the methodology described in example 83, using compounds XII and LVI as starting reagents. Obtain 1.91 g (50%) of the product CIX. Mp 239-241 ⁰ C.

LС-Mass (M + H) ⁺ : 380.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.1 (IH, m); 1.5 (IH, m); 1.7 (IH, m); 1.9 (IH, m); 2.3 (IH, t, J = 7.5 Hz); 2.5 (IH, t, J = 7.5 Hz); 3.2 (2H, m); 3.6 (IH ₅ m); 3.8 (ZN, s); 4.0 (2H, d, J = 5 Hz); 4.5 (IH ₅ d ₅ J = 4.5 Hz); 5.5 (IH ₅ t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H ₅ d, J = 8.5 Hz); 6.8 (IH, d, J = 8.5 Hz); 6.9 (IH, s); 7.5 (IH ₅ d, J = 8.5 Hz); 7.7 (IH, s); 11.5 (IH ₅ broad peak). Example 110

Synthesis of 3 - {[4- (3-Hydroxy-piperidin-l-yl) phenylamino] methyl] -5,6,7-trimethoxy-1 H-quinolin-2-one (CX).

Conducted according to the methodology described in example 83, using compounds XXXXV and LVI as starting reagents. Obtain 2.12 g (48%) of the product CX. Mp 209-210 ⁰ C.

LС-Mass (M + H) ⁺ : 440.

Ni-NMR spectrum (δ, DMSO-d _b ): 1.1 (IH, m); 1.5 (IH, m); 1.7 (IH, m); 1.9 (IH, m); 2.3 (IH, t, J = 7.5 Hz); 2.4 (IH, t, J = 7.5 Hz); 3.2 (2H, m); 3.5 (IH, m); 3.7 (ZN, s); 3.8 (6H, s); 4.1 (2H, d, J = 5 Hz); 4.5 (IH, d, J = 4.5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (ZN, m); 7.8 (IH, s); 11.5 (IH, broad peak).

Example 111

Synthesis of 7- {[4- (3-hydroxypiperidin-1-yl) phenylamino] methyl] -5H-

[1, 3] dioxol of [4,5-g] -quinolin-6-one (CXI).

Conducted according to the methodology described in example 83, using the connection

XX and LVI as starting reagents. Obtain 1.91 g (49%) of the product CXI. Mp 264-267 ° C (razl).

LC-Mass (M + H) ⁺ : 394.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.1 (IH, m); 1.5 (IH, m); 1.7 (IH, m); 1.9 (IH ₅ m); 2.3 (IH, t, J = 7.5 Hz); 2.4 (IH, t, J = 7.5 Hz); 3.0 (2H, m); 3.6 (IH, m); 4.1 (2H, d, J = 5 Hz); 4.6 (IH, d, J = 4.5 Hz); 5.4 (IH, t, J = 5 Hz); 6.0 (2H, s); 6.3 (2H, d, J = 8.5 Hz); 6.6 (2H, d, J = 8.5 Hz); 6.65 (IH, s); 7.1 (IH, s); 7.7 (IH, s); 11.4 (IH, broad peak).

Example 112

Synthesis of 8 - {[4- (3-Hydroxypiperidin-l-yl) phenylamino] methyl] -2,3-dihydro-6H- [l, 4] dioxino [2,3-g] -quinoline-7-one (Cxii). Conducted according to the methodology described in example 83, using compounds

XXII and LGV as starting reagents. Obtain 2.12 g (52%) of product CXII. Mp 270-272 ⁰ C.

LС-Mass (M + H) ⁺ : 408.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.1 (IH, m); 1.5 (IH, m); 1.7 (IH, m); 1.9 (IH, m); 2.3 (IH, t, J = 7.5 Hz); 2.4 (IH, t, J = 7.5 Hz); 3.1 (IH, m); 3.4 (IH, m); 3.5 (IH, m); 4.0 (2H, d, J = 5 Hz); 4.25 (4H, m); 4.5 (IH, d, J = 4.0 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 6.8 (IH, s); 7.0 (IH, s); 7.5 (IH, s); 11.5 (IH, broad peak).

Example 113

Synthesis of 3 - {[4- (4-carboethoxy-piperidin-1-yl) phenylamino] methyl] -7-methyl-III-quinolin-2-one (CXIII).

Conducted according to the methodology described in example 83 using compounds VI. and LVIII as starting reagents. 2.01 g (48%) of product CXIII is obtained. Mp 234-236 ⁰ C.

LC-Mass (M + H) ⁺ : 420.

H-NMR spectrum (δ, DMSO-d ₆ ): 1.1 (3H, t, J = 7.5 Hz); 1.65 (2H, m); 1.90 (2H, m); 2.4 (4H, superposition ZH \ c and IHW); 2.5 (2H, m); 3.4 (2H, m); 4.0 (4H, superposition q \ J = 7.5 Hz and d \ J = 5 Hz); 5.5 (IH, t, J-5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.0 (IH, d, J = 8.5 Hz); 7.1 (IH, d, J = 8.5 Hz); 7.4 (IH, d, J = 8.5 Hz); 7.7 (IH, s); 11.5 (IH, broad peak).

Example 114

Synthesis of 3 - {[4- (4-carboethoxy-sherpidin-1-yl) phenylamino] methyl] -8-methyl-III-quinolin-2-one (CXIV).

Conducted according to the methodology described in example 83, using the connection

GV and LVIII as starting reagents. Obtain 2.08 g (50%) of product CXIV. Mp 178-179 ⁰ C. LC-Mass (MH-H) ⁺ : 420.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.0 (ZN, t, J = 7.5 Hz); 1.6 (2H ₃ m); 2.0 (2H, m); 2.4 (4H, superposition 3H \ c and W \ m); 2.6 (2H, m); 3.4 (2H, m); 4.0 (4H, superposition q \ J = 7.5 Hz and d \ J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.1 (IH, t, J = 8.5 Hz); 7.25 (IH, d, J = 8.5 Hz); 7.5 (IH, d, J = 8.5 Hz); 7.7 (IH, s); 11.0 (IH, broad peak).

Example 115

Synthesis of 3 - {[4- (3-carboethoxy-piperidin-l-yl) phenylamino] methyl] -6-methoxy-W-quinolin-2-one (CXV).

Conducted according to the methodology described in example 83, using the connection

XLII and LX as starting reagents. Obtain 2.10 g (48%) of product CXV. Mp 171-172 ⁰ C.

LС-Mass (M + H) ⁺ : 436.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.2 (ЗН, t, JN7.5 Hz); 1.6 (2H, m); 2.0 (2H, m); 2.55 (2H, m); 2.8 (IH, m); 3.30 (2H, m); 3.60 (ZN, s); 4.0 (4H, superposition q \ J = 7.5 Hz and d \ J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.1 (2H, superposition lH \ c and lH \ d with J = 8.5 Hz); 7.25 (IH, d, J = 8.5 Hz); 7.7 (IH, s); 11.0 (IH, broad peak).

Example 116

Synthesis of 3- {[4- (3-carboethoxy-piperidin-l-yl) phenylamino] methyl] -7-methoxy-W-quinolin-2-one (CXVI).

Conducted according to the methodology described in example 83, using compounds XII and LX as starting reagents. Obtain 1.93 g (44%) of the product CXVI. Mp 193-194 ⁰ C.

LС-Mass (M + H) ⁺ : 436.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.1 (3H, t, J = 7.5 Hz); 1.6 (2H, m); 2.0 (2H, m); 2.6 (2H, m); 2.7 (IH, m); 3.40 (2H, m); 3.75 (ZN, s); 4.0 (4H, superposition q \ J = 7.5 Hz and d \ J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H ₃ d, J = 8.5 Hz); 6.7 (ZN, m); 6.8 (IH, s); 7.5 (IH, d, J = 8.5 Hz); 7.7 (IH, s); 11.0 (IH, broad peak).

Example 117

Synthesis of 3 - {[4- (Cyclohexyl-methyl-amino) -phenylamino] -methyl} -5,8-dimethyl-III-quinolin-2-one (CXVII).

Conducted according to the methodology described in example 83, using compounds X and LXIV as starting reagents. Obtain 1.77 g (46%) of product CXVII. Mp 195-196 ⁰ C.

LС-Mass (M + H) ⁺ : 390.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.0-1.8 (6H, s); 2.3 (ZN, s); 2.35 (ZN, s); 2.5 (ZN, s); 3.2 (IH, m, overlay with H ₂ O); 4.1 (2H, d, J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.6 (2H, d, J = 8.5 Hz); 6.9 (IH, d, J-8.5 Hz); 7.15 (W, d, J = 8.5 Hz); 8.0 (IH, s); 10.5 (IH, broad peak).

Example 118

Synthesis of 7 - {[4- (Cyclohexyl-methyl-amino) -phenylamino] -methyl} -5H-

[1, 3] [4,5-g] -quinolin-6-one dioxol (CXVIII).

Conducted according to the methodology described in example 83, using compounds XX and LXIV as starting reagents. Obtain 2.23 g (55%) of product CXVIII. Mp 209-210 ⁰ C.

LC-Mass (M + H) ⁺ : 406.

H _r NMR spectrum (δ, DMSO-d ₆ ): 1.0-1.9 (6H, s); 2.55 (ZN, s); 3.2 (IH ₅ m, overlay with H ₂ O); 4.0 (2H, d ₅ J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.0 (2H, s); 6.5 (2H, d, J = 8.5 Hz); 6.65 (2H, d, J = 8.5 Hz); 6.8 (IH, s); 7.1 (IH, s); 10.5 (IH, broad peak).

Example 119

Synthesis of 6-methyl-3 - {[4- (4-methyl-piperazin-l-yl) phenylamino] methyl] -H-quinolin-2-one (CXIX). Conducted according to the methodology described in example 83, using compounds

II and LXVI as starting reagents. Obtain 2.27 g (63%) of the product CXIX. T.pl. 275-277 ⁰ C.

LC-Mass (MHhH) ⁺ : 363.

H _r NMR spectrum (δ, DMSO-d _b ): 2.1 (ЗH, s); 2.3 (ZN, s); 2.35 (4H, m); 2.8 (4H, m); 4.1 (2H, d, J = 5 Hz); 5.6 (IH, t, J = 5 Hz); 6.4 (2H, d, J = 8.5 Hz); 6.6 (2H, d, J = 8.5 Hz); 7.2 (2H, m); 7.25 (IH, s); 7.6 (IH, s); 11.6 (IH ₅ broad peak).

Example 120

Synthesis of 5,8-dimethyl-3- {[4- (4-methyl-piperazin-1-yl) -phenylamino] methyl] - 1 H-quinolin-2-one (CXX).

Conducted according to the methodology described in example 83, using compounds X and LXVI as starting reagents. Obtain 1.99 g (53%) of the product CXX. T.pl. 225-226 ⁰ C.

LC-Mass (MH-H) ⁺ : 377.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.1 (S, s); 2.4 (UN, m); 2.9 (4H, m); 4.0 (2H, d, J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 6.9 (IH, d, J = 8.5 Hz); 7.2 (IH, d, J = 8.5 Hz); 8.0 (IH, s); 10.6 (IH, broad peak).

Example 121

Synthesis of 3 - {[4- (4-Acetyl-piperazin-l-yl) -phenylamino] -methyl} -7-ethoxy-Ш-quinolin-2-one (CXXI).

Conducted according to the methodology described in example 83, using compounds XXVI and LXVIII as starting reagents. Obtain 2.05 g (49%) of product CXXl. Mp 266-267 ⁰ C.

LC-Mass (M + H) ⁺ : 421. Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.2 (3H, t, J = 8.5Hz); 2.0 (ZN, s); 2.8 (4H, m); 3.6 (4H, m); 4.0 (4H ₅ superposition q \ J = 8.5 Hz and d \ J = 5 Hz); 5.6 (IH ₃ t, J = 5 Hz); 6.4 (2H, d, J = 8.5 Hz); 6.8 (4H, m); 7.4 (IH ₅ d, J = 8.5 Hz); 7.6 (IH, s); 11.6 (IH, broad peak).

Example 122

Synthesis of 7 - {[4- (4-Acetyl-piperazin-l-yl) -phenylamino] -methyl} -5H-

[1, 3] dioxol of [4,5-g] -quinolin-6-one (CXXII).

Conducted according to the methodology described in example 83, using compounds XX and LXVIII as starting reagents. Obtain 1.97 g (47%) of product CXXII. Mp 280 ° C (razl).

LC-Mass (M + H) ⁺ : 421.

H-NMR spectrum (δ, DMSO-d _b ): 1.9 (S, s); 2.9 (4H, m); 3.6 (4H, m); 4.0 (2H, d, J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.0 (2H ₅ s); 6.5 (2H ₅ d, J = 8.5 Hz); 6.7 (2H ₅ d, J = 8.5 Hz); 6.9 (IH, s); 7.1 (IH, s); 7.8 (IH, s); 11.6 (IH, broad peak).

Example 123

Synthesis of 3 - ({4- [4- (fyran-2-carbonyl) -piperazin-1-yl] -phenylamino} -methyl) -5,7-dimethyl-W-quinolin-2-one (CXXIII).

Conducted according to the methodology described in example 83, using compounds XXVIII and LXX as starting reagents. Obtain 2.12 g (46%) of product CXXIII. Mp 203-204 ⁰ C.

LC-Mass (M + H) ⁺ : 457.

H _r NMR spectrum (δ, DMSO-d ₆ ): 2.25 (S, s); 2.35 (ZN, s); 3.0 (4H ₅ m); 3.75 (4H, ₅ m); 4.05 (2H ₅ d, J = 5 Hz); 5.5 (IH, t, J = 5 Hz); 6.6 (ZN, m); 6.8 (ZN, m); 7.0 (2H ₅ m); 7.8 (IH, s); 7.9 (IH, s); 11.6 (IH, broad peak).

Example 124

Synthesis of 3- ({4- [4- (fyran-2-carbonyl) -piperazin-1-yl] phenylamino} -methyl) -5, 8-dimethyl-1 H-quinolin-2-one (CXXIV). Conducted according to the methodology described in example 83, using compounds

X and LXX as starting reagents. Obtain 1.94 g (42%) of product CXXIV. Mp 219-220 ⁰ C.

LC-Mass (M + H) ⁺ : 457.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.35 (S, s); 2.4 (ZN, s); 3.0 (4H, m); 3.75 (4H, m); 4.2 (2H ₅ d, J = 5 Hz); 5.6 (IH, t, J = 5 Hz); 6.6 (ZN, m); 6.75 (2H, d, J = 8.5 Hz); 6.9 (IH, d, J = 8.5 Hz); 7.0 (IH, d, J = 3.5 Hz); 7.15 (IH, d, J = 8.5 Hz); 7.8 (IH, s); 8.0 (IH, s); 11.6 (IH, broad peak).

Example 125

Synthesis of 7-methyl-3 - {[4- (4-benzyl-piperazin-1-yl) -phenylamino] methyl} - 1 H-quinolin-2-one (CXXV).

Conducted according to the methodology described in example 83, using compounds VI and LXXII as starting reagents. Obtain 2.27 g (63%) of the product CXXV. Mp 236-237 ⁰ C.

LС-Mass (M + H) ⁺ : 439.

Н-NMR spectrum (δ, DMSO-d ₆ ): 2.3 (ЗН, s); 2.8 (4H, m); 3.2 (4H, overlay with H ₂ O); 3.45 (2H, s); 4.0 (2H, d, J = 5 Hz); 5.6 (IH, t, J = 5 Hz); 6.4 (2H, d, JN8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 6.95 (IH, d, J = 8.5 Hz); 7.1 (IH, s); 7.25 (4H, m); 7.4 (IH, d, J = 8.5 Hz); 7.7 (IH, s); 11.6 (IH, broad peak).

Example 126

Synthesis of 5, 6,7-trimethoxy-3 - {[4- (4-phenyl-piperazin-1-yl) -phenylamino] -methyl} -S-quinolin-2-one (CXXVI).

Conducted according to the methodology described in example 83, using compounds XXXIV and LXXIV as starting reagents. 2.63 g (53%) of the product CXXVI are obtained. Mp 253-255 ⁰ C.

LС-Mass (M + H) ⁺ : 501. Ni-NMR spectrum (δ, DMSO-d ₆ ): 3.0 (4H, m); 3.7 (ZN, s); 3.8 (ZN, s); 3.85 (ZN, s); 4.1 (2H, d, J = 5 Hz); 5.5 (IH ₃ t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.6 (IH, s); 6.75 (ZN, m); 6.9 (2H, d, J = 8.5 Hz); 7.2 (2H, t, J = 8.5 Hz); 7.8 (IH, s); 11.6 (IH, broad peak).

Example 127

Synthesis of 3 - {[4- (3,4-dihydro-III-isoxinolin-2-yl) phenylamino] methyl] -7-methyl-III-quinolin-2-one (CXXVII).

Conducted according to the methodology described in example 83, using compounds VI and LXXVI as starting reagents. Obtain 1.98 g (50%) of product CXXVII. Mp 195-197 ^° C (decomp.).

LC-Mass (M + H) ⁺ : 396.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.35 (S, s); 2.8 (2H, t, J = 7.5 Hz); 3.2 (2H, t, J = 7.5 Hz); 4.0 (2H, d, J = 5 Hz); 4.1 (2H, s); 5.6 (IH, t, J = 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.8 (2H, d, J = 8.5 Hz); 6.9 (IH, d, J = 8.5 Hz); 7.1 (5H, m); 7.4 (IH, d, J = 8.5 Hz); 7.6 (IH, s); 11.6 (IH, broad peak).

Example 128

Synthesis of 3 - [(3,4-dihydroxy-phenylamino) methyl] -5,7-dimethyl-III-quinolin-2-one (CXXVIII).

A mixture of 2.0 g (10 mmol) of 5,7-dimethyl-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (XXVIII) and 1.8 g (12 mmol) of aminoveratrol (3,4-dimethoxyaniline) is heated in dimethylformamide to a temperature of 100 -110 ⁰ C. The reaction mixture is cooled. The precipitate formed is filtered off, washed with ethanol (50 ml) and suspended in ethanol. To the resulting suspension, 0.8 g (20 mmol) of sodium borohydride are added portionwise by heating and stirring. The resulting reaction mixture was refluxed for 1 hour. At the end of the reaction, the mixture was diluted with a small amount of water (20 ml), evaporated under reduced pressure. The precipitate formed is filtered off and washed with water. The isolated substance is dried. The dried product (2.14 g, 6.3 mmol) was suspended in 100 ml of methylene chloride and cooled to -78 ⁰ C. To the resulting mixture was added 15 ml BBr ₃ . The reaction mixture was stirred at the indicated temperature for 1 hour, then the temperature was raised to room temperature and held for 8 hours. At the end of the reaction, 10 dry methanol was added dropwise to the reaction mixture. The solvent was evaporated. The resulting residue was recrystallized from ethanol. 0.83 (27%) g of product CXXVIII is obtained. Mp 261-264 ⁰ C (s).

Н-NMR spectrum (δ, DMSO-d ₆ ): 2.3 (ЗН, s); 2.4 (ZN, s); 4.4 (2H, broad peak); 5.2 (broadened peak); 6.8 (ZN, superposition W \ c and 2H \ d, J = 8.5 Hz); 6.9 (2H, m); 7.0 (IH, s); 8.2 (IH, s); 9.6 (2H, broad peak); 12.0 (IH, s).

Example 129

Synthesis of 3 - [(2,4-dihydroxy-phenylamino) methyl] -6,7-dimethyl-1 H-quinolin-2-one (CXXIX).

Conducted according to the methodology described in example 128, using XVIII and 2,4-dimethoxyaniline as starting reagents. Obtain 0.97 g (31%) of the product CXXIX. Mp 261-263 ⁰ C (decomp.).

Н-NMR spectrum (δ, DMSO-d ₆ ): 2.0 (ЗН, s); 2.1 (ZN, s); 4.1 (2H, broad peak); 6.2 (IH, d, J = 8.5 Hz); 6.4 (IH, s); 7.0 (IH, d, J = 8.5 Hz); 7.1 (IH, s); 7.3 (IH ₃ s); 7.9 (IH, s); 9.5 (IH, broad peak); 10.0 (IH, broad peak); 10.5 (IH, broad peak); 12.0 (IH, broad peak).

Example 130

Synthesis of 3 - [(3, 5-dihydroxy-phenylamino) methyl] -6-methyl-1 H-quinolin-2-one (CXXX).

Conducted according to the methodology described in example 128, using II and 3,5-dimethoxyaniline as starting reagents. Obtain 0.71 g (24%) of the product CXXX. Mp 280-286 ⁰ C (decomp.).

H _r NMR spectrum (δ, DMSO-d ₆ ): 2.4 (ЗН, s); 4.1 (2H, broad peak); 6.1 (ZN, m); 7.2 (IH, d, J = 8.5 Hz); 7.4 (IH, d, J = 8.5 Hz); 7.45 (IH, d, J = 3 Hz); 7.8 (IH, s); 8.5-10.5 (ZN, broadened peak); 12.0 (IH, broad peak). Example 131

Synthesis of 3 - [(2-Hydroxy-phenylamino) -methyl] -b-ethyl-Ш-quinolin-2-one

(CXXXI).

Conducted according to the methodology described in example 128, using XIV and 2-methoxyaniline as starting reagents. Obtain 1.11 g (37%) of the product CXXXI. Mp 239-240 ⁰ C.

H-NMR spectrum (δ, DMSO-d ₆ ): 1.2 (3H, t, J = 7.5 Hz); 2.6 (2H, q, J = 7.5 Hz); 4.4 (2H, broad peak); 6.8 (IH, t, J = 8.5 Hz); 6.95 (IH, d, J = 8.5 Hz); 7.1 (2H, superposition d \ t, J = 8.5 Hz); 7.3 (IH, d, J = 8.5 Hz); 7.4 (2H, superposition IH d \ J = 8.5 Hz and W s); 7.9 (IH, s); 10-12 (2H, broad peaks).

Example 132

Synthesis of 6,7-dimethoxy-3 - {[4- (4-pyrimid-2-yl-piperazin-l-yl) -phenylaminoj-methyl} - 1 H-quinolin-2-one (CXXXII).

Conducted according to the methodology described in example 83, using compounds CLXXIII and LXXX as starting reagents. 2.77 g (59%) of product CXXXII are obtained. Mp 267-269 ⁰ C.

LС-Mass (M + H) ⁺ : 473.

H _r NMR spectrum (δ, DMSO-d ₆ ): 2.9 (4H, m); 3.6 (3H ₅ s); 3.65 (ZN, s); 3.70 (4H, m); 4.10 (2H, d, J = 7.5 Hz); 5.5 (IH, t, J = 7.5 Hz); 6.5 (2H, d, J = 5.5 Hz); 6.6 (IH, t, J = 5.5 Hz); 6.8 (2H, d, J = 6.5 Hz); 6.9 (IH, s); 7.1 (IH, s); 7.6 (IH, s); 8.4 (2H, d, J = 7.5 Hz); 11.5 (IH, broad peak).

Example 133

Synthesis of 3 - [(9,9-dioxo-9,10-dihydro-9λ ^* 6 ^* -thia-10-aza-phenanthren-3-ylamino) -methyl] -7-methyl-Ш-quinolin-2-one ( CXXXIII).

Conducted according to the methodology described in example 83, using the connection

VI and 9,9-dioxo-9,10-dihydro-9λ ^* 6 ^* -thia-10-aza-phenanthren-3-ylamine as starting reagents. Obtain 2.16 g (52%) of product CXXXIII. Mp 233-235 ⁰ C. LС-Mass (M + H) ⁺ : 418.

2H NMR spectrum (δ, DMSO-d ₆ ): 2.2 (3H, s); 4.1 (2H, d, J = 7.5 Hz); 5.2 (IH. T, 1 = 1.5 Hz); 6.6 (2H. M); 6.9 (IH, d, J = 8.5 Hz); 7.1 (2H, m); 7.3 (IH, t, J = 8.5 Hz); 7.4 (IH ₅ t, J = 8.5 Hz); 7.5 (IH, d, J = 8.5 Hz); 7.6 (IH, d, J = 8.5 Hz); 7.9 (IH ₅ d, J-8.5 Hz); 7.95 (IH, s); 11.5 (IH, broad peak).

Example 134

Synthesis of 6-methoxy-3 - {[4- (4-pyrid-2-yl-sherpazin-l-yl) -phenylamino] -methyl} -CH-quinolin-2-one (CXXXGV).

Conducted according to the methodology described in example 83, using compounds XLII and LXXVIII as starting reagents. 2.92 g (66%) of CXXXIU product are obtained. Mp 278-280 ⁰ C.

LС-Mass (M + H) ⁺ : 442.

H _t- NMR spectrum (δ, DMSOd ₆ ): 2.4 (4H, m); 3.5 (4H, m); 3.6 (ZN, s); 4.1 (2H, d, J = 5.5 Hz); 5.4 (IH, t, J = 5.5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.6 (IH ₅ d / d, J = 8.5 Hz / 5.0 Hz); 6.65 (2H, m); 7.2 (IH, d, J = 8.5 Hz); 7.3 (IH, t, J = 8.5 Hz); 7.77 (IH, s); 7.9 (IH, d, J = 5.0 Hz); 11.5 (IH, broad peak).

Example 135

Synthesis of 3 - [(2,6-dimethoxy-pyridin-3-ylamino) -methyl] -l, 6,7,8, -tetrahydro-cyclopent [g] quinolin-2-one (CXXXV).

Conducted according to the methodology described in example 83, using the connection

XL and 3-amino-2,6-dimethoxyxypyridine hydrochloride as starting reagents. Obtain 1.81 g (52%) of product CXXXV. Mp 291-293 ⁰ C.

LС-Mass (M + H) ⁺ : 352. Example 136

Synthesis of 3 - [(III, 1 H- [2,5] bisbenzimidazolyl-5-ylamino) methyl] -6,7-dimethoxy-1 H-quinolin-2-one (CXXXVI).

Conducted according to the methodology described in example 83, using the connection

CLXXIII and IH ₅ I H- [2,5] Bisbenzoimidazolyl-5-ylamine as starting reagents. 2.37 g (51%) of the product CXXXVI are obtained. Mp 288-290 ⁰ C.

LC-Mass (M + H) ⁺ : 467.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 3.5 (S, s); 3.55 (ZN, s); 4.0 (2H, d, J = 5.5 Hz); 5.8 (IH, t, J = 5.5 Hz); 6.5 (IH, broad peak); 6.55 (IH, d, J = 8.5 Hz); 6.90 (IH, s); 7.0

(IH, s); 7.4 (IH, d, J = 8.5 Hz); 7.5 (IH, d, J = 8.5 Hz); 7.7 (IH, s); 8.0 (IH, d, J = 8.5 Hz);

8.2 (2H, superposition 2 s); 11.5 (IH, broad peak); 12.0 (IH, broad peak).

Example 137

Synthesis of 3 - [(W-Indazol-5-ylamino) -methyl] -6-methyl-W-quinolin-2-one (CXXXVII).

Conducted according to the methodology described in example 83, using compound 11 and 5-amino-III-indazole as starting reagents. Obtain 2.08 g (68%) of product CXXXVII. Mp 273-275 ⁰ C.

LС-Mass (M + H) ⁺ : 305.

2H-NMR spectrum (δ, DMSO-d ₆ ): 2.1 (3H, s); 4.1 (2H, d, J = 5.5 Hz); 5.6 (IH, t, J = 5.5 Hz); 6.6 (IH, s); 6.9 (IH, d / d, J-8.5 Hz / 3.5 Hz); 7.1 (ZN, m); 7.5 (2H, superposition 22 s); 11.5 (IH, broad peak); 12.5 (IH, broad peak).

Example 138

Synthesis of 2-amino-3-hydroxy-6-methylpyridine (CXXXVIII). Conducted according to the methodology described in example 44, using as the starting 2-nitro-3-hydroxy-6-methylpyridine. The product CXXXVIII thus obtained is used in further transformations without further purification due to its instability.

LС-Mass (M + H) ⁺ : 125.

Example 139

Synthesis of 7-ethoxy-3 - [(3-hydroxy-6-methyl-pyridin-2-ylamino) methyl] - 1 H-quinolin-2-one (CXXXIX).

Conducted according to the methodology described in example 83, using compounds XXVI and CXXXVIII as starting reagents. Obtain 1.94 g (60%) of the product CXXXIX. Mp 231-233 ⁰ C.

LС-Mass (M + H) ⁺ : 326.

Example 140

Synthesis of 3-methyl-4-tetrazolyl-aniline (CXL).

A mixture of 2-methyl-4-nitroaniline (15.2 g, 0.1 mol), sodium azide (12.6 g, 0.2 mol) and triethylorthoformate (15 ml) in 100 ml of glacial acetic acid is heated to 100 ^° C, stirring vigorously. At the end of the reaction, the mixture is cooled and poured into 400 ml of cold water, acidified with hydrochloric acid (15 ml). The precipitate formed is filtered off, washed with water and dried. The nitro derivative thus obtained is reduced according to the procedure described in Example 72. 9.2 g (52%) of the CXL product is obtained, which is used in further syntheses without further characterization.

Example 141

Synthesis of 7-methyl-3 - [(3-methyl-4-tetrazol-l-yl-phenylamino) methyl] -H-quinolin-2-one (CXLI). Conducted according to the methodology described in example 83, using compounds

VI and CXL as starting reagents. Obtain 2.12 g (61%) of the product CXLI. Mp 257-259 ⁰ C.

LС-Mass (M + H) ⁺ : 347.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.9 (S, s); 2.1 (ZN, s); 4.1 (2H ₅ d, J = 5.5 Hz);

6.5 (2H, m); 6.6 (IH, s); 7.0 (W, d, J = 8.5 Hz); 7.1 (2H ₅ m); 7.4 (IH, d, J = 8.5 Hz); 7.7 (IH, s); 9.5 (IH, s); 11.5 (IH, broad peak).

Example 142

Synthesis of 8-methyl-3 - [(2-pyridin-3-yl-1 H-benzoimidazo l-5-amino) - methyl] - 1 H-quinoline-2-one (CXL 11).

Conducted according to the methodology described in example 83, using compound IV and 2-pyridin-3-yl-III-benzonimidazole-5-ylamine as starting reagents. 2.33 g (61%) of the product CXLII are obtained. Mp 280-282 ⁰ C.

LС-Mass (M + H) ⁺ : 382.

Н-NMR spectrum (δ, DMSO-d ₆ ): 2.4 (ЗН, s); 4.1 (2H, d, J = 5.5 Hz); 6.0 (IH, t,

J = 5.5 Hz); 6.5 (IH, s); 6.8 (IH, d, J = 8.5 Hz); 7.0 (IH, t, J = 8.5 Hz); 7.2 (IH, d, J = 8.0 Hz); 7.4 (2H, m); 7.5 (IH d / d, J = 8.0 Hz / 5.0 Hz); 7.8 (IH, s); 8.2 (IH, d, J = 5.0 Hz); 8.5 (IH, d, J = l, 5 Hz); 9.2 (IH, s); 11.5 (W, broad peak).

Example 143

Synthesis of 6-ethyl-3 - [(5-methoxy-quinolin-8-ylamino) -methyl] -S-quinolin-2-one (CXLIII).

Conducted according to the methodology described in example 83, using the compound XIV and 5-methoxy-quinolin-8-ylamine as starting reagents. Obtain 1.81 g (50%) of product CXLIII. Mp 221-223 ⁰ C.

LС-Mass (M + H) ⁺ : 360. Example 144

Synthesis of 7-ethoxy-3 - (quinolin-5-aminomethol L) - 1 H-quinolin-2-one (CXLIV).

Conducted according to the methodology described in example 83, using the compound XXVI and quinolin-5-ylamine as starting reagents. Obtain 1.97 g (57%) of product CXLIV. Mp 254-256 ⁰ C.

LС-Mass (M + H) ⁺ : 346.

Ni-NMR spectrum (δ, DMSO-d ₆ ):

Example 145

Synthesis of 3-Methoxy-4-tetrazolyl-aniline (CXLV).

Conducted according to the methodology described in example 140, using 2-methoxy-4-nitroaniline as the starting material. 12.8 g (67%) of the product CXLV are obtained.

LС-Mass (M + H) ⁺ : 192.

Example 146

Synthesis of 6-Methoxy-3 - [(3-Methoxy-4-tetrazo l-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one (CXLVI).

Conducted according to the methodology described in example 83, using compounds XLII and CXLV as starting reagents. Obtain 2.21 g (58%) of the product CXLVI. Mp 261-263 ⁰ C.

LС-Mass (M + H) ⁺ : 379.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 3.8 (6H, s); 4.2 (2H, d, J = 5.5 Hz); 6.2 (IH, d,

J = 8.5 Hz); 6.5 (IH, s); 6.7 (IH, t, J = 5.5 Hz); 7.0 (IH ₅ d / d, J = 8.5 Hz / 3.5 Hz); 7.2 (IH, s); 7.25 (2H, m); 7.7 (IH, s); 9.5 (IH, s); 11.5 (IH, broad peak).

Example 147

Synthesis of 3-amino-2-hydroxy-5-methylpyridine (CXLVII). Conducted according to the methodology described in example 44, using 2-nitro-3-hydroxy-5-methylpyridine as the starting material. The product CXLVII thus obtained is used in further transformations without further purification due to its instability.

LС-Mass (M + H) ⁺ : 125.

Example 148

Synthesis of 3 - [(2-Hydroxy-5-methyl-pyridin-3-ylamino) methyl] -7-methoxy-Sh-quinolin-2-one (CXLVIII).

Conducted according to the methodology described in example 83, using compounds XII and CXLVII as starting reagents. Obtain 1.92 g (62%) of the product CXLVPI. T.pl. 219-221 ⁰ C.

LС-Mass (M + H) ⁺ : 312.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.9 (S, s); 3.7 (ZN, s); 4.1 (2H, d, J = 5.5 Hz); 5.6 (IH, t, J = 5.5 Hz); 6.0 (IH, s); 6.4 (IH, s); 6.7 (IH, d / d, J = 8.5 Hz / 3.5 Hz); 6.75 (IH, s); 7.5 (IH, d, J = 8.5 Hz); 7.6 (IH, s); 11.0 (IH, broad peak); 11.5 (IH, broad peak).

Example 149

Synthesis of 6-ethoxy-3-aminopyridine (CXLIX).

Conducted according to the methodology described in example 44, using 6-ethoxy-3-nitropyridine as the starting material. The CXLIX product thus obtained is used in further transformations without further purification due to its instability.

LС-Mass (M + H) ⁺ : 139.

Example 150

Synthesis of 3 - [(6-ethoxy-pyridin-3-ylamino) methyl] -6-methoxy-W-quinolin-2-one (CL). Conducted according to the methodology described in example 83, using compounds

VIII and CXLIX as starting reagents. Obtain 1.92 g (62%) of the product CL. Mp 209-211 ⁰ C.

LС-Mass (M + H) ⁺ : 326.

H-NMR spectrum (δ, DMSO-d ₆ ): 1.2 (3H, t, J = 7.5 Hz); 3.8 (3H, s); 4.0 (4H, m);

5.6 (IH, t, J = 5.5 Hz); 6.4 (IH, d, J = 8.5 Hz); 7.1 (ZN, m); 7.2 (IH, d, J = 8.5 Hz); 7.4 (IH, d, J = 3.5 Hz); 7.7 (IH, s); 11.6 (IH).

Example 151

Synthesis of 3 - [(4, b-dimethyl-pyridin-2-ylamino) methyl] -5,7-dimethyl-Ш-quinolin-2-one (CLI).

Conducted according to the method described in example 83, using compound XXVIII and 4,6-dimethyl-2-aminopyridine as starting reagents. Obtain 1.63 g (53%) of CLI product. Mp 199-200 ⁰ C.

LC-Mass (M + H) ⁺ : 308.

Н-NMR spectrum (δ, DMSO-d ₆ ): 2.0 (ЗН, s); 2.1 (ZN, s); 2.2 (ZN, s); 2.4 (ZN, s); 4.4 (2H, d, JN.5.5 Hz); 6.1 (IH, s); 6.2 (IH, s); 6.4 (IH, t, J = 5.5 Hz); 6.7 (IH, s); 7.0 (IH, s); 8.0 (IH, s); 11.5 (IH, broad peak).

Example 152

Synthesis of 6,7-Dimethoxy-3 - [(2-methyl-5-pyrpol-l-yl-phenylamino) methyl] -H-quinolin-2-one (CLII).

Conducted according to the methodology described in example 83, using the compounds CLXXIII and 2-methyl-5-pippol-l-yl-aniline as starting reagents. Obtain 1.73 g (44%) of product CLII. Mp 208-210 ⁰ C.

LС-Mass (M + H) ⁺ : 390.

H _r NMR spectrum (δ, DMSO-d ₆ ): 2.0 (ЗН, s); 3.6 (ZN, s); 3.7 (ZN, s); 4.2 (2H, d,

J = 5.5 Hz); 5.5 (IH, t, J = 5.5 Hz); 6.2 (2H, m); 6.5 (IH, d, J = 3.5 Hz); 6.55 (IH, d, J-8.5 Hz); 6.90 (IH, s); 7.0 (IH ₅ d, J = 8.5 Hz); 7.1 (ZN, m); 7.6 (IH, s); 11.5 (IH, broad peak).

Example 153

Synthesis of 6-methyl-3- (pyridin-3-ylaminomethyl) -Sh-quinolin-2-one (CLSh).

Conducted according to the methodology described in example 83, using the connection

II and 3-aminopyridine as starting reagents. 1.18 g (45%) of product CLIII are obtained. Mp 193-195 ⁰ C.

LС-Mass (M + H) ⁺ : 266.

Example 154

Synthesis of 3 - [(2-Hydroxy-pyridine-3-ylamino) methyl] - 1 H-quinolin-2-one

(CLIV).

Conducted according to the methodology described in example 83, using the compound XXX and 2-hydroxy-3-aminopyridine as starting reagents. Obtain 1.38 g (51%) of product CLIV. Mp 211-213 ⁰ C.

LС-Mass (M + H) ⁺ : 268.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 4.0 (2H, d, J = 5.5 Hz); 5.8 (IH, t, J = 8.5 Hz); 6.0 (IH, t, J = 8.5 Hz); 6.2 (IH, d, J = 8.5 Hz); 6.55 (IH, d, J = 8.5 Hz); 7.0 (IH, t, J = 5.0 Hz); 7.3 (IH, d, J = S ₅ O Hz); 7.5 (IH ₃ t, J = 8.0 Hz); 7.6 (IH, d, J = 6.0 Hz); 7.7 (IH, s); 11.2 (IH, broad peak); 11.5 (IH, broad peak).

Example 155.

Synthesis of 3 - [(10, ll-dihydro-5H-dibenzo [b, f] azepin-3-ylamino) methyl] -7-methoxy-Sh-quinolin-2-one (CLV).

Conducted according to the methodology described in example 83, using compound XII and 10, l l-dihydro-5H-dibenzo [b, f] azepin-3-amine as starting reagents. 2.31 g (58%) of CLV product are obtained. Mp 229-231 ⁰ C. LC-Mass (M + H) ⁺ : 398.

H-NMR spectrum (δ, DMSO-d ₆ ): 2.7 (2H ₅ m); 2.9 (2H ₅ m); 3.7 (ZN, s); 4.1 (2H ₅ d, J = 5 ₅ 5 Hz); 5.6 (IH, t, J = 5.5 Hz); 6.0 (IH, d, J = 8.5 Hz); 6.2 (IH ₅ s); 6.6 (IH ₅ t, J = 8.5 Hz); 6.7 (IH ₅ d, J = 8 ₅ 5 Hz); 6.75 (IH, d / d, J = 8.5 / 3.5 Hz); 6.80 (IH ₅ d ₅ J = 3.5 Hz); 6.90 (3H ₅ m); 7.50 (IH, d, J = 8.5 Hz); 7.7 (IH, s); 7.9 (IH, s); 11.5 (IH ₅ broad peak).

Example 156

Synthesis of 3 - [(3-Quinoxcalil-2-yl-phenylamino) methyl] -Sh-quinolin-2-one (CLVI).

Conducted according to the methodology described in example 83, using the compound XXX and 3-quinoxalil-2-yl-aniline as starting reagents. Obtain 2.03 g (54%) of CLVI product. Mp 277-279 ⁰ C.

LС-Mass (M + H) ⁺ : 379.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 4.1 (2H ₅ d, J = 5.5 Hz); 6.4 (IH ₅ t, J = 5.5 Hz); 6.7 (IH ₅ d, J = 8.5 Hz); 7.25 (IH ₅ t, J = 8.5 Hz); 7.35 (2H ₅ m); 7.45 (2H ₅ m); 7.60 (2H, m); 7.85 (3H ₅ m); 8.1 (2H, m); 9.5 (IH, s); 11.5 (IH ₅ broad peak).

Example 157

Synthesis of 7- ({4- [2- (l-methyl- Ш-benzimidazol-2-yl) -ethyl] -phenylamino} -methyl) -5H- [l ₅ 3] dioxol [4,5-g] quinoline- 6-one (CLVII).

Conducted according to the procedure described in example 83, using the compound XX and 4- [2- (l-Methyl-III-benzonimidazol-2-yl) ethyl] -aniline as starting reagents. 2.01 g (44%) of CLVII product are obtained. Mp 261-263 ⁰ C.

LС-Mass (M + H) ⁺ : 453.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.9 (2H, t, J = 7.5 Hz); 3.0 (2H ₅ t, J = 7.5 Hz); 4.1 (2H. D, J = 5.5 Hz); 6.0 (2H, s); 6.5 (2H ₅ d, J = 8.5 Hz); 6.7 (IH ₅ s); 6.9 (2H ₅ d ₅ J = 8.5 Hz); 7.1 (IH ₅ s); 7.2 (2H ₅ m); 7.4 (IH ₅ d, J = 8.5 Hz); 7.55 (IH ₅ d, J = 8.5 Hz); 7.65 (IH, s). Example 158

Synthesis of N- {5 - [(7-ethoxy-2-oxo-l, 2-dihydro-quinolin-3-ylmethyl) -amino] -benzothiazol-2-yl} -acetamide (CLVIII).

Conducted according to the methodology described in example 83, using the connection

XXVI and N- (5-amino-benzotiazol-2-yl) -acetamide as starting reagents. Obtain 1.92 g (47%) of product CLVIII. Mp 291-293 ⁰ C.

LС-Mass (M + H) ⁺ : 409.

Ni-NMR spectrum (δ, DMSO-d _b ): 1.2 (3H, t, J = 7.5 Hz); 1.9 (ZN, s); 3.9 (2H ₅ q, J = 7.5 Hz); 4.2 (2H, d, J = 5.5 Hz); 6.0 (IH, t, J = 5.5 Hz); 6.7 (ZN, m); 6.65 (IH, s); 7.0 (IH, s); 7.4 (2H, m); 7.7 (IH ₃ s); 11.4 (IH, broad peak); 12.0 (IH, broad peak).

Example 159

Synthesis of 2-ethoxy-3-aminopyridine (CLIX).

Dissolve 2.5 g of sodium metal (0.11 mol) in 200 ml of absolute ethanol. 13 g of 2-chlorop-3-nitropyridine are introduced in portions into the resulting solution. The reaction mixture was stirred at room temperature for 8 hours, diluted with 50 ml of cold water, concentrated under reduced pressure. The resulting solution was extracted with methylene chloride, dried, passed through a layer of silica gel, concentrated. The resulting nitro derivative is reduced according to the procedure described in Example 72. 6.3 g (45%) of the CLIX product are obtained, which is immediately used in further synthesis.

LС-Mass (M + H) ⁺ : 139.

Example 160

Synthesis of 3 - [(2-Ethoxy-pyridin-3-ylamino) methyl] - 8-methyl-1 H-quinolin-2-one (CLX). Conducted according to the methodology described in example 83, using compounds

IV and CLIX as starting reagents. 1.97 g (63%) of the CLX product are obtained. Mp 228-230 ⁰ C.

LС-Mass (M + H) ⁺ : 310.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.1 (3H, t, J = 7.5 Hz); 2.4 (ZN, s); 4.1 (2H, d,

J = 5.5 Hz); 4.5 (2H, q, J = 8.5 Hz); 5.5 (IH, t, J = 5.5 Hz); 6.6 (2H, m); 7.0 (IH, t, J = 8.5 Hz); 7.3 (IH, d, J = 8.5 Hz); 7.35 (IH, d / d, J = 7.5 Hz / 1.5 Hz); 7.45 (IH, d, J = 8.5 Hz); 7.7 (IH, s); 10.8 (IH, broad peak).

Example 161

Synthesis of 2,4-dipiperidyl nitrobenzene (CLXI).

Conducted according to the methodology described in example 43, using instead of 4-chloro-nitrobenzene, 2,4-dichloro-nitrobenzene, and instead of pyrrolidine, piperidine. 21.6 g (75%) of CLXI product are obtained.

LС-Mass (M + H) ⁺ : 290.

Example 162

Synthesis of 2,4-dipiperidyl-aniline (CLXl 1).

Conducted according to the methodology described in example 44 using the connection CLXl. 10.7 g (63%) of product CLXl 1 are obtained.

LС-Mass (M + H) ⁺ : 260.

Example 163.

Synthesis of 3 - [(2,4-Di-piperidine-1-yl-phenylamino) methyl] -5, 7-dimethyl-1 H-quinolin-2-one (CLXIII).

Conducted according to the methodology described in example 83, using compounds XXVIII and CLXII as starting reagents. Obtain 2.37 g (53%) of product CLXIII. T.pl. 214-216 ⁰ C. LС-Mass (M + H) ⁺ : 445.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.5 (12H, m); 2.2 (ZN, s); 2.4 (ZN, s); 2.6 (4H, m); 2.8 (4H, m); 4.0 (2H, d, J = 5.5 Hz); 5.1 (IH, t, J = 5.5 Hz); 6.5 (2H ₅ m); 6.6 (IH ₅ s); 6.7 (IH, s); 7.0 (IH, s); 7.7 (IH ₅ s); 11.5 (IH ₅ broad peak).

Example 164

Synthesis of 1-benzyl- [l, 4] diazepan-5-one (CLXIV).

To a mixture of sulfuric acid (50 ml) and chloroform (180 ml) was added 18.9 g (0.1 mol) of benzyl piperid-4-one. Then 13 g of sodium azide (0.2 mol) are added in portions to the reaction mixture and stirred. At the end of the process, the reaction mixture is diluted with cold water and neutralized with potash. The precipitate formed is filtered off, washed with chloroform, the organic phase is separated, the aqueous solution is extracted with chloroform, the combined organic phases are dried and evaporated. The resulting material was crystallized from ethyl acetate-hexane. Receive 12 g (60%) of the product CLXIV ₅ which is used in further syntheses.

Example 165

Synthesis of [l, 4] diazepan-5-one (CLXV).

Conducted according to the methodology described in example 44. Receive 8 g (80%) of the product CLXV.

LС-Mass (M + H) ⁺ : 115.

Example 166

Synthesis of l- (4-nitrophenyl) - [l, 4] diazepan-5-one (CLXVI).

Conducted according to the procedure described in example 43, using instead of pyrrolidine product CLXV. 17.6 g (85%) of CLXVI product are obtained.

LС-Mass (M + H) ⁺ : 236. Example 167

Synthesis of l- (4-aminophenyl) - [l, 4] diazepan-5-one (CLXVII).

Conducted according to the methodology described in example 44. Receive 12 g (76%) of the product CLXVIL

LС-Mass (M + H) ⁺ : 206.

Example 168

Synthesis of 7-ethyl-3 {[4- (5-oxo- [l, 4] diazepan-1-yl) phenylamino] methyl] - 1 H-quinolin-2-one (CLXVIII).

Conducted according to the methodology described in example 83, using the connection

CLXXXIII and CLXVII as starting reagents. Obtain 2.18 g (56%) of product CLXVIII. Mp 249-251 ⁰ C.

LС-Mass (M + H) ⁺ : 391.

H _r NMR spectrum (δ, DMSO-d ₆ ): 1.2 (ZN, t, J-7.5 Hz); 2.5 (2H, q, J = 7.5 Hz); 3.0 (8H, m); 3.9 (2H, d, J = 5.5 Hz); 5.45 (IH, t, J = 5.5 Hz); 6.4 (2H, d, J = 8.5 Hz); 6.6 (2H, d, J = S ₅ S Hz); 7.0 (IH, d, J = 8.5 Hz); 7.15 (IH, s); 7.4 (IH, d, J = 8.5 Hz); 7.45 (IH, t, J = 8.5 Hz); 7.75 (IH, s); 11.5 (IH, broad peak).

Example 169

Synthesis of l- (2-methoxy-ethyl) -4- (4-nitrophenyl) piperazine (CLXIX).

Conducted according to the methodology described in example 43, using 2-methoxy-ethyl-piperazine instead of pyrrolidine. 16.9 g (64%) of CLXIX product are obtained.

LС-Mass (M + H) ⁺ : 266.

Example 170

Synthesis of 4- [4- (2-Methoxy-ethyl) -piperazin-l-yl] -aniline (CLXX). Conducted according to the methodology described in example 44. Receive 10.2 g (77%) of the product CLXX.

LС-Mass (M + H) ⁺ : 236.

Example 171

Synthesis of 3 - ({4- [4- (2-methoxy-ethyl) -piperazin-l-yl] phenylamino} -methyl) -6-methyl-III-quinolin-2-one (CLXXI).

Conducted according to the methodology described in example 83, using compounds II and CLXX as starting reagents. 2.18 g (54%) of CLXXI product are obtained. Mp 199-201 ⁰ C.

LС-Mass (M + H) ⁺ : 407.

H-NMR spectrum (δ, DMSO-d ₆ ): 2.1 (S, s); 2.9 (4H, m); 3.2 (ZN, s); 3.25 (6H, m); 3.50 (2H, t, J = 7.5 Hz); 4.0 (IH, d, J = 5.5 Hz); 5.5 (IH, t, J = 5.5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.1 (2H, m); 7.3 (IH, s); 7.6 (IH, s); 11.5 (IH, broad peak).

Example 172

Synthesis of 2-chlorop-6,7-dimethoxyxyquinoline-3-carbaldehyde (CLXXII).

Conducted according to the methodology described in example 1. Receive 41 g (66%) of the product. T. pl. 212-214 ⁰ C (lit. 213-215 ° C, [20]).

Ni-NMR spectrum (δ, DMSO-d ₆ ): 3.6 (ЗH, s), 3.7 (ЗH, s), 7.4 (IH, s), 7.6 (IH, s), 8.7 (IH, s), 10.4 ( IH, s).

Example 173

Synthesis of 6,7-dimethoxy-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde

(CLXXIP).

Conducted according to the methodology described in example 2. Receive 23.9 g (71%) of the product. Mp> 300 ° C. Ni-NMR spectrum (δ, DMCO-d ₆ ): 3.65 (3H, s), 3.7 (3H, s), 7.5 (IH, s), 8.0 (IH, s), 8.5 (IH, s), 10.5 ( IH, s).

Example 174

Synthesis of l-ethyl-7-methoxy-quinol-2-one-3-carbaldehyde (CLXXIV).

Obtained according to example 12 aldehyde (XII) in an amount of 5.5 g.

(0.025 mol) is dissolved by heating in 250 ml of methanol, then a KOH solution (2.875 g) is added. 7.5 ml of ethyl bromide was added to the resulting reaction mixture and refluxed for 5 hours. The reaction mixture was poured onto 300 g of finely divided ice and acidified. The precipitate formed is filtered off, washed with a large amount of diluted alkali, then with water until neutral. Recrystallization from acetonitrile gave 2.4 g (41%) of the product (CLXXIV). T. pl. 155-157 ⁰ C.

H ₁ -UMP spectrum (δ, DMSO-d ₆ ): 1.18 (ZN, t, J = 7.5 Hz); 4.17 (2H, q, J = 7.5 Hz); 3.79 (ZN, s); 6.66 (IH, d, J = 3.5 Hz); 6.87 (IH, d / d, J = 8.5 / 3.5 Hz); 7.47 (IH, d, J = 8.5 Hz); 8.45 (IH, s); 10.05 (IH, s).

Example 175.

Synthesis of l-ethyl-6-methyl-quinol-2-one-3-carbaldehyde (CLCXU).

Conducted according to the methodology described in example 174, using as starting material II. 2.9 g (38%) of the product are obtained. Mp 163-165 ⁰ C.

) Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.18 (3H, t, J = 7.5 Hz); 2.21 (ZN, s); 4.17 (2H, q, JN7.5 Hz); 7.10 (IH, d, J = 3.5 Hz); 7.23 (IH, d, J = 8.5 Hz); 7.39 (IH, d / d, J = 8.5 / 3.5 Hz); 8.45 (IH, s); 10.05 (IH, s).

Example 176

Synthesis of l-methyl-7-methoxy-quinol-2-one-3-carbaldehyde (CLXXVI).

Carried out according to the methodology described in example 174, using methyl iodide instead of ethyl bromide. 2.5 g (39%) of product are obtained. Mp 178-180 ⁰ C. H-NMR spectrum (δ, DMSO-d ₆ ): 3.78 (S, s); 3.79 (ZN, s); 6.51 (IH, d, J = 3.5

Hz); 6.80 (IH, d / d, J = 8.5 / 3.5 Hz); 7.56 (IH, d, J = 8.5 Hz); 8.40 (IH, s); 10.16 (IH, s).

Example 177

Synthesis of l-ethyl-6,7-dimethyl-quinol-2-one-3-carbaldehyde (CLXXVII).

Conducted according to the methodology described in example 174, using as the starting substance HUSH. Obtain 2.8 g (38%) of product. Mp 170-171 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.18 (ZN, t, J = 7.5 Hz); 2.25 (ZN, s); 2.46 (ZN, s); 4.17 (2H, q, J = 7.5 Hz); 7.10 (IH, s); 7.20 (IH, s); 8.45 (IH, s); 10.05 (IH, s).

Example 178

Synthesis of l-benzyl-6,7-dimethyl-quinol-2-one-3-carbaldehyde (CLXXVIII).

Conducted according to the methodology described in example 174, using as the starting substance HUSH and benzyl bromide. Obtain 3.6 g (43%) of product. Mp 128-130 ⁰ C.

H _r NMR spectrum (δ, DMSO-d ₆ ): 2.25 (S, s); 2.46 (ZN, s); 5.17 (2H, s); 6.94 (IH, s); 7.29 (IH, s); 7.28 (IH, t, J = 8.5 Hz); 7.34 (2H, t, J = 8.5 Hz); 7.46 (2H, d, J = 8.5 Hz); 8.40 (IH, s); 10.16 (IH, s).

Example 179

Synthesis of 2-chlorop-6- (2,2-propiamido) quinolin-3-carbaldehyde (CLXXIX).

Conducted according to the methodology described in example 1. Receive 38 g (72%) of the product. T. pl. 172-174 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d _b ): 1.09 (9H, s); 7.84 (IH, d / d, J = 8.5 / 3.5 Hz); 7.84 (IH, d, J = 8.5 Hz); 8.83 (IH, d, J = 3.5 Hz); 8.48 (IH, s); 9.76 (IH, broad peak); 10.55 (IH, s).

Example 180 Synthesis of 6- (2,2-propiioamido) -2-oxo-l, 2-dihydroxinolin-3-carbaldehyde

(CLXXX).

Conducted according to the methodology described in example 2. Receive 24.5 g (72%) of the product. Mp 219-221 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.09 (S, s); 6.52 (IH, d, J = 3.5 Hz); 7.61 (IH, l / d, J = 8.5 / 3.5 Hz); 7.65 (IH, d, J = 8.5 Hz); 8.46 (IH, s); 8.69 (IH, broad peak); 10.15 (IH, s); 12.05 (IH, broad peak).

Example 181

Synthesis of 1, 6-dimethyl-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (CLXXXI).

The aldehyde (II) obtained according to Example 2 in an amount of 5.2 g (0.025 mol) is dissolved in 250 ml of methanol, then a KOH solution (2.875 g, 0.05 mol) is added. To the resulting reaction mixture was added 7.5 ml of methyl iodide and refluxed for 5 hours. The reaction mixture was poured onto 300 g of finely divided ice and acidified. The precipitate formed is filtered off, washed with a large amount of diluted alkali, then with water until neutral. Recrystallization from acetonitrile gives 2.2 g (40%) of the product. T. pl. 195-197 ⁰ C. According to the literature, it is 198 ⁰ C (see JP 58-225065).

H-NMR spectrum (δ, DMSO-d ₆ ): 2.2 (S, s), 3.6 (S, s), 7.05 (IH, t, J = 8.5 Hz),

7.15 (IH ₃ d, J = 3.5 Hz), 7.5 (IH, d / d, J = 8.5 Hz / J = 3.5 Hz), 8.4 (S, s), 10.2 (S, s).

Example 182

Synthesis of 2-chlorop-7-ethylquinolin-3-carbaldehyde (CLXXXII).

Conducted according to the methodology described in example 1. Receive 41.5 g (78%) of the product. T. pl. 102-104 ⁰ C.

Ni-NMR spectrum (δ, DMCO-d ₆ ): 1.2 (ЗH, t), 2.4 (2H, q), 7.6 (IH, d, J = 8.5 Hz), 7.7 (IH, d, J = 3.5 Hz) 8.2 (IH, d, J = 8.5 Hz), 8.9 (IH, s), 10.4 (IH, s). Example 183

Synthesis of 7-ethyl-2-oxo-l, 2-dihydroxinolin-3-carbaldehyde (CLXXXIII).

Conducted according to the methodology described in example 2. Obtain 27.2 g (74%) of the product. Mp 212-214 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.15 (3H, t), 2.2 (2H, q); 6.9 (IH, d, J = 8.5 Hz); 7.1 (IH, s); 7.7 (IH, d, J = 8.5 Hz); 8.2 (IH, s); 10.1 (IH, s); 12.0 (IH, broad peak).

Example 184

Synthesis of 1-ethyl-7-methoxy-3 - [(4-morpholin-4-yl-phenylamino) methyl] - 1 H-quinolin-2-one (CLXXXIV).

Conducted according to the methodology described in example 83, using compounds CLXXIV and 4-morpholation as starting reagents. 2.23 g (56%) of the product CLXXXIV are obtained. Mp 134-135 ⁰ C.

LC-Mass (M + H) ⁺ : 394.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.1 (3H, t, J = 7.5 Hz); 2.9 (4H, m); 3.6 (4H, m); 3.8 (ZN, s); 4.0 (2H, d, J = 5.5 Hz); 4.2 (2H, q, J = 7.5 Hz); 5.6 (IH, t, J = 5.5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8 ₅ 5 Hz); 6.9 (IH, d, J = 8.5 Hz); 7.0 (IH, s); 7.5 (IH, d, J = 8.5 Hz); 7.6 (IH, s).

Example 185

Synthesis of 3- ({[4- (4-hydroxy-sherpidin-1-yl) phenyl] methyl-amino} methyl) -6-methoxy-1 H-quinolin-2-one (CLXXXV).

A mixture of XLII (2.05 g, 10 mmol) and LIV (1.8 g, 11 mmol) was dissolved in dichloroethane. The reaction mixture is stirred at a temperature of ~ 70 ⁰ C and sodium triacetoxyborohydride is added portionwise with stirring.

(3.5 g, 16.5 mmol). At the end of the reaction, the mixture is cooled, diluted with water a solution of soda, the layers are separated, the organic layer is dried and concentrated.

The resulting crude secondary amine is dissolved in dichloroethane and 1 ml of a 40% formaldehyde solution is added. The reaction mixture was stirred for 1 hour and then sodium triacetoxyborohydride (3.5 g, 16.5 mmol) was added portionwise. At the end of the reaction, the mixture is cooled, diluted with an aqueous solution of soda, the layers are separated, the organic layer is dried and concentrated. The residue was recrystallized from ethyl acetate. Obtain 1.73 g (44%) of the product CLXXX. Mp 231-233 ⁰ C.

LC-Mass (M + H) ⁺ : 394.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.4 (2H, m); 1.5 (2H, m); 2.6 (2H. M); 3.1 (2H, m); 3.5 (IH, m); 3.7 (ZN, s); 4.0 (2H, d, J = 5.5 Hz); 4.5 (IH, broad peak); 5.5 (IH, t, J = 5 ₅ 5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 7.0 (2H, m); 7.1 (IH, d, J-8.5 Hz); 7.6 (IH, s).

Example 186.

Synthesis of 7-methoxy-1-methyl-3 - {[methyl- (4-morpholin-4-yl-phenyl) amino] -methyl} -Sh-quinolin-2-one (CLXXXVI).

Conducted according to the methodology described in example 185, using the compounds CLXXVI and 4-morpholylaniline as starting reagents. Obtain 2.05 g (57%) of the product CLXXXVI. Mp 143-144 ⁰ C.

LC-Mass (M + H) ⁺ : 394.

H _r NMR spectrum (δ, DMSO-d ₆ ): 2.8 (4H, m); 3.0 (ZN, s); 3.5 (ZN, s); 3.6 (4H, m); 3.8 (ZN, s); 4.2 (2H, s); 6.7 (2H, d, J = 8.5 Hz); 6.8 (2H, d, J = 8.5 Hz); 6.85 (IH, d / d, J = 8.5 Hz / 3.5 Hz); 6.90 (IH, d, J = 3.5 Hz); 7.5 (IH, s); 7.55 (IH, d, J = 8.5 Hz).

Example 187

Synthesis of 3 - [(4-Ethoxy-phenylamino) -methyl] -l-ethyl-7-methoxy-III-quinolin-2-one (CLXXXVII). Conducted according to the methodology described in example 83, using the connection

СLХХГV and para-phenytidine as starting reagents. Obtain 2.08 g (59%) of the product CLXXXVIL So pl. 118-119 ⁰ C.

LС-Mass (M + H) ⁺ : 353.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.1 (3H, t, J = 7.5 Hz); 3.7 (ZN, s); 4.0 (2H, d,

J = 5.5 Hz); 4.2 (2H ₅ q, J = 7.5 Hz); 5.5 (IH, t, J = 5.5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J = 8.5 Hz); 6.8 (IH, d, J = 8.5 Hz); 7.0 (IH, s); 7.5 (IH, d, J = 8.5 Hz); 7.7 (IH, s).

Example 188

Synthesis of l-benzyl-3 - [(2,4-dimethoxy-phenylamino) methyl] -6,7-dimethyl-Sh-quinolin-2-one (CLXXXVIII).

Conducted according to the methodology described in example 83, using the compound CLXXVIII and 2,4-dimethoxyaniline as starting reagents. Obtain 1.88 g (44%) of product CLXXXVIII. Mp 132-133 ⁰ C.

LC-Mass (MH-H) ⁺ : 429.

H-NMR spectrum (δ, DMSO-d _b ): 2.0 (ЗН, s); 2.1 (ZN, s); 3.5 (ZN, s); 3.7 (ZN, s); 4.2 (2H, d, J = 5.5 Hz); 5.01 (IH, t, J = 5.5 Hz); 5.5 (2H, s); 6.3 (IH, d / d, J = 8.5 Hz / 3.5 Hz); 6.4 (IH, d, J = 8.5 Hz); 6.5 (IH, d, J = 3.5 Hz); 7.2 (2H, m); 7.3 (2H, t, J = 8.5 Hz); 7.4 (IH, s); 7.7 (IH, s).

Example 189

Synthesis of l, 6-dimethyl-3 - {[4- (4-methyl-piperazin-l-yl) -phenylamino] -methyl} -

Sh-quinolin-2-one (CLXXXIX).

Conducted according to the methodology described in example 83, using the compounds CLXXXI and LXVI as starting reagents. 1.98 g (53%) of the product CLXXXIX are obtained. Mp 155-156 ⁰ C.

LC-Mass (M + H) ⁺ : 377. Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.3 (S, s); 2.5 (ZN, s); 2.9 (2H, m); 3.0 (4H, m); 3.5 (ZN, s); 4.1 (2H, d, J = 5.5 Hz); 5.5 (2H ₃ t, J = 5.5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.7 (2H, d, J-8.5 Hz); 7.4 (ZN, m); 7.7 (IH, s).

Example 190

Synthesis of 3 - {[(2,4-Dimethoxyphenyl) methyl-amino] methyl} -l, 6-dimethyl-Ш-quinolin-2-one (CLXXXX).

Conducted according to the methodology described in example 185, using the compounds CLXXXI and 2,4-dimethoxyaniline as starting reagents. 2.01 g (57%) of the product CLXXXVII are obtained. Mp 83-84 ⁰ C.

LС-Mass (M + H) ⁺ : 353.

H-NMR spectrum (δ, DMSO-d ₆ ): 2.3 (S, s); 2.6 (ZN, s); 3.5 (ZN, s); 3.6 (ZN, s); 3.8 (ZN, s); 4.0 (2H, s); 6.4 (IH, d / d, J = 8.5 Hz / 3.5 Hz); 6.5 (IH, d, J = 3.5 Hz); 6.9 (IH, d, J = 8.5 Hz); 7.4 (2H, m); 7.45 (IH, s); 7.6 (IH, s).

Example 191

Synthesis of l, 6,7-trimethyl-quinol-2-one-3-carbaldehyde (CLXXXXI).

Conducted according to the methodology described in example 181, using as the starting substance HUSH. Obtain 2.8 g (39%) of product. Mp 221-223 ⁰ C.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 2.25 (S, s); 2.46 (ZN, s); 3.5 (ZN, s); 4.17 (2H, q, J = 7.5 Hz); 7.10 (IH, s); 7.20 (IH, s); 8.45 (IH, s); 10.05 (IH, s).

Example 192.

Synthesis of 3 - [(3,4-Dimethoxy-phenylamino) methyl] -7-methoxy-lH-quinolin-2-one (CLXXXXII).

Conducted according to the methodology described in example 83, using compounds XII and 3,4-dimethoxyaniline as starting reagents. Obtain 1.73 g (53%) of the product. Mp 186-188 ⁰ C. LC-Mass (M + H) ⁺ : 341.

Ni-NMR spectrum (δ, DMSO-d ₆ ): 1.0 (IH, m); 1.5 (IH, m); 1.7 (IH, m); 1.8 (IH, m); 2.1 (ZN, s); 2.4 (ZN, s); 2.3 (IH, m); 2.45 (IH, m); 3.1 (IH, m); 3.2 (IH ₅ m); 3.5 (IH ₅ m); 3.55 (ZN, s); 4.0 (2H ₅ d, J = 5.5 Hz); 4.5 (IH, d ₅ J = 3.5 Hz); 5.5 (IH, t, J = 5.5 Hz); 6.5 (2H, d, J = 8.5 Hz); 6.6 (2H, d, J = 8.5 Hz); 7.3 (IH, s); 7.4 (IH, s); 7.6 (IH, s).

Example 193

Synthesis of 3 - [(Benzo [l, 3] dioxol-5-yl-methyl-amino) -methyl] -6,7-dimethyl-Ш-quinolin-2-one (CLXXXXIII).

Conducted according to the methodology described in example 185, using the compounds XVIII and 4-amino-solvent as starting reagents. Obtain 2.02 g (58%) of product. Mp 219-221 ⁰ C.

LC-Mass (M + H) ⁺ : 351.

2H-NMR spectrum (δ, CDCL ₃ ): 2.25 (ZN, s); 2.64 (3H ₅ s); 2.85 (ZN, s); 3.69 (2H, s); 6.08 (2H ₅ s); 6.22 (2H, d / d, J = 8.5 Hz / 3.5 Hz); 6.42 (IH, d, J = 3.5 Hz); 6.60 (IH, d, J = 8.5 Hz); 7.10 (2H ₅ superposition 2 s); 7.49 (IH, s); 7.6 (IH, broad peak).

Example 194

Synthesis of 7-Methoxy-3- ({4- [4- (2-Methoxy-ethyl) -piperazin-1-yl] -phenylamino} -methyl) - 1 H-quinolin-2-one (CLXXXXIV).

Conducted according to the methodology described in example 83, using compounds XII and CLXX as starting reagents. Obtain 2.12 g (51%) of product CLXXXXIV. Mp 219-221 ⁰ C.

LС-Mass (M + H) ⁺ : 423.

H-NMR spectrum (δ, DMSO-d _b ): 2.9 (6H, m); 3.1 (ZN, s); 3.2 (4H, m); 3.4 (2H ₅ t, J = 7.5 Hz); 3.8 (ZN, s); 4.0 (2H, d, J = 5.5 Hz); 5.4 (IH ₅ t, J = 5 ₅ 5 Hz); 6.45 (2H ₅ d, J = 8.5 Hz); 6.7 (2H ₅ d ₅ J = 8.5 Hz); 6.75 (IH, d / d, J = 8.5 / 3.5 Hz); 6.8 (IH, d, J = 3.5 Hz); 7.44 (IH, d, J = 8.5 Hz); 7.65 (IH, s); 11.5 (IH, broad peak). Example 195

Synthesis of 3 - {[4- (3-Hydroxy-piperidin-l-yl) phenylamino] methyl] -l, 6,7-trimethyl-III-quinolin-2-one (CLXXXXV).

Conducted according to the methodology described in example 83, using the connection

CLXXXXI and LVI as starting reagents. Obtain 2.08 g (53%) of product CLXXXXV. Mp 155-157 ⁰ C.

LС-Mass (M + H) ⁺ : 392.

H _r NMR spectrum (δ, DMSO-d ₆ ): 3.5 (S, s); 3.55 (ZN, s); 3.8 (ZN, s); 4.1 (2H, d, J = 5.5 Hz); 5.5 (IH, t, J = 5.5 Hz); 6.0 (IH, d / d, J = 8.5 / 3.5 Hz); 6.4 (IH, d, J = 3.5 Hz); 6.6 (IH. D, J = 8.5 Hz); 6.75 (IH, d, J = 8.5 / 3.5 Hz); 6.85 (IH, d, J = 3.5 Hz); 7.5 (IH, d, J = 8.5 Hz); 7.6 (IH, s); 11.5 (IH, broad peak).

Example 196. The methodology of biological testing.

To inhibit NO synthetase and cyclooxygenase, the substances described above are used at a concentration of 0.1 nM or higher. Mouse macrophages (cell line RAW 264.7) were grown in DMEM medium containing 10% (v / v) calf serum and 3 mM L-glutamine at 37 ° C / 5% CO ₂ . To induce NO synthetase, lipopolysaccharides (LPS) from Salmopella, turhi at a concentration of 5 μg / ml were added to the reaction mixture containing 400,000 cells / ml. After incubation for 16 hours at the same temperature, the medium was replaced with Krebs-Ringer phosphate buffer with or without test compounds. Under these conditions, the cells were incubated for another 4 hours at 37 ^° C / 5% CO ₂ . To determine the NO concentration at the end of the incubation, an equal volume of a 6 nM solution of diamino-fluorescein diacetate in Krebbs-Ringer phosphate buffer was added to the incubation medium, followed by determination of the fluorescence of the solution. As a result of the subsequent analysis, the concentration of each test compound was determined at which 50% inhibition of NO generation (ICso) was observed. For a standard commercially available LN ^G monomethyl- inhibitor arginine (used as control) IC ₅₀ was determined equal to 37 μM. In the inhibitors protected in this patent, the value of this parameter ranges from 0.5 nM to 100 μM.

When screening on a pure enzyme that allows one to determine the selectivity of the action of the substances described above in relation to various forms of NO synthetase, the enzyme (recombinant mouse inducible, neuronal or endothelial NO synthetase, Sigma) and the test substance were preincubated for 35 minutes, after which, to begin reactions, L-arginine was added to the system. The composition of the incubation medium is ~ 0.25 μCi [3H] arginine / ml, 120 μM NADPH, 1 μM FAD and FMN, 10 μM BH4, 10OnM CaM, 100 mM Heps, 2.4 cM CaC12, 24 μM L-argype, ImM EDTA, ImM DTT, pH 7.4. Incubation continued for 45 minutes, after which the reaction was stopped by the addition of a special stop buffer 10OmM Heps, pH 5.5, 3mM EDTA, 3mM EGTA, and the resulting [ ³ H] -cytryllin was separated from the unreacted substrate on a DOWEX 50 WX 8 ion-exchange resin -400. NOS inhibition was determined by the formation of L- [ ³ H] -titre llin from L- [ ³ H] - arginine. The IC ₅₀ measured in this way for inducible NO synthetase ranges from 25 nM to 7 μM, the degree of binding to the enzyme at a substrate concentration of 10 μM in all cases exceeded 99%. The degree of binding of the proposed compounds with endothelial NO synthetase ranges from 0 to 50%, which indicates a high selectivity of the compounds.

When determining the activity of the described compounds as COX inhibitors in macrophages, the latter (cell line RAW 264.7) were grown in DMEM medium containing 10% (v / v) calf serum and 3 mM L-glutamine at 37 ^° C / 5% CO ₂ . To induce COX, lipopolysaccharides (LPS) from Escherichia with Ii (lμg / ml) were added to the reaction mixture containing 400,000 cells / ml in the presence or absence of test compounds. After an incubation of 18 hours (37 ° C / 5% CO ₂ ), the concentration of the end products of the cyclooxygenase reaction — prostaglandins PGE ₂ , PGF _2α and thromboxane TXB _{2 — was} measured using standard commercially available test systems (South Chemicals, USA). When determining the activity of patented substances as COX inhibitors on a pure enzyme, either a commercially available enzyme manufactured by South Chemicals, USA, was used or the enzyme was isolated from activated macrophages of the RAW 264.7 line. In the latter case, macrophages were grown at 37 ° C / 5% CO ₂ in DMEM medium containing an additional 10% (v / v) bovine serum and 3 mM L-glutamine. To activate them, LPS from Escherichia coli (lμg / ml) was added to the medium and incubated for 18 hours, after which it was washed and transferred to 20 mM HEPES (pH 7.6) containing an additional 1 mM EDTA and protease inhibitors. In this medium, the cells were lysed by ultrasound and the precipitate was separated by centrifugation for 2 hours at 120,000 g (4 ⁰ C), after which it was resuspended in 0.05 M Tris-HCl medium at pH 7.8 (25 ⁰ C), which also contained 1% Twep 20. The resulting suspension was homogenized for 30 minutes and centrifuged for 1 hour at 16,000 g (4 ⁰ C). The studied compounds were preincubated with this supernatant (containing activated cyclooxygenase) for 15 minutes at room temperature in a medium also containing 0.05 M Tris-Hcl (pH 7.8), 0.1% Twep 20 and 1 μM hemin, after which homovaniline and arachidonic acid were added to it acid (concentration in the resulting solution is 4 mm and 100 μM, respectively). 5 minutes after this, the fluorescence intensity was measured, correlating with the activity of patented compounds as COX inhibitors.

When using a commercially available enzyme, the latter was preincubated for 15 minutes with hemin (1 μM) in a medium containing

0.05 M Tris-Hcl (pH 7.8) and 0.1% Twep 20 at 25 ⁰ C). At the end of the process, homovanilinic (4 mM) and arachidonic (100 μM) acids were added to the medium.

The fluorescence intensity was measured 5 minutes after this.

In a subsequent analysis, the concentration of each test compound was determined at which 50% inhibition of cyclooxygenase activity (IC ₅₀ ) was observed. The values obtained for the same substance differed by no more than 5% depending on the source of COX. In the inhibitors protected in this patent, the value of this parameter is in the range from 5 nM to 5 μM. To inhibit the excessive conversion of arginine to NO and the activity of cyclooxygenase-2 in various pathological conditions with the subsequent achievement of a therapeutic effect, dosages are used depending on the specific condition and individual characteristics of the subject. In general, dosages from 1 to 100 μmol of a substance per kilogram of a subject’s weight are used, while the substance is dissolved in water or physiological saline. The route of administration of the substances is oral. If necessary, the introduction of substances can be repeated.

In order to test the ability of substances protected by patent to inhibit pathological effects caused by excessive release of NO and excessive activity of COX-2, studies were performed on Wistar rats. 249 males of 5-7 weeks of age weighing 180 + 15 g were used. Animals were kept in standard conditions (ambient temperature 22 + 2 ⁰ C, synchronized change of light period "day" from 8:00 to 20:00, "night" from 20:00 to 8:00) in cells of 5 pieces on a bed made of cut food paper. Animals received standard granular feed and water in standard ad libitum drinking bottles. The day before the experiment, catheters were implanted in rats under anesthesia (ketamine + xylazine): in the femoral artery for recording blood pressure and in the femoral vein for LPS injection. After the operation and during the experiment, the animals were kept in individual cells.

Test substances were introduced into the stomach with a probe in the form of a suspension of substances in distilled pyrogen-free water. The control group of animals instead of the tested substances was introduced only water. The volume of administration was 0.2 ml / 100 g body weight (2 ml / kg). Each substance was administered in four doses from 1 to 100 μmol / kg, with each dose of each test substance being administered to three animals. For the induction of NO synthetase and COX-2, LPS was diluted in 0.9% NaCl and administered intravenously at a dose of 4 mg / kg in a volume of 100 μl / kg. The effect was determined by the degree of inhibition of the hypotensive shock reaction to the administration of LPS to animals, and the subsequent analysis determined the effective concentration of the substance at which 50% inhibition of the response to LPS administration (ECso) was observed. inhibitors, the value of this parameter ranges from 1.5 to 400 μmol / kg.

To test the anti-arthritic effect of the patented substances associated with the inhibition of iNOS and COX-2, a study was performed on a model of chronic arthritis in Wistar rats. According to this model, arthritis is caused by the introduction of Freund's complete adjuvant into the pad of the rat's right hind paw. An hour before this, the test substance (or physiological saline as a control) is orally administered to her in the required concentration. Subsequently, the introduction of the substance is repeated four more times (once a day). On the fifth, seventh, fourteenth and twenty-first day, the size of the edema of the right hind paw is measured in comparison with the left paw, as well as the pain sensitivity of the paw (in the latter case, the so-called “hot plate” method is used). After the experiment (on the twenty-first day), the animal is killed and the weight of the paw is determined, after which it is histologically examined. It should be noted that the effect achieved in this model may be due not only to the inhibition of COX-2 or iNOS protected by the compounds in the patent, but also to the synergy of these effects.

iNOS IC50 (Sell) - The activity of a substance as an inducible inhibitor

NO synthases measured on cell cultures (μM). iNOS IC50 (test) - The activity of a substance as an inhibitor of inducible NO synthase, measured on an enzyme (μM). iNOS ID50 (ip vivo) - The ability of a substance to inhibit LPS-induced pressure reduction, for other products has not been investigated (μmol / kg). pNOS, IC50 (ex) - Activity of a substance as a neuronal inhibitor

NO synthase measured on the enzyme (μM). COX2, IC50 (Sell) - The activity of a substance as an inhibitor of cyclooxygenase-2, measured on cell cultures (μM).

COX2, IC50 (test) - The activity of a substance as a cyclooxygenase-2 inhibitor, measured on an enzyme (μM).

COXl, IC50 (test) - The activity of a substance as a cyclooxygenase-1 inhibitor, measured on an enzyme (μM).

* - these substances exhibit anti-arthritic activity.

Thus, the obtained new amino and hydro-derivatives of phenyl-3-aminomethyl-quinolone-2, as well as get -yl-3-aminomethylquinolinone-2, exhibit extremely high activity with respect to the inducible and neuronal forms of NO synthetase and COX-2, characterized by pronounced synergistic effects on these enzymes, as well as high selectivity compared with their action on endothelial NO synthetase and COX-I, respectively. This set of properties is unique and not known from the available scientific, technical and patent literature. This, as well as the expressed ability of the proposed compounds to prevent the development of the above pathological conditions in animals, allows them to be used as an active component in biologically active compounds and pharmaceutical compositions.

Claims

Claim

1. Amino derivatives of apyl-3-aminomethylquinolinone-2 of the general formula

(one):

Rl, R2, R3, R4 are independently the same or different, and at least one of Rl, R2, R3, R4 is selected from the group consisting of:

AIk, OAIk, Ar, OAr, CH ₂ C ₆ H ₅ , SAIk, F, Cl, Br, OCF ₃ , NO ₂ , NH ₂ , NHAIk, N (AIk) ₂ ; wherein the other or the other of Rl, R2, R3, R4 are H; or R2 and R3 are taken together and selected from - (CH ₂ ) S-, - (CH ₂ ) 4-, -OCH ₂ O-, -

OCH ₂ CH ₂ O—, at Rl and R4, which are the same or different and independently selected from H, AIk, OAIk, HaI; R5 is independently selected from H or AIk; R6 is independently selected from H, AIk, CH ₂ NO ₂ ; R7, R8, RlO, RIl are independently the same or different, and at least one of R7, R8, RlO, RIl is selected from AIk, OAIk, CH ₂ OH, SAIk, Ar, OAr, F, Cl, Br, CF ₃ , OCF ₃ , COORi ₄ , COONRi ₅ Ri ₆ , NR _n Ri ₈ , NHCORi ₉ , SO ₂ NR ₂₀ R ₂ I, NO ₂ ; where R14, R15, R16, R17, R18, R19, R20, R21 are the same or different and are independently selected from H or AIk; wherein the other or other of R7, R8, RlO, RIl are H;

R9 is independently selected from H or from the following substituents:

where (*) corresponds to the point of attachment of the bond of the substituent R9 to the phenyl moiety in the formula (I);

n is 1, 2, 3 or 4;

X is independently selected from OH or AIk;

Y is independently selected from AIk, OAIk, Ar, or He;

R22, R23 are independently selected from H, AIk, OAIk, SAIk, HaI, COOH, COOAIk, SO ₂ AIk ₅ NO ₂ , CN;

R24, R25 are the same or different and are independently selected from H, AIk;

R26 is independently selected from H or AIk;

R27, R28 are independently selected from H, AIk, OAIk, HaI, NO ₂ , CN; or

R8 and R9 are taken together and selected from - (CH ₂ ) s-, - (CH ₂ ) ₄ -, -OCH ₂ O-, - OCH ₂ CH ₂ -, while R7, RIl are independently the same or different and are selected from H, HaI, NO ₂ ; and RlO is H.

Rl 2, Rl 3 are independently the same or different and are selected from the group consisting of H, AIk, Bz.

2. Amino derivatives of apyl-3-aminomethylquinolinone-2 according to claim 1, characterized in that they are selected from the group including:

3 - [(4-dimethylamino-phenylamino) methyl] -5,6,7-trimethoxy-1 H-quinolin-2-one;

3 - [(4-dimethylamino-phenylamino) methyl] -6-ethyl-III-quinolin-2-one;

6-ethoxy-3 - [(4-pyppolidin-l-yl-phenylamino) methyl] -Sh-quinolin-2-one;

7-methoxy-3 - [(4-piperidin-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one;

7-ethoxy-3 - [(4-piperidin-l-yl-phenylamino) methyl] -Sh-quinolin-2-one;

7-methyl-3 - [(4-morpholin-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one;

6-ethoxy-3 - [(4-morpholin-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one;

6-isopropyl-3 - [(4-morpholin-l-yl-phenylamino) methyl] -lH-quinolin-2-one;

7 - [(4-morpholin-l-yl-phenylamino) -m-ethyl] -5H- [l, 3] dioxol [4.5] quinolin-6-one;

b-methyl-3 {[4- (4-methyl-piperidin-l-yl) phenylamino] methyl} -Sh-quinolin-2-one;

7-methoxy-3 {[4- (4-methyl-piperidin-1-yl) phenylamino] methyl] - 1 H-quinoline-2-one;

7-methyl-3 {[4- (4-methyl-piperidin-l-yl) phenylamino] methyl} -Sh-quinolin-2-one;

6-methyl-3 {[4- (3-methyl-piperidin-l-yl) phenylamino] methyl} -Sh-quinolin ~ 2-one; 5,6,7-trimethoxy-3 {[4- (3-methyl-piperidin-1-yl) -phenylamino] methyl] -1 H-quinolin-2-one;

6-ethoxy-3 {[4- (3, 5-dimethyl-piperidine-1-l) -phenyl l amino] -methyl} - 1 N-quinoline-2-one;

3 - {[4- (4-hydroxy-piperidin-1-yl) phenylamino] methyl} - 1 H-quinoline-2-one;

3- {[4- (4-hydroxy-piperidin-1-yl) phenylamino] methyl] -8-methyl-1 H-quinolin-2-one;

3 - {[4- (4-hydroxy-piperidin-l-yl) phenylamino] methyl] -7,8-dimethyl-Sh-quinolin-2-one;

8 - {[4- (4-hydroxy-piperidin-l-yl) phenylamino] methyl] -2,3-dihydro-6H- [l, 4] dioxino [2,3-g] quinolin-7-one ;

7 - {[4- (4-hydroxy-piperidin-l-yl) phenylamino] methyl] -5H- [l, 3] dioxolo [4,5-g] quinolin-6-one;

3- {[4- (3-hydroxy-piperidin-1-yl) phenylamino] methyl] -6-ethyl-1 H-quinolin-2-one;

3 - {[4- (3-Hydroxy-piperidin-1-yl) phenylamino] methyl} -6-propyl-1 H-quinolin-2-one;

3- {[4- (3-Hydroxy-piperidin-1-yl) phenylamino] methyl] -6-isopropyl-1 H-quinolin-2-one;

3 - {[4- (3-hydroxy-piperidin-l-yl) phenylamino] methyl] -6-tert-butyl-Sh-quinolin-2-one;

3- {[4- (3-Hydroxy-piperidin-1-yl) phenylamino] methyl} -6,7-dimethyl-1 H-quinolin-2-one;

3 - {[4- (3-Hydroxy-piperidin-1-yl) phenylamino] methyl] -7-methoxy 1 H-quinoline-2-one; 3 - {[4- (3-Hydroxy-sheridin-1-yl) -phenylamino] methyl] -5,6,7-thimethoxy-1 H-quinolin-2-one;

7 - {[4- (3-hydroxy-piperidin-l-yl) phenylamino] methyl] -5H- [l, 3] dioxolo [4,5-g] quinolin-6-one;

8 - {[4- (3-hydroxy-piperidin-l-yl) phenylamino] methyl] -2,3-dihydro-6H- [l, 4] dioxino [2,3-g] quinolin-7-one ;

3- {[4- (4-carboethoxy-piperidin-1-yl) phenylamino] methyl] -7-methyl-1 H-quinolin-2-one;

3- {[4- (4-carboethoxy-piperidin-1-yl) phenylamino] methyl] -8-methyl-1 H-quinolin-2-one;

3 - {[4- (3-Carboethoxy-piperidin-1-yl) phenylamino] methyl] -6-methoxy-1 H-quinolin-2-one;

3 - {[4- (3-Carboethoxy-piperidin-1-yl) phenylamino] methyl} -7-methoxy-1 H-quinolin-2-one;

3 - {[4- (cyclohexyl-methyl-amino) -phenylamino] -methyl} -5,8-dimethyl-III-quinolin-2-one;

7 - {[4- (cyclohexyl-methyl-amino) phenylamino] methyl} -5H- [l, 3] dioxole [4,5-g] quinolin-6-one;

6-methyl-3- {[4- (4-methyl-piperazin-1-yl) phenylamino] methyl] -1 H-quinolin-2-one;

5,8-dimethyl-3 - {[4- (4-methyl-piperazin-l-yl) phenylamino] methyl] -H-quinolin-2-one;

3- {[4- (4-acetyl-piperazin-1-yl) phenylamino] methyl] -7-ethoxy-1 H-quinolin-2-one;

7- {[4- (4-acetyl-piperazin-1-yl) -phenylamino] methyl] -5H- [1, 3] dioxolo [4,5-g] quinolin-6-one; 3 - ({4- [4- (pyran-2-carbonyl) -piperazin-l-yl] phenylamino} methyl) -5,7-dimethyl-1 H-quinolin-2-one;

3 - ({4- [4- (fyran-2-carbonyl) -piperazin-l-yl] phenylamino} methyl) -5,8-dimethyl-1 H-quinolin-2-one;

7-methyl-3 - {[4- (4-benzyl-piperazin-l-yl) phenylamino] methyl] -Sh-quinolin-2-one;

5, 6,7-trimethoxy-3 {[4- (4-phenyl-piperazin-1-yl) -phenylamino] methyl] - 1 H-quinolin-2-one;

3- {[4- (3,4-dihydro-1 H-isoxinolin-2-yl) phenylamino] methyl] -7-methyl-1 H-quinolin-2-one;

6,7-dimethoxy-3- {[4- (4-pyrimid-2-yl-piperazin-1-yl) -phenylamino] methyl} -1 H-quinolin-2-one;

6-methoxy-3 - {[4- (4-pyrid-2-yl-piperazin-l-yl) -phenylamino] methyl] -H- quinolin-2-one;

6,7-dimethoxy-3 - [(2-methyl-1-yl-phenylamino) methyl] - 1 H-quinolin-2-one;

l-ethyl-7-methoxy-3 - [(4-morpholin-4-yl-phenylamino) methyl] -Sh-quinolin-2-one; 3 - ({[4- (4-hydroxy-piperidin-1-yl) phenyl] methyl-amino} -6-methoxy-1 H-quinolin-2-one;

7-methoxy-l-methyl-3 - {[methyl- (4-morpholin-4-yl-phenyl) -amino] -methyl} -Sh- quinolin-2-osch

3 - [(4-ethoxy-phenylamino) methyl] -l-ethyl-7-methoxy-III-quinolin-2-one;

l-benzyl-3 - [(2,4-dimethoxy-phenylamino) methyl] -6,7-dimethyl-W-quinolin-2-one;

1, 6-dimethyl-3- {[4- (4-methyl-piperazin-1-yl) phenylamino] methyl] -1 H-quinolin-2-one;

3 - {[(2,4-dimethoxy-phenyl) methyl-amino] methyl} -l, 6-dimethyl-III-quinolin-2-one;

3 - [(3,4-dimethoxy-phenylamino) methyl] -7-methoxy-III-quinolin-2-one; 3 - [(benzene [l, 3] dioxol-5-yl-methyl-amino) -methyl] -6,7-dimethyl-Shch-chinolin-2-one;

7-methoxy-3- {4- [4- (2-methoxy-ethyl) -piperazin-l-yl] phenylamino} -methyl) -S-quinolin-2-one;

3 - {[4- (3-hydroxy-p-hypieridin-1-yl) -phenylamino] methyl] - 1, 6,7-trimethyl-1 H-quinolin-2-one;

3. Hydroxy derivatives of phenyl-3-aminomethyl-quinolone-2 of the general formula (2):

Where:

Rl, R2, R3, R4 are independently the same or different, and at least one of Rl, R2, R3, R4 is selected from the group consisting of:

AIk, OAIk, Ar, OAr, CH ₂ C ₆ H ₅ , SAIk, F, Cl, Br, OCF ₃ , NO ₂ , NH ₂ , NHAIk, N (AIk) ₂ ; wherein the other or the other of Rl, R2, R3, R4 are H; or

R2 and R3 are taken together and selected from - (CH ₂ ) s-, - (CH ₂ ).) -, -OCH ₂ O-, - OCH ₂ CH ₂ O-, with Rl and R4 being the same or different and selected independently from H, AIk, OAIk, HaI;

R5 is independently selected from H or AIk;

R6 is independently selected from H, AIk, CH ₂ NO ₂ ; at least one of R7, R8, R9, RlO, RIl is OH, and the other or the other of R7, R8, R9, RlO, RIl are independently the same or different and are selected from H, AIk, OAIk, Ar, OAr, SAIk;

R12, R13 are independently the same or different and are selected from the group consisting of H, AIk, Bz.

4. Hydroxy derivatives of phenyl-3-aminomethyl-quinolone-2 according to claim 3, characterized in that they are selected from the group including:

3 - [(3,4-dihydroxy-phenylamino) methyl] -5,7-dimethyl-III-quinolin-2-one; "3 - [(2,4-Dihydroxy-phenylamino) methyl] -6,7-dimethyl-III-quinolin-2-one;

3 - [(3, 5 - dihydroxy-phenylamino) methyl] -6-methyl-1 H-quinolin-2-one; 3 - [(2-hydroxy-phenylamino) methyl] -6-ethyl-III-quinolin-2-one;

5. Derivatives of heteryl-3-aminomethylquinolinone-2 of the general formula (3):

where: Rl, R2, RZ, R4 are independently the same or different, and at least one of Rl, R2, RZ, R4 is selected from the group consisting of: AIk, OAIk, Ar, OAr, CH ₂ C ₆ H ₅ , SAIk, F, Cl, Br, OCF ₃ , NO ₂ , NH ₂ , NHAIk,

N (AIk) ₂ ; wherein the other or the other of Rl, R2, R3, R4 are H; or

R 2 and R 3 are taken together and selected from - (CH ₂ ) s -, - (CH ₂ ) _r, -OCH ₂ O-, - OCH ₂ CH ₂ O-, with Rl and R4 being the same or different and independently selected from H, AIk, OAIk, HaI; R5 is independently selected from H or AIk; R6 is independently selected from H, AIk, CH ₂ NO ₂ ;

Rl 2, Rl 3 are independently the same or different and are selected from the group consisting of H, AIk, Bz.

R29 is independently selected from the following substituents:

where (*) corresponds to the attachment site of the heterocyclic substituent bond

R29 to the nitrogen atom in the formula (3);

RZO, R31 are the same or different and are independently selected from H, AIk, OAIk, SAIk, OH, HaI, COOH, CONH ₂ , COOAIk, COR34; where R34 is independently selected from the following substituents:

where (*) corresponds to the attachment site of the heterocyclic substituent R34 to the carbon atom of the carbonyl group; R32, RZZ are independently selected from H, AIk, OAIk;

6. Derivatives of heteryl-3-aminomethylquinolone-2 according to claim 5, characterized in that they are selected from the group including:

3 - [(9,9-dioxo-9, 10-dihydro-9λ ^* 6 ^* -thia-10-aza-phenanth-Z-ylamino) -methyl] -7-methyl-Щ-quinolin-2-one;

3 - [(2,6-dimethoxy-pyridin-3-ylamino) methyl] -l, 6,7,8-tetrahydrocyclopenta [g]

quinolin-2-one;

3 - [(W, 1 H [2,5] bisbenzimidazolyl-5-ylamino) methyl] -6,7-dimethoxy-Sh-quinolin-2-one;

3 - [(lH-indazol-5-ylamino) methyl] -6-methyl-III-quinolin-2-one;

7-ethoxy-3 - [(3-hydroxy-b-methyl-pyridin-2-ylamino) methyl] - 1 H-quinolin-2-one;

7-methyl-3 - [(3-methyl-4-tetrazol-l-yl-phenylamino) methyl] -Sh-quinolin-2-one;

8-methyl-3 - [(2-pyridin-3-yl-1 H-benzoimidazo l-5-yl amino) -methyl] - 1 H-quinolin-2-one;

6-ethyl-3 - [(5-methoxy-quinolin-8-ylamino) -methyl] -S-quinolin-2-one;

7-ethoxy-3- (quinolin-5-ylaminomethyl) -Sh-quinolin-2-one;

6-methoxy-3 - [(3-methoxy-4-tetrazol-l-yl-phenylamino) methyl] -lH-quinolin-2-one;

3 - [(2-Hydroxy-5-methyl-pyridin-3-ylamino) methyl] -7-methoxy-Sh-quinolin-2-one; 3 - [(b-ethoxy-pyridin-3-ylamino) methyl] -6-methoxy-III- ^χ inolin-2-one;

3 - [(4,6-dimethyl-pyridin-2-ylamino) methyl] -5,7-dimethyl-III-quinolin-2-one;

6,7-dimethoxy-3 - [(2-methyl-5-pyrpol-l-yl-phenylamino) -methyl] -Sh- quinolin-2-one;

6-methyl-3 - (pyridin-3-aminomethyl) - 1 H-quinoline-2-one;

3 - [(2-hydroxy-pyridin-3-ylamino) methyl] -Sh-quinolin-2-one;

3 - [(10, ll-dihydro-5H-dibenzo [b, f] azepin-3-ylamino) methyl] -7-methoxy-1 H-quinolin-2-one;

3 - [(3-quinoxcalil-2-yl-phenylamino) methyl] - 1 H-quinolin-2-one;

7- ({4- [2- (1-methyl- 1 H-benzimidazol-2-yl) ethyl] phenylamino} methyl) -5H- [l, 3] dioxole [4,5-g] quinoline- 6-one;

N- {5 - [(7-ethoxy-2-oxo-l, 2-dihydro-quinolin-3-ylmethyl) -amino] -benzothiazol-2-yl} -acetamide;

3 - [(2-ethoxy-pyridin-3-ylamino) methyl] -8-methyl-III-quinolin-2-one;

3 - [(2,4-di-piperidin-l-yl-phenylaminaminamino) methyl] -5,7-dimethyl-Sh-quinolin-2-one;

7-ethyl-3 {[4- (5-oxo [l, 4] diazepan-l-yl) phenylamino] methyl] -Sh-quinolin-2-one;

3- {4- [4- (2-methoxy-ethyl) -piperazin-l-yl] phenylamino} -methyl) -6-methyl-

1 H-quinolin-2-one;

7. A method of obtaining amino derivatives of phenyl-3-aminomethyl-quinolone-

2 by. p. 1, including the interaction of the corresponding substituted 2-quinolone-3-carbaldehyde with the corresponding derivatives of phenylenediamine and subsequent recovery of the resulting Schiff bases to obtain the desired product.

8. The method according to p. 7, characterized in that the corresponding substituted 2-quinolone-3-carbaldehyde is obtained by hydrolysis of the corresponding 2-chloroquinoline-3-carbidedehyde formed from their substituted acetanilides containing electron-donating substituents in the benzene ring.

9. The method according to p. 7, characterized in that the Schiff base is restored without isolation from the reaction mixture.

10. The method according to p. 7, characterized in that the Schiff base before recovery is isolated from the reaction mixture.

11. The method according to p. 7, characterized in that the target product is purified by recrystallization or on chromatographic columns with silica gel.

12. The method of producing hydroxy derivatives of phenyl-3-aminomethyl-quinolin-2 according to claim 3, comprising reacting the corresponding substituted 2-quinolin-3 carbaldehydes with the corresponding anisidines with the formation of Schiff bases, their reduction with the formation of the corresponding alkyl esters and subsequent cleavage with acids Lewis with the final product.

13. The method according to p. 12, characterized in that the corresponding substituted 2-quinolone-3-carbaldehyde is obtained by hydrolysis of the corresponding 2-chloroquinoline-3-carbaldehydes formed from their substituted acetanilides containing electron-donating substituents in the benzene ring.

14. The method according to p. 12, characterized in that the Schiff base is restored without isolation from the reaction mixture.

15. The method according to p. 12, characterized in that the Schiff base before recovery is isolated from the reaction mixture.

16. The method according to any one of paragraphs. 12-15, characterized in that the cleavage of the alkyl esters by Lewis acids is carried out in inert solvents at temperatures below -50 ° C.

17. The method according to p. 12, characterized in that the target product is purified by recrystallization or on chromatographic columns with silica gel.

18. A method for producing derivatives of geta-3-aminomethyl-quinolone-2 according to claim 5, comprising reacting the corresponding substituted 2-quinolone-3-carbaldehydes with the corresponding amino derivatives of heterocyclic compounds and subsequent reduction of the resulting Schiff bases to obtain the desired product.

19. The method according to p. 18, characterized in that the corresponding substituted 2-quinolone-3-carbaldehyde is obtained by hydrolysis of the corresponding 2-chloroquinoline-3-carbaldehyde formed from their substituted acetanilides containing electron-donating substituents in the benzene ring.

20. The method according to p. 18, characterized in that the IPiff bases are reduced without isolation from the reaction mixture under the conditions of a reductive amination reaction.

21. The method according to p. 18, characterized in that the Schiff base before recovery is isolated from the reaction mixture.

22. The method according to p. 18, characterized in that the target product is purified by recrystallization or on chromatographic columns with silica gel.

23. A biologically active compound that inhibits NO synthetase and cyclooxygenase-2, characterized in that it contains as an active component the compound according to any one of claims 1-6.

24. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of paragraphs. 1-6 in combination with a pharmaceutically acceptable excipient.