Quinazoline substituted derivatives and their using as inhibitors

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

 

The present invention relates to certain derivatives of hintline for use in the treatment of some diseases, including proliferative diseases such as cancer, and in the manufacture of medicinal products intended for the treatment of proliferative diseases, new hinazolinam compounds and to methods for their preparation and to pharmaceutical compounds containing them as active ingredient.

Cancer (and other hyperproliferative disease) is characterized by uncontrolled cell proliferation. This loss of normal regulation of cell proliferation, apparently, often occurs as a result of genetic damage to cellular pathways regulating development within the cell cycle.

The eukaryotic cell cycle is largely controlled by an ordered cascade of protein phosphorylation. So far it has identified several families of protein kinases, which play a key role in this cascade. The activity of many of these kinases is increased in human tumors compared to normal tissue. This may occur either due to elevated levels of expression of this protein (for example, amplification of the gene), or by changes in the expression of coactivators, or inhibiting proteins.

Of these reg is of the batteries of the cell cycle were identified and the most widely studied of cyclin-dependent kinase (or CDKs). The activity of certain CDKs during certain periods of time is important for the initiation and for the coordinated development during the cell cycle. For example, CDK4 protein, apparently, regulates entry into the cell cycle (G0-G1-S transition) by phosphorylation product pRb retinoblastoma gene. It stimulates the release of transcription factor E2F from pRb, which then increases the transcription of genes required for entry into S phase. The catalytic activity of CDK4 increase by linking with a protein partner, cyclin D. One of the first evidence of a direct connection between cancer and the cell cycle was done on the basis of the observation that the gene Collina D was expanded and protein levels Collina D increased (and, therefore, increased activity of CDK4) in many human cancers (review in Sherr, 1996, Science 274: 1672-1677; Pines, 1995, Seminars in Cancer Biology 6: pp.63-72). Other studies (Loda et al., 1997, Nature Medicine 3(2): 231-234; Gemma et al., 1996, International Journal of Cancer 68(5): 605-11; Elledge et al., 1996, Trends in Cell Biology 6; 388-392) showed that negative regulators of CDK function in human tumors often reduced or destroyed, again leading to inappropriate activation of these kinases.

Were later identified protein kinase that is structurally different from the CDK family, which play a crucial role in regulating the cell cycle and which, apparently, VA the us for oncogenesis. They include the recently identified human homologues of proteins of Drosophila aurora and S.cerevisiae Ip11, which are highly homologous at the level of consistently amino acids encode a serine/threonine protein kinase. It is known that as the aurora and Ip11 involved in the regulation of the transition from the G2 phase of the cell cycle through mitosis, the centrosome, the formation of the mitotic spindle and proper chromosome separation/segregation into daughter cells. Two human homologs of these genes, called aurora 1 and aurora 2, encode regulated cell cycle protein kinases. They show peak expression and activity of the kinase on the border G2/M (aurora 2) and the mitosis (aurora 1). Some observations imply participation in cancer proteins aurora man and, in particular, aurora 2. Gene aurora 2 is mapped to chromosome 20q13, a region, which is often increased in human tumors, including tumors like breast and colon. Aurora 2 may be a major gene is a target of this amplicon, as DNA aurora 2 is increased, and mRNA aurora 2 sverkhekspressiya more than 50% of cases of primary colorectal cancer. In such tumors, the levels of proteins aurora 2 seem to be greatly elevated compared to adjacent normal tissue. In addition, transfection of rodent fibroblasts in aurora 2 people leads to transformation, giving you the ability to grow in soft yeah the e and to form tumors in Nude mice (Bischoff et al., 1998, The EMBO Journal. 17(11): 3052-3065). In another paper (Zhou et al., 1998, Nature Genetics. 20(2): 189-93) it was shown that artificial overexpression of aurora 2 leads to an increase in the number of centrosomes and increase aneuploidy.

More importantly, it was also shown that the termination of the expression and function of aurora 2 with antisense oligonucleotide treatment of cell lines of human tumor (WO 97/22702 and WO 99/37788) leads to cell cycle arrest in the G2 phase of the cell cycle and exerts an antiproliferative effect in these cell lines tumor. This means that the inhibition of this function aurora 2 will result in antiproliferative effect, which may be useful in the treatment of human tumors and other hyperproliferative diseases.

Up to the present time for use for the inhibition of various kinases have been proposed a number of derivative hintline. Examples of such proposals are WO 92/20642 and ER-IN-584222, which are bicyclic compounds, inhibiting the epidermal growth factor (EGF) and growth factor-based platelets (PDGF) receptor tyrosine kinase, WO 95/15758, which describes the use of bicyclic systems for the selective inhibition of tyrosine kinase activity of CSF-1R, and WO 99/09016, WO 97/03069 and U.S. patent 570158, which describes the use of certain khinazolinov compounds as inhibitors tires skenazy in a different context.

Applicants have found several compounds inhibiting effect of aurora kinase 2, and which, therefore, can be used in the treatment of proliferative diseases, such as cancer, in particular, when such diseases as colon cancer or breast, which, as you know, the aurora 2 kinase is active.

The present invention presents the use of the compounds of formula (I)

or its salts of ester or amide;

where X is O or S, S(O), or S(O)2or NR6where R6represents hydrogen or C1-6alkyl;

R5represents an optionally substituted 5-membered heteroaromatic ring;

R1, R2, R3, R4independently selected from halogeno, cyano, nitro, trifloromethyl,1-3of alkyl, -NR7R8(where each of R7and R8that may be the same or different, is hydrogen or C1-3alkyl), or-X1R9(where X1represents a direct bond, -O-, -CH2-, -OCO-, carbonyl, -S-, -SO-, -SO2-, -NR10CO-, -CONR11-, -SO2NR12-, -NR13SO2- or-NR14(where each of R10, R11, R12, R13and R14independently represents hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl), and R9choose from one of with EBUSY groups:

1) hydrogen or C1-5of alkyl, which may be unsubstituted or may be substituted by one or more groups selected from hydroxy, fluoro or amino,

2)1-5alkyl2COR15(where X2represents-O - or-NR16- (in which R15represents hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl), and R16is1-3alkyl, -NR17R18or19(where each of R17, R18and R19that may be the same or different, represents hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl));

3)1-5alkyl3R20(where X3represents-O-, -S-, -SO-, -SO2-, -OCO-, -NR21CO-, -CONR22-, -SO2NR23-, -NR24SO2- or-NR25(where each of R21, R22, R23, R24and R25independently represents hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl), and R20represents hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms independently selected from O, S and N, With1-3the alkyl group may contain 1 or 2 substituent selected from oxo, hydroxy, halogen and C1-4alkoxy, with a cyclic group can contain 1 or 2 substituent selected from oxo, hydroxy, shall halogen, With1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy);

4)1-5alkyl4With1-5alkyl5R26(where each of X4and X5that may be the same or different, represents-O-, -S-, -SO-, -SO2-, -NR27CO-, -CONR28-, -SO2NR29-, -NR30SO2- or-NR31(where each of R27, R28, R29, R30and R31independently represents hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl), and R26represents hydrogen or C1-3alkyl);

5) R32(where R32represents a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms independently selected from O, S and N, while the heterocyclic group may contain 1 or 2 substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl,1-4alkoxy, C1-4alkoxyl1-4the alkyl and C1-4alkylsulfonyl1-4the alkyl);

6)1-5R32(where R32defined above);

7)2-5R32(where R32defined above);

8)2-5R32(where R32defined above);

9) R33(where R33is Spiridonova group, phenyl group or a 5-6-membered aromatic heterocyclic group (linked via carbon or nitrogen) is 1 to 3 heteroatoms, selected from O, N and S, with Spiridonova, phenyl or aromatic heterocyclic group may contain up to 5 substituents on an available carbon atom selected from hydroxy, halogen, amino, C1-4of alkyl, C1-4alkoxy, C1-4hydroxyalkyl,1-4aminoalkyl,1-4alkylamino,1-4hydroxyalkoxy, carboxy, trifloromethyl, cyano, -CONR34R35and-NR36COR37(where each of R34, R35, R36and R37that may be the same or different, represents hydrogen, C1-4alkyl or C1-3alkoxyl2-3alkyl));

10)1-5R33(where R33defined above);

11)2-5R33(where R33defined above);

12)2-5R33(where R33defined above);

13)1-5alkyl6R33(where X6represents-O-, -S-, -SO-, -SO2-, -NR38CO-, -CONR39-, -SO2NR40-, -NR41SO2- or-NR42(where each of R38, R39, R40, R41and R42independently represents hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl), and R33defined above);

14)2-5alkenyl7R33(where X7represents-O-, -S-, -SO-, -SO2-, -NR43CO-, -CONR44-, -SO2NR45-, -NR46SO2- or-NR47(where each of R 43, R44, R45, R46and R47independently represents hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl), and R33defined above);

15)2-5alkynyl8R33(where X8represents-O-, -S-, -SO-, -SO2-, -NR48CO-, -CONR49-, -SO2NR50-, -NR51SO2- or-NR52(where each of R48, R49, R50, R51and R52independently represents hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl), and R33defined above);

16)1-3alkyl9With1-3R33(where X9represents-O-, -S-, -SO-, -SO2-, -NR53CO-, -CONR54-, -SO2NR55-, -NR56SO2- or-NR57(where each of R53, R54, R55, R56and R57independently represents hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl), and R33defined above); and

17)1-3alkyl9With1-3R32(where X9and R32defined above)

when getting medicines for use for inhibiting aurora 2 kinase. In particular, these drugs are useful in the treatment of proliferative diseases such as cancer and in particular, in such cancers, in which aurora 2 sverhnegativny, such as cancer of the bowel or breast.

In this description of the term is h "alkyl", used alone or as suffix, includes linear, branched structure. Unless otherwise noted, these groups can contain up to 10, preferably up to 6 and, most preferably up to 4 carbon atoms. Similarly, the terms "alkenyl" and "quinil" refer to unsaturated linear or branched structures containing, for example, from 2 to 10, preferably from 2 to 6 carbon atoms. Cyclic fragments, such as cycloalkyl, cycloalkenyl and cycloalkenyl have a similar nature, but contain at least 3 carbon atoms. Terms such as "alkoxy"includes alkyl groups, as understood in this technical field.

The term "halogen" includes fluorine, chlorine, bromine and iodine. Links to aryl groups include aromatic carbocyclic groups such as phenyl and naphthyl. The term "heterocyclyl" includes an aromatic or non-aromatic ring, for example, containing from 4 to 20, preferably from 5 to 8 atoms in the cycle, of which at least one is a heteroatom, such as oxygen, sulfur or nitrogen. Examples of such groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, chinoline, ethenolysis, Hinoki inil, benzothiazolyl, benzoxazolyl, benzothiazyl or benzofuran.

"Heteroaryl" refers to those groups described above, which have aromatic character. The term "aralkyl" refers to aryl-substituted alkyl groups such as benzyl.

Other expressions used in this description, include "hydrocarbon", which refers to any structure containing carbon atoms and hydrogen. For example, they may represent an alkyl, alkenyl, quinil, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkenyl.

The term "functional group" refers to the reactive substituents such as nitro, cyano, halogen, oxo, =CR78R79C(O)xR77, OR77, S(O)yR77, NR78R79C(O)NR78R79, OC(O)NR78R79, =NOR77, -NR77C(O)xR78, -NR77C(O)NR78R79, -N=CR78R79, S(O)yNR78R79or-NR77S(O)yR78where R77, R78and R79independently selected from hydrogen or optionally substituted hydrocarbon, or R78and R79together form an optionally substituted cycle which optionally contains further heteroatoms such as S(O)y, oxygen and nitrogen, x is an integer equal to 1 or 2, y is 0 or an integer equal to 1-3.

On the walking optional substituents of the hydrocarbon groups R 77, R78and R79include halogen, perfluoroalkyl such as trifluoromethyl, mercapto, hydroxy, carboxy, alkoxy, aryl, heteroaryl, heteroaromatic, alkenylacyl, alkyloxy, alkoxyalkyl, aryloxy (where the aryl group may be substituted with halogen, nitro, or hydroxy), cyano, nitro, amino, mono - or dialkylamino, oximino or S(O)ywhere y is defined above.

Preferably R4represents hydrogen.

Preferably R1represents hydrogen or a group defined for R2or R3below. Often R1is hydrogen.

In a preferred method embodiment, at least one group R1, R2or R3preferably R3contains a chain of at least three, and preferably at least four optionally substituted carbon atoms or heteroatoms, such as oxygen, nitrogen or sulfur. Most preferably, the chain is substituted with a polar group that promotes solubility.

Preferably, R3represents a group X1R9. Preferably, in this case, X1is oxygen, and R9choose from a group of the formula (1) or (10)above. Specific group, R9represent groups of the above groups (1), in particular alkyl, such as methyl or halogen-substituted Ala is l, or groups of the above groups (10). In one of the preferred ways embodiment, at least one of R2or R3represents a group-OC1-5R33and R33is a heterocyclic ring, such as N-linked morpholine ring, such as 3-morpholinopropan.

Preferably, R2selected from halogen, cyano, nitro, trifloromethyl,1-3of alkyl, -NR9R10(where each of R9and R10that may be the same or different, is hydrogen or C1-3alkyl), or group-X1R11. Preferred examples X1R11for R2include the groups listed above in relation to R3.

Other examples for R2and R3include methoxy or 3,3,3-triptoreline.

Preferably X is NH or O, and most preferably NH.

Examples of 5-membered aromatic cycles R5include loops containing one or more heteroatoms selected from sulfur, oxygen and nitrogen. Such cycles include pyrrole, pyrazole, pyrazolone, imidazole, oxazole, furan, tetrazole, triazole, thiazole, thiophene or thiadiazole, each of which may be optionally substituted. In particular, R5includes at least one of the heteroatoms nitrogen, or sulfur. Preferred cycles for R5VK is ucaut in itself pyrrole, pyrazole, imidazole, triazole, thiazole, thiophene or thiadiazole.

In a preferred method embodiment R5is the cycle containing sulfur. Preferably, R5is optionally substituted thiazole, optionally substituted thiophene or optionally substituted thiadiazole, and preferably, optionally substituted thiazole, or optionally substituted thiophene.

More preferably, R5is substituted thiazole or substituted thiophene group.

In particular, R5represents a group of formula (a), (b), (C) or (d), and preferably (a) or (b):

where R60, R61and R62independently selected from hydrogen or a replacement group, and * indicates the place of attachment to the group X in formula (I). In particular, one of R60, R61and R62represents a substitutional group, and others are either hydrogen or a Deputy, such as1-3alkyl, for example methyl. Preferably, R62represents hydrogen. Preferably, R61different from hydrogen.

Alternative, R5represents optionally substituted nitrogen cycle, such as a group form the s (f), (g), (h), (i) or (j):

Suitable substituents for the groups R5include optionally substituted hydrocarbon, optionally substituted heterocyclyl or above a certain functional group.

In particular, R60, R61or R62represent a group of formula (K)

where p and q are independently 0 or 1 and where R1' and R1" independently represent hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl. Optionally substituted alkyl or quinil may be substituted with halogen, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4the alkyl, C2-4alkenyl,2-4the quinil,

With3-6cycloalkyl,3-6cycloalkenyl,1-4alkoxy-,

With1-4alkanoyl,1-4alkanoyloxy, N-(C1-4alkyl), N(C1-4alkyl)2,

With1-4alkanolamine, (C1-4alkanoyl)2amino,

N-(C1-4alkyl)carbamoyl, N,N-(C1-4)2carbamoyl, (C1-4)S,

With1-4S(O), (C1-4alkyl)S(O) 2, (C1-4)alkoxycarbonyl,

N-(C1-4alkyl)sulfamoyl, N,N-(C1-4alkyl)sulfamoyl,

With1-4alkylsulfonate or heterocyclyl. R preferably represents C1-4alkyl, C2-4alkenyl or2-4quinil, and R1' can form with R1" 3-6-membered cycle.

T represents C=O, SOnC(=NOR)CO, C(O)C(O), C=NCN or CV=NO, where n=0, 1, or 2, and V is independently R63or N(R63R64where R63or R64independently selected from hydrogen, optionally substituted hydrocarbon or optionally substituted heterocyclyl, or R63or R64together with the nitrogen atom to which they are bound, form an optionally substituted heterocyclic ring.

Examples of groups for R63or R64include group

-(CH2)qR70where q and R70defined below in relation to formula (II).

Preferably, one of R63or R64represents hydrogen or methyl, ethyl or propyl, optionally substituted hydroxy, and preferably, one of R63or R64represents hydrogen. In this case, the other is preferably large Deputy containing at least 4 carbon atoms or heteroatoms, and is optionally substituted hydrocarbon or optionally substituted Goethe what Ollila. Concrete optionally substituted hydrocarbon group in the case of R63or R64include alkyl, cycloalkyl, alkenyl or aryl, any of which may be optionally substituted, defined above, functional groups or, in the case of aryl groups, alkyl group, and in the case of alkyl group, aryl or heterocyclic group, any of which may itself be optionally substituted alkyl or a functional group. Examples of optionally substituted aryl groups, R63or R64include phenyl, optionally substituted by one or more groups selected from C1-4alkyl group such as methyl or ethyl (any of which may be optionally substituted by a functional group such as hydroxy), or a functional group as defined above (such as halogen, for example fluorine, chlorine or bromine, hydroxy, alkoxy, such as methoxy, trifluoromethyl, nitro, cyano, triptoreline, CONH2C(O)CH3, amino or dimethylamino).

In the case when R63or R64is an optionally substituted alkyl group, it preferably represents a C1-6alkyl group, optionally substituted one or more functional groups, in particular methoxy, Coolkill such as SOOSN3or aryl, the optional samewe the hydrated functional group, defined above (in particular, in respect of themselves, R63or R64or optionally substituted heterocyclic group, such as N-methylpyrrole).

In the case when R63and R64is optionally substituted by cycloalkyl, it preferably is cyclohexyl, optionally substituted by a functional group such as hydroxy.

In the case when R63and R64is optionally substituted by alkenyl, it is preferably prop-2-enyl.

In the case when R63and R64is optionally substituted by heterocyclyl or R63and R64together form a heterocyclic group, it may be aromatic or non-aromatic and includes, in particular, piperidine, piperazine, morpholino, pyrrolidin or pyridine, each of which may be optionally substituted functional group, such as hydroxy, alkoxy, such as methoxy, or alkyl, such as methyl, which itself can be substituted, for example, hydroxy-group.

Alternatively, at least one of R60, R61or R62represents a functional group, and, in particular, one of R60, R61or R62represents the functional group of the formula (CR2)pC(O)xR77where R, p, x and R77are defined above and, in particular, x is equal to 2, and R77represents hydrogen or alkyl, such as methyl.

Alternative, R5substituted by one or more groups selected from nitro, halogen, C1-6the alkyl, optionally substituted C1-6alkoxy, C1-4alkoxyethyl, di(C1-4alkoxy)methyl, C1-6alkanoyl, trifloromethyl, cyano, amino, C2-6alkenyl, C2-6the quinil, phenyl group, benzyl group or a 5-6-membered heterocyclic group with 1-3 heteroatoms independently selected from O, S and N, while the heterocyclic group may be aromatic or non-aromatic and may be saturated (linked via a carbon atom or nitrogen cycle) or unsaturated (linked via a carbon atom of the cycle), and phenyl, benzyl or heterocyclic group may contain one or more carbon atoms of the cycle to 5 substituents selected from hydroxy, halogen, C1-3of alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifloromethyl, cyano, amino, nitro, C2-4alkanoyl,1-4alkanolamine,1-4alkoxycarbonyl,1-4alkylsulfanyl,1-4alkylsulfonyl,1-4alkylsulfonyl, carbamoyl,N-C1-4allylcarbamate,N,Ndi(C1-4alkyl)carbamoyl, aminosulfonyl,N-C1-4alkylaminocarbonyl,N,Ndi(C1-4alkyl)aminosulfonyl,1-4Ala is sulfonylamino, and a saturated heterocyclic group selected from morpholino, thiomorpholine, pyrrolidinyloxy, piperazinilnom, piperidinyloxy, imidazolidinyl and pyrazolidinone of groups, and the saturated heterocyclic group may contain 1 or 2 substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifloromethyl, cyano, amino, nitro and C1-4alkoxycarbonyl.

Preferably, R5substituted by at least one group containing at least 4 atoms, which may represent carbon or heteroatoms, forming a chain. Specific examples of such substituent is optionally substituted alkoxy or alkoxymethyl. Suitable substituents for the alkoxy group include the substituents listed above in relation to R77, R78and R79.

Another specific group substituent for R5is a group of formula (II)

where p and q are independently 0 or 1 and r is 0, 1, 2, 3 or 4, and R1', R1" and T are such as previously defined above;

R70represents hydrogen, hydroxy (except when q is equal to 0), C1-6alkyl, C1-6alkoxy, amino, N-C1-6alkylamino,

N,N-(C1-6alkyl)2amino, hydroxys2-6alkoxy,

With1-6/sub> alkoxyl2-6alkoxy, amino2-6alkoxy,

N-C1-6alkylamino2-6alkoxy, N,N-(C1-6alkyl)2aminos2-6alkoxy or3-7cycloalkyl,

or R70has the formula (III):

where J represents aryl, heteroaryl or heterocyclyl, and represents bond, oxy, imino, N-(C1-6alkyl)imino,

axis1-6alkylen, imino1-6alkylen, N-(C1-6alkyl)imino1-6alkylene, -NHC(O)-, -SO2NH-, -NHSO2- or-NHC(O)-C1-6alkylene-,

and any aryl, heteroaryl or heterocyclyl group in the group R70may be optionally substituted by one or more groups selected from hydroxy, halogen, trifloromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulfamoyl,1-6of alkyl, C2-6alkenyl,

With2-6the quinil,1-6alkoxy, -O-(C1-3alkyl)-O-, C1-6S(O)n- (where n is 0-2), N-C1-6alkylamino, N,N-(C1-6alkyl)2amino,

With1-6alkoxycarbonyl, N-C1-6allylcarbamate,

N,N-(C1-6alkyl)2carbamoyl,2-6alkanoyl,1-6alkanoyloxy,

With1-6alkanolamine, N-C1-6alkylsulfonyl,

N,N-(C1-6alkyl)2sulfamoyl,1-6alkylsulfonamides and

With1-6alkylsulfonyl-N-(C1-6alkyl)amino,

or any aryl, heteroaryl or heterocyclyl group in the group R70may be optionally substituted by one or more groups of the formula (IV):

where a1is halogen, hydroxy, C1-6alkoxy, cyano, amino, N-C1-6alkylamino, N,N-(C1-6alkyl)2amino, carboxy,

With1-6alkoxycarbonyl, carbarnoyl, N-C1-6allylcarbamate or

N,N-(C1-6alkyl)2carbarnoyl, p is 1-6, and1represents a bond, oxy, imino, N-(C1-6alkyl)imino or-NHC(O)-, provided that p is 2 or more, except when In1represents a bond or-NHC(O)-;

or any aryl, heteroaryl or heterocyclyl group in the group R70may be optionally substituted by one or more groups of the formula (V):

where D1represents aryl, heteroaryl or heterocyclyl, and E1is link1-6alkylen, axis1-6alkylene, hydroxy, imino, N-(C1-6alkyl)imino, imino1-6alkylen,

N-(C1-6alkyl)imino1-6alkylen,1-6alkylen-axis1-6alkylen,

With1-6alkylen-imino1-6alkylen,

With1-6alkylen-N-(C1-6alkyl)imino1-6alkylene, -NHC(O)-, -NHSO2-,

-SO2NH - or-NHC(O)-C1-6alkylen, and any aryl, GE is ereally or heterocyclyl group Deputy when D 1may be optionally substituted by one or more groups selected from hydroxy, halogen, C1-6of alkyl, C1-6alkoxy, carboxy, C1-6alkoxycarbonyl, carbamoyl, N-C1-6allylcarbamate, N-(C1-6alkyl)2carbamoyl,2-6alkanoyl, amino, N-C1-6alkylamino and N,N-(C1-6alkyl)2amino,

any3-7cycloalkyl or heterocyclyl group in R70the group may be optionally substituted by one or two oxo or thioxo-substituents,

and any R70groups defined previously containing SN2group associated with the 2 carbon atoms, or CH3group associated with the carbon atom, may optionally contain each of the specified CH2or CH3group Deputy selected from hydroxy, amino, C1-6alkoxy, N-C1-6alkylamino and N,N-(C1-6alkyl)2amino and heterocyclyl.

A preferred example of the substituent of formula (II) is a group, where q is equal to 0.

A specific example of the group R70in the formula (II) is phenyl.

Another preferred group of the substituent for R5is a group of the formula (VI)

where R71and R72independently selected from hydrogen or C1-4the alkyl or R71and R72together form a bond, and R73to depict the defaults group OR 74, NR75R76where R74, R75and R76independently selected from optionally substituted hydrocarbon or optionally substituted heterocyclic group, and R75and R76may also form together with the nitrogen atom to which they are attached, an aromatic or nonaromatic ring which may contain additional heteroatoms.

Suitable optional substituents for the hydrocarbon or heterocyclic groups, R74, R75and R76include functional groups defined above. Heterocyclic group, R74, R75and R76may also be substituted hydrocarbon groups.

In particular, R71and R72in the formula (VI) are hydrogen.

Specific examples of R73are group OR74in which R74is1-4alkyl.

Additional examples R73are group NR75R76in which one of R75and R76represents hydrogen and the other represents an optionally substituted C1-6alkyl, optionally substituted aryl or optionally substituted heterocyclyl.

In particular, one of R75or R76represents hydrogen and the other represents C1-6alkyl, optionally substituted by trifluoromethyl,1-3is laksi, such as methoxy, cyano, tios1-4the alkyl, such as methylthio or heterocyclyl, optionally substituted hydrocarbons, such as indan, furan, optionally substituted C1-4the alkyl, such as methyl.

In another method embodiment, one of R75or R76represents hydrogen and the other represents an optionally substituted heterocyclic group such as pyridine or phenyl group, optionally substituted, e.g. by one or more groups selected from halogeno, nitro, alkyl, such as methyl, or alkoxy, such as methoxy.

Suitable pharmaceutically acceptable salts of compounds of formula (I) or formula (IA) include salts accession acid, such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid. Depending on the number of charged functional groups and valence of the cations or anions may be more than one cation or anion. When the compound of formula (I) or formula (IA) include acid functional group, salts can be salts of the base, such as a salt of an alkali metal, e.g. sodium, salt of alkaline-earth metal, e.g. calcium or magnesium salt of an organic amine, such as triethylamine, research, N-methylpiperidine, N-ethylpiperidine, prokai is a, dibenzylamine, N,N-dibenzylamine or amino acids, for example lysine. Preferred pharmaceutically acceptable salt is a sodium salt.

Hydrolyzable in vivo ester compounds of formula (I) or formula (IA)containing carboxy or hydroxy group is, for example, pharmaceutically acceptable ester which is hydrolysed in the body of man or animal, leading to the formation of the original acid or alcohol.

Suitable pharmaceutically acceptable esters in the case of carboxy include1-6alkalemia esters, such as methyl or ethyl esters, With1-6alkoxymethyl esters, for example methoxymethyl,1-6alkanoyloxy esters, for example pivaloyloxymethyl, telegrafie esters, With3-8cycloalkane-carbonyloxy1-6alkalemia esters, for example 1-cyclohexyloxycarbonyloxy; 1,3-dioxolan-2-animecrave esters, for example 5-methyl-1,3-dioxolan-2-animationy; and (C1-6alkoxycarbonylmethyl esters, for example 1-methoxycarbonylmethylene, and can be formed at any carboxy group in the compounds of the present invention.

Hydrolyzable in vivo ester compounds of formula (I) or formula (IA)containing a hydroxy group includes reorganize is such esters, such as phosphate esters and α-aryloxyalkyl ethers and related compounds which as a result of the hydrolysis of ester in vivo decompose, giving the original hydroxy group. Examples α-aryloxyalkanoic ethers include acetoxymethyl and 2,2-dimethylphenylacetate. Set hydrolyzable in vivo groups, forming esters, includes alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (forming alkalicarbonate esters), dialkylamino and N-(dialkylaminoalkyl)-N-allylcarbamate (forming carbamates), dialkylaminoalkyl and carboxyethyl.

Suitable amides are obtained from compounds of formula (I) or formula (IA)having a carboxy group, which is transferred to the amide, such as N-C1-6alkyl and N,N-di-(C1-6alkyl)amide, such as N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-diethylamide.

Preferred compounds of formula (I) or formula (IA) are compounds that are stable in the serum of mice, rats or serum of human blood, preferably the compounds are stable in the serum of a person.

Esters, which are not hydrolyzed in vivo, are useful as intermediates in obtaining the compounds of formula (I) or formula (IA).

Specific examples of compounds f is rmula (I) or formula (IA) are shown in tables 1 through 30 below.

Table 1
Connection # HRR'Connection # NRR'
115
216
3
417
518
619
720
8
921
10
1122
1223
1324
1425

Table 1 (continued)
2639
2740
2841
2942
3043
31 44
3245
3346
3447
3548
3649
3750
38

Table 2
Connection # NRR'
51
52
53
54
55
56
57
58

Table 3
Connection # NRR'
59
60
61
62
63
64
85
66

Table 4
Connection # NRR'
67
68
69
70
71
72
73

Table 5
Connection # NRR'
74
75
76
77
78
Table 6
Connection # NRR'
79
80
81
82
83
84
85
86

Table 7
No.R2R3R60R61
200Och3Och3CH2SOON2CH3N
201Och3Och3CH2COOHN
202Och3Och3CH3SOON2CH3
203Och3O(CH2)3-N-morpholinoCH3 SOON2CH3
204Och3O(CH2)3-N-morpholinoCH3COOH
205Och3O(CH2)3-N-morpholinoCH2SOON2CH3N
2061Och3O(CH2)3-N-morpholinoCOOCH2CH3N
207Och3O(CH2)3-N-morpholinoCOOHN
208Och3O(CH2)3-N-morpholinoNSOON2CH3
209Och3O(CH2)3-N-morpholinoNCOOH
210Och3O(CH2)3-N-morpholinoCH2SOON2CH3CH3
211Och3O(CH2)3-N-morpholinoCH2COOHCH3

Table 8
/td>
No.R2R3R61
212Och3O(CH2)3-N-morpholinoCOOH
213
214Och3Och3COOH

Table 9
R"'R"
250CH3Och3
251CH3HE
252CH3
253CH3
254CH3
255CH3
256NOch2CH3
257NHE
258N
259 N

Table 10
Connection # R"
260COOEt3
261COOH
262
263
264
265
266
267

Table 11
Connection # R"
286COOCH2CH3
269COOH
270
271
272
Table 12
Connection # R"'
300H
301SOON2CH3

Table 13
No.NRR'No.NRR'
3024-methoxyaniline3202-methyl-4-ftoranila
3034-methylaniline3212-fluoro-5-methylaniline
3042-aminopyridine3224-forbindelsen
3052-aminobenzoyl alcohol3233,4-differentiatin
3064-methoxybenzylamine3243-methylaniline
3073-nitroaniline3252-(methylthio)aniline
308aminoacetonitrile3265-aminoindole
3092-methyl-5-nitroaniline3273-aminobenzonitrile
310cyclopropylamine3282,4-differentiatin
3114 nitrobenzo the Amin 3293-(2-amino-ethyl)pyridine
3122-anilinomethyl330N-methylisobutyl
313Furfurylamine3312-aminobenzoylamino
3143-Chloroaniline3323-methylbutylamine
3152-methoxyaniline3331-aminomethyl-1-cyclohexanol
316thiophene-2-methylamine3342-aminomethylpyridine
317neopentylene3353-methoxyaniline
3182,6-differentiatin3364-chlorobenzylamino
3192-methylethylamine

Table 14
No.NRR'No.NRR'
337Aniline3572-methoxyaniline
3383-chloro-4-ftoranila3582-ftoranila
3394-Chloroaniline359thiophene-2-methylamine
3403,4-diptiranjan3602-amino-1-phenylethanol
3413-methoxyaniline3613-(1-hydroxyethyl)aniline
3422-Chloroaniline362neopentylene
3434-methoxyaniline3633-fluoro-4-methoxyaniline
3444-methylaniline3642-methyl-4-ftoranila
3452-methylaniline3652,5-diptiranjan
3462-aminopyridine3662-fluoro-4-Chloroaniline
3472-aminobenzoyl alcohol3672-fluoro-4-methylaniline
3482-amino-3-methyl-1-butanol3683-methylaniline
3492-anilinomethyl3692-(methylthio)aniline
3503-chloro-4-methylaniline3705-aminoindole
3513-nitroaniline3712,4-diptiranjan
352aminoacetonitrile3722-fluoro-4-methylaniline
3532-methyl-5-nitroaniline3733-Canaan the Lin
3542-amino-5-chloropyridin3742-methyl-5-ftoranila
3554-triptorelin3752-methyl-5-Chloroaniline
3563-Chloroaniline
Table 15
No.NRR'No.NRR'
376aniline3903-fluoro-4-methoxyaniline
3773-chloro-4-ftoranila3912-methyl-4-ftoranila
3782-aminopyridine3922-amino-4-methylpyridin
3793,4-diptiranjan3932,5-diptiranjan
3802=Chloroaniline3942-fluoro-4-Chloroaniline
3814-methylaniline3952-fluoro-5-methylaniline
3822-methylaniline3963-methylaniline
3834-Chloroaniline3972,4-diptiranjan
3844-ftoranila3982-fluoro-4-methylaniline
385 2-amino-6-methylpyridin3993-cyanoaniline
3863-methoxyaniline4002-methyl-5-ftoranila
3872-amino-5-chloropyridin4013,5-diptiranjan
3883-Chloroaniline4023-ftoranila
3892-ftoranila

Table 16
No.NRR'No.NRR'
403Aniline
4043,4-diptiranjan
4052-aminopyridine4182-fluoro-4-methylaniline
4063-chloro-4-ftoranila4193-fluoro-4-methoxyaniline
4072-Chloroaniline4202-methyl-4-ftoranila
4084-methylaniline4212-amino-4-methylpyridin
4092-methylaniline4222,5-diptiranjan
4104-Chloroaniline4232-fluoro-4-Chloroaniline
4114-ftoranila4242-fluoro-5-methylaniline
4122-amino-6-methylpyridin4253-methylaniline
4133-methoxyaniline4262,4-diptiranjan
4142-amino-5-chloropyridin4272-methyl-5-ftoranila
4153-Chloroaniline4283,5-diptiranjan
4162-ftoranila4293-ftoranila
4173-cyanoaniline

Table 17
No.R"NRR'
430pyrrolidin3-Chloroaniline
431pyrrolidin3,4-diptiranjan
432dimethylamino3,5-diptiranjan
4332-amino-2-methyl-1-propanol3-chloro-4-ftoranila
4342-amino-2-methyl-1-propanol3-ftoranila
4354-hydroxypiperidine3,4-diptiranjan
436N,N-dimethylethylenediamine3,4-diptiranjan
437piperidine3,4-diptiranjan
4382-methylaminoethanol3,4-diptiranjan
4391,2-diamino-2-methylpropan3,4-diptiranjan
440cyclohexylamin3,4-diptiranjan
441N,N,N'-trimethylethylenediamine3,4-diptiranjan
442D-prolinol3,4-diptiranjan
443L-prolinol3,4-diptiranjan
4443-pyrrolidino3,4-diptiranjan
4451-(2-amino-ethyl)pyrrolidin3,4-diptiranjan
4461-acetylpiperidine3,4-diptiranjan
4471-(2-morpholinoethyl)piperazine3,4-diptiranjan
4482-(2-hydroxyethyl)piperidine3,4-diptiranjan
4491-(2-hydroxyethyl)piperazine3,4-diptiranjan
450cyclopentylamine3,4-diptiranjan
4514-(2-hydroxyethyl)piperidine3,4-diptiranjan
452tert-butyl methyl ether3,4-diptiranjan
L-alanine
4533-hydroxypiperidine3,4-diptiranjan
4544-hydroxyethylpiperazine3,4-diptiranjan
4551-amino-2-propanol3,4-diptiranjan
456tert-butyl methyl ether3-Chloroaniline
L-alanine
4572-methylaminoethanol3-Chloroaniline
4581,2-diamino-2-3-Chloroaniline
methylpropan
459cyclohexylamin3-Chloroaniline
460N,N-dimethylethylenediamine3-Chloroaniline
461N,N,N'-trimethylethylenediamine3-Chloroaniline
462D-prolinol3-Chloroaniline
463L-prolinol3-Chloroaniline
4644-hydroxypiperidine3-Chloroaniline
4653-pyrrolidino3-Chloroaniline
4661-(2-amino-ethyl)pyrrolidin3-Chloroaniline
4674-hydroxyethylpiperazine3-Chloroaniline
4681-(2-hydroxyethyl)piperazine3-Chloroaniline
469cyclopentylamine3-Chloroaniline
4704-(2-hydroxyethyl)piperidine3-Chloroaniline
4713-hydroxypiperidine3-Chloroaniline
472(S)-1-amino-2-propanol3-Chloroaniline
473(R)-1-the Mino-2-propanol 3-Chloroaniline
474piperazine3-Chloroaniline
4752-(2-hydroxyethyl)piperidine3-Chloroaniline
4762-amino-2-methyl-1-propanol3-Chloroaniline
4771-(2-dimethylaminoethyl)piperazine3-Chloroaniline
478dimethylamine3-Chloroaniline
479aminomethylpropanol3-Chloroaniline
480piperidine3-Chloroaniline
4811-(2-dimethylaminoethyl)piperazine3,5-diptiranjan
482(S)-(+)-2-pyrrolidineethanol3,5-diptiranjan
4834-hydroxypiperidine3,5-diptiranjan
4843-pyrrolidino3,5-diptiranjan
4851-(2-amino-ethyl)pyrrolidin3,5-diptiranjan
4864-hydroxyethylpiperazine3,5-diptiranjan
4872-(2-g is proxetil)piperidine 3,5-diptiranjan
4881-(2-hydroxyethyl)piperazine3,5-diptiranjan
4894-(2-hydroxyethyl)piperidine3,5-diptiranjan
4903-hydroxypiperidine3,5-diptiranjan
491N,N,N'-trimethylethylenediamine3,5-diptiranjan
492piperidine3,5-diptiranjan
493pyrrolidin3,5-diptiranjan
4942-amino-2-methyl-1-propanol3,5-diptiranjan
4952-methylaminoethanol3,5-diptiranjan
496N,N-dimethylethylenediamine3,5-diptiranjan
497(S)-(+)-1-amino-2-propanol3,5-diptiranjan
498(R)-(-)-1-amino-2-propanol3,5-diptiranjan
499piperazine3,5-diptiranjan
500N-arylpiperazine3,5-diptiranjan
501 (R)-(-)-2-pyrrolidineethanol3,5-diptiranjan
502cyclopentylamine3,5-diptiranjan
5032-methylaminoethanol3-chloro-4-ftoranila
504N,N,N'-trimethylethylenediamine3-chloro-4-ftoranila
505N-arylpiperazine3-chloro-4-ftoranila
5064-hydroxypiperidine3-chloro-4-ftoranila
5073-pyrrolidino3-chloro-4-ftoranila
5081-(2-amino-ethyl)pyrrolidin3-chloro-4-ftoranila
509N-acetylpiperidine3-chloro-4-ftoranila
5102-(2-hydroxyethyl)piperidine3-chloro-4-ftoranila
5111-(2-hydroxyethyl)piperazine3-chloro-4-ftoranila
512cyclopentylamine3-chloro-4-ftoranila
5134-(2-hydroxyethyl)piperidine3-chloro-4-ftoranila
5143-hydroxypiperidine 3-chloro-4-ftoranila
5154-hydroxyethylpiperazine3-chloro-4-ftoranila
5161-amino-2-propanol3-chloro-4-ftoranila
517piperazine3-chloro-4-ftoranila
5181-(2-morpholinoethyl)piperazine3-chloro-4-ftoranila
519pyrrolidin3-chloro-4-ftoranila
5202-methylaminoethanol3-ftoranila
5211,2-diamino-2-methylpropan3-ftoranila
522N,N-dimethylethylenediamine3-ftoranila
523N,N,N'-trimethylethylenediamine3-ftoranila
524N-arylpiperazine3-ftoranila
5254-hydroxypiperidine3-ftoranila
5263-pyrrolidino3-ftoranila
5271-(aminoethyl)pyrrolidin3-ftoranila
528N-acetylpiperidine the 3-ftoranila
5291-(2-hydroxyethyl)piperazine3-ftoranila
530cyclopentylamine3-ftoranila
5314-(2-hydroxyethyl)piperidine3-ftoranila
5323-hydroxypiperidine3-ftoranila
5334-hydroxyethylpiperazine3-ftoranila
5341-amino-2-propanol3-ftoranila
535(R)-(-)-2-pyrrolidineethanol3-ftoranila
536(S)-(+)-2-pyrrolidineethanol3-ftoranila
537piperazine3-ftoranila
5381-(2-morpholinoethyl)piperazine3-ftoranila
5392-amino-2-methyl-1-propanol3-ftoranila
Table 18
No.NRR'
540N-ethylaniline
5413-chloro-4-fluoro-N-methylaniline
542ethyl-2-(3-chloro-4-foronline)acetate
5432-anilinomethyl
5443-anilinopyrimidines
545N-(2-tert-butoxyethyl)-3-chloro-4-ftoranila
546N-allylamines
547N-ethyl-3,4-(methylenedioxy)aniline
548ethyl-4-(N-butylamino)benzoate
549N-ethyl-m-toluidine
550N-(2-hydroxyethyl)-3-chloro-4-ftoranila

3,4-diptiranjan
Table 19
No.NRR'
551aniline
5523-chloro-4-ftoranila
5532-aminopyridine
554
Table 20
No.R"NBR'
555piperidine3-chloro-4-ftoranila
556pyrrolidin3-chloro-4-ftoranila
5574-hydroxypiperidine3-chloro-4-ftoranila
558piperazine3-chloro-4-ftoranila
559cyclopentylamine3-chloro-4-ftoranila
5602-amino-2-methyl-1-propanol3-chloro-4-ftoranila
561piperidine3,4-diptiranjan
562pyrrolidin3,4-diptiranjan
5634-hydroxypiperidine3,4-diptiranjan
565cyclopentylamine3,4-diptiranjan
566pyrrolidin3-Chloroaniline
5674-hydroxypiperidine3-Chloroaniline
568cyclopentylamine3-Chloroaniline
5692-amino-2-methyl-1-propanol3-Chloroaniline
570piperazine/td> 3-Chloroaniline
571OMe3-Chloroaniline
572piperidine3-Chloroaniline
573piperidine3,5-diptiranjan
574pyrrolidin3,5-diptiranjan
5752-amino-2-methyl-1-propanol3,5-diptiranjan
576piperazine(acetate)3,5-diptiranjan
577piperazine3,5-diptiranjan
578pyrrolidin3-ftoranila
579piperidine3-ftoranila
580piperazine3-ftoranila
581piperazine(acetate)3-ftoranila
582cyclopentylamine3-ftoranila

Table 21
No.NRR'
5833,5-diptiranjan
5843-Chloroaniline
5853-chloro-4-ftoranila
5863,4-diptiranjan
Table 22
No.R"XNRR'
587morpholineHEaniline
588morpholineHE3,4-diptiranjan
589N-Me-piperazineHE3,4-diptiranjan
590piperidineHE3-ftoranila
591piperidineHE3-Chloroaniline
592N-Me-piperazine=N-OH3,4-diptiranjan

Table 23
No.NRR'No.NRR'
5932-aminopyridine6012-methoxyaniline
5944-methylaniline6023-(2-hydroxyethyl)aniline
5952-methylaniline603H-fluoro-4-methoxyaniline
5963-methoxyaniline604 2-methyl-4-ftoranila
5972-hydrosilylation6052-fluoro-5-methylaniline
5983-nitroaniline6063-cyanoaniline
5994-triptorelin607isoamylamine
6003-Chloroaniline6082-Chloroaniline
Table 24

No.NRR'
609aniline
6104-ftoranila
6113-hydroxyanisol
6123-(methylthio)aniline
6134-fluoro-3-Chloroaniline
6142,4-differentiatin
6153-ftoranila
Table 25
No.NRR'
616aniline
6174-ftoranila
618allylamine
Table 26

No.NRR'
619aniline
620allylamine
Table 27
No.R2R4R5
621COOMeNN
Table 28
No.R3R4R5
622CONH2NIsopropyl
623NNCoolly

tr>
Table 29
No.R4R5
626PhN
627MeCOCH3
628CF3COOEt
629PhCOOEt
630 -(CH2)4-4-
631acetylaminophenolN
632CF3Ph
633CF3N
634tert-butylN
635MeMe
636MeN
637Me-C(=N-OH)-Me
638N-NHCOO-tert-butyl
639Me-C(=NOMe)-Me
640Me-C(=NOPh)-Me
641N4-methoxyphenyl
642NPh
643NEt
644Nisopropyl
645N-CH2Ph
646NMe
647Nn-butyl
648NCHO
649N-CH=N-OH
Table 30
No.XR5
650Stert-butyl
651Scyclopropyl
652S-S-CH2-CH3
653S-Ph
654NH-NH-Ph

Other compounds of formula (I) or formula (IA), in particular compounds in which R5contains a carboxy or carboxylic ester Deputy, described below in the examples.

The compounds of formula (I) or formula (IA) can be obtained in various ways which will be obvious from the literature. For example, the compounds of formula (I)in which X is NH, can be obtained by the interaction of the compounds of formula (VII)

in which R1,R2, R3and R4such as defined in relation to formula (I), and R85represents a group NR86R87in which R86and R87independently selected from alkyl, such as methyl, with a compound of formula (VIII)

in which R5'represents a group R5defined in relation to formula (I), or a group of the precursor; and thereafter if desired or necessary, converting the group-the predecessor of R5'the group R5and/or by changing the substituents in the group R 5. This reaction is suitably carried out in an organic solvent, such as acetic acid, at elevated temperatures, usually at the boiling temperature of the solvent.

Examples of reactions in which the group is the predecessor of R5'turn to the group R5and/or changing the substituents in the group R5represent the standard chemical reactions such as the conversion of esters into acids, and then, if necessary, in the preferred amides. Examples of such reactions are given below.

The compounds of formula (VII) appropriately get in the interaction of the compounds of formula (IX)

with the corresponding acetal, such as dimethylacetal N,N-dimethylformamide. This reaction is suitably carried out in an organic solvent, such as benzene, at elevated temperatures, usually at the boiling point of this solvent.

Alternatively, the compounds of formula (I)in which X is NH, can be obtained by rearrangement of compounds of formula (X)

in which R1, R2, R3and R4such as defined in relation to formula (I), and R5'such as defined in relation to the above formula (VIII), and thereafter if desired or necessary, aravada group-the predecessor of R 5'the group R5and/or by changing the substituents in the group R5for example, as in the General form described above.

The rearrangement reaction of suitably carried out in an organic solvent, such as Elgiloy alcohol, in particular methanol, ethanol or cyclohexanol, acetic acid or dimethylformamide, using a strong base such as sodium hydroxide, sodium acetate, sodium methylate or dimethylamine. Use elevated temperatures, for example from 20°-120°and preferably at about 75°C.

The compounds of formula (X) is appropriately obtained when the interaction of the compounds of formula (XI)

in which R1, R2, R3and R4such as defined in relation to formula (I), and R86represents an alkyl group such as methyl; with the compound of the formula (XII)

in which R5'such as defined in relation to formula (VIII). The reaction is suitably carried out in an organic solvent such as methylene chloride, in the presence of salts such as pyridinium hydrochloride. Use moderate temperatures, e.g. from 0°-50°and usually the ambient temperature.

The compounds of formula (XI) accordingly receive when interacting compounds Faure the uly (IX), defined above, with trialkylaluminium, such as triethylorthoformate. The reaction is suitably carried out at elevated temperature, for example, from 50°to 120°and preferably, at about 100°With, in the presence of catalytic amount of acid such as p-toluensulfonate.

The compounds of formula (IX) are either known compounds or they can be obtained in the usual way. In particular, the compounds of formula (IX) can be obtained by recovery of the corresponding nitro compounds of formula (XIII)

in which R1, R2, R3and R4such as defined in relation to formula (I). Suitable reaction conditions are given below.

The compounds of formula (XIII) can be obtained by nitration of compounds of formula (XIV)

for example, when using nitric acid as nitrouse agent. Again, suitable reaction conditions are given below.

The compounds of formula (I) and formula (IA) are inhibitors of aurora 2 kinase. As a result, these compounds can be used in the treatment of disease, intermediaries which are the agents, in particular in the proliferative disease.

In accordance with the following aspect of the present invention provides a method of inhibiting aurora 2 kinase in a warm the blood of the animal, such as man, in need of such treatment, which includes the introduction of a specified animal an effective amount of the compounds of formula (I), or formula (IA), or pharmaceutically acceptable salt or hydrolyzable in vivo complex ether.

Some compounds of formula (I) are new, and these compounds constitute another aspect of the present invention. Thus, the invention includes, in addition, the compound of formula (IA)

or its salt, ester or amide;

in which X is as defined in relation to formula (I);

R1', R2', R3'and R4'equivalent to R1, R2, R3and R4defined in relation to formula (I), and R5arepresents an optionally substituted 5-membered heteroaromatic cycle, provided that:

(i) when R5arepresenting pyrazol group, it contains a Deputy of the formula (k), (II) from (VI)above,

(ii) when X is NH, and R5athat represents a substituted pyrazolones or tetrazolyl group, at least one of R1', R2', R3'and R4'different from hydrogen; or

(iii) when X represents O, and R5athat represents 1-methyl-4-nitro-1H-imidazol-5-yl, at least one of R1', R2', R3'and R4'about the while from hydrogen.

Preferably, at least one of R1', R2', R3'and R4'different from hydrogen.

Suitably, R5achoose from the groups of formulae (a)to(j)above.

Preferably R5ais pyrrole, imidazole, triazole, thiazole, thiophene or thiadiazole, each of which may be optionally substituted.

In particular, R5asubstituted by at least one group of formula (K), (II) or (VI)above.

Other preferred or specific groups and the substituents in the formula (IA) such as shown in the case of the equivalent groups in the above formula (I).

In accordance with the following aspect of the invention is provided a compound of formula (IA), as defined here, its pharmaceutically acceptable salt or hydrolyzable in vivo ester, for use in a method of treatment of an animal body or person by therapy. In particular, these compounds used in the methods of treatment of proliferative diseases such as cancer and, in particular, such types of cancer, like colon cancer or breast, which are sverhnegativny aurora 2.

The invention also provided a pharmaceutical composition comprising a compound of formula (IA), as defined here, its pharmaceutically acceptable salt or hydrolyzable in vivo ester, in combination with farmaci is almost acceptable carrier. Preferred or specific compounds of formula (IA) for use in the compositions of the invention are compounds described above in relation to preferred compounds of formula (I).

Compositions of the invention can be in the form suitable for oral use (for example, in the form of tablets, pellets, hard or soft capsules, suspensions in water or oil, emulsions, dispersible powders or granules, syrups or suspensions), for topical use (for example, in the form of creams, ointments, gels or solutions or suspensions in water or oil), for administration by inhalation (for example, in the form of fine powder or a liquid aerosol), for administration by insufflation (for example, in the form of a fine powder)or for parenteral administration (for example, in the form of a sterile solution in water or oil for intravenous, subcutaneous or intramuscular dosing or as a suppository for rectal dosing).

Compositions of the invention can be obtained according to conventional procedures using conventional pharmaceutical excipients, well known in this field. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavouring and/or preservative agents.

Suitable pharmaceutically pickup is acceptable excipients for preparation of tablets include, for example, inert diluents, such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating or loosening agents such as corn starch or alginic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl - or propyl-p-hydroxybenzoate, and antioxidants, such as ascorbic acid. The compositions of the tablets can be uncoated, or coated or to modify their dispersion and subsequent adsorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in any case, using conventional agents for coatings and techniques, well known in this field.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions generally contain the active ingredient in micronized form in combination with one or more suspendresume agent and, such as carboxymethylcellulose sodium, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and Arabic gum; dispersing or wetting agents such as lecithin, or condensation products of oxide alkylene with fatty acids (for example, polyoxyethylenated), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and exit, such as polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of exit, such as polyethylenterephthalat. Aqueous suspensions may also contain one or more preservatives (such as ethyl - or propyl-p-hydroxybenzoate), antioxidants (such as ascorbic acid), colorants, flavorings and/or sweeteners (such as sucrose, saccharin or aspartame).

Suspensions in oil can be by suspension of the active ingredient in a vegetable oil (such as peanut butter, olive oil, sesame oil or coconut oil) or mineral oil such as liquid paraffin). Suspensions in oil may also contain acoustical, such as beeswax, hard paraffin or cetyl alcohol. To provide a pleasant preparation for oral administration can be added sweeteners, such as those cited above, and flavoring agents. Song data can be preserved by adding an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of aqueous slurry by adding water, usually contain the active ingredient in combination with a wetting agent, suspenders agent and one or more preservatives. Examples of suitable dispersing or wetting agents represented by the agents mentioned above. In addition, there may also be additional excipients, such as sweetening, flavoring and coloring agents.

The pharmaceutical composition of the invention may also be in the form of emulsions of oil in water. The oil phase may be a vegetable oil, such as olive oil or peanut oil, mineral oil such as liquid paraffin, or a mixture of any of these oils. Suitable emulsifying agents may be, for example, natural resins such as Arabian gum or tragacanth gum, natural phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acid is t and anhydrides of exit (for example, orbitonasal), and condensation products of these partial esters and ethylene oxide, such as polyoxyethylenesorbitan. These emulsions may also contain sweetening, flavouring and preservative agents.

Syrups and elixirs can be with sweeteners, such as glycerin, propylene glycol, sorbitol, aspartame or sucrose, and they may contain, in addition, demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical composition may also take the form of a sterile aqueous or oily suspension for injection, which can be in accordance with known methods using one or more appropriate dispersing or wetting agents or suspendida agents which have been mentioned above. A sterile preparation for injection may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.

Formulations of suppositories can be prepared by mixing the active ingredient with a suitable non-irritating by excipients, which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum with the release of drug is wow tools. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

Compositions for topical application such as creams, ointments, gels, and solutions or suspensions in water or oil, you can usually cook, combining the active ingredient with ordinary, acceptable for local use, a carrier or diluent, in the usual manner, well known in this field.

Compositions for administration by inhalation may be in the form of finely ground powder containing particles of average diameter of, for example 30 MK or a lot less, but this powder contains either only active ingredient, or diluted with one or more physiologically acceptable carriers such as lactose. Then the powder for inhalation is usually placed in a capsule containing, for example, from 1 to 50 mg of active ingredient, for use in turbomaschinen device, such as used for inhalation is known agent sodium cromoglycate.

Compositions for administration by inhalation can be conventional, pressurized aerosol, arranged so that dispersing the active ingredient or in the form of an aerosol containing finely ground solid matter or liquid droplets. You can use conventional aerosol propellants such as volatile ferrovanadium or hydrocarbons, and aerosol apparatus is arranged in the usual manner for controlled dispersion amount of the active ingredient.

For additional information regarding composition of the reader refer to Chapter 25.2 5 volume Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

The amount of the active ingredient, together with one or more excipients to obtain a dosage form will necessarily vary depending on the "host", which they were treated and the particular route of administration. For example, a composition intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent, connect it to the appropriate and suitable amount of excipients which may vary from about 5 to about 98 weight percent of the total composition. Usually, dosage forms will contain from about 1 mg to about 500 mg of active ingredient. For more information on routes of administration and dosing regimens of the reader refer to Chapter 25.3 5 volume Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

The size of the dose of the compounds of formula I for therapeutic or prophylactic purposes, of course, will vary in accordance with the nature and severity of the condition, age and sex of the animal or patient and the way BB is Denia according to well-known rules of medicine. As noted above, the compounds of formula I useful in the treatment of diseases or medical conditions that occur wholly or partly due to the influence of the aurora kinase 2, and it can be administered by itself or in the form of a composition.

When using the compounds of formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose has been taken in the interval, for example, from 0.5 mg to 75 mg per kg of body weight, given, if necessary, in divided doses. Typically, when using parenteral method will be introduced smaller doses. Thus, for example, for intravenous administration will typically be used doses in the range of from 0.5 mg to 30 mg per kg of body weight. Similarly, for administration by inhalation will be used doses in the range of, for example, from 0.5 mg to 25 mg per kg of body weight.

Another aspect of the invention includes a compound of formula (I) or formula (IA), as defined above, or its pharmaceutically acceptable salt or hydrolyzable in vivo ester, for use when obtaining drugs for the treatment of proliferative diseases.

The invention is illustrated by the following examples.

The General scheme 1

Connection

AMI is ontril And (534 mg, 3 mmol) in benzene (15 ml) was administered in cooperation with dimethylacetal N,N-dimethylformamide (535 mg, 4.5 mmol) at 90°With, in a flask equipped with a nozzle Dean-stark. After 4.5 hours of boiling, the solution was concentrated and the resulting oil triturated with ether, getting mentioned in the title compound as a solid (680 mg, 90%).

1H NMR (CDCl3): 3.08 (s, 6N); 3.86 (s, 3H); 3,91 (s, 3H); 6.48 (s, 1H); 6.94 (s, 1H); 7.58 (s, 1H).

MS ES+: 234 (M+N)+

The connection 200

A mixture of amidine In (1.4 g, 6 mmol), ethyl-2-amino-4-thiazoleacetate (1.4 g, 7.5 mmol) in acetic acid (14 ml) was heated at 130°C for 3 hours. The solvent was removed in vacuo, the residue triturated with ethanol (5 ml) and a solution of NaHCO3(pH 8) for 10 minutes. The solid was isolated by filtration, washed with water, dissolved in CH2Cl2and was dried over MgSO4·CH2Cl2, evaporated, the remaining oil is triturated with ether and petroleum ether, getting mentioned in the title compound (1.8 mg, 80%).

1H NMR (DMSO-d6): 1.2 (t, 3H); 3.74 (s, 2H); 3.95 (s, 6N); 4.1 (q, 2H); 7.02 (s, 1H); 7.26 (s, 1H); 8.14 (s, 1H); 8.68 (s, 1H).

Connection 201

Ester 200 (1.8 g, 4.8 mmol) was injected into the interaction with 2 N. NaOH (4.8 ml, 9.6 mmol) in ethanol (20 ml) at room temperature for 2 hours. The mixture was cooled to room temperature, acidified EtOH, HCl (2 BC) to pH 3. Mixing the OS is Westley within 15 minutes and was isolated by filtration yellow solid - specified in the title compound (1.7 g, 100%).

1H NMR (DMSO-d6): 3.71 (s, 2H); 3.96 (s, 3H); 3.97 (s, 3H); 7.11 (s, 1H); 7.28 (s, 1H); 8.3 (user, 1H); 8.88 (s, 1H).

Synthesis of amide with, the General procedure

Acid 201 (86,5 mg, 0.25 mmol) in DMF (1 ml) was injected into the interaction with various amines (2.6 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)N,N,N',N'-tetramethylurea (98 mg, 0.26 mmol), DIEA (33 mg, 0.26 mmol) at room temperature for 0.5 hours. To the mixture was added a solution of NaHCO3(1 ml) and water (7 ml). The mixture was left overnight, and then the precipitation was isolated by filtration, washed with water and dried under vacuum in the presence of P2About5receiving the connection formulas listed below.

Example 1

Using the reaction described in General scheme 1, from 4-aminomethylpyridine (27 mg, 0.25 mmol), obtained compound No. 1 in table 1 (50 mg, 46%).

1H NMR (DMSO-d6): 3.64 (s, 2H); 3.95 (s, 3H); 3.96 (s, 3H); 4.32 (d, 2H); 6.98 (s, 1H); 7.26 (m, 3H); 8.15 (s, 1H); 8.49 (m, 3H); 8.68 (s, 1H).

Example 2

By a reaction similar to that described in General scheme 1, based on the research (23 mg, 0.26 mmol), obtained compound No. 2 in table 1 (70 mg, 67%).

1H NMR (DMSO-d6, TFA): 3.55 (user m, 8H); 3.88 (s, 2H); 3.97 (s, 3H); 4.0 (s, 3H); 7.15 (s, 1H); 7.27 (s, 1H); 7.92 (s, 1H); 9.07 (s, 1H).

Example 3

By a reaction similar to that described in General scheme 1, from 4-foronline (29 mg, 0.26 mmol), obtained compounds is their No. 3 in table 1 (75 mg, 68%).

1H NMR (DMSO-d6): 3.74 (s, 2H); 3.93 (s, 6N); 7.00 (s, 1H); 7.15 (t, 2H); 7.25 (s, 1H); 7.64 (m, 2H); 8.12 (s, 1H); 8.67 (s, 1H); 10.20 (s, 1H).

MS ES+: 440 (M+N)+

Example 4

By a reaction similar to that described in General scheme 1, based on N,N-dimethyl-1,4-phenylenediamine (35 mg, 0.26 mmol), obtained compound 4 in table 1 (65 mg, 56%).

1H NMR (DMSO-d6, TFA): 3.2 (s, 6N); 3.9 (s, 2H); 3.97 (s, 3H); 4.0 (s, 3H); 7.27 (s, 1H); 7.3 (s, 1H); 7.65 (d, 2H); 7.8 (d, 2H); 7.99 (s, 1H).

MS ES+: 465 (M+N+)

Example 5

By a reaction similar to that described in General scheme 1, from 4-methoxyaniline (32 mg, 0.26 mmol), obtained compound 5 in table 1 (80 mg, 71%).

1H NMR (DMSO-d6): 3.71 (s, 5H); 3.93 (s, 3H); 3.94 (s, 3H); 6.88 (d, 2H); 6.99 (s, 1H); 7.25 (s, 1H); 7.53 (d, 2H); 8.13 (s, 1H); 8.67 (s, 1H); 9.99 (s, 1H).

MS ES+: 452 (M+N+)

Example 6

By a reaction similar to that described in General scheme 1, starting from 5-methoxy-2-methylaniline (36 mg, 0.26 mmol), obtained compound 6 in table 1 (87 mg, 75%).

1H NMR (DMSO-d6): 2.13 (s, 3H); 3.69 (s, 3H); 3.81 (s, 2H); 3.96 (s, 6N); 6.65 (m, 1H); 7.05 (m, 1H); 7.09 (d, 1H); 7.21 (s, 1H); 7.26 (s, 1H); 8.13 (s, 1H); 8.68 (s, 1H); 9.3 (s, 1H).

MS ES+: 466 (M+N+)

Example 7

By a reaction similar to that described in General scheme 1, based on dimethylacetal of aminoacetaldehyde (27 mg, 0.26 mmol), obtained compound 7 in table 1 (80 mg, 74%).

1H NMR (DMSO-d6): 3.2 (t, 1H); 3.29 (s, 3H); 3.31 (s, 3H); 3.55 (s, 2H); 3.94 (s, 6N); 4.37 (who, 1H); 6.92 (s, 1H); 7.26 (s, 1H); 8.02 (t, 1H); 8.14 (s, 1H); 8.67 (s, 1H).

MS ES+: 434 (M+N+)

Example 8

By a reaction similar to that described in General scheme 1, based on 3-formatlarina (42 mg, 0.26 mmol), obtained compound 8 in table 1 (72 mg, 59%).

1H NMR (DMSO-d6): 3.80 (s, 2H); 3.93 (s, 3H); 3.94 (s, 3H); 7.04 (s, 1H); 7.26 (s, 1H); 7.41 (d, 1H); 7.55 (t, 1H); 7.81 (d, 1H); 8.13 (s, 1H); 8.69 (s, 1H); 10.50 (s, 1H).

MS ES+: 490 (M+N+)

Example 9

By a reaction similar to that described in General scheme 1, based on N-methylpiperazine (26 mg, 0.26 mmol), obtained compound 9 in table 1 (65 mg, 61%).

1H NMR (DMSO-d6): 2.73 and 2.77 (TT, 4H); 2.86 and 3.10 (SS, 3H); 3.56 and 3.74 (TT, 4H); 3.79 and 3.84 (SS, 2H); 3.95 (s, 6N); 6.95 (m, 1H); 7.26 (s, 1H); 8.14 (s, 1H); 8.68 (s, 1H).

MS ES+: 429 (M+N+)

Example 10

By a reaction similar to that described in General scheme 1, based on 2-methoxyethylamine (20 mg, 0.26 mmol), obtained compound 10 in table 1 (68 mg, 67%).

1H NMR (DMSO-d6): 3.25 (s, 3H); 3.3 (m, 6N); 3.54 (s, 2H); 3.94 (s, 6N); 6.92 (s, 1H); 7.26 (s, 1H); 8.0 (t, 1H); 8.14 (s, 1H); 8.67 (s, 1H).

MS ES+: 404 (M+N+)

Example 11

By a reaction similar to that described in General scheme 1, based on 2-(2-amino-ethyl)-N-methylpyrrole (32 mg, 0.26 mmol), obtained compound 11 in table 1 (93 mg, 82%).

1H NMR (DMSO-d6): 3.3 (m, 4H); 3.5 (s, 2H); 3.94 (s, 6N); 5.78 (s, 1H); 5.84 (m, 1H); 6.58 (s, 1H); 6.89 (s, 1H); 7.24 (s, 1H); 8.01 (t, 1H); 8.13 (s, 1H); 8.66 (s, 1H).

MS ES+: 453 (M+N+)

Example 12

By a reaction similar to that described in General scheme 1, based on 3-(methylamino)propionitrile (22 mg, 0.26 mmol), obtained compound 12 in table 1 (60 mg, 58%).

1H NMR (DMSO-d6): 2.15 (s, 3H); 3.45 (m, 4H); 3.77 (s, 2H); 3.96 (s, 6N); 6.91 (s, 1H); 7.25 (s, 1H); 8.14 (s, 1H); 8.67 (s, 1H).

MS ES+: 413 (M+N+)

Example 13

By a reaction similar to that described in General scheme 1, from 4-forbindelsen (33 mg, 0.26 mmol), obtained compound 13 in table 1 (81 mg, 81%).

1H NMR (DMSO-d6): 3.59 (s, 2H); 3.95 (m, 6N); 4.27 (d, 2H); 6.94 (s, 1H); 7.15 (m, 2H); 7.26 (s, 1H); 7.31 (m, 2H); 7.95 (s, 1H); 8.14 (s, 1H); 8.41 (t, 1H); 8.67 (s, 1H).

MS ES+: 454 (M+N+)

Example 14

By a reaction similar to that described in General scheme 1, from 4-hydroxypiperidine (26 mg, 0.26 mmol), obtained compound 14 in table 1 (86 mg, 80%).

1H NMR (DMSO-d6): 1.21 (m, 2H); 1.65 (m, 2H); 3.02 (m, 1H); 3.16 (m, 1H); 3.65 (m, 1H); 3.78 (m, 3H); 4.71 (d, 1H); 6.91 (s, 1H); 7.26 (s, 1H); 8.14 (s, 1H); 9.67 (s, 1H).

MS ES+: 430 (M+N+)

Example 15

By a reaction similar to that described in General scheme 1, based on 3-aminoacetophenone (35 mg, 0.26 mmol), obtained compound 15 in table 1 (92 mg, 79%).

1H NMR (DMSO-d6): 2.59 (s, 3H); 3.78 (s, 2H); 3.90 (s, 3H); 3.93 (s, 3H); 7.02 (s, 1H); 7.26 (s, 1H); 7.47 (t, 1H); 7.67 (d, 1H); 8.12 (s, 1H); 8.2 (s, 1H); 8.68 (s, 1H); 10.36 (s, 1H).

MS ES+: 464 (M+N+)

Example 16

By a reaction similar to that described in General scheme 1, based on 3,5-di is cornilia (34 mg, 0.26 mmol), obtained compound 16 in table 1 (71 mg, 64%).

1H NMR (DMSO-d6, TFA): 3.90 (s, 2H); 3.93 (s, 3H); 3.97 (s, 3H); 6.89 (m, 1H); 7.27 (s, 1H); 7.29 (s, 1H); 7.35 (m, 2H); 7.96 (m, 1H); 9.10 (s, 1H).

MS ES+: 458 (M+N+)

Example 17

By a reaction similar to that described in General scheme 1, based on 3-cyanoaniline (31 mg, 0.26 mmol), obtained compound 17 in table 1 (90 mg, 84%).

MS ES+: 447 (M+H)+

Example 18

By a reaction similar to that described in General scheme 1, based on 2-foronline (29 mg, 0.26 mmol), obtained compound 18 in table 1 (86 mg, 82%).

MS ES+: 440 (M+H)+

Example 19

By a reaction similar to that described in General scheme 1, from 3-(1-hydroxyethyl)aniline (36 mg, 0.26 mmol), obtained compound 19 in table 1 (92 mg, 82%).

MS ES+: 466 (M+H)+

Example 20

By a reaction similar to that described in General scheme 1, based on 2,3-diferencia (34 mg, 0.26 mmol), obtained compound 20 in table 1 (51 mg, 47%).

1H NMR (DMSO-d6, TFA): 3.98 (s, 3H); 4.01 (s, 3H); 4.03 (s, 2H); 7.19 (m, 2H); 7.27 (s, 1H); 7.29 (s, 1H); 7.73 (m, 1H); 7.99 (s, 1H); 9.11 (s, 1H).

MS ES+: 458 (M+N+)

Example 21

By a reaction similar to that described in General scheme 1, based on 2-methyl-4-foronline (33 mg, 0.26 mmol), obtained compound 21 in table 1 (94 mg, 86%).

MS ES+: 454 (M+H)+

Example 22

By a reaction similar to that described in General scheme 1, from 2-fluoro-3-Chloroaniline 38 mg, 0.26 mmol), received the connection 22 in table 1 (60 mg, 53%).

1H NMR (DMSO-d6, TFA): 3.95 (s, 3H); 3.98 (s, 3H); 4.01 (s, 2H); 7.20 (m, 1H); 7.24 (s, 1H); 7.26 (s, 1H); 7.31 (m, 1H); 7.88 (m, 1H); 7.96 (s, 1H); 9.08 (s, 1H).

MS ES+: 474 (M+H)+

Example 23

By a reaction similar to that described in General scheme 1, from 2,5-diferencia (34 mg, 0.26 mmol), obtained compound 23 in table 1 (52 mg, 48%).

1H NMR (DMSO-d6, TFA): 3.97 (s, 3H); 4.00 (s, 2H); 4.01 (s, 3H); 6.97 (m, 1H); 7.26 (s, 1H); 7.29 (s, 1H); 7.33 (m, 1H); 7.94 (m, 1H); 7.98 (s, 1H); 9.11 (s, 1H).

MS ES+: 458 (M+H)+

Example 24

By a reaction similar to that described in General scheme 1, based on 3-aminobenzamide (36 mg, 0.26 mmol), obtained compound 24 in table 1 (94 mg, 84%).

MS ES+: 465 (M+H)+

Example 25

By a reaction similar to that described in General scheme 1, from 4-aminophenol (29 mg, 0.26 mmol), obtained compound 25 in table 1 (89 mg, 84%).

1H NMR (DMSO-d6, TFA): 3.81 (s, 2H); 3.97 (s, 3H); 4.00 (s, 3H); 6.71 (d, 2H); 7.23 (s, 1H); 7.27 (s, 1H); 7.40 (d, 2H); 7.95 (s, 1H); 9.09 (s, 1H).

MS ES+: 438 (M+H)+

Example 26

By a reaction similar to that described in General scheme 1, from 2-fluoro-5-methylaniline (33 mg, 0.26 mmol), obtained compound 26 in table 1 (88 mg, 81%).

MS ES+: 454 (M+H)+

Example 27

By a reaction similar to that described in General scheme 1, from 2-bromo-4-foronline (50 mg, 0.26 mmol), obtained compound 27 in table 1 (68 mg, 55%).

1H NMR (DMSO-d6, TFA): 3.89 (s, 2H); 3.94 (s, 3H); 3.97 (s, 3H); 7.21 (m, 1H); 7.25 (s, 1H); 7.6 (s, 1H); 7.61 (m, 1H); 7.92 (m, 1H); 7.95 (s, 1H); 9.07 (s, 1H).

MS ES+: 518, 520 (M+H)+

Example 28

By a reaction similar to that described in General scheme 1, based on 3,4-diferencia (34 mg, 0.26 mmol), obtained compound 28 in table 1 (81 mg, 74%).

MS ES+: 458 (M+H)+

Example 29

By a reaction similar to that described in General scheme 1, based on isonipecotamide (34 mg, 0.26 mmol), obtained compound 29 in table 1 (96 mg, 88%).

MS ES+: 457 (M+H)+

Example 30

By a reaction similar to that described in General scheme 1, from 4-triphtalocyaninine (47 mg, 0.26 mmol), obtained compound 30 in table 1 (105 mg, 87%).

MS ES+: 506 (M+H)+

Example 31

By a reaction similar to that described in General scheme 1, starting from 5-amino-2-methoxypyridine (33 mg, 0.26 mmol), obtained compound 31 in table 1 (86 mg, 79%).

MS ES+: 453 (M+H)+

Example 32

By a reaction similar to that described in General scheme 1, from 2,4-diferencia (34 mg, 0.26 mmol), obtained compound 32 in table 1 (81 mg, 74%).

MS ES+: 458 (M+H)+

Example 33

By a reaction similar to that described in General scheme 1, based on the hydrochloride of 4-aminotetraline (43 mg, 0.26 mmol), obtained compound 33 in table 1 (84 mg, 77%).

MS ES+: 454 (M+H)+

Example 34

By the reaction, similar opisannoi General scheme 1, based on 3-aminopyridine (25 mg, 0.26 mmol), obtained compound 34 in table 1 (101 mg, 100%).

MS ES+: 423 (M+H)+

Example 35

By a reaction similar to that described in General scheme 1, from 4-Chloroaniline (34 mg, 0.26 mmol), received the connection 35 in table 1 (109 mg, 100%).

MS ES+: 456, 458 (M+H)+

Example 36

By a reaction similar to that described in General scheme 1, based on pyrrolidine (19 mg, 0.26 mmol), obtained compound 36 in table 1 (33 mg, 35%).

MS ES+: 400 (M+H)+

Example 37

By a reaction similar to that described in General scheme 1, based on 3-methoxyaniline (33 mg, 0.26 mmol), received the connection 37 in table 1 (94 mg, 87%).

1H NMR (DMSO-d6, TFA): 3.72 (s, 3H); 3.87 (s, 2H); 3.96 (s, 3H); 4.0 (s, 3H); 6.64 (m, 1H); 7.14 (d, 1H); 7.21 (d, 1H); 7.22 (s, 1H); 7.24 (s, 1H); 7.27 (s, 1H); 7.95 (s, 1H); 9.09 (s, 1H).

MS ES+: 452 (M+H)+

Example 38

By a reaction similar to that described in General scheme 1, based on 3-hydroxy-4-methoxyaniline (37 mg, 0.26 mmol), obtained compound 38 in table 1 (95 mg, 85%).

MS ES+: 468 (M+H)+

Example 39

By a reaction similar to that described in General scheme 1, based on 3-nitroaniline (36 mg, 0.26 mmol), obtained compound 39 in table 1 (87 mg, 78%).

MS ES+: 467 (M+H)+

Example 40

By a reaction similar to that described in General scheme 1, from 1-methyl-3-nitroaniline (40 mg, 0.26 mmol), obtained compound 40, table 1 (50 mg, 44%.

MS ES+: 481 (M+H)+

Example 41

By a reaction similar to that described in General scheme 1, based on 2-anilinomethyl (36 mg, 0.26 mmol), received the connection 41 in table 1 (45 mg, 41%).

MS ES+: 466 (M+H)+

Example 42

By a reaction similar to that described in General scheme 1, from 4-triptorelin (43 mg, 0.26 mmol), received the connection 42 in table 1 (86 mg, 73%).

MS ES+: 490 (M+H)+

Example 43

By a reaction similar to that described in General scheme 1, based on 3-amino-6-chloropyridine (33 mg, 0.26 mmol), received the connection 43 in table 1 (90 mg, 82 %).

1H NMR (DMSO-d6, TFA): 3.92 (s, 2H); 3.96 (s, 3H); 4.0 (s, 3H); 7.27 (s, 1H); 7.28 (s, 1H); 7.46 (d, 1H); 7.98 (s, 1H); 8.1 (d, 1H); 9.1 (s, 1H).

MS ES+: 457, 459 (M+H)+

Example 44

By a reaction similar to that described in General scheme 1, from 2-methoxy-5-Chloroaniline (42 mg, 0.26 mmol), received the connection 44 in table 1 (90 mg, 77%).

MS ES+: 486, 488 (M+H)+

Example 45

By a reaction similar to that described in General scheme 1, based on 2-methylaminoethanol (20 mg, 0.26 mmol), obtained compound 45 in table 1 (83 mg, 86%).

MS ES+: 404 (M+H)+

Example 46

By a reaction similar to that described in General scheme 1, based on 4-aminopyridine (25 mg, 0.26 mmol), obtained compound 46 in table 1 (101 mg, 100%).

MS ES+: 423 (M+H)+

Example 47

By a reaction similar to that described in General scheme 1 based on 3-methyl-4-bromoaniline (49 mg, 0.26 mmol), obtained compound 47 in table 1 (120 mg, 97%).

MS ES+: 516, 517 (M+H)+

Example 48

By a reaction similar to that described in General scheme 1, from 2-chloro-5-methoxyaniline (42 mg, 0.26 mmol)was received by the connection 48 in table 1 (65 mg, 56%).

1H NMR (DMSO-d6, TFA): 3.73 (s, 2H); 3.98 (m, N); 6.78 (m, 1H); 7.28 (s, 2H); 7.39 (d, 1H); 7.50 (d, 1H); 7.98 (s, 1H); 9.10 (s, 1H).

MS ES+: 486, 488 (M+H)+

Example 49

By a reaction similar to that described in General scheme 1, from 4-aminotoluene (28 mg, 0.26 mmol), obtained compound 49 in table 1 (89 mg, 85%).

MS ES+: 436 (M+H)+

Example 50

By a reaction similar to that described in General scheme 1, based on the R(-)-2-pyrrolidineethanol (27 mg, 0.26 mmol), received the connection 50 in table 1 (81 mg, 78%).

MS ES+: 430 (M+H)+

Example 50A

The connection 202

Amicin In (117 mg, 0.5 mmol) in acetic acid (12 ml) was injected into the interaction with ethyl-2-amino-4-methylthiazole-5-carboxylate (112 mg, 0.6 mmol) at 130°C for 3 hours. The solvent is evaporated, the residue was dissolved in ethanol and was stirred for 10 minutes with a solution of NaHCO3. The solid was isolated by filtration, washed with water, ether and dried in vacuum, obtaining mentioned in the title compound as a yellow solid (157 mg, 84%).

1H NMR (DMSO-d6): 1.31 (t, 3H); 2.6 (who, 3H); 3.96 (s, 6N); 4.27 (q, 2H); 7.28 (s, 1H); 8.11 (s, 1H); 8.77 (s, 1H).

MS ES+: 375 (M+H)+

The General scheme 2

Connection E

Vanilla or 30.4 g, 0.2 mol) was dissolved in DMF (200 ml) in the presence of K2CO3at 50°C. for 30 minutes, N-(3-chloropropyl)morpholine was slowly added to the mixture which was heated over night at 80°C. the Resulting KCl was removed by filtration, the solvent evaporated and the resulting orange oil was dissolved in AcOEt, washed twice with water, dried over MgSO4, filtered and concentrated. The oil obtained crystallizes, giving specified in the title compound as a white solid (45.6 g, 82%).

1H NMR (DMSO-d6, TFA): 2.22 (m, 2H); 3.13 (t, 2H); 3.32 (t, 2H); 3.52 (d, 2H); 3.67 (t, 2H); 3.84 (s, 3H); 4.02 (d, 2H); 4.18 (t, 2H); 7.20 (d, 1H); 7.43 (d, 1H); 7.58 (d, 1H); 9.90 (s, 1H).

MS ES+: 280 (M+H)+

Connection F

To a solution of sodium acetate (3.3 g, 40 mmol) and hydroxylamine hydrochloride (2.8 g, 40 mmol) in acetic acid (25 ml) was added the aldehyde E (5.6 g, 20 mmol). The mixture is boiled for 18 hours, cooled, diluted with water and was extracted with methylene chloride, dried over MgSO4was filtered , concentrated, getting mentioned in the title compound (5.1 g, 93%).

1H NMR (DMSO-d6, TFA): 2.19 (m, 2H); 3.12 (t, 2H); 3.29 (t, 2H); 3.50 (d, 2H); 3.67 (t, 2H); 3.81 (s, 3H); 4.01 (d, 2H); 4.15 (t, 2H); 7.12 (d, 1H); 7.9 (s, 1H); 7.41 (d, 1H).

MS ES+: 277 (M+H)+

Connection G

To a solution of nitric acid (d=1,42) (180 ml) was added nitrile F (37,2 g, 135 mmol) in acetic acid (100 ml) at such a rate that the temperature was kept below 30°C. the Mixture was stirred at room temperature overnight. To the solution was slowly added a solution of potassium hydroxide (10h, 370 ml) at 0°With, leading to a final pH of 11-12. The reaction mixture was extracted with CH2Cl2, the organic phase was dried over MgSO4was filtered , evaporated, receiving a yellow solid, which was washed with ether, dried, obtaining mentioned in the title compound (22 g, 50%).

1H NMR (DMSO-d6, TFA): 2.22 (m, 2H); 3.13 (t, 2H); 3.3 (t, 2H); 3.53 (d, 2H); 3.67 (t, 2H); 3.99 (s, 3H); 4.01 (d, 2H); 4.31 (t, 2H); 7.74 (s, 1H); 7.90 (s, 1H).

Connection N

Compound G (21 g, 65 mmol) in a solution of CH2Cl2(250 ml) was injected into interaction with the Hydrosulphite solution of sodium (92 mg, 458 mmol) in water (250 ml) in the presence of tetrabutylammonium chloride (12.7 g, with 45.8 mmol) at room temperature over night. After this was added sodium hydroxide (2 BC) and the reaction was extracted with a mixture of CH2Cl2, the organic phase is washed with water, dried over MgSO4was filtered , evaporated. The residue was purified by chromatography on silica gel, eluent: AcOEt/CH2Cl2:50:50, then MeOH/AcOEt/CH2Cl25/45/50, recip what I mentioned in the title compound (12.5 g, 66%).

1H NMR (DMSO-d6, TFA): 2.2 (m, 2H); 3.13 (t, 2H); 3.31 (t, 2H); 3.53 (d, 2H); 3.68 (t, 2H); 3.71 (s, 3H); 4.05 (m, 4H); 6.56 (s, 1H); 7.02 (s, 1H).

MS ES+: 292 (M+H)+

Compound J

Aminonitriles N (only 2.91 g, 10 mmol) in a solution of toluene (50 ml) was administered in cooperation with dimethylacetal N,N-dimethylformamide (1,79 g, 15 mmol) at 105°C for 5 hours in a flask equipped with a nozzle Dean-stark. The solvent is evaporated, the residue triturated with ether, getting mentioned in the title compound (3.4 g, 98%).

1H NMR (DMSO-d6, TFA): 1.87 (m, 2H); 2.36 (m, 6N); 2.95 (s, 3H); 3.04 (s, 3H); 3.56 (t, 4H); 3.72 (s, 3H); 4.06 (t, 2H); 6.72 (s, 1H); 7.07 (s, 1H); 7.89 (s, 1H).

MS ES+: 347 (M+H)+

Connection 203

Amidin J (173 mg, 0.5 mmol) was dissolved in Asón (1.7 ml) in the presence of ethyl-2-amino-4-methylthiazole-5-carboxylate (112 mg, 0.6 mmol) and was heated at 130°C for 3 hours. The solvent was removed by evaporation and the remaining solid was stirred in ethanol and diluted solution of NaHCO3within 10 minutes. The solid is washed with water, dried in vacuum over P2About5getting yellow powder specified in the title compound (170 mg, 70%).

1H NMR (DMSO-d6, TFA): 1.32 (t, 3H); 2.30 (m, 2H); 2.68 (s, 3H); 3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.99 (s, 3H); 4.03 (d, 2H); 4.32 (m, 4H); 7.38 (s, 1H); 8.01 (s, 1H); 9.26 (s, 1H).

MS ES+: 488 (M+H)+

Connection 204

Ester 203 (122 mg, 0.25 mm is l) suspended in ethanol (5 ml) and was introduced in the interaction with sodium hydroxide (10 N., 0.5 ml) at 80°C for 1 hour. The reaction mixture was cooled, acidified (pH 3.5), the yellow precipitate was filtered, washed with water, dried in vacuum, obtaining mentioned in the title compound (100 mg, 87%).

1H NMR (DMSO-d6, TFA): 2.32 (m, 2H); 2.62 (s, 3H); 3.16 (t, 2H); 3.36 (t, 2H); 3.57 (d, 2H); 3.71 (t, 2H); 3.99 (s, 3H); 4.03 (d, 2H); 4.33 (t, 2H); 7.35 (s, 1H); 7.98 (s, 1H); 9.23 (s, 1H).

MS ES+: 460 (M+H)+

The General scheme 3

Connection 205

Amidin J (2,08 g, 6 mmol) was injected into the interaction with ethyl 2-amino-4-thiazoleacetate (1,34 g, 7.2 mmol) in acetic acid (2 ml) at 130°C for 4 hours in argon atmosphere. The solvent is evaporated, the obtained residue oil triturated with ether/petroleum ether and was filtered solid. This solid is suspended in water at pH 9 (NaHCO3) and was extracted with CH2Cl2, dried, evaporated, getting mentioned in the title compound (2 g, 68%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 3.87 (s, 2H); 4.0 (s, 3H); 4.04 (d, 2H); 4.15 (q, 2H); 4.31 (t, 2H); 7.28 (s, 1H); 7.34 (s, 1H); 8.06 (s, 1H); 9.15 (s, 1H).

MS ES+: 488 (M+H)+

The connection 206

Ester 205 (2 g, 4.1 mmol) suspended in ethanol (20 ml). To this suspension, which was stirred for 3 hours at room temperature, was added 2 n sodium hydroxide (4,1 ml, 8.2 mmol). To dissolve the have added 2 N. HCl, the yellow precipitate was filtered, washed with water, ethanol, ether and dried in vacuum, obtaining mentioned in the title compound (1.98 g, 99%).

1H NMR (DMSO-d6, TFA): 2.31 (m, 2H); 3.16 (t, 2H); 3.55 (d, 2H); 3.71 (t, 2H); 3.79 (s, 2H); 4.0 (s, 3H); 4.03 (d, 2H); 7.25 (s, 1H); 7.34 (s, 1H); 8.01 (s, 1H); 9.12 (s, 1H).

MS ES+: 460 (M+H)+

Synthesis of amides To, the General procedure

Acid 206 (83 mg, 0,17 mmol) in DMF (0.8 ml) was injected into interaction with the amine (0,17 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)N,N,N',N'-tetramethylurea (78 mg, 0,204 mmol), DIEA (52 mg, 0.4 mmol) for 6 hours at room temperature. After the reaction mixture was treated with a solution of NaHCO3(6 ml) under stirring for 2 hours, washed with water, cooled to 5°and the solid was filtered, triturated with ether, dried in vacuum over P2About5getting listed in the connection header.

Example 51

By a reaction similar to that described in General scheme 3, on the basis of aniline (19 mg, 0.2 mmol), received the connection 51 table 2 (73 mg, 81%).

1H NMR (DMSO-d6, TFA): 2.29 (m, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.88 (s, 2H); 3.98 (s, 3H); 4.03 (d, 2H); 4.3 (t, 2H); 7.09 (t, 1H); 7.27 (s, 1H); 7.33 (m, 3H); 7.63 (d, 2H); 7.99 (s, 1H); 9.12 (s, 1H).

MS ES+: 353 (M+H)+

Example 52

The reaction similar to the reaction described in General scheme 3, from 4-foronline (23 mg, 0.2 mmol), Paul is the beginning of the connection 52 table 2 (79 mg, 84%).

1H NMR (DMSO-d6, TFA): 2.29 (m, 2H); 3.15 (t, 2H); 3.34 (t, 2H); 3.54 (d, 2H); 3.67 (t, 2H); 3.87 (s, 2H); 3.98 (s, 3H); 4.02 (d, 2H); 4.3 (t, 2H); 7.17 (t, 2H); 7.27 (s, 1H); 7.32 (s, 1H); 7.63 (m, 2H); 7.99 (s, 1H); 9.11 (s, 1H).

MS ES+: 553 (M+H)+

Example 53

By a reaction similar to that described in General scheme 3, from 4-dimethylaminopyridine (28 mg, 0.2 mmol), received the connection 53 table 2 (52 mg, 53%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.19 (s, 6N); 3.34 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.91 (s, 2H); 3.98 (s, 3H); 4.03 (d, 2H); 4.30 (t, 2H); 7.28 (s, 1H); 7.33 (s, 1H); 7.64 (d, 1H); 7.77 (d, 1H); 8.01 (s, 1H); 9.12 (s, 1H).

MS ES+: 578 (M+H)+

Example 54

By a reaction similar to that described in General scheme 3, from 4-Chloroaniline (26 mg, 0.2 mmol), received the connection 54 table 2 (72 mg, 75%).

1H NMR (DMSO-d6, TFA): 2.31 (m, 2H); 3.14 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.89 (s, 2H); 3.98 (s, 3H); 4.03 (d, 2H); 4.3 (t, 2H); 7.27 (s, 1H); 7.32 (s, 1H); 7.38 (d, 1H); 7.65 (d, 1H); 8.0 (s, 1H); 9.12 (s, 1H).

MS ES+: 567, 569 (M+H)+

Example 55

By a reaction similar to that described in General scheme 3, based on 3-amino-6-chloropyridine (26 mg, 0.2 mmol)was received by the connection 55 table 2 (80 mg, 83%).

1H NMR (DMSO-d6, TFA): 2.28 (m, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.93 (s, 2H); 3.98 (s, 3H); 4.04 (d, 2H); 4.3 (t, 2H); 7.29 (s, 1H); 7.33 (s, 1H); 7.49 (d, 1H); 8.01 (s, 1H); 8.09 (d, 1H); 8.66 (d, 1H); 9.13 (s, 1H).

MS ES+: 570, 572 (M+H)+

Example 56

In reactions similar to those described in the overall scheme 3, based on the research (18 mg, 0.2 mmol), received the connection 56 in table 2 (14 mg, 16%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.17 (t, 2H); 3.37 (t, 2H); 3.6 (m, N); 3.9 (s, 2H); 3.99 (s, 3H); 4.03 (d, 2H); 4.3 (t, 2H); 7.17 (s, 1H); 7.3 (s, 1H); 7.95 (s, 1H); 9.09 (s, 1H).

MS ES+: 529 (M+H)+

Example 57

By a reaction similar to that described in General scheme 3, based on pyrrolidine (14 mg, 0.2 mmol), received the connection 57 table 2 (73 mg, 84%).

1H NMR (DMSO-d6, TFA): 1.82 (m, 2H); 1.93 (m, 2H); 2.28 (m, 2H); 3.16 (t, 2H); 3.36 (m, 4H); 3.55 (m, 4H); 3.68 (t, 2H); 3.71 (s, 2H); 3.99 (s, 3H); 4.04 (d, 2H); 4.3 (t, 2H); 7.17 (s, 1H); 7.3 (s, 1H); 7.94 (s, 1H); 9.08 (s, 1H).

MS ES+: 513 (M+H)+

Example 58

By a reaction similar to that described in General scheme 3, based on cyclohexylamine (20 mg, 0.2 mmol), received the connection 58 table 2 (80 mg, 87%).

1H NMR (DMSO-d6, TFA): 1.25 (m, 4H); 1.75 (m, 4H); 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.56 (d, 2H); 3.6 (s, 2H); 3.69 (t, 2H); 3.99 (s, 3H); 4.04 (d, 2H); 4.3 (t, 2H); 7.15 (s, 1H); 7.97 (s, 1H); 9.09 (s, 1H).

MS ES+: 541 (M+H)+

The General scheme 4

The connection 2061

Amidin J (1,38 g, 4 mmol) in acetic acid (14 ml) was injected into the interaction with ethyl-2-amino-4-thiazolecarboxamide (0,72 g, 4.2 mmol) at 130°C for 6 hours. The solvent is evaporated, the residue was dissolved in ethanol and mixed with a saturated solution of NaHCO3. The mixture was extracted with CH2Cl2, dried and cleaned is whether chromatography on silica gel, eluent CH2Cl2/Meon 98/2→90/10, getting mentioned in the title compound (0,738 g, 52%).

1H NMR (DMSO-d6, TFA): 1.34 (t, 3H); 2.28 (m, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 4.03 (s, 3H); 4.04 (d, 2H); 4.34 (m, 4H); 7.45 (s, 1H); 8.33 (s, 1H); 8.44 (s, 1H); 9.26 (s, 1H).

MS ES+: 474 (M+H)+

Connection 207

Ester 2061(946 mg, 2 mmol) in suspension in ethanol (20 ml) was treated with sodium hydroxide (6 N., 4 ml) at 75°C for 45 minutes. Then the reaction mixture was cooled to room temperature, acidified (pH 3) using 6 N. HCl. The precipitate was filtered, washed with ethanol, washed with ether, dried in vacuum, obtaining mentioned in the title compound (795 mg, 80%).

1H NMR (DMSO-d6, TFA): 2.34 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.76 (t, 2H); 4.03 (m, 5H); 4.35 (t, 2H); 7.48 (s, 1H); 8.26 (s, 1H); 8.41 (s, 1H); 9.29 (s, 1H).

Synthesis of amides of the General structure M, the General procedure

Acid 207 (79 mg, 0.16 mmol) in DMF (1 ml) was injected into interaction with the amine (0,19 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)N,N,N',N'-tetramethylurea (73 mg, 0,19 mmol), DIEA (52 mg, 0.4 mmol) for 1 hour at room temperature. After the reaction mixture was treated with a solution of NaHCO3(5 ml) with stirring for 0.5 hours, and the solid was filtered, dried in vacuum over P2About5. In the case of compounds that are not wypadaniu sediment the solution was concentrated to dryness, the residues were washed methylene chloride/methanol, was filtered. To a solution of methylene chloride/methanol was added to the alumina and the solvent evaporated. Purification of compounds was carried out by chromatography on alumina, eluent CH2Cl2; CH2Cl2/MeOH: 95/5, getting listed in the connection header.

Example 59

By a reaction similar to that described in General scheme 4, based on the aniline (18 mg, 0,19 mmol), received the connection 59 in table 3 (50 mg, 60%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.03 (d, 2H); 4.05 (s, 3H); 4.34 (t, 2H); 7.14 (t, 1H); 7.39 (t, 2H); 7.45 (s, 1H); 7.8 (d, 2H); 8.29 (s, 1H); 8.41 (s, 1H); 9.29 (s, 1H).

MS ES+: 521 (M+H)+

Example 60

By a reaction similar to that described in General scheme 4, from 4-foronline (21 mg, 0,19 mmol), received the connection 60 in table 3 (70 mg, 82%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.33 (t, 2H); 3.56 (d, 2H); 3.68 (t, 2H); 4.03 (d, 2H); 4.04 (s, 3H); 4.35 (t, 2H); 7.22 (t, 2H); 7.45 (s, 1H); 7.83 (m, 2H); 8.28 (s, 1H); 8.4 (s, 1H); 9.27 (s, 1H).

MS ES+: 539 (M+H)+

Example 61

By a reaction similar to that described in General scheme 4, from 4-Chloroaniline (24 mg, 0,19 mmol), received the connection 61 in table 3 (70 mg, 79%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.68 (t, 2H); 4.04 (m, 5H); 4.35 (t, 2H); 7.45 (m, 3H); 7.84 (d, 2H); 8.29 (s, 1H); 8.4 (s, 1H); 9.27 (s, 1H)./p>

MS ES+: 555, 557 (M+H)+

Example 62

By a reaction similar to that described in General scheme 4, based on cyclohexylamine (19 mg, 0,19 mmol), received the connection 62 table 3 (60 mg, 72%).

1H NMR (DMSO-d6, TFA): 1.32 (m, 5H); 1.62 (m, 1H); 1.73 (m, 2H); 1.87 (m, 2H); 2.33 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.75 (m, 1H); 4.03 (s, 3H); 4.05 (d, 2H); 4.33 (t, 2H); 7.42 (s, 1H); 8.07 (s, 1H); 8.32 (s, 1H); 9.24 (s, 1H).

MS ES+: 527 (M+H)+

Example 63

By a reaction similar to that described in General scheme 4, from 3-(methylamino)-propionitrile (16 mg, 0,19 mmol), obtained compound 63 in table 3 (40 mg, 49%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 2.88 (m, 3H); 3.14 (m, 4H); 3.35 (t, 2H); 3.54 (d, 2H); 3.71 (t, 2H); 3.75 (m, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 7.44 (s, 1H); 7.85 (s, 1H); 8.73 (s, 1H); 9.27 (s, 1H).

MS ES+: 512 (M+H)+

Example 64

By a reaction similar to that described in General scheme 4, from 4-hydroxypiperidine (19 mg, 0,19 mmol), received the connection 64 in table 3 (45 mg, 54 M).

1H NMR (DMSO-d6, TFA): 1.36 (m, 2H); 1.78 (m, 2H); 2.3 (m, 2H); 3.15 (t, 2H); 3.29 (m, 2H); 3.37 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.77 (m, 2H); 3.84 (m, 1H); 4.02 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 7.42 (s, 1H); 7.75 (s, 1H); 8.35 (s, 1H); 9.27 (s, 1H).

MS ES+: 529 (M+H)+

Example 65

By a reaction similar to that described in General scheme 4, from 4-aminopyridine (18 mg, 0,19 mmol)was received by the connection 65 in table 3 (35 mg, 42%).

1H NMR (DMSO-d6, TFA): 1.29 (m, 2H); 3.15 (t, 2H); 3.34 (who, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 4.03 (m, 5H); 4.34 (t, 2H); 7.48 (s, 1H); 8.41 (d, 2H); 8.43 (s, 1H); 8.52 (s, 1H); 8.81 (d, 2H); 9.24 (s, 1H).

MS ES+: 522 (M+H)+

Example 66

By a reaction similar to that described in General scheme 4, from 4-Chloroaniline (24 mg, 0,19 mmol), obtained compound 66 in table 3 (25 mg, 28%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.04 (d, 2H); 4.05 (s, 3H); 4.35 (t, 2H); 7.24 (t, 1H); 7.42 (t, 1H); 7.47 (s, 1H); 7.6 (d, 1H) (M+H)+

The General scheme 5

Connection 208

Amidin J (1.52 g, 4.4 mmol) in Asón (15 ml) was injected into the interaction with ethyl-2-amino-5-thiazolecarboxamide (757 mg, 4.4 mmol) at 130°C in argon atmosphere for 3 hours. The solvent is evaporated, the obtained residue oil was dissolved in methylene chloride and purified by chromatography on silica gel, eluent CH2Cl2CH2Cl2/Meon:95/5, getting mentioned in the title compound as a yellow solid (1.44 g, 70%).

1H NMR (DMSO-d6, TFA): 1.33 (t, 3H); 2.3 (m, 2H); 3.15 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.35 (m, 4H); 7.41 (s, 1H); 8.14 (s, 1H); 8.44 (s, 1H); 9.3 (s, 1H).

MS ES+: 474 (M+H)+

Connection 209

A suspension of ester 208 (1.6 g, 3.4 mmol) in ethanol (32 ml) was injected into the interaction with sodium hydroxide (6 BC, 6 ml) at 75°C for 1 hour. The cooled solution was acidified with HCl (6 BC) to pH 4. Solid substances is the primary objective was filtered, washed with EtOH, ether, dried, obtaining a yellow solid (1.65 g, 86%).

1H NMR (DMSO-d6, TFA): 2.28 (m, 2H); 3.12 (t, 2H); 3.32 (t, 2H); 3.51 (d, 2H); 3.66 (t, 2H); 3.97 (s, 3H); 3.99 (d, 2H); 4.31 (t, 2H); 7.37 (s, 1H); 8.06 (s, 1H); 8.32 (s, 1H); 9.24 (s, 1H).

MS ES+: 446 (M+H)+

Synthesis of amides of the General structure R, the General procedure

Acid 209 (95 mg, 0,17 mmol) in DMF, 1 ml, was injected into interaction with the amine (0.2 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)N,N,N',N'-tetramethylurea (91 mg, 0.24 mmol), DIEA (110 mg, 0.85 mmol) for 14 hours at room temperature and 5 hours at 50°C. After the reaction mixture was treated with a solution of NaHCO3(1 ml) with stirring for 0.5 hour and concentrated. The residue was washed with a mixture of methylene chloride/methanol (1/1, 25 ml). The aluminum oxide was added to the organic phase, which is then evaporated. Purification of compounds was carried out by chromatography on alumina, eluent CH2Cl2CH2Cl2/Meon/95/5, getting listed in the connection header.

Example 67

By a reaction similar to that described in General scheme 5 starting from aniline (19 mg, 0.2 mmol), received the connection 67 table 4 (30 mg, 34%).

1H NMR (DMSO-d6, TFA): 2.31 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 7.14 (t, 1H); 7.39 (m, 3H); 7.73 (d, 2H); 8.05 (s, 1H); 8.61 (s, 1H); 9.28 (s, 1H).

MS ES+: 521 (M+H)+

Por the measures 68

By a reaction similar to that described in General scheme 5 starting from 4-foronline (23 mg, 0.2 mmol), received the connection 68 table 4 (58 mg, 64%).

1H NMR (DMSO-d6, TFA): 2.31 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H); 7.20 (t, 1H); 7.38 (s, 1H); 7.73 (m, 1H); 8.05 (s, 1H); 8.57 (s, 1H); 9.28 (s, 1H).

MS ES+: 539 (M+H)+

Example 69

By a reaction similar to that described in General scheme 5 starting from 4-Chloroaniline (26 mg, 0.2 mmol), obtained compound 69 in table 4 (32 mg, 34%).

1H NMR (DMSO-d6, TFA): 2.32 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.33 (t, 2H); 7.39 (s, 1H); 7.44 (d, 2H); 7.76 (d, 2H); 8.06 (s, 1H); 8.6 (s, 1H); 9.29 (s, 1H).

MS ES+: 555, 557 (M+H)+

Example 70

By a reaction similar to that described in General scheme 5, based on allylamine (12 mg, 0.2 mmol), received the connection 70 table 4 (32 mg, 39%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.7 (t, 2H); 3.92 (d, 2H); 4.0 (s, 3H); 4.03 (d, 2H); 4.33 (t, 2H); 5.16 (d, 1H); 5.25 (d, 1H); 5.9 (m, 1H); 7.38 (s, 1H); 8.02 (s, 1H); 8.36 (s, 1H); 9.24 (s, 1H).

MS ES+: 485 (M+H)+

Example 71

By a reaction similar to that described in General scheme 5 starting from 3-(methylamino)-propionitrile (17 mg, 0.2 mmol), received the connection 71 table 4 (32 mg, 39%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 2.89 (m, 3H); 3.15 (t, 2H); 3.34 (m, 4H); 3.55 (d, 2H); 3.69 (t, 2H); 3.8 (m, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.33 (t, 2H); 7.38 (s, 1H); 8.07 (s, 1H); 8.22 (s, 1H); 9.25 (s, 1 is).

MS ES+: 512 (M+H)+

Example 72

By a reaction similar to that described in General scheme 5 starting from 4-hydroxypiperidine (20 mg, 0.2 mmol), received the connection 72 table 4 (12 mg, 13%).

1H NMR (DMSO-d6, TFA): 1.45 (m, 2H); 1.82 (m, 2H); 2.31 (m, 2H); 3.15 (m, 4H); 3.35 (t, 2H); 3.4 (m, 2H); 3.54 (d, 2H); 3.7 (t, 2H); 3.79 (m, 1H); 4.01 (s, 3H); 4.03 (d, 2H); 4.32 (t, 1H); 7.38(s, 1H); 8.06 (s, 1H); 8.09 (s, 1H); 9.23 (s, 1H).

MS ES+: 529 (M+H)+

Example 73

By a reaction similar to that described in General scheme 5 starting from 4-aminopyridine (19 mg, 0.2 mmol), received the connection 73 table 4 (50 mg, 57%).

1H NMR (DMSO-d6, TFA): 2.29 (m, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.7 (t, 2H); 4.02 (s, 3H); 4.03 (d, 2H); 4.34 (t, 2H); 7.46 (s, 1H); 8.15 (s, 1H); 8.27 (d, 2H); 8.78 (s, 1H); 8.8 (d, 2H); 9.31 (s, 1H).

MS ES+: 522 (M+H)+

The General scheme 6

Connection 210

Amidin J (450 mg, 1.3 mmol) was injected into the interaction with methyl-2-amino-5-methyl-4-thiazoleacetate (242 mg, 1.3 mmol) in acetic acid (5 ml) at 130°C for 3 hours in argon atmosphere. The solvent is evaporated, the obtained residue oil was added ethyl acetate and water, brought the pH to 9 using saturated solution of sodium bicarbonate and was extracted with a mixture of ethyl acetate. The organic phase was washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered, concentrated. The obtained residue is aslo was purified by chromatography on silica gel, eluent CH2Cl2/Meon: from 98/2 to 95/5, getting mentioned in the title compound (380 mg, 60%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 2.35 (s, 3H); 3.15 (t, 2H); 3.34 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.68 (s, 3H); 3.83 (s, 2H); 3.98 (s, 3H); 4.03 (d, 2H); 4.29 (t, 2H); 7.31 (s, 1H); 7.96 (s, 1H); 9.06 (s, 1H).

MS ES+: 488 (M+H)+

Connection 211

Ester 210 (360 mg, of 0.74 mmol) in ethanol was injected into the interaction with sodium hydroxide (6 N., 1 ml) at room temperature for 1 hour. Then cooled to 0°the solution was added HCl (6 BC) and brought the pH to 3-4. The solid was isolated by filtration, washed with ethanol, ether, dried in vacuum, obtaining mentioned in the title compound as hydrochloride (550 mg, 83%).

1H NMR (DMSO-d6, TFA): 2.34 (m, 5H); 3.13 (t, 2H); 3.32 (t, 2H); 3.52 (d, 2H); 3.74 (s, 2H); 3.78 (t, 2H); 3.98 (s, 3H); 4.01 (d, 2H); 4.31 (t, 2H); 7.37 (s, 1H); 7.91 (s, 1H); 9.03 (s, 1H).

MS ES+: 474 (M+H)+

Synthesis of amides of the structure of Q, the General procedure

Acid 211 (87 mg, 0.13 mmol) in DMF (1 ml) was injected into interaction with the amine (0,169 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)N,N,N',N'-tetramethylurea (69 mg, of 0.182 mmol), diisopropylethylamine (84 mg, of 0.65 mmol) overnight at room temperature. The reaction mixture was diluted with water (5 ml) and a concentrated solution of sodium bicarbonate (1 ml). The solid was filtered, washed with water, etano the Ohm, with ether, and dried in vacuum, obtaining listed in the connection header. In the case of compounds, which did not precipitate, the solution was concentrated to dryness, the residues were washed methylene chloride, methanol, filtered. To a solution in methylene chloride/methanol was added to the alumina and the solvent evaporated. Purification of compounds was carried out by chromatography on alumina, eluent CH2Cl2/Meon: from 98/2 to 95/5, getting listed in the connection header.

Example 74

By a reaction similar to that described in General scheme 6, on the basis of aniline (16 mg, 0,17 mmol), received the connection 74 in table 5 (50 mg, 70%).

1H NMR (DMSO-d6, TFA): 2.28 (m, 2H); 2.37 (s, 3H); 3.15 (t, 2H); 3.34 (t, 2H); 3.56 (d, 2H); 3.68 (t, 2H); 3.84 (s, 2H); 3.96 (s, 3H); 4.03 (d, 2H); 4.28 (t, 2H); 7.07 (t, 1H); 7.29 (s, 1H); 7.3 (t, 2H); 7.61 (d, 2H); 7.89 (s, 1H); 9.02 (s, 1H).

MS ES+: 549 (M+H)+

Example 75

By a reaction similar to that described in General scheme 6, from 4-foronline (19 mg, 0,17 mmol), received the connection 75 table 5 (50 mg, 67%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 2.38 (s, 3H); 3.16 (t, 2H); 3.34 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.84 (s, 2H); 3.97 (s, 3H); 4.03 (d, 2H); 4.29 (t, 2H); 7.16 (t, 2H); 7.29 (s, 1H); 7.64 (m, 2H); 7.9 (s, 1H); 9.03 (s, 1H).

MS ES+: 567 (M+H)+

Example 76

By a reaction similar to that described in General scheme 6, from 4-Chloroaniline (22 mg, 0,17 mmol), received the connection 76 table 5 (45 mg, 59%).

1N I Is R (DMSO-d 6, TFA): 2.28 (m, 2H); 2.37 (s, 3H); 3.15 (t, 2H); 3.34 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.85 (s, 2H); 3.97 (s, 3H); 4.03 (d, 2H); 4.29 (t, 2H); 7.29 (s, 1H); 7.37 (d, 2H); 7.65 (d, 2H); 7.9 (s, 1H); 9.03 (s, 1H).

MS ES+: 583 (M+H)+

Example 77

By a reaction similar to that described in General scheme 6, from 4-hydroxypiperidine (17 mg, 0,17 mmol), obtained compound 77 in table 5 (45 mg, 62%).

1H NMR (DMSO-d6, TFA): 1.42 (m, 2H); 1.82 (m, 2H); 2.31 (m, 5H); 3.08 (m, 1H); 3.16 (t, 2H); 3.27 (m, 1H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.78 (m, 2H); 3.83 (s, 2H); 3.92 (m, 1H); 3.97 (s, 3H); 4.03 (d, 2H); 4.29 (t, 2H); 7.28 (s, 1H); 7.85 (s, 1H); 9.0 (s, 1H).

MS ES+: 557 (M+H)+

Example 78

By a reaction similar to that described in General scheme 6, from 4-aminopyridine (16 mg, 0,17 mmol), received the connection 78 in table 5 (35 mg, 49%).

1H NMR (DMSO-d6, TFA): 2.29 (m, 2H); 2.39 (s, 3H); 3.15 (t, 2H); 3.34 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.96 (s, 3H); 4.02 (d, 2H); 4.04 (s, 2H); 4.29 (t, 2H); 7.33 (s, 1H); 7.92 (s, 1H); 8.1 (d, 2H); 8.76 (d, 2H); 9.06 (s, 1H).

MS ES+: 550 (M+H)+

The General scheme 7

Connection U

Aminonitriles N (only 2.91 g, 10 mmol) was injected into interaction with triethylorthoformate (10 ml) in the presence of p-toluenesulfonic acid (38 mg, 2 mmol) at 80°C for 6 hours. The solvent is evaporated, the residue was led from the air, getting mentioned in the title compound (3,01 g, 90.4 percent).

1H NMR (DMSO-d6, TFA): 1.9 (t, 2H); 2.4 (m, 6N); 3.58 (t, 4H); 3.78 (s, 3H); 3.85 (s, 3H); 4.08 (t, 2H); 6.88 (s, 1H); 7.28 (s, 1H); 8.2 (s, 1H).

MS ES+: 334 (M+H)+

Connection V

Imidate U (0.25 g, 0.75 mmol) in CH2Cl2(5 ml) was injected into the interaction with ethyl-2-amino-5-thiophenecarboxylate (0,13 g of 0.79 mmol) in the presence of pyridine hydrochloride (0.09 g, 0.75 mmol) at room temperature over night. After this was added ethyl acetate, and the solid was isolated by filtration, washed with ethyl acetate, dried in vacuum, obtaining the product (0,23 g, 65%).

1H NMR (DMSO-d6, TFA): 1.33 (t, 3H); 2.28 (m, 2H); 3.12 (t, 2H); 3.32 (t, 2H); 3.53 (d, 2H); 3.73 (t, 2H); 3.96 (s, 3H); 4.02 (d, 2H); 4.37 (m, 4H); 7.45 (s, 1H); 7.67 (d, 1H); 7.95 (d, 1H); 8.12 (s, 1H); 8.52 (s, 1H).

MS ES+: 473 (M+H)+

The connection 212

Ester V (1.1 g, 2.3 mmol) in methanol (20 ml) was treated with sodium hydroxide (2 N., 20 ml) at 75°C for 4 hours and at room temperature over night. The methanol is evaporated and kept the remaining aqueous solution for 24 hours at 5°C. the Solid was filtered, washed with water, the mixture Meon/CH2Cl2:1/1, dried in vacuum, obtaining mentioned in the title compound (0.9 g, 87%).

1H NMR (DMSO-d6, TFA): 2.31 (m, 2H); 3.14 (t, 2H); 3.33 (t, 2H); 3.53 (d, 2H); 3.76 (t, 2H); 4.01 (d, 2H); 4.07 (s, 3H); 4.33 (t, 2H); 7.44 (s, 1H); 7.54 (d, 1H); 7.68 (d, 2H); 8.54 (s, 1H); 9.22 (s, 1H).

MS ES+: 445 (M+H)+

Synthesis of amides of the General structure W, the General procedure

Acid 212 (80 mg, 0.18 m is ol) in DMF (1.5 ml) was injected into interaction with the amine (0,216 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)N,N,N',N'-tetramethylurea (80 mg, 0.21 mmol), DIEA (80 μl, 0.46 mmol) for 3 hours at room temperature. Then the reaction mixture was treated with a solution of NaHCO3under stirring for 0.5 hours, the solid was filtered, washed with water, ether and dried in vacuum over P2About5getting listed at the beginning of the connection.

Example 79

By a reaction similar to that described in General scheme 7, on the basis of aniline (17 μl, 0,186 mmol), obtained compound 79 in table 6 (80 mg, 86%).

1H NMR (DMSO-d6, TFA): 2.32 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.53 (d, 2H); 3.69 (t, 2H); 4.01 (d, 2H); 4.03 (s, 3H); 4.3 (t, 2H); 7.7 (t, 1H); 7.32 (m, 4H); 7.73 (d, 2H); 7.98 (d, 1H); 8.18 (s, 1H); 9.22 (s, 1H).

MS ES+: 520 (M+H)+

Example 80

By a reaction similar to that described in General scheme 7, from 4-foronline (24 mg, 0,216 mmol), received the connection 80 in table 6 (62 mg, 64%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 4.05 (m, 5H); 4.33 (t, 2H); 4.21 (t, 2H); 7.33 (d, 1H); 7.4 (s, 1H); 7.77 (m, 2H); 7.98 (d, 1H); 8.2 (s, 1H); 9.25 (s, 1H).

MS ES+: 538 (M+H)+

Example 81

By a reaction similar to that described in General scheme 7, from 3-aminophenol (24 mg, 0,216 mmol), received the connection 81 table 6 (60 mg, 66%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.7 (t, 2H); 4.04 (d, 2H); 4.06 (s, 3H); 4.33 (t, 2H); 6.53 (m, 1H); 7.13 (m, 2H); 7.3 (d, 1H); 7.36 (d, 1H); 7.4 (s, 1H); 7.96 (s, 1H); 8.0 (d, 1H); 8.26 (s, 1H); 9.25 (s, 1H).

MS ES+: 536 (M+H) +

Example 82

By a reaction similar to that described in General scheme 7, from 4-aminopyridine (20 mg, 0,216 mmol), received the connection 82 table 6 (16 mg, 19%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 4.03 (d, 2H); 4.05 (s, 3H); 4.32 (t, 2H); 7.01 (d, 1H); 7.03 (s, 1H); 8.18 (d, 1H); 8.22 (s, 1H); 8.3 (d, 2H); 8.76 (d, 2H); 9.3 (s, 1H).

MS ES+: 521 (M+H)+

Example 83

By a reaction similar to that described in General scheme 7, from 4-amino-1-butanol (19 mg, 0,216 mmol), obtained compound 83 in table 6 (22 mg, 28%).

1H NMR (DMSO-d6, TFA): 1.46 (m, 2H); 1.58 (m, 2H); 2.3 (m, 2H); 3.16 (t, 2H); 3.26 (t, 2H); 3.4 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.04 (m, 5H); 4.32 (t, 2H); 7.26 (d, 1H); 7.39 (s, 1H); 7.7 (d, 2H); 8.19 (s, 1H); 9.21 (s, 1H).

MS ES+: 516 (M+H)+

Example 84

By a reaction similar to that described in General scheme 7, from 3-aminobenzamide (29 mg, 0,216 mmol), received the connection 84 table 6 (60 mg, 77%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.67 (t, 2H); 4.03 (d, 2H); 4.05 (s, 3H); 4.32 (t, 2H); 7.34 (d, 1H); 7.39 (s, 1H); 7.42 (t, 1H); 7.62 (d, 1H); 7.96 (d, 1H); 8.05 (d, 1H); 8.21 (m, 2H); 9.27 (s, 1H).

MS ES+: 563 (M+H)+

Example 85

By a reaction similar to that described in General scheme 7, based on allylamine (12 mg, 0,216 mmol)were specified in the title compound 85 in table 6 (20 mg, 43%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.91 (d, 2H); 4.04 (m, 5H); 4.32 (who, 2H); 5.12 (d, 1H); 5.2 (d, 1H); 5.91 (m, 1H); 7.26 (d, 1H); 7.38 (s, 1H); 7.75 (d, 1H); 8.19 (s, 1H); 9.22 (s, 1H).

MS ES+: 484 (M+H)+

Example 86

By a reaction similar to that described in General scheme 7, based on methyl-4-aminobutyrate (25 mg, 0,216 mmol), received the connection 86 table 6 (18 mg, 23%).

1H NMR: 1.8 (t, 2H); 2.3 (m, 2H); 2.39 (t, 2H); 3.16 (t, 2H); 3.28 (t, 2H); 3.35 (t, 2H); 3.56 (d, 2H); 3.6 (s, 3H); 3.67 (t, 2H); 4.04 (m, 5H); 4.32 (t, 2H); 7.26 (d, 1H); 7.38 (s, 1H); 7.69 (d, 1H); 8.19 (s, 1H); 9.22 (s, 1H).

MS ES+: 544 (M+H)+

The General scheme 8

Connection S

Aminonitriles And (1.78 g, 10 mmol) was treated with trimethylchlorosilane (10 ml) and a catalytic amount of p-toluenesulfonic acid at 100°C for 1 hour. The mixture was cooled to room temperature, was added ethyl acetate and removing insoluble residue by filtration, then the solvent is evaporated, the residue triturated with ether, getting mentioned in the title compound as a yellow solid (1.56 g, 71%).

1H NMR (DMSO-d6): 3.77 (s, 3H); 3.83 (s, 3H); 3.84 (s, 3H); 6.87 (s, 1H); 7.26 (s, 1H); 8.19 (s, 1H).

MS ES+: 221 (M+H)+

Connection 213

Imidate S (0,165 g, 0.75 mmol) was injected into the interaction with ethyl 2-amino-5-thiophenecarboxylate (0,13 g of 0.79 mmol) in methylene chloride (4 ml) in the presence of pyridine hydrochloride (88 mg, 0.75 mmol) at room temperature for 4 hours. The solvent viparis the Lee, and the residue was purified by chromatography on silica gel, eluent: AcOEt/CH2Cl2, 1/1; then Meon/AcOEt/CH2Cl2, 1/4/5, receiving specified in the header of the connection (is 0.135 g, 50%).

1H NMR (DMSO-d6, TFA): 1.33 (t, 3H); 3.95 (s, 3H); 4.03 (s, 3H); 4.38 (q, 2H); 7.43 (s, 1H); 7.67 (d, 1H); 7.95 (d, 1H); 8.05 (s, 1H); 8.52 (s, 1H).

MS ES+: 360 (M+H)+

Connection 214

Ester 213 (72 mg, 0.2 mmol) in methanol (2 ml) was treated with sodium hydroxide (2 ad, 2 ml) at 75°C for 1.5 hours. The reaction mixture was cooled to room temperature and brought the pH to 3 by adding 2 N. HCl. The solid was isolated by filtration, washed with water, dried in vacuum in the presence of P2About5getting listed in the title compound (83 mg, 100%).

1H NMR (DMSO-d6, TFA): 4.02 (s, 3H); 4.04 (s, 3H); 7.38 (s, 1H); 7.42 (d, 1H); 7.68 (d, 1H); 8.35 (s, 1H); 9.21 (s, 1H).

MS ES+: 332 (M+H)+

Example 87

The synthesis of compounds of General formula T, where NRR'=NHPh (Compound 87)

Hinzelin 214 (45 mg, to 0.108 mmol) in DMF (1 ml) was injected into the interaction with aniline (12 μl, 0.13 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)N,N,N',N'-tetramethylurea (50 mg, 0.13 mmol), DIEA (75 μl, 0.43 mmol) for 1.5 hours at room temperature. A saturated solution of sodium bicarbonate (2 ml) was added to the mixture, which was stirred for 0.5 hour. The solid was filtered off, washed with the water and was purified by chromatography on aluminium oxide, eluent from AcOEt/CH2Cl2:1:1 to Meon/AcOEt/CH2Cl2:1/4/5, getting mentioned in the title compound (15 mg, 34%).

1H NMR (DMSO-d6): 3.97 (s, 3H); 4.01 (s, 3H); 7.05 (d, 1H); 7.09 (t, 1H); 7.29 (s, 1H); 7.36 (t, 2H); 7.74 (d, 2H); 7.91 (d, 1H); 7.92 (s, 1H); 8.72 (s, 1H).

MS ES+: 406 (M+H)+

Example 88

Synthesis of compound 88 General formula T, where NRR' represents NHPh (4-F)

By a reaction similar to that described in example 87, based on hintline 213 (60 mg, 0.14 mmol), 4-foronline (17 μl, 0,17 mmol)were specified in the title compound (15 mg, 24%).

1H NMR (DMSO-d6, TFA): 4.04 (s, 3H); 4.06 (s, 3H); 7.18 (t, 2H); 7.32 (d, 1H); 7.35 (s, 1H); 7.75 (t, 2H); 7.98 (d, 1H); 8.17 (s, 1H); 9.23 (s, 1H).

MS ES+: 425 (M+H)+

The General scheme 9

Example 89. Getting connection 250 in table 9

Amidin J (1.04 g, 3 mmol) in acetic acid (10 ml) was injected into interaction with the hydrochloride of methyl 4-amino-1-methyl-2-errorcorrection (686 mg, 3.6 mmol) and dimethylamine in methanol (1.25 M, 2.9 ml, 3.6 mmol) at 130°C for 5.5 hours. The solvent is evaporated, to the residue was added water and aqueous sodium hydrogen carbonate solution, the precipitate was filtered, dried in vacuum over P2About5. The solid was again dissolved in a large volume of tetrahydrofuran, methylene chloride, methanol, the solution was concentrated, the solid was washed with ether, dried,obtaining mentioned in the title compound (1.18 g, 86%).

1H NMR (DMSO-d6, TFA): 2.31 (m, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.8 (s, 3H); 3.95 (s, 3H); 4.01 (s, 3H); 4.03 (d, 2H); 4.29 (t, 2H); 7.26 (d, 1H); 7.32 (s, 1H); 7.69 (d, 1H); 8.06 (s, 1H); 8.94 (s, 1H).

MS ES+: 456 [M+H]+

Example 90. Getting connection 251 table 9

Ester 250 (of 1.34 g, 3 mmol) was treated with sodium hydroxide (6 N., 3 ml) in ethanol (25 ml) at 75°C for 2 hours. Then the solution was cooled to room temperature, acidified to pH 3 using HCl (6 BC), the precipitate was isolated by filtration, washed with ethanol, ether, dried in vacuum, obtaining mentioned in the title compound (636 mg, 42%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.34 (t, 2H); 3.54 (d, 2H); 3.72 (t, 2H); 4.02 (m, 5H); 4.3 (t, 2H); 7.19 (s, 1H); 7.32 (s, 1H); 7.62 (s, 1H); 8.17 (s, 1H); 8.93 (s, 1H).

MS ES+: 428 [M+H]+

Example 91. Synthesis of amides N, the General procedure

Acid 251 (79 mg, 0.15 mmol) in DMF (1 ml) was injected into interaction with hexaphosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (62 mg, 0,165 mmol), corresponding amine (1, 65 mmol) and DIEA (68 mg, 0,525 mmol) at room temperature for 1.5 hours. Then the reaction mixture was diluted with water (4 ml) and aqueous sodium hydrogen carbonate solution (1 ml). The solid was isolated by filtration, re-dissolved in tetrahydrofuran, methylene chloride and then concentrated, precipitated solid was isolated, washed with ether, sushi is whether in vacuum, getting listed at the beginning of the connection.

Example 92. Getting connection 252 table 9

Compound 252 was obtained by reaction

N-hydroxybenzotriazole of ester 251 (56 mg, 0.1 mmol) with aniline (11 mg, 0.12 mmol) in DMF (1 ml) at 105°C for 3 hours. To the cooled reaction mixture was added water, was extracted with a mixture of ethyl acetate, the organic phase is washed with water, dried over MgSO4was filtered and concentrated, obtaining mentioned in the title compound (12 mg, 23%). N-hydroxybenzotriazole ester was obtained as described in the General method of example 91.

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.97 (s, 3H); 4.02 (s, 3H); 4.04 (d, 2H); 4.29 (t, 2H); 7.08 (t, 1H); 7.33 (m, 3H); 7.4 (s, 1H); 7.63 (s, 1H); 7.74 (d, 2H); 8.1 (s, 1H); 8.93 (s, 1H).

MS ES+: 517 [M+H]+

Example 93. Getting connection 253 table 9

By a reaction similar to that described in example 92, but on the basis of 4-foronline (22 mg, of € 0.195 mmol)were specified in the title compound (40 mg, 57%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.72 (t, 2H); 3.97 (s, 3H); 4.02 (s, 3H); 4.04 (d, 2H); 4.3 (t, 2H); 7.18 (t, 2H); 7.34 (s, 1H); 7.4 (d, 1H); 7.63 (d, 1H); 7.76 (m, 1H); 8.11 (s, 1H); 8.94 (s, 1H).

MS ES+: 535 [M+H]+

Example 94. Getting connection 254 in table 9

By a reaction similar to that described in example 92, but on the basis of cyclohexylamine (16 mg, 0,17 mmol who), got mentioned in the title compound (60 mg, 76%).

1H NMR (DMSO-d6, TFA): 1.14 (m, 1H); 1.3 (m, 4H); 1.62 (m, 1H); 1.8 (m, 4H); 2.29 (m, 2H); 3.15 (t, 2H); 3.34 (t, 2H); 3.54 (d, 2H); 3.68 (m, 3H); 3.9 (s, 3H); 4.0 (s, 3H); 4.03 (d, 2H); 4.28 (t, 2H); 7.14 (d, 1H); 7.31 (s, 1H); 7.49 (d, 1H); 8.07 (s, 1H); 8.9 (s, 1H).

MS ES+: 523 [M+H]+

Example 95. The connection is 255 in table 9

By a reaction similar to that described in example 92, but based on N,N-dimethyl-1,4-phenylenediamine (23 mg, 0,17 mmol)were specified in the title compound (61 mg, 73%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.21 (c,6N); 3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.97 (s, 3H); 4.01 (s, 3H); 4.03 (d, 2H); 4.29 (t, 2H); 7.35 (s, 1H); 7.45 (d, 1H); 7.77 (m, 3H); 7.93 (d, 2H); 8.1 (s, 1H); 8.93 (s, 1H).

MS ES+: 560 [M+H]+

The General scheme 10

Example 96. The connection is 256 in table 9

Amidin J (1,38 g, 4 mmol) in acetic acid (14 ml) was injected into the interaction with ethyl 4-amino-2-errorcorrection (0,702 g, 4,56 mmol) at 130°C for 5 hours. The solution was concentrated, the solid was isolated by filtration and washed with ether. Then, this solid was treated with diluted sodium hydrogen carbonate solution, filtered, washed with water and dried in vacuum over P2About5getting listed in the title compound (1,34 g, 73%).

1H NMR (DMSO-d6, TFA): 1.3 (t, 3H); 1.95 (t, 2H); 2.38 (m, 4H); 2.44 (t, 2H); 3.58 (m, 4H); 3.4 (s, 3H); 4.16 (d, 2H); 4.23 (q, 2H); 7.05 (d, 1H); 7.14 (s, 1H); 7.59 (d, 1H); 7.75 (s, 1H); 8.46 (s, 1H); 9.53 (s, 1H); 11.72 (s, 1H).

MS ES+: 456 [M+H]+

Example 961. Getting connection 257 table 9

Ester 256 (1,34 g, 3 mmol) in ethanol (25 ml) was treated with sodium hydroxide (6 N., 3 ml) at 75°C for 2 hours. The solution was cooled and acidified with hydrochloric acid (6 BC) to pH 3. The precipitate was filtered, washed with ethanol, ether, dried in vacuum over P2About5getting listed in the title compound (0,63 g, 42%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.34 (t, 2H); 3.54 (d, 2H); 3.72 (t, 2H); 4.02 (s, 3H); 4.03 (d, 2H); 4.3 (t, 2H); 7.19 (d, 1H); 7.32 (s, 1H); 7.62 (d, 1H); 8.17 (s, 1H); 8.93 (s, 1H).

MS ES+: 428 [M+H]+

Example 97. Getting connection 258 table 9

Acid 257 (75 mg, 0.15 mmol) in DMF (0.7 ml) was injected into interaction with hexaphosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (68, 0.18 mmol), aniline (17 mg, 0.18 mmol) and DIEA (62 mg, 0.48 mmol) at room temperature over night. After the reaction mixture was diluted with a saturated solution of sodium bicarbonate (5 ml) and was stirred for 1 hour. The solid was filtered, washed with water, dried in vacuum over P2About5getting listed in the title compound (30 mg, 40%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.37 (t, 2H); 3.54 (d, 2H); 3.69 (t, 3H); 4.01 (s, 3H); 4.03 d, 2H); 4.31 (t, 2H); 7.08 (t, 1H); 7.35 (m, 3H); 7.46 (d, 1H); 7.56 (d, 1H); 7.77 (d, 1H); 8.1 (s, 1H); 8.93 (s, 1H).

MS ES+: 503 [M+H]+

Example 98. Getting connection 259 table 9

By a reaction similar to that described in example 97, but on the basis of cyclohexylamine (18 mg, 0.18 mmol)were specified in the title compound (30 mg, 39%).

1H NMR (DMSO-d6, TFA): 1.13 (m, 1H); 1.3 (m, 4H); 1.63 (m, 1H); 1.8 (m, 4H); 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.76 (m, 1H); 4.0 (s, 1H); 4.03 (d, 2H); 4.3 (t, 2H); 7.2 (d, 1H); 7.3 (s, 1H); 7.43 (d, 1H); 8.0 (s, 1H); 8.9 (s, 1H).

MS ES+: 509 [M+H]+

The General scheme 11

Example 99. Getting connection 260 table 10

Amidin J (1.04 g, 3 mmol) in acetic acid (10 ml) was injected into interaction with the hydrochloride of ethyl 4-amino-1-methyl-2-imidazolecarboxamide (0.74 g, 3.6 mmol) in the presence of dimethylamine/Meon (1,25 N., 2,9 ml, 3.6 mmol) at 130°C for 3 hours. The solvent is evaporated, the residue triturated with ether and filtered. The solid is suspended in water, brought the pH to 9 using aqueous sodium hydrogen carbonate solution, the suspension was filtered, washed with ether, dried in vacuum over P2About5getting listed in the title compound (1.1 g, 78%).

1H NMR (DMSO-d6, TFA): 1.32 (t, 3H); 1.96 (m, 2H); 2.37 (m, 4H); 2.44 (t, 2H); 3.58 (m, 4H); 3.98 (s, 3H); 4.0 (s, 3H); 4.17 (t, 2H); 4.28 (q, 2H); 7.16 (s, 1H); 7.99 (s, 1H); 8.07 (s, 1H); 8.53 (s, 1H) 10.55 (s, 1H.

Example 100. Getting connection 261 table 10

Ester 260 (1.1 g, 2.34 mmol) in ethanol was injected into the interaction with sodium hydroxide (6 N., 2,3 ml) at 80°C for 2.5 hours. The mixture was cooled and acidified with hydrochloric acid (6 BC) to pH 3. The suspension was isolated by centrifugation, washed with ethanol, ether, dried in vacuum over P2About5getting listed in the title compound (930 mg, 73%).

1H NMR (DMSO-d6, TFA): 2.31 (m, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.76 (t, 2H); 4.01 (s, 3H); 4.05 (m, 5H); 4.32 (t, 2H); 7.41 (s, 1H); 8.03 (s, 1H); 8.38 (s, 1H); 9.0 (s, 1H).

MS ES+: 443 [M+H]+

Example 101. Obtaining compounds of the General structure L

Acid 261 (88 mg, 0.16 mmol) in DMF (1 ml) was injected into interaction with hexaphosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (73 mg, 0,19 mmol), corresponding amine (0.18 mmol) and DIEA (82 mg, 0.4 mmol) at room temperature for 3 hours. Then the solution was diluted with a saturated solution of sodium bicarbonate (4 ml) and stirred at room temperature for 3 hours. The precipitate was filtered, washed with water, dried in vacuum over P2About5getting listed at the beginning of the connection.

Example 102. Getting connection 262 table 10

By a reaction similar to that described in example 101, but on the basis of aniline (17 mg, 0.18 mmol)were specified in the header link is (37 mg, 44%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.02 (m, 5H); 4.06 (s, 3H); 4.31 (t, 2H); 7.13 (t, 1H); 7.38 (m, 3H); 7.78 (d, 2H); 7.99 (s, 1H); 8.27 (s, 1H); 9.01 (s, 1H).

MS ES+: 518 [M+H]+

Example 103. Getting connection 263 table 10

By a reaction similar to that described in example 101, but on the basis of 4-foronline (20 mg, 0.18 mmol)were specified in the title compound (84 mg, 97%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.1 (s, 3H); 4.31 (t, 2H); 7.21 (t, 2H); 7.39 (s, 1H); 7.82 (m, 2H); 7.98 (s, 1H); 8.32 (s, 1H); 9.01 (s, 1H).

MS ES+: 536 [M+H]+

Example 104. Getting connection 264 table 10

By a reaction similar to that described in example 101, but based on N,N-dimethyl-1,4-phenylenediamine (24 mg, 0.18 mmol)were specified in the title compound (80 mg, 88%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.17 (t, 2H); 3.21 (s, 6N); 3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.02 (m, 5H); 4.1 (s, 3H); 4.31 (t, 2H); 7.4 (s, 1H); 7.66 (d, 2H); 7.98 (d, 2H); 8.01 (s, 1H); 8.32 (s, 1H); 9.01 (s, 1H).

MS ES+: 561 [M+H]+

Example 105. Getting connection 265 table 10

By a reaction similar to that described in example 101, but on the basis of 4-Chloroaniline (23 mg, 0.18 mmol)were specified in the title compound (55 mg, 62%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.17 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.1 (s, 3H); 4.32 (t, 2H); 7.39 (s, 1H); 7.43 (d, 2H); 7.84 (d, 2H); 7.99 (1H); 8.32 (s, 1H); 9.01 (s, 1H).

MS ES+: 552, 554 [M+H]+

Example 106. Getting connection 266 table 10

By a reaction similar to that described in example 101, but on the basis of pyrrolidine (13 mg, 0.18 mmol)were specified in the title compound (50 mg, 62%).

1H NMR (DMSO-d6, TFA): 1.85 (m, 4H); 2.28 (m, 2H); 3.15 (t, 2H); 3.32 (t, 2H); 3.5 (m, 4H); 3.66 (t, 2H); 3.89 (m, 5H); 3.98 (m, 5H); 4.27 (t, 2H); 7.33 (s, 1H); 7.85 (s, 1H); 8.29 (s, 1H); 8.96 (s, 1H).

MS ES+: 496 [M+H]+

Example 107. Getting connection 267 table 10

By a reaction similar to that described in example 101, but on the basis of cyclohexylamine (18 mg, 0.18 mmol)were specified in the title compound (54 mg, 64%).

1H NMR (DMSO-d6, TFA): 1.19 (m, 1H); 1.35 (m, 4H); 1.61 (m, 1H); 1.71 (m, 2H); 1.85 (m, 2H); 2.31 (m, 2H); 3.16 (t, 2H); 3.34 (t, 2H); 3.54 (d, 2H); 3.69 (t, 2H); 3.75 (m, 1H); 4.01 (s, 3H); 4.04 (m, 5H); 4.3 (t, 2H); 7.37 (s, 1H); 7.9 (s, 1H); 8.29 (s, 1H); 8.99 (s, 1H).

MS ES+: 524 [M+H]+

The General scheme 12

Example 108

Stage (a) the production of intermediate compounds of General formula Z1

Imidate U (2 g, 6 mmol) in dimethylformamide (40 ml) was injected into interaction with the hydrochloride of the ethyl 5-amino-4H-1,2,4-triazole-3-carboxylate (1,16 g, 6 mmol) in the presence of sodium hydride (60%, 504 mg, 12.6 mmol) at 110°C for 7 hours in an argon atmosphere. Then the mixture was cooled to room temperature and was added acetic acid (of 1.03 ml, 18 mmol who), the solvent is evaporated in vacuo, the residue was purified by chromatography on silica gel, eluent: CH2Cl2/Meon 90/10, getting mentioned in the title compound (1.07 g, 39%).

1H NMR (DMSO-d6, TFA): 1.39 (t, 3H); 2.28 (m, 2H); 3.15 (t, 2H); 3.32 (t, 2H); 3.56 (d, 2H); 3.68 (t, 3H); 3.98 (s, 3H); 4.05 (d, 2H); 4.37 (t, 2H); 4.52 (q, 2H); 7.49 (s, 1H); 8.12 (s, 1H); 8.71 (s, 1H).

MS ES+: 458 [M+H]+

Stage (b): Obtaining connection 268 table 11

Triazole ester Z1(80 mg, 0,17 mmol) in dimethylformamide (3 ml) was treated with dimethylamine acetate (0.52 mmol) at 70°C for 20 minutes. The mixture was cooled, the solvent evaporated and the residue was purified by chromatography on silica gel, eluent CH2Cl2/Meon/NH3, 90/10/1, getting listed in title product (60 mg, 75%).

1H NMR (DMSO-d6, TFA): 1.34 (t, 3H); 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 4.0 (s, 3H); 4.04 (d, 2H); 4.36 (m, 4H); 7.48 (s, 1H); 8.26 (s, 1H); 9.01 (s, 1H).

MS ES+: 458 [M+H]+

Example 109. Getting connection 269 table 11

Ester triazole 268 (900 mg, 1.97 mmol) in methanol (20 ml) was treated with sodium hydroxide (2 N., 20 ml) at 80°C for 1.5 hours. The mixture was cooled and acidified to a pH of 2.5 with hydrochloric acid (6 BC), the solid was isolated by filtration, dried in vacuum over P2About5getting listed in the title compound (843 mg, 100%).

1H NMR (DMSO-d6 , TFA): 2.37 (m, 2H); 3.12 (t, 2H); 3.3 (t, 2H); 3.5 (d, 2H); 3.87 (t, 2H); 3.97 (d, 2H); 4.01 (s, 3H); 4.35 (t, 2H); 7.63 (s, 1H); 8.32 (s, 1H); 8.97 (s, 1H).

MS ES+: 430 (M+H)+

Example 110. Getting connection 270 table 11

Acid 269 (120 mg, 0.28 mmol) in DMF (2 ml) was injected into the interaction with aniline (of 0.025 ml, 0.28 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (106 mg, 0.28 mmol) and DIEA (of 0.12 ml, 0.7 mmol) at room temperature for 4 hours. The solvent is evaporated, the residue was dissolved in a mixture of methylene chloride/methanol and was treated with a methanol solution of dimethylamine (2 M, 1 ml) at room temperature over night. The solvent is evaporated and the residue was purified flash chromatography on silica gel, eluent CH2Cl2/Meon, 90/10, getting mentioned in the title compound (12 mg, 9%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.18 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.33 (t, 2H); 7.16 (t, 1H); 7.39 (t, 2H); 7.45 (s, 1H); 7.83 (d, 2H); 8.2 (s, 1H); 8.95 (s, 1H).

MS ES+: 505 [M+H]+

Example 111. Getting connection 271 in table 11

By a reaction similar to that described in example 110, but on the basis of 4-foronline made (0.13 ml, 1.4 mmol)were specified in the title compound (44 mg, 18%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 4.0 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 7.23 (t, 2H); 7.44 (s, 1H); 7.86 (m, 1H); 8.18 (s, 1H); 8.93 (s, 1H).

MS ES +: 523 [M+H]+

Example 112. Getting connection 272 in table 11

By a reaction similar to that described in example 110, but on the basis of allylamine (0,13 ml of 1.75 mmol)were specified in the title compound (26 mg, 10%).

1H NMR (DMSO-d6, TFA): 2.29 (m, 2H); 3.16 (t, 2H); 3.34 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.94 (d, 2H); 3.99 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H); 5.13 (d, 1H); 5.18 (d, 1H); 5.92 (m, 1H); 7.41 (s, 1H); 8.17 (s, 1H); 8.91 (s, 1H).

MS ES+: 469 [M+H]+

The General scheme 13

Example 113. The connection is 300 table 12

Stage 1. The connection AA

Imidate U (200 mg, 0.6 mmol) in DMF (4 ml) are condensed with sulfate 2-aminoimidazole (160 mg, 0.6 mmol) in the presence of sodium hydride (60%, 50 mg of 1.26 mmol) at 90aboutC for 2 hours. The mixture was cooled, was added acetic acid (0.01 ml, 1.8 mmol), the solvent evaporated and the residue was purified by chromatography on silica gel, eluent CH2Cl2/Meon, 90/10, getting mentioned in the title compound (112 mg, 48%).

1H NMR (DMSO-d6, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.33 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.97 (s, 3H); 4.03 (d, 2H); 4.36 (t, 2H); 7.41 (s, 2H); 7.47 (s, 1H); 8.13 (s, 1H); 8.66 (s, 1H).

MS ES+: 385 [M+H]+

Stage 2: Getting connection 300

The imidazole AA (105 mg, 0,273 mmol) in DMF (2 ml) was heated at 80°C for 0.3 hours in the presence of dimethylamine acetate (0,819 mmol), the solvent evaporated, and the OST is OK purified by chromatography on silica gel, eluent CH2Cl2/Meon feast upon. NH3, 90/10, getting mentioned in the title compound (78 mg, 74%).

1H NMR (DMSO-d6, TFA): 1.96 (m, 2H); 2.39 (m, 4H); 2.46 (t, 2H); 3.6 (m, 4H); 3.9 (s, 3H); 4.18 (t, 2H); 6.9 (s, 2H); 7.14 (s, 1H); 7.84 (s, 1H); 8.39 (s, 1H).

MS ES+: 385 [M+H]+

Example 114. The connection 301 table 12

Stage 1. The connection ab

Imidate u (250 mg, 0,751 mmol) in DMF (4 ml) are condensed with ethyl 2-aminoimidazole-4-carboxylate (117 mg, 0,751 mmol) in the presence of sodium hydride (60%, 30 mg, 0,826 mmol) at 100°C for 3 hours. The mixture was cooled, was added acetic acid (0,13 ml, 2.25 mmol), the solvent evaporated and the residue was purified by chromatography on silica gel, getting mentioned in the title compound (125 mg, 36%).

1H NMR (DMSO-d6, TFA): 1.32 (t, 3H); 2.3 (m, 2H); 3.15 (t, 2H); 3.34 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.98 (s, 3H); 4.03 (d, 2H); 4.33 (q, 2H); 4.37 (t, 2H); 7.49 (s, 1H); 8.11 (s, 1H); 8.2 (s, 1H); 8.65 (s, 1H).

MS ES+: 457 [M+H]+

Stage 2: Getting connection 301 table 12

The imidazole 3 (122 mg, 0,268 mmol) in DMF (2 ml) was heated at 80°C for 0.3 hours in the presence of dimethylamine acetate (0,802 mmol), the solvent evaporated and the residue was purified by chromatography on silica gel, eluent CH2Cl2/Meon feast upon. NH3from 95/5 to 90/10, getting mentioned in the title compound (105 mg, 86%).

1H NMR (DMSO-d6, TFA): 1.32 (t, 3H); 2.3 (m, 2H); 3.15 (t, 2 is); 3.34 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.94 (s, 3H); 4.03 (d, 2H); 4.27 (t, 2H); 4.33 (q, 2H); 7.27 (s, 1H); 7.84 (s, 1H); 7.92 (s, 1H); 8.76 (s, 1H).

MS ES+: 457 [M+H]+

Example 115. Getting connection 302 in table 13

By a reaction similar to that described in General scheme 5 starting from 4-methoxyaniline (32 mg, 0.26 mmol)were specified in the header connection 302 in table 13 (24 mg, 21%).

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.76 (s, 3H); 4.02 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 6.96 (d, 2H); 7.38 (s, 1H); 7.62 (d, 2H); 8.04 (s, 1H); 8.55 (s, 1H); 9.27 (s, 1H).

Example 116. The connection 303 in table 13

By a reaction similar to that described in General scheme 5 starting from 4-methylaniline (28 mg, 0.26 mmol)were specified in the header connection 303 in table 13 (23 mg, 22%).

MS ES+: 535 (M+H)+

1H NMR (DMSO-d6, TFA): 2.29 (s, 3H); 2.33 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.01 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 7.19 (d, 1H); 7.38 (s, 1H); 7.60 (d, 2H); 8.05 (s, 1H); 8.58 (s, 1H); 9.28 (s, 1H).

Example 117. The connection 304 in table 13

By a reaction similar to that described in General scheme 5 starting from 2-aminopyridine (24 mg, 0.26 mmol)were specified in the header connection 304 in table 13 (12 mg, 11%).

MS ES+: 522 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.34 (t, 2H); 7.33 (m, 1H); 7.41 (s, 1H); 8.07 (m, 2H); 8.09 (s, 1H); 8.46 (d, 1H); 8.81 (s, 1H); 9.30 (s, 1H).

Example 118. Getting connection 305 table 13

By a reaction similar to that described in General scheme 5 starting from 2-aminobenzamide alcohol (32 mg, 0.26 mmol)were specified in the header connection 305 in table 13 (54 mg, 60%).

MS ES+: 551 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 3.78 (s, 2H); 4.02 (s, 3H); 4.05 (d, 2H); 4.34 (t, 2H); 6.73 (d, 1H); 7.30 (m, 2H); 7.39 (s, 1H); 7.40 (m, 1H); 8.07 (s, 1H); At 8.62 (s, 1H); 9.3 (s, 1H).

Example 119. Getting connection 306 in table 13

By a reaction similar to that described in General scheme 5 starting from 4-methoxybenzylamine (36 mg, 0.26 mmol)were specified in the header connection 306 in table 13 (29 mg, 26%).

MS ES+: 565 (M+H)+

1H NMR (DMSO-d6, TFA): 2.28 (t, 2H); 3.14 (t, 2H); 3.31 (t, 2H); 3.50 (d, 2H); 3.68 (t, 2H); 3.69 (s, 3H); 3.94 (s, 3H); 3.98 (d, 2H); 4.24 (t, 2H); 4.37 (s, 2H); 6.89 (m, 2H); 7.12 (m, 2H); 7.35 (s, 1H); 7.90 (s, 1H); 8.31 (s, 1H); 9.15 (s, 1H).

Example 120. Getting connection 307 table 13

By a reaction similar to that described in General scheme 5 starting from 3-nitroaniline (36 mg, 0.26 mmol)were specified in the header connection 307 in table 13 (27 mg, 24%).

MS ES+: 566 (M+H)+

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 7.40 (s, 1H); 7.71 (t, 1H); 7.99 (d, 1H); 8.08 (s, 1H); 8.14 (d, 1H); 8.64 (s, 1H); 8.71 (s, 1H); 9.31 (s, 1H).

Example 121. Getting connection 308 in table 13

By Rea the tion, similar to that described in General scheme 5, based on aminoacetonitrile (24 mg, 0.26 mmol)were specified in the header connection 308 in table 13 (29 mg, 30%).

MS ES+: 484 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 4.00 (s, 3H); 4.02 (d, 2H); 4.32 (t, 2H); 4.37 (s, 2H); 7.39 (s, 1H); 8.06 (s, 1H); 8.36 (s, 1H); 9.27 (s, 1H).

Example 122. Getting connection 309 in table 13

By a reaction similar to that described in General scheme 5 starting from 2-methyl-5-nitroaniline (40 mg, 0.26 mmol)were specified in the header connection 309 in table 13 (14 mg, 12%).

MS ES+: 580 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H); 7.39 (s, 1H); 7.58 (d, 1H); 8.04 (d, 1H); 8.08 (s, 1H); 8.34 (d, 1H); at 8.62 (s, 1H); 9.29 (s, 1H).

Example 123. Getting connection 310 in table 13

By a reaction similar to that described in General scheme 5, based on cyclopropylamine (15 mg, 0.26 mmol)were specified in the header connection 310 in table 13 (6 mg, 6%).

MS ES+: 485 (M+H)+

1H NMR (DMSO-d6, TFA): 0.68 (m, 2H); 0.74 (m, 2H); 2.27 (t, 2H); 2.67 (m, 2H); 3.12 (t, 2H); 3.31 (t, 2H); 3.51 (d, 2H); 3.69 (t, 2H); 3.95 (s, 3H); 3.98 (d, 2H); 4.29 (t, 2H); 7.32 (s, 1H); 7.96 (s, 1H); 8.24 (s, 1H); 9.20 (s, 1H).

Example 124. Getting connection 311 in table 13

By a reaction similar to that described in General scheme 5 starting from 4-nitrobenzylamine (49 mg, 0.26 mmol)were specified the title compound 311 in table 13 (5 mg, 4%).

MS ES+: 580 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H); 4.63 (s, 2H); 7.38 (s, 1H); 7.62 (d, 2H); 8.04 (s, 1H); 8.23 (d, 2H); 8.40 (s, 1H); 9.25 (s, 1H).

Example 125. The connection 312 in table 13

By a reaction similar to that described in General scheme 5 starting from 2-anilinomethyl (36 mg, 0.26 mmol)were specified in the header connection 312 in table 13 (49 mg, 44%).

MS ES+: 565 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.7 (m, 4H); 4.01 (s, 3H); 4.03 (d, 2H); 4.33 (t, 2H); 4.49 (t, 2H); 7.15 (t, 1H); 7.26 (d, 2H); 7.41 (t, 2H); 7.43 (s, 1H); 8.15 (s, 1H); 8.48 (s, 1H); 9.31 (s, 1H).

Example 126. Getting connection 313 in table 13

By a reaction similar to that described in General scheme 5, based on furfurylamine (25 mg, 0.26 mmol)were specified in the header connection 313 in table 13 (20 mg, 19%).

MS ES+: 525 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.69 (t, 2H); 3.99 (s, 3H); 4.02 (d, 2H); 4.32 (t, 2H); 4.48 (s, 2H); 6.33 (d, 1H); 6.41 (d, 1H); 7.37 (s, 1H); 7.59 (s, 1H); 8.01 (s, 1H); 8.37 (s, 1H); 9.24 (s, 1H).

Example 127. The connection 314 in table 13

By a reaction similar to that described in General scheme 5 starting from 3-Chloroaniline (33 mg, 0.26 mmol)were specified in the header connection 314 in table 13 (21 mg, 19%).

MS ES+: 555, 557 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, N); 3.36 (t, 2H); 3.54 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.32 (t, 2H); 7.20 (d, 1H); 7.39 (s, 1H); 7.42 (t, 1H); 7.63 (d, 1H); 7.91 (s, 1H); 8.07 (s, 1H); 8.61 (s, 1H); 9.30 (s, 1H).

Example 128. The connection 315 in table 13

By a reaction similar to that described in General scheme 5 starting from 2-methoxyaniline (32 mg, 0.26 mmol)were specified in the header connection 315 in table 13 (67 mg, 61%).

MS ES+: 551 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 3.87 (s, 3H); 4.02 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 6.99 (t, 1H); 7.13 (d, 1H); 7.23 (t, 1H); 7.40 (s, 1H); 7.66 (d, 1H); 8.04 (s, 1H); 8.64 (s, 1H); 9.27 (s, 1H).

Example 139. Getting connection 316 in table 13

By a reaction similar to that described in General scheme 5 starting from thiophene-2-methylamine (29 mg, 0.26 mmol)were specified in the header connection 316 in table 13 (25 mg, 23%).

MS ES+: 541 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 4.01 (s, 3H); 4.04 (d, 2H); 4.34 (t, 2H); 4.67 (s, 2H); 6.99 (m, 1H); 7.08 (m, 1H); 7.39 (s, 1H); 7.41 (d, 1H); 8.04 (s, 1H); 8.36 (s, 1H); 9.27 (s, 1H).

Example 140. Getting connection 317 table 13

By a reaction similar to that described in General scheme 5, based on neopentylene (23 mg, 0.26 mmol)were specified in the title compound 317 table 13 (31 mg, 30%).

MS ES+: 515 (M+H)+

1H NMR (DMSO-d6, TFA): 0.91 (s, N); 2.31 (t, 2H); 3.10 (s, 2H); 3.17 (t, 2H); 3.35 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.03 (who, 2H); 4.32 (t, 2H); 7.35 (s, 1H); 8.00 (s, 1H); 8.45 (s, 1H); 9.23 (s, 1H).

Example 141. Getting connection 318 in table 13

By a reaction similar to that described in General scheme 5 starting from 2,6-differentiatin (37 mg, 0.26 mmol)were specified in the header connection 318 in table 13 (35 mg, 31%).

MS ES+: 571 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.99 (s, 3H); 4.03 (d, 2H); 4.31 (t, 2H); 4.54 (s, 2H); 7.11 (t, 2H); 7.36 (s, 1H); 7.42 (m, 1H); 8.00 (s, 1H); 8.35 (s, 1H); 9.24 (s, 1H).

Example 142. Getting connection 319 table 13

By a reaction similar to that described in General scheme 5 starting from 2-methylethylamine (28 mg, 0.26 mmol)were specified in the title compound 319 table 13 (16 mg, 16%).

MS ES+: 499 (M+H)+

1H NMR (DMSO-d6, TFA): 1.72 (s, 3H); 2.31 (t, 1H); 3.15 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.72 (s, 2H); 3.99 (s, 3H); 4.02 (d, 2H); 4.31 (t, 2H); 4.82 (s, 2H); 4.86 (s, 1H); 7.36 (s, 1H); 8.01 (s, 1H); 8.37 (s, 1H); 9.23 (s, 1H).

Example 143. Getting connection 320 in table 13

By a reaction similar to that described in General scheme 5 starting from 2-methyl-4-foronline (33 mg, 0.26 mmol)were specified in the header connection 320 in table 13 (47 mg, 43%).

MS ES+: 553 (M+H)+

1H NMR (DMSO-d6, TFA): 2.26 (s, 3H); 2.31 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.33 (t, 2H); 7.07 (m, 1H); 7.18 (d, 1H); 7.36 (m, 1H); 7.38 (s, 1H); 8.06 (s, 1H); 8.53 (s, 1H); 9.27 (s, 1H).

Example 144. Recip is the connection 321 table 13

By a reaction similar to that described in General scheme 5 starting from 2-fluoro-5-methylaniline (33 mg, 0.26 mmol)were specified in the header connection 321 in table 13 (60 mg, 54%).

MS ES+: 553 (M+H)+

Example 145. The connection 322 in table 13

By a reaction similar to that described in General scheme 5 starting from 4-forbindelsen (33 mg, 0.26 mmol)were specified in the header connection 322 in table 13 (33 mg, 30%).

MS ES+: 553 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.99 (s, 3H); 4.02 (d, 2H); 4.33 (t, 2H); 4.47 (s, 2H); 7.15 (t, 2H); 7.36 (s, 1H); 7.37 (m, 2H); 8.02 (s, 1H); 8.36 (s, 1H); 9.24 (s, 1H).

Example 146. Getting connection 323 table 13

By a reaction similar to that described in General scheme 5 starting from 3,4-differentiatin (37 mg, 0.26 mmol)were specified in the header connection 323 table 13 (17 mg, 15%).

MS ES+: 571 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 4.48 (s, 2H); 7.21 (m, 1H); 7.38 (s, 1H); 7.38 (m, 2H); 8.03 (s, 1H); 8.38 (s, 1H); 9.24 (s, 1H).

Example 147. The connection 324 in table 13

By a reaction similar to that described in General scheme 5 starting from 3-methylaniline (28 mg, 0.26 mmol)were specified in the header connection 324 in table 13 (57 mg, 53%).

MS ES+: 535 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (m, 5H); 3.17 (t, 2H); 3.36 (t, 2H); 3.6 (d, 2H); 3.69 (t, 2H); 4.01 (s, 3H); 4.04 (d, 2H); 6.95 (d, 1H); 7.24 (t, 1H); 7.38 (s, 1H); 7.53 (m, 2H); 8.04 (s, 1H); 8.59 (s, 1H); 9.28 (s, 1H).

Example 148. Getting connection 325 in table 13

By a reaction similar to that described in General scheme 5 starting from 2-(methylthio)aniline (36 mg, 0.26 mmol)were specified in the header connection 325 in table 13 (73 mg, 64%).

MS ES+: 567 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.44 (s, 3H); 3.16 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H); 7.22 (t, 1H); 7.37 (m, 4H); 8.06 (s, 1H); 8.52 (s, 1H); 9.27 (s, 1H).

Example 149. Getting connection 326 in table 13

By a reaction similar to that described in General scheme 5, starting from 5-aminoindole (34 mg, 0.26 mmol)were specified in the header connection 326 in table 13 (16 mg, 15%).

MS ES+: 560 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.37 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.32 (t, 2H); 7.36 (m, 5H); 7.94 (s, 1H); 8.04 (s, 1H); 8.28 (s, 1H); 9.28 (s, 1H).

Example 150. Getting connection 327 table 13

By a reaction similar to that described in General scheme 5 starting from 3-aminobenzonitrile (31 mg, 0.26 mmol)were specified in the title compound 317 table 13 (30 mg, 28%).

MS ES+: 546 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.67 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 7.40 (s, 1H); 7.60 (m, 2H); 7.97 (m, 1H); 8.08 (s, 1H); 8.21 (s, 1H); 8.61 (s, 1H); 9.30 (s, 1H).

Example 151. Receiving from the organisations 328 in table 13

By a reaction similar to that described in General scheme 5 starting from 2,4-differentiatin (37 mg, 0.26 mmol)were specified in the header connection 328 in table 13 (27 mg, 24%).

MS ES+: 571 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.70 (t, 2H); 4.00 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H); 4.49 (s, 2H); 7.09 (m, 1H); 7.21 (m, 1H); 7.38 (s, 1H); 8.02 (s, 1H); 8.38 (s, 1H); 9.24 (s, 1H).

Example 152. Getting connection 329 table 13

By a reaction similar to that described in General scheme 5 starting from 3-(2-amino-ethyl)pyridine (32 mg, 0.26 mmol)were specified in the title compound 329 in table 13 (33 mg, 30%).

MS ES+: 550 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (t, 2H); 3.11 (t, 2H); 3.18 (t, 2H); 3.35 (t, 2H); 3.57 (d, 2H); 3.66 (t, 2H); 3.68 (t, 2H); 4.01 (s, 3H); 4.05 (d, 2H); 4.34 (t, 2H); 7.41 (s, 1H); 8.05 (s, 1H); 8.08 (DD, 2H); 8.28 (s, 1H); 8.59 (d, 1H); 8.87 (d, 1H); 8.95 (s, 1H); 9.25 (s, 1H).

Example 153. Getting connection 330 table 13

By a reaction similar to that described in General scheme 5 starting from N-methylethanolamine (23 mg, 0.26 mmol)were specified in the header connection 330 table 13 (23 mg, 22%).

MS ES+: 515 (M+H)+

1H NMR (DMSO-d6, TFA): 0.88 (d, 6N); 2.02 (m, 1H); 2.31 (t, 2H); 3.16 (t, 2H); 3.27 (m, 5H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H); 7.37 (s, 1H); 8.03 (s, 1H); 8.18 (s, 1H); 9.23 (s, 1H).

Example 154. Getting connection 331 in table 13

By a reaction similar to that described in General scheme , based on 2-aminobenzoylamino (32 mg, 0.26 mmol)were specified in the header connection 331 in table 13 (6 mg, 6%).

MS ES+: 550 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.37 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 4.00 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H); 4.47 (s, 2H); 7.41 (s, 1H); 7.46 (m, 4H); 8.06 (s, 1H); 8.42 (s, 1H); 9.24 (s, 1H).

Example 155. Getting connection 332 in table 13

By a reaction similar to that described in General scheme 5 starting from 3-methylbutylamine (23 mg, 0.26 mmol)were specified in the header connection 332 in table 13 (48 mg, 47%).

MS ES+: 515 (M+H)+

1H NMR (DMSO-d6, TFA): 0.90 (d, 6N); 1.43 (q, 2H); 1.62 (m, 1H); 2.31 (t, 2H); 3.15 (t, 2H); 3.28 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.99 (s, 3H); 4.02 (d, 2H); 4.31 (t, 2H); 7.35 (s, 1H); 8.00 (s, 1H); 8.31 (s, 1H); 9.23 (s, 1H).

Example 156. Getting connection 333 in table 13

By a reaction similar to that described in General scheme 5 starting from 1-aminomethyl-1-cyclohexanol (43 mg, 0.26 mmol)were specified in the title compound 333 in table 13 (7 mg, 6%).

MS ES+: 557 (M+H)+

1H NMR (DMSO-d6, TFA): 1.37 (m, 10H); 2.28 (t, 2H); 3.11 (t, 2H); 3.23 (s, 2H); 3.32 (t, 2H); 3.51 (d, 2H); 3.65 (t, 2H); 3.96 (s, 3H); 3.99 (d, 2H); 4.28 (t, 2H); 7.32 (s, 1H); 7.95 (s, 1H); 8.43 (s, 1H); 9.19 (s, 1H).

Example 157. Getting connection 334 in table 13

By a reaction similar to that described in General scheme 5 starting from 3-aminomethylpyridine (38 mg, 0.26 mmol)were specified in the header is connected to the e 334 in table 13 (25 mg, 24%).

MS ES+: 537 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (t, 2H); 3.13 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.05 (d, 2H); 4.30 (t, 2H); 4.65 (s, 2H); 7.38 (s, 1H); 8.03 (s, 1H); 8.40 (s, 1H); 8.57 (d, 1H); at 8.62 (d, 1H); 8.70 (s, 1H); 9.24 (s, 1H).

Example 158. Getting connection 335 in table 13

By a reaction similar to that described in General scheme 5 starting from 3-methoxyaniline (32 mg, 0.26 mmol)were specified in the header connection 335 in table 13 (60 mg, 54%).

MS ES+: 551 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H); 3.58 (d, 2H); 3.70 (t, 2H); 3.79 (s, 3H); 4.03 (s, 3H); 4.06 (d, 2H); 4.34 (t, 2H); 6.73 (d, 1H); 7.29 (d, 1H); 7.32 (d, 1H); 7.41 (m, 2H); 8.07 (s, 1H); At 8.62 (s, 1H); 9.30 (s, 1H).

Example 159. The connection 336 in table 13

By a reaction similar to that described in General scheme 5 starting from 4-chlorobenzylamino (19 mg, 0.26 mmol)were specified in the header connection 336 in table 13 (31 mg, 54%).

MS ES+: 569, 571 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.03 (d, 2H); 4.32 (t, 1H); 4.48 (s, 2H); 7.42 (m, 5H); 8.02 (s, 1H); 8.37 (s, 1H); 9.24 (s, 1H).

Example 160. Getting connection 337 in table 14

4-((2-amino-1,3-triazole-5-yl)acetic acid)-6-methoxy-7-(3-morpholinopropan)hinzelin (78 mg, 0,17 mmol) in DMF (1 ml) was injected into the interaction with aniline (19 mg, 0.2 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (76 m is, 0.2 mmol) and DIEA (44 mg, 0.34 mmol) at 50°With during the night. The reaction mixture was cooled, and treated with NaHCO3(1 ml), concentrated. The yellow solid was isolated, dissolved in a mixture of CH2Cl2/Meon (60/40) 20 ml To the mixture was added aluminum oxide, the solvent evaporated and made this a solid substance on the top of the column of alumina, which was suirable CH2Cl2/Meon (from 10/0 to 9/1), getting mentioned in the title compound (43 mg, 47%).

MS ES+: 535 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.37 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.99 (m, 5H); 4.04 (d, 2H); 4.30 (t, 2H); 7.08 (t, 1H); 7.32 (m, 3H); 7.62 (m, 3H); 7.91 (s, 1H); 9.09 (s, 1H).

4-(ethyl(2-amino-1,3-triazole-5-yl)acetate)-6-methoxy-7-(3-morpholinopropan)hinzelin.

Amidin J of scheme 2 (4.5 g, 13 mmol) in acetic acid (45 ml) was injected into the interaction with ethyl(2-amino-1,3-triazole-5-yl)acetate (2,54 g, 13,65 mmol) at boiling for 5.5 hours in argon atmosphere. The mixture was concentrated and the residue was purified by chromatography on silica gel, eluent CH2Cl2/Meon, from 95/5 to 90/10, getting mentioned in the title compound (4.5 g, 63%).

1H NMR (DMSO-d6): 1.22 (t, 3H); 1.96 (t, 2H); 2.37 (m, 4H); 3.35 (t, 2H); 3.58 (m, 4H); 3.91 (s, 2H); 3.95 (s, 3H); 4.13 (q, 2H); 4.20 (t, 2H); 7.25 (s, 1H); 7.36 (s, 1H); 8.10 (s, 1H); 8.66 (s, 1H).

4-((2-amino-1,3-triazole-5-yl)acetic acid)-6-methoxy-7-(3-morpholinopropan)hinzelin.

4-(Ethyl(2-the Mino-1,3-triazole-5-yl)acetate)-6-methoxy-7-(3-morpholinopropan)hinzelin (of 4.38 g, 8 mmol) in ethanol (44 ml) was treated with sodium hydroxide (2 N., 10 ml) at 50°C for 4 hours. The mixture was cooled to room temperature and brought the pH to 3.5 using 2 N. HCl. The residue was dissolved in CH2Cl2/Meon, 60/40, was added DIEA (3 g, 24 mmol), the mixture was stirred 10 minutes, filtered and concentrated solution, obtaining an oily residue. This residue was dissolved in ethanol and partially the solvent evaporated. The crystalline solid was isolated, suspended in ethanol, washed with ether and dried in vacuum, obtaining mentioned in the title compound (3.7 g, 100%).

1H NMR (DMSO-d6, TFA): 2.28 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.70 (t, 2H); 3.92 (s, 2H); 3.99 (s, 3H); 4.03 (d, 2H); 4.30 (t, 2H); 7.32 (s, 1H); 7.60 (s, 1H); 7.90 (s, 1H); 9.08 (s, 1H).

Example 161. Getting connection 338 in table 14

By a reaction similar to that described in example 160, but on the basis of 3-chloro-4-foronline (30 mg, 0.2 mmol)were specified in the title compound (24 mg, 24%).

MS ES+: 587 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.34 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 3.99 (m, 5H); 4.03 (d, 2H); 4.30 (t, 2H); 7.30 (s, 1H); 7.39 (t, 1H); 7.50 (m, 1H); 7.65 (s, 1H); 7.85 (s, 1H); 7.97 (d, 1H); 9.09 (s, 1H).

Example 162. Getting connection 339 table 14

By a reaction similar to that described in example 160, but on the basis of 4-Chloroaniline (26 mg, 0.2 mmol)were specified in the title compound (73 mg, 76%).

MS ES+: 569 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.89 (m, 5H); 4.04 (d, 2H); 4.30 (t, 2H); 7.30 (s, 1H); 7.39 (d, 2H); 7.64 (s, 1H); 7.65 (d, 2H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 163. Getting connection 340 in table 14

By a reaction similar to that described in example 160, but on the basis of 3,4-diferencia (26 mg, 0.2 mmol)were specified in the title compound (75 mg, 77%).

MS ES+: 571 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.72 (t, 2H); 3.99 (m, 5H); 4.04 (d, 2H); 4.30 (t, 2H); 7.31 (s, 1H); 7.32 (m, 1H); 7.41 (q, 1H); 7.65 (s, 1H); 7.81 (m, 1H); 7.92 (s, 1H); 9.09 (s, 1H).

Example 164. Getting connection 341 in table 14

By a reaction similar to that described in example 160, but on the basis of 3-methoxyaniline (25 mg, 0.2 mmol)were specified in the title compound (40 mg, 42%).

MS ES+: 565 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.70 (t, 2H); 3.74 (s, 3H); 3.97 (s, 2H); 3.99 (s, 3H); 4.04 (d, 2H); 4.31 (t, 2H); 6.68 (d, 1H); 7.15 (d, 1H); 7.23 (t, 1H); 7.29 (s, 1H); 7.33 (s, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 165. The connection 342 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-Chloroaniline (26 mg, 0.2 mmol)were specified in the title compound (15 mg, 16%).

MS ES+: 569 (M+H)+

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 3.99 (s, 3H); 4.05 (m, 4H); 4.31 t, 2H); 7.22 (t, 1H); 7.30 (s, 1H); 7.35 (t, 1H); 7.51 (d, 1H); 7.65 (s, 1H); 7.75 (d, 1H); 7.91 (s, 1H); 9.08 (s, 1H).

Example 166. Getting connection 343 in table 14

By a reaction similar to that described in example 160, but on the basis of 4-methoxyaniline (26 mg, 0.21 mmol)were specified in the title compound (55 mg, 57%).

MS ES+: 565.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.19 (t, 2H); 3.39 (t, 2H); 3.58 (d, 2H); 3.73 (t, 2H); 3.80 (s, 3H); 3.97 (s, 2H); 4.02 (s, 3H); 4.07 (d, 2H); 4.33 (t, 2H); 6.93 (d, 2H); 7.09 (s, 1H); 7.33 (s, 1H); 7.56 (d, 2H); 7.66 (s, 1H); 7.94 (s, 1H); 9.12 (s, 1H).

Example 167. Getting connection 344 in table 14

By a reaction similar to that described in example 160, but on the basis of 4-methylaniline (23 mg, 0.21 mmol)were specified in the title compound (51 mg, 54%).

MS ES+: 549.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.29 (s, 3H); 2.31 (t, 2H); 3.19 (t, 2H); 3.38 (t, 2H); 3.58 (d, 2H); 3.72 (t, 2H); 3.99 (s, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 7.16 (d, 2H); 7.33 (s, 1H); 7.54 (d, 2H); 7.67 (s, 1H); 7.94 (s, 1H); 9.12 (s, 1H).

Example 168. Getting connection 345 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-methylaniline (23 mg, 0.21 mmol)were specified in the title compound (42 mg, 45%).

MS ES+: 549.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.24 (s, 3H); 2.31 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 3.99 (s, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.30 (t, 2H); 7.12 (t, 1H); 7.19 (t, 1H); 7.24 (d, 1H); 7.31 (s, 1H); 7.43 (t, 1H); 7.66 (s, 1H); 7.92 (s, 1H); 9.08 (s, 1H).

Example 169 Getting connection 346 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-aminopyridine (20 mg, 0.21 mmol)were specified in the title compound (12 mg, 13%).

MS ES+: 536.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 4.00 (m, 5H); 4.04 (d, 2H); 4.33 (t, 2H); 7.34 (s, 1H); 7.37 (t, 1H); 7.68 (s, 1H); 7.93 (d, 1H); 7.94 (s, 1H); 8.10 (t, 1H); 8.42 (d, 1H); 9.10 (s, 1H).

Example 170. Getting connection 347 table 14

By a reaction similar to that described in example 160, but on the basis of 2-aminobenzamide alcohol (26 mg, 0.21 mmol)were specified in the title compound (24 mg, 24%).

MS ES+: 565.7 (M+H)+

1H NMR (DMSO-d6, TFA): 1.97 (t, 2H); 2.41 (m, 6N); 3.59 (m, 4H); 3.91 (s, 2H); 3.97 (s, 3H); 4.21 (t, 2H); 4.50 (d, 2H); 5.27 (t, 1H); 7.18 (t, 1H); 7.25 (d, 1H); 7.26 (s, 1H); 7.42 (m, 2H); 7.52 (d, 1H); 8.67 (s, 1H); 9.59 (s, 1H).

Example 171. Getting connection 348 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-amino-3-methyl-1-butanol (22 mg, 0.21 mmol)were specified in the title compound (25 mg, 27%).

MS ES+: 545.7 (M+H)+

1H NMR (DMSO-d6, TFA): 0.87 (d, 3H); 0.89 (d, 3H); 1.86 (m, 1H); 2.31 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H); 3.44 (2s, 2H); 3.57 (d, 2H); 3.63 (q, 1H); 3.70 (t, 2H); 3.80 (d, 2H); 4.01 (t, 3H); 4.07 (d, 2H); 4.31 (t, 2H); 7.32 (s, 1H); 7.58 (s, 1H); 7.92 (s, 1H); 9.09 (s, 1H).

Example 172. Getting connection 349 table 14

By a reaction similar to that described in example 160, but on the basis of 2-anilinomethyl (29 is g, 0.21 mmol)were specified in the title compound (11 mg, 11%).

MS ES+: 579.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.38 (t, 2H); 3.40 (m, 2H); 3.50 (t, 2H); 3.54 (d, 2H); 3.67 (m, 2H); 3.75 (t, 2H); 3.98 (s, 3H); 4.07 (d, 2H); 4.31 (t, 2H); 7.30 (s, 1H); 7.40 (s, 1H); 7.45 (m, 2H); 7.52 (m, 3H); 7.89 (s, 1H); 9.08 (s, 1H).

Example 173. The connection is 350 in table 14

By a reaction similar to that described in example 160, but on the basis of 3-chloro-4-methylamine (30 mg, 0.21 mmol)were specified in the title compound (3 mg, 3%).

MS ES+: 583.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (m, 5H); 3.20 (t, 2H); 3.40 (t, 2H); 3.60 (d, 2H); 3.72 (t, 2H); 4.01 (s, 2H); 4.02 (s, 3H); 4.07 (d, 2H); 4.33 (t, 2H); 7.32 (m, 1H); 7.42 (d, 1H); 7.68 (s, 1H); 7.87 (s, 1H); 7.95 (s, 1H); 9.13 (s, 1H).

Example 174. Getting connection 351 table 14

By a reaction similar to that described in example 160, but on the basis of 3-nitroaniline (29 mg, 0.21 mmol)were specified in the title compound (20 mg, 21%).

MS ES+: 580.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (t, 2H); 3.20 (t, 2H); 3.39 (t, 2H); 3.60 (d, 2H); 3.73 (t, 2H); 4.02 (s, 3H); 4.06 (d, 2H); 4.09 (s, 2H); 4.34 (t, 2H); 7.34 (s, 1H); 7.67 (d, 1H); 7.70 (s, 1H); 7.95 (s, 1H); 7.98 (m, 2H); 8.74 (s, 1H); 9.15 (s, 1H).

Example 175. Getting connection 352 in table 14

By a reaction similar to that described in example 160 but judging from aminoacetonitrile (19 mg, 0.21 mmol)were specified in the title compound (28 mg, 31%).

MS ES+: 498.6 (M+H)+

1Mr. YAM is (DMSO-d 6, TFA): 2.31 (t, 2H); 3.18 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 3.84 (s, 2H); 3.99 (s, 3H); 4.04 (d, 2H); 4.21 (s, 2H); 4.31 (t, 2H); 7.31 (s, 1H); 7.60 (s, 1H); 9.10 (s, 1H).

Example 176. The connection 353 table 14

By a reaction similar to that described in example 160, but on the basis of 2-methyl-5-nitroaniline (32 mg, 0.21 mmol)were specified in the title compound (11 mg, 11%).

MS ES+: 594.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 2.44 (s, 3H); 3.19 (t, 2H); 3.40 (t, 2H); 3.59 (d, 2H); 3.73 (t, 2H); 4.03 (s, 3H); 4.07 (d, 2H); 4.16 (s, 2H); 4.34 (t, 2H); 7.34 (s, 1H); 7.57 (d, 1H); 7.71 (s, 1H); 7.95 (s, 1H); 8.01 (d, 1H); 8.58 (s, 1H); 9.13 (s, 1H).

Example 177. The connection 354 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-amino-5-chloropyridine (27 mg, 0.21 mmol)were specified in the title compound (13 mg, 13%).

MS ES+: 570.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H); 3.57 (d, 2H); 3.70 (t, 2H); 3.99 (s, 3H); 4.04 (d, 2H); 4.07 (s, 2H); 4.31 (t, 2H); 7.02 (d, 1H); 7.36 (s, 1H); 7.64 (s, 1H); 7.92 (s, 1H); 7.98 (DD, 1H); 8.21 (d, 1H); 9.1 (s, 1H).

Example 178. Getting connection 355 in table 14

By a reaction similar to that described in example 160, but on the basis of 3-triptorelin (34 mg, 0.21 mmol)were specified in the title compound (26 mg, 25%).

MS ES+: 603.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.72 (t, 2H); 3.99 (s, 3H); 4.05 (m, 4H); 4.31 (t, 2H); 7.31 (s, 1H); 7.66 (s, 1H); 7.70 (d, 2H); 7.84 (d,2H); 7.92 (s, 1H); 9.10 (s, 1H).

Example 179. Getting connection 356 in table 14

By a reaction similar to that described in example 160, but on the basis of 3-Chloroaniline (27 mg, 0.21 mmol)were specified in the title compound (47 mg, 48%).

MS ES+: 569.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.37 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 3.99 (s, 3H); 4.00 (s, 2H); 4.04 (d, 2H); 4.31 (t, 2H); 7.14 (d, 1H); 7.30 (s, 1H); 7.37 (t, 1H); 7.47 (d, 1H); 7.65 (s, 1H); 7.87 (s, 1H); 7.92 (s, 1H); 9.10 (s, 1H).

Example 180. Getting connection 357 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-methoxyaniline (26 mg, 0.21 mmol)were specified in the title compound (44 mg, 46%).

MS ES+: 565.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (t, 2H); 3.20 (t, 2H); 3.40 (t, 2H); 3.60 (d, 2H); 3.73 (t, 2H); 3.91 (s, 3H); 4.03 (s, 3H); 4.08 (d, 2H); 4.11 (s, 2H); 4.34 (t, 2H); 6.96 (t, 1H); 7.12 (m, 1H); 7.34 (s, 1H); 7.66 (s, 1H); 7.95 (s, 1H); 8.01 (d, 1H); 9.12 (s, 1H).

Example 181. Getting connection 358 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-foronline (23 mg, 0.21 mmol)were specified in the title compound (43 mg, 46%).

MS ES+: 553.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H); 3.57 (d, 2H); 3.70 (t, 2H); 4.00 (s, 3H); 4.05 (d, 2H); 4.08 (s, 2H); 4.31 (t, 2H); 7.19 (m, 2); 7.28 (mn); 7.31 (s, 1H); 7.64 (s, 1H); 7.93 (m, 2H); 9.06 (s, 1H).

Example 182. Getting connection 359 in table 14

In reactions similar to those described in the example 160, but based on thiophene-2-methylamine (24 mg, 0.21 mmol)were specified in the title compound (50 mg, 53%).

MS ES+: 555.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.18 (t, 2H); 3.38 (t, 2H); 3.58 (d, 2H); 3.72 (t, 2H); 3.80 (s, 2H); 4.01 (s, 3H); 4.06 (d, 2H); 4.33 (t, 2H); 4.52 (s, 2H); 6.98 (DD, 1H); 7.02 (DD, 1H); 7.32 (s, 1H); 7.41 (DD, 1H); 7.60 (q, 1H); 7.93 (s, 1H); 9.11 (s, 1H).

Example 183. Getting connection 360 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-amino-1-phenylethanol (29 mg, 0.21 mmol)were specified in the title compound (32 mg, 33%).

MS ES+: 579.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.18 (m, 3H); 3.36 (m, 3H); 3.56 (d, 2H); 3.69 (t, 2H); 3.74 (s, 2H); 3.99 (s, 3H); 4.05 (d, 2H); 4.30 (t, 2H); 4.66 (m, 1H); 7.3 (m, 6N); 7.53 (s, 1H); 7.90 (s, 1H); 9.09 (s, 1H).

Example 184. Getting connection 361 in table 14

By a reaction similar to that described in example 160, but on the basis of 3-(1-hydroxyethyl)aniline (29 mg, 0.21 mmol)were specified in the title compound (50 mg, 50%).

MS ES+: 579.7 (M+H)+

1H NMR (DMSO-d6, TFA): 1.34 (d, 3H); 2.31 (t, 2H); 3.18 (t, 2H); 3.38 (t, 2H); 3.58 (d, 2H); 3.72 (t, 2H); 4.00 (s, 2H); 4.02 (s, 3H); 4.07 (d, 2H); 4.33 (t, 2H); 4.72 (q, 1H); 7.07 (d, 1H); 7.29 (t, 1H); 7.33 (s, 1H); 7.53 (d, 1H); 7.67 (s, 2H); 7.93 (s, 1H); 9.12 (s, 1H).

Example 185. The connection 362 in table 14

By a reaction similar to that described in example 160 but judging from neopentylene (18 mg, 0.21 mmol)were specified in the header with the Association (57 mg, 64%).

MS ES+: 529.7 (M+H)+

1H NMR (DMSO-d6, TFA): 0.89 (s, N); 2.33 (t, 2H); 2.97 (s, 2H); 3.19 (t, 2H); 3.39 (t, 2H); 3.59 (d, 2H); 3.80 (s, 2H); 4.02 (s, 3H); 4.07 (d, 2H); 4.32 (t, 2H); 7.33 (s, 1H); 7.60 (s, 1H); 7.93 (s, 1H); 9.11 (s, 1H).

Example 186. The connection is 363 in table 14

By a reaction similar to that described in example 160, but on the basis of 3-fluoro-4-methoxyaniline (30 mg, 0.21 mmol)were specified in the title compound (64 mg, 65%).

MS ES+: 583.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H); 3.57 (d, 2H); 3.70 (t, 2H); 3.82 (s, 3H); 3.96 (s, 2H); 4.00 (s, 3H); 4.04 (d, 2H); 4.31 (t, 2H); 7.15 (t, 1H); 7.30 (d, 1H); 7.31 (s, 1H); 7.61 (s, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 9.10 (s, 1H).

Example 187. Getting connection 364 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-methyl-4-foronline (26 mg, 0.21 mmol)were specified in the title compound (60 mg, 62%).

MS ES+: 567.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 4.00 (s, 3H); 4.01 (s, 2H); 4.04 (d, 2H); 4.31 (t, 2H); 7.02 (t, 1H); 7.10 (d, 1H); 7.31 (s, 1H); 7.41 (q, 1H); 7.66 (s, 1H); 7.92 (s, 1H); 9.09 (s, 1H).

Example 188. The connection is 365 in table 14

By a reaction similar to that described in example 160, but on the basis of 2,5-diferencia (27 mg, 0.21 mmol)were specified in the title compound (14 mg, 14%).

MS ES+: 571.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.19 (t, 2H); 3.39 (t, 2H); 3.58 (d, 2H); 3.72 (t, 2H); 4.01 (s, 3H); 4.06 (d, 2H); 4.12 (s, 2H); 4.33 (t, 2H); 7.00 (m, 1H); 7.33 (m, 2H); 7.65 (s, 1H); 7.95 (m, 2H); 9.11 (s, 1H).

Example 189. Getting connection 366 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-fluoro-4-Chloroaniline (31 mg, 0.21 mmol)were specified in the title compound (12 mg, 12%).

MS ES+: 587.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 3.99 (s, 3H); 4.04 (m, 4H); 4.31 (t, 2H); 7.29 (d, 1H); 7.52 (DD, 1H); 7.64 (s, 1H); 7.97 (d, 1H); 9.09 (s, 1H).

Example 190. Getting connection 367 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-fluoro-4-methylaniline (26 mg, 0.21 mmol)were specified in the title compound (20 mg, 20%).

MS ES+: 567.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (s, 3H); 2.32 (t, 2H); 3.20 (t, 2H); 3.39 (t, 2H); 3.59 (d, 2H); 3.73 (t, 2H); 4.03 (s, 3H); 4.07 (d, 2H); 4.09 (s, 2H); 4.34 (t, 2H); 7.02 (m, 1H); 7.18 (DD, 1H); 7.34 (s, 1H); 7.67 (s, 1H); 7.77 (d, 1H); 7.95 (s, 1H); 9.12 (s, 1H).

Example 191. Getting connection 368 in table 14

By a reaction similar to that described in example 160, but on the basis of 3-methylaniline (23 mg, 0.21 mmol)were specified in the title compound (45 mg, 48%).

MS ES+: 549.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (m, 5H); 3.19 (t, 2H); 3.39 (t, 2H); 3.58 (d, 2H); 3.72 (t, 2H); 4.00 (s, 2H); 4.02 (s, 3H); 4.07 (d, 2H); 4.33 (t, 2H); 6.93 (d, 1H); 7.24 (t, 1H); 7.33 (s, 1H); 7.43 (d, 1H); 7.51 (s, 1H); 7.67 (s, 1H); 7.94 (s, 1H); 9.12 (s, 1H).

Example 192. Getting connected is of 369 table 14

By a reaction similar to that described in example 160, but on the basis of 2-(methylthio)aniline (29 mg, 0.21 mmol)were specified in the title compound (13 mg, 13%).

MS ES+: 581.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.46 (s, 3H); 3.19 (t, 2H); 3.39 (t, 2H); 3.59 (d, 2H); 3.72 (t, 2H); 3.99 (s, 3H); 4.02 (s, 2H); 4.07 (d, 2H); 4.33 (t, 2H); 7.22 (t, 1H); 7.27 (t, 1H); 7.34 (s, 1H); 7.39 (d, 1H); 7.45 (d, 1H); 7.68 (s, 1H); 7.93 (s, 1H); 9.10 (s, 1H).

Example 193. Getting connection 370 in table 14

By a reaction similar to that described in example 160, but starting from 5-aminoindole (28 mg, 0.21 mmol)were specified in the title compound (33 mg, 34%).

MS ES+: 574.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.18 (t, 2H); 3.36 (t, 2H); 3.57 (d, 2H); 3.70 (t, 2H); 3.97 (s, 2H); 4.00 (s, 3H); 4.03 (d, 2H); 4.31 (t, 2H); 7.32 (m, 6N); 7.65 (s, 1H); 7.91 (s, 1H); 9.10 (s, 1H).

Example 194. Getting connection 371 in table 14

By a reaction similar to that described in example 160, but on the basis of 2,4-diferencia (27 mg, 0.21 mmol)were specified in the title compound (28 mg, 29%).

MS ES+: 571.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.19 (t, 2H); 3.39 (t, 2H); 3.59 (d, 2H); 3.72 (t, 2H); 4.02 (s, 3H); 4.07 (d, 2H); 4.08 (s, 2H); 4.34 (t, 2H); 7.12 (t, 1H); 7.34 (s, 1H); 7.36 (m, 1H); 7.89 (m, 1H); 7.95 (s, 1H); 9.12 (s, 1H).

Example 195. Getting connection 372 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-fluoro-4-methylaniline (26 mg, 0.21 mmol)were specified in sagola the ECS compound (35 mg, 37%).

MS ES+: 567.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (s, 5H); 3.19 (t, 2H); 3.39 (t, 2H); 3.58 (d, 2H); 3.72 (t, 2H); 4.02 (s, 3H); 4.07 (s, 2H); 4.08 (d, 2H); 4.33 (t, 2H); 7.04 (d, 1H); 7.12 (d, 1H); 7.34 (s, 1H); 7.66 (s, 1H); 7.78 (t, 1H); 7.94 (s, 1H); 9.12 (s, 1H).

Example 196. Getting connection 373 in table 14

By a reaction similar to that described in example 160, but on the basis of 3-cyanoaniline (25 mg, 0.21 mmol)were specified in the title compound (21 mg, 22%).

MS ES+: 560.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.19 (t, 2H); 3.39 (t, 2H); 3.58 (d, 2H); 3.72 (t, 2H); 4.02 (s, 3H); 4.06 (s, 2H); 4.07 (d, 2H); 4.33 (t, 2H); 7.34 (s, 1H); 7.6 (m, 2H); 7.69 (s, 1H); 7.85 (m, 1H); 7.95 (s, 1H); 8.18 (s, 1H); 9.13 (s, 1H).

Example 197. Getting connection 374 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-methyl-5-foronline (26 mg, 0.21 mmol)were specified in the title compound (15 mg, 16%).

MS ES+: 567.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.27 (s, 3H); 2.32 (t, 2H); 3.20 (t, 2H); 3.39 (t, 2H); 3.59 (d, 2H); 3.72 (t, 2H); 4.02 (s, 3H); 4.07 (d, 2H); 4.09 (s, 2H); 4.33 (t, 2H); 6.96 (t, 1H); 7.29 (t, 1H); 7.34 (s, 1H); 7.48 (d, 1H); 7.69 (s, 1H); 7.95 (s, 1H); 9.12 (s, 1H).

Example 198. The connection is 375 in table 14

By a reaction similar to that described in example 160, but on the basis of 2-methyl-5-Chloroaniline (30 mg, 0.21 mmol)were specified in the title compound (20 mg, 21%).

MS ES+: 583.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.26 (s, 3H); 2.32 (t, 2H); 3.17 (t, 2H); 3.3 (t, 2H); 3.58 (d, 2H); 3.71 (t, 2H); 4.01 (s, 3H); 4.05 (d, 2H); 4.07 (s, 2H); 4.32 (t, 2H); 7.16 (DD, 1H); 7.27 (d, 1H); 7.31 (s, 1H); 7.65 (d, 1H); 7.65 (s, 1H); 7.93 (s, 1H); 9.10 (s, 1H).

Example 199. Getting connection 376 table 15

4-((2-Amino-1,3-thiazol-5-yl)acetic acid)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)hinzelin (89 mg, 0.2 mmol) in DMF (1.5 ml) was injected into the interaction with aniline (22 mg, 0.24 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (99 mg, 0.26 mmol) and DIEA (50 mg, 0.4 mmol) at 60°With during the night. After cooling to room temperature the reaction mixture was diluted with methylene chloride and purified by chromatography on silica gel, consistently elwira CH2Cl2CH2Cl2/Meon 90/10 and CH2Cl2/Meon feast upon. NH390/10, getting mentioned in the title compound (50 mg, 42%).

MS ES+: 519.6 (M+H)+

1H NMR (DMSO-d6, TFA): 1.58 (m, 2H); 2.02 (m, 2H); 2.13 (m, 1H); 2.80 (s, 3H); 3.03 (t, 2H); 3.52 (d, 2H); 3.98 (s, 2H); 3.98 (s, 3H); 4.10 (d, 2H); 7.06 (t, 1H); 7.29 (s, 1H); 7.33 (t, 2H); 7.60 (d, 2H); 7.61 (s, 1H); 7.90 (s, 1H); 9.08 (s, 1H).

The NMR spectrum of example 199 in the presence of acid shows the existence of two forms in a ratio of about 9:1. Signals related to minor form, are at 1.95 (m), 3,23 (m), 3,32 (m), 4,28 (d), 9,38 (m).

4-Benzyloxy-3-methoxybenzonitrile

4-Benzyloxy-3-methoxybenzaldehyde (4,84 g, 20 mmol) in acetic acid (25 ml) and acetate NAT is s (3.3 grams, 40 mmol) was injected into interaction with hydroxylamine hydrochloride (2.8 g, 40 mmol) at boiling for 6 hours. The mixture was cooled, diluted with water, was extracted with methylene chloride, dried over MgSO4concentrated, getting mentioned in the title compound (4.8 g, 100%).

1H NMR (DMSO-d6): 3.83 (s, 3H); 5.20 (s, 2H); 7.21 (d, 1H); 7.40 (m, 7H).

2-Nitro-4-benzyloxy-5-methoxybenzonitrile

4-benzyloxy-3-methoxybenzonitrile (4,78 g, 20 mmol) in acetic acid (10 ml) was slowly added to nitric acid (25 ml) at a temperature of from 20°With 30°C. the Mixture was stirred at room temperature for 6 hours, podlachian (pH 10-11) with cooling (CON 10 BC), was extracted with methylene chloride, dried over MgSO4that was evaporated. The solid was recrystallize from hot EtOAc, received a yellow solid is specified in the connection header (3,62 g, 64%).

MS ES+: 285 (M+H)+

1H NMR (DMSO-d6): 3.97 (s, 3H); 5,33 (s, 2H); 7.40 (m, 5H); 7.71 (s, 1H); 8.01 (s, 1H).

2-Nitro-4-hydroxy-5-methoxybenzonitrile

2-Nitro-4-benzyloxy-5-methoxybenzonitrile (3 g, 10.6 mmol) was treated triperoxonane acid (30 ml) by boiling for 0.5 hours. The solvent is evaporated, the residue triturated with ether, receiving a yellow precipitate indicated in the title compound (1.27 g, 62%).

1H NMR (DMSO-d6): 3.95 (s, 3H); 7.63 (s, 1H); 7.70 (s, N).

2-Nitro-4-((1-tert-butoxycarbonylamino-4-yl)methoxy-5-methoxybenzonitrile

2-Nitro-4-hydroxy-5-methoxybenzonitrile (388 mg, 2 mmol) in DMF (5 ml) and acetonitrile (5 ml) was injected into the interaction with 4-(4-tolylsulfochloride)-1-tert-butoxycarbonylamino (738 mg, 2 mmol) and K2CO3(414 mg, 3 mmol) at 110°C for 3.5 hours. The mixture was diluted with water, extracted with ethyl acetate, washed with HCl (2 BC), dried over MgSO4was evaporated, getting mentioned in the title compound (630 mg, 80%).

1H NMR (CDCl3): 1.31 (m, 2H); 1.47 (s, N); 1.85 (m, 2H); 2.07 (m, 1H); 2.77 (m, 2H); 3.96 (d, 2H); 3.99 (s, 3H); 4.19 (m, 2H); 7.19 (s, 1H); 7.75 (s, 1H).

2-Nitro-4-(1-piperidine-4-ylethoxy)-5-methoxybenzonitrile

2-Nitro-4-((1-tert-butoxycarbonylamino-4-yl)methoxy-5-methoxybenzonitrile (1,17 g, 3 mmol) in CH2Cl2(12 ml) was treated with TFA (2.4 ml) for 1 hour at room temperature. The solvent is evaporated, the residue was dissolved in a mixture of CH2Cl2and concentrated sodium bicarbonate, extracted with CH2Cl2. The organic phase was dried over MgSO4concentrated, getting mentioned in the title compound (770 mg, 88%).

1H NMR (CDCl3): 1.33 (m, 2H); 1.86 (d, 2H); 2.03 (m, 1H); 2.71 (t, 2H); 3.15 (d, 2H); 3.96 (d, 2H); 3.99 (s, 3H); 7.18 (s, 1H); 7.76 (s, 1H).

2-Nitro-4-(1-methylpiperidin-4-ylethoxy)-5-methoxybenzonitrile

2-Nitro-4-(1-piperidine-4-yl is ethoxy)-5-methoxybenzonitrile (771 mg, to 2.65 mmol) in CH2Cl2(8 ml) and Meon (4 ml) was injected into the interaction for 0.5 hours with formaldehyde (13.3 M, 300 μl, 4 mmol)slowly over 15 minutes was added acetic acid (191 mg, 3,18 mmol) and NaBH(OAc)3(674 mg, 3,18 mmol). The solution was evaporated, the oily residue was dissolved in a mixture of Na2CO3and ethyl acetate, was extracted with ethyl acetate. The organic phase was dried over MgSO4was evaporated, getting mentioned in the title compound as a yellow solid (698 mg, 86%).

1H NMR (CDCl3): 4.7 (m, 2H); 1.88 (d, 2H); 1.90 (m, 1H); 2.0 (m, 2H); 2.3 (s, 3H); 2.91 (d, 2H); 2.95 (d, 2H); 2.99 (s, 3H); 7.18 (s, 1H); 7.76 (s, 1H).

2-Amino-4-(1-methylpiperidin-4-ylethoxy)-5-methoxybenzonitrile

2-Nitro-4-(1-methylpiperidin-4-ylethoxy)-5-methoxybenzonitrile (1.1 g, 3.6 mmol) in THF (20 ml) in the presence of chloride designed (334 mg, 1.8 mmol) was treated by slow addition of Na2S2O4(3.1 g, 18 mmol) in water (20 ml). After 0.5 h HCl (6 N., 20 ml) was added to the mixture, which was stirred at 60°C for 5 hours. The mixture was cooled to room temperature, extracted with ethyl acetate. The aqueous phase was podslushivaet Na2CO3(solid) and extracted with ethyl acetate. The organic phase was dried over MgSO4concentrated, receiving a yellow precipitate (748 mg, 75%) specified in the connection header.

1H NMR (DMSO-d6/sub> ): 1.29 (m, 2H); 1.70 (m, 3H); 1.85 (t, 2H); 2.14 (s, 3H); 2.76 (d, 2H); 3.64 (s, 3H); 3.75 (d, 2H); 5.57 (s, 2H); 6.40 (s, 1H); 6.87 (s, 1H).

N'-(2-cyano-4-methoxy-5-(1-methylpiperidin-4-ylethoxy)phenyl)-N,N-dimethylaminopropane.

2-Amino-4-(1-methylpiperidin-4-ylethoxy)-5-methoxybenzonitrile (710 mg, 2.58 mmol) was injected into the interaction with DMA DMF (414 mg, 3.5 mmol) in toluene (15 ml) by boiling for 5 hours. The solution was concentrated, the oily residue is triturated with ether, getting mentioned in the title compound as a yellow solid (680 mg, 80%).

1H NMR (DMSO-d6): 1.28 (m, 2H); 1.72 (m, 3H); 1.85 (t, 2H); 2.14 (s, 3H); 2.76 (d, 2H); 2.95 (s, 3H); 3.05 (s, 3H); 3.72 (s, 3H); 3.86 (d, 2H); 6.71 (s, 1H); 7.07 (s, 1H); 7.89 (s, 1H).

4-(Methyl(2-amino-1,3-triazole-5-yl)acetate)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)hinzelin

N'-(2-cyano-4-methoxy-5-(1-methylpiperidin-4-ylethoxy)phenyl)-N,N-dimethylaminopropane (627 mg, 1.9 mmol) was injected into the interaction with methyl-2-amino-1,3-triazole-5-acetate (360 mg, 2.1 mmol) in acetic acid (6.3 ml) at boiling for 4.5 hours under nitrogen atmosphere. The mixture was concentrated, and the oily residue was purified by chromatography on silica gel, eluent: CH2Cl2/Meon 90/10 and CH2Cl2/Meon feast upon. NH390/10, getting mentioned in the title compound (552 mg, 63%).

1H NMR (DMSO-d6): 1.35 (m, 2H); 1.76 (m, 3H); 1.87 (t, 2H); 2.16 (d, 2H); 2.78 (d, 2H); 3.67 (s, 3H); 3.93 (s, 2H); 3.96 (s, 3H); 4.01 (d, 2H); 7.24 (who, 1H); 7.36 (s, 1H); 8.10 (s, 1H); 8.66 (s, 1H).

4-((2-Amino-1,3-triazole-5-yl)acetic acid)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)hinzelin

4-(Methyl(2-amino-1,3-triazole-5-yl)acetate)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)hinzelin (137 mg, 0.3 mmol) in ethanol (1.4 ml) was treated with NaOH (2 N., of 3.75 ml, 7.5 mmol) at room temperature for 0.5 hours. Was added HCl (2 BC) to bring the pH to 3. The solution was evaporated, the solid was dissolved in CH2Cl2(6 ml), Meon (4 ml), was added DIEA (excess). The insoluble precipitate was filtered, the filtrate was concentrated, added ethanol, washed with ether, getting mentioned in the title compound (102 mg, 77%).

MS ES+: 444.6 (M+H)+

1H NMR (DMSO-d6, TFA): 1.61 (m, 2H); 2.03 (d, 2H); 2.16 (m, 1H); 2.80 (s, 3H); 3.03 (t, 2H); 3.5 (d, 2H); 3.92 (s, 2H); 3.98 (s, 3H); 4.10 (d, 2H); 7.32 (s, 1H); 7.59 (s, 1H); 7.89 (s, 1H); 9.07 (s, 1H).

Example 200. Getting connection 377 table 15

By a reaction similar to that described in example 199, but on the basis of 3-chloro-4-foronline (44 mg, 0.3 mmol)were 377 connection in table 15 (63 mg, 60%).

MS ES+: 571 (M+H)+

1H NMR (DMSO-d6, TFA): 1.64 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H); 2.8 (s, 3H); 3.04 (t, 2H); 3.51 (d, 2H); 3.99 (s, 3H); 4.0 (s, 2H); 4.11 (d, 2H); 7.34 (s, 1H); 7.39 (t, 1H); 7.5 (m, 1H); 7.65 (s, 1H); 7.91 (DD, 1H); 9.09 (s, 1H).

Example 201. Getting connection 378 table 15

By a reaction similar to that described in example 199, but based on the 2-amino Regina (40 mg, 0.42 mmol), received the connection 378 in table 15 (100 mg, 53%).

MS ES+: 520 (M+H)+

1H NMR (DMSO-d6, TFA): 1.65 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H); 2.78 (s, 3H); 3.02 (t, 2H); 3.48 (d, 2H); 3.99 (s, 3H); 4.1 (d, 2H); 4.14 (s, 2H); 7.32 (m, 1H); 7.39 (s, 1H); 7.66 (s, 1H); 7.91 (s, 1H); 7.97 (d, 1H); 8.16 (t, 1H); 8.4 (d, 1H); 9.079 (s, 1H).

Example 202. Getting connection 379 table 15

By a reaction similar to that described in example 199, but based on 3,4-diferencia (54 mg, 0.42 mmol), obtained compound 379 in table 15 (120 mg, 72%).

MS ES+: 555 (M+H)+

1H NMR (DMSO-d6, TFA): 1.63 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H); 2.79 (s, 3H); 3.03 (t, 2H); 3.49 (d, 2H); 3.99 (s, 3H); 4.0 (s, 2H); 4.10 (d, 2H); 7.35 (s, 1H); 7.39 (m, 2H); 7.64 (s, 1H); 7.82 (DD, 1H); 7.90 (s, 1H); 9.08 (s, 1H).

Example 203. Getting connection 380 in table 15

By a reaction similar to that described in example 199, but on the basis of 2-Chloroaniline (54 mg, 0.42 mmol), received the connection 380 in table 15 (29 mg, 16%).

MS ES+: 553 (M+H)+

1H NMR (DMSO-d6, TFA): 1.62 (m, 2H); 2.03 (m, 2H); 2.15 (m, 1H); 2.81 (s, 3H); 3.04 (t, 2H); 3.51 (d, 2H); 4.0 (s, 3H); 4.08 (s, 2H); 4.11 (d, 2H); 7.24 (t, 1H); 7.31 (s, 1H); 7.34 (DD, 1H); 7.53 (d, 1H); 7.66 (s, 1H); 7.75 (d, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 204. Getting connection 381 table 15

By a reaction similar to that described in example 199, but on the basis of 4-methylaniline (45 mg, 0.42 mmol), obtained compound 381 in table 15 (155 mg, 85%).

MS ES+: 533 (M+H)+

1H NMR (DMSO-d6, TFA): 1.65 (m, 2H); 2.02 (m, 2H);2.16 (m, 1H); 2.27 (s, 3H); 2.8 (s, 3H); 3.05 (t, 2H); 3.50 (d, 2H); 3.97 (s, 2H); 3.99 (s, 3H); 4.11 (d, 2H); 7.14 (d, 2H); 7.34 (s, 1H); 7.52 (d, 2H); 7.63 (s, 1H); 7.91 (s, 1H); 9.08 (s, 1H).

Example 205. Getting connection 382 table 15

By a reaction similar to that described in example 199, but on the basis of 2-methylaniline (45 mg, 0.42 mmol), received the connection 382 in table 15 (126 mg, 69%).

MS ES+: 533 (M+H)+

1H NMR (DMSO-d6, TFA): 1.62 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H); 2.24 (s, 3H); 2.8 (s, 3H); 3.04 (t, 2H); 3.51 (d, 2H); 3.99 (s, 3H); 4.02 (s, 2H); 4.10 (d, 2H); 7.11 (t, 1H); 7.19 (t, 1H); 7.24 (d, 1H); 7.33 (s, 1H); 7.43 (d, 1H); 7.65 (s, 1H); 7.91 (s, 1H); 9.07 (s, 1H).

Example 206. Getting connection 383 table 15

By a reaction similar to that described in example 199, but on the basis of 2-Chloroaniline (54 mg, 0.42 mmol), received the connection 383 in table 15 (128 mg, 68%).

MS ES+: 553 (M+H)+

1H NMR (DMSO-d6, TFA): 1.65 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H); 2.79 (s, 3H); 3.04 (t, 2H); 3.50 (d, 2H); 3.99 (s, 3H); 4.0 (s, 2H); 4.1 (d, 2H); 7.36 (s, 1H); 7.38 (d, 2H); 7.64 (s, 1H); 7.68 (d, 2H); 7.9 (s, 1H); 9.08 (s, 1H).

Example 207. The connection is 384 in table 15

By a reaction similar to that described in example 199, but on the basis of 4-foronline (47 mg, 0.42 mmol), received the connection 384 in table 15 (136 mg, 84%).

MS ES+: 537 (M+H)+

1H NMR (DMSO-d6, TFA): 1.62 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H); 2.79 (s, 3H); 3.03 (t, 2H); 3.50 (d, 2H); 3.97 (s, 2H); 3.98 (s, 3H); 4.1 (d, 2H); 7.16 (t, 2H); 7.34 (s, 1H); 7.63 (s, 1H); 7.65 (m, 2H); 7.9 (s, 1H); 9.07 (s, 1H).

Example 208. Getting connected is of 385 in table 15

By a reaction similar to that described in example 199, but on the basis of 2-amino-6-methylpyrimidine (45 mg, 0.42 mmol), received the connection 385 in table 15 (91 mg, 57%).

MS ES+: 534 (M+H)+

1H NMR (DMSO-d6, TFA): 1.61 (m, 2H); 2.05 (m, 2H); 2.15 (m, 1H); 2.50 (s, 3H); 2.8 (s, 3H); 3.03 (t, 2H); 3.52 (d, 2H); 4.02 (s, 3H); 4.1 (s, 2H); 4.11 (d, 2H); 7.15 (m, 1H); 7.33 (s, 1H); 7.65 (s, 1H); 7.8 (m, 2H); 7.91 (s, 1H); 9.07 (s, 1H).

Example 209. The connection 386 in table 15

By a reaction similar to that described in example 199, but based on 3-methoxyaniline (52 mg, 0.42 mmol), received the connection 386 in table 15 (125 mg, 67%).

MS ES+: 549 (M+H)+

1H NMR (DMSO-d6, TFA): 1.63 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H); 2.8 (s, 3H); 3.04 (t, 2H); 3.52 (d, 2H); 3.75 (s, 3H); 3.98 (s, 2H); 3.99 (s, 3H); 4.11 (d, 2H); 6.68 (m, 1H); 7.17 (d, 1H); 7.24 (t, 1H); 7.33 (s, 1H); 7.35 (d, 1H); 7.64 (s, 1H); 7.92 (s, 1H); 9.09 (s, 1H).

Example 210. Getting connection 387 table 15

By a reaction similar to that described in example 199, but on the basis of 2-amino-5-chloropyridine (54 mg, 0.42 mmol), obtained compound 387 in table 15 (22 mg, 11%).

MS ES+: 554 (M+H)+

1H NMR (DMSO-d6, TFA): 1.61 (m, 2H); 2.03 (m, 2H); 2.15 (m, 1H); 2.8 (s, 3H); 3.03 (t, 2H); 3.5 (d, 2H); 3.98 (s, 3H); 4.07 (s, 2H); 4.11 (d, 2H); 7.30 (s, 1H); 7.63 (s, 1H); 7.9 (s, 1H); 7.93 (DD, 1H); 8.12 (d, 1H); 8.41 (d, 1H).

Example 211. Getting connection 388 table 15

By a reaction similar to that described in example 199, but on the basis of 3-Chloroaniline (54 mg, 0.42 mmol), received the connection 388 in that the face 15 (130 mg, 69%).

MS ES+: 553 (M+H)+

1H NMR (DMSO-d6, TFA): 1.62 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H); 2.78 (s, 3H); 3.02 (t, 2H); 3.49 (d, 2H); 3.97 (s, 3H); 3.99 (s, 2H); 4.08 (d, 2H); 7.13 (d, 1H); 7.3 (s, 1H); 7.38 (t, 1H); 7.64 (s, 1H); 7.86 (s, 1H); 7.90 (s, 1H); 9.07 (s, 1H).

Example 212. The connection is 389 in table 15

By a reaction similar to that described in example 199, but based on the 2-foronline (47 mg, 0.42 mmol), obtained compound 389 in table 15 (116 mg, 63%).

MS ES+: 537 (M+H)+

1H NMR (DMSO-d6, TFA): 1.64 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H); 2.79 (s, 3H); 3.03 (t, 2H); 3.50 (d, 2H); 3.99 (s, 3H); 4.07 (s, 2H); 4.10 (d, 2H); 7.19 (m, 2H); 7.25 (m, 1H); 7.35 (s, 1H); 7.63 (s, 1H); 7.90 (s, 1H); 7.91 (m, 1H); 9.07 (s, 1H).

Example 213. Getting connection 390 in table 15

By a reaction similar to that described in example 199, but on the basis of 3-fluoro-4-methoxyaniline (59 mg, 0.42 mmol), received the connection 390 in table 15 (151 mg, 85%).

MS ES+: 567 (M+H)+

1H NMR (DMSO-d6, TFA): 1.62 (m, 2H); 2.01 (m, 2H); 2.15 (m, 1H); 2.79 (s, 3H); 3.03 (t, 2H); 3.51 (d, 2H); 3.81 (s, 3H); 3.96 (s, 2H); 3.98 (s, 3H); 4.10 (d, 2H); 7.14 (t, 1H); 7.28 (d, 1H); 7.34 (s, 1H); 7.59 (DD, 1H); 7.6 (s, 1H); 7.90 (s, 1H); 9.07 (s, 1H).

Example 214. Getting connection 391 table 15

By a reaction similar to that described in example 199, but on the basis of 2-methyl-4-foronline (53 mg, 0.42 mmol), obtained compound 391 in table 15 (151 mg, 81%).

MS ES+: 551 (M+H)+

1H NMR (DMSO-d6, TFA): 1.62 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H); 2.33 (s, 3H); 2.79 (s, 3H); 2.93 (t, 2H); 3.48 d, 2H); 3.97 (s, 3H); 3.99 (s, 2H); 4.09 (d, 2H); 7.01 (dt, 1H); 7.1 (DD, 1H); 7.37 (s, 1H); 7.39 (m, 1H); 7.64 (s, 1H); 7.89 (s, 1H); 9.05 (s, 1H).

Example 215. Getting connection 392 in table 15

By a reaction similar to that described in example 199, but on the basis of 2-amino-4-methylpyridine (45 mg, 0.42 mmol), received the connection 392 in table 15 (119 mg, 66%).

MS ES+: 534 (M+H)+

1H NMR (DMSO-d6, TFA): 1.66 (m, 2H); 2.05 (m, 2H); 2.15 (m, 1H); 2.77 (s, 3H); 3.03 (t, 2H); 3.48 (d, 2H); 3.97 (s, 3H); 4.09 (d, 2H); 4.21 (s, 2H); 7.35 (m, 1H); 7.45 (s, 1H); 7.69 (s, 1H); 7.70 (s, 1H); 7.90 (s, 1H); 8.31 (d, 1H); 9.06 (s, 1H).

Example 216. Getting connection 393 table 15

By a reaction similar to that described in example 199, but based on 2,5-diferencia (54 mg, 0.42 mmol), received the connection 393 in table 15 (42 mg, 22%).

MS ES+: 555 (M+H)+

1H NMR (DMSO-d6, TFA): 1.60 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H); 2.81 (s, 3H); 3.04 (t, 2H); 3.52 (d, 2H); 3.99 (s, 3H); 4.10 (s, 2H); 4.11 (d, 2H); 7.02 (m, 2H); 7.32 (s, 1H); 7.34 (m, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 7.92 (m, 1H); 9.08 (s, 1H).

Example 217. Getting connection 394 table 15

By a reaction similar to that described in example 199, but on the basis of 2-fluoro-4-Chloroaniline (61 mg, 0.42 mmol), received the connection 394 in table 15 (97 mg, 50%).

MS ES+: 571 (M+H)+

1H NMR (DMSO-d6, TFA): 1.63 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H); 2.77 (s, 3H); 3.03 (t, 2H); 3.48 (d, 2H); 3.98 (s, 3H); 4.07 (s, 2H); 4.09 (d, 2H); 7.26 (d, 1H); 7.38 (s, 1H); 7.5 (DD, 1H); 7.62 (s, 1H); 7.89 (s, 1H); 7.96 (t, 1H); 9.06 (s, 1H).

Example 218. Getting soedineniya in table 15

By a reaction similar to that described in example 199, but on the basis of 2-fluoro-5-methylaniline (53 mg, 0.42 mmol), received the connection 395 in table 15 (119 mg, 63%).

MS ES+: 551 (M+H)+

1H NMR (DMSO-d6, TFA): 1.63 (m, 2H); 2.03 (m, 2H); 2.15 (m, 1H); 2.28 (s, 3H); 2.77 (s, 3H); 3.03 (t, 2H); 3.49 (d, 2H); 3.98 (s, 3H); 4.05 (s, 2H); 4.09 (d, 2H); 6.98 (m, 1H); 7.15 (DD, 1H); 7.38 (s, 1H); 7.62 (s, 1H); 7.72 (m, 1H); 7.89 (s, 1H); 9.06 (s, 1H).

Example 219. Getting connection 396 table 15

By a reaction similar to that described in example 199, but on the basis of 3-methylpyridine (45 mg, 0.42 mmol), received the connection 396 in table 15 (144 mg, 79%).

MS ES+: 533 (M+H)+

1H NMR (DMSO-d6, TFA): 1.64 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H); 2.3 (s, 3H); 2.79 (s, 3H); 3.04 (t, 2H); 3.51 (d, 2H); 3.98 (s, 2H); 3.99 (3H); 4.10 (d, 2H); 6.90 (d, 1H); 7.21 (t, 1H); 7.36 (s, 1H); 7.42 (d, 1H); 7.49 (s, 1H); 7.63 (s, 1H); 7.9 (s, 1H); 9.07 (s, 1H).

Example 220. Getting connection 397 table 15

By a reaction similar to that described in example 199, but on the basis of 2,4-diferencia (54 mg, 0.42 mmol), obtained compound 397 in table 15 (121 mg, 74%).

MS ES+: 555 (M+H)+

1H NMR (DMSO-d6, TFA): 1.63 (m, 2H); 2.03 (m, 2H); 2.15 (m, 1H); 2.78 (s, 3H); 3.03 (t, 2H); 3.5 (d, 2H); 3.98 (s, 3H); 4.04 (s, 2H); 4.1 (d, 2H); 7.08 (m, 1H); 7.33 (m, 1H); 7.36 (s, 1H); 7.63 (s, 1H); 7.86 (m, 1H); 7.90 (s, 1H); 9.07 (s, 1H).

Example 221. The connection is 398 in table 15

By a reaction similar to that described in example 199, but on the basis of 2-fluoro-4-methylaniline (53 mg, 0.42 mmol), obtained from the Association 398 in table 15 (147 mg, 79%).

MS ES+: 551 (M+H)+

1H NMR (DMSO-d6, TFA): 1.63 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H); 2.3 (s, 3H); 2.79 (s, 3H); 3.04 (t, 2H); 3.51 (d, 2H); 3.99 (s, 3H); 4.04 (s, 2H); 4.1 (d, 2H); 6.99 (d, 1H); 7.10 (d, 1H); 7.35 (s, 1H); 7.62 (s, 1H); 7.75 (t, 1H); 7.90 (s, 1H); 9.07 (s, 1H).

Example 222. The connection is 399 in table 15

By a reaction similar to that described in example 199, but based on 3-cyanoaniline (50 mg, 0.42 mmol), obtained compound 399 in table 15 (118 mg, 71%).

MS ES+: 544 (M+H)+

1H NMR (DMSO-d6, TFA): 1.66 (m, 2H); 2.07 (m, 2H); 2.17 (m, 1H); 2.81 (s, 3H); 3.06 (t, 2H); 3.53 (d, 2H); 4.0 (s, 3H); 4.05 (s, 2H); 4.11 (d, 2H); 7.36 (s, 1H); 7.54 (m, 2H); 7.65 (s, 1H); 7.86 (DD, 1H); 7.92 (s, 1H); 8.18 (s, 1H); 9.09 (s, 1H).

Example 223. Getting connection 400 V table 15

By a reaction similar to that described in example 199, but on the basis of 2-methyl-5-foronline (53 mg, 0.42 mmol), received the connection 400 V table 15 (107 mg, 57%).

MS ES+: 551 (M+H)+

1H NMR (DMSO-d6, TFA): 1.65 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H); 2.24 (s, 3H); 2.76 (s, 3H); 3.02 (t, 2H); 3.47 (d, 2H); 3.98 (s, 3H); 4.07 (s, 2H); 4.08 (d, 2H); 6.92 (m, 1H); 7.25 (t, 1H); 7.4 (s, 1H); 7.43 (m, 1H); 7.64 (s, 1H); 7.88 (s, 1H); 9.04 (s, 1H).

Example 224. The connection 401 in table 15

By a reaction similar to that described in example 199, but based on 3,5-diferencia (54 mg, 0.42 mmol), received the connection 401 in table 15 (83 mg, 44%).

MS ES+: 555 (M+H)+

1H NMR (DMSO-d6, TFA): 1.66 (m, 2H); 2.02 (m, 2H); 2.16 (m, 1H); 2.76 (s, 3H); 3.03 (t, 2H); 3.45 (d, 2H); 397 (, 3H); 4.03 (s, 2H); 4.08 (d, 2H); 6.90 (DD, 1H); 7.38 (m, 2H); 7.39 (s, 1H); 7.87 (s, 1H); 9.05 (s, 1H).

Example 225. The connection 402 in table 15

By a reaction similar to that described in example 199, but based on 3-foronline (47 mg, 0.42 mmol), received the connection 402 in table 15 (142 mg, 77%).

MS ES+: 537 (M+H)+

1H NMR (DMSO-d6, TFA): 1.62 (m, 2H); 2.03 (m, 2H); 2.15 (m, 1H); 2.78 (s, 3H); 3.02 (t, 2H); 3.49 (d, 2H); 3.98 (s, 3H); 4.0 (s, 2H); 4.1 (d, 2H); 6.9 (s, 1H); 7.35 (s, 1H); 7.36 (m, 2H); 7.62 (m, 1H); 7.64 (s, 1H); 7.9 (s, 1H); 9.08 (s, 1H).

Example 226. Getting connection 403 table 16

4-((2-Amino-1,3-thiazol-5-yl)acetic acid)-6-methoxy-7-(3-N-methylpiperazine)hinzelin (142 mg, 0.3 mmol) in NMP (1.5 ml) was injected into the interaction with aniline (42 μl, 0.45 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (173 mg, 0.45 mmol) and diisopropylethylamine (105 μl, 0.6 mmol) at 65°C in nitrogen atmosphere overnight. After cooling to room temperature the reaction mixture was diluted with methylene chloride and purified by chromatography on silica gel, eluent CH2Cl2CH2Cl2/Meon, 9/1, CH2Cl2/Meon feast upon. NH3, 9/1, getting mentioned in the title compound (24 mg, 15%).

MS ES+: 548 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.94 (s, 3H); 3.2-4.2 (m, 8H); 3.45 (t, 2H); 3.99 (s, 5H); 4.30 (t, 2H); 7.08 (t, 1H); 7.31 (s, 1H); 7.33 (s, 2H); 7.62 (d, 2H); 7.64 (s, 1H); 7.90 (s, 1H); 9.09 (s, 1H)./p>

2-Nitro-4-(3-N-methylpiperazine)-5-methoxybenzonitrile

2-Nitro-4-hydroxy-5-methoxybenzonitrile (45 g, 25 mmol) in CH2Cl2(125 ml) was injected into interaction with titrebordureparam (6.9 g, 30 mmol) and triphenylphosphine (7,86 g, 30 mmol) at room temperature for 2 hours. Added an ethereal solution of (2,3 N. HCl, 55 ml). The solid was isolated, washed with CH2Cl2, ether. The solid was dissolved in Meon, processed Meon/NH3, the solvents evaporated and the residue was purified by chromatography on silica gel, eluent: CH2Cl2/AcOEt 50/50, CH2Cl2/Meon 90/10, getting mentioned in the title compound (8.2 g, 98%).

MS ES+: 335.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.29 (t, 2H); 3.95 (s, 3H); 3.2-4 (m, 8H); 3.38 (t, 2H); 3.98 (s, 3H); 4.32 (t, 2H); 7.70 (s, 1H); 7.89 (s, 1H).

2-Amino-4-(3-N-methylpiperazine)-5-methoxybenzonitrile

2-Nitro-4-(3-N-methylpiperazine)-5-methoxybenzonitrile (1,67 g, 5 mmol), chloride designed ones (0.46 g, 2.5 mmol) in methylene chloride (40 ml) was treated with hydrosulfite sodium (4.35 g, 5 mmol) in water (40 ml) at room temperature for 1 hour. Was added HCl (6 N., 28 ml) to the mixture, which was heated at 60aboutC for 2.5 hours. The mixture was cooled, extracted with ethyl acetate. The aqueous phase was treated with Na2CO3(solid), were extracted ethylacetate is. The organic phase was dried over MgSO4concentrated, receiving specified in the header connection (0,93 g, 61%).

MS ES+: 305.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.18 (t, 2H); 2.93 (s, 3H); 3.1-4.1 (m, 8H); 3.39 (t, 2H); 3.66 (s, 3H); 4.05 (t, 2H); 6.54 (s, 1H); 7.00 (s, 1H).

N'-(2-Cyano-4-methoxy-5-(3-N-methylpiperazine)phenyl)-N,N-dimethylaminopropane

2-Amino-4-(3-N-methylpiperazine)-5-methoxybenzonitrile (16.4 g, 54 mmol) was injected into interaction with dimethylacetal dimethylformamide (12 ml, 90 mmol) in toluene (400 ml) by boiling for 4 hours. The solvent is evaporated, getting mentioned in the title compound (19,4 g, 100%).

MS ES+: 360.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.28 (t, 2H); 2.96 (s, 3H); 3.26 (s, 3H); 3.35 (s, 3H); 3.40 (t, 2H); 3.1-4 (m, 8H); 3.88 (s, 3H); 4.21 (t, 2H); 7.32 (s, 1H); 7.53 (s, 1H); 8.56 (s, 1H).

4-(Methyl(2-amino-1,3-thiazol-5-yl)acetate)-6-methoxy-4-((3-N-methylpiperazine)hinzelin

N'-(2-cyano-4-methoxy-5-(3-N-piperidinyloxy)phenyl)-N,N-dimethylaminopropane (9.7 g, 27 mmol) in acetic acid (100 ml) was injected into the interaction with methyl (2-amino-1,3-thiazol-5-yl)acetate (5.2 g, 30 mmol) at boiling for 4 hours. The solvent is evaporated and the residue was purified by chromatography on silica gel, eluent: CH2Cl2/Meon from from 99/1 97/3, getting mentioned in the title compound (9,15 g, 70%).

MS ES+: 487.6 (M+H)+

1H NMR (DMSO-d6, FA): 2.32 (t, 2H); 2.97 (s, 3H); 3.2-4.2 (m, 8H); 3.48 (t, 2H); 3.97 (s, 2H); 4.00 (s, 3H); 4.33 (t, 2H); 7.61 (s, 1H); 7.93 (s, 1H); 9.10 (s, 1H).

4((2-Amino-1,3-thiazol-5-yl)acetic acid)-6-methoxy-7-(3-(N-methylpiperazine)hinzelin

4-(Methyl(2-Amino-1,3-thiazol-5-yl)acetate)-6-methoxy-7-(3-(N-methylpiperazine)hinzelin (8,25 g, 17 mmol) in ethanol (80 ml) was treated with sodium hydroxide (2 N., 42,5 ml, 85 mmol) at room temperature for 1 hour. To the solution was added hydrochloric acid (2 BC) (pH 3). The solution was evaporated, the solid was isolated, dried, obtaining specified in the header connection (7,44 g, 93%).

MS ES+: 473,5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 2.94 (s, 3H); 3.2-4.1 (m, 8H); 3.45 (t, 2H); 3.89 (s, 2H); 3.97 (s, 3H); 4.29 (t, 2H); 7.30 (s, 2H); 7.56 (s, 1H); 7.90 (s, 1H); 7.90 (s, 1H); 9.06 (s, 1H).

Example 227. Getting connection 404 in table 16

By a reaction similar to that described in example 226, but based on 3,4-diferencia (77 mg, 0.6 mmol)were specified in the title compound (105 mg, 60%).

MS ES+: 584.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 2.94 (s, 3H); 3.2-4.1 (m, 8H); 3.44 (t, 2H); 3.99 (s, 5H); 4.30 (t, 2H); 7.32 (m, 1H); 7.40 (kun); 7.65 (s, 1H); 7.81 (m, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 228. Getting connection 405 in table 16

By a reaction similar to that described in example 226, but on the basis of 2-aminopyridine (56 mg, 0.6 mmol)were specified in the title compound (53 mg, 36%).

MS ES+: 549.6 M+H) +

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 2.94 (s, 3H); 3.1-4.1 (m, 8H); 3.41 (t, 2H); 3.99 (s, 3H); 4.02 (s, 2H); 4.32 (t, 2H); 7.21 (m, 1H); 7.34 (s, 1H); 7.64 (s, 1H); 7.91 (m, 2H); 8.03 (d, 1H); 8.37 (m, 1H); 9.98 (, 1H).

Example 229. Getting connection 406 in table 16

By a reaction similar to that described in example 226, but on the basis of 3-chloro-4-foronline (87 mg, 0.6 mmol)were specified in the title compound (134 mg, 74%).

MS ES+: 600.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.94 (s, 3H); 3.43 (t, 2H); 3.1-4.1 (m, 8H); 3.99 (s, 5H); 4.32 (t, 2H); 7.33 (s, 1H); 7.38 (t, 1H); 7.50 (m, 1H); 7.64 (s, 1H); 7.90 (s, 1H); 7.96 (m, 1H); 9.09 (s, 1H).

Example 230. Getting connection 407 table 16

By a reaction similar to that described in example 226, but on the basis of 3-Chloroaniline (77 mg, 0.6 mmol)were specified in the title compound (46 mg, 26%).

MS ES+: 582,6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.95 (s, 3H); 3.2-4.1 (m, 8H); 3.45 (t, 2H); 3.99 (s, 2H); 4.07 (s, 2H); 4.30 (t, 2H); 7.22 (t, 1H); 7.31 (s, 1H); 7.35 (m, 2H); 7.53 (d, 1H); 7.65 (s, 1H); 7.74 (d, 1H); 7.92 (with, 1H); 9.08 (s, 1H).

Example 231. Getting connection 408 in table 16

By a reaction similar to that described in example 226, but on the basis of 4-methylaniline (64 mg, 0.6 mmol)were specified in the title compound (105 mg, 62%).

MS ES+: 562.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.26 (s, 3H); 2.31 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H); 3.43 (t, 2H); 3.95 (s, 2H); 3.98 (s, 3H); 4.30 (t, 2H); 7.12 (d, 2H); 7.31 (s, 1H); 7.50 (d, 2H); 7.63 (s, 1H); 7.90 (s, 1H); 9.08 (N).

Example 232. Getting connection 409 table 16

By a reaction similar to that described in example 226, but on the basis of 2-methylaniline (64 mg, 0.6 mmol)were specified in the title compound (127 mg, 75%).

MS ES+: 562.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.24 (s, 3H); 2.31 (t, 2H); 2.95 (s, 3H); 3.2-4.1 (m, 8H); 3.44 (t, 2H); 3.99 (s, 3H); 4.02 (s, 2H); 4.31 (t, 2H); 7.12 (t, 1H); 7.19 (t, 1H); 7.24 (d, 1H); 7.33 (s, 1H); 7.44 (d, 1H); 7.66 (, 1H); 7.91 (s, 1H); 9.08 (s, 1H).

Example 233. Getting connection 410 in table 16

By a reaction similar to that described in example 226, but on the basis of 4-Chloroaniline (77 mg, 0.6 mmol)were specified in the title compound (101 mg, 58%).

MS ES+: 582.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H); 3.44 (t, 2H); 4.00 (s, 5H); 4.31 (t, 2H); 7.33 (s, 1H); 7.40 (d, 2H); 7.65 (s, 1H); 7.66 (d, 2H); 7.92 (s, 1H); 9.10 (s, 1H).

Example 234. Getting connection 411 table 16

By a reaction similar to that described in example 226, but on the basis of 4-foronline (67 mg, 0.6 mmol)were specified in the title compound (97 mg, 57%).

MS ES+: 566.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.94 (s, 3H); 3.1-4.1 (m, 8H); 3.44 (t, 2H); 3.97 (s, 2H); 3.99 (s, 3H); 4.30 (t, 2H); 7.17 (t, 2H); 7.34 (s, 1H); 7.64 (m, 3H); 7.90 (s, 1H); 9.09 (s, 1H).

Example 235. Getting connection 412 in table 16

By a reaction similar to that described in example 226, but on the basis of 2-amino-6-methylpyridine (65 mg, 0.6 mmol)were specified in the header with the unity (70 mg, 42%).

MS ES+: 563.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 2.46 (s, 3H); 2.94 (s, 3H); 3.10-4.10 (m, 8H); 3.43 (t, 2H); 3.98 (s, 3H); 4.06 (s, 2H); 4.30 (t, 2H); 7.08 (d, 1H); 7.32 (s, 1H); 7.63 (s, 1H); 7.79 (t, 1H); 7.88 (d, 1H); 7.91 (, 1H); 9.09 (s, 1H).

Example 236. The connection 413 table 16

By a reaction similar to that described in example 226, but based on the 2-methoxyaniline (74 mg, 0.6 mmol)were specified in the title compound (99 mg, 57%).

MS ES+: 578.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 2.94 (s, 3H); 3.1-4.1 (m, 8H); 3.43 (t, 2H); 3.74 (s, 3H); 3.97 (s, 2H); 3.99 (s, 3H); 4.30 (t, 2H); 6.67 (d, 1H); 7.15 (d, 1H); 7.24 (t, 1H); 7.33 (SN); 7.64 (s, 1H); 7.90 (s, 1H); 9.09 (s, 1H).

Example 237. Getting connection 414 in table 16

By a reaction similar to that described in example 226, but on the basis of 2-amino-5-chloropyridine (77 mg, 0.6 mmol)were specified in the title compound (23 mg, 13%).

MS ES+: 583.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 2.94 (s, 3H); 3.10-4.10 (m, 8H); 3.45 (t, 2H); 3.98 (s, 3H); 4.06 (s, 2H); 4.30 (t, 2H); 7.31 (s, 1H); 7.63 (s, 1H); 7.90 (s, 1H); 7.91 (DD, 1H); 8.11 (d, 1H); 8.40 (d, 1H); 9.09 (, 1H).

Example 238. The connection 415 table 16

By a reaction similar to that described in example 226, but on the basis of 3-Chloroaniline (77 mg, 0.6 mmol)were specified in the title compound (96 mg, 55%).

MS ES+: 582.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.94 (s, 3H); 3.2-4.2 (m, 8H); 3.45 (t, 2H); 3.98 (s, 5H); 4.28 (t, 2H); 7.12 (d, 1H); 7.31 (s, 1 is); 7.34 (t, 1H); 7.46 (d, 1H); 7.62 (s, 1H); 7.85 (s, 1H); 7.91 (s, 1H); 9.07 (s, 1H).

Example 239. Getting connection 416 in table 16

By a reaction similar to that described in example 226, but based on the 2-foronline (67 mg, 0.6 mmol)were specified in the title compound (68 mg, 40%).

MS ES+: 596.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.28 (t, 2H); 2.91 (s, 3H); 3.1-4.1 (m, 8H); 3.40 (t, 2H); 3.95 (s, 3H); 4.03 (s, 2H); 4.26 (t, 2H); 7.13 (m, 2H); 7.25 (m, 2H); 7.28 (s, 1H); 7.60 (s, 1H); 7.87 (s, 1H); 9.05 (s, 1H).

Example 240. Getting connection 417 table 16

By a reaction similar to that described in example 226, but based on 3-cyanoaniline (71 mg, 0.6 mmol)were specified in the title compound (101 mg, 63%).

MS ES+: 573.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H); 3.45 (t, 2H); 4.00 (s, 3H); 4.04 (s, 2H); 4.31 (t, 2H); 7.33 (s, 1H); 7.56 (s, 1H); 7.57 (m, 1H); 7.66 (s, 1H); 7.82 (m, 1H); 7.92 (s, 1H); 8.15 (, 1H); 9.10 (s, 1H).

Example 241. Getting connection 418 table 16

By a reaction similar to that described in example 226, but on the basis of 2-fluoro-4-methylamine (75 mg, 0.6 mmol)were specified in the title compound (109 mg, 63%).

MS ES+: 580.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.29 (m, 5H); 2.94 (s, 3H); 3.1-4.1 (m, 8H); 3.44 (t, 2H); 3.98 (s, 3H); 4.03 (s, 2H); 4.30 (t, 2H); 6.98 (d, 1H); 7.09 (d, 1H); 7.32 (s, 1H); 7.63 (s, 1H); 7.74 (t, 1H); 7.90 (s, 1H); 9.08 (, 1H).

Example 242. Getting connection 419 table 16

By a reaction similar to that described in example 226, but ex is Dublin core from 3-fluoro-4-methoxyaniline (85 mg, 0.6 mmol)were specified in the title compound (121 mg, 68%).

MS ES+: 596.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H); 3.44 (t, 2H); 3.81 (s, 3H); 3.95 (s, 2H); 3.99 (s, 3H); 4.30 (t, 2H); 7.13 (t, 1H); 7.27 (m, 1H); 7.31 (s, 1H); 7.60 (m, 1H); 7.64 (s, 1H); 7.90 (, 1H); 9.09 (s, 1H).

Example 243. The connection 420 in table 16

By a reaction similar to that described in example 226, but on the basis of 2-methyl-4-foronline (75 mg, 0.6 mmol)were specified in the title compound (130 mg, 75%).

MS ES+: 580.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.23 (s, 3H); 2.29 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H); 3.44 (t, 2H); 3.99 (s, 3H); 4.00 (s, 2H); 4.30 (t, 2H); 7.01 (m, 1H); 7.09 (DD, 1H); 7.32 (s, 1H); 7.40 (m, 1H); 7.65 (s, 1H); 7.91 (, 1H); 9.09 (s, 1H).

Example 244. Getting connection 421 table 16

By a reaction similar to that described in example 226, but on the basis of 2-amino-4-methylpyridine (65 mg, 0.6 mmol)were specified in the title compound (87 mg, 52%).

MS ES+: 563.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.29 (t, 2H); 2.45 (s, 3H); 2.94 (s, 3H); 3.1-4.1 (m, 8H); 3.44 (t, 2H); 3.99 (s, 3H); 4.15 (s, 2H); 4.30 (t, 2H); 7.24 (d, 1H); 7.37 (s, 1H); 7.67 (s, 1H); 7.72 (s, 1H); 7.92 (s, 1H); 8.29 (d, 1H); 9.08 (s, 1H).

Example 245. Getting connection 422 in table 16

By a reaction similar to that described in example 226, but based on 2,5-diferencia (77 mg, 0.6 mmol)were specified in the title compound (56 mg, 32%).

MS ES+: 584.6 (M+H)+

1H NMR (DMSO-d6

Example 246. Getting connection 423 table 16

By a reaction similar to that described in example 226, but on the basis of 2-fluoro-4-Chloroaniline (87 mg, 0.6 mmol)were specified in the title compound (69 mg, 38%).

MS ES+: 600.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 2.94 (s, 3H); 3.2-4.2 (m, 8H); 3.44 (t, 2H); 3.99 (s, 3H); 4.07 (s, 2H); 4.30 (t, 2H); 7.20 (DD, 1H); 7.33 (s, 1H); 7.51 (DD, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 7.97 (t, 1H); 9.09 (, 1H).

Example 247. Getting connection 424 table 16

By a reaction similar to that described in example 226, but on the basis of 2-fluoro-5-methylaniline (75 mg, 0.6 mmol)were specified in the title compound (81 mg, 46%).

MS ES+: 580.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.27 (s, 3H); 2.32 (t, 2H); 2.94 (s, 3H); 3.1-4.1 (m, 8H); 3.44 (t, 2H); 3.99 (s, 3H); 4.05 (s, 2H); 4.30 (t, 2H); 6.97 (m, 1H); 7.13 (DD, 1H); 7.34 (s, 1H); 7.63 (s, 1H); 7.74 (d, 1H); 7.91 (, 1H); 9.09 (s, 1H).

Example 248. The connection 425 table 16

By a reaction similar to that described in example 226, but on the basis of 3-methylaniline (64 mg, 0.6 mmol)were specified in the title compound (116 mg, 69%).

MS ES+: 584.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.28 (s, 3H); 2.31 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H); 3.45 (t, 2H); 3.96 (s, 2H); 3.98 (s, 3H); 4.30 (t, 2H); 6.88 (d, 1H); 7.19 (t, 1H); 7.30 (s, 1H); 7.39 (d, 1H); 7.47 (s, 1H); 7.62 (with, 1H); 7.91 (s, 1H); 9.08 (s, 1H).

the example 249. Getting connection 426 table 16

By a reaction similar to that described in example 226, but on the basis of 2,4-diferencia (77 mg, 0.6 mmol)were specified in the title compound (84 mg, 48%).

MS ES+: 584.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H); 3.99 (s, 3H); 4.05 (s, 2H); 4.30 (t, 2H); 7.07 (t, 1H); 7.32 (m, 2H); 7.64 (s, 1H); 7.86 (m, 1H); 7.91 (s, 1H); 9.08 (s, 1H).

Example 250. Getting connection 427 table 16

By a reaction similar to that described in example 226, but on the basis of 2-methyl-5-foronline (75 mg, 0.6 mmol)were specified in the title compound (98 mg, 57%).

MS ES+: 580.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.23 (s, 3H); 2.31 (t, 2H); 2.94 (s, 3H); 3.1-4.1 (m, 8H); 3.43 (t, 2H); 3.98 (s, 3H); 4.05 (s, 2H); 4.30 (t, 2H); 6.91 (m, 1H); 7.25 (t, 1H); 7.32 (s, 1H); 7.44 (DD, 1H); 7.65 (s, 1H); 7.91 (, 1H); 9.08 (s, 1H).

Example 251. Getting connection 428 table 16

By a reaction similar to that described in example 226, but based on 3,5-diferencia (77 mg, 0.6 mmol)were specified in the title compound (54 mg, 31%).

MS ES+: 584.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H); 3.45 (t, 2H); 3.99 (s, 3H); 4.02 (s, 2H); 4.31 (t, 2H); 6.92 (m, 1H); 7.33 (s, 1H); 7.35 (m, 2H); 7.66 (s, 1H); 7.92 (s, 1H); 9.10 (s, 1H).

Example 252. Getting connection 429 table 16

By a reaction similar to that described in example 226, but based on 3-foronline (67 mg, 0.6 mmol)were specified in the header link is (120 mg, 70%).

MS ES+: 566.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.94 (s, 3H); 3.2-4.2 (m, 8H); 3.44 (t, 2H); 3.98 (s, 3H); 3.99 (s, 2H); 4.30 (t, 2H); 6.90 (s, 1H); 7.34 (s, 1H); 7.36 (m, 2H); 7.61 (m, 1H); 7.64 (s, 1H); 7.90 (s, 1H); 9.09 (, 1H).

Example 253. Getting connection 430 in table 17

N-(3-chloranil)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazol-5-yl)ndimethylacetamide (141 mg, 0.22 mmol) in acetonitrile (2 ml) was injected into interaction with pyrrolidine (3.3 mmol) in the presence of potassium iodide (100 mg, 0.6 mmol) at 80aboutAt least 15 hours/30 hours. Upon completion of reaction (TLC) was added DMF (2 ml), silica gel, the mixture was evaporated and the residue was purified by chromatography on silica gel, eluent: CH2Cl2/Meon 95/5, CH2Cl2/Meon feast upon. NH390/10, getting mentioned in the title compound (81 mg, 29%).

MS ES+: 553.4, 554.4 (M+H)+

1H NMR (DMSO-d6, TFA): 1.90 (m, 2H); 2.06 (m, 2H); 2.26 (t, 2H); 3.09 (m, 2H); 3.36 (t, 2H); 3.67 (m, 2H); 3.99 (s, 3H); 4.00 (s, 2H); 4.29 (t, 2H); 7.14 (d, 1H); 7.30 (s, 1H); 7.37 (t, 1H); 7.47 (d, 1H); 7.65 (s, 1H); 7.85 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

3-Methoxy-4-benzyloxybenzoate

3-Methoxy-4-benzyloxybenzaldehyde (4,87 g, 20 mmol) in acetic acid (25 ml) was treated with hydroxylamine HCl (2.8 g, 40 mmol), sodium acetate (3.3 g, 40 mmol) at boiling for 6 hours. The mixture was cooled, extracted with water and methylene chloride, dried over MgSO4was evaporated, receiving specified in the header is EDINENIE (4.8 g, 100%).

1H NMR (DMSO-d6, TFA): 3.72 (s, 3H); 5.15 (s, 2H); 7.18 (d, 1H); 7.39 (m, 7H).

2-Nitro-4-benzyloxy-5-methoxybenzonitrile

2-Methoxy-4-benzyloxybenzoate (4,78 g, 20 mmol) in acetic acid (10 ml) was slowly added to nitric acid (d=1,42, 25 ml) and cooled to 20-30° in a bath with ice. After that, the mixture was stirred at room temperature for 6 hours. The reaction mixture was treated with potassium hydroxide (10 BC) at 0°C. the Bulk mixture (pH 10) was extracted with CH2Cl2, the organic phase was dried over MgSO4concentrated, receiving specified in the header connection (3,62 g, 64%)

MS ES+: 285 (M+H)+

1H NMR (DMSO-d6, TFA): 3.97 (s, 3H); 5.33 (s, 2H); 7.42 (m, 5H); 7.70 (s, 1H); 8.03 (s, 1H).

2-Amino-4-benzyloxy-5-methoxybenzonitrile

2-Nitro-4-benzyloxy-5-methoxybenzonitrile (40 g, 125 mmol), tetrabutylammonium chloride (21 g, 75 mmol) in methylene chloride (500 ml) was treated with Na2S2O4(180 g, 87.9 mmol) in N2O (700 ml)during 45 minutes were added hydrosulfite sodium and the mixture was stirred at room temperature for 2 hours. Was added sodium hydroxide (pH 8.2), the mixture was extracted with methylene chloride. The organic phase was acidified with HCl-ether (2,3 N., 250 ml), the solid was isolated, suspended in methanol (250 ml) and treated with a saturated solution of sodium bicarbonate (pH 8.1). TV is Joe substance was isolated, washed with water, ether, receiving specified in the header connection (30,7 g, 97%).

1H NMR (DMSO-d6): 3.65 (s, 3H); 5.04 (s, 2H); 5.61 (s, 2H); 6.51 (s, 1H); 6.91 (s, 1H); 7.40 (m, 5H).

N'-(2-Cyano-4-methoxy-5-benzyloxyphenyl)-N,N-dimethylaminopropane.

2-Amino-4-benzyloxy-5-methoxybenzonitrile (102 g, 400 mmol) in toluene (1.5 l) was injected into the interaction with DMA, DMF (110 ml, 780 mmol) by boiling for 5 hours. The solvent is evaporated, the residue triturated with ether, getting mentioned in the title compound as a yellow solid.

1H NMR (DMSO-d6): 2.96 (s, 3H); 3.06 (s, 3H); 3.73 (s, 3H); 5.15 (s, 2H); 6.87 (s, 1H); 7.11 (s, 1H); 7.40 (m, 5H); 7.89 (s, 1H).

N'-(2-Cyano-4-methoxy-5-hydroxyphenyl)-N,N-dimethylaminopropane.

N'-(2-Cyano-4-methoxy-5-benzyloxyphenyl)-N,N-dimethylaminopropane (15,45 g, 50 mmol) in TFA (200 ml) was irradiated in a microwave oven at 75°C for 45 minutes. The solvent is evaporated, the residue dissolved in methylene chloride, washed with sodium bicarbonate, dried over magnesium sulfate, evaporated, obtaining a pale yellow solid (10,26 g, 94%).

1H NMR (DMSO-d6, TFA): 3.24 (s, 3H); 3.34 (s, 3H); 3.87 (s, 3H); 7.02 (s, 1H); 7.49 (s, 1H); 8.56 (s, 1H).

N'-(2-Cyano-4-methoxy-5-(3-chloropropanesulfonyl)-N,N-dimethylaminopropane

N'-(2-Cyano-4-methoxy-5-hydroxyphenyl)-N,N-dimethylaminopropane (439 mg, 2 mmol) in acetonitrile (5 ml) was injected into the interaction with 1-bromo-3 is Acropora (0,22 ml, 2.2 mmol) and cesium carbonate (1,95 g, 5,98 mmol) at 85°C for 0.5 hour. The reaction mixture was evaporated, dissolved in methylene chloride, water, was extracted with CH2Cl2, dried over MgSO4was evaporated, getting mentioned in the title compound as a pale yellow solid (450 mg, 76%).

MS ES+: 296.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.26 (t, 2H); 3.26 (s, 3H); 3.37 (s, 3H); 3.81 (t, 2H); 3.87 (s, 3H); 4.23 (t, 2H); 7.34 (s, 1H); 7.53 (s, 1H); 8.56 (s, 1H).

g) N-(3-chlorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-ylamino)1,3-thiazol-5-yl)ndimethylacetamide

N'-(2-Cyano-4-methoxy-5-(3-chloropropanesulfonyl)-N,N-dimethylaminopropane (296 mg, 1 mmol) and 2-(2-amino-1,3-thiazol-5-yl)-N-(3-chlorophenyl)ndimethylacetamide (268 mg, 1 mmol) in Asón (1.5 ml) was irradiated in a microwave oven at 120°C for 40 minutes. The mixture was cooled, the solid was filtered, getting mentioned in the title compound (445 mg, 72%).

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.84 (t, 2H); 3.98 (s, 3H); 3.99 (s, 2H); 4.32 (t, 2H); 7.13 (d, 1H); 7.29 (s, 1H); 7.36 (t, 1H); 7.46 (d, 1H); 7.63 (s, 1H); 7.85 (s, 1H); 7.88 (s, 1H); 9.07 (s, 1H).

Example 254. Getting connection 431 table 17

By a reaction similar to that described in example 253, but proceeding from N-(3,4-differenl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazol-5-yl)ndimethylacetamide (52 mg, 0.1 mmol) and pyrrolidine (150 μl, 1.8 mmol)were specified in the title compound (26 mg, 47%).

1H NMR(DMSO-d 6, TFA): 1.91 (m, 2H); 2.07 (m, 2H); 2.28 (t, 2H); 3.10 (m, 2H); 3.37 (t, 2H); 3.67 (m, 2H); 3.99 (s, 5H); 4.30 (t, 2H); 7.30 (s, 1H); 7.33 (m, 1H); 7.40 (q, 1H); 7.65 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

The original compound N-(3,4-differenl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazol-5-yl)ndimethylacetamide was obtained by a reaction similar to that described in example 130, but on the basis of 2-(2-amino-1,3-thiazol-5-yl)-N-(3,4-differenl)ndimethylacetamide (540 mg, 2 mmol), getting mentioned in the title compound (980 mg, 78%).

MS ES+: 520.4, 522.4 (M+H)+

1H NMR (DMSO-d6): 1.26 (t, 2H); 3.82 (t, 2H); 3.88 (s, 2H); 3.97 (s, 3H); 4.29 (t, 2H); 7.29 (s, 1H); 7.32 (m, 1H); 7.36 (s, 1H); 7.39 (t, 1H); 7.80 (m, 1H); 8.12 (s, 1H); 8.68 (s, 1H).

Example 255. Getting connection 432 table 17

By a reaction similar to that described in example 253, but proceeding from N-(3,5-differenl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazol-5-yl)ndimethylacetamide (138 mg, 0.22 mmol) and dimethylamine (3.6 M in CH2Cl2, 3 ml, 3.6 mmol)were specified in the title compound (47 mg, 40%).

MS ES+: 529.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.25 (t, 2H); 3.28 (t, 2H); 3.99 (s, 3H); 4.01 (s, 2H); 4.28 (t, 2H); 6.93 (m, 1H); 7.30 (s, 1H); 7.34 (m, 2H); 7.65 (s, 1H); 7.90 (s, 1H); 9.09 (s, 1H).

The source connection of the N-(3,5-differenl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazol-5-yl)ndimethylacetamide was obtained by a reaction similar to that described in example 130, but on the basis of 2-(2-amino-1,3-thiazol-5-yl)-N-(3,5-differenl)acetone is Yes (810 mg, 3 mmol), getting mentioned in the title compound (630 mg, 40%).

MS ES+: 520.4, 522.4 (M+H)+

1H NMR (DMSO-d6, TFA): 2.26 (t, 2H); 3.84 (t, 2H); 3.92 (s, 2H); 3.98 (s, 3H); 4.30 (t, 2H); 6.94 (m, 1H); 7.30 (s, 1H); 7.35 (m, 2H); 7.40 (s, 1H); 8.14 (s, 1H); 8.69 (s, 1H); 10.64 (s, 1H).

Example 256. Getting connection 433 table 17

By a reaction similar to that described in example 253, but proceeding from N-(3-chloro-4-forfinal)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazol-5-yl)ndimethylacetamide (123 mg, 0.22 mmol) and 2-amino-2-methyl-1-propanol (89,1 mg, 3.3 mmol)were specified in the title compound (6 mg, 5%).

MS ES+: 589.4 (M+H)+

1H NMR (DMSO-d6, TFA): 1.24 (s, 6N); 2.22 (t, 2H); 3.10 (t, 2H); 3.45 (s, 2H); 3.98 (s, 3H); 4.31 (t, 2H); 7.29 (s, 1H); 7.38 (t, 1H); 7.50 (m, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 7.97 (s, 1H); 9.09 (s, 1H).

The source connection of the N-(3-chloro-4-forfinal)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazol-5-yl)ndimethylacetamide was obtained by a reaction similar to that described in example 130, but on the basis of 2-(2-amino-1,3-thiazol-5-yl)-N-(3-chloro-4-forfinal)ndimethylacetamide (to 2.29 g, 8.0 mmol), receiving specified in the header connection (3,62 g, 84%).

MS ES+: 536.3, 538.3 (M+H)+

1H NMR (DMSO-d6, TFA): 2.26 (t, 2H); 3.82 (t, 2H); 3.88 (s, 2H); 3.96 (s, 3H); 4.29 (t, 2H); 7.28 (s, 1H); 7.38 (t, 1H); 7.39 (s, 1H); 7.48 (m, 1H); 7.93 (m, 1H); 8.12 (s, 1H); 8.67 (s, 1H); 10.47 (s, 1H).

Example 257. Getting connection 434 table 17

By a reaction similar to that described in example 253, n is based on N-(3-forfinal)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazol-5-yl)ndimethylacetamide (116 mg, 0.22 mmol) and 2-amino-2-methyl-1-propanol (89 mg, 3.3 mmol)were specified in the title compound (40 mg, 33%).

MS ES+: 555.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.22 (t, 2H); 3.09 (t, 2H); 3.16 (s, 2H); 3.97 (s, 3H); 4.30 (t, 2H); 6.86 (t, 1H); 7.28 (s, 1H); 7.33 (m, 2H); 7.58 (m, 1H); 7.62 (s, 1H); 7.91 (s, 1H); 9.07 (s, 1H).

The source connection of the N-(3-forfinal)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazol-5-yl)ndimethylacetamide was obtained by a reaction similar to that described in example 253, but on the basis of 2-(2-amino-1,3-thiazol-5-yl)-N-(3-forfinal)ndimethylacetamide (2,01 g, 8 mmol), receiving specified in the header of the connection (is 3.08 g, 77%).

MS ES+: 502.4, 504.4 (M+H)+

1H NMR (DMSO-d6): 2.28 (t, 2H); 3.84 (t, 2H); 3.90 (s, 2H); 3.98 (s, 3H); 4.31 (t, 2H); 6.91 (t, 1H); 7.30 (s, 1H); 7.35 (m, 2H); 7.39 (s, 1H); 7.63 (d, 1H); 8.14 (s, 1H); 8.69 (s, 1H); 10.48 (s, 1H).

Example 258. Getting connection 435 table 17

By a reaction similar to that described in example 254, but on the basis of 4-hydroxypiperidine (405 mg, 4.0 mmol), received the connection 435 in table 17 (82 mg, 70%).

MS ES+: 585.5 (M+H)+

1H NMR (DMSO-d6): 1.43 (m, 2H); 1.73 (m, 2H); 1.95 (m, 2H); 2.03 (t, 2H); 2.44 (t, 2H); 2.74 (m, 2H); 3.38 (m, 1H); 3.90 (s, 2H); 3.97 (s, 3H); 4.20 (t, 1H); 4.53 (d, 1H); 7.26 (s, 1H); 7.31 (m, 1H); 7.39 (s, 1H); 7.42 (DDD, 1H); 7.83 (m, 1H); 8.12 (s, 1H); 8.68 (s, 1H); 10.50 (s, 1H).

Example 259. Getting connection 436 table 17

By a reaction similar to that described in example 254, but based on N,N-dimethylaniline (of 0.44 ml, 4.0 mmol) received connection 436 in table 17 (40 mg, 35%).

MS ES+: 572.5 (M+H)+

1H NMR (DMSO-d6): 1.95 (m, 2H); 2.14 (s, 6N); 2.33 (t, 2H); 2.63 (t, 2H); 2.73 (t, 2H); 3.89 (s, 2H); 3.97 (s, 3H); 4.22 (t, 1H); 7.26 (s, 1H); 7.34 (m, 1H); 7.38 (s, 1H); 7.41 (DDD, 1H); 7.82 (m, 1H); 8.11 (s, 1H); 8.67 (s, 1H); 10.50 (s, 1H).

Example 260. Getting connection 437 table 17

By a reaction similar to that described in example 254, but on the basis of piperidine (0.4 ml, 3.0 mmol), obtained compound 437 table 17 (67 mg, 59%).

MS ES+: 569.5 (M+H)+

1H NMR (DMSO-d6): 1.40 (m, 2H); 1.52 (m, 4H); 1.95 (m, 2H); 2.42 (m, 4H); 2.48 (t, 2H); 3.89 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 7.25 (s, 1H); 7.33 (m, 1H); 7.39 (s, 1H); 7.41 (DDD, 1H); 7.82 (m, 1H); 8.11 (s, 1H); 8.68 (s, 1H); 10.51 (s, 1H).

Example 261. Getting connection 438 table 17

By a reaction similar to that described in example 254, but based on the 2-methylaminoethanol (248 mg, 3.3 mmol), received the connection 438 table 17 (23 mg, 19%).

MS ES+: 559 (M+H)+

1H NMR (DMSO-d6): 1.95 (m, 2H); 2.23 (s, 3H); 2.47 (m, 2H); 3.32 (m, 2H); 3.49 (m, 2H); 3.90 (s, 2H); 3.98 (s, 3H); 4.21 (t, 1H); 4.37 (m, 1H); 7.27 (s, 1H); 7.34 (m, 1H); 7.38 (s, 1H); 7.40 (DD, 1H); 7.82 (DDD, 1H); 8.13 (user s, 1H); 8.68 (s, 1H); 10.50 (s, 1H).

Example 262. Getting connection 439 table 17

By a reaction similar to that described in example 254, but on the basis of 1,2-diamino-2-methylpropane (291 mg, 3.3 mmol), obtained 439 connection in table 17 (16 mg, 13%).

MS ES+: 572 (M+H)+

1H NMR (DMSO-d6): 1.10 (s, 6N); 1.96 (m, 2H); 2.48 (s, 2H); 2.75 (t, 2H); 3.89 (s, 2H); 3.97 (s, 3H);4.26 (t, 2H); 7.27 (s, 1H); 7.34 (m, 1H); 7.37 (s, 1H); 7.42 (DD, 1H); 7.83 (DDD, 1H); 8.10 (s, 1H); 8.66 (s, 1H); 10.50 (s, 1H).

Example 263. Getting connection 440 in table 17

By a reaction similar to that described in example 254, but on the basis of cyclohexylamine (327 mg, 3.3 mmol), received the connection 440 in table 17 (70 mg, 55%).

MS ES+: 583 (M+H)+

1H NMR (DMSO-d6): 1.12 (m, 1H); 1.27 (m, 4H); 1.63 (user d, 1H); 1.78 (m, 2H); 2.04 (m, 2H); 2.16 (m, 2H); 3.03 (m, 1H); 3.16 (t, 2H); 3.90 (s, 2H); 3.98 (s, 3H); 4.29 (t, 2H); 7.31 (s, 1H); 7.34 (m, 1H); 7.40 (s, 1H); 7.42 (DD, 1H); 7.82 (DDD, 1H); 8.16 (user s, 1H); 8.70 (s, 1H); 10.51 (s, 1H).

Example 264. Getting connection 441 table 17

By a reaction similar to that described in example 254, but based on N,N,N'-trimethylethylenediamine (337 mg, 3.3 mmol), received the connection 441 table 17 (63 mg, 49%).

MS ES+: 587 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (m, 2H); 2.88 (s, 6N); 2.93 (s, 3H); 3.38 (m, 2H); 3.56 (m, 4H); 3.98 (s, 5H); 4.30 (t, 2H); 7.29 (m, 1H); 7.33 (s, 1H); 7.35 (DD, 1H); 7.63 (s, 1H); 7.80 (DDD, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 265. Getting connection 442 table 17

By a reaction similar to that described in example 254, but on the basis of (R)-(-)-2-pyrrolidineethanol (334 mg, 3.3 mmol), received the connection 442 in table 17 (90 mg, 70%).

MS ES+: 585 (M+H)+

1H NMR (DMSO-d6, TFA): 1.79 (m, 1H); 1.91 (m, 1H); 2.03 (m, 1H); 2.11 (m, 1H); 2.29 (m, 2H); 3.21 (m, 1H); 3.62 (m, 4H); 3.77 (m, 1H); 3.98 (s, 5H); 4.29 (t, 2H); 7.30 (s, 1H); 7.32 (m, 1H); 7.39 (DD, 1H); 7.64 (s, 1H); 7.80 (DDD, 1H); 7.90 (s, 1H); 9.08 (s, 1H).

P the emer 266. Getting connection 443 table 17

By a reaction similar to that described in example 254, but on the basis of (S)-(+)-2-pyrrolidineethanol (334 mg, 3.3 mmol), received the connection 443 table 17 (82 mg, 63%).

MS ES+: 585 (M+H)+

1H NMR (DMSO-d6, TFA): 1.76 (m, 1H); 1.88 (m, 1H); 2.01 (m, 1H); 2.10 (m, 1H); 2.26 (m, 2H); 3.21 (m, 2H); 3.59 (m, 4H); 3.74 (DD, 1H); 3.95 (s, 5H); 4.27 (t, 2H); 7.27 (s, 1H); 7.28 (m, 1H); 7.34 (DD, 1H); 7.60 (s, 1H); 7.77 (DDD, 1H); 7.88 (s, 1H); 9.05 (s, 1H).

Example 267. Getting connection 444 table 17

By a reaction similar to that described in example 254, but based on 3-pyrrolidinone (288 mg, 3.3 mmol), received the connection 444 in table 17 (15 mg, 12%).

MS ES+: 571 (M+H)+

1H NMR (DMSO-d6, TFA): 1.85-2.04 (m, 2H); 2.28 (m, 2H); 3.03-3.54 (m, 4H); 3.75 (m, 2H); 3.99 (s, 5H); 4.28 (m, 2H); 4.40-4.52 (m, 1H); 7.29 (s, 1H); 7.33 (m, 1H); 7.39 (DD, 1H); 7.64 (s, 1H); 7.81 (DDD, 1H); 7.91 (s, 1H); 9.08 (s, 1H).

Example 268. Getting connection 445 table 17

By a reaction similar to that described in example 254, but on the basis of 1-(2-aminoethyl)pyrrolidine (377 mg, 3.3 mmol), received the connection 445 table 17 (20 mg, 15%).

MS ES+: 598 (M+H)+

1H NMR (DMSO-d6, TFA): 1.92 (m, 2H); 2.06 (m, 2H); 2.24 (m, 2H); 3.11 (m, 2H); 3.23 (t, 2H); 3.42 (m, 2H); 3.49 (m, 2H); 3.52 (m, 2H); 4.00 (s, 5H); 4.32 (t, 2H); 7.32 (s, 1H); 7.33 (m, 1H); 7.39 (DD, 1H); 7.65 (s, 1H); 7.81 (DDD, 1H); 7.92 (s, 1H); 9.10 (s, 1H).

Example 269. Getting connection 446 table 17

By a reaction similar to that described in example 254, but on the basis of 1-Clipperton (423 mg, 3.3 mmol), received the connection 446 in table 17 (100 mg, 74%).

MS ES+: 612 (M+H)+

1H NMR (DMSO-d6): 2.00 (s, 5H); 2.35 (m, 2H); 2.42 (m, 2H); 3.92-3.06 (m, 1H); 3.45 (m, 4H); 3.56 (t, 1H); 3.90 (s, 2H); 3.98 (s, 3H); 4.23 (t, 2H); 7.28 (s, 1H); 7.34 (m, 1H); 7.40 (s, 1H); 7.42 (DD, 1H); 7.83 (DDD, 1H); 8.13 (user s, 1H); 8.69 (s, 1H).

Example 270. Getting connection 447 table 17

By a reaction similar to that described in example 254, but on the basis of 1-(2-morpholinoethyl)-piperazine (658 mg, 3.3 mmol), obtained compound 447 table 17 (44 mg, 29%).

MS ES+: 683 (M+H)+

1H NMR (DMSO-d6): 1.98 (m, 1H); 2.30-2.70 (m, N); 3.58 (m, 4H); 3.90 (s, 2H); 3.97 (s, 3H); 4.21 (t, 2H); 7.26 (s, 1H); 7.33 (m, 1H); 7.40 (s, 1H); 7.41 (DD, 1H); 7.82 (DDD, 1H); 8.13 (user s, 1H); 8.69 (s, 1H); 10.54 (s, 1H).

Example 271. Getting connection 448 table 17

By a reaction similar to that described in example 254, but based on the 2-piperidinemethanol (426 mg, 3.3 mmol), obtained compound 448 in table 17 (19 mg, 14%).

MS ES+: 613 (M+H)+

1H NMR (DMSO-d6, TFA): 1.45-1.92 (m, 7H); 2.00-2.15 (m, 1H); 2.20-2.40 (m, 2H); 3.10-3.70 (m, 7H); 3.99 (s, 5H); 4.30 (m, 2H); 7.30 (s, 1H); 7.34 (m, 1H); 7.40 (DD, 1H); 7.64 (s, 1H); 7.81 (DDD, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 272. Getting connection 449 table 17

By a reaction similar to that described in example 254, but on the basis of 1-(2-hydroxyethyl)-piperazine (430 mg, 3.3 mmol), obtained compound 449 table 17 (90 mg, 66%).

MS ES+: 614 (M+H)+

1H NMR (DMSO-d6): 1.96 (m, 2H); 2.352.47 (m, N); 3.49 (q, 2H); 3.90 (s, 2H); 3.97 (s, 3H); 4.20 (t, 1H); 4.37 (t, 1H); 7.25 (s, 1H); 7.33 (m, 1H); 7.39 (s, 1H); 7.41 (DD, 1H); 7.81 (DDD, 1H); 8.12 (user s, 1H); 8.68 (s, 1H); 10.50 (s, 1H); 12.03 (user with, 1H).

Example 273. Getting connection 450 table 17

By a reaction similar to that described in example 254, but based on cyclopentylamine (281 mg, 3.3 mmol), received the connection 450 in table 17 (43 mg, 34%).

MS ES+: 614 (M+H)+

1H NMR (DMSO-d6): 1.53 (m, 4H); 1.69 (m, 2H); 1.93 (m, 2H); 2.10 (m, 2H); 3.00 (m, 2H); 3.38 (m, 2H); 3.90 (s, 2H); 3.98 (s, 3H); 4.28 (t, 2H); 7.30 (s, 1H); 7.32 (m, 1H); 7.42 (DD, 1H); 7.81 (DDD, 1H); 8.15 (user s, 1H); 8.70 (s, 1H); 10.51 (s, 1H).

Example 274. Getting connection 451 table 17

By a reaction similar to that described in example 254, but on the basis of 4-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol), received the connection 451 table 17 (53 mg, 39%).

MS ES+: 613 (M+H)+

1H NMR (DMSO-d6): 1.14 (m, 2H); 1.36 (m, 3H); 1.63 (user d, 2H); 1.87 (m, 2H); 1.95 (m, 2H); 2.45 (m, 1H); 2.86 (m, 2H); 3.44 (m, 2H); 3.90 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.32 (t, 1H); 7.26 (s, 1H); 7.31 (m, 1H); 7.40 (s, 1H); 7.42 (DD, 1H); 7.82 (DDD, 1H); 8.13 (user s, 1H); 8.68 (s, 1H); 10.50 (s, 1H); 12.02 (user s, 1H).

Example 275. Getting connection 452 table 17

By a reaction similar to that described in example 254, but on the basis of the hydrochloride of L-alanine tert-butyl ester (599 mg, 3.3 mmol)and treated crude reaction mixture with a solution of CH2Cl2-TFA 1:1 (4 ml), was awarded the connection 452 in table 17 (75 mg, 60%).

MS ES+: 73 (M+H) +

1H NMR (DMSO-d6, TFA): 1.48 (d, 3H); 2.24 (m, 2H); 3.22 (m, 2H); 3.97 (s, 5H); 4.15 (q, 1H); 4.30 (m, 2H); 7.30 (s, 1H); 7.34 (m, 1H); 7.40 (DD, 1H); 7.64 (s, 1H); 7.81 (DDD, 1H); 7.90 (s, 1H); 9.08 (s, 1H); 10.60 (s, 1H).

Example 276. Getting connection 453 table 17

By a reaction similar to that described in example 254, but based on 3-hydroxypiperidine (334 mg, 3.3 mmol), obtained compound 453 table 17 (84 mg, 65%).

MS ES+: 585 (M+H)+

1H NMR (DMSO-d6): 1.07 (m, 1H); 1.41 (m, 1H); 1.62 (m, 1H); 1.76 (m, 2H); 1.87 (m, 1H); 1.95 (m, 2H); 2.47 (m, 2H); 2.68 (m, 1H); 2.85 (m, 1H); 3.48 (m, 1H); 3.90 (s, 2H); 3.98 (s, 3H); 4.20 (t, 2H); 4.59 (d, 1H); 7.26 (s, 1H); 7.31 (m, 1H); 7.39 (s, 1H); 7.42 (DD, 1H); 7.81 (DDD, 1H); 8.12 (user s, 1H); 8.68 (s, 1H); 10.50 (s, 1H); 12.02 (user s, 1H).

Example 277. Getting connection 454 table 17

By a reaction similar to that described in example 254, but on the basis of 4-hydroxyethylpiperazine (380 mg, 3.3 mmol), received the connection 454 in table 17 (42 mg, 32%).

MS ES+: 599 (M+H)+

1H NMR (DMSO-d6): 1.13 (m, 1H); 1.33 (m, 1H); 1.62 (user d, 2H); 1.90 (m, 2H); 1.95 (m, 2H); 2.44 (m, 2H); 2.88 (m, 2H); 3.22 (t, 2H); 3.86 (s, 2H); 3.93 (s, 3H); 4.17 (t, 2H); 4.38 (t, 1H); 7.22 (s, 1H); 7.31 (m, 1H); 7.36 (s, 1H); 7.38 (DD, 1H); 7.80 (DDD, 1H); 8.09 (user s, 1H); 8.65 (s, 1H); 10.46 (s, 1H); 12.00 (user s, 1H).

Example 278. Getting connection 455 table 17

By a reaction similar to that described in example 254, but on the basis of 1-amino-2-propanol (248 mg, 3.3 mmol), obtained compound 455 in table 17 (52 mg, 42%).

MS ES+: 573 (M+H)+

1H NMR (DMSO-d6): 1.06 (d, 3H); 1.95 (m, 2H); 2.48 (m, 2H); 2.72 (t, 2H); 3.68 (m, 1H); 3.89 (s, 2H); 3.97 (s, 3H); 4.23 (t, 2H); 4.46 (m, 1H); 7.26 (s, 1H); 7.32 (m, 1H); 7.38 (s, 1H); 7.41 (DD, 1H); 7.81 (DDD, 1H); 8.11 (s, 1H); 8.67 (s, 1H); 10.49 (s, 1H).

Example 279. Getting connection 456 in table 17

By a reaction similar to that described in example 253, but on the basis of the hydrochloride of L-alanine tert-butyl ester (599 mg, 3.3 mmol) and treated crude reaction mixture is CH2Cl2-TFA, (1/1, 4 ml), was awarded the connection 456 in table 17 (106 mg, 84%).

MS ES+: 571 (M+H)+

1H NMR (DMSO-d6, TFA): 1.40 (d, 3H); 2.25 (m, 2H); 3.20 (m, 2H); 3.98 (s, 3H); 4.00 (s, 2H); 4.14 (m, 1H); 4.31 (t, 2H); 7.13 (DD, 1H); 7.32 (s, 1H); 7.35 (t, 1H); 7.47 (DD, 1H); 7.63 (s, 1H); 7.86 (t, 1H); 7.90 (s, 1H); 8.30 (m, 1H); 9.08 (s, 1H); 10.60 (s, 1H).

Example 280. Getting connection 457 table 17

By a reaction similar to that described in example 253, but based on the 2-methylaminoethanol (248 mg, 3.3 mmol), received the connection 457 table 17 (86 mg, 70%).

MS ES+: 557 (M+H)+

1H NMR (DMSO-d6): 1.93 (m, 2H); 2.20 (s, 3H); 2.43 (t, 2H); 2.48 (m, 1H); 2.55 (m, 1H); 3.47 (DD, 2H); 3.89 (s, 2H); 3.96 (s, 3H); 4.19 (t, 2H); 4.34 (t, 1H); 7.13 (user d, 1H); 7.25 (s, 1H); 7.35 (t, 1H); 7.38 (s, 1H); 7.47 (s, 1H); 7.84 (s, 1H); 8.11 (DD, 1H); 8.66 (s, 1H); 10.44 (s, 1H); 12.00 (DD, 1H).

Example 281. Getting connection 458 table 17

By a reaction similar to that described in example 253, but on the basis of 1,2-diamino-2-methylpropane (291 mg, 3.3 mmol), received the connection 458 in table 17 (21 mg, 17%).

MS ES+: 570 (M+H)+

1H NMR (DMSO-d6, TFA): 1.39 (s, 1H); 2.28 (m, 2H); 3.23 (m, 4H); 3.98 (s, 3H); 4.00 (s, 2H); 4.32 (m, 2H); 7.14 (DDD, 1H); 7.31 (s, 1H); 7.36 (t, 1H); 7.47 (DDD, 1H); 7.64 (s, 1H); 7.86 (t, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 282. Getting connection 459 table 17

By a reaction similar to that described in example 253 but based on cyclohexylamine (327 mg, 3.3 mmol), obtained compound 459 table 17 (85 mg, 66%).

MS ES+: 581 (M+H)+

1H NMR (DMSO-d6): 1.13 (m, 1H); 1.26 (m, 4H); 1.62 (user d, 1H); 1.77 (m, 2H); 2.03 (m, 2H); 3.15 (m, 2H); 3.07 (m, 1H); 3.14 (t, 2H); 3.90 (s, 2H); 3.97 (s, 3H); 4.29 (t, 2H); 7.13 (user d, 1H); 7.29 (s, 1H); 7.36 (t, 1H); 7.39 (s, 1H); 7.46 (DD, 1H); 8.16 (DD, 1H); 8.26 (user s, 1H); 8.69 (s, 1H); 10.45 (s, 1H).

Example 283. Getting connection 460 in table 17

By a reaction similar to that described in example 253, but based on N,N-dimethylethylenediamine (291 mg, 3.3 mmol), received the connection 460 in table 17 (41 mg, 32%).

MS ES+: 570 (M+H)+

1H NMR (DMSO-d6): 2.00 (m, 1H); 2.17 (s, 6N); 2.38 (t, 2H); 2.72 (t, 2H); 2.81 (t, 2H); 3.91 (s, 2H); 3.98 (s, 3H); 4.24 (t, 2H); 7.14 (DD, 1H); 7.27 (s, 1H); 7.37 (t, 1H); 7.40 (s, 1H); 7.49 (DD, 1H); 7.86 (t, 1H); 8.13 (s, 1H); 8.69 (s, 1H); 10.50 (s, 1H).

Example 284. Getting connection 461 table 17

By a reaction similar to that described in example 253, but based on N,N,N'-trimethylethylenediamine (337 mg, 3.3 mmol), received the connection 461 table 17 (11 mg, 8%).

MS ES+: 584 (M+H)+

1H NMR (DMSO-d6): 1.91 (m, 2H); 2.12 (s, 6N; 2.20 (m, 3H); 2.33 (m, 3H); 2.42 (m, 3H); 3.76 (s, 2H); 3.91 (s, 3H); 4.12 (t, 2H); 6.98 (s, 1H); 7.11 (DD, 1H); 7.16 (s, 4H); 7.35 (t, 1H); 7.52 (DD, 1H); 7.83 (s, 1H); 7.88 (t, 1H); 8.37 (s, 1H); 10.56 (s, 1H).

Example 285. Getting connection 2 in table 17

By a reaction similar to that described in example 253, but on the basis of (R)-(-)-2-pyrrolidineethanol (334 mg, 3.3 mmol), received the connection 462 in table 17 (76 mg, 59%).

MS ES+: 583 (M+H)+

1H NMR (DMSO-d6, TFA): 1.77 (m, 1H); 1.89 (m, 1H); 2.02 (m, 1H); 2.4 (m, 1H); 2.29 (m, 2H); 3.21 (m, 2H); 3.62 (m, 4H); 3.76 (m, 1H); 3.98 (s, 3H); 3.99 (s, 2H); 4.29 (t, 2H); 7.13 (DD, 1H); 7.29 (s, 1H); 7.35 (t, 1H); 7.46 (DD, 1H); 7.63 (s, 1H); 7.85 (t, 1H); 7.90 (s, 1H); 9.08 (s, 1H).

Example 286. Getting connection 463 table 17

By a reaction similar to that described in example 253, but on the basis of (S)-(+)-2-pyrrolidineethanol (334 mg, 3.3 mmol), received the connection 463 table 17 (72 mg, 56%).

MS ES+: 583 (M+H)+

1H NMR (DMSO-d6, TFA): 1.78 (m, 1H); 1.90 (m, 1H); 2.03 (m, 1H); 2.13 (m, 1H); 2.30 (m, 2H); 3.23 (m, 2H); 3.62 (m, 4H); 3.77 (m, 1H); 3.98 (s, 3H); 4.00 (s, 2H); 4.30 (t, 2H); 7.14 (DD, 1H); 7.30 (s, 1H); 7.36 (t, 1H); 7.46 (DD, 1H); 7.64 (s, 1H); 7.85 (s, 1H); 7.90 (s, 1H); 9.09 (s, 1H).

Example 287. Getting connection 464 table 17

By a reaction similar to that described in example 253, but on the basis of 4-hydroxypiperidine (334 mg, 3.3 mmol), received the connection 464 table 17 (63 mg, 49%).

MS ES+: 583 (M+H)+

1H NMR (DMSO-d6): 1.41 (m, 2H); 1.73 (m, 2H); 1.96 (m, 2H); 2.04 (m, 2H); 2.74 (m, 2H); 2.50 (m, 2H); 3.43 (s, 1H); 3.91 (s, 2H) 3.97 (s, 3H); 4.20 (t, 2H); 4.54 (d, 1H); 7.14 (d, 1H); 7.26 (s, 1H); 7.37 (t, 1H); 7.40 (s, 1H); 7.49 (d, 1H); 7.86 (t, 1H); 8.13 (user s, 1H); 8.69 (s, 1H); 10.46 (s, 1H).

Example 288. Getting connection 465 table 17

By a reaction similar to that described in example 253, but based on 3-pyrrolidinone (288 mg, 3.3 mmol), received the connection 465 table 17 (57 mg, 45%).

MS ES+: 569 (M+H)+

1H NMR (DMSO-d6): 1.56 (m, 1H); 1.99 (m, 4H); 2.36 (m, 1H); 2.56 (m, 4H); 2.74 (m, 1H); 3.91 (s, 2H); 3.98 (s, 3H); 4.21 (t, 2H); 4.70 (d, 1H); 7.14 (DD, 1H); 7.26 (s, 1H); 7.37 (t, 1H); 7.40 (s, 1H); 7.49 (DD, 1H); 7.86 (t, 1H); 8.12 (s, 1H); 8.68 (s, 1H); 10.47 (s, 1H); 12.03 (user s, 1H).

Example 289. Getting connection 466 table 17

By a reaction similar to that described in example 253, but on the basis of 1-(2-amino-ethyl)pyrrolidine (377 mg, 3.3 mmol), received the connection 466 table 17 (39 mg, 29%).

MS ES+: 596 (M+H)+

1H NMR (DMSO-d6, TFA): 1.91 (m, 2H); 2.06 (m, 2H); 2.240 (m, 2H); 3.11 (m, 2H); 3.23 (t, 2H); 3.42 (m, 2H); 3.48 (m, 2H); 4.67 (m, 2H); 3.98 (s, 3H); 3.99 (s, 2H); 4.31 (t, 2H); 7.14 (d, 1H); 7.31 (s, 1H); 7.35 (t, 1H); 7.47 (d, 1H); 7.64 (s, 1H); 7.85 (t, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 290. Getting connection 467 table 17

By a reaction similar to that described in example 253, but on the basis of 4-hydroxyethylpiperazine (380 mg, 3.3 mmol), obtained compound 467 table 17 (64 mg, 49%).

MS ES+: 597 (M+H)+

1H NMR (DMSO-d6): 1.14 (m, 2H); 1.35 (m, 1H); 1.65 (user d, 2H); 1.88 (m, 2H); 1.97 (m, 2H); 2.47 (m, 2H); 2.90 (user d, 2H); 3.35 (t, 2H); 3.91 (s, 2H); 3.97 (s, 3H); 4.20(t, 2H); 4.41 (t, 1H); 7.14 (d, 1H); 7.25 (s, 1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.48 (s, 1H); 7.86 (s, 1H); 8.12 (user s, 1H); 8.68 (s, 1H); 10.46 (s, 1H); 12.03 (s, 1H).

Example 291. Getting connection 468 table 17

By a reaction similar to that described in example 253, but on the basis of 1-(2-hydroxyethyl)piperazine (430 mg, 3.3 mmol), received the connection 468 table 17 (63 mg, 47%).

MS ES+: 612 (M+H)+

1H NMR (DMSO-d6): 1.96 (m, 2H); 2.41 (m, N); 3.50 (q, 2H); 3.91 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.37 (t, 1H); 7.14 (DD, 1H); 7.25 (s, 1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.48 (d, 1H); 7.86 (t, 1H); 8.12 (user s, 1H); 8.68 (s, 1H); 10.46 (s, 1H); 12.04 (s, 1H).

Example 292. Getting connection 469 table 17

By a reaction similar to that described in example 253 but judging from cyclopentylamine (281 mg, 3.3 mmol), obtained compound 469 table 17 (77 mg, 61%).

MS ES+: 567 (M+H)+

1H NMR (DMSO-d6): 1.58 (m, 4H); 1.73 (m, 2H); 2.00 (m, 2H); 2.17 (m, 2H); 3.12 (t, 2H); 3.56 (m, 1H); 3.92 (s, 3H); 3.99 (s, 3H); 4.31 (t, 2H); 7.15 (d, 1H); 7.31 (s, 1H); 7.37 (t, 1H); 7.41 (s, 1H); 7.48 (d, 1H); 7.86 (s, 1H); 8.16 (user s, 1H); 8.71 (s, 1H); 10.47 (s, 1H); 12.03 (user s, 1H).

Example 293. Getting connection 470 table 17

By a reaction similar to that described in example 253, but on the basis of 4-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol), received the connection 470 in table 17 (78 mg, 58%).

MS ES+: 611 (M+H)+

1H NMR (DMSO-d6): 1.16 (m, 2H); 1.36 (m, 3H); 1.63 (d, 2H); 1.88 (t, 2H); 1.96 (m, 2H); 2.44 (t, 2H); 2.87 (d, 2H); 3.44 (m, 2H); 3.9 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.33 (t, 1H; 7.14 (d, 1H); 7.25 (s, 1H); 7.37 (t, 1H); 7.40 (s, 1H); 7.49 (d, 1H); 7.86 (t, 1H); 8.12 (user s, 1H); 8.68 (s, 1H); 10.46 (s, 1H); 12.04 (s, 1H).

Example 294. Getting connection 471 table 17

By a reaction similar to that described in example 253, but based on 3-hydroxypiperidine (339 mg, 3.3 mmol), received the connection 471 table 17 (117 mg, 91%).

MS ES+: 583 (M+H)+

1H NMR (DMSO-d6): 1.07 (m, 1H); 1.41 (m, 1H); 1.62 (m, 1H); 1.70-1.90 (m, 3H); 1.95 (m, 2H); 2.46 (m, 2H); 2.67 (m, 1H); 2.83 (user d, 1H); 3.47 (m, 1H); 3.89 (s, 2H); 3.96 (s, 3H); 4.20 (t, 2H); 4.57 (d, 1H); 7.13 (DDD, 1H); 7.24 (s, 1H); 7.36 (t, 1H); 7.38 (s, 1H); 7.47 (d, 1H); 7.84 (t, 1H); 8.11 (user s, 1H); 8.67 (s, 1H); 10.46 (s, 1H); 12.00 (user s, 1H).

Example 295. Getting connection 472 table 17

By a reaction similar to that described in example 253, but on the basis of (S)-1-amino-2-propanol (248 mg, 3.3 mmol), received the connection 472 in table 17 (55 mg, 45%).

MS ES+: 557 (M+H)+

1H NMR (DMSO-d6): 1.06 (d, 3H); 1.96 (m, 2H); 2.48 (m, 2H); 2.73 (t, 2H); 3.70 (m, 1H); 3.91 (s, 2H); 3.97 (s, 3H); 4.24 (t, 2H); 4.48 (user s, 1H); 7.14 (d, 1H); 7.27 (s, 1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.49 (d, 1H); 7.86 (t, 1H); 8.12 (s, 1H); 8.68 (s, 1H); 10.46 (s, 1H).

Example 296. Getting connection 473 table 17

By a reaction similar to that described in example 253, but on the basis of (R)-1-amino-2-propanol (248 mg, 3.3 mmol), received the connection 473 table 17 (84 mg, 68%).

MS ES+: 557 (M+H)+

1H NMR (DMSO-d6): 1.04 (d, 3H); 1.93 (m, 2H); 2.45 (m, 2H); 2.70 (t, 2H); 3.67 (m, 1H); 3.88 (s, 2H); 3.95 (s, 3H); 4.21 (t, 2H); 4.46 (the RRS, 1H); 7.12 (d, 1H); 7.24 (s, 1H); 7.35 (t, 1H); 7.37 (s, 1H); 7.47 (d, 1H); 7.84 (t, 1H); 8.09 (s, 1H); 8.65 (s, 1H); 10.45 (s, 1H).

Example 297. Getting connection 474 table 17

By a reaction similar to that described in example 253, but based on tert-butyl-1-piperidinecarboxylate (615 mg, 3.3 mmol) and the processing of crude reaction mixture of hydrochloric acid in 1,4-dioxane (4.0 M, 2 ml), was awarded the connection 474 (3 HCl) in table 17 (89 mg, 61%).

MS ES+: 568 (M+H)+

1H NMR (DMSO-d6, TFA): 2.34 (m, 2H); 3.25-3.68 (m, 10H); 3.99 (s, 3H); 4.01 (s, 2H); 4.33 (t, 2H); 7.14 (DD, 1H); 7.35 (s, 1H); 7.37 (t, 1H); 7.49 (d, 1H); 7.65 (s, 1H); 7.86 (t, 1H); 7.91 (s, 1H); 7.09 (s, 1H); 10.66 (, 1H).

Example 298. Getting connection 475 table 17

By a reaction similar to that described in example 253, but on the basis of 2-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol), received the connection 475 table 17 (29 mg, 22%).

MS ES+: 611 (M+H)+

1H NMR (DMSO-d6): 1.30 (m, 2H); 1.48 (m, 4H); 1.60 (m, 2H); 1.76 (m, 1H); 1.93 (m, 2H); 2.26 (m, 1H); 2.48 (m, 1H); 2.79 (m, 2H); 3.46 (m, 2H); 3.89 (s, 2H); 3.96 (s, 3H); 4.18 (t, 2H); 4.40 (user s, 1H); 7.13 (d, 1H); 7.24 (s, 1H); 7.35 (t, 1H); 7.38 (s, 1H); 7.47 (d, 1H); 7.84 (s, 1H); 8.11 (user s, 1H); 8.67 (s, 1H); 10.44 (s, 1H).

Example 299. Getting connection 476 table 17

By a reaction similar to that described in example 253, but on the basis of 2-amino-2-methyl-1-propanol (294 mg, 3.3 mmol), received the connection 476 in table 17 (49 mg, 39%).

MS ES+: 571 (M+H)+

1H NMR (DMSO-d6, TFA): 1.25 (s, 6N); 2.22 (m, N); 3.10 (m, 2H); 3.46 (s, 2H); 3.99 (s, 3H);4.00 (s, 2H); 4.32 (t, 2H); 7.15 (d, 1H); 7.30 (s, 1H); 7.37 (t, 1H); 7.47 (d, 1H); 7.65 (s, 1H); 7.86 (s, 1H); 7.91 (s, 1H); 9.09 (s, 4H); 10.56 (s, 1H)).

Example 300. Getting connection 477 table 17

By a reaction similar to that described in example 253, but on the basis of 1-(2-dimethylaminoethyl)piperazine (519 mg, 3.3 mmol), obtained compound 477 table 17 (19 mg, 15%).

MS ES+: 639 (M+H)+

1H NMR (DMSO-d6): 1.96 (m, 2H); 2.13 (s, 6N); 2.30-2.52 (m, 14N); 3.89 (s, 2H); 3.95 (s, 3H); 4.18 (t, 2H); 7.13 (d, 1H); 7.23 (s, 1H); 7.35 (t, 1H); 7.38 (s, 1H); 7.84 (t, 1H); 8.10 (s, 1H); 8.67 (s, 1H); 10.45 (s, 1H).

Example 301. Getting connection 478 table 17

By a reaction similar to that described in example 253, but on the basis of the solution of dimethylamine in chloroform (3.6 M, 3 ml, 3.6 mmol), received the connection 478 table 17 (44 mg, 34%).

MS ES+: 527 (M+H)+

1H NMR (DMSO-d6): 1.95 (m, 2H); 2.17 (s, 6N); 2.41 (t, 2H); 3.89 (s, 2H); 3.96 (s, 3H); 4.18 (t, 2H); 7.12 (d, 1H); 7.23 (s, 1H); 7.35 (t, 1H); 7.38 (s, 1H); 7.47 (d, 1H); 7.84 (t, 1H); 8.11 (s, 1H); 8.67 (s, 1H); 10.45 (s, 1H).

Example 302. Obtaining compounds 479 table 17

By a reaction similar to that described in example 253 but judging from aminomethylpropanol (234 mg, 3.3 mmol), obtained compound 479 table 17 (88 mg, 65%).

MS ES+: 553 (M+H)+

1H NMR (DMSO-d6): 0.18 (m, 2H); 0.46 (m, 2H); 0.94 (m, 1H); 2.01 (m, 2H); 2.51 (d, 2H); 2.79 (t, 2H); 3.94 (s, 2H); 4.01 (s, 3H); 4.28 (t, 2H); 7.18 (d, 1H); 7.31 (s, 1H); 7.41 (t, 1H); 7.43 (s, 1H); 7.53 (d, 1H); 7.90 (s, 1H); 8.16 (s, 1H) 8.72 (s, 1H); 10.53 (s, 1H).

Example 303. The connection is 480 in table 17

By a reaction similar to that described in example 253 but judging from piperidine (344 mg, 4.0 mmol), received the connection 480 in table 17 (52 mg, 40%).

MS ES+: 565 (M-H)+

1H NMR (DMSO-d6, TFA): 1.43 (m, 1H); 1.69 (m, 3H); 1.87 (d, 2H); 2.30 (m, 2H); 2.96 (t, 2H); 3.27 (t, 2H); 3.55 (d, 2H); 3.99 (s, 3H); 4.00 (s, 2H); 4.31 (t, 2H); 7.15 (d, 1H); 7.31 (s, 1H); 7.37 (t, 1H); 7.47 (d, 1H); 7.65 (s, 1H); 7.86 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H); 10.56 (s, 1H).

Example 304. Getting connection 481 table 17

By a reaction similar to that described in example 255, but on the basis of 1-(2-dimethylaminoethyl)piperazine (281 mg, 3.3 mmol), received the connection 481 table 17 (81 mg, 64%).

MS ES+: 641 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (m, 2H); 2.80-3.70 (m, 14N); 2.84 (s, 6N); 3.98 (s, 3H); 4.01 (s, 2H); 4.30 (user t, 1H); 6.90 (m, 1H); 7.32 (s, 2H); 7.35 (DD, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 305. Getting connection 482 table 17

By a reaction similar to that described in example 255, but on the basis of (S)-(+)-2-pyrrolidineethanol (344 mg, 3.3 mmol), received the connection 482 in table 17 (58 mg, 45%).

MS ES+: 585 (M+H)+

1H NMR (DMSO-d6, TFA): 1.79 (m, 1H); 1.90 (m, 1H); 2.02 (m, 1H); 2.13 (m, 1H); 2.30 (m, 2H); 3.33 (m, 2H); 3.62 (m, 4H); 3.77 (DD, 1H); 3.99 (s, 3H); 4.01 (s, 2H); 4.30 (user t, 2H); 6.91 (t, 1H); 7.30 (s, 1H); 7.35 (DD, 2H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 306. Getting connection 483 table 17

In reactions similar to those outlined in the example 255, but based on the 4-hydroxypiperidine (334 mg, 3.3 mmol), received the connection 483 table 17 (28 mg, 22%).

MS ES+: 585 (M+H)+

1H NMR (DMSO-d6): 1.40 (m, 2H); 1.73 (m, 2H); 1.96 (m, 2H); 2.03 (m, 2H); 2.45 (m, 2H); 2.74 (m, 2H); 3.45 (m, 1H); 3.92 (s, 2H); 3.97 (s, 3H); 3.97 (t, 2H); 4.54 (d, 1H); 6.95 (m, 1H); 7.26 (s, 1H); 7.36 (DD, 2H); 7.40 (s, 1H); 8.14 (user s, 1H); 8.68 (s, 1H); 10.65 (s, 1H); 12.04 (user s, 1H).

Example 307. Getting connection 484 table 17

By a reaction similar to that described in example 255, but based on 3-pyrrolidinone (288 mg, 3.3 mmol), received the connection 484 table 17 (30 mg, 23%).

MS ES+: 571 (M+H)+

1H NMR (DMSO-d6): 1.57 (m, 1H); 1.97 (m, 4H); 2.37 (m, 1H); 2.58 (m, 4H); 2.74 (m, 1H); 3.92 (s, 2H); 3.98 (s, 3H); 4.22 (user t, 2H); 4.72 (user s, 1H); 6.95 (m, 1H); 7.26 (s, 1H); 7.36 (DD, 2H); 7.40 (s, 1H); 8.13 (user with, 1H); 8.69 (s, 1H); 10.65 (s, 1H).

Example 308. Getting 485 connection table 17

By a reaction similar to that described in example 255, but on the basis of 1-(2-amino-ethyl)pyrrolidine (377 mg, 3.3 mmol)were 485 connection in table 17 (25 mg, 19%).

MS ES+: 598 (M+H)+

1H NMR (DMSO-d6, TFA): 1.91 (m, 2H); 2.06 (m, 2H); 2.24 (m, 2H); 3.11 (m, 2H); 3.23 (t, 2H); 3.41 (1m, 2H); 3.49 (m, 2H); 3.67 (m, 2H); 3.99 (s, 3H); 4.01 (s, 2H); 4.31 (t, 2H); 6.89 (t, 1H); 7.32 (s, 1H); 7.34 (d, 2H); 7.64 (s, 1H); 7.92 (s, 1H); 9.09 (s, 1H).

Example 309. Getting connection 486 table 17

By a reaction similar to that described in example 255, but on the basis of 4-hydroxyethylpiperazine (380 mg, 3.3 mmol)received soy is inania 486 in table 17 (62 mg, 47%).

MS ES+: 599 (M+H)+

1H NMR (DMSO-d6): 1.14 (m, 2H); 1.34 (m, 1H); 1.65 (d, 2H); 1.88 (t, 2H); 1.96 (m, 2H); 2.45 (t, 2H); 2.90 (d, 2H); 3.25 (t, 2H); 3.92 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.41 (t, 1H); 6.94 (m, 1H); 7.26 (s, 1H); 7.36 (DD, 2H); 7.40 (s, 1H); 8.13 (user s, 1H); 8.68 (s, 1H); 10.64 (s, 1H); 12.07 (user s, 1H).

Example 310. Obtaining compounds 487 table 17

By a reaction similar to that described in example 255, but on the basis of 2-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol), obtained compound 487 table 17 (61 mg, 45%).

MS ES+: 613 (M+H)+

1H NMR (DMSO-d6, TFA): 1.47-1.90 (m, 7H); 2.09 (m, 1H); 2.27 (m, 2H); 3.08-3.70 (m, 7H); 3.99 (s, 3H); 4.00 (s, 2H); 4.30 (m, 2H); 6.84 (m, 1H); 7.29 (d, 1H); 7.34 (DD, 1H); 7.62 (s, 1H); 7.92 (s, 1H); 9.08 (s, 1H).

Example 311. Getting connection 488 table 17

By a reaction similar to that described in example 255, but on the basis of 1-(2-hydroxyethyl)piperidine (430 mg, 3.3 mmol), received the connection 488 table 17 (124 mg, 92%).

MS ES+: 614 (M+H)+

1H NMR (DMSO-d6, TFA): 1.96 (m, 2H); 2.40 (m, N); 2.70 (m, 1H); 3.48 (m, 2H); 3.90 (s, 2H); 3.95 (s, 3H); 4.18 (t, 2H); 4.35 (user t, 1H); 6.43 (m, 1H); 7.23 (s, 1H); 7.34 (DD, 2H); 7.38 (s, 1H); 8.10 (s, 1H); 8.66 (s, 1H); 10.63 (s, 1H).

Example 312. Getting connection 489 table 17

By a reaction similar to that described in example 255, but on the basis of 4-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol), received the connection 489 table 17 (54 mg, 40%).

MS ES+: 613 (M+H)+

1H NMR (DMSO-d6): 1.15 (m, 2H); 1.36 (m, 3H); 1.3 (user d, 2H); 1.88 (m, 2H); 1.96 (m, 2H); 2.44 (m, 2H); 2.87 (user d, 2H); 3.44 (m, 2H); 3.92 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.33 (t, 1H); 6.95 (m, 1H); 7.26 (s, 1H); 7.36 (DD, 2H); 7.40 (s, 1H); 8.13 (user with, 1H); 8.68 (s, 1H); 10.64 (s, 1H); 12.04 (user s, 1H).

Example 313. Getting connection 490 table 17

By a reaction similar to that described in example 255, but based on 3-hydroxypiperidine (334 mg, 3.3 mmol), received the connection 490 in table 17 (53 mg, 41%).

MS ES+: 559 (M+H)+

1H NMR (DMSO-d6): 1.09 (m, 1H); 1.43 (m, 1H); 1.64 (m, 1H); 1.79 (m, 2H); 1.87 (m, 1H); 1.96 (m, 2H); 2.47 (m, 2H); 2.69 (m, 2H); 2.85 (m, 1H); 3.49 (m, 1H); 3.92 (s, 2H); 3.98 (s, 3H); 4.21 (t, 2H); 4.60 (d, 1H); 6.95 (t, 1H); 7.26 (s, 1H); 7.36 (d, 2H); 7.40 (s, 1H); 8.13 (user s, 1H); 8.69 (s, 1H); 10.65 (s, 1H); 12.04 (user s, 1H).

Example 314. Getting connection 491 table 17

By a reaction similar to that described in example 255, but based on N,N,N'-trimethylethylenediamine (337 mg, 3.3 mmol), received the connection 491 table 17 (54 mg, 42%).

MS ES+: 586 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (m, 1H); 2.34 (m, 1H); 2.88 (s, 6N); 2.93 (s, 2H); 3.39 (m, 2H); 3.56 (m, 4H); 3.99 (s, 3H); 4.01 (s, 2H); 4.30 (t, 2H); 6.91 (m, 1H); 7.33 (s, 1H); 7.35 (DD, 2H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 315. Getting connection 492 table 17

By a reaction similar to that described in example 255, but on the basis of piperidine (281 mg, 3.3 mmol), received the connection 492 table 17 (81 mg, 64%).

MS ES+: 569 (M+H)+

1H NMR (DMSO-d6): 1.38 (m, 2H); 1.50 (m, 4H); 2.34 (user s, 4H); 2.41 (t, 2H); 3.90 (s, 2H); 396 (, 3H); 4.19 (t, 2H); 6.93 (t, 1H); 7.24 (s, 1H); 7.34 (d, 2H); 7.38 (s, 1H); 8.11 (user s, 1H); 8.67 (s, 1H); 10.63 (s, 1H); 11.98 (user s, 1H).

Example 316. Getting connection 493 table 17

By a reaction similar to that described in example 255, but based on pyrrolidine (235 mg, 3.3 mmol), obtained compound 493 table 17 (66 mg, 54%).

MS ES+: 555 (M+H)+

1H NMR (DMSO-d6, TFA): 1.90 (m, 2H); 2.06 (m, 2H); 2.28 (m, 2H); 3.09 (m, 2H); 3.36 (m, 2H); 3.68 (m, 2H); 3.99 (s, 3H); 4.01 (s, 2H); 4.29 (t, 2H); 6.93 (m, 1H); 7.30 (s, 1H); 7.34 (DD, 2H); 7.65 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 317. Getting connection 494 table 17

By a reaction similar to that described in example 255, but on the basis of 2-amino-2-methyl-1-propanol (294 mg, 3.3 mmol), received the connection 494 table 17 (28 mg, 22%).

MS ES+: 573 (M+H)+

1H NMR (DMSO-d6, TFA): 1.24 (s, 6N); 2.23 (m, 2H); 3.10 (t, 2H); 3.45 (s, 2H); 3.99 (s, 3H); 4,01 (s, 2H); 4.31 (t, 2H); 4.91 (m, 1H); 7.30 (s, 1H); 7.34 (DD, 2H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 318. Getting connection 495 table 17

By a reaction similar to that described in example 255, but based on the 2-methylaminoethanol (248 mg, 3.3 mmol), received the connection 495 table 17 (33 mg, 27%).

MS ES+: 559 (M+H)+

1H NMR (DMSO-d6): 1.95 (m, 2H); 2.24 (s, 3H); 2.48 (m, 2H); 2.45 (m, 2H); 3.49 (m, 2H); 3.93 (s, 2H); 3.98 (s, 3H); 4.21 (t, 2H); 4.38 (m, 1H); 6.95 (m, 1H); 7.27 (s, 1H); 7.36 (DD, 2H); 7.40 (s, 1H); 8.13 (user s, 1H); 8.69 (s, 1H); 10.65 (s, 1H); 12.04 (user s, 1H).

Example 319. Getting connection 496 table 17

p> By a reaction similar to that described in example 255, but based on N,N-dimethylethylenediamine (291 mg, 3.3 mmol), received the connection 496 table 17 (22 mg, 17%).

MS ES+: 572 (M+H)+

1H NMR (DMSO-d6, TFA): 2.23 (m, 2H); 2.89 (s, 6N); 3.22 (m, 2H); 3.41 (s, 4H); 3.96 (s, 3H); 4.01 (s, 2H); 4.31 (t, 1H); 6.92 (m, 1H); 7.31 (s, 1H); 7.35 (DD, 2H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 320. Getting connection 497 table 17

By a reaction similar to that described in example 255, but on the basis of (S)-(+)-1-amino-2-propanol (248 mg, 3.3 mmol), received the connection 497 table 17 (32 mg, 26%).

MS ES+: 559 (M+H)+

1H NMR (DMSO-d6, TFA): 1.15 (d, 3H); 2.24 (m, 2H); 2.83 (DD, 1H); 3.06 (DD, 1H); 3.15 (t, 2H); 3.95 (m, 1H); 3.99 (s, 3H); 4.01 (s, 3H); 4.29 (t, 1H); 6.92 (m, 1H); 7.28 (s, 1H); 7.34 (DD, 2H); 7.65 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 321. Getting connection 498 table 17

By a reaction similar to that described in example 255, but on the basis of (R)-(-)-1-amino-2-propanol (248 mg, 3.3 mmol), received the connection 498 table 17 (40 mg, 32%).

MS ES+: 559 (M+H)+

1H NMR (DMSO-d6, TFA): 1.15 (d, 3H); 2.24 (m, 2H); 2.83 (DD, 1H); 3.06 (DD, 1H); 3.15 (t, 2H); 3.95 (m, 1H); 3.99 (s, 3H); 4.01 (s, 3H); 4.29 (t, 1H); 6.90 (m, 1H); 7.28 (s, 1H); 7.34 (DD, 2H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 322. The connection is 499 in table 17

By a reaction similar to that described in example 255, but based on tert-butyl-1-piperidinecarboxylate (615 mg, 3.3 mmol) and treating the crude reaction mixture chlorite is todarodes acid in 1,4-dioxane (4 M, 2 ml), was awarded the connection 499 in table 17 (66 mg, 45%, 3 HCl).

MS ES+: 570 (M+H)+

1H NMR (DMSO-d6, TFA): 2.35 (m, 2H); 3.20-3.94 (m, 10H); 3.99 (s, 3H); 4.03 (s, 2H); 4.33 (t, 2H); 6.93 (m, 1H); 7.36 (s, 1H); 7.37 (DD, 2H); 7.65 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 323. The connection is 500 table 17

By a reaction similar to that described in example 255, but based on N-arylpiperazine (416 mg, 3.3 mmol), received the connection 500 in table 17 (33 mg, 25%).

MS ES+: 610 (M+H)+

1H NMR (DMSO-d6): 1.96 (m, 2H); 2.30-2.50 (m, 10H); 2.93 (d, 2H); 3.92 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 5.12 (d, 1H); 5.18 (d, 1H); 5.82 (m, 1H); 6.95 (m, 1H); 7.25 (s, 1H); 7.35 (DD, 2H); 7.40 (s, 1H); 8.12 (s, 1H); 8.68 (s, 1H); 10.64 (s, 1H); 11.99 (user s, 1H).

Example 324. The connection is a 501 table 17

By a reaction similar to that described in example 255, but on the basis of (R)-(-)-1-pyrrolidineethanol (334 mg, 3.3 mmol), received the connection 501 in table 17 (51 mg, 40%).

MS ES+: 585 (M+H)+

1H NMR (DMSO-d6, TFA): 1.57 (m, 1H); 1.67 (m, 2H); 1.82 (m, 1H); 1.96 (m, 2H); 2.18 (q, 1H); 2.45 (m, 3H); 2.98 (m, 1H); 3.10 (m, 1H); 3.20 (m, 1H); 3.92 (s, 2H); 3.98 (s, 3H); 4.22 (t, 2H); 4.35 (user s, 1H); 6.95 (m, 1H); 7.27 (s, 1H); 7.36 (DD, 2H); 7.40 (s, 1H); 8.13 (s, 1H); 8.68 (s, 1H); 10.66 (s, 1H); 12.00 (user s, 1H).

Example 325. Getting connection 502 in table 17

By a reaction similar to that described in example 255, but based on cyclopentylamine (281 mg, 3.3 mmol), received the connection 502 in table 17 (28 mg, 22%).

MS ES+: 569 (M+H)+

1The NMR (DMSO-d 6): 1.31 (m, 2H); 1.47 (m, 2H); 1.62 (m, 2H); 1.73 (m, 2H); 1.93 (m, 2H); 2.70 (t, 2H); 3.03 (m, 1H); 3.92 (s, 2H); 3.97 (s, 3H); 4.23 (t, 2H); 6.94 (m, 1H); 7.26 (s, 1H); 7.36 (DD, 2H); 7.39 (s, 1H); 8.11 (s, 1H); 8.67 (s, 1H); 10.66 (s, 1H).

Example 326. Getting connection 503 table 17

By a reaction similar to that described in example 256, but based on the 2-methylaminoethanol (248 mg, 3.3 mmol), received the connection 503 in table 17 (31 mg, 24%).

MS ES+: 575 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (m, 2H); 2.88 (s, 3H); 3.16-3.45 (m, 4H); 3.77 (t, 2H); 3.99 (s, 5H); 4.29 (t, 2H); 7.30 (s, 1H); 7.38 (t, 1H); 7.50 (m, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 7.97 (DD, 1H); 9.09 (s, 1H).

Example 327. Getting connection 504 in table 17

By a reaction similar to that described in example 256, but based on N,N,N'-trimethylethylenediamine (337 mg, 3.3 mmol), received the connection 504 in table 17 (28 mg, 21%).

MS ES+: 602 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (m, 2H); 2.89 (s, 6N); 2.93 (s, 3H); 3.38 (m, 2H); 3.56 (user s, 4H); 3.99 (s, 5H); 4.40 (t, 2H); 7.35 (s, 1H); 7.39 (t, 1H); 7.50 (m, 1H); 7.65 (s, 1H); 7.91 (s, 1H); 7.97 (DD, 1H); 9.09 (s, 1H).

Example 328. Getting connection 505 table 17

By a reaction similar to that described in example 256, but based on N-arylpiperazine (416 mg, 3.3 mmol), received the connection 505 in table 17 (42 mg, 30%).

MS ES+: 626 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (m, 2H); 3.20-3.80 (m, 10H); 3.91 (d, 2H); 3.99 (s, 5H); 4.32 (t, 2H); 5.60 (m, 2H); 5.94 (m, 1H); 7.33 (s, 1H); 7.39 (t, 1H); 7.50 (m, 1H); 7.65 (s, 1H); 7.91 (s, 1H); 7.97 (DD, 1H); 9.09 (, 1H).

Example one connection 506 in table 17

By a reaction similar to that described in example 256, but on the basis of 4-hydroxypiperidine (334 mg, 3.3 mmol), received the connection 506 in table 17 (32 mg, 25%).

MS ES+: 601 (M+H)+

1H NMR (DMSO-d6): 1.41 (m, 2H); 1.73 (m, 2H); 1.96 (m, 2H); 2.03 (m, 2H); 2.45 (m, 2H); 2.74 (m, 2H); 3.46 (m, 1H); 3.90 (s, 2H); 3.98 (s, 3H); 4.21 (t, 2H); 4.55 (user s, 1H); 7.26 (s, 1H); 7.40 (s, 1H); 7.41 (t, 1H); 7.51 (m, 1H); 7.97 (DD, 1H); 8.13 (user s, 1H); 8.69 (s, 1H); 10.49 (s, 1H); 12.03 (user s, 1H).

Example 330. Getting connection 507 in table 17

By a reaction similar to that described in example 256, but based on 3-pyrrolidinone (288 mg, 3.3 mmol), received the connection 507 in table 17 (24 mg, 19%).

MS ES+: 587 (M+H)+

1H NMR (DMSO-d6): 1.57 (m, 1H); 1.98 (m, 3H); 2.30-2.81 (m, 6N); 3.38 (m, 1H); 3.90 (s, 2H); 3.98 (s, 3H); 4.22 (t, 2H); 4.74 (user s, 1H); 7.27 (s, 1H); 7.39 (s, 1H); 7.40 (t, 1H); 7.50 (m, 1H); 7.96 (DD, 1H); 8.13 (user with, 1H); 8.69 (s, 1H); 10.49 (s, 1H); 12.05 (user s, 1H).

Example 331. Getting connection 508 table 17

By a reaction similar to that described in example 256, but on the basis of 1-(2-amino-ethyl)pyrrolidine (377 mg, 3.3 mmol), received the connection 508 in table 17 (18 mg, 13%).

MS ES+: 614 (M+H)+

1H NMR (DMSO-d6, TFA): 1.91 (m, 2H); 2.06 (m, 2H); 2.23 (m, 2H); 3.11 (m, 2H); 3.22 (t, 2H); 3.41 (m, 2H); 3.47 (m, 2H); 3.67 (m, 2H); 3.98 (s, 5H); 4.30 (t, 2H); 7.30 (s, 1H); 7.36 (t, 1H); 7.49 (m, 1H); 7.63 (s, 1H); 7.91 (s, 1H); 7.95 (DD, 1H); 9.09 (s, 1H).

Example 332. Obtaining compounds 509 table 17

In reactions similar to those described in PR is least 256, but based on N-acetylpiperidine (423 mg, 3.3 mmol), received the connection 509 table 17 (113 mg, 82%).

MS ES+: 628 (M+H)+

1H NMR (DMSO-d6): 1.98 (m, 2H); 2.00 (s, 3H); 2.36 (t, 2H); 2.42 (t, 2H); 2.92 (t, N); 2.99 (t, N); 3.45 (m, 4H); 3.55 (t, 1H); 3.90 (s, 2H); 3.98 (s, 3H); 4.23 (t, 2H); 7.27 (s, 1H); 7.40 (s, 1H); 7.41 (t, 1H); 7.52 (m, 1H); 7.97 (DD, 1H); 8.13 (s, 1H); 8.69 (s, 1H); 10.51 (s, 1H).

Example 333. Getting connection 510 in table 17

By a reaction similar to that described in example 256, but on the basis of 2-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol), received the 510 connection in table 17 (34 mg, 24%).

MS ES+: 629 (M+H)+

1H NMR (DMSO-d6, TFA): 1.48-1.90 (m, 7H); 2.08 (m, 1H); 2.27 (m, 2H); 3.09-3.69 (m, 7H); 3.99 (s, 5H); 4.30 (m, 2H); 7.30 (d, 1H); 7.38 (t, 1H); 7.50 (m, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 7.97 (DD, 1H); 9.09 (s, 1H).

Example 334. Getting connection 511 table 17

By a reaction similar to that described in example 256, but on the basis of 2-(2-hydroxyethyl)piperazine (430 mg, 3.3 mmol), received the connection 511 in table 17 (80 mg, 58%).

MS ES+: 630 (M+H)+

1H NMR (DMSO-d6): 1.96 (m, 2H); 2.42 (m, N); 3.49 (DD, 2H); 3.90 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.37 (t, 1H); 7.25 (s, 1H); 7.39 (s, 1H); 7.40 (t, 1H); 7.51 (m, 1H); 7.97 (DD, 1H); 8.12 (s, 1H); 8.68 (s, 1H); 10.42 (s, 1H); 12.02 (user s, 1H).

Example 335. The connection is 512 in table 17

By a reaction similar to that described in example 256, but based on cyclopentylamine (281 mg, 3.3 mmol), received the connection 512 in table 17 (12 mg, 9%).

MS ES+/sup> : 585 (M+H)+

1H NMR (DMSO-d6, TFA): 1.59 (m, 4H); 1.73 (m, 2H); 2.00 (m, 2H); 2.21 (m, 2H); 3.13 (t, 2H); 3.56 (m, 1H); 3.99 (s, 5H); 4.31 (t, 2H); 7.29 (s, 1H); 7.37 (t, 1H); 7.49 (m, 1H); 7.64 (s, 1H); 7.92 (s, 1H); 7.96 (DD, 1H); 9.09 (s, 1H).

Example 336. Getting connection 513 table 17

By a reaction similar to that described in example 256, but on the basis of 4-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol), received the connection 513 table 17 (54 mg, 39%).

MS ES+: 629 (M+H)+

1H NMR (DMSO-d6): 1.15 (m, 2H); 1.36 (m, 3H); 1.63 (d, 2H); 1.88 (t, 2H); 1.96 (m, 2H); 2.44 (t, 2H); 2.87 (d, 2H); 3.44 (m, 2H); 3.90 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2J); 4.33 (t, 1H); 7.25 (s, 1H); 7.40 (s, 1H); 7.41 (t, 1H); 7.51 (m, 1H); 7.97 (DD, 1H); 8.12 (s, 1H); 8.68 (s, 1H); 10.48 (s, 1H); 12.03 (user s, 1H).

Example 337. The connection 514 table 17

By a reaction similar to that described in example 256, but based on 3-hydroxypiperidine (334 mg, 3.3 mmol), received the connection 514 in table 17 (96 mg, 73%).

MS ES+: 601 (M+H)+

1H NMR (DMSO-d6): 1.09 (m, 1H); 1.43 (m, 1H); 1.63 (m, 1H); 1.78 (m, 2H); 1.87 (m, 1H); 1.96 (m, 2H); 2.47 (m, 2H); 2.68 (m, 1H); 2.84 (user d, 1H); 3.50 (m, 1H); 3.90 (s, 2H); 3.98 (s, 3H); 4.20 (t, 2H); 4.59 (d, 1H); 7.26 (s, 1H); 7.40 (s, 1H); 7.41 (t, 1H); 7.51 (m, 1H); 7.97 (DD, 1H); 8.13 (user s, 1H); 8.68 (s, 1H); 10.48 (s, 1H); 12.03 (user s, 1H).

Example 338. Getting connection 515 table 17

By a reaction similar to that described in example 256, but on the basis of 4-hydroxyethylpiperazine (380 mg, 3.3 mmol), received the connection 515 in table 17 (18 mg, 13%).

MS ES+/sup> : 615 (M+H)+

1H NMR (DMSO-d6): 1.15 (m, 2H); 1.35 (m, 1H); 1.65 (d, 2H); 1.88 (m, 2H); 1.97 (m, 2H); 2.46 (m, 2H); 2.91 (m, 2H); 3.25 (t, 2H); 3.90 (s, 2H); 3.97 (s, 3H); 4.21 (t, 2H); 4.41 (t, 1H); 7.26 (s, 1H); 7.40 (s, 1H); 7.41 (t, 1H); 7.50 (m, 1H); 7.97 (DD, 1H); 8.13 (user s, 1H); 8.68 (s, 1H); 10.49 (s, 1H); 12.03 (user s, 1H).

Example 339. The connection 516 table 17

By a reaction similar to that described in example 256, but on the basis of 1-amino-2-propanol (248 mg, 3.3 mmol), received the connection 516 in table 17 (14 mg, 11%).

MS ES+: 575 (M+H)+

1H NMR (DMSO-d6): 1.06 (d, 3H); 1.96 (m, 2H); 2.49 (m, 2H); 2.74 (t, 2H); 3.71 (m, 2H); 3.90 (s, 2H); 3.98 (s, 3H); 4.24 (t, 2H); 4.50 (user s, 1H); 7.27 (s, 1H); 7.39 (s, 1H); 7.41 (t, 1H); 7.51 (m, 1H); 7.97 (DD, 1H); 8.12 (s, 1H); 8.68 (s, 1H); 10.49 (s, 1H).

Example 340. Getting connection 517 table 17

By a reaction similar to that described in example 256, but based on tert-butyl-1-piperidinecarboxylate (615 mg, 3.3 mmol) and the processing of crude reaction mixture of hydrochloric acid in 1,4-dioxane (4 M, 2 ml), was awarded the connection 517 table 17 (61 mg, 47%).

MS ES+: 586 (M+H)+

1H NMR (DMSO-d6TFA): 2.31 (m, 2H); 3.00-3.95 (m, 10H); 3.99 (s, 5H); 4.31 (t, 2H); 7.32 (s, 1H); 7.39 (t, 1H); 7.50 (m, 1H); 7.65 (s, 1H); 7.91 (s, 1H); 7.97 (DD, 1H); 9.10 (s, 1H).

Example 341. Getting connection 518 table 17

By a reaction similar to that described in example 256, but on the basis of 1-(2-morpholinoethyl)piperazine (519 mg, 3.3 mmol), received the connection 518 in table 17 (69 mg, 48%).

M ES +: 699 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (m, 2H); 2.98 (m, 2H); 3.10-37.5 (m, N); 3.86 (m, 4H); 3.99 (s, 5H); 4.31 (t, 2H); 7.33 (s, 1H); 7.39 (t, 1H); 7.50 (m, 1H); 7.65 (s, 1H); 7.92 (s, 1H); 7.97 (DD, 1H); 9.10 (s, 1H).

Example 342. Getting connection 519 table 17

By a reaction similar to that described in example 256, but based on pyrrolidine (235 mg, 3.3 mmol), received the connection 519 table 17 (55 mg, 44%).

MS ES+: 571 (M+H)+

1H NMR (DMSO-d6, TFA): 1.90 (m, 2H); 2.06 (m, 2H); 2.27 (m, 2H); 3.09 (m, 2H); 3.36 (t, 2H); 3.66 (m, 2H); 3.98 (s, 5H); 4.29 (t, 2H); 7.29 (s, 1H); 7.39 (t, 1H); 7.50 (m, 1H); 7.64 (s, 1H); 7.90 (s, 1H); 7.96 (DD, 1H); 9.09 (s, 1H).

Example 343. Getting connection 520 in table 17

By a reaction similar to that described in example 257, but based on the 2-methylaminoethanol (248 mg, 3.3 mmol), received the connection 520 in table 17 (34 mg, 29%).

MS ES+: 541 (M+H)+

1H NMR (DMSO-d6, TFA): 2.30 (m, 2H); 3.57 (s, 3H); 3.16-3.45 (m, 4H); 3.75 (t, 2H); 3.98 (s, 3H); 3.99 (s, 2H); 4.29 (t, 2H); 6.89 (t, 1H); 7.29 (s, 1H); 7.30-7.40 (m, 2H); 7.62 (d, 1H); 7.63 (s, 1H); 7.91 (s, 1H); 9.08 (s, 1H).

Example 344. Getting connection 521 table 17

By a reaction similar to that described in example 257, but on the basis of 1,2-diamino-2-methylpropane (291 mg, 3.3 mmol), received the connection 521 in table 17 (10 mg, 8%).

MS ES+: 554 (M+H)+

1H NMR (DMSO-d6, TFA): 1.39 (s, 6N); 2.327(m, 2H); 3.22 (m, 4H); 3.97 (s, 3H); 3.98 (s, 2H); 4.32 (t, 2H); 6.89 (m, 1H); 7.29-7.39 (m, 3H); 7.62 (d, 1H); 7.63 (s, 1H); 7.92 (s, 1H); 9.08 (s, 1H).

Example 345 connection 522 table 17

By a reaction similar to that described in example 257, but based on N,N-dimethylethylenediamine (291 mg, 3.3 mmol), received the connection 522 in table 17 (26 mg, 22%).

MS ES+: 554 (M+H)+

1H NMR (DMSO-d6): 1.95 (m, 2H); 2.15 (s, 6N); 2.33 (t, 2H); 2.63 (t, 2H); 2.73 (t, 2H); 3.90 (s, 2H); 3.97 (s, 3H); 4.23 (t, 2H); 6.91 (m, 1H); 7.26 (s, 1H); 7.31-7.42 (m, 2H); 7.39 (s, 1H); 7.64 (d, 1H); 8.11 (s, 1H); 8.68 (s, 1H); 10.48 (s, 1H).

Example 346. Getting connection 523 table 17

By a reaction similar to that described in example 257, but based on N,N,N'-trimethylethylenediamine (337 mg, 3.3 mmol), received the connection 523 table 17 (37 mg, 30%).

MS ES+: 568 (M+H)+

1H NMR (DMSO-d6, TFA): 2.34 (m, 2H); 2.88 (s, 6N); 2.93 (s, 3H); 3.38 (m, 2H); 3.55 (m, 4H); 3.98 (s, 3H); 3.99 (s, 2H); 4.29 (t, 2H); 6.89 (m, 1H); 7.29-7.41 (m, 2H); 7.33 (s, 1H); 7.63 (d, 1H); 7.64 (s, 1H); 7.91 (, 1H); 9.09 (s, 1H).

Example 347. Getting connection 524 table 17

By a reaction similar to that described in example 257, but based on N-arylpiperazine (416 mg, 3.3 mmol), received the connection 524 in table 17 (77 mg, 59%).

MS ES+: 592 (M+H)+

1H NMR (DMSO-d6, TFA): 2.34 (m, 2H); 3.00-3.08 (m, 8H); 2.86 (d, 2H); 3.92 (m, 2H); 3.98 (s, 3H); 3.99 (s, 2H); 4.31 (t, 2H); 5.53-5.66 (m, 2H); 5.60-5.87 (m, 1H); 6.89 (m, 1H); 7.31-7.40 (m, 3H); 7.62 (d, 1H); 7.63 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 348. Getting connection 525 table 17

By a reaction similar to that described in example 257, but on the basis of 4-hydroxypiperidine (334 mg, 3.3 mmol), received the connection 525 the table 17 (21 mg, 17%).

MS ES+: 567 (M+H)+

1H NMR (DMSO-d6, TFA): 1.59 (m, 1H); 1.85 (m, 2H); 2.01 (d, 1H); 2.28 (m, 2H); 3.03 (t, 1H); 3.21 (m, 1H); 3.28 (m, 2H); 3.40 (m, 1H); 3.57 (d, 1H); 3.68 (m, 1H); 3.98 (s, 3H); 3.99 (s, 2H); 4.28 (t, 2H); 6.90 (t, 1H); 7.29 (s, 1H); 7.30-7.40 (m, 2H); 7.63 (d, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 349. Getting connection 526 table 17

By a reaction similar to that described in example 257, but based on 3-pyrrolidinone (288 mg, 3.3 mmol), received the connection 526 in table 17 (18 mg, 15%).

MS ES+: 553 (M+H)+

1H NMR (DMSO-d6, TFA): 1.84-2.03 (m, 2H); 2.27 (m, 2H); 3.02-3.79 (m, 6N); 3.99 (s, 3H); 4.00 (s, 2H); 4.29 (m, 2H); 4.41-4.51 (m, 1H); 6.91 (m, 1H); 7.28 (d, 1H); 7.31-7.41 (m, 2H); 7.63 (d, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

Example 350. Getting connection 527 table 17

By a reaction similar to that described in example 257, but on the basis of 1-(aminoethyl)pyrrolidine (377 mg, 3.3 mmol), received the connection 527 table 17 (34 mg, 27%).

MS ES+: 580 (M+H)+

1H NMR (DMSO-d6): 1.68 (m, 4H); 1.97 (m, 2H); 2.47 (m, 6N); 2.70 (t, 2H); 2.77 (t, 2H); 3.91 (s, 2H); 3.97 (s, 3H); 4.24 (t, 2H); 6.91 (m, 1H); 7.27 (s, 1H); 7.30-7.42 (m, 2H); 7.39 (s, 1H); 7.64 (d, 1H); 8.12 (s, 1H); 8.68 (s, 1H); 10.49 (s, 1H).

Example 351. Getting connection 528 table 17

By a reaction similar to that described in example 257, but based on N-acetylpiperidine (423 mg, 3.3 mmol), received the connection 528 in table 17 (93 mg, 71%).

MS ES+: 594 (M+H)+

1H NMR (DMSO-d6): 1.99 (m, 2H); 2.00 (s, 3H); 2.35 (t, 2H); 2.41 (t, 2H);2.49 (m, 2H); 3.45 (m, 4H); 3.91 (s, 2H); 3.91 (s, 2H); 3.97 (s, 3H); 4.23 (t, 2H); 6.92 (m, 1H); 7.27 (s, 1H); 7.32-7.42 (m, 2H); 7.40 (s, 1H); 7.63 (d, 1H); 8.13 (user s, 1H); 8.69 (s, 1H); 10.48 (s, 1H).

Example 352. Getting connection 529 table 17

By a reaction similar to that described in example 257, but on the basis of 1-(2-hydroxyethyl)piperazine (430 mg, 3.3 mmol), received the connection 529 table 17 (91 mg, 69%).

MS ES+: 596 (M+H)+

1H NMR (DMSO-d6): 1.96 (m, 2H); 2.41 (m, N); 3.50 (q, 2H); 3.91 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.37 (t, 1H); 6.91 (t, 1H); 7.25 (s, 1H); 7.32-7.42 (m, 2H); 7.39 (s, 1H); 7.65 (d, 1H); 8.12 (s, 1H); 8.68 (s, 1H); 10.48 (s, 1H); 12.04 (user s, 1H).

Example 353. Getting connection 530 in table 17

By a reaction similar to that described in example 257, but based on cyclopentylamine (281 mg, 3.3 mmol), received the connection 530 in table 17 (47 mg, 39%).

MS ES+: 551 (M+H)+

1H NMR (DMSO-d6): 1.39 (m, 2H); 1.50 (m, 2H); 1.65 (m, 2H); 1.80 (m, 2H); 2.00 (m, 1H); 2.80 (t, 2H); 3.16 (m, 1H); 3.91 (s, 2H); 3.98 (s, 3H); 4.25 (t, 2H); 6.98 (t, 1H); 7.28 (s, 1H); 7.31-7.42 (m, 2H); 7.40 (s, 1H); 7.64 (d, 1H); 8.13 (s, 1H); 8.69 (s, 1H); 10.49 (s, 1H).

Example 354. Getting connection 531 table 17

By a reaction similar to that described in example 257, but on the basis of 4-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol), received the connection 531 table 17 (65 mg, 50%).

MS ES+: 595 (M+H)+

1H NMR (DMSO-d6): 1.15 (m, 2H); 1.36 (m, 3H); 1.63 (d, 2H); 1.88 (m, 2H); 1.96 (m, 2H); 2.44 (m, 2H); 2.87 (d, 2H); 3.44 (m, 2H); 3.91 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.33 (t, 1H); 6.9 (t, 1H); 7.25 (s, 1H); 7.32-7.42 (m, 2H); 7.40 (s, 1H); 7.63 (d, 1H); 8.12 (user s, 1H); 8.68 (s, 1H); 10.48 (s, 1H); 12.03 (s, 1H).

Example 355. Getting connection 532 table 17

By a reaction similar to that described in example 257, but based on 3-hydroxypiperidine (334 mg, 3.3 mmol), received the connection 532 in table 17 (72 mg, 58%).

MS ES+: 567 (M+H)+

1H NMR (DMSO-d6): 1.09 (m, 1H); 1.43 (m, 1H); 1.63 (m, 1H); 1.78 (m, 2H); 1.87 (m, 1H); 1.96 (t, 2H); 2.47 (m, 2H); 2.69 (m, 1H); 2.85 (user d, 1H); 3.49 (m, 1H); 3.91 (s, 2H); 3.98 (s, 3H); 4.20 (t, 2H); 4.60 (d, 1H); 6.91 (t, 1H); 7.26 (s, 1H); 7.31-7.42 (m, 2H); 7.40 (s, 1H); 7.64 (d, 1H); 8.13 (user s, 1H); 8.68 (s, 1H); 10.48 (s, 1H); 12.02 (user s, 1H).

Example 356. Getting connection 533 table 17

By a reaction similar to that described in example 257, but on the basis of 4-hydroxypiperidine (380 mg, 3.3 mmol), received the connection 533 table 17 (56 mg, 44%).

MS ES+: 581 (M+H)+

1H NMR (DMSO-d6): 1.14 (m, 2H); 1.34 (m, 1H); 1.65 (d, 2H); 1.88 (t, 2H); 1.97 (m, 2H); 2.45 (t, 2H); 2.90 (d, 2H); 3.25 (t, 2H); 3.91 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.41 (t, 1H); 6.93 (t, 1H); 7.25 (s, 1H); 7.32-7.42 (m, 2H); 7.40 (s, 1H); 7.63 (d, 1H); 8.12 (user s, 1H); 8.68 (s, 1H); 10.48 (s, 1H); 12.03 (user s, 1H).

Example 357. Getting connection 534 table 17

By a reaction similar to that described in example 257, but on the basis of 1-amino-2-propanol (248 mg, 3.3 mmol), received the connection 534 in table 17 (36 mg, 30%).

MS ES+: 541 (M+H)+

1H NMR (DMSO-d6): 1.06 (d, 3H); 1.95 (m, 2H); 2.48 (m, 2H); 2.72 (t, 2H); 3.69 (m, 1H); 3.90 (s, 2H); 3.97 (who, 3H); 4.23 (t, 2H); 4.47 (user s, 1H); 6.91 (t, 1H); 7.26 (s, 1H); 7.32-7.41 (m, 2H); 7.39 (s, 1H); 7.63 (d, 1H); 8.11 (s, 1H); 8.67 (s, 1H); 10.48 (s, 1H).

Example 358. Getting connection 535 table 17

By a reaction similar to that described in example 257, but on the basis of (R)-(-)-2-pyrrolidineethanol (334 mg, 3.3 mmol), received the connection 535 table 17 (66 mg, 53%).

MS ES+: 567 (M+H)+

1H NMR (DMSO-d6): 1.57 (m, 1H); 1.67 (m, 2H); 2.82 (m, 1H); 1.96 (m, 2H); 2.18 (m, 1H); 2.45 (m, 2H); 2.98 (m, 1H); 3.10 (m, 1H); 3.20 (m, 1H); 3.41 (m, 1H); 3.91 (s, 2H); 3.98 (s, 3H); 4.22 (t, 2H); 4.35 (user s, 1H); 6.91 (t, 1H); 7.26 (s, 1H); 7.31-7.42 (m, 2H); 7.39 (s, 1H); 7.64 (d, 1H); 8.13 (s, 1H); 8.68 (s, 1H); 10.48 (s, 1H); 12.01 (user s, 1H).

Example 359. Getting connection 536 table 17

By a reaction similar to that described in example 257, but on the basis of (S)-(+)-2-pyrrolidineethanol (334 mg, 3.3 mmol), received the connection 536 table 17 (59 mg, 48%).

MS ES+: 567 (M+H)+

1H NMR (DMSO-d6, TFA): 1.78 (m, 1H); 1.90 (m, 1H); 2.03 (m, 1H); 2.13 (m, 1H); 2.31 (m, 2H); 3.23 (m, 2H); 3.61 (m, 4H); 3.77 (q, 1H); 3.98 (s, 3H); 3.99 (s, 2H); 4.29 (t, 2H); 6.89 (t, 1H); 7.29 (s, 1H); 7.30-7.40 (m, 2H); 7.63 (d, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 9.08 (s, 1H).

Example 360. Getting connection 537 table 17

By a reaction similar to that described in example 257, but based on tert-butyl-1-piperidinecarboxylate (615 mg, 3.3 mmol) and the processing of crude reaction mixture of hydrochloric acid in 1,4-dioxane (4 M, 2 ml), was awarded the connection 537 table 17 (35 mg, 27%).

MS ES+: 552 (M+H) +

1H NMR (DMSO-d6): 1.96 (m, 2H); 2.33 (user s, 4H); 2.42 (t, 2H); 2.73 (t, 4H); 3.89 (s, 2H); 3.95 (s, 3H); 4.19 (t, 2H); 6.89 (t, 1H); 7.24 (s, 1H); 7.32-7.42 (m, 2H); 7.37 (s, 1H); 7.62 (d, 1H); 8.10 (s, 1H); 8.66 (s, 1H); 10.47 (s, 1H).

Example 361. Getting connection 538 table 17

By a reaction similar to that described in example 257, but on the basis of 1-(2-morpholinoethyl)piperazine (519 mg, 3.3 mmol), received the connection 538 in table 17 (50 mg, 37%).

MS ES+: 665 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (m, 2H); 2.99 (t, 2H); 3.05-3.75 (m, N); 3.86 (user s, 4H); 3.99 (s, 3H); 4.00 (s, 2H); 4.29 (t, 2H); 6.90 (t, 1H); 7.32 (s, 1H); 7.41-7.31 (m, 2H); 7.62 (d, 1H); 7.64 (s, 1H); 7.92 (s, 1H); 9.09 (s, 1H).

Example 362. The connection of 539 table 17

By a reaction similar to that described in example 257, but on the basis of 2-amino-2-methyl-1-propanol (294 mg, 3.3 mmol), received the connection 539 table 17 (40 mg, 33%).

MS ES+: 555 (M+H)+

1H NMR (DMSO-d6): 0.96 (s, 6N); 1.91 (m, 2H); 2.67 (t, 2H); 3.19 (s, 2H); 3.90 (s, 2H); 3.97 (s, 3H); 4.24 (t, 2H); 4.53 (user s, 1H); 6.91 (m, 1H); 7.26 (s, 1H); 7.36 (m, 2H); 7.38 (s, 1H); 7.63 (d, 1H); 8.11 (s, 1H); 8.67 (s, 1H); 10.48 (s, 1H).

Example 363. Getting connection 540 table 18

4-((2-Amino-1,3-thiazol-5-yl)acetic acid)-6-methoxy-7-(3-morpholinopropan)hinzelin (125 mg, 0.27 mmol) in DMF (2.5 ml) was injected into the interaction with N-ethylaniline (84,3 μl, 0,707 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (136 mg, and 0.37 mmol) and DIEA (95 μl, 0.54 mmol is) at 50° C for 18 hours. The reaction mixture was cooled, was added sodium bicarbonate (feast upon, 1 ml) and 3 g of aluminum oxide, the mixture was evaporated to dryness and the residue was purified by chromatography on alumina, eluent CH2Cl2CH2Cl2/Meon from 99/1 to 95/5, getting mentioned in the title compound (68 mg, 44%).

MS ES+: 563.6 (M+H)+

1H NMR (DMSO-d6, TFA): 1.05 (t, 3H); 2.31 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.65 (m, 6N); 3.97 (s, 3H); 4.03 (d, 2H); 4.29 (t, 2H); 7.31 (s, 1H); 7.38 (s, 1H); 7.40 (m, 2H); 7.46 (m, 1H); 7.53 (m, 2H); 7.87 (s, 1H); 9.06 (s, 1H).

Example 364. Getting connection 541 table 18

By a reaction similar to that described in example 363, but on the basis of 3-chloro-4-fluoro-N-methylaniline (97 mg, 0.35 mmol)were specified in the title compound (98 mg, 60%).

MS ES+: 601.5, 603.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 1H); 3.15 (t, 2H); 3.21 (s, 3H); 3.35 (t, 2H); 3.54 (d, 2H); 3.7 (m, 4H); 3.97 (s, 3H); 4.03 (d, 2H); 4.29 (t, 2H); 7.31 (s, 1H); 7.41 (s, 1H); 7.50 (m, 2H); 7.80 (m, 1H); 7.87 (s, 1H); 9.06 (s, 1H).

N-(tert-butyloxycarbonyl)-3-chloro-4-ftoranila

3-Chloro-4-ftoranila (2 g, 13.7 mmol) in THF (12.5 ml) in an argon atmosphere was treated with NaHMDS (1 M, 27.5 ml, 27.5 mmol) at room temperature for 15 minutes. To the reaction mixture was slowly added di-tert-BUTYLCARBAMATE in THF (10 ml) and the mixture was stirred at room temperature for 45 minutes. The solvent is evaporated, diluted HCl was added (0.1 N.) and the feature was extracted with ethyl acetate, dried, purified by chromatography on silica gel, elwira a mixture of ether/petroleum ether 10-20/90-80, getting mentioned in the title compound (2,77 g, 82%).

1H NMR (CDCl3): 1.49 (s, N); 6.42 (s, 1H); 7.01 (t, 1H); 7.01 (m, 1H); 7.54 (m, 1H).

3-Chloro-4-fluoro-N-methylaniline

To a solution of N-(tert-butyloxycarbonyl)-3-chloro-4-foronline (250 mg, of 1.02 mmol) in THF (4 ml) at 0°With added sodium hydride (60%, 45 mg, 1.12 mmol) and the mixture was stirred for 20 minutes. Was added methyl iodide (70 μl, 1.12 mmol) to the mixture, which was stirred at room temperature for 4 hours. The solvent is evaporated, was added a saturated solution of sodium chloride and was extracted with a mixture of CH2Cl2, was dried and purified by chromatography on silica gel, elwira a mixture of ether/petroleum ether 8/2, obtaining the compound (235 mg). This compound was dissolved in CH2Cl2(2 ml) and TFA (2 ml), was added N2About (200 μl), the mixture was stirred for 1 hour at room temperature, the solvent evaporated, getting mentioned in the title compound (256 g, 89%).

1H NMR (CDCl3): 2.89 (s, 3H); 7.3 (m, 3H).

Example 365. Getting connection 542 table 18

By a reaction similar to that described in example 363, but based on ethyl-2-(3-chloro-4-ftoranila)acetate (151 mg, of 0.65 mmol)were specified in the title compound (10 mg, 4.5 per cent).

MS ES+: 673.6 (M+H)+

1H NMR (DSO-d 6, TFA): 1.18 (t, 3H); 2.30 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.83 (s, 1H); 3.97 (s, 3H); 4.03 (m, 4H); 4.13 (s, 2H); 4.29 (t, 2H); 4.41 (s, 1H); 7.30 (s, 1H); 7.44 (s, 1H); 7.55 (m, 2H); 7.78 (m, 1H); 7.87 (s, 1H); 9.06 (s, 1H).

Example 366. Getting connection 543 table 18

By a reaction similar to that described in example 363, but based on the 2-anilinomethyl (371 mg, of 2.72 mmol)were specified in the title compound (110 mg, 18%).

MS ES+: 574.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.77 (s, 1H); 3.97 (s, 3H); 4.04 (d, 2H); 4.30 (t, 2H); 4.81 (s, 2H); 7.31 (s, 1H); 7.43 (s, 1H); 7.57 (m, 5H); 7.88 (s, 1H); 9.09 (s, 1H).

Example 367. Getting connection 544 table 18

By a reaction similar to that described in example 363, but based on 3-anilinomethyl (335 mg, to 2.18 mmol)were specified in the title compound (100 mg, 18%).

MS ES+: 588.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.29 (t, 2H); 2.75 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (m, 4H); 3.95 (t, 2H); 3.97 (s, 3H); 4.04 (d, 2H); 4.29 (t, 2H); 7.29 (s, 1H); 7.42 (s, 1H); 7.48 (m, 3H); 7.55 (m, 2H); 7.87 (s, 1H); 9.08 (s, 1H).

Example 368. Getting connection 545 table 18

By a reaction similar to that described in example 363, but proceeding from N-(2-tert-butylether)-3-chloro-4-foronline (346 mg, of 1.42 mmol)were specified in the title compound (147 mg, 30%).

MS ES+: 687.6 (M+H)+

1H NMR (DMSO-d6, TFA): 1.08 (s, N); 2.31 (t, 2H); 3.14 (t, 2H); 4.3-4.5 (m, 4H); 3.55 (d, 2H); 3.68 (m, 6N); 3.7 (s, 3H); 4.03 (d, 2H); 4.29 (t, 2H); 7.30 (s, 1H); 7.41 (s, 1H); 7.51 (m, 2H); 7.78 (m, 1H); 7.87 (s, 1H); 9.06 (s, 1H).

N-(2-Hydroxyethyl)-3-chloro-4-ftoranila

Ethyl-2-(3-chloro-4-foronline)acetate (J. Med. Chem., 1965, 405-407) (2 g, 8.6 mmol) in THF (15 ml), ether (10 ml) was treated with LiAlH4(460 mg, 12.1 mmol) at 40°C for 4 hours. The mixture is then poured on ice, and treated with NaOH (2 N., 10 ml)and was extracted with ethyl acetate, dried, evaporated, getting mentioned in the title compound (1.48 g, 90%).

1H NMR (CDCl3): 1.67 (s, 1H); 3.24 (t, 2H); 3.84 (t, 2H); 3.92 (s, 1H); 6.47 (m, 1H); 6.64 (m, 1H); 6.95 (t, 1H).

N-(2-tert-butoxyethyl)-3-chloro-4-ftoranila

N-hydroxyethyl-3-chloro-4-ftoranila (1.48 g, 7,81 mmol) in CH2Cl2(20 ml) was injected into the interaction with N,N-aminobutiramida O-tert-utilizationa (6.25 g, and 31.2 mmol) at room temperature over night. The product was purified by chromatography on silica gel, eluent ether/petroleum ether 5/95, 10/90, getting mentioned in the title compound (1,15 g, 60%).

1H NMR (CDCl3): 1.20 (s, N); 3.18 (t, 2H); 3.55 (t, 2H); 4.00 (s, 1H); 6.44 (m, 1H); 6.62 (m, 1H); 6.93 (t, 1H).

Example 369. Getting connection 546 table 18

By a reaction similar to that described in example 363, but based on N-allylanisole (0.3 ml, to 2.18 mmol)were specified in the title compound (252 mg, 50%).

MS ES+: 575.7 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (m, 4H); 3.97 (s, 3H); 4.03 (d, 2H); 4.8 (m, 4H); 5.12 (m, 2H); 5.82 (m, 1H); 7.30 (s, 1H); 7.38 (m, 3H); 7.40 (s, 1H); 7.51 (m, 2H); 7.87 (s, 1H); 9.07 (s, 1H).

Example 370. Getting connection 547 table 18

By a reaction similar to that described in example 363, but on the basis of N-ethyl-3,4-(methylenedioxy)aniline (320 μl, of 2.18 mmol)were specified in the title compound (351 mg, 66%).

MS ES+: 607.7 (M+H)+

1H NMR (DMSO-d6, TFA): 1.04 (t, 3H); 2.31 (t, 2H); 3.16 (t, 2H); 3.34 (t, 2H); 3.54 (d, 2H); 3.68 (m, 6N); 3.97 (s, 3H); 4.09 (d, 2H); 4.29 (t, 2H); 6.12 (s, 2H); 6.83 (d, 1H); 7.02 (m, 2H); 7.30 (s, 1H); 7.42 (s, 1H); 7.86 (s, 1H); 9.06 (s, 1H).

Example 371. Getting connection 548 table 18

By a reaction similar to that described in example 363, but based on ethyl-4-(N-butylamino)benzoate (482 mg, to 2.18 mmol)were specified in the title compound (58 mg, 10%).

MS ES+: 663.7 (M+H)+

1H NMR (DMSO-d6, TFA): 0.85 (t, 3H); 1.32 (m, 7H); 2.31 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.70 (m, 6N); 3.97 (s, 3H); 4.04 (d, 2H); 4.29 (t, 2H); 4.35 (s, 2H); 7.30 (s, 1H); 7.41 (s, 1H); 7.54 (d, 2H); 7.87 (s, 1H); 8.07 (d, 2H); 9.07 (s, 1H).

Example 372. Getting connection 549 table 18

By a reaction similar to that described in example 363, but on the basis of N-ethyl-m-toluidine (294 mg, to 2.18 mmol)were specified in the title compound (294 mg, 58%).

MS ES+: 577.7 (M+H)+

1H NMR (DMSO-d6, TFA): 1.05 (t, N); 2.31 (t, 2H); 2.38 (s, 3H); 3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.67 (m, 6N); 3.97 (s, 3H); 4.04 (d, 2H); 4.29 (t, 2H); 7.18 (m, 2H); 7.28 (d, 1H); 7.30 (s, 1H); 7.39 (s, 1H); 7.42 (d, 1H); 7.86 (who, 1H); 9.07 (s, 1H).

Example 373. Getting connection 550 table 18

Connection 545 (120 mg) in CH2Cl2(2 ml) was treated with TFA (3 ml) and N2About (200 μl) at room temperature for 3 hours. The solvent is evaporated, got mentioned in the title compound (45 mg, 41%).

MS ES+: 631.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.29 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.51 (t, 2H); 3.54 (d, 2H); 3.70 (m, 6N); 3.97 (s, 3H); 4.03 (d, 2H); 4.30 (t, 2H); 7.30 (s, 1H); 7.42 (s, 1H); 7.54 (m, 2H); 7.78 (d, 1H); 7.87 (s, 1H); 9.06 (s, 1H).

Example 374. Getting connection 551 in table 19

4-((2-Amino-4-methyl-1,3-thiazol-5-yl)acetic acid)-6-methoxy-7-(3-morpholinopropan)hinzelin (118 mg, 0.25 mmol) in DMF (1.5 ml) was injected into the interaction with aniline (32 mg, 0.35 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (142 mg, the 0.375 mmol) and DIEA (65 mg, 0.5 mmol) at 65°With during the night. The mixture was cooled, was added sodium bicarbonate and evaporated the mixture. The residue was dissolved in CH2Cl2/Meon 92/8 and was purified by chromatography on alumina, eluent CH2Cl2CH2Cl2/Meon from 92/8 to 95/5; was carried out by a second purification on silica gel, eluent CH2Cl2/Meon from 95/5 to 90/10, getting mentioned in the title compound (86 mg, 62%).

MS ES+: 549.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.34 (s, 3H); 3.15 (t, 2H); 3.34 (t, 1H); 3.54 (d, 2H); 3.72 (t, 2H); 3.90 (s, 2H); 3.98 (s, 3H); (4.04); (d, 2H); 4.30 (t, 2H); 7.08 (t, 2H); 7.29 (s, 1H); 7.31 (t, 2H); 7.62 (d, 2H); 7.85 (s, 1H); 9.05 (s, 1H).

4-(Ethyl(2-amino-4-methyl-1,3-thiazol-5-yl)acetate)-6-methoxy-7-(3-morpholinopropan)hinzelin

N'-(2-cyano-4-methoxy-5-(3-morpholinoethoxy)phenyl)-N,N-dimethylaminopropane (1,38 g, 4 mmol) in acetic acid was injected into the interaction with ethyl-2-amino-4-methyl-1,3-thiazol-5-yl)acetate boiling within 3.5 hours. The mixture was cooled, evaporated, was added HCl (1 BC) and was extracted with a mixture of ethyl acetate. Was carefully added sodium bicarbonate to the water phase, which was extracted with ethyl acetate. The organic fraction was dried, evaporated, the residue was purified by chromatography on alumina, eluent CH2Cl2CH2Cl2/AcOEt 1/1, CH2Cl2/AcOEt/Meon 50/45/5, receiving the original connection in the form of a yellow solid (1.12 g, 52%).

MS ES+: 502.6 (M+H)+

1H NMR (DMSO-d6, TFA): 1.24 (t, 3H); 2.28 (m, 5H); 3.15 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.92 (s, 2H); 3.98 (s, 3H); 4.04 (d, 2H); 4.15 (q, 2H); 4.30 (t, 2H); 7.30 (s, 1H); 7.86 (s, 1H); 9.05 (s, 1H).

4-(2-amino-4-methyl-1,3-thiazol-5-yl)acetic acid)-6-methoxy-7-(3-morpholinopropan)hinzelin

4-(Ethyl(2-amino-4-methyl-1,3-thiazol-5-yl)acetate)-6-methoxy-7-(3-morpholinopropan)hinzelin (1.1 g, 2.2 mmol) in ethanol (11 ml) was treated with NaOH (2 N., 5.5 ml, 11 mmol) at room temperature for 1 hour. Then the mixture was acidified with HCl 2 N.) to pH 3. The solution was evaporated, the solid is suspended in CH2Cl2(8 ml), Meon (6 ml) was added DIEA (852 mg, 6.6 mmol). The mixture was stirred 10 minutes, filtered. The filtrate was concentrated, was added ethanol, and provided solid, getting mentioned in the title compound (980 mg, 94%).

MS ES+: 474.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.28 (m, 5H); 3.16 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.70 (t, 2H); 3.83 (s, 2H); 3.98 (s, 3H); 4.04 (d, 2H); 4.30 (t, 2H); 7.30 (s, 1H); 7.86 (s, 1H); 9.05 (s, 1H).

Example 375. Getting connection 552 in table 19

By a reaction similar to that described in example 374, but on the basis of 3-chloro-4-foronline (51 mg, 0.35 mmol)were specified in the title compound (60 mg, 40%).

MS ES+: 601.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 2.33 (s, 3H); 3.16 (t, 2H); 3.36 (t, 2H); (3.55) (d, 2H); 3.69 (t, 2H); 3.90 (s, 2H); 3.98 (s, 3H); 4.04 (d, 2H); 4.30 (t, 2H); 7.28 (s, 1H); 7.39 (t, 1H); 7.49 (m, 1H); 7.86 (, 1H); 7.96 (m, 1H); 9.05 (s, 1H).

Example 376. Getting connection 553 in table 19

By a reaction similar to that described in example 374, but on the basis of 2-aminopyridine (33 mg, 0.35 mmol)were specified in the title compound (45 mg, 32%).

MS ES+: 550.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.35 (s, 3H); 3.16 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.98 (s, 3H); 4.04 (m, 4H); 4.30 (t, 2H); 7.30 (m, 2H); 7.87 (s, 1H); 7.95 (d, 1H); 8.05 (m, 1H); 8.40 (d, 1H); 9.04 (s, 1H).

Example 377. Getting connection 554 in table 19

On react and, similar to that described in example 374, but based on 3,4-diferencia (50 mg, 0,39 mmol)were specified in the title compound (120 mg, 74%).

MS ES+: 585.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 2.33 (s, 3H); 3.16 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.67 (t, 2H); 3.90 (s, 2H); 3.98 (s, 3H); 4.05 (d, 2H); 4.31 (t, 2H); 7.28 (s, 1H); 7.32 (m, 1H); 7.40 (q, 1H); 7.80 (m, 1H); 7.86 (s, 1H); 9.05 (s, 1H).

Example 378. Getting connection 555 in table 20

N'-(2-cyano-5-((2S)-2-hydroxy-3-piperidinyloxy)-4-methoxyphenyl)-N,N-dimethylaminopropane (381 mg, 0.96 mmol) in acetic acid (6 ml) was irradiated in a microwave oven in the presence of N-(4-fluoro-3-chloranil)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (275 mg, 0.96 mmol) by boiling for 0.5 hours. The solvent is evaporated and the residue was purified by chromatography on silica gel, eluent CH2Cl2/Meon feast upon. NH3from 95/5 to 93/7, getting mentioned in the title compound (230 mg, 40%).

MS ES+: 601.5 (M+H)+

1H NMR (DMSO-d6, TFA): 1.42 (m, 1H); 1.6-1.9 (m, 5H); 3.02 (m, 2H); 3.28 (m, 2H); 3.52 (m, 2H); 3.99 (s, 5H); 4.19 (d, 2H); 4.43 (m, 1H); 7.35 (s, 1H); 7.40 (t, 1H); 7.48 (m, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 7.95 (m, 1H); 9.08 (s, 1H).

N'-(2-cyano-5-((2S)-2-hydroxy-3-piperidinyloxy)-4-methoxyphenyl)-N,N-dimethylaminopropane

N'-(2-cyano-5-((2S)-oxiranylmethyl-4-methoxyphenyl)-N,N-dimethylaminopropane (850 mg, to 3.09 mmol) in chloroform (6 ml) and ethanol (12 ml) was irradiated with pyridine (0,46 ml, 4.6 mmol) in a microwave pécs is boiling for 10 minutes. The solvent is evaporated and the residue was purified by chromatography on silica gel, eluent CH2Cl2/Meon 90/10, getting mentioned in the title compound (954 mg, 86%).

MS ES+: 361.6 (M+H)+

1H NMR (DMSO-d6): 1.43 (m, 6N); 2.4 (m, 6N); 2.97 (s, 3H); 3.06 (s, 3H); 3.75 (s, 3H); 3.95 (d, 2H); 4.03 (m, 1H); 4.83 (s, 1H); 6.75 (s, 1H); 7.10 (s, 1H); 7.90 (s, 1H).

N'-(2-cyano-5-((2S)-oxiranylmethyl-4-methoxyphenyl)-N,N-dimethylaminopropane

N'-(2-cyano-4-methoxy-5-hydroxyphenyl)-N,N-dimethylaminopropane (1 g, of 4.57 mmol) in DMF (25 ml) was injected into the interaction with (2S) gliciltirosin (1,15 g 5,02 mmol) in the presence of cesium carbonate (5,95 g, and 18.3 mmol) at 60°C in argon atmosphere for 2 hours. The solvent is evaporated, added water and was extracted with a mixture of ethyl acetate, dried, concentrated and the residue was purified by chromatography on silica gel, eluent CH2Cl2/AcOEt from 80/20 to 70/30, getting mentioned in the title compound (1.18 g, 94%).

MS ES+: 276.6 (M+H)+

1H NMR (DMSO-d6): 2.70 (m, 1H); 2.86 (m, 1H); 2.95 (s, 3H); 3.01 (s, 3H); 3.35 (m, 1H); 3.75 (s, 3H); 3.90 (m, 1H); 4.37 (m, 1H); 6.75 (s, 1H); 7.11 (s, 1H); 7.89 (s, 1H).

Methyl-(2-trailmen-1,3-thiazol-5-yl)acetate

Methyl-(2-amino-1,3-thiazol-5-yl)acetate (1 g, 5.8 mmol) in CH2Cl2(15 ml) was administered in cooperation with triphenylmethylchloride (1.73 g, 6.2 mmol) and triethylamine (of 0.89 ml, 6.4 mmol) at 0°C for 1.5 hours. Added water to the mixture, to the which was extracted with ethyl acetate, dried, purified by chromatography on silica gel, receiving specified in the header of the connection (of 2.21 g, 91%).

1H NMR (DMSO-d6): 3.58 (s, 3H); 3.59 (s, 2H); 6.57 (s, 1H); 7.23 (m, 15 NM); 8.40 (s, 1H).

(2 Trailmen-1,3-thiazol-5-yl)acetic acid

Methyl(2-trailmen-1,3-thiazol-5-yl)acetate (2 g, 4.8 mmol) in THF (10 ml) and ethanol (10 ml) was injected into the interaction with sodium hydroxide (1 N., 7.2 ml, 7.2 mmol) at room temperature for 1.5 hours. The solvent is evaporated, was added HCl (6 BC), was isolated solid by filtration, getting mentioned in the title compound (1,96 g).

1H NMR (DMSO-d6): 3.63 (s, 2H); 5.70 (s, 1H); 7.32 (m, 15 NM).

N-(4-fluoro-3-chlorophenyl)-2-trailmen-1,3-thiazol-5-yl)ndimethylacetamide

(2 Trailmen-1,3-thiazol-5-yl)acetic acid (1,96 g, 4.9 mmol) in DMF (25 ml) was injected into the interaction with 3-chloro-4-fornerino (1.07 g, 7,3 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (2,42 g, 6,37 mmol) and DIEA (1.7 g, 9.8 mmol) at 50°C for 18 hours. DMF is evaporated, the residue was dissolved in a mixture of CH2Cl2/AcOEt, washed with a saturated solution of sodium bicarbonate. Precipitated from the organic phase, the solid was isolated, the organic phase was evaporated and to the residue was added Meon, receiving solid, thus, allocated second portion is specified in the header connection, receiving only (1,38 g, 53%).

1H NMR (DMSO-d6): 3.56 (s, 2H); 6.61 (s, 1H); 7.28 (m, 17H); 7.88 (m, 1H); 8.41 (s, 1H).

N-(4-fluoro-3-chlorophenyl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide

N-(4-fluoro-3-chlorophenyl)-2-(2-trailmen-1,3-thiazol-5-yl)ndimethylacetamide (to 12.28 g, 23 mmol) was dissolved in TFA (100 ml) and water (10 ml). The mixture was stirred at room temperature for 45 minutes. To the reaction mixture were added water (300 ml), the solid was isolated by filtration, washed with water and ether. The solid was dissolved in Meon and was treated with a solution of ammonia (pH 8), then the Meon partially evaporated, was added water (300 ml) and the precipitate was isolated specified in the connection header, dried (lower than the 5.37 g, 81%).

1H NMR (DMSO-d6): 3.64 (s, 2H); 6.76 (m, 3H); 7.38 (t, 1H); 7.48 (m, 1H); 7.92 (m, 1H).

Example 379. Getting connection 556 in table 20

By a reaction similar to that described in example 378, but on the basis of N'-(2-cyano-5-((2S)-2-hydroxy-3-pyrrolidinyloxy)-4-methoxyphenyl)-N,N-diethylmetatoluamide (267 mg, 0.77 mmol)were specified in the title compound (213 mg, 52%).

MS ES+: 587.5 (M+H)+

1H NMR (DMSO-d6): 1.68 (m, 4H); 2.5 (m, 5H); 2.66 (m, 1H); 3.88 (s, 2H); 3.96 (s, 3H); 4.00 (m, 1H); 4.07 (m, 1H); 4.20 (m, 1H); 4.95 (m, 1H); 7.26 (s, 1H); 7.36 (s, 1H); 7.37 (m, 1H); 7.47 (m, 1H); 7.95 (m, 1H); 8.11 (s, 1H); 8.66 (s, 1H).

N'-(2-cyano-5-((2S)-2-hydroxy-3-pyrrolidinyloxy)-4-methoxyphenyl)-N,N-dimethylaminopropane

By a reaction similar to that described in example 378, but on the basis of Pirro is Idina (1,4 ml, 16 mmol)were specified in the title compound (2.8 g, 74%).

MS ES+: 347.6 (M+H)+

1H NMR (DMSO-d6): 1.67 (m, 4H); 1.45 (m, 4H); 1.63 (m, 2H); 2.95 (s, 3H); 3.05 (s, 3H); 3.73 (s, 3H); 3.95 (m, 2H); 4.04 (m, 1H); 4.93 (m, 1H); 6.73 (s, 1H); 7.08 (s, 1H); 7.89 (s, 1H).

Example 380. Getting connection 557 table 20

By a reaction similar to that described in example 378, but based on

N'-(2-cyano-5-((2S)-2-hydroxy-3-(4-piperidinyl)propoxy)-4-methoxyphenyl)-N,N-diethylmetatoluamide (195 mg, 0.52 mmol)were specified in the title compound (88 mg, 30%).

MS ES+: 617.5 (M+H)+

1H NMR (DMSO-d6): 1.40 (m, 2H); 1.70 (m, 2H); 2.13 (m, 2H); 3.43 (m, 2H); 2.77 (m, 2H); 3.43 (m, 1H); 3.88 (s, 2H); 3.96 (s, 3H); 4.03 (m, 2H); 4.19 (m, 1H); 4.52 (d, 1H); 4.87 (m, 1H); 7.27 (s, 1H); 7.39 (m, 2H); 7.49 (m, 1H); 7.99 (m, 1H); 8.67 (s, 1H).

N'-(2-cyano-5-((2S)-2-hydroxy-3-(4-piperidinyl)propoxy)-4-methoxyphenyl)-N,N-dimethylaminopropane

By a reaction similar to that described in example 378, but on the basis of 4-hydroxypiperidine (131 mg, of 1.27 mmol)were specified in the title compound (200 mg, 58%).

MS ES+: 377.6 (M+H)+

1H NMR (DMSO-d6): 1.39 (m, 1H); 1.68 (m, 2H); 2.10 (m, 2H); 2.40 (m, 2H); 2.75 (m, 2H); 2.95 (s, 3H); 3.05 (s, 3H); 3.21 (s, 3H); 3.31 (m, 1H); 3.95 (m, 2H); 4.00 (m, 1H); 4.52 (m, 1H); 4.82 (m, 1H); 6.73 (s, 1H); 7.08 (s, 1H); 7.88 (s, 1H).

Example 381. Getting connection 558 table 20

By a reaction similar to that described in example 378, but on the basis of N'-(2-cyano-5-((2S)-2-hydroxy-3-(4-tert-butelek carbonylmethyl)propoxy)-4-methoxyphenyl)-N,N-diethylmetatoluamide (355 mg, 0.77 mmol)were specified in the title compound (70 mg, 17%).

MS ES+: 602.4 (M+H)+

1H NMR (DMSO-d6): 2.42 (m, 6N); 2.73 (d, 4H); 3.88 (s, 2H); 3.96 (s, 3H); 4.04 (m, 2H); 4.19 (m, 1H); 4.90 (m, 1H); 7.28 (s, 1H); 7.37 (m, 2H); 7.47 (m, 1H); 7.94 (m, 1H); 8.11 (s, 1H); 8.66 (s, 1H).

N'-(2-cyano-5-((2S)-2-hydroxy-3-(4-tert-butyloxycarbonyl)propoxy)-4-methoxyphenyl)-N,N-dimethylaminopropane

By a reaction similar to that described in example 378, but on the basis of tert-butyloxycarbonyl (284 mg, 1.53 mmol)were specified in the title compound (444 mg, 88%).

MS ES+: 462.6 (M+H)+

1H NMR (DMSO-d6): 1.39 (s, N); 2.40 (m, 6N); 2.95 (s, 3H); 3.04 (s, 3H); 3.30 (m, 4H); 3.72 (s, 3H); 3.95 (m, 2H); 4.02 (m, 1H); 4.91 (d, 1H); 6.74 (s, 1H); 7.09 (s, 1H); 7.88 (s, 1H).

Example 382. The connection is 559 in table 20

By a reaction similar to that described in example 378, but based on

N'-(2-cyano-5-((2S)-2-hydroxy-3-cyclopentylpropionic)-4-methoxyphenyl)-N,N-diethylmetatoluamide (290 mg, 0.77 mmol)were specified in the title compound (226 mg, 54%).

MS ES+: 601.4 (M+H)+

1H NMR (DMSO-d6): 1.32 (m, 2H); 1.48 (m, 2H); 1.62 (m, 2H); 1.73 (m, 2H); 2.63 (m, 1H); 2.71 (m, 1H); 3.05 (m, 1H); 3.89 (s, 2H); 3.98 (m, 4H); 4.09 (m, 1H); 4.17 (m, 1H); 5.03 (m, 1H); 7.27 (s, 1H); 7.40 (m, 2H); 7.51 (m, 1H); 7.97 (m, 1H); 8.12 (s, 1H); 8.67 (s, 1H).

N'-(2-cyano-5-((2S)-2-hydroxy-3-cyclopentylpropionic)-4-methoxyphenyl)-N,N-dimethylaminopropane

In reactions similar to the op is pulling in example 378, but based on cyclopentylamine (2.7 ml, 27 mmol)were specified in the title compound (1.6 mg, 82%).

MS ES+: 361.6 (M+H)+

1H NMR (DMSO-d6): 1.30 (m, 2H); 1.48 (m, 2H); 1.60 (m, 2H); 1.72 (m, 2H); 2.56 (m, 1H); 2.67 (m, 1H); 2.97 (s, 3H); 3.01 (m, 1H); 3.07 (s, 3H); 3.75 (s, 3H); 3.89 (m, 1H); 4.00 (m, 2H); 5.01 (m, 1H); 6.75 (s, 1H); 7.10 (s, 1H); 7.91 (s, 1H).

Example 383. Getting connection 560 in table 20

By a reaction similar to that described in example 378, but on the basis of N'-(2-cyano-5-((2S)-2-hydroxy-3-((2-hydroxy-1,1-dimethylethyl)amino)propoxy)-4-methoxyphenyl)-N,N-diethylmetatoluamide (350 mg, 0.77 mmol)were specified in the title compound (147 mg, 34%).

MS ES+: 305.4 (M+H)+

1H NMR (DMSO-d6): 0.97 (s, 3H); 0.98 (s, 3H); 2.63 (m, 2H); 3.19 (DD, 2H); 3.89 (m, 3H); 3.98 (s, 3H); 4.10 (m, 1H); 4.18 (m, 1H); 4.56 (m, 1H); 7.29 (s, 1H); 7.39 (m, 2H); 7.50 (m, 1H); 7.97 (m, 1H); 8.13 (s, 1H); 8.68 (s, 1H).

N'-(2-cyano-5-((2S)-2-hydroxy-3-((2-hydroxy-1,1-dimethylethyl)amino)propoxy)-4-methoxyphenyl)-N,N-dimethylaminopropane

By a reaction similar to that described in example 378, but on the basis of 2-amino-2-methyl-1-propanol (1.8 ml, 18.2 mmol)were specified in the title compound (1.25 g, 93%).

1H NMR (DMSO-d6): 0.93 (s, 3H); 0.94 (s, 3H); 2.58 (m, 2H); 3.19 (m, 2H); 3.73 (s, 3H); 3.80 (m, 1H); 3.97 (m, 1H); 4.03 (m, 1H); 4.50 (m, 1H); 4.95 (m, 1H); 6.75 (s, 1H); 7.10 (s, 1H); 7.91 (s, 1H).

Example 384. Getting connection 561 table 20

By a reaction similar to that described in example 378, but proceeding from N-(3,differenl)-2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, to 0.74 mmol) and acetic acid (3 ml)were specified in the title compound (263 mg, 60%).

MS ES+: 585.5 (M+H)+

1H NMR (DMSO-d6): 1.37 (m, 2H); 1.50 (m, 4H); 2.41 (m, 6N); 3.88 (s, 2H); 3.96 (s, 3H); 4.03 (m, 2H); 4.18 (d, 1H); 4.88 (m, 1H); 7.28 (s, 1H); 7.40 (s, 1H); 7.40 (m, 2H); 7.80 (m, 1H); 8.11 (s, 1H); 8.66 (s, 1H).

N-(3,4-differenl)-2-amino-1,3-thiazol-5-yl)ndimethylacetamide.

By a reaction similar to that described in example 378, but proceeding from N-(3,4-differenl)-2-(2-trailmen-1,3-thiazol-5-yl)ndimethylacetamide (1,75 g of 3.42 mmol)were specified in the title compound (642 mg, 70%).

1H NMR (DMSO-d6): 3.62 (s, 2H); 6.73 (s, 1H); 6.74 (s, 2H); 7.28 (m, 1H); 7.37 (q, 1H); 7.77 (m, 1H).

N-(3,4-differenl)-2-(2-trailmen-1,3-thiazol-5-yl)ndimethylacetamide

By a reaction similar to that described in example 378, but based on 3,4-diferencia (0,97 ml of 9.75 mmol)were specified in the title compound (1.75 g, 46%).

MS ES+: 512.5 (M+H)+

1H NMR (DMSO-d6): 3.54 (s, 2H); 6.58 (s, 1H); 7.25 (m, 17H); 7.71 (m, 1H); 8.39 (s, 1H).

Example 385. Getting connection 562 table 20

By a reaction similar to that described in example 379, but proceeding from N-(3,4-differenl)-2-(2(amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, of 0.74 mmol)were specified in the title compound (226 mg, 53%).

MS ES+: 571.5 (M+H)+

1H NMR (DMSO-d6): 1.70 (m, 4H); 2.52 (m, 5H); 2.68 (m, 1H); 3.89 (s, 2H); 3.98 (s, 3H); 4.06 (m, 2H); 4.21 (m, 1H); 4.95 (m, 1H); 7.28 (s, 1H); 7.33 (m, 1H); 7.39 (s, 1H); 7.40 (m, 1H); 7.81 (m, 1H); 812 (C, 1H); 8.68 (s, 1H).

Example 386. The connection is 563 in table 20

By a reaction similar to that described in example 380, but proceeding from N-(3,4-differenl)-2-(2(amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, of 0.74 mmol)were specified in the title compound (220 mg, 49%).

MS ES+: 601.5 (M+H)+

1H NMR (DMSO-d6): 1.40 (m, 2H); 1.70 (m, 2H); 2.12 (m, 2H); 3.40 (m, 2H); 2.78 (m, 2H); 3.43 (m, 1H); 3.88 (s, 2H); 3.96 (s, 3H); 4.03 (m, 2H); 4.18 (m, 1H); 4.51 (d, 1H); 4.87 (m, 1H); 7.27 (s, 1H); 7.32 (m, 1H); 7.38 (s, 1H); 7.40 (m, 1H); 7.80 (m, 1H); 8.11 (s, 1H); 8.67 (s, 1H).

Example 387. Getting connection 565 table 20

By a reaction similar to that described in example 382, but proceeding from N-(3,4-differenl)-2-(2(amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, of 0.74 mmol)were specified in the title compound (233 mg, 53%).

MS ES+: 585.5 (M+H)+

1H NMR (DMSO-d6): 1.32 (m, 2H); 1.47 (m, 2H); 1.61 (m, 2H); 1.72 (m, 2H); 2.63 (m, 1H); 2.72 (m, 1H); 3.05 (m, 1H); 3.89 (s, 2H); 3.97 (m, 4H); 4.09 (m, 1H); 4.16 (m, 1H); 5.05 (m, 1H); 7.27 (s, 1H); 7.34 (m, 1H); 7.38 (s, 1H); 7.42 (m, 1H); 7.82 (m, 1H); 8.12 (s, 1H); 8.67 (s, 1H).

Example 388. Getting connection 566 table 20

By a reaction similar to that described in example 379, but proceeding from N-(3-chlorophenyl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, of 0.74 mmol)were specified in the title compound (238 mg, 56%).

MS ES+: 569.5 (M+H)+

1H NMR (DMSO-d6): 1.70 (s, 1H); 2.52 (m, 5H); 2.68 (m, 1H); 3.90 (s, 2H); 3.98 (s, 3H); 4.06 (m, 2H); 4.21 (m, 1H); 4.97 (m, 1H); 7.14 (d, 1H); 7.27 (t, 1H); 7.37 (m, 1H) 7.48 (d, 1H); 7.85 (m, 1H); 8.12 (s, 1H); 8.68 (s, 1H).

N-(3-chlorophenyl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide

By a reaction similar to that described in example 378, but proceeding from N-(3-chlorophenyl)-2-(2-trailmen-1,3-thiazol-5-yl)ndimethylacetamide (3,62 g, 7.1 mmol)were specified in the title compound (1.6 g, 84%).

1H NMR (DMSO-d6): 3.64 (s, 2H); 6.74 (m, 3H); 7.11 (m, 1H); 7.33 (t, 1H); 7.42 (d, 1H); 7.79 (m, 1H).

N-(3-chlorophenyl)-2-(2-trailmen-1,3-thiazol-5-yl)ndimethylacetamide

By a reaction similar to that described in example 378, but on the basis of 3-Chloroaniline (1.4 ml, 13 mmol)were specified in the header connection (3,62 g, 71%).

1H NMR (DMSO-d6): 3.55 (s, 2H); 6.59 (s, 1H); 7.21 (m, N); 7.76 (m, 1H); 8.39 (s, 1H).

Example 389. Getting connection 567 table 20

By a reaction similar to that described in example 380, but proceeding from N-(3-chlorophenyl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, 0.75 mmol)were specified in the title compound (156 mg, 35%).

MS ES+: 599.4, 601.4 (M+H)+

1H NMR (DMSO-d6): 1.40 (m, 2H); 1.70 (m, 2H); 2.12 (m, 2H); 2.42 (m, 2H); 2.77 (m, 2H); 3.42 (m, 1H); 3.89 (s, 2H); 3.96 (s, 3H); 4.02 (m, 2H); 4.18 (m, 1H); 4.52 (d, 1H); 4.89 (m, 1H); 7.12 (d, 1H); 7.26 (s, 1H); 7.35 (t, 1H); 7.38 (s, 1H); 7.46 (d, 1H); 7.84 (m, 1H); 8.11 (s, 1H); 8.67 (s, 1H).

Example 390. Getting connection 568 table 20

By a reaction similar to that described in example 382, but proceeding from N-(3-chlorophenyl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, 0.75 mmol)were specified in the title compound (255 mg, 5%).

MS ES+: 583.5, 585.5 (M+H)+

1H NMR (DMSO-d6): 1.32 (m, 2H); 1.48 (m, 2H); 1.62 (m, 2H); 1.73 (m, 2H); 2.63 (m, 1H); 2.72 (m, 1H); 3.04 (m, 1H); 3.90 (s, 2H); 3.97 (m, 4H); 4.09 (m, 1H); 4.16 (m, 1H); 5.05 (m, 1H); 7.12 (d, 1H); 7.27 (s, 1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.48 (m, 1H); 8.12 (s, 1H); 8.68 (s, 1H).

Example 391. Getting connection 569 table 20

By a reaction similar to that described in example 383, but proceeding from N-(3-chlorophenyl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, of 0.74 mmol)were specified in the title compound (130 mg, 30%).

MS ES+: 587.5, 589.5 (M+H)+

1H NMR (DMSO-d6): 0.97 (s, 6N); 2.63 (m, 2H); 3.19 (m, 2H); 3.90 (m, 3H); 3.98 (s, 3H); 4.10 (m, 1H); 4.18 (m, 1H); 4.55 (m, 1H); 5.03 (m, 1H); 7.13 (d, 1H); 7.29 (s, 1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.48 (d, 1H); 7.86 (m, 1H); 8.13 (s, 1H); 8.68 (s, 1H).

Example 392. Getting connection 570 in table 20

By a reaction similar to that described in example 381, but proceeding from N-(3-chlorophenyl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, 0.75 mmol)were specified in the title compound (211 mg, 48%).

MS ES+: 584.4 (M+H)+

1H NMR (DMSO-d6): 2.37 (m, 6N); 2.70 (m, 4H); 3.89 (s, 2H); 3.96 (s, 3H); 4.05 (m, 2H); 4.19 (m, 1H); 4.90 (m, 1H); 7.12 (d, 1H); 7.27 (s, 1H); 7.35 (t, 1H); 7.37 (s, 1H); 7.47 (d, 1H); 7.84 (m, 1H); 8.10 (s, 1H); 8.66 (s, 1H).

Example 393. Getting connections 571 table 20

By a reaction similar to that described in example 388, but on the basis of N'-(2-cyano-5-((2S)-2-hydroxy-3-methoxy)propoxy)-N,N-diethylmetatoluamide (252 mg, 0.82 mmol)were specified in which the head of the compound (200 mg, 50%).

MS ES+: 530.4, 532.4 (M+H)+

1H NMR (DMSO-d6): 3.22 (s, 3H); 3.42 (m, 2H); 3.91 (s, 2H); 3.98 (s, 2H); 4.10 (m, 3H); 5.21 (d, 1H); 7.13 (d, 1H); 7.26 (s, 1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.48 (d, 1H); 7.85 (m, 1H); 8.13 (m, 1H); 8.69 (s, 1H).

N'-(2-cyano-5-((2S)-2-hydroxy-3-methoxy)propoxy-4-methoxyphenyl)-N,N-dimethylaminopropane

N'-(2-cyano-5-(2S)-oxiranylmethyl-4-methoxyphenyl)-N,N-dimethylaminopropane (1 g, 3.6 mmol) in methanol (80 ml) was treated with sodium methylate (10 g, 218 mmol) by boiling in a microwave oven for 0.5 hour. The solvent is evaporated and the mixture was purified by chromatography on silica gel, eluent CH2Cl2/Meon 95/5, getting mentioned in the title compound (896 mg, 80%).

1H NMR (DMSO-d6): 2.97 (s, 1H); 3.07 (s, 1H); 3.29 (s, 1H); 3.38 (m, 2H); 3.75 (s, 3H); 3.98 (m, 3H); 5.16 (d, 1H); 6.75 (s, 1H); 7.10 (s, 1H); 7.93 (s, 1H).

Example 394. Getting connection 572 table 20

By a reaction similar to that described in example 378, but proceeding from N-(3-chlorophenyl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, 0.75 mmol)were specified in the title compound (268 mg, 61%).

MS ES+: 583.5 (M+H)+

1H NMR (DMSO-d6): 1.38 (m, 2H); 1.50 (m, 4H); 2.43 (m, 6N); 3.91 (s, 2H); 3.98 (s, 3H); 4.05 (m, 2H); 4.21 (m, 1H); 4.88 (m, 1H); 7.14 (d, 1H); 7.29 (s, 1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.48 (d, 1H); 7.85 (m, 1H); 8.12 (s, 1H); 8.68 (s, 1H).

Example 395. The connection is 573 in table 20

By a reaction similar to that described in example 378, but proceeding from N-(3,5-differenl)2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, to 0.74 mmol)were specified in the title compound (157 mg, 36%).

MS ES+: 585.5 (M+H)+

1H NMR (DMSO-d6): 1.37 (m, 2H); 1.50 (m, 4H); 2.40 (m, 6N); 3.90 (s, 2H); 3.96 (s, 3H); 4.05 (m, 2H); 4.19 (m, 1H); 4.88 (m, 1H); 6.92 (m, 1H); 7.28 (s, 1H); 7.34 (m, 2H); 7.38 (s, 1H); 8.11 (s, 1H); 8.67 (s, 1H).

N-(3,5-differenl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide

By a reaction similar to that described in example 378, but proceeding from N-(3,5-differenl)-2-(2-trailmen-1,3-thiazol-5-yl)ndimethylacetamide (11.4 g, 28.5 mmol)were specified in the header connection and 4.75 g, 62%).

1H NMR (DMSO-d6): 3.64 (s, 2H); 6.74 (s, 1H); 6.76 (s, 2H); 6.89 (m, 1H); 7.29 (m, 2H).

N-(3,5-differenl)-2-(2-trailmen-1,3-thiazol-5-yl)ndimethylacetamide

By a reaction similar to that described in example 378, but based on 3,5-diferencia (1.68 g, 13 mmol)were specified in the header connection (3,53 g, 69%).

1H NMR (DMSO-d6): 3.56 (s, 2H); 6.59 (s, 1H); 6.90 (m, 1H); 7.28 (m, 17H); 8.40 (s, 1H).

Example 396. Getting connection 574 table 20

By a reaction similar to that described in example 379, but proceeding from N-(3,5-differenl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, of 0.74 mmol)were specified in the title compound (200 mg, 47%).

MS ES+: 571.5 (M+H)+

1H NMR (DMSO-d6): 1.65 (m, 4H); 2.50 (m, 5H); 2.65 (m, 1H); 3.91 (s, 1H); 3.96 (s, 3H); 4.04 (m, 2H); 4.20 (m, 1H); 4.95 (m, 1H); 6.92 (m, 1H); 7.26 (s, 1H); 7.34 (m, 2H); 7.38 (s, 1H); 8.11 (s, 1H); 8.66 (s, 1H).

Example 397. Getting connection 575 table 20

On the eakly, similar to that described in example 383, but proceeding from N-(3,5-differenl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, of 0.74 mmol)were specified in the title compound (177 mg, 40%).

MS ES+: 589.4 (M+H)+

1H NMR (DMSO-d6): 0.96 (s, 3H); 0.97 (s, 3H); 2.64 (m, 2H); 3.19 (DD, 2H); 3.92 (m, 3H); 3.98 (s, 3H); 4.09 (m, 1H); 4.20 (m, 1H); 4.56 (m, 1H); 5.05 (m, 1H); 6.94 (m, 1H); 7.29 (s, 1H); 7.35 (m, 2H); 7.39 (s, 1H); 8.12 (s, 1H); 8.68 (s, 1H).

Example 398. The connection is 576 in table 20

By a reaction similar to that described in example 381, but proceeding from N-(3,5-differenl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, of 0.74 mmol)were specified in the title compound (40 mg, 9%).

MS ES+: 628.5 (M+H)+

1H NMR (DMSO-d6): 2.05 (s, 3H); 2.40 (m, 4H); 2.57 (m, 2H); 2.69 (m, 4H); 3.91 (s, 2H); 3.97 (s, 3H); 4.35 (m, 2H); 5.31 (m, 1H); 6.93 (m, 1H); 7.33 (s, 1H); 7.35 (m, 2H); 7.39 (s, 1H); 8.13 (s, 1H); 8.68 (s, 1H).

Example 399. Getting connection 577 table 20

By a reaction similar to that described in example 381, but proceeding from N-(3,5-differenl)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, of 0.74 mmol)were specified in the title compound (192 mg, 44%).

MS ES+: 586.5 (M+H)+

1H NMR (DMSO-d6): 2.42 (m, 6N); 2.74 (m, 4H); 3.92 (s, 2H); 3.98 (s, 3H); 4.09 (m, 2H); 4.20 (m, 1H); 4.92 (m, 1H); 6.93 (m, 1H); 7.29 (s, 1H); 7.35 (m, 2H); 7.39 (s, 1H); 8.12 (s, 1H); 8.68 (s, 1H).

Example 400. The connection is obtained 578 table 20

By a reaction similar to that described in example 379, but proceeding from N-(3-Fortini is)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, 0.8 mmol)were specified in the title compound (156 mg, 35%).

MS ES+: 553.5 (M+H)+

1H NMR (DMSO-d6): 1.70 (m, 4H); 2.5 (m, 5H); 2.67 (m, 1H); 3.90 (s, 2H); 3.98 (s, 3H); 4.06 (m, 2H); 4.20 (m, 1H); 4.97 (m, 1H); 6.92 (m, 1H); 7.28 (m, 1H); 7.35 (m, 2H); 7.39 (s, 1H); 7.63 (m, 1H); 8.12 (s, 1H), 8.68 (s, 1H).

N-(3-forfinal)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide

By a reaction similar to that described in example 378, but proceeding from N-(3-forfinal)-2-(2-trailmen-1,3-thiazol-5-yl)ndimethylacetamide (14.6 g, 38.4 mmol)were specified in the header connection (6,21 g, 65%).

1H NMR (DMSO-d6: 3.65 (s, 2H); 6.76 (m, 3H); 6.89 (t, 1H); 7.35 (m, 2H); 7.59 (d, 1H).

N-(3-forfinal)-2-(2-trailmen-1,3-thiazol-5-yl)ndimethylacetamide

By a reaction similar to that described in example 378, but based on 3-foranyone got mentioned in the title compound (14.6 g, 79%).

1H NMR (DMSO-d6): 3.56 (s, 2H); 6.61 (s, 1H); 6.89 (t, 1H); 7.25 (m, 17H); 7.56 (d, 1H); 8.41 (s, 1H).

Example 401. Getting connection 579 table 20

By a reaction similar to that described in example 378, but proceeding from N-(3-forfinal)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, 0.8 mmol)were specified in the title compound (214 mg, 47%).

MS ES+: 567.6 (M+H)+

1H NMR (DMSO-d6): 1.38 (m, 2H); 1.52 (m, 4H); 2.42 (m, 6N); 3.91 (s, 2H); 3.98 (s, 3H); 4.04 (m, 2H); 4.20 (m, 1H); 4.89 (m, 1H); 6.91 (m, 1H); 7.29 (s, 1H); 7.37 (m, 2H); 7.39 (s, 1H); 7.63 (m, 1H); 8.13 (s, 1H); 8.68 (s, 1H).

Example 402. Getting connection 580 in table 20

For the reactions is, similar to that described in example 381, but proceeding from N-(3-forfinal)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, 0.8 mmol)were specified in the title compound (210 mg, 46%).

MS ES+: 568.5 (M+H)+

1H NMR (DMSO-d6): 2.38 (m, 6N); 2.70 (m, 4H); 3.89 (s, 2H); 3.96 (s, 3H); 4.02 (m, 2H); 4.19 (m, 1H); 4.98 (m, 1H); 6.89 (m, 1H); 7.27 (s, 1H); 7.32 (m, 2H); 7.37 (s, 1H); 7.61 (m, 1H); 8.10 (s, 1H); 8.66 (s, 1H).

Example 403. Getting connection 581 table 20

By a reaction similar to that described in example 381, but proceeding from N-(3-forfinal)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, 0.8 mmol)were specified in the title compound (35 mg, 7%).

MS ES+: 610.5 (M+H)+

1H NMR (DMSO-d6): 2.03 (s, 3H); 2.38 (m, 4H); 2.57 (m, 2H); 2.69 (m, 4H); 3.88 (s, 2H); 3.95 (s, 3H); 4.34 (m, 2H); 5.30 (m, 1H); 6.89 (m, 1H); 7.31 (s, 1H); 7.34 (m, 2H); 7.37 (s, 1H); 7.62 (m, 1H); 8.11 (s, 1H); 8.66 (s, 1H).

Example 404. Getting connection 582 table 20

By a reaction similar to that described in example 382, but proceeding from N-(3-forfinal)-2-(2-amino-1,3-thiazol-5-yl)ndimethylacetamide (200 mg, 0.8 mmol)were specified in the title compound (196 mg, 43%).

MS ES+: 567.5 (M+H)+

1H NMR (DMSO-d6): 1.30 (m, 2H); 1.47 (m, 2H); 1.61 (m, 2H); 1.73 (m, 3H); 2.62 (m, 1H); 2.71 (m, 1H); 3.0 (m, 1H); 3.89 (m, 1H); 3.97 (s, 3H); 4.07 (m, 1H); 4.13 (m, 1H); 5.03 (m, 1H); 6.90 (m, 1H); 7.25 (s, 1H); 7.35 (m, 2H); 7.37 (s, 1H); 7.62 (m, 1H); 8.10 (s, 1H); 8.66 (s, 1H).

Example 405. Getting connection 583 in table 21

4-((2-Amino-1,3-thiazol-5-yl)acetic acid)-67-dimethoxyquinazolin (173 mg, 0.5 mmol) in NMP (2 ml) was injected into interaction with 3.5-diftorhinolonom (98 mg, 0.75 mmol) in the presence of hexaphosphate O-(7-asobancaria-1-)-N,N,N',N'-tetramethylurea (285 mg, 0.75 mmol) and DIEA (130 μl, 0.75 mmol) at 50°C for 20 hours. The mixture was cooled, was added dimethylamine (2 M Meon, 2 ml) and the resulting solution was stirred at room temperature for 15 hours, the Meon evaporated and added to a mixture of water (20 ml), the precipitate was isolated, washed with water and purified by chromatography on silica gel, eluent CH2Cl2/Meon 50/40/10, getting mentioned in the title compound (22 mg, 10%).

1H NMR (DMSO-d6): 3.90 (s, 2H); 3.95 (s, 6N); 6.93 (t, 1H); 7.26 (s, 1H); 7.34 (d, 2H); 7.39 (s, 1H); 8.12 (s, 1H); 8.68 (s, 1H).

4-((2-Amino-1,3-thiazol-5-yl)acetic acid)-6,7-dimethoxyquinazolin

4-((2-Amino-1,3-thiazol-5-yl)acetate)-6,7-dimethoxyquinazolin (to 3.92 g, 10.9 mmol) in ethanol (50 ml) was treated with sodium hydroxide (2 N., 27 ml of 54.5 mmol) for 45 minutes. The solvent is evaporated, the residue was dissolved in a mixture of CH2Cl2/Meon, was added triethylamine (3 EQ.), the solid was isolated by filtration, the filtrate was evaporated and triturated with ethanol, getting mentioned in the title compound as a solid (1.88 g, 50%).

1H NMR (DMSO-d6): 3.83 (s, 2H); 3.96 (s, 6N); 7.27 (s, 1H); 7.35 (s, 1H); 8.13 (s, 1H); 8.69 (s, 1H).

4-(Methyl(2-amino-1,3-thiazol-5-yl)acetate)-6,7-dimethoxyquinazolin

N'-(2-cyano-,5-acid)-N,N-dimethylformamide (3.5 g, 15 mmol) in acetic acid (35 ml) was injected into the interaction with methyl (2-amino-1,3-thiazol-5-yl)acetate (3,22 g, to 18.7 mmol) at boiling for 4 hours. The solvent is evaporated and the residue was purified by chromatography on silica gel, eluent CH2Cl2/Meon 95/5, receiving specified in the header connection (to 3.92 g, 73%).

1H NMR (DMSO-d6): 3.69 (s, 3H); 3.95 (s, 2H); 3.96 (s, 6N); 7.27 (s, 1H); 7.38 (s, 1H); 8.12 (s, 1H); 8.69 (s, 1H).

Example 406. Getting connection 584 in table 21

By a reaction similar to that described in example 405, but on the basis of 3-Chloroaniline (80 μl, 0.75 mmol)were specified in the title compound (81 mg, 26%).

MS ES+: 456.4, 458.4 (M+H)+

1H NMR (DMSO-d6): 3.91 (s, 2H); 3.96 (s, 6N); 7.14 (d, 1H); 7.28 (s, 1H); 7.37 (t, 1H); 7.48 (d, 1H); 7.85 (m, 1H); 8.13 (s, 1H); 8.69 (s, 1H).

Example 407. The connection is 585 in table 21

By a reaction similar to that described in example 405, but on the basis of 3-chloro-4-foronline (110 mg, 0.75 mmol)were specified in the header connection (93,7 mg, 40%).

MS ES+: 474.4, 476.4 (M+H)+

1H NMR: 3.90 (s, 2H); 3.97 (s, 3H); 7.28 (s, 1H); 7.40 (m, 1H); 7.40 (s, 1H); 7.50 (m, 1H); 7.96 (m, 1H); 8.14 (s, 1H); 8.70 (s, 1H).

Example 408. Getting connection 586 in table 21

By a reaction similar to that described in example 405, but based on 3,4-diferencia (75 mg, 0.75 mmol)were specified in the title compound (130 mg, 60%).

MS ES+: 458.5 (M+H)+

1H NMR:3.89 (s, 2H); 3.97 (s, 6N); 7.28 (s, 1H); 7.33 (m, 1H); 7.40 (s, 1H); 7.41 (m, 1H); 7.82 (m, 1H); 8.14 (s, 1H); 8.69 (s, 1H).

Example 409. Getting connection 587 in table 22

4-((2-Amino-1,3-thiazol-5-yl)(hydroxy)acetic acid)-6-methoxy-7-(3-morpholinopropan)hinzelin (143 mg, 0.3 mmol) in DMF (4 ml) was injected into the interaction with aniline (36 mg, 0,39 mmol), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (63 mg, 0.33 mmol), 2-hydroxypyridine N-oxide (33 mg, 0.3 mmol) and DIEA (36 mg, 0.3 mmol) at 90°C for 1 hour. The mixture was cooled, diluted with CH2Cl2(8 ml) and purified by chromatography on silica gel, eluent CH2Cl2/Meon from 90/10 to 85/15. Combined fractions containing the product were evaporated, the residue was dissolved in Meon, was added water and the precipitate was isolated, dissolved in Meon/CH2Cl2, dried, concentrated, getting mentioned in the title compound (145 mg, 88%).

MS ES+: 551.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.15 (t, 2H); 3.34 (t, 2H); 3.55 (d, 2H); 3.71 (t, 2H); 3.98 (s, 3H); 4.03 (d, 2H); 4.31 (t, 2H); 5.47 (s, 1H); 7.11 (t, 1H); 7.31 (s, 1H); 7.33 (t, 2H); 7.70 (s, 1H); 7.73 (d, 2H); 7.92 (s, 1H); 9.12 (s, 1H).

4-((2-Amino-1,3-thiazol-5-yl)-6-methoxy-7-(3-morpholinopropan)hinzelin

N'-(2-Cyano-4-methoxy-5-(3-morpholinoethoxy)phenyl)-N,N-dimethylaminopropane (692 mg, 2 mmol) was introduced in the interaction with the amino-1,3-thiazole (240 mg, 2.4 mmol) in acetic acid (6.9 ml) at boiling for 4 hours. A mixture of the end of what was tarawali, the residue was dissolved in AcOEt, washed with an aqueous solution of sodium bicarbonate, the organic phase was dried, concentrated, the obtained residue oil is triturated with ether, receiving solid (560 mg, 70%).

MS ES+: 402.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.29 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 3.99 (s, 3H); 4.04 (d, 2H); 4.31 (t, 2H); 7.32 (s, 1H); 7.47 (d, 1H); 7.75 (d, 1H); 7.95 (s, 1H); 9.11 (s, 1H).

4-((2-Amino-1,3-thiazol-5-yl)(hydroxy)acetic acid)-6-methoxy-7-(3-morpholinopropan)hinzelin

4-(2-Amino-1,3-thiazol-5-yl)-6-methoxy-7-(3-morpholinopropan)hinzelin (1.6 g, 4 mmol) in water (16 ml), Meon (16 ml) was injected into the interaction with Glyoxylic acid (740 mg, 8 mmol) at pH of 11.5 (NaOH 6 N.) and 45-40°C for 6 hours. The methanol is evaporated and brought the pH of the aqueous phase to 3 (HCl 6 N.) and made the solution into the column with a strong cation exchange resin (isolute®), washed with water (120 ml), methanol (120 ml) and was suirable a mixture of CH2Cl2/Meon, NH3(3 H.) 1/1, 200 ml, receiving specified in the header connection (1,58 g, 83%).

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.98 (s, 3H); 4.03 (d, 2H); 4.30 (t, 2H); 5.38 (s, 1H); 7.32 (s, 1H); 7.68 (s, 1H); 7.91 (s, 1H); 9.12 (s, 1H).

Example 410. Getting connection 588 in table 22

By a reaction similar to that described in example 409, but based on 3,4-diferencia (34 mg, 0.26 mmol)were specified in the title compound (30 mg, 26%).

MS ESsup> +: 587.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.69 (t, 2H); 3.98 (s, 3H); 4.04 (d, 2H); 4.30 (t, 2H); 5.48 (s, 1H); 7.32 (s, 1H); 7.40 (q, 1H); 7.57 (m, 1H); 7.70 (s, 1H); 7.92 (m, 2H); 9.12 (s, 1H).

Example 411. Getting connection 589 in table 22

N'-(2-cyano-4-methoxy-5-(3-N-methylpiperazine)-4-methoxyphenyl)-N,N-dimethylaminopropane (144 mg, 0.4 mmol) was injected into the interaction with N-(3,4-differenl)-2-(2-amino-1,3-thiazol-5-yl)-2-hydroxyacetamido (137 mg, 0.4 mmol) in acetic acid (350 ml) by boiling for 40 minutes. The solvent was removed and the residue was purified by chromatography on silica gel, eluent CH2Cl2/Meon/Et3N, 90.10.1, getting mentioned in the title compound (180 mg, 37%).

MS ES+: 600.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 2.94 (s, 3H); 3.1-4.1 (m, 8H); 3.44 (t, 2H); 3.99 (s, 3H); 4.30 (t, 2H); 5.48 (s, 1H); 7.32 (s, 1H); 7.40 (q, 1H); 7.57 (m, 1H); 7.70 (s, 1H); 7.92 (m, 2H); 9.12 (s, 1H).

Methyl(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)acetate

Methyl(2-amino-1,3-thiazol-5-yl)acetate (4.3 g, 25 mmol) was injected into the interaction with di-tert-BUTYLCARBAMATE (up 10.9 g, 50 mmol), without solvent, at 100°C for 2 hours. The cold mixture is triturated with ether, getting mentioned in the title compound as a solid (4.3 g, 63%).

1H NMR (DMSO-d6): 1.48 (s, N); 3.66 (s, 3H); 3.86 (s, 2H); 7.17 (s, 1H).

Methyl(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl(OK what about)acetate

Methyl(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)acetate (4,08 g, 15 mmol) in dioxane (60 ml) was injected into interaction with selenium dioxide (4 g, 36 mmol) by boiling for 45 minutes. The mixture was cooled, added CH2Cl2/Meon 8/2 (150 ml), nerastvorim product was filtered, the organic phase is washed with a saturated solution of sodium bicarbonate and was extracted with CH2Cl2, dried, purified by chromatography through alumina, eluent CH2Cl2/Meon 9/1, getting mentioned in the title compound (1 g, 23%).

1H NMR (DMSO-d6, TFA): 1.57 (s, N); 3.94 (s, 3H); 8.48 (s, 1H).

(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)(oxo)acetic acid.

Methyl(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)(oxo)acetate (1,14 g, 4 mmol) in ethanol (10 ml) was treated with sodium hydroxide (2 ad, 4 ml, 8 mmol) for 3 min at room temperature. The ethanol was removed, the aqueous solution was acidified (pH 3). The solid was isolated, dried, obtaining mentioned in the title compound (900 mg, 82%).

1H NMR (DMSO-d6,): 1.53 (s, N); 8.41 (s, 1H).

N-(3,4-differenl)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)(oxo)ndimethylacetamide

2-Tert-butoxycarbonylamino-1,3-thiazol-5-yl)(oxo)acetic acid (136 mg, 0.5 mmol) in DMF (2 ml) was injected into the interaction with 3,4-diftorhinolonom (77 mg, 0.6 mmol) in the presence of hexaflurophosphate O-(7-asaresult the-1-yl)-N,N,N',N'-tetramethylurea (203 mg, 0.55 mmol) and DIEA (77 mg, 0.6 mmol) for 15 minutes. The mixture was diluted with water, the solid was filtered, washed with water, dried, obtaining mentioned in the title compound (162 mg, 84%).

1H NMR (DMSO-d6): 1.53 (s, N); 7.48 (q, 1H); 7.68 (m, 1H); 7.98 (m, 1H); 8.61 (s, 1H).

N-(3,4-differenl)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)-2-hydroxyacetamido

N-(3,4-differenl)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)(oxo)ndimethylacetamide (938 mg, 2.4 mmol) in THF (50 ml) and Meon (10 ml) was treated with sodium borohydride (93 mg, 2.4 mmol) for 30 minutes. The mixture was evaporated, the residue was dissolved in ethanol (3 ml), was added water (25 ml) and brought the pH up to 6, adding more water, the solid was isolated, dried, recrystallized from a mixture of ether/petroleum ether, getting mentioned in the title compound (850 mg, 90%).

1H NMR (DMSO-d6): 1.48 (s, N); 5.34 (d, 1H); 6.78 (d, 1H); 7.33 (s, 1H); 7.40 (s, 1H); 7.56 (m, 1H); 7.90 (m, 1H).

N-(3,4-differenl)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)-2-hydroxyacetate (847 mg, 2.2 mmol) in CH2Cl2(12 ml) and TFA (4 ml) was stirred at room temperature for 3 hours. The solvent is evaporated, the residue was dissolved in Meon/N2Oh, the pH was brought to 7 and was extracted with a mixture of ethyl acetate. The organic layer was dried, evaporated, the residue triturated with ether, the solid was filtered, receiving specified in the header link is (515 mg, 82%).

1H NMR (DMSO-d6): 5.17 (d, 1H); 6.51 (d, 1H); 6.91; (m, 3H); 7.39 (s, 1H); 7.52 (m, 1H); 7.87 (m, 1H).

Example 412. Getting connection 590 in table 22

N'-(2-cyano-4-methoxy-5-(3-piperidinyloxy)-4-methoxyphenyl)-N,N-dimethylaminopropane (100 mg, 0.29 mmol) was injected into the interaction with N-(3-forfinal)-2-(2-amino-1,3-thiazol-5-yl)-2-hydroxyacetamido (82 mg, 0.3 mmol) in acetic acid (260 mg) at 105aboutC for 40 minutes. The mixture was evaporated and purified by chromatography on silica gel, eluent CH2Cl2/Meon (NH3,3 N.) 9/1, getting mentioned in the title compound (42 mg, 26%).

MS ES+: 567.5 (M+H)+

1H NMR (DMSO-d6): 1.4 (m, 2H); 1.51 (m, 4H); 1.95 (t, 2H); 2.40 (m, 6N); 3.95 (s, 3H); 4.19 (t, 2H); 5.41 (d, 1H); 6.78 (d, 1H); 6.91 (m, 1H); 7.25 (s, 1H); 7.35 (q, 1H); 7.50 (s, 1H); 7.55 (d, 1H); 7.71 (m, 1H); 8.10 (s, 1H); 8.68 (s, 1H).

N'-(2-cyano-4-methoxy-5-(3-piperidinyloxy)-4-methoxyphenyl)-N,N-dimethylaminopropane

N'-(2-cyano-4-methoxy-5-(3-chloropropoxy)-4-methoxyphenyl)-N,N-dimethylaminopropane (3 g, 10 mmol) in acetonitrile (50 ml) was administered in cooperation with piperidine (10 ml, 100 mmol) in the presence of KI (300 mg, 1.8 mmol) and K2CO3(2.1 g, 0.015 mmol) at 75°C in argon atmosphere for 3 hours. The solvent is evaporated and the residue was purified by chromatography on silica gel, eluent CH2Cl2/Meon, NH3,3 N., 95/5, getting mentioned in the title compound (3,48 g, 100%).

p> MS ES+: 345.6 (M+H)+

1H NMR (DMSO-d6): 1.4 (m, 2H); 1.50 (m, 4H); 1.88 (m, 2H); 2.35 (m, 6N); 2.95 (s, 3H); 3.05 (s, 3H); 3.72 (s, 3H); 4.05 (t, 2H); 6.72 (s, 1H); 7.07 (s, 1H); 7.89 (s, 1H).

N-(3-forfinal)-2-amino-1,3-thiazol-5-yl)-2-hydroxyacetamido

By a reaction similar to that described in example 411, but proceeding from N-(3-terbisil)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)-2-hydroxyacetamido (2.55 g, 0.69 mmol)were specified in the header connection (1,37 g, 75%).

MS ES+: 268.5 (M+H)+

1H NMR (DMSO-d6): 5.16 (d, 1H); 6.45 (d, 1H); 6.90 (m, 4H); 7.34 (q, 1H); 7.49 (d, 1H); 7.70 (m, 1H).

N-(3-forfinal)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)-2-hydroxyacetamido.

By a reaction similar to that described in example 411, but proceeding from N-(3-forfinal)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)(oxo)ndimethylacetamide (2,92 g, 8 mmol)were specified in the header connection (2,59 g, 88%).

1H NMR (DMSO-d6): 1.48 (s, N); 5.34 (d, 1H); 6.74 (d, 1H); 6.90 (m, 1H); 7.33 (m, 2H); 7.54 (d, 1H); 7.70 (m, 1H).

N-(3-forfinal)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)(oxo)ndimethylacetamide

By a reaction similar to that described in example 411, but based on 3-foronline (1.6 g, 14.4 mmol)were specified in the header connection (4,06 g, 93%).

1H NMR (DMSO-d6): 1.54 (s, N); 7.01 (m, 1H); 7.42 (m, 1H); 7.69 (m, 1H); 7.80 (m, 1H); 8.6 (s, 1H).

Example 413. Getting connection 591 table 22

By a reaction similar to that described in example 41, but proceeding from N-(3-chlorophenyl)-2-(2-amino-1,3-thiazol-5-yl)-2-hydroxyacetamido (99 mg, 0.35 mmol)were specified in the title compound (47 mg, 23%).

MS ES+: 583.4 (M+H)+

1H NMR (DMSO-d6): 1.38 (m, 2H); 1.51 (m, 4H); 1.95 (m, 2H); 2.38 (m, 6N); 3.95 (s, 3H); 4.19 (t, 2H); 5.40 (d, 1H); 6.79 (d, 1H); 7.14 (d, 1H); 7.24 (s, 1H); 7.35 (t, 1H); 7.50 (s, 1H); 7.67 (d, 1H); 7.95 (s, 1H); 8.10 (s, 1H); 8.68 (s, 1H).

N-(3-chlorophenyl)-2-(2-amino-1,3-thiazol-5-yl)-2-hydroxyacetamido

By a reaction similar to that described in example 412, but proceeding from N-(3-chlorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)-2-hydroxyacetamido (2,13 g, 5.5 mmol)were specified in the header connection (1,02 g, 65%).

1H NMR (DMSO-d6): 5.15 (d, 1H); 6.45 (d, 1H); 6.90 (m, 3H); 7.12 (DD, 1H); 7.33 (t, 1H); 7.62 (d, 1H); 7.89 (m, 1H).

N-(3-chlorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)-2-hydroxyacetamido

By a reaction similar to that described in example 412, but proceeding from N-(3-chlorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)(oxo)ndimethylacetamide (2.5 g, 6.5 mmol)were specified in the header connection (2,23 g, 89%).

1H NMR (DMSO-d6): 1.48 (s, N); 5.34 (d, 1H); 6.74 (d, 1H); 7.14 (m, 1H); 7.34 (m, 2H); 7.65 (m, 1H); 7.92 (m, 1H).

N-(3-chlorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)(oxo)ndimethylacetamide

By a reaction similar to that described in example 412, but on the basis of 3-Chloroaniline (1.84 g, 14 mmol)were specified in the title compound (3.6 g, 79%).

1H NMR (DMS-d 6): 1.54 (s, N); 7.24 (d, 1H); 7.43 (t, 1H); 7.79 (d, 1H); 8.03 (s, 1H); 8.61 (s, 1H).

Example 414. Getting connection 592 in table 22

N'-(2-cyano-4-methoxy-5-(N-methyl-3-piperazinylcarbonyl)-N,N-dimethylaminopropane (140 mg, 0,39 mmol) in acetic acid (0.5 ml) in the presence of N-(3,4-differenl)-2-(2-amino-1,3-thiazol-5-yl)-2-(hydroxyimino)ndimethylacetamide (116 mg, 0,39 mmol) was heated at 110°C for 16 hours. The mixture was concentrated and purified by chromatography on silica gel, eluent CH2Cl2/Meon, NH3,3 N., from 95/5 to 90/10, getting mentioned in the title compound (23 mg, 10%).

MS ES+: 613.5 (M+H)+

1H NMR (DMSO-d6): 2.0 (m, 2H); 2.22 (s, 3H); 2.47 (m, 10H); 4.0 (s, 3H); 4.22 (t, 2H); 7.29 (m, 1H); 7.47 (m, 1H); 7.57 (m, 1H); 7.97 (m, 1H); 8.2 (s, 1H); 8.38 (s, 1H); 8.80 (s, 1H).

N-(3,4-differenl)-2-(2-amino-1,3-thiazol-5-yl)-2-(hydroxyimino)ndimethylacetamide

N-(3,4-differenl)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)-2-(hydroxyimino)ndimethylacetamide (600 mg, 1.5 mmol) in CH2Cl2(12 ml) and TFA (4 ml) was stirred at room temperature for 2 hours. The mixture was evaporated, dissolved in methanol, brought the pH to 6 with sodium bicarbonate was added water, extracted sediment was dried, obtaining mentioned in the title compound (388 mg, 86%).

MS ES+: 299.4 (M+H)+

1H NMR (DMSO-d6) mixture of isomers: 7.05, 7.8 (3s, 1H); 7.43 (m, 4H); 7.88 (m, 1H).

N-(3,4-differenl)-2-(2-tert-butoxycarbonyl the Mino-1,3-thiazol-5-yl)-2-(hydroxyimino)ndimethylacetamide

N-(3,4-differenl)-2-(2-tert-butoxycarbonylamino-1,3-thiazol-5-yl)(oxo)ndimethylacetamide (100 mg, 0.26 mmol) in pyridine (8 ml) was administered in cooperation with hydroxylamine hydrochloride (27 mg, 0,39 mmol) at 70°C for 15 hours. The solvent is evaporated, to the residue was added water, the solid was filtered, washed with water, dried, obtaining mentioned in the title compound (84 mg, 81%).

1H NMR (DMSO-d6) mixture of isomers: 7.41, 8.18 (2s, 1H); 7.50 (m, 2H); 7.90 (m, 1H).

Example 415. Getting connection 593 table 23

5-((6-Methoxy-7-(3-morpholinopropan)hinzelin-4-yl)amino)thiophene-2-carboxylic acid (80 mg, 0.18 mmol) in DMF (2 ml) was injected into the interaction with 2-aminopyridine (17 mg, 0.18 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (70 mg, 0.18 mmol) and DIEA (80 μl, 0.46 mmol) at 50°C for 6 hours. Was added a saturated solution of sodium bicarbonate (2 ml) and the mixture was stirred for 0.5 hours. The solid was isolated by filtration, washed with water, dried, obtaining mentioned in the title compound (15 mg, 16%).

MS ES+: 521 (M+H)+

1H NMR (DMSO-d6, TFA): 3.31 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.03 (d, 2H); 4.05 (s, 3H); 4.32 (t, 2H); 7.43 (m, 2H); 7.53 (t, 1H); 7.94 (d, 1H); 8.21 (m, 2H); 8.35 (t, 1H); 8.49 (d, 1H); 9.30 (s, 1H).

Example 416. Getting connection 594 table 23

In reactions similar to described the example 415, but on the basis of 4-methylaniline (19 mg, 0.18 mmol)were specified in the title compound (69 mg, 72%).

MS ES+: 535 (M+H)+

1H NMR (DMSO-d6, TFA): 2.34 (s, 3H); 2.40 (t, 2H); 3.11 (t, 2H); 3.38 (t, 2H); 3.60 (d, 2H); 3.90 (t, 2H); 4.03 (d, 2H); 4.05 (s, 3H); 4.35 (t, 2H); 7.15 (d, 2H); 7.27 (d, 1H); 7.52 (s, 1H); 7.62 (d, 2H); 7.85 (d, 1H); 8.15 (s, 1H); 8.87 (s, 1H).

Example 417. Getting connection 595 table 23

By a reaction similar to that described in example 415, but on the basis of 2-methylaniline (19 mg, 0.18 mmol)were specified in the title compound (28 mg, 729%).

MS ES+: 535 (M+H)+

1H NMR (DMSO-d6, TFA): 2.28 (s, 3H); 2.32 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 4.05 (d, 2H); 4.07 (s, 3H); 7.30 (m, 4H); 7.35 (d, 1H); 7.41 (s, 1H); 7.96 (d, 1H); 8.22 (s, 1H); 9.26 (s, 1H).

Example 418. The connection is 596 in table 23

By a reaction similar to that described in example 415, but based on 3-methoxyaniline (22 mg, 0.18 mmol)were specified in the title compound (14 mg, 14%).

MS ES+: 550.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H); 3.57 (d, 2H); 3.70 (t, 2H); 3.78 (s, 3H); 4.04 (d, 2H); 4.06 (s, 3H); 4.33 (t, 2H); 6.7 (d, 1H); 7.28 (s, 1H); 7.35 (s, 1H); 7.36 (d, 1H); 7.41 (s, 1H); 7.45 (s, 1H); 8.01 (d, 1H); 8.22 (s, 1H); 9.27 (s, 1H).

Example 419. Getting connection 597 table 23

By a reaction similar to that described in example 415, but based on the 2-hydroxymethylbilane (22 mg, 0.18 mmol)were specified in the title compound (7 mg, 7%).

MS ES+ : 550.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (m, 2H); 3.18 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.06 (m, 5H); 4.32 (t, 2H); 4.65 (s, 2H); 7.22 (t, 1H); 7.32 (t, 1H); 7.37 (d, 1H); 7.40 (s, 1H); 7.46 (d, 1H); 7.22 (d, 1H); 7.81 (d, 1H); 8.22 (s, 1H); 9.27 (s, 1H).

Example 420. Getting connection 598 table 23

By a reaction similar to that described in example 415, but based on 3-nitroaniline (25 mg, 0.18 mmol)were specified in the title compound (6 mg, 6%).

MS ES+: 565.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.18 (t, 2H); 3.38 (t, 2H); 3.58 (d, 2H); 3.70 (t, 2H); 4.05 (d, 2H); 4.07 (s, 3H); 4.33 (t, 2H); 7.39 (d, 1H); 7.42 (s, 1H); 7.68 (t, 1H); 7.98 (d, 1H); 8.08 (d, 1H); 8.20 (m, 1H); 8.23 (s, 1H); 8.77 (s, 1H); 9.3 (s, 1H).

Example 421. The connection is 599 in table 23

By a reaction similar to that described in example 415, but on the basis of 4-triptorelin (29 mg, 0.18 mmol)were specified in the title compound (8 mg, 8%).

MS ES+: 588.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (m, 2H); 3.19 (t, 2H); 3.41 (t, 2H); 3.61 (d, 2H); 3.75 (t, 2H); 4.05 (d, 2H); 4.08 (s, 1H); 4.37 (t, 2H); 7.39 (d, 1H); 7.43 (s, 1H); 7.72 (d, 2H); 8.03 (d, 2H); 8.10 (d, 1H); 8.23 (s, 1H); 9.29 (s, 1H).

Example 422. The connection is 600 table 23

By a reaction similar to that described in example 415, but on the basis of 3-Chloroaniline (23 mg, 0.18 mmol)were specified in the title compound (21 mg, 21%).

1H NMR (DMSO-d6, TFA): 2.32 (m, 2H); 3.19 (t, 2H); 3.37 (t, 2H); 3.57 (d, 2H); 3.70 (t, 2H); 4.03 (d, 2H); 4.07 (s, 3H); 4.34 (t, 2H); 7.17 (d, 1H); 7.37 (who, 1H); 7.40 (m, 2H); 7.70 (d, 1H); 7.95 (m, 1H); 8.02 (d, 1H); 8.22 (s, 1H); 9.29 (s, 1H).

Example 423. Getting connection 601 in table 23

By a reaction similar to that described in example 415, but based on the 2-methoxyaniline (22 mg, 0.18 mmol)were specified in the title compound (32 mg, 32%).

1H NMR (DMSO-d6, TFA): 2.35 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 3.87 (s, 3H); 4.05 (d, 2H); 4.06 (s, 3H); 4.34 (t, 2H); 6.99 (t, 1H); 7.11 (d, 1H); 7.20 (s, 1H); 7.33 (d, 1H); 7.40 (s, 1H); 7.73 (DD, 1H); 7.97 (d, 1H); 8.22 (s, 1H); 9.27 (s, 1H).

Example 424. The connection 602 in table 23

By a reaction similar to that described in example 415, but on the basis of 3-(2-hydroxyethyl)aniline (25 mg, 0.18 mmol)were specified in the title compound (27 mg, 26%).

MS ES+: 564.7 (M+H)+

1H NMR (DMSO-d6, TFA): 1.37 (d, 3H); 2.32 (t, 2H); 3.19 (t, 2H); 3.38 (t, 2H); 3.58 (d, 2H); 3.62 (t, 2H); 4.06 (d, 2H); 4.08 (s, 3H); 4.36 (t, 2H); 4.76 (q, 1H); 7.08 (d, 1H); 7.29 (t, 1H); 7.35 (d, 1H); 7.42 (s, 1H); 7.70 (d, 1H); 7.76 (s, 1H); 8.05 (d, 1H); 8.23 (s, 1H); 9.28 (s, 1H).

Example 425. Getting connection 603 table 23

By a reaction similar to that described in example 415, but on the basis of 3-fluoro-4-methoxyaniline (25 mg, 0.18 mmol)were specified in the title compound (14 mg, 14%).

MS ES+: 568.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.19 (t, 2H); 3.38 (t, 2H); 3.57 (d, 2H); 3.72 (t, 2H); 3.85 (s, 3H); 4.04 (d, 2H); 4.07 (s, 3H); 4.35 (t, 2H); 7.17 (t, 1H); 7.36 (d, 1H); 7.42 (s, 1H); 7.47 (DD, 1H); 7.73 (DD, 1H); 7.98 (d, 1H); 8.24 (s, 1H); 9.27 (s, 1H).

Example 46. The connection 604 in table 23

By a reaction similar to that described in example 415, but on the basis of 2-methyl-4-foronline (23 mg, 0.18 mmol)were specified in the title compound (27 mg, 27%).

MS ES+: 552.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.28 (s, 3H); 2.31 (t, 2H); 3.18 (t, 2H); 3.38 (t, 2H); 3.57 (d, 2H); 3.71 (t, 2H); 4.05 (d, 2H); 4.07 (s, 3H); 7.07 (dt, 1H); 7.15 (DD, 1H); 7.35 (d, 1H); 7.36 (m, 1H); 7.41 (s, 1H); 7.95 (d, 1H); 8.23 (s, 1H); 9.26 (s, 1H).

Example 427. Getting connection 605 table 23

By a reaction similar to that described in example 415, but on the basis of 2-fluoro-5-methylaniline (23 mg, 0.18 mmol)were specified in the title compound (9 mg, 9%).

MS ES+: 552.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (m, 5H); 3.19 (t, 2H); 3.38 (t, 2H); 3.56 (d, 2H); 3.71 (t, 2H); 4.04 (d, 2H); 4.07 (s, 3H); 4.35 (t, 2H); 7.09 (m, 1H); 7.18 (m, 1H); 7.35 (d, 1H); 7.40 (s, 1H); 7.41 (m, 1H); 8.0 (d, 1H); 8.23 (s, 1H); 9.27 (s, 1H).

Example 428. Getting connection 606 in table 23

By a reaction similar to that described in example 415, but based on 3-cyanoaniline (21 mg, 0.18 mmol)were specified in the title compound (9 mg, 9%).

MS ES+: 545.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (t, 2H); 3.21 (t, 2H); 3.39 (t, 2H); 3.60 (d, 2H); 3.72 (t, 2H); 4.07 (d, 2H); 4.10 (s, 3H); 4.37 (t, 2H); 7.40 (d, 1H); 7.44 (s, 1H); 7.62 (s, 1H); 7.63 (m, 1H); 8.06 (m, 1H); 8.06 (d, 1H); 8.26 (s, 1H); 8.30 (s, 1H); 9.32 (s, 1H).

Example 429. Getting connection 607 table 23

By a reaction similar to that described in example 415, but recognize who I am from isoamylamine (16 mg, 0.18 mmol)were specified in the title compound (15 mg, 17%).

MS ES+: 514.7 (M+H)+

1H NMR (CDCl3): 0.96 (d, 6N); 1.77 (m, 5H); 2.11 (m, 2H); 2.5 (m, 4H); 2.56 (t, 2H); 3.73 (m, 4H); 4.03 (s, 3H); 4.22 (t, 2H); 6.05 (t, 1H); 6.88 (d, 1H); 7.24 (s, 1H); 7.39 (d, 1H); 7.58 (s, 1H); 8.70 (s, 1H).

Example 430. Getting connection 608 in table 23

By a reaction similar to that described in example 415, but on the basis of 2-Chloroaniline (23 mg, 0.18 mmol)were specified in the title compound (5 mg, 5%).

MS ES+: 554.5, 556.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.19 (t, 2H); 3.39 (t, 2H); 3.57 (d, 2H); 3.70 (t, 2H); 4.04 (d, 2H); 4.07 (s, 3H); 4.34 (t, 2H); 7.32 (t, 1H); 7.36 (d, 1H); 7.41 (s, 1H); 7.41 (t, 1H); 7.57 (d, 1H); 7.63 (d, 1H); 8.0 (d, 1H); 8.23 (s, 1H); 9.27 (s, 1H).

Example 431. Getting connection 609 table 24

By a reaction similar to that described in example 415, but starting from 5-((6-methoxy-7-(3-morpholinopropan)hinzelin-4-yl)amino)thiophene-3-carboxylic acid (80 mg, 0.18 mmol) and aniline (20 μl, 0.22 mmol)were specified in the title compound (28 mg, 30%).

MS ES+: 520 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.18 (t, 2H); 3.38 (t, 2H); 3.56 (d, 2H); 3.71 (t, 2H); 4.05 (d, 2H); 4.06 (s, 3H); 4.34 (t, 2H); 7.12 (t, 1H); 7.37 (t, 2H); 7.40 (s, 1H); 7.76 (d, 1H); 7.79 (d, 2H); 8.18 (s, 1H); 8.21 (d, 1H); 9.17 (s, 1H).

5-((6-Methoxy-7-(3-morpholinopropan)hinzelin-4-yl)amino)thiophene-3-carboxylic acid

Ethyl-5-((6-methoxy-7-(3-morpholinopropan)hinzelin-4-yl)amino)thiophene-3-carboxylate of 1.05 g, 2.2 mmol) in methanol (10 ml) was treated with sodium hydroxide (2 N., 10 ml) at 75aboutC for 1.5 hours. The methanol is evaporated, was added HCl(2 BC) (pH 3), the solid was filtered, re-dissolved in a mixture of CH2Cl2/Meon 1/1, was added DIEA (1.5 ml, 8,8 mmol), the solid was isolated by filtration, the filtrate was concentrated, and the residue was dissolved in ethanol, is listed in the title compound was obtained as a solid (0.7 g, 71%).

MS ES+: 445 (M+H)+

1H NMR (DMSO-d6, TFA): 2.36 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.79 (t, 2H); 4.03 (d, 2H); 4.08 (s, 3H); 4.35 (t, 2H); 7.45 (s, 1H); 7.81 (s, 1H); 8.03 (s, 1H); 8.50 (s, 1H); 9.15 (s, 1H).

Ethyl-5-((6-methoxy-7-(3-morpholinopropan)hinzelin-4-yl)amino)thiophene-3-carboxylate

4-Chloro-6-methoxy-7-(3-morpholinopropan)hinzelin (1 g, 3 mmol) in isopropanol (25 ml) and isopropanol saturated with HCl (0.5 ml), was injected into the interaction with ethyl 5-aminothiophene-3-carboxylate (0.6 g, 3.3 mmol) at 110°C for 1 hour. The mixture was cooled, diluted with EtOAc, filtered, getting listed in zahalka connection (1,58 g, 99%).

MS ES+: 473 (M+H)+

1H NMR (DMSO-d6, TFA): 1.33 (t, 3H); 2.33 (t, 2H); 3.17 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.75 (t, 2H); 4.03 (d, 2H); 4.06 (s, 3H); 4.30 (q, 2H); 4.33 (t, 2H); 7.42 (s, 1H); 7.73 (s, 1H); 8.09 (s, 1H); 8.35 (s, 1H); 9.15 (s, 1H).

Example 432. Getting connection 610 in table 24

By a reaction similar to that described in example 431,but on the basis of 4-foronline (24 mg, 0.18 mmol)were specified in the title compound (20 mg, 22%).

MS ES+: 538.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.20 (t, 2H); 3.40 (t, 2H); 3.60 (d, 2H); 3.72 (t, 2H); 4.04 (d, 2H); 4.07 (s, 3H); 4.34 (t, 2H); 7.9 (s, 1H); 7.20 (m, 2H); 7.41 (s, 1H); 7.76 (d, 1H); 7.82 (m, 1H); 8.19 (s, 1H); 8.21 (d, 1H); 9.17 (s, 1H).

Example 433. Getting connection 611 in table 24

By a reaction similar to that described in example 431, but based on 3-hydroxyanisole (24 mg, 0.18 mmol)were specified in the title compound (15 mg, 17%).

MS ES+: 536.6 (M+H)+

Example 434. Getting connection 612 in table 24

By a reaction similar to that described in example 431, but on the basis of 3-(methylthio)aniline (30 mg, 0.18 mmol)were specified in the title compound (23 mg, 24%).

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.04 (m, 5H); 4.33 (t, 2H); 7.24 (t, 1H); 7.32 (t, 1H); 7.41 (s, 1H); 7.43 (m, 2H); 7.72 (d, 2H); 8.16 (m, 2H); 9.17 (s, 1H).

Example 435. Getting connection 613 in table 24

By a reaction similar to that described in example 431, but on the basis of 4-fluoro-3-Chloroaniline (32 mg, 0.18 mmol)were specified in the title compound (21 mg, 21%).

MS ES+: 577 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.19 (t, 2H); 3.37 (t, 2H); 3.57 (d, 2H); 3.71 (t, 2H); 4.06 (m, 5H); 4.34 (t, 2H); 7.41 (m, 2H); 7.75 (m, 2H); 8.11 (m, 1H); 8.18 (s, 1H); 8.21 (s, 1H); 9.18 (s, 1H).

Example 436. Getting connection 614 in table 24

In reactions similar to opican the th in example 431, but based on 2,4-differentiatin (31 mg, 0.18 mmol)were specified in the title compound (22 mg, 22%).

MS ES+: 570.5 (M+H)+

1H NMR (DMSO-d6, TFA): 2.34 (t, 2H); 3.19 (t, 2H); 3.39 (t, 2H); 3.58 (d, 2H); 3.72 (t, 2H); 4.06 (m, 5H); 4.34 (t, 2H); 4.51 (s, 2H); 7.06 (t, 1H); 7.15 (t, 1H); 7.40 (s, 1H); 7.48 (m, 1H); 7.69 (d, 1H); 8.03 (d, 1H); 8.17 (s, 1H); 9.14 (s, 1H).

Example 437. Getting connection 615 in table 24

By a reaction similar to that described in example 431, but based on 3-foronline (24 mg, 0.18 mmol)were specified in the title compound (27 mg, 29%).

MS ES+: 538.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (t, 2H); 3.18 (t, 2H); 3.38 (t, 2H); 3.58 (d, 2H); 3.72 (d, 2H); 4.04 (d, 2H); 4.07 (s, 3H); 4.35 (t, 2H); 6.91 (m, 1H); 7.42 (m, 2H); 7.59 (d, 1H); 7.78 (d, 1H); 7.79 (m, 1H); 8.19 (s, 1H); 8.24 (d, 1H); 9.18 (s, 1H).

Example 438. Getting connection 616 in table 25

2-((6-Methoxy-7-(3-morpholinopropan)hinzelin-4-yl)amino)imidazole-5-carboxylic acid (200 mg, 0.47 mmol) in DMF (3 ml) was injected into the interaction with aniline (43 μl, 0.47 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (178 mg, 0.47 mmol) and DIEA (120 μl, 0.7 mmol) at 40°C for 3 hours. Was added a solution of dimethylamine in methanol (2 M, 1 ml) and continued stirring for 3 hours. The solvent is evaporated and the mixture was purified by chromatography on silica gel, eluent CH2Cl2/Meon NH3(feast upon.) 95/5, receiving the specified reception in the e compound (80 mg, 34%).

MS ES+: 504.1 (M+H)+

1H NMR (DMSO-d6, TFA): 2.29 (t, 2H); 3.18 (t, 2H); 3.35 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 3.96 (s, 3H); 4.04 (d, 2H); 4.27 (t, 2H); 7.15 (t, 1H); 7.25 (s, 1H); 7.40 (t, 2H); 7.74 (d, 2H); 7.81 (s, 1H); 8.09 (s, 1H); 8.75 (s, 1H).

Example 439. Getting connection 617 in table 25

By a reaction similar to that described in example 438, but on the basis of 4-foronline (60 μl, of 0.58 mmol)were specified in the title compound (120 mg, 39%).

MS ES+: 522.1 (M+H)+

1H NMR (DMSO-d6, TFA): 2.29 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.55 (d, 1H); 3.69 (t, 2H); 3.96 (s, 3H); 4.04 (d, 2H); 4.27 (t, 2H); 7.22 (m, 3H); 7.74 (m, 2H); 7.82 (s, 1H); 8.07 (s, 1H); 8.76 (s, 1H).

Example 440. Getting connection 618 in table 25

By a reaction similar to that described in example 438, but on the basis of allylamine (50 μl, 0.7 mmol)were specified in the title compound (133 mg, 40%).

MS ES+: 468.1 (M+H)+

1H NMR (DMSO-d6, TFA): 2.28 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.94 (m, 5H); 4.04 (d, 2H); 4.26 (t, 2H); 5.14 (DD, 1H); 5.25 (DD, 1H); 5.88 (m, 1H); 7.23 (s, 1H); 7.77 (s, 1H); 7.86 (s, 1H); 8.71 (s, 1H).

2-((6-Methoxy-7-(3-morpholinopropan)hinzelin-4-yl)amino)imidazole-5-carboxylic acid

Ethyl-2-((4-imino-6-methoxy-7-(3-morpholinopropan)hinzelin-3-(4H)-yl)amino)imidazole-5-carboxylate (650 mg, of 1.42 mmol) in methanol (14 ml) was treated with hydrazido of narie (2 N., 14 ml) at 80°C for 1.5 hours. The methanol is evaporated, added carisoptodol acid (6 BC) (the H 2,5), the precipitate was isolated by filtration, dried, obtaining mentioned in the title compound (650 mg, 100%).

1H NMR (DMSO-d6, TFA): 2.35 (t, 2H); 3.13 (t, 2H); 3.32 (t, 2H); 3.5 (d, 2H); 3.95 (m, 7H); 4.28 (t, 2H); 7.42 (s, 1H); 7.8 (s, 1H); 7.86 (s, 1H); 8.72 (s, 1H).

Example 441. Getting connection 619 in table 26

4-Chloro-6-methoxy-7-(3-morpholinopropan)hinzelin (265 mg, of 0.79 mmol) in 2-propanol (14 ml) was injected into the interaction hydrochloride 4-amino-N-phenylthiophene-3-carboxamide (210 mg, 0.82 mmol) at 100°C for 2 hours. The solvent is evaporated and the residue was purified by chromatography on silica gel, eluent CH2Cl2/Meon, NH3the feast upon. 95/5, getting mentioned in the title compound (330 mg, 81%).

MS ES+: 520.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 4.03 (s, 3H); 4.04 (d, 2H); 4.32 (t, 2H); 7.13 (t, 1H); 7.35 (t, 2H); 7.39 (s, 1H); 7.69 (d, 2H); 7.79 (s, 1H); 8.13 (d, 1H); 8.58 (d, 1H); 8.95 (s, 1H).

4-(Tert-butoxycarbonylamino-N-phenylthiophene-3-carboxamide

4-(Tert-butoxycarbonylamino)thiophene-3-carboxylic acid obtained according to the literature method, Tetrahedron Letters 1997, 2637, (385 mg, was 1.58 mmol) in DMF (5 ml), was injected into the interaction with aniline (140 μl, was 1.58 mmol) in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (602 mg, was 1.58 mmol) at 40aboutWith over 7 hours. The solvent is evaporated and the residue was purified by chromatography on silica gel, e is UNT petroleum ether/EtOAc: 80/20, getting listed in the title compound (348 mg, 70%).

1H NMR (CDCl3): 1.50 (s, N); 7.19 (t, 1H); 7.39 (t, 2H); 7.54 (d, 2H); 7.69 (s, 2H); 7.71 (s, 1H); 9.45 (s, 1H).

4-Amino-N-phenylthiophene-3-carboxamide

4-(Tert-butoxycarbonylamino-N-phenylthiophene-3-carboxamide (300 mg, of 0.94 mmol) in CH2Cl2(3 ml) was treated with TFA (0,36 ml, 4,71 mmol) at room temperature for 2.5 hours. The solvent is evaporated, the residue was dissolved in methanol/HCl, the solution was added ether, the precipitate was isolated, getting mentioned in the title compound (210 mg, 87%)which was used as received on the next stage.

Example 442. Getting connection 620 in table 26

By a reaction similar to that described in example 441, but on the basis of 4-amino-N-allylthio-3-carboxamide (218 mg, 1.06 mmol)were specified in the title compound (366 mg, 75%).

MS ES+: 484.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.28 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.95 (d, 2H); 4.03 (m, 5H); 4.32 (t, 2H); 5.14 (DD, 1H); 5.24 (DD, 1H); 5.91 (m, 1H); 7.41 (s, 1H); 7.59 (s, 1H); 8.28 (d, 1H); 8.51 (d, 1H); 9.04 (s, 1H).

4-(Tert-butoxycarbonylamino)-N-allylthio-3-carboxamide

By a reaction similar to that described in example 319, but on the basis of allylamine (150 μl, of 2.06 mmol)were specified in the title compound (385 mg, 66%).

1H NMR (CDCl3): 1.51 (s, N); 4.04 (m, 2H); 5.21 (DD, 1H); 5.29 (DD, 1H); 5.92 (m, 1H); 6.1 (m, 1H); 7.54 (d, 1H); 7.64 (m, 1H); 9.64 (s, 1H).

4-Amino-N-allylthio-3-carboxamide

By a reaction similar to that described in example 441, but on the basis of 4-(tert-butoxycarbonylamino)-N-allylthio-3-carboxamide (320 mg, 1.13 mmol), getting mentioned in the title compound (218 mg, 94%)which was used as received on the next stage.

Example 443. Getting connection 621 in table 27

4-Chloro-6-methoxy-7-(3-morpholinopropan)hinzelin (100 mg, 0.29 mmol) in isopropanol (5 ml) was injected into the interaction hydrochloride methyl-4-aminothiophene-4-carboxylate (63,6 mg, 0.33 mmol) at boiling for 1 hour. To the reaction mixture was added ethyl acetate, the solid was isolated by filtration, dried, obtaining mentioned in the title compound (140 mg, 89%).

MS ES+: 459.1 (M+H)+

1H NMR (DMSO-d6, TFA): 2.39 (t, 2H); 3.19 (t, 2H); 3.40 (t, 2H); 3.58 (d, 2H); 3.77 (m, 5H); 4.06 (m, 5H); 4.37 (t, 2H); 7.42 (s, 1H); 7.95 (s, 1H); 8.01 (d, 1H); 8.49 (d, 1H); 8.93 (s, 1H).

Example 444. Getting connection 622 in table 28

4-Chloro-6-methoxy-7-(3-morpholinopropan)hinzelin (110 mg, 0.3 mmol) in 2-pentanol (5 ml) and isopropanol/HCl (55 ml) was introduced into an interaction with 2-amino-5-isopropylthio-3-carboxamide (60 mg, 0.33 mmol) at 100°C for 1 hour, was added to the reaction mixture ethyl acetate, the precipitate was filtered, getting mentioned in the title compound (155 mg, 93%).

MS ES+: 486.6 (M+H)+

1H NMR (DMSO-d6, TF): 1.38 (d, 6N); 2.38 (t, 2H); 3.20 (m, 3H); 3.38 (t, 2H); 3.57 (d, 2H); 3.82 (t, 2H); 4.05 (d, 2H); 4.08 (s, 3H); 4.39 (t, 2H); 7.40 (s, 1H); 7.47 (s, 1H); 7.52 (s, 1H); 9.23 (s, 1H).

Example 445. Getting connection 623 in table 28

By a reaction similar to that described in example 444, but based on the allyl-5-aminothiophene-2-carboxylate (67 mg, 0.33 mmol) at 100°C for 2 hours, got mentioned in the title compound (151 mg, 85%).

MS ES+: 485.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.38 (t, 2H); 3.18 (t, 2H); 3.38 (t, 2H); 3.57 (d, 2H); 3.80 (t, 2H); 4.06 (d, 2H); 4.12 (s, 3H); 4.38 (t, 2H); 4.84 (d, 2H); 5.33 (d, 1H); 5.45 (d, 1H); 6.10 (m, 1H); 7.48 (s, 1H); 7.65 (d, 1H); 7.84 (d, 1H); 8.64 (s, 1H); 9.30 (s, 1H).

Example 446. Getting connection 624 in table 28

By a reaction similar to that described in example 444, but based on the 2-aminothiophene-3-carboxamide (46 mg, 0.33 mmol)were specified in the title compound (154 mg, 99%).

MS ES+: 444.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.34 (t, 2H); 3.15 (t, 2H); 3.36 (t, 2H); 3.54 (d, 2H); 3.76 (t, 2H); 4.02 (d, 2H); 4.05 (s, 3H); 4.36 (t, 2H); 7.32 (d, 1H); 7.41 (s, 1H); 7.48 (s, 1H); 7.66 (d, 1H); 9.23 (s, 1H).

Example 447. Getting connection 625 in table 28

By a reaction similar to that described in example 444, but on the basis of 2-amino-5-ethylthiophen-3-carboxamide (55 mg, 0.33 mmol)were specified in the title compound (147 mg, 90%).

MS ES+: 472.5 (M+H)+

1H NMR (DMSO-d6, TFA): 1.34 (t, 3H); 2.38 (t, 2H); 2.86 (q, 2H); 3.18 (t, 2H); 3.38 (t, 2H); 3.57 (d, 2H); 3.80 (t, 2H); 4.05 (d, 2H); 4.07 (s, 3H); 438 (t, 2H); 7.40 (s, 1H); 7.43 (s, 1H); 7.52 (s, 1H); 9.21 (s, 1H).

Example 448. Getting connection 626 in table 29

Methyl-2-cyano-4-methoxy-5-(3-morpholinopropan)phenylenediamine (100 mg; 0.3 mmol) in DMF (1.5 ml) was injected into the interaction with 2-amino-4-phenyl-1,3-thiazole (58 mg; 0.33 mmol) in the presence of sodium hydride (13.2 mg; 0.33 mmol) in 75aboutC for 1.5 h was Added acetic acid (1.5 EQ.) and the solvent evaporated, getting 6-methoxy-7-(3-formalisations)-3-(4-phenyl-1,3-thiazol-2-yl)hinzelin-4-(3H)-Imin as an intermediate compound, which was re-dissolved in DMF (1.5 ml) was added ammonium acetate (95 mg; 0.9 mmol). The mixture was stirred at 75°C for 1 h, the solvent evaporated and the residue was purified by chromatography on silica gel, CH2Cl2/Meon 95/5→90/10, getting mentioned in the title compound (44 mg, 31%).

1H NMR (DMSO-d6, TFA): 2.30 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 4.05 (m, 5H); 4.33 (t, 2H); 7.42 (m, 2H); 7.51 (t, 2H); 7.90 (s, 1H); 8.00 (d, 2H); 8.35 (s, 1H); 9.27 (s, 1H).

Example 449. Getting connection 627 in table 29

By a reaction similar to that described in example 448, but on the basis of 2-amino-4-methyl-5-acetyl-1,3-thiazole (103 mg, 0.66 mmol), when heated at 75°C for 1 h in the first stage and the mixing of the intermediate compounds of the above conditions at room temperature for 1 h, has been specified in the header of the giving (71 mg, 52%).

MS ES+: 458 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 2.55 (s, 3H); 2.67 (s, 3H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.0 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H); 7.37 (s, 1H); 7.99 (s, 1H); 9.26 (s, 1H).

Example 450. Getting connection 628 in table 29

By a reaction similar to that described in example 448, but based on ethyl-2-amino-4-trifluoromethyl-1,3-thiazole-5-carboxylate (79 mg, 0.33 mmol)were specified in the title compound (81 mg, 50%).

MS ES+: 542 (M+H)+

1H NMR (DMSO-d6, TFA): 1.34 (t, 3H); 2.32 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.03 (s, 3H); 4.04 (d, 2H); 4.36 (m, 4H); 7.47 (s, 1H); 8.41 (s, 1H); 9.34 (s, 1H).

Example 451. Getting connection 629 in table 29

By a reaction similar to that described in example 448, but based on ethyl-2-amino-4-phenyl-1,3-thiazole-5-carboxylate (82 mg, 0.33 mmol)were specified in the title compound (133 mg, 81%).

MS ES+: 550 (M+H)+

1H NMR (DMSO-d6, TFA): 1.25 (t, 2H); 2.32 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.02 (s, 1H); 4.04 (d, 2H); 4.26 (q, 2H); 4.35 (t, 2H); 7.45 (s, 1H); 7.50 (m, 3H); 7.79 (m, 2H); 8.33 (s, 1H); 9.37 (s, 1H).

Example 452. The connection 630 in table 29

By a reaction similar to that described in example 448, but on the basis of 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine (51 mg, 0.33 mmol)were specified in the title compound (97 mg, 71%).

MS ES+: 456 (M+H)+

1H NMR (DMSO-d6, TFA): 1.83 (m, 4H); 2.29 (t, 2H); 2.61 (m, 2H); 2.67 (m, 2H) 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.97 (s, 3H); 4.04 (d, 2H); 4.29 (t, 2H); 7.28 (s, 1H); 7.84 (s, 1H); 9.0 (s, 1H).

Example 453. Getting connection 631 in table 29

By a reaction similar to that described in example 448, but proceeding from N-(4-(2-amino-1,3-thiazol-4-yl)phenyl)ndimethylacetamide (77 mg, 0.33 mmol)were specified in the title compound (58 mg, 36%).

MS ES+: 535 (M+H)+

1H NMR (DMSO-d6, TFA): 2.09 (s, 3H); 2.32 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 4.05 (s, 3H); 4.06 (d, 2H); 4.35 (t, 2H); 7.40 (s, 1H); 7.72 (d, 2H); 7.77 (s, 1H); 7.92 (d, 2H); 8.33 (s, 1H); 9.25 (s, 1H).

Example 454. Getting connection 632 in table 29

By a reaction similar to that described in example 448, but starting from 5-phenyl-4-(trifluoromethyl)-1,3-thiazol-2-amine (81 mg, 0.33 mmol)were specified in the title compound (144 mg, 88%).

MS ES+: 546 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.04 (d, 2H); 4.05 (s, 3H); 4.36 (t, 2H); 7.49 (s, 1H); 7.54 (s, 5H); 8.46 (s, 1H); 9.30 (s, 1H).

Example 455. Getting connection 633 in table 29

By a reaction similar to that described in example 448, but on the basis of 4-(trifluoromethyl)-1,3-thiazol-2-amine (55 mg, 0.33 mmol)were specified in the title compound (62 mg, 44%).

MS ES+: 470 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.04 (s, 3H); 4.05 (d, 2H); 4.36 (t, 2H); 7.49 (s, 1H); 8.23 (s, 1H); 8,44 (s, 1H); 9.34 (s, 1H).

Example 456. Getting connection 634 in tablica

By a reaction similar to that described in example 448, but on the basis of 4-tert-butyl-1,3-thiazol-2-amine (52 mg, 0.33 mmol)were specified in the title compound (90 mg, 65%).

MS ES+: 458 (M+H)+

1H NMR (DMSO-d6, TFA): 1.46 (s, N); 2.32 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.03 (d, 2H); 4.32 (d, 2H); 7.38 (s, 1H); 7.95 (s, 1H); 9.18 (s, 1H).

Example 457. Getting connection 635 in table 29

By a reaction similar to that described in example 448, but based on 4,5-methyl-1,3-thiazol-2-amine (42 mg, 0.33 mmol)were specified in the title compound (61 mg, 47%).

MS ES+: 430 (M+H)+

1H NMR (DMSO-d6, TFA): 2.25 (s, 3H); 2.30 (m, 5H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.96 (s, 3H); 4.04 (d, 2H); 4.28 (t, 1H); 7.28 (s, 1H); 7.82 (s, 1H); 8.98 (s, 1H).

Example 458. The connection is 636 in table 29

By a reaction similar to that described in example 448, but on the basis of 4-methyl-1,3-thiazol-2-amine (38 mg, 0.33 mmol)were specified in the title compound (40 mg, 32%).

MS ES+: 415 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.34 (s, 3H); 3.15 (t, 2H); 3.37 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.99 (s, 3H); 4.04 (d, 2H); 4.29 (t, 2H); 7.03 (s, 1H); 7.29 (s, 1H); 7.87 (s, 1H); 9.05 (s, 1H).

Example 459. Getting connection 637 in table 29

1-(2-((6-Methoxy-7-(3-morpholinopropan)hinzelin-4-yl)amino)-4-methyl-1,3-thiazol-5-yl)alanon (50 mg, 0.11 mmol) in ethanol (4 ml) and pyridine (1 ml) was administered in cooperation with the hydrochloride hydrox lamina (19.5 mg, 0.27 mmol) by boiling for 3 hours. The solvent is evaporated, to the residue was added water and was isolated solid was washed with water, getting mentioned in the title compound (14 mg, 27%).

MS ES+: 473 (M+H)+

1H NMR (DMSO-d6, TFA): 2.25 (s, 3H); 2.30 (t, 2H); 2.53 (s, 3H); 3.17 (t, 2H); 3.38 (t, 2H); 3.58 (d, 2H); 3.69 (t, 2H); 3.99 (s, 3H); 4.05 (d, 2H); 4.32 (t, 2H); 7.32 (s, 1H); 7.88 (s, 1H); 9.12 (s, 1H).

Example 460. Getting connection 638 in table 29

2-((6-Methoxy-7-(morpholinoethoxy)hinzelin-4-yl)amino)-1,3-thiazole-5-carboxylic acid (89 mg, 0.2 mmol) in DMF (1.5 ml) was treated with diphenylphosphorylacetate (66 mg, 0.24 mmol) and triethylamine (26 mg, 0.26 mmol). The solution was stirred at room temperature for 1 h and at 45°C for 1 h was Added tert-butanol (1 ml) and the mixture was heated at 90°C for 2 hours the Mixture was diluted with ethyl acetate, was added aqueous sodium bicarbonate, the organic phase was separated, dried over MgSO4was filtered , concentrated and purified by chromatography on silica gel, eluent CH2Cl2/Meon from 95/5 to 85/15, getting mentioned in the title compound as a yellow solid (25 mg, 24%).

MS ES+: 517 (M+H)+

1H NMR (DMSO-d6, TFA): 1.50 (s, N); 2.31 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.97 (s, 3H); 4.04 (d, 2H); 4.29 (t, 2H); 7.13 (s, 1H); 7.26 (s, 1H); 7.94 (s, 1H); 9.11 (s, 1H).

Example 461. Getting connection 639 table is e 29

By a reaction similar to that described in example 459, but on the basis of the hydrochloride of O-methylhydroxylamine (18 mg, 0.22 mmol) and heated to boiling for 72 h, were obtained is indicated in the title compound (39 mg, 63%).

MS ES+: 487 (M+H)+

1H NMR (DMSO-d6, TFA): 2.26 (s, 3H); 2.31 (t, 2H); 3.53 (s, 3H); 3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.76 (s, 2H); 3.94 (s, 3H); 3.99 (s, 3H); 4.02 (d, 2H); 4.33 (t, 2H); 7.35 (s, 1H); 7.89 (s, 1H); 9.11 (s, 1H).

Example 462. The connection is 640 in table 29

By a reaction similar to that described in example 459, but on the basis of the hydrochloride of O-methylhydroxylamine (32 mg, 0.22 mmol)were specified in the title compound (8 mg, 12%).

MS ES+: 549 (M+H)+

1H NMR (DMSO-d6, TFA): 2.28 (t, 2H); 3.12 (t, 2H); 3.32 (t, 2H); 3.52 (d, 2H); 3.65 (t, 2H); 3.96 (s, 3H); 4.0 (d, 2H); 4.27 (t, 2H); 7.06 (t, 1H); 7.20 (d, 2H); 7.28 (s, 1H); 7.34 (t, 2H); 7.91 (s, 1H); 9.17 (s, 1H).

Example 463. Getting connection 641 in table 29

By a reaction similar to that described in example 448, but on the basis of 2-amino-5-(4-methoxyphenyl)-1,3-thiazole, HBr (86 mg, 0.33 mmol)were specified in the title compound (105 mg, 77%).

MS ES+: 508.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.33 (t, 2H); 3.20 (t, 2H); 3.40 (t, 2H); 3.60 (d, 2H); 3.73 (t, 2H); 3.86 (s, 3H); 4.08 (s, 3H); 4.09 (d, 2H); 4.36 (t, 2H); 7.10 (d, 2H); 7.44 (s, 1H); 7.76 (s, 1H); 7.96 (d, 2H); 8.33 (s, 1H); 9.26 (s, 1H).

Example 464. Getting connection 642 in table 29

By a reaction similar to that described in example 448, but the walking of 2-amino-5-phenyl-1,3-thiazole (58 mg, 0.33 mmol)were specified in the title compound (120 mg, 84%).

MS ES+: 478.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 4.01 (s, 3H); 4.05 (d, 2H); 4.32 (t, 2H); 7.34 (s, 1H); 7.41 (t, 1H); 7.51 (t, 2H); 7.72 (d, 2H); 7.97 (s, 1H); 8.24 (s, 1H); 9.16 (s, 1H).

Example 465. Getting connection 643 in table 29

Methyl-2-cyano-4-methoxy-5-(3-morpholinoethoxy)phenyl-imageformat (300 mg, 0.9 mmol) in DMF (4.5 ml) was injected into the interaction with 2-amino-5-phenyl-1,3-thiazole (127 mg, 0,99 mmol)in the presence of sodium hydride (to 39.6 mg, 0,99 mmol) at 75°C for 2 hours To the mixture was added acetic acid (77 μl, 1.35 mmol) at room temperature, the Meon/IU2NH (2M) (90 μl, 0.18 mmol) and stirred the mixture at 75°C for 1 h, the Solvent evaporated and the mixture was purified by chromatography on silica gel, eluent CH2Cl2/Meon from 95/5→90/10, got mentioned in the title compound (193 mg, 50%).

MS ES+: 430.6 (M+H)+

1H NMR (DMSO-d6, TFA): 1.29 (t, 3H); 2.32 (t, 2H); 2.81 (q, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 3.98 (s, 3H); 4.05 (d, 2H); 4.30 (t, 2H); 7.30 (s, 1H); 7.50 (s, 1H); 7.87 (s, 1H); 9.04 (s, 1H).

Example 466. Getting connection 644 in table 29

By a reaction similar to that described in example 465, but on the basis of 2-amino-5-isopropyl-1,3-thiazole (141 mg, 0,99 mmol)were specified in the title compound (107 mg, 26%).

MS ES+: 444.6 (M+H)+

1N the Mr (DMSO-d 6, TFA): 1.33 (d, 6N); 2.32 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.98 (s, 3H); 4.04 (d, 2H); 4.30 (t, 2H); 7.29 (s, 1H); 7.49 (s, 1H); 7.87 (s, 1H); 9.05 (s, 1H).

Example 467. Getting connection 645 in table 29

By a reaction similar to that described in example 465, but on the basis of 2-amino-5-benzyl-1,3-thiazole (188 mg, 0,99 mmol)were specified in the title compound (370 mg, 84%).

MS ES+: 492.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.98 (s, 3H); 4.04 (d, 2H); 4.18 (s, 2H); 4.29 (t, 2H); 7.27 (s, 1H); 7.28 (m, 1H); 7.35 (m, 4H); 7.61 (s, 1H); 7.88 (s, 1H); 9.02 (s, 1H).

Example 468. Getting connection 646 in table 29

By a reaction similar to that described in example 465, but on the basis of 2-amino-5-methyl-1,3-thiazole (113 mg, 0,99 mmol)were specified in the title compound (300 mg, 80%).

MS ES+: 416.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 2.42 (s, 3H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.97 (s, 3H); 4.04 (d, 2H); 4.29 (t, 2H); 7.30 (s, 1H); 7.48 (s, 1H); 7.86 (s, 1H); 9.03 (s, 1H).

Example 469. Getting connection 647 in table 29

By a reaction similar to that described in example 465, but on the basis of 2-amino-5-butyl-1,3-thiazole (155 mg, 0,99 mmol)were specified in the title compound (385 mg, 93%).

MS ES+: 458.6 (M+H)+

1H NMR (DMSO-d6, TFA): 0.93 (t, 3H); 1.36 (m, 2H); 1.64 (MN); 2.29 (t, 2H); 2.79 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.97 (s, 3H); 4.04 (d, 2H); 4.29 (t, 2H); 7.29 (s, 1H); 7.51 (s, 1H); 7.86 (s, 1H); 9.03, 1H).

Example 470. Getting connection 648 in table 29

By a reaction similar to that described in example 465, but on the basis of 2-amino-5-formyl-1,3-thiazole (499,4 mg, 3.9 mmol)were specified in the title compound (244 mg, 39%).

MS ES+: 430.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H); 3.57 (d, 2H); 3.70 (t, 2H); 4.03 (s, 3H); 4.06 (d, 2H); 4.35 (t, 2H); 7.45 (s, 1H); 8.12 (s, 1H); 8.71 (s, 1H); 9.32 (s, 1H).

Example 471. Getting connection 649 in table 29

By a reaction similar to that described in example 459, but on the basis of 2-((6-methoxy-7-(3-morpholinopropan)hinzelin-4-yl))amino-1,3-thiazole-5-carbaldehyde (100 mg, 0.23 mmol) and heated at 80°C for 4 h, the received specified in the title compound (21 mg, 20%).

MS ES+: 445.6 (M+H)+

1H NMR (DMSO-d6, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 4.00 (s, 3H); 4.05 (d, 2H); 4.32 (t, 2H); 7.36 (s, 1H); 7.92 (s, 1H); 7.98 (s, 1H); 8.33 (s, 1H); 9.20 (s, 1H).

Example 472. The connection is 650 in table 29

By a reaction similar to that described in example 448, but on the basis of 2-amino-5-tert-butyl-1,3,4-thiadiazole (52 mg, 0.33 mmol)were specified in the title compound (80 mg, 58%).

MS ES+: 458 (M+H)+

1H NMR (DMSO-d6, TFA): 1.45 (s, N); 2.32 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.02 (d, 2H); 4.32 (t, 2H); 7.38 (s, 1H); 7.95 (s, 1H); 9.18 (s, 1H).

Example 473. Getting connection 651 in table 29

By the reaction, similar to the offered described in example 448, but on the basis of 2-amino-5-cyclopropyl-1,3,4-thiadiazole (47 mg, 0.33 mmol)were specified in the title compound (105 mg, 83%).

MS ES+: 443 (M+H)+

1H NMR (DMSO-d6, TFA): 1.08 (m, 2H); 1.23 (m, 3H); 1.23 (m, 3H); 2.32 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.99 (s, 3H); 4.04 (d, 2H); 4.32 (t, 2H); 7.38 (s, 1H); 7.93 (s, 1H); 9.14 (s, 1H).

Example 474. Getting connection 652 in table 30

By a reaction similar to that described in example 448, but on the basis of 2-amino-5-ethylthio-1,3,4-thiadiazole (53 mg, 0.33 mmol)were specified in the title compound (103 mg, 75%).

MS ES+: 463 (M+H)+

1H NMR (DMSO-d6, TFA): 1.41 (t, 3H); 2.31 (t, 2H); 3.15 (t, 2H); 3.31 (q, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 7.41 (s, 1H); 8.08 (s, 1H); 9.19 (s, 1H).

Example 475. Getting connection 653 in table 30

By a reaction similar to that described in example 448, but on the basis of 2-amino-5-phenyl-1,3,4-thiadiazole (91 mg, 0.33 mmol)were specified in the title compound (110 mg, 76%).

MS ES+: 479 (M+H)+

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.37 (t, 2H); 3.57 (d, 2H); 3.69 (t, 2H); 4.03 (s, 3H); 4.05 (d, 2H); 4.34 (t, 2H); 7.42 (s, 1H); 7.61 (m, 3H); 7.99 (m, 2H); 8.06 (s, 1H); 9.25 (s, 1H).

Example 476. Getting connection 654 in table 30

By a reaction similar to that described in example 448, but based on N-phenyl-4H-1,2,4-triazole-3,5-diamine (58 mg, 0.33 mmol)were specified in the title compound (70 mg, 49%).

MS ES+: 477 (M+H)

1H NMR (DMSO-d6, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.37 (t, 2H); 3.57 (d, 2H); 3.70 (t, 2H); 4.02 (s, 3H); 4.05 (d, 2H); 4.34 (t, 2H); 6.92 (t, 1H); 7.30 (t, 1H); 7.42 (s, 1H); 7.58 (d, 2H); 8.19 (s, 1H); 8.95 (s, 1H).

Biological data

The compounds of this invention inhibit the activity of serine/threonine kinase aurora 2 kinase and thereby inhibit the cell cycle and cell proliferation. These properties can be estimated, for example, using one or more of the methods below:

(a) Analysis for the inhibition of aurora kinase 2 in vitro

In this analysis, determine the ability of test compounds to inhibit the activity of serine/threonine kinases. DNA encoding aurora 2, can be obtained by total gene synthesis or cloning. Then this DNA can be Express in expressing appropriate system to obtain a polypeptide having serine/threonine kinase activity. In the case of aurora 2 coding sequence was isolated from cDNA by polymerase chain reaction (PCR) and cloned in endonuclease restriction sites BamH1 and Not1 baculovirus expression vector pFastBac HTc (GibcoBRL/Life technologies). 5'PCR primer contained the sequence of recognition for the restriction endonuclease BamH1 5' to the coding sequence of the aurora 2. This gave the opportunity to enter aurora 2 gene in frame with a 6 his-tag residues spacer elements region and site split what I rTEV protease, coded pFastBac vector. 3'PCR primer was replaced by a stop codon aurora 2 additional coding sequence followed by a stop codon and sequence recognition for restriction enzyme Not1. This additional coding sequence (5' TAC CCA TAC GAT GTT CCA GAT TAC GCT TCT TAA 3') encodes the polypeptide sequence YPYDVPDYAS. This sequence was obtained from hemaglutination protein of the virus, is often used as a labeled epitope sequences of antigenic determinants, which can be identified using specific monoclonal antibodies. Recombinant pFastBac vector, thus, encode the N-terminal labeled with 6-his, C-terminal hemaglutinin epitope of influenza labeled aurora 2 protein. Details of the method of Assembly of recombinant DNA molecules can be found in the usual texts, for example, Sambrook et al., 1989, Molecular Cloning - A Laboratory Manual, 2ndEdition, Cold Spring Harbor Laboratory press, and in Ausubel et al., 1999, Current Protocols in Molecular Biology, John Wiley and Sons Inc.

Production of recombinant virus can be performed by following the Protocol of the manufacturer Gibco BRL. Briefly, pFastBac-1 vector carrying the gene aurora 2, transformed into cells of E. coli DH10Bac containing the baculovirus genome (bacmid DNA), and by vnutripolostnoe translocation in the cell region pFastBac vector containing gentamicin-resistant gene and gene aurora 2, including himself baculovirus polyhedrin promoter, have transposed directly into the bacmid DNA. Through breeding for gentamicin, kanamycin, tetracycline and X-gal produced white colonies should contain the recombinant bacmid DNA encoding aurora 2. Bacmid DNA was extracted from small-scale culture of several white colonies BH10Bac and transfectional in cells of Spodoptera frugiperda Sf21 grown in the medium TS (GibcoBRL)containing 10% serum, using CellFECTIN reagent (GibcoBRL)following the manufacturer's instructions. The virus particles were collected by sampling the cell culture medium after 72 h after transfection. To infect 100 ml suspension culture Sf21s containing 1×107cells/ml, were used 0.5 ml of medium. Cell culture medium was collected after 48 h after infection and determined the titer of the virus using standard methods of analysis belascoaran. To infect Sf9 cells and "High 5" used strains of the virus at multiplicity of infection (MOI), part 3, to determine the expression of the recombinant protein aurora 2.

For large-scale expression and activity of aurora 2 kinase grew Sf21 cells insects in the 28aboutWith the environment TS, with the addition of 10%fetal calf serum (Viralex) and 0.2% Pluronic F68 (Sigma) on roller stand Wheaton at 3 rpm When the cell density reached 1.2×106cells ml-1they were not infected with trombi the tov recombinant virus aurora 2 if the multiplicity of infection of 1 and harvested 48 hours later. The next stage of the purification were performed at 4°C. Frozen precipitation insect cells in test tubes after centrifugation was thawed and diluted Lisinym buffer (25 mm HEPES (N-[2-hydroxyethyl]piperazine-N'-[2-econsultation]) pH 7.4 at 4aboutC, 100 mm KCl, 25 mm NaF, 1 mm Na3VO4, 1 mm PMSF (phenylmethylsulfonyl), 2 mm 2-mercaptoethanol, 2 mm imidazole, 1 mg/ml of Aprotinin, 1 μg/ml of pepstatin, 1 μg/ml leupeptin), using 1.0 ml at 3x107cells. Lysis was performed using a standard homogenizer, after which the lysate was centrifuged at 41,000 g for 35 minutes. The supernatant layer of separated liquid is injected in the chromatographic column with a diameter of 5 mm, containing 500 ál of Ni-NTA (nitrilotriacetic acid) agarose (Qiagen, product # 30250), which was balanced in Lisina buffer. Level baseline UV absorption eluent was reached after washing the column 12 ml lisanova buffer, then 7 ml of wash buffer (25 ml HEPES pH 7.4 at 4°C, 100 mm KCl, 20 mm imidazole, 2 mm 2-mercaptoethanol). Related aurora 2 protein was suirable from the column using an eluting buffer (25 ml HEPES pH 7.4 at 4°C, 100 mm KCl, 400 mm imidazole, 2 mm 2-mercaptoethanol). Collected elyuirovaniya fraction (2.5 ml), corresponding to the peak of UV absorption. Performed a full dialysis elyuirovaniya fractions containing active aurora 2 CIN the memory, regarding dialysis buffer (25 ml HEPES pH 7.4 at 4°, 45% glycerol (V/V), 100 mm KCl, And 0.25% Nonidet P40 (V/V), 1 mm dithiothreitol).

Each new batch of enzyme aurora 2 was titrated in the analysis by dilution with enzyme diluent (25 mm Tris-HCl pH 7.5, 12.5 mm KCl, 0.6 mm DTT). For a normal portion of the original enzyme solution diluted 1 to 666 enzyme diluent and for each well used for the analysis of 20 ál of diluted enzyme. Test compounds (at 10 mm in dimethyl sulfoxide (DMSO)) was diluted with water and transferred to 10 μl of diluted compound in the wells of tablets for analysis. "General" and "blank" control wells contained a 2.5% DMSO instead of compound. Added twenty microlitres swierzbinski enzyme to all wells except the blank wells. Twenty microlitres diluent enzyme were added to empty wells. After that to start a reaction in all the tested wells were added twenty microliters reaction mixture (25 mm Tris-HCl, 78,4 mm KCl, 2.5 mm NaF, 0.6 mm dithiothreitol, 6.25 mm MnCl2, 6.25 mm ATP, 7.5 μm protein substrate [Biotin-LRRWSLGLRRWSLGLRRWSLGLRRWSLG])containing 0.2 MX [γ33P]ATP (Amersham Pharmacia, specific activity ≥2500 Curie/mmol). The plates were incubated at room temperature for 60 minutes. To stop the reaction in each well was added 100 μl of 20%V/V orthophosphoric acid. The peptide substrate has captured the and positively charged nitrocellulose filter paper P30 (Whatman) using a 96-hole tablet harvester (TomTek), and then analyzed for the implementation of33R using tablet counter beta particles. "Empty" (without enzyme) and "common" (without connections) of the control values used to determine the interval dilution of test compound that gave 50% inhibition of enzyme activity. In this test compound 52 in table 2 showed 50% inhibition of enzyme activity at a concentration of 0,167 μm, and the connection 253 table 9 showed 50% inhibition of enzyme activity at a concentration of 0,089 mm.

(a) Analysis of cell proliferation in vitro

In this analysis, we determined the ability of test compounds to inhibit the growth of fused cell lines mammals, for example cell line MCF7 tumors of the person. Usually MCF7 (ATSS NTV-22) or other fused cells were sown at 1×103cells per well (excluding the peripheral wells) in DMEM (Sigma Aldrich) without phenol red, adding 10% fetal calf serum, 1% L-glutamine and 1% penicillin/streptomycin in 96-well transparent tablet-treated tissue culture (Costar). The next day (day 1) Wednesday were removed from untreated control tablet and kept the plate at -80°C. In the remaining tablets were made of the dose of compound (diluted from a 10 mm solution in DMSO using DMEM (without phenol red, 10% FCS, 1% L-glutamine, 1% penicil the on/streptomycin)). Each tablet was left untreated control wells. After 3 days in the presence/absence of connection (day 4) the medium was removed and kept the tablets at -80°C. twenty-four hours the tablets were thawed at room temperature and determined cell density using a set of analysis on the CyQUANT cell proliferation (c-7026/c-7027 Molecular Probes Inc.) in accordance with the manufacturer's instructions. Briefly, to each well was added 200 μl of a mixture of cell lysis/dye (10 ál 20X cell lisanova buffer, 190 μl of sterilized water, and 0.25 μl of CYQUANT dye GR) and incubated tablets at room temperature for 5 minutes in the dark. Then measured the fluorescence of the wells using a microplate fluorescence reader (gain 70, 2 measurements per well, 1 cycle at excitation 485 nm and emission 530 nm using a CytoFluor tablet reader (PerSeptive Biosystems Inc.)). The values obtained from day 1 and day 4 (processed connection), together with the values from untreated wells were used to determine the interval of dilution of the test compounds, which showed 50% inhibition of cell proliferation. Compound 52 in table 2 was effective in this test when to 0.61 μm, and the connection 253 in table 9 was effective in at 5.9 microns.

Data testing the program could also be used to calculate the interval dilution of test compounds in which cell density falls below the reference value of 1 day. This indicates that the cytotoxicity of the compounds.

(a) Analysis of cell cycle in vitro

In this analysis, we determined the ability of test compounds to stop cells in certain phases of the cell cycle. In this analysis could be used many different cell lines of mammalian cells and MCF7 included here as an example. Cells MCF-7 were sown at 3×105cells on KZT25 flask (Costar) in 5 ml of DMEM (without phenol red, 10% FCS, 1% L-glutamine, 1% penicillin/streptomycin). Then the flasks were incubated overnight in a humidified incubator at 37°With 5% CO2. The next day the flask was added 1 ml of DMEM (without phenol red, 10% FCS, 1% L-glutamine, 1% penicillin/streptomycin)containing a defined concentration of test compounds dissolved in DMSO. In addition, they also included a control treatment without connection (0.5% DMSO). After that, cells were incubated for a certain period of time (usually 24 hours) with the connection. After this time the medium was removed from the cells and washed with 5 ml of preheated (37° (C) PBSA, then was extracted from the flask with a brief incubation with trypsin followed by re-suspendirovanie in 10 ml of 1% bovine zavorotnova albumin (BSA, Sigma Aldrch Co.) in sterile PBSA. Then samples were centrifuged at 2200 rpm for 10 minutes was Collected supernatant liquid layer and re-suspended cell precipitate in 200 μl of 0.1% (weight/about) Tris sodium citrate, 0,0564% (mass/V) NaCl, 0.03 per cent (V/V) Nonidet NP40 [pH 7,6]. Added iodide propride (Sigma Aldrich Co.) to 40 μg/ml and RNase A (Sigma Aldrich Co.) to 100 mcg/ml After the cells were incubated at 37°C for 30 minutes. Samples were centrifuged at 2200 rpm for 10 minutes, the supernatant liquid layer was removed, and the remaining sediment (core), re-suspended in 200 ál of sterile PBSA. After that, each sample was passed through a syringe 10 times using needle 21 size. Then the sample was transferred into a LPS tubes and analyzed the DNA content per cell by sorting fluorescently-activated cells (FACS) using a FACScan flow cytometer (Becton Dickinson). Usually counted 25,000 events and recorded using the software CellQuest v1.1 (Verity Software). The distribution of cell cycle populations was calculated using the software Modfit (Verity Software) and expressed as the percentage of cells in G0/G1, S and G2/M phases of the cell cycle.

Treatment of MCF7 cells 1 mm compound 52 in table 2 for 24 hours caused the following changes in the distribution of cell cycle:

Processing% the notches in the G2/M
DMSO (control)9,27%
1 m connection 52>50%

1. The compound of formula (IA)

where X is NH;

R5arepresents an optionally substituted 5-membered heteroaromatic ring selected from the group of formula (a), (b), (d), (e), (f), (g), (h), (i) or (j), consisting of

where * indicates the place of attachment to the group X in formula (IA), a R60and R61from the group of the formula (K)

where p and q are independently 0 or 1,

a R1' and R1" independently represent hydrogen, hydroxy;

where T represents C=O, S, C(=NOR)CO, C(O)C(O), where R is hydrogen, C1-6alkyl and phenyl;

V independently represents hydrogen, hydroxyl, C1-6alkyl, C1-6alkoxy, C2-6alkenylacyl, trifluoromethyl, phenyl optionally substituted C1-6alkoxy or C1-6alkanoyloxy or37 cycloalkyl; or V is N(R63R64;

where one of R63and R64independently selected from hydrogen, C1-10the alkyl, optionally substituted by a hydroxy-group, C1-6alkoxycarbonyl and C1-6alkoxyl; and (C2-6alkenyl,

and the other With1-6alkyl, optionally substituted 1 or 21-4alkoxyl, cyano, C1-4alkoxycarbonyl,2-4alkanoyloxy or hydroxy;

heteroaryl1-6alkyl, where heteroaryl represents a 5-6 membered ring containing 1-2 heteroatoms selected from O, S and N, and optionally substituted C1-6by alkyl;

phenyl or panels1-6alkyl, optionally substituted by 1, 2 or 3 groups selected from a halogen, N,N-di(C1-6alkyl)amino, N-(C1-6alkyl)amino, C1-6alkoxy, C2-6alkanoyl, trifloromethyl, cyano, C1-6the alkyl, optionally substituted by hydroxy or cyano, carbamoyl, hydroxy, triptoreline, nitro, C1-6alkylthio, amino, -OC1-3alkyla - and C1-6alkylcarboxylic;

heteroaryl selected from pyridyl, furanyl and indolyl, optionally substituted by 1 or 2 hydroxy groups, halogen, C1-6the alkyl or C1-6alkoxy;

With3-7cycloalkyl or3-7cycloalkyl1-6alkyl, optionally substituted hydroxy-group;

or R 63and R64together with the nitrogen atom to which they are attached, form a 5-6-membered ring which may optionally contain heteroatom N or O and, which can be optionally substituted C1-6by alkyl, hydroxy-group, hydroxys1-6the alkyl or carbamoyl, and

R62represents hydrogen, C1-6alkyl, C1-6alkoxycarbonyl or carbarnoyl;

R1'represents hydrogen;

R2'is1-6alkoxy;

R3'is-X1R9where X1represents-O-, and R9choose from one of the following groups:

1) With the1-5the alkyl

2) C1-5alkyl3R20where X3is-NR25-where R25represents hydrogen or C1-3

alkyl, and R20represents C1-3alkyl, cyclopentyl, cyclohexyl, with C1-3the alkyl group may contain 1 or 2 substituent selected from oxo, hydroxy, halogen and C1-4alkoxy;

3)1-5alkyl4C1-5alkyl5R26where each of X4and X5is-NR31-where R31represents hydrogen or C1-3alkyl, and R26represents hydrogen or C1-3alkyl;

4)1-5R32where R32represents a 5-6-membered saturated heterocyclic groups which, linked via carbon or nitrogen) with 1-2 heteroatoms independently selected from O and N, while the heterocyclic group may contain 1 or 2 substituent selected from a hydroxy-group, With1-4the alkyl and C1-4hydroxyalkyl;

5)1-3-talking9C1-3R32where X9is-NR57and R57represents hydrogen or C1-3alkyl, and R32defined above; and

R4'represents hydrogen;

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which R5achoose from a group of formula (a), (b), (C), (d) or (e).

3. The compound according to claim 1, in which R5achoose from a group of formula (a) or (b).

4. The compound according to any preceding paragraph, in which R61different from hydrogen.

5. The compound according to any preceding paragraph, in which R62is hydrogen.

6. The compound according to any preceding paragraph, in which one of R63or R64is phenyl, optionally substituted by 1, 2 or 3 groups selected from a halogen, N,N-di(C1-6alkyl)amino, N-(C1-6alkyl)amino, C1-6alkoxy, C2-6alkanoyl, trifloromethyl, cyano, C1-6the alkyl, optionally substituted by hydroxy or cyano, carbamoyl, hydroxy, triptoreline, nitro, C1-6alkylthio, amino, -OC1-3alkalo and C1-6alquiler the onila.

7. The compound according to any one of claims 1 to 5, in which one of R63or R64is substituted C1-6alkyl group optionally substituted by 1 or 2 C1-4alkoxyl, cyano, C1-4alkoxycarbonyl,2-4alkanoyloxy or hydroxy; or heteroaryl1-6the alkyl, where heteroaryl represents a 5-6 membered ring containing 1-2 heteroatoms selected from O, S and N, and optionally substituted C1-6the alkyl.

8. The compound according to any one of claims 1 to 5, in which one of R63or R64is heteroaryl selected from pyridyl, furanyl and indolyl, optionally substituted by 1 or 2 hydroxy groups, halogen, C1-6the alkyl or C1-6alkoxy; or

With3-7cycloalkyl or3-7cycloalkyl1-6the alkyl, optionally substituted hydroxy-group.

9. The compound according to any one of claims 1 to 5, in which R63and R64together with the nitrogen atom to which they are attached, form a 5-6-membered ring which may optionally contain heteroatom N or O and, which can be optionally substituted C1-6by alkyl, hydroxy-group, hydroxys1-6the alkyl or carbamoyl.

10. The compound according to any preceding paragraph, in which R3'represents a group-OC1-5R32and R32is a heterocyclic ring as defined in claim 1.

11. Pharmaceutical to notice for inhibiting aurora 2 kinase, containing the compound according to any one of claims 1 to 10 in combination with a pharmaceutically acceptable carrier.

12. The compound according to any one of claims 1 to 10, designed to produce drugs for the treatment of proliferative diseases.

13. The compound according to any one of claims 1 to 10, designed to produce drugs for the treatment of cancer.

14. A method of obtaining a compound according to any one of claims 1 to 10, including the interaction of the compounds of formula (VII)

where R1', R2', R3', R4'defined in any one of claims 1 to 10 and R85represents a group NR86R87where R86and R87independently selected from C1-10of alkyl, with a compound of formula (VIII)

where R5'is the group R5adefined in any one of claims 1 to 10.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: organic chemical, pharmaceuticals.

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

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

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

SUBSTANCE: invention relates to a method for preparing an antidiabetic agent pioglitazone of the formula (I): . Method involves condensation of 4-substituted phenol or phenolate of the general formula (II): wherein R represents organic radical comprising amino-group and chosen from group comprising group of the general formula: -NHRa (IIa) wherein Ra means hydrogen atom or protective group that is removed before the following treatment, and group of the general formula: wherein Rb represents carboxyl group as free acid or as salt or ester; M represents hydrogen atom or alkaline metal with pyridine base of the general formula (III): wherein Z means a removing group distinguishing from halogen atom and wherein the following steps are carried out: (a) diazotization reaction of amino-group as a moiety of organic radical R; (b) conversion of diazotized radical R to derivative of 2-halogenpropionate or 2-halogenpropionitrile of the formula: wherein Rb is determined above; X represents halogen atom; (c) cyclization of derivative of 2-halogenpropionate or 2-halogenpropionitrile with thiourea, and (d) hydrolysis of imine prepared. In case when R represents group of the formula (IIa) method involves firstly carrying out the condensation reaction followed by carrying out steps (a)-(d) to obtain agent of the formula (I); or in case when R represents group of the formula (IIb) then method involves firstly carrying out steps (a)-(d) followed by condensation with pyridine base of the general formula (III) to obtain agent of the formula (I). Also, invention describes compounds of the formula (V): wherein Ra represents a protective group chosen from group comprising acyl, n-alkoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-cyanoethoxycarbonyl as an intermediate substance in synthesis of compound of the formula (I).

EFFECT: improved preparing method of agent.

12 cl, 5 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, cosmetics, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means radical of the following formulae: (a) or (b) wherein R2 and R3 are similar or different and mean hydrogen atom, alkyl with 10-12 carbon atoms, aryl, radical -OR7; X means a binding fragment of the following formula: -(CH2)m-(Z)n-(CO)p-(W)q- wherein a binding fragment can be read from the left to the right or inversely; R4 means alkyl with 1-12 carbon atoms, aryl, aralkyl, heteroaryl or 9-fluorenylmethyl; Y means radical -CH2 or sulfur atom; R5 means hydroxyl, alkoxyl with 1-6 carbon atoms, radical -NH-OH or radical -N(R8)(R9); R6 means alkyl with 1-12 carbon atoms, radical -OR10 or radical -(CH2)r-COR11; R7 means hydrogen tom or aralkyl; Z means oxygen atom or radical -NR12; W means oxygen atom, radical -NR13 or radical -CH2; m, n, p and q are similar or different and can mean 0 or 1 under condition that the sum (m + n + p + q) = 2 or above, and when p = 0 then n or q = 0; R8 means hydrogen atom; R9 means hydrogen atom or aryl; r means 0 or 1; R10 means alkyl with 1-12 carbon atoms; R11 means hydroxyl or radical -OR14; R12 means hydrogen atom or alkyl with 1-12 carbon atoms; R13 means hydrogen atom or alkyl with 1-12 carbon atoms; R14 means alkyl with 1-12 carbon atoms; and optical and geometric isomers of abovementioned compounds of the formula (I), and their salts also. These compounds are useful as activating agents of receptors of type PPAR-γ in pharmaceutical compositions designated for using in medicine, in particular, in dermatology, in treatment of cardiovascular diseases and related to immunity of diseases and/or diseases associated with lipid metabolism, and in cosmetic compositions also.

EFFECT: valuable properties of compounds and compositions.

19 cl, 1 tbl, 2 dwg, 37 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted bicyclic heterocyclic compounds of the formula (I): their tautomeric forms, stereoisomers, polymorphous forms, pharmaceutically acceptable salts and pharmaceutically acceptable solvates wherein groups R1, R2, R3 and R4, and groups R5 and R6 when they are bound with carbon atom they represent hydrogen, halogen atom, hydroxy-group, alkyl, alkoxy-group; R5 and R6 as a single group or both can represent also an oxo-group when they are bound with carbon atom; when R5 and R6 are bound with nitrogen atom then they represent hydrogen atom, hydroxy-group or such unsubstituted groups as alkyl, alkoxy-group, aralkyl. X means oxygen or sulfur atom; Ar means phenylene, naphthylene or benzofuryl. Proposed compounds can be used against obesity and hypercholesterolemia. Also, the invention describes methods for preparing compounds, pharmaceutical compositions, method for treatment and using compounds proposed.

EFFECT: valuable medicinal properties of compounds and compositions.

52 cl, 77 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

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

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemical, pharmaceuticals.

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

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

FIELD: organic chemistry, chemical technology, medicine, veterinary science.

SUBSTANCE: invention describes the compound R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylmethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole of the formula (I) and its salts, in particular, its mononitrate. Also, invention relates to a method for preparing compound of the formula (I) possessing antifungal effect based on compound of the formula (I), and using compound of the formula (I) as an active component of the antifungal composition. Compound of the formula (I) can be used in compositions for treatment of fungal infections in humans or animals and against diseases of agricultural crops.

EFFECT: improved preparing method, valuable properties of compound and composition.

15 cl, 1 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of diphenylazathedinone of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another (0-C30)-alkylene-L wherein one or some C-atoms of alkylene residue can be substituted with -O-, -(C=O)- or -NH- and, except for, R1-R6 can represent hydrogen atom (H), fluorine atom (F), and L represents compound of the formula: , and their pharmaceutically tolerated salts also. Compounds of the formula (I) elicit hypolipidemic effect and can be used in therapeutic aims. Also, invention describes a medicinal agent and its using.

EFFECT: valuable medicinal properties of compounds.

7 cl, 31 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

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

28 cl, 10 tbl, 16 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino}-3,3-diphenylpropanoyl}-2-pyrrolidine carboxamide maleate of the formula (1): . Also, invention relates to a method for preparing this compound by interaction of free compound of the formula (1) with maleic acid in the presence of organic solvent. This salt can be used as thrombin inhibitor.

EFFECT: improved preparing method, valuable medicinal properties of compound.

4 cl, 2 tbl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

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

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

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