Cyclic azaindole-3-carboxamide, production and use thereof as therapeutic preparations

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to cyclic azaindole-3-carboxamides of formula (I) in any of its stereoisomeric forms or in the form of a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof or a physiologically acceptable solvate of any of them: wherein A is specified in O, S and C(Ra)2; Ra is specified in hydrogen and (C1-C4)-alkyl wherein the two groups Ra are independent from each other and may be identical or different; R is specified from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, phenyl-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-CO-CuH2u- and R1-NH-CO-CuH2u-, wherein all the groups R are independent from each other and may be identical or different; R1 is specified from hydrogen, (C1-C4)-alkyl and H2N-CO-(C1-C4)-alkyl-; R10 is specified from hydrogen, (C1-C6)-alkyl-O-CO-; R20 is specified from phenyl which is optionally substituted by one or more identical or different substitutes specified in halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O-; R30 is specified from (C3-C7)-cycloalkyl and phenyl, wherein phenyl is optionaly substituted by one or more identical or different substitutes specified in halogen and (C1-C6)-alkyl; R40 is specified in halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl-, hydroxy, (C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O- and (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, wherein all the substitutes R40 are independent from each other and may be identical or different; one of the groups Y1, Y2, Y3 and Y4 represents N, while the others are identical or different groups CH or CR40; n is specified in 0, 1, 2 and 3; p and q which are independent from each other and may be identical or different being specified in 2 and 3; n is specified in 0, 1 and 2, wherein all the values are independent from each other and may be identical or different; wherein all the alkyl groups are independently from each other optionally substituted by one or more fluorine atoms; wherein all the phenyl groups found in R and R40 are independently from each other optionally substituted by one or more identical or different substitutes specified in halogen and (C1-C4)-alkyl. Besides, the invention describes a method for preparing a compound of formula I, a pharmaceutical compositions having renin inhibitory activity and containing the compound of formula I and to using the compound of formula I for making a therapeutic preparation.

EFFECT: described and prepared are the new compounds that inhibit the enzyme renin, and modulate activity of the renin-angiotensin system, and are effective for treating the diseases such as, eg hypertension.

7 cl, 141 ex, 8 tbl

 

The present invention relates to cyclic azaindole-3-carboxamide formula I:

,

in which A, R, R10, R20, R30, R40, Y1, Y2, Y3, Y4n, p and q have the meanings shown below, which are valuable pharmaceutically active compounds. Specifically, they inhibit the enzyme renin and modulate the activity of the renin-angiotensine system, and are suitable for the treatment of diseases, such as hypertension. In addition, the present invention relates to a method for producing compounds of the formula I, their use and containing pharmaceutical compositions.

The renin-angiotensin system (RAS; also denoted as the system renin-angiotensin-aldosterone, RAAS) is a key regulator of cardiovascular function as well as the balance of electrolytes and maintain the volume of body fluids, and is a determinant of blood pressure (see, for example, E. Lonn, Can. J. Cardiol. 20 (Suppl. B) (2004), 83B; I. A. Reid, Am. J. Physiol.: Advances in discrimination Education 20 (1998), S236). It operates through angiotensin II, octapeptide hormone that is associated with angiotenzinovymi receptors. The formation of angiotensin II involves two major phases. In the first stage of the renin (EC 3.4.23.15; formerly EC 3.4.99.19 and EC 3.4.4.15), expertiserating, consisting of 340 amino acids, breaks down angit sinogen, forming a biologically inactive Decapeptide angiotensin I. In the second stage, angiotensin I is converted to angiotensin II by using the zinc-dependent proteases angiotensin-converting enzyme (ACE). Renin is synthesized in juxtaglomerular kidney cells, initially in the form biologically inactive prorenin. He is released from the kidneys and is activated, and subsequent RAS activation in people with normal blood pressure stimulates a decrease or reduction in the number of sodium ions, or lower blood pressure.

RAS activity is the major determinant of several pathological conditions, as angiotensin II, the main effector molecule of this system, increases blood pressure, or directly by the narrowing of blood vessels, or indirectly by the release of aldosterone, which inhibits the sodium hormone from the adrenal gland, which is accompanied by increase in the volume of extracellular fluid and has accelerating growth effect on the tissues of blood vessels, heart and kidneys, which contributes to damage of target organs.

Pharmacological blockade of the RAS is a well-known method of treatment of various diseases such as hypertension (see, for example, Handbook of Hypertension, W. H. Birkenhager et al. (ed.), Elsevier Science Publishers, Amsterdam (1986), vol.8, 489). However, therapeutic about the wet, achieved with the currently used types of RAS blockers, ACE inhibitors and blockers of the angiotensin receptor, albeit effective, but is limited. This may be the result of increasing the concentration of renin, which is caused by these agents and results in increased concentrations of angiotensin I, which is converted to angiotensin II via other ways than through ACE. Inhibition of renin, which controls the initial and limiting the speed stage in RAS catalysis of the cleavage of Leu 10-Val 11 peptide bond of angiotensinogen, which results in the formation of angiotensinogen peptides to inhibit full RAS and thus will be more efficient. In addition, while the ACE inhibition also affects the concentration of other peptides, which are ACE, such as, for example, bradykinin, which is associated with side effects ACE inhibitors, like coughing or angioedema, renin is specific in that angiotensinogen is the only natural substrate. Thus, inhibition of renin offers specific and powerful way to reduce blood pressure (see, M. Moser et al., J. Clin. Hypertension, 9 (2007), 701), and protects organs such as the heart, kidneys and brain, and in the treatment of hypertension, therefore, is the tsya suitable for treatment of disorders of the cardiovascular system, such as heart failure, heart failure, valvular disease, myocardial infarction, cardiac hypertrophy, vascular hypertrophy, left ventricular dysfunction, in particular dysfunction of the left ventricle after myocardial infarction, restenosis and angina; renal diseases, such as fibrosis of the renal tissue, kidney failure and weakness of the kidneys; diabetic complications such as nephropathy and retinopathy; glaucoma and cerebral diseases such as cerebral hemorrhage, for example (in relation to the effect of RAS on kidney and heart disorders, see, for example, U. C. Brewster, Am. J. Med. 116 (2004), 263; J. Gaedeke et al., Expert Opin. Pharmacother. 7 (2006), 377; B. Pilz et al., Hypertension 46 (2005), 569).

A large number of peptide and peptide-mileticova inhibitors of human renin with different stable analogues in transition fissile peptide bond developed around 1980, and they contributed to the recognition of renin as a therapeutic target (see, for example, B. B. Scott et al., Curr. Protein Pept. Sci. 7 (2006), 241; J. Maibaum et al., Expert Opin. Ther. Patents 13 (2003), 589). However, these compounds generally have disadvantages, such as poor bioavailability (see, H. D. Kleinert, Cardiovasc. Drugs Therapy 9 (1985), 645) or duration of action, or the high cost of obtaining. Recently appeared in the sale of orally active renin inhibitor, aliskiren (see Drugs Fut. 26 (2001), 1139; J. Wood et al., J. Hypertens. 23 (2005), 417; M. Azizi et al., J. Hypertens. 24 (2006), 243). But the profile of properties of aliskiren is not yet perfect, for example, with regard to oral bioavailability, and a particular lack of aliskiren is its complex molecular structure with four chiral centers and multi-stage synthesis. Thus, there is a need for new ones, the small size of the renin inhibitors, which have suitable properties, for example, with regard to oral bioavailability, or have a simple structure and are easy to synthesize. The present invention satisfies this need by providing a renin-inhibiting cyclic azaindole-3-carboxamido formula I.

Various azaindole derivatives already described. For example, in WO 01/62255 describe antivirus azaindole derivatives suitable for the treatment of human immunodeficiency virus 1, which contain in the 3-position azaindole ring carboxamido or glycylamino group, in which the amide nitrogen atom is a ring member of piperazinone molecule, which carries the second ring nitrogen atom benzoyloxy group, pyridine-2-carbonyl, furan-2-carbonyl group or thiophene-2-carbonyl group, and which optional, you can substitute in the 2-position azaindole number is CA Deputy for example, such as saturated or unsaturated alkyl or cycloalkyl. In EP 1452525 describe isoindoline derivatives, which, among other things, may contain in the 3-position azaindole ring carboxamido group, in which the amide nitrogen atom is a ring member diazoalkane, which is the second ring nitrogen atom of the pyridine, pyrazinone, pyridazinone or pyrimidine group, which are inhibitors of the transforming growth factor β (TGF-β), suitable for the treatment of, for example, fibroproliferative diseases. WO 2005/121175 refers to CD4 mimetic compounds which form a complex with envelope proteins of human immunodeficiency virus and are suitable for inducing an immune response, in General they include isoindoline derivatives, which may contain carboxamido group, the amide nitrogen atom which is part of the ring. In the US 2005/0054631 describe certain azaindole derivatives that contain the amino group in 2-position isoindoline rings and which are inhibitors of the polymerase poly(adenosine 5'-diphosphoribose) (PARP), suitable for the treatment of various diseases, including diseases associated with the Central nervous system, and cardiovascular disease. WO 93/20078, which refers to the bicyclic heterocycles suitable for treatment the various diseases, such as a head injury, subarachnoid hemorrhage, or asthma, usually include, among other things, azaindole, which replaces the two aminosalicylate. Azaindole-3-carboxamide of the present invention, in which the amide nitrogen atom is a ring member of a 1,4 - or 1,5-diazacyclooctadecane ring system, the nitrogen atom in position 1 azaindole ring system is a cyclic group, and the carbon atom in position 2 azaindole ring system is (hetero)aromatic group, yet to be described.

Thus, an object of the present invention are the compounds of formula I in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically acceptable solvate of any of them:

,

in which

A is chosen from O, S, N((C1-C4)-alkyl) and C(Ra)2;

Raselected from hydrogen, fluorine and (C1-C4)-alkyl, where two groups Raare independent from each other and can be identical or different, or two groups Ratogether represent divalent (C2-C8)-alkyl group;

R is chosen from hydrogen, fluorine, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl which is, phenyl-(C1-C4)-alkyl-, heteroaryl-(C1-C4)-alkyl, (C1-C4)-alkyl-O-CO-CuH2u-, R1-NH-CO-CuH2uand (C1-C4)-alkyl-O-, where all groups R are independent of each other and can be identical or different;

R1selected from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl -, and H2N-CO-(C1-C4)-alkyl-;

R10selected from hydrogen, (C1-C6)-alkyl-O-CO - (C3-C7-cycloalkyl-CvH2v-O-CO-;

R20selected from phenyl and heteroaryl that are not necessarily replace one or more identical or different substituents selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-S(O)m-, hydroxy and cyano;

R30choose from a (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl, tetrahydropyranyl, phenyl and heteroaryl where cycloalkyl and cycloalkenyl optionally substituted by one or more identical or different substituents chosen from fluorine, (C1-C4)-alkyl and hydroxy, and phenyl and heteroaryl optionally substituted by one or more identical or different substituents selected from halogen, (C1-C6)-alkyl, (C3-C7-cycloalkyl-CvH2v-, hydroxy-(C -C6)-alkyl, (C1-C4)-alkyl-O-(C1-C6)-alkyl, (C3-C7-cycloalkyl-CvH2v-O-(C1-C6)-alkyl, (C1-C4)-alkyl-CO-NH-(C1-C6)-alkyl, hydroxy, (C1-C6)-alkyl-O-, (C3-C7-cycloalkyl-CvH2v-O-, hydroxy-(C1-C6)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C6)-alkyl-O-, (C3-C7-cycloalkyl-CvH2V-O-(C1-C6)-alkyl-O-, (C1-C4)-alkyl-CO-NH-(C1-C6)-alkyl-O-, (C1-C6)-alkyl-S(O)mand cyano;

R40selected from halogen, (C1-C4)-alkyl, (C3-C7-cycloalkyl-CvH2v-, phenyl-(C1-C4)-alkyl-, heteroaryl-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl, (C3-C7-cycloalkyl-CvH2V-O-(C1-C4)-alkyl-, phenyl-O-(C1-C4)-alkyl-, heteroaryl-O-(C1-C4)-alkyl-, di((C1-C4)-alkyl)N-(C1-C4)-alkyl-, HO-CO-(C1-C4)-alkyl, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-, H2N-CO-(C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-, (C3-C7-cycloalkyl-CvH2v-O-, phenyl-(C1-C4)-alkyl-O-, heteroaryl-(C1-C4)-alkyl-O-, hydroxy-C 1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, (C3-C7-cycloalkyl-CvH2v-O-(C1-C4)-alkyl-O-, phenyl-O-(C1-C4)-alkyl-O-, heteroaryl-O-(C1-C4)-alkyl-O-, di((C1-C4)-alkyl)N-(C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, H2N-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-CO-O-, (C3-C7-cycloalkyl-CvH2v-CO-O-, (C1-C4)-alkyl-NH-CO-O-, (C3-C7-cycloalkyl-CvH2v-NH-CO-O-, (C1-C4)-alkyl-S(O)m-, nitro, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkyl-CO-NH-, (C3-C7-cycloalkyl-CvH2v-CO-NH-, (C1-C4)-alkyl-S(O)2-NH-, HO-CO-, (C1-C4)-alkyl-O-CO-, H2N-CO-, ((C1-C4)-alkyl)-NH-CO-, di((C1-C4)-alkyl)N-CO-, cyano, HO-S(O)2-, H2N-S(O)2-, ((C1-C4)-alkyl)-NH-S(O)2- and di((C1-C4)-alkyl)N-S(O)2-where all substituents R40are independent from each other and can be identical or different;

one of the groups Y1, Y2, Y3and Y4represents N and the others are the same or different groups CH or CR40;

heteroaryl is particularly the aromatic monocyclic, 5-membered or 6-membered heterocyclic group which contains 1, 2 or 3 identical or different ring heteroatoms selected from N, O and S, where one of the ring nitrogen atoms can carry a hydrogen atom or a (C1-C4)-alkyl group, and where the heteroaryl group attached via a ring carbon atom;

m is chosen from 0, 1 and 2, where all values of m are independent from each other and can be identical or different;

n is chosen from 0, 1, 2, and 3;

p and q, which are independent from each other and can be identical or different, chosen from 2 and 3;

u is chosen from 0, 1 and 2, where all values of u are independent of each other and can be identical or different;

v is chosen from 0, 1 and 2, where all values v are independent of each other and can be identical or different;

where all alkyl groups, independently of each other, optionally substituted one or more fluorine atoms;

where all cycloalkyl groups, independently of each other, optionally substituted one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl, unless otherwise specified;

where all phenyl and heteroaryl groups present in R and R40independently from each other, optionally substituted one or more identical or different Zam is a Fort worth, selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-S(O)2and cyano.

If structural elements such as groups, substituents or value may occur more than once in the compounds of the formula I, they are all independent of each other and can in each case be any of these values, and can in each case be identical or different from any other given element.

Alkyl groups, saturated hydrocarbon residues, can be a normal chain (linear) or branched. This also applies if these groups are substituted, or if they are part of another group, for example, alkyl-O-group (alkyloxy group, alkoxy group or alkyl-S(O)m-group. Depending on the definition, the number of carbon atoms in the alkyl group may be 1, 2, 3, 4, 5, 6, 7 or 8. Examples of alkyl are methyl, ethyl, propyl, including n-propyl and isopropyl, butyl, including n-butyl, sec-butyl, isobutyl and tert-butyl, pentyl, including n-pentyl, 1-methylbutyl, isopentyl, neopentyl and tert-pentyl, hexyl, including n-hexyl, 3,3-dimethylbutyl and isohexyl, heptyl, including n-heptyl, and octyl, including n-octyl. Examples of the alkyl-O - are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and n-pentox. Examples of lcil-S(O) m- are methanesulfonyl- (CH3-S-, methylsulfonyl-), methanesulfonyl- (CH3-S(O)-), methanesulfonyl- (CH3-S(O)2-), econsultancy- (CH3-CH2-S-, ethylsulfanyl-), econsulting- (CH3-CH2-S(O)-), econsultancy- (CH3-CH2-S(O)2-), 1-methylaminoethanol- ((CH3)2CH-S-, 1-methylaminoethanol-), 1-methylaminomethyl- ((CH3)2CH-S(O)-) and 1-methylaminomethyl-((CH3)2CH-S(O)2-). In one embodiment of the present invention, the value of m is chosen from 0 and 2, where all values of m are independent from each other and can be identical or different.

Substituted alkyl group can be a substitute for any provisions, provided that the resulting compound is sufficiently stable and is suitable as pharmaceutically active compounds. Prerequisite to a specific group, and the compound of formula I has been quite stable and was suitable as pharmaceutically active compounds usually applied with respect to all groups in the compounds of formula I. If the alkyl group can be monogamistic or polysemantic fluorine, it is possible not to replace, i.e. it shall not be fluorine atoms, or substitute, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 fluorine atoms, preferably 1, 2, 3, 4 or 5 fluorine atoms, which can PR is to attend in any the provisions. For example, a fluorine-substituted alkyl group one or more methyl groups can carry three fluorine atom, each may be present in the form of triptoreline groups, and/or one or more methylene group (CH2can carry two fluorine atom each and be present in the form of deformationof groups. Explanations regarding the substitution group fluorine is also applicable if the group additionally carries other substituents and/or is part of another group, for example, alkyl-O-group. Examples of the fluorine-substituted alkyl groups are trifluoromethyl, 2-foretel, 1,1-dottorati, 2,2,2-triptorelin, pentafluoroethyl, 3,3,3-cryptochromes, 2,2,3,3,3-pentafluoropropyl, 4,4,4-triptorelin and heptafluoroisopropyl. Examples of the fluorine-substituted alkyl-O-groups are triptoreline, 2,2,2-triptoreline, pentaborate and 3,3,3-cryptocracy. Examples of the fluorine-substituted alkyl-S(O)mgroups are trifloromethyl- (CF3-S-, trifloromethyl-), trifloromethyl- (CF3-S(O)-) and trifloromethyl- (CF3-S(O)2-).

If possible, the above explanation alkyl groups apply correspondingly to divalent alkyl groups (elendilmir groups), including divalent alkyl group, a CuH2uand CvH2vwhere groups can also be alkyl part Zam is on the alkyl group. Thus, divalent alkyl groups, including divalent alkyl group, a CuH2uand CvH2vcan also be a normal chain or branched, neighboring groups may be located in any positions and can start with a single carbon atom or from different carbon atoms, and may be replaced by fluorine. Examples divalent alkyl groups are-CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -C(CH3)2-CH2- and-CH2-C(CH3)2-. Examples of the fluorine-substituted divalent alkyl groups which may contain 1 to 2, 3, 4, 5 or 6 fluorine atoms, for example, are-CHF-, -CF2-, -CF2-CH2-, -CH2-CF2-, -CF2-CF2-, -CF(CH3)-, -C(CF3)2-, -C(CH3)2-CF2- and-CF2-C(CH3)2-. If the value of u in divalent alkyl group, a CuH2uor the value v in divalent alkyl group, a CvH2v0 (zero), the two neighboring groups that are attached to this group are directly connected to each other by a single bond. For example, the SSI group, R 40is a group (C3-C7-cycloalkyl-CvH2v-where the group is connected with the remainder of the molecule via CvH2vthe group, as symbolically shown by a line on the end (hyphen) after CvH2vgroups representing the free bond, and the value v it is 0, (C3-C7)-cycloalkyl group linked directly via a single bond to the carbon atom which carries the group R40. In one embodiment of the present invention, the value v is chosen from 0 and 1, where all values v are independent of each other and can be identical or different.

The number of ring carbon atoms in cycloalkyl group may be 3, 4, 5, 6 or 7. The number of ring carbon atoms in cycloalkenyl group may be 5, 6 or 7. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, examples cycloalkenyl are cyclopentenyl, cyclohexenyl and cycloheptenyl. The double bond in cycloalkenyl group may be present in any position relative to the carbon atom in position 1, through which the group is connected with azaindole group, and, thus, cycloalkenyl may, for example, be a cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex the-3-enyl, cyclohepta-1-enyl, cyclohepta-2-enyl, cyclohepta-3-enyl, cyclohepta-4-enyl. In preferred embodiments, the implementation of the present invention cycloalkyl group, such as (C3-C7-cycloalkyl, in the definition of any group selected from subgroups of any two or more of these specific cycloalkyl groups, for example, from cyclopropyl and cyclobutyl, or from cyclopropyl, cyclobutyl and cyclopentyl, or from cyclopropyl, cyclopentyl and cyclohexyl, or from cyclopentyl and cyclohexyl, or from cyclopentyl, cyclohexyl and cycloheptyl. Similarly, in preferred embodiments, the implementation cycloalkenyl group selected from subgroups of any two or more of these specific cycloalkenyl groups, for example, from cyclopentenyl and cyclohexenyl, or cyclohexenyl and cycloheptenyl, or cyclopent-1-Anila, cyclopent-2-Anila, cyclohex-1-Anila, cyclohex-2-Anila, cyclohepta-1-Anila and cyclohepta-2-Anila, or from cyclopent-2-Anila, cyclopent-3-Anila, cyclohex-2-Anila, cyclohex-3-Anila, cyclohepta-2-Anila, cyclohepta-3-Anila and cyclohepta-4-Anila, or from cyclopent-2-Anila and cyclohex-2-Anila, or from cyclopent-2-Anila, cyclohex-2-Anila and cyclohepta-2-Anila. In one embodiment of the present invention, the carbon atom through which cycloalkenyl group representing R30connected with and is indolinyl ring, is not part of a double bond, i.e. cycloalkenyl group is not cyclol-1-Tilney group. Cycloalkyl group and cycloalkenyl groups are usually not necessarily replace one or more (C1-C4)-alkyl substituents. I.e. they do not replace, i.e. they do not bear alkyl substituents, or substituted, for example, 1, 2, 3 or 4 identical or different (C1-C4)-alkyl substituents, for example, methyl groups and/or ethyl groups and/or ISO-propyl groups and/or tert-utilname groups, especially methyl groups, where the substituents can be present in any positions. Examples of alkyl-substituted cycloalkyl groups are 1-methylcyclopropyl, 2,2-dimethylcyclopropane, 1-methylcyclopentene, 2,3-dimethylcyclobutyl, 1-methylcyclohexyl, 4-methylcyclohexyl, 4-isopropylcyclohexane, 4-tert-butylcyclohexyl and 3,3,5,5-tetramethylsilane. Examples of alkyl-substituted cycloalkenyl groups are 1-methylcyclopentene-2-enyl, 2-Methylcyclopentane-2-enyl, 3-methylcyclopentene-2-enyl, 3,4-dimethylthiophene-3-enyl, 1-methylcyclohex-2-enyl, 2-methylcyclohex-2-enyl, 3-methylcyclohex-2-enyl, 4-methylcyclohex-2-enyl, 2-methylcyclohex-3-enyl, 3-methylcyclohex-3-enyl, 4-methylcyclohex-3-enyl, 2,3-dimethylcyclohex-2-enyl, 4,4-dimethylcyclohex-2-enyl, 3,4-dimethylcyclohex-3-enyl. Cycloalkyl group and cloonkeelane groups are also optionally substituted by one or more fluorine atoms. I.e. they do not replace, i.e. they do not bear the fluorine atoms, or substituted, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 fluorine atoms, preferably 1, 2, 3, 4, 5 or 6 fluorine atoms. Cycloalkyl group and cycloalkenyl group also replace both fluorine and alkyl. The fluorine atoms may be present in any positions and may also be present in the alkyl substituent. Examples of the fluorine-substituted cycloalkyl groups are 1-forciblepoppy, 2,2-divorcecare, 3,3-diversilobum, 1-forcelogix, 4,4-diverticulosis and 3,3,4,4,5,5-hexaferrites. Examples of the fluorine-substituted cycloalkenyl groups are 1-forticlient-2-enyl, 1-forcelogix-2-enyl, 4-forcelogix-2-enyl, 4,4-diverticulosis-2-enyl. In one embodiment, the present invention cycloalkyl do not not replace substituents selected from fluorine and (C1-C4)-alkyl. If cycloalkyl group or cycloalkenyl group, you can substitute additional substituents, such hydroxy, as in the case of cycloalkyl group or cycloalkenyl group representing R30they can replace one or more of these additional substituents, such only hydroxy, and cannot substituents selected from fluorine and (C1-C4)-alkyl, or one or more additional data mandated what teli and simultaneously one or more substituents, selected from fluorine and (C1-C4)-alkyl. The number of these additional substituents, such hydroxy, which may be present in cycloalkenes or cycloalkenyl group, preferably equal to 1, 2 or 3, more preferably 1 or 2, for example, 1. The total number of all deputies in cycloalkyl group or cycloalkenyl group preferably equal to 1, 2, 3, 4, 5, 6, 7 or 8, more preferably 1, 2, 3, 4, or 5, e.g. 1, 2 or 3. These additional substituents, such hydroxy, may be present in any positions, provided that the resulting compound is sufficiently stable and is suitable as a subgroup in a pharmaceutically active compound. Preferably hydroxy Deputy is not present in position 1 cycloalkenyl group or cycloalkyl group representing R30and cycloalkenyl hydroxy group Deputy is not present at the carbon atom that is part of a double bond. Examples of hydroxy-substituted cycloalkyl groups are 3-hydroxycinnamates, 2-hydroxycyclopent, 3-hydroxycyclopent, 3,4-dihydrocyclopenta, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 2,3-dihydroxytoluene, 2,4-dihydroxytoluene, 3,4-dihydroxytoluene, 3,5-dihydroxytoluene 3,4,5 - trihydroxystilbene, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl. Examples of hydroxy-substituted cycloalkenyl groups are 5-hydroxycyclopent-2-enyl, 4-hydroxycyclopent-2-enyl, 5-hydroxycyclopent-2-enyl, 6-hydroxycyclopent-2-enyl, 6-hydroxycyclopent-3-enyl. Examples of the group cycloalkenyl-that can be present in the group (C3-C7-cycloalkyl-CvH2v-are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl-, 1-cyclopropylethyl-, 2-cyclopropylethyl-, 1-cyclobutylmethyl-, 2-cyclobutylmethyl-, 1-cyclopentylmethyl-, 2-cyclopentylmethyl-, 1-cyclohexylethyl-, 2-cyclohexylethyl-, 1-cycloheptylmethyl-, 2-cycloheptylmethyl-.

Tetrahydropyranyl group representing R30where the group can also be defined as ossanlou group or a tetrahydro-2H-pyranyloxy group, can be connected through any carbon atom, and may represent tetrahydropyran-2-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl. Preferably tetrahydropyranyl is tetrahydropyran-3-yl or tetrahydropyran-4-yl. In one embodiment, the present invention tetrahydropyranyl is tetrahed operan-4-yl.

In the substituted phenyl groups, the substituents can be present in any positions. In monosubstituted phenyl groups Deputy may be present in the 2-position, 3-position or 4-position. In disubstituted phenyl groups, the substituents can be present in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisemester phenyl groups, the substituents can be present in the 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position. If the phenyl group carries four Vice, of which one, two, three or four deputies, for example, can be fluorine atoms, unsubstituted ring carbon atom may be present in the 2-position, 3-position or 4-position. If polyamidine phenyl group or heteroaryl group carries different substituents, each Deputy may be present in any suitable position, and the present invention includes all isomers of the situation. The number of substituents in the substituted phenyl group can be 1, 2, 3, 4 or 5. Preferably a substituted phenyl group, and similarly substituted heteroaryl group bears 1, 2 or 3, especially 1 or 2, identical or different substituent. In preferred embodiments, the implementation of the present invention, the substituents in the Zam is on the phenyl and heteroaryl groups are selected from any subset of substituents, listed in this definition, for example, substituents selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O - (C1-C4)-alkyl-S(O)m-, or halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O - and cyano, or halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O-, in the case of a phenyl group or heteroaryl group representing R20where all alkyl groups can not replace or substitute one or more fluorine atoms, and as examples of the substituents containing fluorine-substituted alkyl, the substituents containing a group of CF3(trifluoromethyl)such as CF3, CF3-O -, or-CF3-S-, can be included in each list of substituents in addition to the substituents containing unsubstituted alkyl.

In the heteroaryl group which is a residue of an aromatic monocyclic, 5-membered or 6-membered heterocyclic ring system, the ring heteroatoms provided in the definition of this group can be present in any combination and may be present in any suitable position, provided that the group meets its definition, and the resulting compound of formula I is stable and suitable as pharmaceutically active compounds. One of the ring atomo is nitrogen, specifically mentioned in the definition of heteroaryl group, which may carry a hydrogen atom or a Deputy, such as alkyl, represents a ring nitrogen atom in the 5-membered ring system, such as pyrrole, pyrazole, imidazole or triazole, attached ekzoticeski atom or group. Examples of ring systems, which are heteroaryl group, are pyrrole, furan, thiophene, imidazole, pyrazole, triazole, such as [1,2,3]triazole and [1,2,4]triazole, oxazole ([1,3]oxazol)isoxazol ([1,2]oxazole), thiazole ([1,3]thiazole), isothiazol ([1,2]thiazole), oxadiazole, such as [1,2,4]oxadiazole, [1,3,4]oxadiazol and [1,2,5]oxadiazol, thiadiazole, such as [1,3,4]thiadiazole, pyridine, pyridazine, pyrimidine piratin, triazine, such as [1,2,3]triazine, [1,2,4]triazine and [1,3,5]triazine. In one embodiment, the present invention heteroaryl group contains one or two identical or different ring heteroatoms, in another embodiment, the present invention heteroaryl contains a single ring heteroatom, which is determined, as shown. In another embodiment, heteroaryl choose from thiophenyl, thiazolyl and pyridinyl. In another embodiment, heteroaryl choose from thiophenyl and pyridinyl. In another embodiment, heteroaryl is thiophenyl. Heteroaryl the groups can be attached via any ring carbon atom. For example, teofilina group (thienyl group) can be a thiophene-2-yl (2-thienyl) or thiophene-3-yl (3-thienyl), furanyl may be a furan-2-yl or furan-3-yl, pyridinyl (pyridyl) can be a pyridine-2-yl, pyridin-3-yl or pyridin-4-yl, pyrazolyl may constitute 1H-pyrazole-3-yl, 1H-pyrazole-4-yl or 2H-pyrazole-3-silt, imidazolyl can be a 1H-imidazol-2-yl, 1H-imidazol-4-yl or 3H-imidazolyl-4-yl, thiazolyl can be a thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, [1,2,4]triazolyl can be a 1H-[1,2,4]triazole-3-yl, 2H-[1,2,4]triazole-3-yl or 4H-[1,2,4]triazole-3-yl.

In the substituted heteroaryl groups in the substituents can be present in any positions, for example, thiophene-2-ilen group or furan-2-ilen group in 3-position and/or 4-position and/or 5-position, thiophene-3-ilen group or furan-3-ilen group in the 2-position and/or 4-position and/or 5-position in the pyridine-2-ilen group in 3-position and/or 4-position and/or in the 5-position and/or 6-position in the pyridine-3-ilen group in the 2-position and/or 4-position and/or 5-position and/or 6-position in the pyridine-4-ilen group in the 2-position and/or 3-position and/or 5-position and/or 6-position. Preferably the substituted heteroaryl group is substituted one, two or three, especially one or two,for example, one, same or different substituents. If there is a ring nitrogen atom, which may carry a hydrogen atom or a Deputy, the Deputy when this nitrogen atom may represent, for example, methyl group, ethyl group, through group or tert-boutelou group, and groups can also monogamistic or polysemantic fluorine. Usually suitable ring nitrogen atoms in the aromatic ring heteroaryl group, for example, the nitrogen atom in pyridinoline group or a nitrogen atom in [1,2,5]oxadiazolyl group and the ring nitrogen atom in the 6-membered ring azaindole group may also be oxido Deputy-O-and the compounds of formula I, thus, may be present in the form of N-oxide.

Halogen represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, in particular fluorine or chlorine.

The present invention includes all stereoisomeric forms of the compounds of the formula I, for example, all possible enantiomers and diastereoisomers, including CIS/TRANS isomers. The present invention also includes a mixture of two or more stereoisomeric forms, for example, mixtures of enantiomers and/or diastereomers, including CIS/TRANS isomers in any ratio. Asymmetric centers contained in the compounds of the formula I, for example, unsubstituted or substituted alkyl group is or diazacyclooctadecane ring, depicted in formula I, can all independently of one another have the S-configuration or R-configuration. The present invention relates to enantiomers, and to levogyrate and programada the antipode, in enantiomerically pure form and virtually enantiomerically pure form and in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. The present invention also relates to the diastereomers in the form of pure and nearly pure diastereomers or in the form of mixtures of two or more diastereomers, in all ratios. The present invention also includes all CIS/TRANS isomers of compounds of formula I in pure form and in practically pure form and in the form of mixtures of the CIS isomer and the TRANS isomer in all relationships. CIS/TRANS isomerism may occur, for example, substituted cycloalkane rings and diazacyclooctadecane the ring depicted in formula I. Obtaining the individual stereoisomers, if desired, can be carried out by separation of the mixture according to conventional methods, e.g. by chromatography or crystallization, or by applying a uniform stereochemical starting compounds in the synthesis or stereoselective reactions. Not necessarily, before the separation of stereoisomers are possible derivatization. Separation of a mixture of stereoisomers can be done at the stage of the compounds of formula I or to study the intermediate compounds in the synthesis process. The present invention also includes all tautomeric forms of compounds of formula I.

Physiologically acceptable salts of the compounds of formula I are in particular salts with non-toxic salt components, and preferably they are pharmaceutically usable salts. They may contain inorganic or organic salt components. These salts can be obtained, for example, from compounds of the formula I which contain an acid group, for example, carboxyl group (HO-CO-) or a sulfonic group (HO-S(O)2-), and non-toxic inorganic or organic bases. Suitable bases are, for example, compounds of alkali metals or compounds of alkaline earth metals such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate, or ammonium, organic amino compounds and Quaternary ammonium hydroxides. The reaction of compounds of formula I with bases to obtain the salts are usually carried out according to standard techniques in the solvent or diluent. On the basis of physiological and chemical stability of the preferred salts of acid groups are, in many cases, sodium, potassium, magnesium or calcium salts, or ammonium salts, which may also bear one or more organic groups at the atom and the PTA. The compounds of formula I which contain a basic group, i.e. a group capable of protonemata, for example, an amino group, diazacyclooctadecane group depicted in formula I, when R10represents a hydrogen or other basic heterocycle, such as 6-membered ring in azaindole group may be present in the form of their salts accession acid with physiologically acceptable acids, for example, in the form of a salt with chloroethanol acid, Hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, benzoic acid, methanesulfonic acid, p-toluensulfonate acid, which is usually derived from compounds of the formula I by reaction with an acid in a solvent or diluent according to conventional methods. As is customary, particularly in the case of salts accession acid compounds containing two or more basic groups, the salts, the ratio of salt components may deviate more or less than the stoichiometric ratio, such as a molar ratio of 1:1 or 1:2, in the case of salt accession acid compounds of formula I containing one or two main groups with monovalent acid, and varies depending on the applied conditions. The present invention also includes salts containing components when nestehiometrical the count value, and indicating that the salt accession acid compounds of the formula I contains an acid in a twofold molar ratio, for example, is also applicable to a smaller or greater amount of acid in the obtained salts, for example, about 1.8 or about 2.1 mol of acid per mol of compound of formula I. If the compounds of formula I simultaneously contain acidic and basic group in the molecule, the present invention also includes an inner salt (betaine, zwitterionic) in addition to the aforementioned salt forms. The present invention also includes all salts of the compounds of the formula I which, owing to low physiological tolerance, not suitable directly for use as a pharmaceutical product, but are suitable as intermediates for chemical reactions or to obtain physiologically acceptable salts, for example, by anion exchange or cation exchange. The object of the present invention are also solvate of the compounds of formula I and their salts, such as hydrates and adducts with alcohols, such (C1-C4)-alkanols, in particular physiologically acceptable solvate, as well as active metabolites of compounds of formula I and prodrugs of the compounds of formula I, i.e. compounds which in vitro may not necessarily possess pharmacological activity is, but which in vivo are converted into pharmacologically active compounds of the formula I, for example, compounds which are converted in the metabolic hydrolysis of compounds of formula I. Examples of these prodrugs are compounds in which the nitrogen atom, which can be allievate, for example, the nitrogen atom carrying the group R10in diazacyclooctadecane group depicted in formula I, when R10represents hydrogen, a is alkyl-O-CO-group or acyl group, such as alkyl-CO-group, for example, and thus converted into a urethane group or amide group, or compounds in which the carboxyl group is etherification.

The group A is preferably selected from O, S, NCH3and C(Ra)2more preferably from O, S and C(Ra)2especially preferably from O and C(Ra)2. In one embodiment of the present invention to A group chosen from O and S. In another embodiment of the present invention, the group A represents O, in another embodiment, the group A represents C(Ra)2.

If two groups of Ratogether represent divalent (C2-C8)-alkyl group, the aforementioned alkyl group is preferably combined with the carbon atom carrying the group Ratwo different carbon atoms, and she's education is the duty to regulate, together with the carbon atom, carrying the group Ra, cycloalkane ring, which is connected to isoindoline ring depicted in formula I, and R20connected in the same position in the ring. Mentioned cycloalkane ring, such cycloalkanones ring in the compounds of formula I in General, can carry one or more (C1-C4)-alkyl groups, for example one, two, three or four methyl groups, and/or one or more, e.g. one, two, three or four atoms of fluorine. Preferably mentioned cycloalkane ring is cyclopropenone, CYCLOBUTANE, cyclopentane or cyclohexane ring, which all can be not to replace or be replaced by alkyl and/or fluorine, as shown. In one embodiment of the present invention mentioned cycloalkane ring is cyclopropane ring, which can not replace or be replaced by alkyl and/or fluorine, as shown, i.e. in this embodiment, dimalanta (C2-C8)-alkyl group represents ethane-1,2-dialnow group (1,2-ethylene group which is not substituted or is substituted by alkyl and/or fluorine, as shown. Preferably dimalanta (C2-C8)-alkyl group represents a (C2-C5)-alkyl group, more preferably a (C2-C4)-alkyl group, for example, C2-alkyl the second group. In one embodiment of the present invention the group Raselected from hydrogen and fluorine, in another embodiment from hydrogen and (C1-C4)-alkyl, where two groups Raare independent from each other and can be identical or different, or in all these cases the implementation of the two groups Ratogether represent divalent (C2-C8)-alkyl group. In one embodiment of the present invention the group Raare the same or different groups selected from hydrogen and fluorine, in another embodiment, they are the same or different groups selected from hydrogen and (C1-C4)-alkyl. In another embodiment of the present invention the group Raare the same and are selected from hydrogen, fluorine and (C1-C4)-alkyl, or two groups Ratogether represent divalent (C2-C8)-alkyl group. In another embodiment of the present invention, both groups Rarepresent hydrogen, or two groups Ratogether represent divalent (C2-C8)-alkyl group. In the following embodiment of the present invention, both groups Rarepresent hydrogen, i.e. the group C(Ra)2predstavljaju A, represents a group CH2. (C1-C4)-alkyl group representing Rapreferably represents methyl.

In diazacyclooctadecane group depicted in formula I, preferably one, two, three or four, more preferably one, two or three, particularly preferably one or two, for example, one of the groups R, which are independent from each other and can be identical or different, determined as shown above or below, and select from all values included by the definition, including hydrogen and all other groups R are hydrogen. In one embodiment of the present invention all groups R are hydrogen, and diazacyclooctadecane group depicted in formula I, is a pieperazinove ring, homopiperazine ring or 1.5-diisocyanate ring, especially pieperazinove ring, which is the group of R10but that does not replace the substituents on ring carbon atoms. The groups R, which are different from hydrogen, can be present in any positions diazacyclooctadecane group, provided that the resulting compound of formula I is stable and suitable as a subgroup in a pharmaceutically active compound. In one embodiment of the present invention (C1 -C4)-alkyl-O-group, R represents, not bound to atoms of carbon in diazacyclooctadecane the ring depicted in formula I which are adjacent to the ring nitrogen atom. Preferably only one or two, for example, only one of the groups R is a (C1-C4)-alkyl-O-.

In one embodiment of the present invention the group R is chosen from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, phenyl-(C1-C4)-alkyl, (C1-C4)-alkyl-O-CO-CuH2uand R1-NH-CO-CuH2u-, in another embodiment from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl-, phenyl-(C1-C4)-alkyl and R1-NH-CO-CuH2u-, in another embodiment from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl and R1-NH-CO-CuH2u-, in another embodiment from hydrogen, (C1-C4)-alkyl and hydroxy-(C1-C4)-alkyl-, in another embodiment from hydrogen, (C1-C4)-alkyl, and R1-NH-CO-CuH2U-, in another embodiment from hydrogen and (C1-C4)-alkyl, in another embodiment from hydrogen and R1-NH-CO-CuH2u-where all the groups R are not avasimibe from each other and can be identical or different, and phenyl optionally substituted, as shown. In one embodiment of the present invention one of the groups R are selected from (C1-C4)-alkyl-O-CO-CuH2uand R1-NH-CO-CuH2uand in particular it is an R1-NH-CO-CuH2U-and all other groups R are hydrogen. The groups R, which are different from hydrogen, can be connected with any of the ring carbon atoms in diazacyclooctadecane the ring depicted in formula I. In the case when there are two or more groups R, which are different from hydrogen, the ring carbon atom may bear either one or two data groups R, which are different from hydrogen. When diazacyclooctadecane ring depicted in formula I, is a pieperazinove ring, bearing one group R, which is different from hydrogen, the group R may be present in the 2-position or 3-position to the ring nitrogen atom that is linked to the CO group depicted in formula I. In the case when diazacyclooctadecane ring depicted in formula I, is a pieperazinove ring, bearing two groups R, which are different from hydrogen, both of these groups R may be present in the 2-position, or both, may be present in 3-position, or both is present in positions 2 and 3, or in positions 2 and 5, or in positions 2 and 6, or in positions 3 and 5, relative to the ring nitrogen atom that is linked to the CO group depicted in formula I, where in the case of two different R groups, each of them may be present at each position. In one embodiment of the present invention, the value of u is chosen from 0 and 1, in another embodiment, u is chosen from 1 and 2, in another embodiment, u is 0, in another embodiment, u is 1, in another embodiment, u is 2, where all values of u are independent of each other and can be identical or different.

In one embodiment of the present invention R1choose from a (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl -, and H2N-CO-(C1-C4)-alkyl-, in another embodiment from (C1-C4)-alkyl and hydroxy-(C1-C4)-alkyl-, in another embodiment from (C1-C4)-alkyl and H2N-CO-(C1-C4)-alkyl. In one embodiment of the present invention R1represents hydrogen, in another embodiment, R1is a (C1-C4)-alkyl, in another embodiment, R1represents a hydroxy-(C1-C4)-alkyl-, in another embodiment, R1is the th H 2N-CO-(C1-C4)-alkyl-.

R10preferably selected from hydrogen and (C1-C6)-alkyl-O-CO-, more preferably from hydrogen and (C1-C4)-alkyl-O-CO-. In one embodiment of the present invention R10represents hydrogen.

In one embodiment of the present invention R20selected from phenyl and heteroaryl where heteroaryl choose from thiophenyl, thiazolyl and pyridinyl, in another embodiment from phenyl and heteroaryl where heteroaryl is thiophenyl, all of which are optionally substituted, as shown. In another embodiment, the present invention R20represents phenyl which is optionally substituted by one or more identical or different substituents selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-S(O)m-, hydroxy and cyano. Preferably the number of substituents in the substituted group R20equal to one, two, three or four, more preferably one, two or three, for example, one or two. The substituents in the substituted group R20may be present at the carbon atoms in any positions, as shown above, relative to the substituted phenyl and heteroaryl groups in General. Thus, for example, in the case of mannose is esenkoy phenyl group, representing R20the Deputy may be present in the 2-position, 3-position or 4-position, and in the case of a disubstituted phenyl group, the substituents may be present at positions 2 and 3, or positions 2 and 4 or positions 2 and 5, or positions 2 and 6, or positions 3 and 4 or positions 3 and 5. Also tizamidine phenyl group representing R20may bear substituents at any positions and may be a group such as 3-chloro-2,6-dimetilfenil, 3-fluoro-2,6-dimetilfenil, 6-chloro-3-fluoro-2-were-or 2-chloro-3-fluoro-6-were, for example, in the case of a phenyl group, tizamidine fluorine and/or chlorine and stands. The substituents that may be present in the group R20preferably selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-S(O)mand cyano, more preferably from halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O - (C1-C4)-alkyl-S(O)m-, particularly preferably from halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O-, more preferably from halogen and (C1-C4)-alkyl, for example, from chlorine, fluorine and methyl, where in one embodiment of the present invention the alkyl group in the substituents in the group R20you can not replace or substitute one or more fluorine atoms and, as the second example of the substituents, containing fluorine-substituted alkyl, the substituents containing triptorelin group, such as CF3, CF3-O -, or-CF3-S-, can be included in each list of substituents in addition to the substituents containing unsubstituted alkyl, and in another embodiment of the present invention the alkyl groups in the substituents in the group R20do not replace fluorine and in this last embodiment, the above-mentioned alkyl, therefore, denotes unsubstituted alkyl. Specific groups in addition to the above specific groups, which can represent a group of R20and from whom, or from any of the subgroups, we can choose R20in the compounds of formula I include, for example, phenyl, i.e. unsubstituted phenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-were (o-tolyl), 3-were (m-tolyl), 4-were (p-tolyl), 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-differenl, 2,4-differenl, 2,5-differenl, 2,6-differenl, 3,4-differenl, 3,5-differenl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-3-forfinal, 2-chloro-4-forfinal, 2-chloro-5-forfinal, 2-chloro-6-forfinal, 3-chloro-2-forfinal, 3-chloro-4-forfinal, 3-chloro-5-forfinal, 4-chloro-2-forfinal, 4-chloro-3-forfinal, 5-chloro-2-FPO is phenyl, 2,3-dimetilfenil, 2,4-dimetilfenil, 2,5-dimetilfenil, 2,6-dimetilfenil, 3,4-dimetilfenil, 3, 5dimethylphenyl, 2-fluoro-3-were, 2-fluoro-4-were, 2-fluoro-5-were, 2-fluoro-6-were, 3-fluoro-2-were, 3-fluoro-4-were, 3-fluoro-5-were, 4-fluoro-2-were, 4-fluoro-3-were, 5-fluoro-2-were, 2-chloro-3-were, 2-chloro-4-were, 2-chloro-5-were, 2-chloro-6-were, 3-chloro-2-were, 3-chloro-4-were, 3-chloro-5-were, 4-chloro-2-were, 4-chloro-3-were, 5-chloro-2-were, 2-methoxy-3-were, 2-methoxy-4-were, 2-methoxy-5-were, 2-methoxy-6-were, 3-methoxy-2-were, 3-methoxy-4-were, 3-methoxy-5-were, 4-methoxy-2-were, 4-methoxy-3-were, 5-methoxy-2-were.

In one embodiment of the present invention R30choose from a (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl, tetrahydropyranyl and phenyl, in another embodiment from (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl and phenyl, in another embodiment from (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl and tetrahydropyranyl, in another embodiment from (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl, phenyl and heteroaryl, in another embodiment from (C3-C7)-cycloalkyl, phenyl which heteroaryl, in another embodiment, (C3-C7)-cycloalkyl and (C5-C7)-cycloalkenyl, in another embodiment from (C3-C7)-cycloalkyl and phenyl, where all cycloalkyl, cycloalkenyl, phenyl and heteroaryl group optionally substituted, as shown, and cycloalkyl preferably represents a (C5-C7-cycloalkyl, more preferably (C5-C6-cycloalkyl, for example, cyclohexyl, cycloalkenyl preferably represents a (C5-C6)-cycloalkenyl, for example, cyclohexenyl, and heteroaryl preferably selected from thiophenyl and pyridinyl and more preferably represents thiophenyl. In another embodiment, the present invention R30represents phenyl which is optionally substituted, as shown. Preferably the number of substituents in the substituted group R30equal to one, two, three or four, more preferably one, two or three, particularly preferably one or two, e.g. one. The substituents in the substituted group R30may be present at the carbon atoms in any positions, as shown above, a relatively substituted cycloalkyl, cycloalkenyl, phenyl and heteroaryl groups in General. For example, in the case of monosubstituted phenyl group, presented the managing R 30the Deputy may be present in the 2-position, 3-position or 4-position, and in the case of a disubstituted phenyl group, the substituents may be present at positions 2 and 3, or positions 2 and 4 or positions 2 and 5, or positions 2 and 6, or positions 3 and 4 or positions 3 and 5. The substituents that may be present in cycloalkenes or cycloalkenyl group representing R30preferably selected from fluorine, methyl and hydroxy for example, fluorine and methyl. In one embodiment of the present invention, the substituents in cycloalkenes or cycloalkenyl group representing R30represent hydroxy. In another embodiment, the present invention cycloalkyl or cycloalkenyl group representing R30not replace. The substituents that may be present in the phenyl or heteroaryl group representing R30preferably selected from halogen, (C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, (C1-C4)-alkyl-O-(C1-C6)-alkyl, (C1-C4)-alkyl-CO-NH-(C1-C4)-alkyl, hydroxy, (C1-C6)-alkyl-O-, hydroxy-(C1-C6)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C6)-alkyl-O-, (C1-C4)-alkyl-CO-NH-(C1-C4)-alkyl-O-, (C1-C6)-alkyl-S(O) and cyano, more preferably from halogen, (C1-C6)-alkyl, (C1-C4)-alkyl-O-(C1-C6)-alkyl, hydroxy, (C1-C6)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C6)-alkyl-O-, (C1-C6)-alkyl-S(O)mand cyano, especially preferably from halogen, (C1-C6)-alkyl, (C1-C4)-alkyl-O-(C1-C6)-alkyl, hydroxy, (C1-C6)-alkyl-O - (C1-C4)-alkyl-O-(C1-C6)-alkyl-O-, more preferably from halogen, (C1-C6)-alkyl, hydroxy, (C1-C6)-alkyl-O - (C1-C4)-alkyl-O-(C1-C6)-alkyl-O-, particularly preferably from halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O - (C1-C4)-alkyl-O-(C1-C6)-alkyl-O-, for example, from halogen, (C1-C6)-alkyl-O - (C1-C4)-alkyl-O-(C1-C6)-alkyl-O - or halogen, (C1-C6)-alkyl and (C1-C6)-alkyl-O - or halogen and (C1-C4)-alkyl, where in one embodiment of the present invention the alkyl groups in the substituents in the phenyl and heteroaryl groups representing R30,you can not replace or substitute one or more fluorine atoms, and as examples of the substituents containing fluorine-substituted alkyl, the substituents containing trifluoromethyl who ing group, such as CF3, CF3-O -, or-CF3-S-, can be included in each list of substituents in addition to the substituents containing unsubstituted alkyl, and in another embodiment of the present invention the alkyl groups in the substituents in the group R30do not replace fluorine, and in the latter embodiment, the above-mentioned alkyl, therefore, denotes unsubstituted alkyl. In one embodiment of the present invention (C1-C6)-alkyl group in the substituent in R30is a (C1-C4)-alkyl group. In one embodiment of the present invention the substituents that are present in the phenyl or heteroaryl group representing R30choose from halogen, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine. Specific groups that may be present in the group R30and from whom, or from any of the subgroups, we can choose R30in the compounds of formula I include, for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclopent-2-enyl, cyclohex-2-enyl, cyclohepta-2-enyl, 4-fluoro-cyclohexyl, 4-methylcyclohexyl, 2-hydroxycyclopent, 3-hydroxycyclopent, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxyzine is heptyl, 4,4-diverticulosis, 3,3-dimethylcyclohexyl, 4,4-dimethylcyclohexyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, phenyl, i.e. unsubstituted phenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 2-were, 3-were, 4-were 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-(2 methoxyethoxy)phenyl, 3-(2-methoxyethoxy)phenyl, 4-(2-methoxyethoxy)phenyl, 2-(3-methoxypropane)phenyl, 3-(3-methoxypropane)phenyl, 4-(3-methoxypropane)phenyl, thiophene-2-yl, thiophene-3-yl, pyridin-2-yl, pyridin-3-yl, pyridine-4-yl, 2-hydroxypyridine-3-yl, 4-hydroxypyridine-3-yl, 5-hydroxypyridine-3-yl, 6-hydroxypyridine-3-yl, 2-methoxypyridine-3-yl, 4-methoxypyridine-3-yl, 5-methoxypyridine-3-yl, 6-methoxypyridine-3-yl, 2-hydroxypyridine-4-yl, 3-hydroxypyridine-4-yl, 2-methoxypyridine-4-yl, 3-methoxypyridine-4-yl.

The substituents R40may be present at the ring carbon atoms in any of the positions 4 and/or 5 and/or 6 and/or 7 in a 6-membered ring azaindole group depicted in formula I, provided that the ring atom in the corresponding position is a carbon atom. In the case when the value of n substituents R40is less than 3, all the carbon atoms in positions 4, 5, 6 and 7 azaindole rings that do not bear the substituent R40bear atom in which aroda, i.e. suitable groups Y1, Y2, Y3and Y4represent a CH group. In the case when the value of n is 0, all ring carbon atoms in positions 4, 5, 6 and 7 azaindole rings are hydrogen atoms. Preferably the value of n substituents R40is 0, 1 or 2, more preferably 0 or 1. In one embodiment of the present invention the value of n is 1. In another embodiment, the value of n is 0, i.e. the substituent R40not present in the compound of formula I. R40preferably selected from halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-, hydroxy-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, phenyl-O-(C1-C4)-alkyl-O-, di((C1-C4)-alkyl)N-(C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-CO-O-, (C1-C4)-alkyl-NH-CO-O-, (C1-C4)-alkyl-S(O)m-, HO-CO-, (C1-C4)-alkyl-O-CO-, H2N-CO -, and cyano, more preferably from halogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl, hydroxy, (C1 -C4)-alkyl-O-, hydroxy-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, phenyl-O-(C1-C4)-alkyl-O-, di((C1-C4)-alkyl)N-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-CO-O-, (C1-C4)-alkyl-NH-CO-O-, (C1-C4)-alkyl-S(O)m-, HO-CO-, (C1-C4)-alkyl-O-CO-, H2N-CO -, and cyano, especially preferably from halogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-, hydroxy-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, phenyl-O-(C1-C4)-alkyl-O-, di((C1-C4)-alkyl)N-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-CO-O-, (C1-C4)-alkyl-NH-CO-O-, HO-CO-, (C1-C4)-alkyl-O-CO - and H2N-CO-, more preferably from halogen, (C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-CO-O-, (C1-C4)-alkyl-NH-CO-O-, (C1-C4)-alkyl-O-CO - and H2N-CO-, especially preferably from halogen, (C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO - and H2N-CO-, where all substituents R40are independent and from each other and can be identical or different, and where are all phenyl groups, independently of each other optionally substituted, as shown. In one embodiment of the present invention R40selected from halogen, (C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-CO-O-, (C1-C4)-alkyl-NH-CO-O-, (C1-C4)-alkyl-O-CO-, HO-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O - and H2N-CO-, preferably from halogen, (C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO - and H2N-CO-, where all substituents R40are independent from each other and can be identical or different. In another embodiment, the present invention R40selected from halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-, hydroxy-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-CO-O-, (C1-C4)-alkyl-NH-CO-O - (C1-C4)-alkyl-S(O)m-, p is edocfile from halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O - (C1-C4)-alkyl-S(O)m-, more preferably from halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O - and HO-CO-(C1-C4)-alkyl-O-, particularly preferably from halogen, (C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O - and HO-CO-(C1-C4)-alkyl-O-, more preferably from halogen, (C1-C4)-alkyl, hydroxy and (C1-C4)-alkyl-O-, where all substituents R40are independent from each other and can be identical or different, and where all phenyl groups, independently of each other optionally substituted, as shown. Preferably not more than two Deputy R40are NO2. In one embodiment of the present invention the value of n is chosen from 1, 2 and 3, preferably from 1 and 2, and it can be set, for example, 1. Ie, in this last embodiment, at least one substituent R40present in the compounds of formula I, preferably one or two substituent R40for example , one Deputy R40.

In one embodiment of the present invention at least one substituent R 40that may be present in the compounds of formula I, preferably one or two substituent R40for example , one Deputy R40is a Deputy, in which the atom at the Deputy, through which it is linked to the carbon atom at the 6-membered ring azaindole group, a represents an oxygen atom, i.e. it is chosen from hydroxy, (C1-C4)-alkyl-O-, (C3-C7-cycloalkyl-CvH2v-O-, phenyl-(C1-C4)-alkyl-O-, heteroaryl-(C1-C4)-alkyl-O-, hydroxy-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, (C3-C7-cycloalkyl-CvH2v-O-(C1-C4)-alkyl-O-, phenyl-O-(C1-C4)-alkyl-O-, heteroaryl-O-(C1-C4)-alkyl-O-, di((C1-C4)-alkyl)N-(C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, H2N-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-CO-O-, (C3-C7-cycloalkyl-CvH2v-CO-O-, (C1-C4)-alkyl-NH-CO-O - (C3-C7-cycloalkyl-CvH2v-NH-CO-O-, where these substituents are independent from each other and can be identical or different, and where all phenyl and heteroaryl groups can independently of each to replace, as shown. Preferably the data Zam is stitely selected from hydroxy, (C1-C4)-alkyl-O-, hydroxy-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, phenyl-O-(C1-C4)-alkyl-O-, di((C1-C4)-alkyl)N-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-CO-O - (C1-C4)-alkyl-NH-CO-O-, and more preferably from hydroxy, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, phenyl-O-(C1-C4)-alkyl-O-, di((C1-C4)-alkyl)N-(C1-C4)-alkyl-O - (C1-C4)-alkyl-CO-O-, particularly preferably from hydroxy, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, phenyl-O-(C1-C4)-alkyl-O - and di((C1-C4)-alkyl)N-(C1-C4)-alkyl-O-, more preferably selected from hydroxy, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O - and phenyl-O-(C1-C4)-alkyl-O-, particularly preferably from hydroxy, (C1-C4)-alkyl-O - (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, more preferably from hydroxy and (C1-C4)-alkoxy. In one embodiment, the data substituents selected from hydroxy, (C1-C4)-alkyl-O-, hydroxy-(C1-C4)-alkyl-O-, (C1-C4)-O-alkyl-O-(C1-C4)-alkyl-O-, phenyl-O-(C1-C4)-alkyl-O-, di((C1-C4)-alkyl)N-(C1-C 4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, H2N-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-CO-O - (C1-C4)-alkyl-NH-CO-O-, preferably from hydroxy, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, di((C1-C4)-alkyl)N-(C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O - and H2N-CO-(C1-C4)-alkyl-O-, more preferably from hydroxy, (C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O - and H2N-CO-(C1-C4)-alkyl-O-, particularly preferably from hydroxy, (C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O - (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, more preferably from hydroxy, (C1-C4)-alkyl-O and HO-CO-(C1-C4)-alkyl-O-, where these substituents are independent from each other and can be identical or different. If in addition to these substituents, attached via an oxygen atom further substituents R40present in the compound of formula I, selected from all other values of R40listed above and preferably selected from halogen and (C1-C4)-alkyl, where all data Ni is sustained fashion substituents are independent from each other and can be identical or different. In one embodiment, this one substituent R40attached via the oxygen atom is present at the ring carbon atom in position 5, or when the ring carbon atom in position 6.

In the compound of formula I, which contains one substituent R40the Deputy may be present at the ring carbon atom in position 4 or in position 5 or position 6 or position 7 azaindole rings. In the compound of formula I, which contains two Deputy R40the substituents may be present at the ring carbon atoms in positions 4 and 5, or positions 4 and 6, or positions 4 and 7, or in positions 5 and 6, or the provisions of articles 5 and 7, or positions 6 and 7 azaindole rings. In one embodiment of the present invention the compounds of formula I contain zero, one or two Deputy R40where the substituents R40present at the ring carbon atoms in position 4 or position 5, or in positions 4 and 5, and the other ring carbon atoms in positions 4, 5, 6 and 7 are hydrogen atoms. In another embodiment of the present invention the compounds of formula I contain zero, one or two Deputy R40where the substituents R40present at the ring carbon atoms in position 4 or 6 position or in positions 4 and 6, and the other ring carbon atoms in position the deposits 4, 5, 6 and 7 are hydrogen atoms. In another embodiment of the present invention the compounds of formula I contain zero, one or two Deputy R40where the substituents R40present at the ring carbon atoms in position 4 or position 7 or in positions 4 and 7, and the other ring carbon atoms in positions 4, 5, 6 and 7 are hydrogen atoms. In another embodiment of the present invention the compounds of formula I contain zero, one or two Deputy R40where the substituents R40present at the ring carbon atoms in position 5 or position 6 or in the provisions of articles 5 and 6, and the other ring carbon atoms in positions 4, 5, 6 and 7 are hydrogen atoms. In another embodiment of the present invention the compounds of formula I contain zero, one or two Deputy R40where the substituents R40present at the ring carbon atoms in position 5 or position 7 or in positions 5 and 7, and the other ring carbon atoms in positions 4, 5, 6 and 7 are hydrogen atoms. In another embodiment of the present invention the compounds of formula I contain zero, one or two Deputy R40where the substituents R40present at the ring carbon atoms at position 6 or 7 or in positions 6 and 7, and the other ring carbon atoms in positions 4, 5, 6 and 7 are hydrogen atoms.

In one embodiment of the present invention, the group Y1represents a nitrogen atom, and a group Y2, Y3and Y4are the same or different groups CH or CR40, i.e. the compound of formula I is a 4-azaindole(1H-pyrrolo[3,2-b]pyridine derivative of formula Ia. In another embodiment of the present invention, the group Y2represents a nitrogen atom, and a group Y1, Y3and Y4are the same or different groups CH or CR40, i.e. the compound of formula I is a 5-azaindole(1H-pyrrolo[3,2-c]pyridine derivative of the formula Ib. In another embodiment of the present invention, the group Y3represents a nitrogen atom, and a group Y1, Y2and Y4are the same or different groups CH or CR40, i.e. the compound of formula I is 6-azaindole(1H-pyrrolo[2,3-c]pyridine derivative of the formula Ic. In another embodiment of the present invention, the group Y4represents a nitrogen atom, and a group Y1, Y2and Y3are the same or different groups CH or CR40, i.e. the compound of formula I is a 7-azaindole(1H-pyrrolo[2,3-b]pyridine derivative of formula Id. A, R, R10, R20, R30, R40n, p and q in the formulas Ia, Ib, Ic and Id defines the K in the formula I.

In another embodiment of the present invention the compound of formula I is a compound of any two or three of formulas Ia, Ib, Ic and Id, for example, the compound of formula Ia or formula Id, or a compound of formula Ib or formula Ic, or a compound of formula Ia or formula Ic or formula Id. Otherwise, typical data of the last three editions of the implementation of one of the groups Y1and Y4in the formula I represents N and the other of Y1and Y4,and Y2and Y3are the same or different groups CH or CR40or one of the groups Y2and Y3in the formula I represents N and the other of Y2and Y3and Y1and Y4are the same or different groups CH or CR40or one of the groups Y1, Y3and Y4in the formula I represents N and the other of Y1, Y3and Y4and Y2are the same or different groups CH or CR40.

In one embodiment of the present invention the value of p is 2, and the value of q is chosen from 2 and 3. In another embodiment of the present invention, and p and q are equal to 2, i.e. diazacyclooctadecane ring depicted in formula I, is a pieperazinove ring, and the compound of formula I is a compound of formula Ie. In others the GOM embodiment of the present invention p is 2, and q is 3, i.e. diazacyclooctadecane ring depicted in formula I, is homopiperazine ring, and the compound of formula I is a compound of formula If. In another embodiment of the present invention, and p and q are equal to 3, i.e. diazacyclooctadecane ring depicted in formula I represents 1,5-diisocyanate ring, and the compound of formula I is a compound of formula Ig. A, R, R10, R20, R30, R40, Y1, Y2, Y3, Y4and n in the formulae Ie, If and Ig determined as in formula I.

In the preferred compounds of the present invention any one or more structural elements such as groups, substituents and values that determine how any of the preferred definitions of the elements or from any mentioned embodiment, and/or they may have one or more specific values, which are mentioned as examples of elements, where all combinations of one or more preferred definitions and embodiments and/or specific values are the object of the present invention. Also with respect to all preferred compounds of the formula I, in all their stereoisomeric forms and mixtures of stereoisomeric forms in all ratios, and their physiologically acceptable salts and physiologically pickup is the acceptable solvate of any of them are the object of the present invention. Similarly, also with respect to all of the specific compounds described in the present invention, such as exemplary compounds that represent embodiments of the present invention, where different groups and values in the General definition of the compounds of formula I have the specific values presented in the relevant specific connection, all their stereoisomeric forms and mixtures of stereoisomeric forms in all ratios, and their physiologically acceptable salts and physiologically acceptable solvate of any of them are the object of the present invention. In particular, an object of the present invention are all of the specific compounds described in the present invention, no matter described whether they are in the form of a free compound and/or as a specific salt, or in form of the free compounds or in the form of all its physiologically acceptable salts, and describe if the particular salt, optionally in the form of specific salts and physiologically acceptable solvate.

As an example, compounds of the present invention, in which any one or more of the structural elements define, as in the preferred definitions, can be mentioned the compounds of formula I, in which p and q is 2, R10represents hydrogen and A is chosen from O and C(Ra)2, i.e. compounds of formulas is Ie, in which R10represents hydrogen, and A is chosen from O and C(Ra)2and all other groups and values determine how the General definition of the compounds of formula I or in any of the preferred definitions or embodiments of the present invention, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically acceptable solvate of any of them.

Other data examples are the compounds of formula I, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically acceptable solvate of any of them, in which

A is chosen from O, S, NCH3and C(Ra)2;

Raselected from hydrogen, fluorine and methyl, where two groups Raare independent from each other and can be identical or different, or two groups Ratogether represent divalent (C2-C5)-alkyl group;

R is selected from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, phenyl-(C1-C4)-alkyl, (C1-C4)-alkyl-O-CO-CuH2uand R1-NH-CO-CuH2u-where all groups R are independent from each other may be the same or different;

R1choose from a (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl -, and H2N-CO-(C1-C4)-alkyl-;

R10selected from hydrogen, (C1-C6)-alkyl-O-CO - (C3-C7-cycloalkyl-CvH2v-O-CO-;

R20selected from phenyl and heteroaryl that are not necessarily replace one or more identical or different substituents selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-S(O)m-, hydroxy and cyano;

R30choose from a (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl, tetrahydropyranyl, phenyl and heteroaryl where cycloalkyl and cycloalkenyl optionally substituted by one or more identical or different substituents chosen from fluorine, (C1-C4)-alkyl and hydroxy, and phenyl and heteroaryl optionally substituted by one or more identical or different substituents selected from halogen, (C1-C6)-alkyl, (C1-C4)-alkyl-O-(C1-C6)-alkyl, hydroxy, (C1-C6)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C6)-alkyl-O-, (C1-C6)-alkyl-S(O)mand cyano;

R40selected from halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-Alki is-O-(C 1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-, hydroxy-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, phenyl-O-(C1-C4)-alkyl-O-, di((C1-C4)-alkyl)N-(C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-CO-O-, (C1-C4)-alkyl-NH-CO-O-, (C1-C4)-alkyl-S(O)m-, HO-CO-, (C1-C4)-alkyl-O-CO-, H2N-CO -, and cyano, where all substituents R40are independent from each other and can be identical or different;

one of the groups Y1, Y2, Y3and Y4represents N and the others are the same or different groups CH or CR40;

heteroaryl choose from thiophenyl and pyridinyl;

m is chosen from 0, 1 and 2, where all values of m are independent from each other and can be identical or different;

n is chosen from 0, 1 and 2;

p is 2 and q is chosen from 2 and 3;

u is chosen from 0, 1 and 2, where all values of u are independent of each other and can be identical or different;

v is chosen from 0, 1 and 2;

where all alkyl groups, independently of each other, optionally substituted one or more fluorine atoms;

where cycloalkyl group optionally substituted by one or more identical or different will fill the roles, selected from fluorine and (C1-C4)-alkyl, unless otherwise specified;

where all of the phenyl groups present in R and R40independently from each other, optionally substituted one or more identical or different substituents selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-S(O)2and cyano.

Other data examples are the compounds of formula I, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically acceptable solvate of any of them, where

A is chosen from O, S and C(Ra)2;

Raselected from hydrogen, fluorine and methyl, where two groups Raare independent from each other and can be identical or different, or two groups Ratogether represent divalent (C2-C5)-alkyl group;

R is selected from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, phenyl-(C1-C4)-alkyl, (C1-C4)-alkyl-O-CO-CuH2uand R1-NH-CO-CuH2u-where all groups R are independent of each other and can be identical or different;

R1choose from a (C1-C4)-alkyl, hydroxy-(C1 4)-alkyl -, and H2N-CO-(C1-C4)-alkyl-;

R10selected from hydrogen, (C1-C6)-alkyl-O-CO - (C3-C7-cycloalkyl-CvH2v-O-CO-;

R20represents phenyl which is optionally substituted by one or more identical or different substituents selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-S(O)m-, hydroxy and cyano;

R30choose from a (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl and phenyl, where cycloalkyl and cycloalkenyl optionally substituted by one or more identical or different substituents chosen from fluorine, (C1-C4)-alkyl and hydroxy, and phenyl optionally substituted by one or more identical or different substituents selected from halogen, (C1-C6)-alkyl, (C1-C4)-alkyl-O-(C1-C6)-alkyl, hydroxy, (C1-C6)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C6)-alkyl-O-, (C1-C6)-alkyl-S(O)mand cyano;

R40selected from halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-, hydroxy-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C 1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-CO-O-, (C1-C4)-alkyl-NH-CO-O - (C1-C4)-alkyl-S(O)m-where all substituents R40are independent from each other and can be identical or different;

one of the groups Y1, Y2, Y3and Y4represents N and the others are the same or different groups CH or CR40;

m is chosen from 0, 1 and 2, where all values of m are independent from each other and can be identical or different;

n is chosen from 0, 1 and 2;

p and q are equal to 2;

u is chosen from 0, 1 and 2, where all values of u are independent of each other and can be identical or different;

v is chosen from 0, 1 and 2;

where all alkyl groups, independently of each other, optionally substituted one or more fluorine atoms;

where cycloalkyl group optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl, unless otherwise specified;

where all of the phenyl groups present in R and R40independently from each other, optionally substituted one or more identical or different substituents selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O-, (C1-C )-alkyl-S(O)2and cyano.

Other data examples are the compounds of formula I, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically acceptable solvate of any of them, where

A is chosen from O and C(Ra)2;

Rarepresents hydrogen;

R is selected from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl and R1-NH-CO-CuH2u-where all groups R are independent of each other and can be identical or different;

R1choose from a (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl -, and H2N-CO-(C1-C4)-alkyl-;

R10represents hydrogen;

R20represents phenyl which is optionally substituted by one or more identical or different substituents selected from halogen and (C1-C4)-alkyl;

R30choose from a (C5-C7)-cycloalkyl, (C5-C7)-cycloalkenyl and phenyl, where phenyl optionally substituted by one or more identical or different substituents selected from halogen, (C1-C6)-alkyl, hydroxy, (C1-C6)-alkyl-O - (C1-C4)-alkyl-O-(C1-C6)-alkyl-O-;

R40selected from halogen, (C1-C4)-alkyl is, hydroxy, (C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, (C1-C4)-alkyl-O-CO - and H2N-CO-, where all substituents R40are independent from each other and can be identical or different;

one of the groups Y1, Y2, Y3and Y4represents N and the others are the same or different groups CH or CR40;

n is chosen from 0, 1 and 2;

p and q are equal to 2;

u is chosen from 0, 1 and 2, where all values of u are independent of each other and can be identical or different;

where all alkyl groups, independently of each other, optionally substituted one or more fluorine atoms.

Another object of the present invention are methods for producing compounds of formula I, including their salts and solvate, which are outlined below and with the help of which you can get a connection. For example, obtaining compounds of formula I it is possible to carry out the first reaction of azaindole formula II on the ring nitrogen atom in the 5-membered ring alkylating or alleroisk compound of formula III to obtain a compound of formula IV, which is then converted into 1,3-dihydroindol-2-he (apoxina) formula V.

Group R30, R40, Y1, Y2, Y3and Y4and the value of n in the compounds of formulas II, III, IV and V determine Aut, as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a group, which is a precursor, which is subsequently transformed into the target group. Group X1in compounds of formula III represents a substitutable group, allowing the nucleophilic substitution reaction or the reaction of the other type of mechanism, including radical reactions and reactions catalyzed by transition metals, which results in the replacement of this substituted group ring nitrogen atom in the 5-membered ring in the compound of formula II, for example, halogen or arylsulfonate or alkylsulfonate group or a group containing boron.

In the case when R30optionally substituted by phenyl or heteroaryl, which replaces a suitable electron-dilatory group, or it contains depleted electron density heterocyclic ring, or R30optional override cycloalkyl or cycloalkenyl, or it is tetrahydropyranyl, X1can be a halogen, in particular chlorine, bromine or iodine, or arylsulfonate or alkylsulfonate group, such as benzosulfimide, toluensulfonate, nitrobenzenesulfonate, methanesulfonate or tripterocalyx, and the reaction can be about the contain in the conditions of the reaction, nucleophilic substitution, usually in a solvent, for example, an inert aprotic solvent such as an ether like tetrahydrofuran (THF), dioxane (1,4-dioxane) or dimethyl ether of ethylene glycol (DME), amide such as dimethylformamide (DMF) or N-methylpyrrolidine-2-ONU (NMP)or dimethyl sulfoxide (DMSO), or mixtures thereof, and in the presence of a base, such as an alcoholate, such ethoxide or sodium tert-piperonyl potassium hydride such as sodium hydride, amide, such sodium amide or diisopropylamide lithium carbonate, carbonate such potassium or cesium carbonate, or an amine, such ethyldiethanolamine.

In the case when R30optionally substituted by phenyl or heteroaryl, X1may be a chlorine, bromine or iodine, i.e. the compound of formula III can be an optionally substituted chlorobenzene, Brabanthal, iadanza, largetree, progeterone or togetherare, and the reaction of the compounds of formulas II and III can be carried out at reaction conditions of arilirovaniya Ullman in the presence of catalytic compounds containing copper, for example, bromide, copper(I)iodide copper(I) or acetylacetone copper(II), at elevated temperatures, e.g. at temperatures from about 100°C to about 150°C, usually in an inert aprotic solvent such as DMSO, DMF, NMP, acetonitrile, dioxane or toluene, in the presence of a base, such the AK carbonate, like potassium carbonate or cesium carbonate, or phosphate such as potassium phosphate, and preferably amine like N,N'-dimethylethylenediamine, 1,2-diaminocyclohexane, Proline or 8-hydroxyquinoline. The reaction arilirovaniya, like other reactions carried out in the synthesis of compounds of formula I, can also be carried out in a microwave reactor.

In another method of preparing compounds of formula IV, the compound of formula II can react with the compound of the formula III in which R30optionally substituted by phenyl or heteroaryl, and X1represents halogen, in particular chlorine, bromine or iodine, or alkylsulfonate group, such as tripterocalyx, in the presence of palladium catalyst, which may be formed from Tris(dibenzylideneacetone)diplegia(0), and, for example, phosphine ligand, and a base, such as tert-piperonyl sodium or rejonowy potassium phosphate in an inert solvent such as a hydrocarbon such as toluene, or an ether such as dioxane, at temperatures from about 60°C to about 120°C, as described, for example, in D. W. Old et al., Org. Lett. 2 (2000), 1403.

The following method of obtaining compounds of formula IV, a compound of the formula II can react with Bronevoy acid, i.e. the compound of formula III in which X1represents the balance Bronevoy acid B(OH)2 in reactions catalyzed by transition metals, for example, according to modification of the Chan-Evans-Lam the condensation reaction, Suzuki-Miyaura in the presence of copper compounds such as copper acetate(II), in a solvent such as chlorinated hydrocarbons, such dichloromethane or chloroform, at temperatures from about 20°C to about 40°C, for example, at room temperature and in the presence of a tertiary amine such as triethylamine, ethyldiethanolamine or pyridine, as described, for example, in D. M. T. Chan et al., Tetrahedron Lett. 39 (1998), 2933. Instead of applying Bronevoy acid, the compound of formula IV can also be obtained from compounds of formula II using organotitanate salts, i.e. compounds of formula III in which X1is a negatively charged trevormoran group BF3-containing cation, such as a cation of an alkali metal such as cesium cation, potassium, sodium or lithium or Quaternary ammonium cation or a phosphonium, particularly potassium cation as counterion (see, R. A. Batey et al., Tetrahedron Lett. 42 (2001), 9099), in the presence of catalytic compounds containing a transition metal, such as copper compound such as copper acetate(II), in a solvent such as chlorinated hydrocarbons, such dichloromethane or chloroform, at temperatures from about 20°C d is approximately 50°C in the presence of oxygen and molecular sieves, as described, for example, in T. D. Quach et al., Org. Lett. 5 (2003), 4397.

Subsequent conversion of compounds of formula IV in asaxena formula V can be done first by treating compound of formula IV with N-chlorosuccinimide in a solvent such as chlorinated hydrocarbons, such dichloromethane, at temperatures from about 10°to about 30°C, for example, at room temperature, and then processing the crude intermediate product of 85% phosphoric acid in acetic acid at elevated temperatures from about 110°C to 140°C, as described in R. Sarges et al., J. Med. Chem. 32 (1989), 437. The transformation of compounds of formula IV in asaxena formula V can also be the first treatment of compounds of formula IV bromine or a source of bromine, such as N-bromosuccinimide or the bromide perbromide pyridinium (tribromide pyridinium), in a solvent such as chlorinated hydrocarbons, such dichlormethane, or alcohol, like tert-butanol or amyl alcohol, or mixture of alcohol and water or aqueous buffer solution such as a phosphate buffer having a pH approximately equal to 5, for example, at temperatures from approximately 0°to approximately 50°C. Then restore intermediate bromine-containing products or hydrolysis to azaxanthone formula V can be accomplished by treatment with a metal such as zinc or jelly what about in acetic acid or mixtures of acetic acid and solvent, such as an alcohol like methanol, ethanol or tert-butanol, or an ether like diethyl ether or THF, or by hydrogenation in the presence of a hydrogenation catalyst such as palladium hydroxide or palladium on coal or Raney Nickel, for example, in a solvent such as an alcohol like methanol or ethanol, or an ether such as ethyl acetate, at temperatures from approximately 0°to approximately 60°C and a hydrogen pressure from about 1 bar to about 100 bar, as described, for example, in J. Parrick et al., Tetrahedron Lett. 25 (1984), 3099; A. Marfat et al., Tetrahedron Lett. 28 (1987), 4027; or R. P. Robinson et al., J. Org. Chem. 56 (1991), 4805.

The compounds of formula V can also be obtained by reaction of ethoxide formula VI, in which groups R40, Y1, Y2, Y3and Y4and the value of n is determined, as in the compound of the formula I and additionally functional groups can be present in protected form or in the form of a group, which is a precursor, which is subsequently transformed into the target group, with a compound of formula III, as defined above, in which X1represents a halogen or arylsulfonate or alkylsulfonate group or a group containing boron, such as the balance Bronevoy acid, or group BF3-containing a cation such as potassium cation as counterion, in the reaction of nucleophilic samewe the Oia or the Ullman reaction or other reactions, catalyzed by transition metals, as described above. The explanations given above on the reaction of the compounds of formulas II and III, for example, concerning palladium-catalyuna and copper-catalyzed reactions are applicable, respectively, on the reaction of the compounds of formulas VI and III.

Then, in the process of synthesis of compounds of formula I, esocidae formula V can be formirovanie on Vilsmeier with concomitant chlorination to obtain 1-R30-2-horizantal-3-carboxaldehyde formula VII, in which groups R30, R40, Y1, Y2, Y3and Y4and the value of n is determined, as in the compound of the formula I and additionally functional groups can be present in protected form or in the form of a group, which is a precursor, which is subsequently transformed into the target group.

Reagent for formirovaniya on Vilsmeier can conveniently be obtained in situ from dimethylformamide and a suitable inorganic or organic chloride such as phosgene, oxalicacid or phosphorus oxychloride in an inert aprotic solvent such as a hydrocarbon or chlorinated hydrocarbon such as benzene, dichloromethane or the chloroform, ether, like DME or excess DMF, or a mixture thereof, at temperatures from about 0°C to priblizitelen is 10°C. Preferably apply phosphorus oxychloride. The reaction of the reagent of Vilsmeier with the compound of the formula V is usually carried out at temperatures from about 0°to about 30°C, preferably in the presence of a base, such as pyridine. Hydrolytic treatment of the reaction mixture, which is similar to the processing of all reactions produce compounds of formula I are usually carried out in standard conditions, then gives the aldehyde of formula VII.

The compounds of formula VII can also be obtained, initially exposing asaxena formula VI formirovanie on Vilsmeier with concomitant chlorination in the 2-position similarly as above to obtain 2-horizantal-3-carboxaldehyde formula VIII, in which groups R40, Y1, Y2, Y3and Y4and the value of n is determined, as in the compound of the formula I and additionally functional groups can be present in protected form or in the form of a group, which is a precursor, which is subsequently transformed into the target group, and then the introduction of the group R30in the 1-position azaindole ring in the compound of formula VIII by reaction with a compound of formula III, as defined above, in which X1represents a halogen or arylsulfonate or alkylsulfonate group or a group containing boron, such as the balance Bronevoy acid and the and group BF 3-containing a cation such as potassium cation as counterion, in the reaction of nucleophilic substitution or the Ullman reaction or other reactions catalyzed by transition metals, as described above. The explanations given above on the reaction of the compounds of formulas II and III, for example, related palladium-catalyzed and copper-catalyzed reactions can be applied, respectively, on the reaction of the compounds of formulas VIII and III.

Then azaindole-3-carboxaldehyde formula VII can oxidize under standard conditions for the oxidation of aldehydes to carboxylic acids, in order to get azaindole-3-carboxylic acid of the formula IX, in which the group R30, R40, Y1, Y2, Y3and Y4and the value of n is determined, as in the compound of the formula I and additionally functional groups can be present in protected form or in the form of a group, which is a precursor, which is subsequently transformed into the target group. For example, the oxidation can be carried out by permanganate such as potassium permanganate in a mixture of water and an inert organic solvent such as ketone, similar to acetone, or an ether like THF, at temperatures from about 10°to about 30°C, for example, at room temperature, at approximately neutral pH values. Conveniently also be OK is slena chlorite, such as sodium chlorite in the presence of 2-methylbut-2-ene in the mixture of water and an inert organic solvent, such as alcohol, like tert-butanol, or an ether like THF, at temperatures from about 10°to about 30°C, for example, at room temperature, in the presence of weakly acidic pH values, for example, in the presence of dihydrophosphate.

Then the carboxylic acid of formula IX can be condensing in the standard conditions for the formation of amide linkages with diazoalkanes formula X, in order to obtain the compound of formula XI. Groups R, R30, R40, Y1, Y2, Y3and Y4and values of n, p and q in the compounds of formulae X and XI define, as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a group, which is a precursor, which is subsequently transformed into the target group. The compounds of formula VII define, as above. The group R50in the compounds of formulae X and XI may have values of the group R10in the compounds of formula I except hydrogen, i.e. it can represent a (C1-C6)-alkyl-O-CO - or (C3-C7-cycloalkyl-CvH2v-O-CO-, these groups protect the nitrogen atom carrying the R50from the reaction with the compound of the formula IX, or R50can be an on the natives protective group, which prevents reaction on the said nitrogen atom and may subsequently be removed in order to obtain the target compound of the formula I, in which R10represents hydrogen. Examples of groups that prevent reaction on the said nitrogen atom, are benzyloxycarbonyl group, which can subsequently be split by hydrogenation in the presence of a catalyst such as a palladium catalyst, tert-butyloxycarbonyl group, which can subsequently be split by treatment with an acid, such as triperoxonane acid or chloromethane acid, or fluoren-9-intoxicatingly group, which can subsequently be split by treatment with piperidine. For the formation of amide linkages carboxylic acid of formula IX is usually converted into a reactive derivative, which you can select or to obtain in situ, or that activate in situ conventional reagent for amide condensation. For example, the compound of formula IX can be converted into the acid chloride of the acid by treatment with thionyl chloride, oxalylamino or (1-chloro-2-methylpropenyl)dimethylamine, reactive ester or a mixed anhydride by treatment with alkylchlorosilanes like ethylchloride or isobutylacetate, or it can be activated with a reagent such as papapostolou anhydride, N,N'-carbonyl is eazol, such N,N'-carbonyldiimidazole (CDI), carbodiimide, such N,N'-diisopropylcarbodiimide (DIC), N,N'-dicyclohexylcarbodiimide (DCC) or the hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC), carbodiimide together with additives, such 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-isobenzofuranone (HOAT), condensing reagent based Urania like hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (HATU), hexaflurophosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (HBTU) or tetrafluoroborate O-(cyano(etoxycarbonyl)methylamino)-N,N,N',N'-tetramethylurea (TOTU), condensing reagent-based phosphonium, such hexaflurophosphate (benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium (BOP), hexaflurophosphate (benzotriazol-1 yloxy)triprolidine (PyBOP) or hexaphosphate patrimonialization (PyBroP). The activation of the compounds of formula IX and the reaction of the activated compounds of formula IX or a reactive derivative of the compound of formula IX with the compound of the formula X is usually carried out in an inert solvent such as an ether like THF, dioxane or DME, hydrocarbons, such as toluene, chlorinated hydrocarbons, such dichloromethane or chloroform, or an amide such as DMF or NMP, for example, or in a mixture of solvents, at temperatures from approximately 0°to approximately 60°C in the presence of p is thedamage Foundation, such as a tertiary amine like triethylamine, ethyldiethanolamine, N-methylmorpholine or pyridine, or in the presence of a basic compound of an alkali metal, such carbonate of an alkali metal, such, for example, sodium carbonate, potassium carbonate or cesium carbonate.

Then, the resulting compound of formula XI can react with the compound of the formula XII, in order to obtain the compound of formula XIII. Groups A, R, R20, R30, R40, Y1, Y2, Y3and Y4and values of n, p and q in the compounds of formulas XII and XIII determine, as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a group, which is a precursor, which is subsequently transformed into the target group. The group R50in the compound of formula XIII determine, as in the compounds of formulae X and XI. In the case of group A in the compound of formula XII represents O, S or N((C1-C4)-alkyl), the group X2represents hydrogen, and the reaction of the compounds of formulas XI and XII represents a nucleophilic substitution reaction. In this case, as used in General all of the original compounds and intermediate compounds in the synthesis of compounds of formula I, including compounds of formulas IX, X and XII, for example, the compound of formula XII in which X2is dorod, can also be used in salt form. All the products obtained in the process of synthesis of compounds of formula I, including the final compounds of formula I, can be obtained in salt form. Examples of suitable salts of compounds of formula XII, which can also be obtained in situ, are alkali metal salts such as sodium salts and potassium salts, and salts containing inert ammonium cation in the form of a Quaternary ammonium salt. The reaction of the compound of formula XII, in which A represents O, S or N((C1-C4)-alkyl) and X2represents hydrogen, with a compound of formula XI is usually conducted in a solvent, for example, an inert aprotic solvent such as an amide like DMF or NMP, or DMSO, or a mixture of solvents, in the presence of a base, such as an alcoholate, such ethoxide or sodium tert-piperonyl potassium hydride such as sodium hydride or potassium hydride or amide, such sodium amide or diisopropylamide lithium at elevated temperatures from about 80°C to about 180°C. Preferably the reaction can be performed in a microwave reactor. In the case of group A in the compound of formula XII represents C(Ra)2reaction of compounds of formulas XI and XII, in order to obtain the compound of formula XIII is preferably carried out through organometallics connection. For example,in this case, the compound of formula XII can be organometallics connection, such as tsinkorganicheskih compound such as chloride organozinc or bromide organozinc, and, then, the group X2in the compound of formula XII is a group of Zn-Cl or Zn-Br, or organoboron compound that is similar to the 9-organo-9-borabicyclo[3,3,1]nonane, and, then, the group X2in the compound of formula XII is a 9-borabicyclo[3,3,1]nonan-9-ilen group. Regarding the compounds of formula XII, which is really used in the reaction, in the case when A is C(Ra)2the group X2in the compound of formula XII can also be seen as halogen, such as chlorine or bromine, and then this compound of formula XII transform in situ by treatment with zinc in the corresponding tsinkorganicheskih compound or organoboron compound. The reaction tsinkorganicheskih the compounds of formula XII with the compound of the formula XI is usually conducted in an inert aprotic solvent such as a hydrocarbon such as hexane, benzene or toluene, an ether like THF or dioxane, or an amide like DMF or NMP, or a mixture of solvents, at temperatures from approximately 0°to approximately 120°C, preferably in the presence of a catalyst based on a transition metal, such as in the presence of palladium compounds such as palladium(II)acetate, Tris(dibenzylideneacetone)diplegia(0) or bis(dibenzyl inceton)palladium(0) together with a phosphine ligand, such 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, for example, and additionally alkoxygroup derived similar to the B-methoxy-9-borabicyclo[3.3.1]nonane, or in the presence of Nickel compounds such as acetylacetone Nickel. In the reaction of organoboron compounds of formula XII with the compound of the formula XI usually add a base, such as potassium phosphate.

In another method of obtaining the compounds of formula XIII of the compounds of formula XI and the compounds of formula XII, in which A represents C(Ra)2the compound of formula XI is first converted into the corresponding organolithium the compound containing lithium atom instead of a chlorine atom in the 2-position, for example, by reaction with alkyllithium compound, such as n-utility, and this intermediate organolithium compound then reacts substitution with a compound of formula XII, in which the group X2represents substituted by a nucleophile leaving group such as halogen, in particular chlorine, bromine or iodine, or arylsulfonate or alkylsulfonate group, such as benzosulfimide, toluensulfonate, methanesulfonate or tripterocalyx. Litvinovna the compounds of formula XI and the subsequent alkylation is usually carried out in an inert aprotic solvent such as a hydrocarbon like hexane is or benzene, or an ether like THF or dioxane, or a mixture of solvents, at temperatures from about -80°C to about 30°C.

In the case when R50in the compound of formula XIII has any of the values group, R10in the compounds of formula I, and all other groups have the required values included in the definition of compounds of the formula I thus obtained compound of formula XIII is the final compound of formula I. In the case when R50represents a protective group, and you need to obtain the compound of formula I, in which R10represents hydrogen, and/or any other groups are present in protected form or in the form of a group, which is a precursor thus obtained compound of the formula XIII can in the end be converted into the desired compound of formula I by removal of protective groups and/or conversion of any other groups. As shown above, in order to avoid undesirable direction reaction or side reactions, in any one or more stages of the synthesis of compounds of formula I of the functional groups can be present in protected form or in the form of a group, which is the predecessor. In addition, at the final stage of synthesis of the compounds of formula I can remove the protective group and make the group, which predecessors, also at any stage of the synthesis is. Appropriate strategies for the synthesis and information about suitable protective groups and their introduction and removal are well known to experts in the art and can be found, for example, in P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis, 4. ed. (2007), John Wiley & Sons. Examples of protective groups which may be mentioned are benzyl protective groups such as benzyl esters of hydroxy groups and benzyl esters of carboxylic groups, of which the benzyl group can be removed by catalytic hydrogenation in the presence of a palladium catalyst, tert-butyl protective groups such as tert-butyl esters of carboxylic groups, of which tert-boutelou group can be removed by treatment triperoxonane acid, acyl protective groups, which are used to protect the hydroxy groups and amino groups in the form of esters and amides, and which can be split acidic or basic hydrolysis, and allyloxycarbonyl protective groups such as tert-butoxycarbonyl derivatives of amino groups, including cyclic amino group, which is part diazacyclooctadecane group depicted in formula I, when R10represents hydrogen, which can be removed by treatment triperoxonane acid. Examples of groups that are precursors that may be mentioned are nitrogroup the dust, which can be transformed into an amino group by catalytic hydrogenation or restoring dithionite sodium, for example, and ceanography, which can be turned into carboxamide group and carboxyl group by hydrolysis.

In addition, in order to obtain additional compounds of formula I, various other transformations of functional groups can be made in the compounds of the formula I or compounds of the formula XIII or other compounds used in the synthesis of compounds of formula I. for Example, the hydroxy-group in the compound of formula I or XIII can be converted into a simple ether or ester, or it can react with isocyanate to obtain the carbamate under standard conditions. The transformation into the ethers of the hydroxy groups can be preferably carried out by alkylation of the corresponding halogen compound, especially a bromide or iodide, in the presence of a base such as a carbonate of an alkali metal such as potassium carbonate or cesium carbonate, in an inert solvent such as an amide like DMF or NMP, or a ketone, similar to acetone or butane-2-ONU, or by reaction with the appropriate alcohol under the reaction conditions, Mitsunobu in the presence of azodicarboxylate like diethylazodicarboxylate or diisopropylcarbodiimide, and phosphine such as triphenylphosphine or tributylphosphine is, in an inert aprotic solvent such as an ether like THF or dioxane (see, O. Mitsunobu, Synthesis (1981), 1). The amino group in the compound of formula I or XIII is possible to modify the standard conditions for alkylation, for example, by reaction with a halogen compound or by reductive amination of carbonyl compounds, or in standard conditions for acylation or sulfonylurea, for example, by reaction with an activated carboxylic acid or carboxylic acid derivative such as acid chloride of carboxylic acid or anhydride or sulfonic acid chloride. Carboxyl group in the compound of formula I or XIII can be activated or converted into a reactive derivative, as described above relative to the compounds of formula IX, and subjected to reaction with an alcohol or amine to obtain the ester or amide. Alkyl-S-group in the compound of formula I or XIII can oxidize peroxide like hydrogen peroxide, or nagkalat to get alkyl-S(O)- or alkyl-S(O)2group, and a protected mercaptopropyl in the compound of formula XIII can remove the protective group and to oxidize it to get sulfonic acid, which can then be activated and subjected to a reaction with an amine under standard conditions in order to obtain the sulfonamide.

The order in which you enter the group what s in the process of synthesis of compounds of formula I, may also be different from the order specified above. For example, instead of the original introduction diazacyclooctadecane group and then the group-A-R20the reaction of the compound of formula IX with the compound of the formula X and the reaction of the obtained compound of formula XI with the compound of the formula XII, it is also possible to enter the first group-A-R20and then diazacyclooctadecane group by reaction of the compound of formula IX or a protected form, such as ether, with a compound of formula XII, and, optionally, after removal of the protective group, the reaction of the obtained compound of formula XIV with a compound of formula X to obtain a compound of formula XIII, which in the end is transformed into the desired compound of formula I, for example, the removal of the protective group R50in the case of obtaining the compounds of formula I in which R10in the compound of formula I is hydrogen.

Group A, R20, R30, R40, Y1, Y2, Y3and Y4and the value of n in the compounds of formula XIV determine, as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a group, which is a precursor, which is subsequently converted into the target group. Not only that, as mentioned, applied in the compounds of formula IX carboxylic acid represented HUF who Ulai, can be present in protected form, for example in the form of an ether, such tert-butyl ether, or benzyl ether, the reaction of compounds of formulas IX and XII, and the carboxyl group in the compound of formula XIV can thus also be present in protected form, and from it you can remove the protective group before the reaction of the compound of formula X and XIV. Compounds of formulas IX, X, XII and XIII define, as above. All the explanations given above on the reaction of the compounds of formula XI with compounds of formula XII and the reaction of the compounds of the formula IX with compounds of formula X are applicable to the reaction of compounds of formula IX with compounds of formula XII and the reaction of the compounds of formula X with compounds of formula XIV, respectively. Thus, for example, for the formation of amide bond in the reaction of compounds of formulae X and XIV carboxyl group is usually converted into a reactive derivative or activate through the conventional condensing reagent for the formation of amide linkages and subjected to the reaction with the compound of the formula X in the presence of a base, as described above.

The following strategy for the synthesis of compounds of formula I, the group-A-R20you can also enter in the aldehyde of formula VII by reaction with a compound of formula XII in order to obtain the compound of formula XV, aldehyde group in the compound of formula XV is then akilles, to obtain the compound of formula XIV, and the latter compound is then subjected to reaction with a compound of formula X to the end of to obtain the compound of formula I, as already mentioned above.

Group A, R20, R30, R40, Y1, Y2, Y3and Y4and the value of n in the compounds of formula XV determine, as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a group, which is a precursor, which is subsequently converted into the target group. Compounds of formulas VII, X, XII and XIV define, as above. All the explanations given above on the reaction of the compounds of formula XI or formula IX with compounds of formula XII and the oxidation of compounds of formula VII to compounds of formula IX are applicable to the reaction of compounds of formula VII with compounds of formula XII and the oxidation of compounds of formula XV to compounds of the formula XIV, respectively. Thus, for example, oxidation of the aldehyde group in compounds of formula XIV can conveniently be carried out by the sodium chlorite in the presence of 2-methylbut-2-ene or potassium permanganate in a mixture of water and organic solvent, as described above.

All reactions carried out upon receipt of the compounds of formula I are known per se and can be carried out in the manner known work, Islam in the art, or similar techniques, which are described in the standard literature, for example, in Houben-Weyl, Methods of Organic Chemistry, Thieme; or Organic Reactions, John Wiley & Sons; or R. C. Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd. ed. (1999), John Wiley & Sons, and the references referred to in the present invention.

The initial compounds and building blocks for the synthesis of compounds of formula I are commercially available or can be obtained according to methods described in the literature or analogously to these methods. As examples of articles that describe the synthesis and reactions of 4-azaindole, 5-azaindole, 6-azaindole and 7-azaindole, mention can be made of L. N. Yakhontov, Russ. Chem. Rev. 37 (1968), 551; L. N. Yakhontov et al., Russ. Chem. Rev. 49 (1980), 428; F. Popowycz et al., Tetrahedron 63 (2007), 8689 ladies leather strap; and F. Popowycz et al., Tetrahedron 63 (2007), 1031. For example, azaindole formula II can be conveniently obtained from appropriately substituted pyridines as starting compounds, such as nitro-substituted pyridine or amino-substituted pyridine. In nitro-substituted pyridine, which have a methyl group at the adjacent position, the 5-membered ring isoindoline rings can be obtained by reaction of methyl groups derived from orthomorphisms acid, such as dimethylaminoethylmethacrylate or tert-butoxy-bis(dimethylamino)methane, or W oxalic acid, recovery of the nitro group, for example, hydrogen, in the presence of a catalyst, t is anyone as Raney Nickel or palladium on charcoal, and by saponification and decarboxylation in the case of reactions with fluids of oxalic acid, as described in I. Mahadevan et al., J. Heterocycl. Chem 29 (1992), 359; K-H. Buchheit et al., Bioorg. Med. Chem. Lett. 5 (1995), 2495; and B. Frydman et al., J. Org. Chem 33 (1968), 3762. Nitro-substituted pyridine can be directly converted into 4-azaindole and 6-azaindole formula II by reaction with miniministerial, as described in Zhang et al., J. Org. Chem. 67 (2002), 2345. Amino-substituted pyridine that bear halogen atom such as chlorine, bromine or iodine, in the adjacent position, can react with trimethylsilylacetamide in the presence of a palladium catalyst, such as chloride bis(triphenylphosphine)palladium(II), and copper compounds such as copper iodide(I), to obtain 1-(amino-substituted pyridyl)-3-trimethylsilylacetamide, which then cyclist to azaindole, as described, for example, in Mazéas et al., Heterocycles 50 (1999), 1065; and Song et al., Chem Soc. Rev. 36 (2007), 1120. As another example, methods of obtaining the initial compounds and building blocks, can be mentioned methods of obtaining substituted phenols described in US 2006/0160786 and in Organikum, 12. ed., VEB Deutscher Verlag der Wissenschaften, Berlin (1973), 588, whereby it is possible to obtain the compounds of formula XII in which X2represents hydrogen, A represents O, and R20substituted by phenyl, such as, for example, 3-fluoro-2-METHYLPHENOL, 2-fluoro-6-METHYLPHENOL or 3.5 debtor-2-METHYLPHENOL.

The other volume is the volume of the present invention are new original compounds and intermediate compounds appearing in the synthesis of compounds of formula I, including compounds of formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV and XV, in which A, R, R20, R30, R40, R50X1X2, Y1, Y2, Y3, Y4n, p and q define, as above, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their salts, and a solvate of any of them, and their use as intermediates. General explanations, preferred definitions of the groups and values and embodiments of the present invention, the data above relative to compounds of formula I, are applicable, respectively, to the above intermediate compounds and source connections. The object of the present invention are particularly certain new original compounds and intermediate compounds described in this invention. Regardless of this invention, describe them in the form of a free compound and/or as a specific salt, they are the object of the present invention and in the form of free compounds or in the form of their salts, and describe if the particular salt, optionally in the form of this specific salt, and in the form of a solvate of any of them.

The compounds of formula I inhibit renin, which is the enzyme, as can be demonstrated in the pharmacological tests described by the who, in other pharmacological tests, which are known to experts in the art, for example, in in vitro tests, which determine the inhibition of human renin, or in animal models, in which antihypertensive activity and other effects to determine in vivo. The compounds of formula I are suitable for the treatment of hypertension, including, for example, pulmonary hypertension, and other diseases of the cardiovascular system and heart diseases, such as heart disease, myocardial infarction, angina, heart failure, cardiac insufficiency, cardiac hypertrophy, fibrosis of the heart, vascular hypertrophy, left ventricular dysfunction, in particular left ventricular dysfunction after myocardial infarction, endothelial dysfunction, coronary heart disorder and disorder, with obstructive peripheral circulation and restenosis, including restenosis after plastic surgery on vessels, for the treatment of diseases of the kidney, such as renal fibrosis, renal ischemia, the weakness of the kidneys, renal failure, and for treatment of other diseases, for example, diabetic complications such as nephropathy and retinopathy, brain diseases, such as intracerebral hemorrhage, glaucoma, and damage of a target organ. Treatment of diseases should be understood in the sense and therapy exists, is adequate pathological changes or dysfunctions of the body or existing symptoms with the aim of weakening, relief or treatment, and prevention or prevention of pathological changes or dysfunctions of the body or symptoms in humans or animals that are affected by them and are in need of the prevention or prevention, to prevent or suppress their occurrence or mitigate in case of their occurrence. For example, in patients who, based on their medical history, are prone to ventricular dysfunction after myocardial infarction through prophylactic or preventive drug treatment the occurrence of ventricular dysfunction may be prevented or reduced its degree and weakened consequences. Treatment can be carried out in acute and in chronic cases.

The compounds of formula I and their physiologically acceptable salts and physiologically acceptable solvate can therefore be used on animals, particularly mammals, and specifically to the people, as a pharmaceutical or medicinal product per se, in mixtures with other pharmaceutical drug or medicinal product or in the form of pharmaceutical compositions. The object of the present invention are also the compounds of formula I and their physiologically acceptable salts and physiologically acceptable solvate for use as a pharmaceutical product, and t is the train pharmaceutical compositions and medicaments, which contain an effective dose of at least one of the compounds of formula I and/or physiologically acceptable salts and/or physiologically acceptable MES any of them as the active ingredient and pharmaceutically acceptable carrier, i.e. one or more pharmaceutically safe environment, and/or auxiliary substance. The object of the present invention are the compounds of formula I and their physiologically acceptable salts and physiologically acceptable solvate for use in the treatment of the diseases mentioned above or below, for example, hypertension, or for inhibition of renin, as well as the use of compounds of the formula I and their physiologically acceptable salts and physiologically acceptable solvate to obtain drugs for the treatment of diseases mentioned above or below, for example, hypertension, or to obtain drugs for inhibition of renin, where treatment includes therapy and prevention. The object of the present invention are methods of treatment of the diseases mentioned above or below, which include the introduction of an effective amount of at least one compound of formula I or its physiologically acceptable salt or physiologically acceptable MES any one person or an animal that needs n the m The compounds of formula I and a pharmaceutical composition and medicines containing them, you can enter enterline, for example, oral, transbukkalno, sublingual or rectal introduction, parenteral, for example intravenous, intramuscular or subcutaneous injection or infusion, or by other routes of administration, such as local, transcutaneous, transdermal, intrathecal, intranasal or intraocular administration.

Pharmaceutical compositions and medicaments according to the present invention typically contain from about 0.5 to about 90% weight. compounds of the formula I and/or their physiologically acceptable salts and/or their physiologically acceptable solvate. The amount of the active ingredient of the formula I and/or physiologically acceptable salts and/or physiologically acceptable MES any of them in the pharmaceutical compositions and medicinal product is typically from about 0.2 mg to about 1000 mg, preferably from about 0.2 mg to about 500 mg, particularly preferably from about 1 mg to about 300 mg in a single dose. Obtaining pharmaceutical compositions and medicines can be made by the method known per se. For this purpose the compounds of formula I and/or physiologically acceptable salts and/or etiologichesky acceptable solvate mixed together with one or more solid or liquid medium and/or auxiliary substance, optionally in combination with one or more other active ingredients, such as, for example, angiotensin-converting enzyme receptor antagonist of angiotensin, a diuretic, an antagonist of the endothelin receptor, an inhibitor of endothelin-converting enzyme inhibitor neutral endopeptidase, calcium channel blocker, a nitrate, such isosorbidedinitrate blocker β-receptor antagonist of α1 adrenergic receptors antagonist canabinoid receptor, a modulator of potassium channels, the inhibitor thrombogenicity, antiserotoninergic agent or any other agent suitable for the treatment of hypertension, heart disease, vascular diseases associated with diabetes, or kidney disease such as acute or chronic renal failure, and transferred into a suitable form for dosing and administration, which can then be used in medical products for humans or animals. The object of the present invention is also in particular a pharmaceutical composition that contains an effective dose of at least one of the compounds of formula I and/or physiologically acceptable salts and/or physiologically acceptable MES any of them, and one or more other active ingredients and a pharmaceutically acceptable carrier, where other active ingredientibus suitable for the treatment of hypertension, myocardial infarction, heart disease, vascular diseases associated with diabetes, damage to target organs, such as heart failure, kidney disease, such as acute or chronic heart failure, restenosis or glaucoma, and where the sample data of other active ingredients may be mentioned inhibitors of the angiotensin converting enzyme, receptor antagonists angiotensin, diuretics, antagonists of the endothelin receptor, inhibitors of endothelin converting enzyme inhibitors, neutral endopeptidase, calcium channel blockers, nitrates, like isosorbidedinitrate, blockers of β-receptor antagonists of α1 adrenergic receptors antagonists canabinoid receptor modulators of potassium channels inhibitors thrombogenicity, antiserotoninergic agents.

As environments and auxiliary substances can be applied suitable organic and inorganic substances which do not react in an undesirable way with the compounds of the formula I. Examples which may be mentioned are water, vegetable oils, waxes, alcohols, such as ethanol, isopropanol, 1,2-propandiol, benzyl alcohols or glycerol, polyols, glycols, polypropylenglycol, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, stearic acid and its salts,such as magnesium stearate, talc, lanolin, liquid paraffin, or mixtures thereof, for example, a mixture of water with one or more organic solvents, such as mixtures of water with alcohols. For oral and rectal may be used, in particular, pharmaceutical forms, such as, for example, tablets, film-coated tablets, tablets with sugar coating, granules, hard and soft gelatine capsules, suppositories, solutions, preferably oily, alcoholic or aqueous solutions, syrups, juices or drops, in addition, suspensions or emulsions. For parenteral administration, e.g. by injection or infusion, can be used in particular pharmaceutical forms, such as solutions, preferably aqueous solutions. For local application can be applied, in particular, pharmaceutical forms, such as ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions or powders. Additional suitable pharmaceutical forms are, for example, implants and patches and forms adapted for inhalation. The compounds of formula I and their physiologically acceptable salts and physiologically acceptable solvate of any of them can also be lyophilisate and apply lyophilizate, for example, to obtain the injectable compositions. Liposomal compositions are also suitable in particular for local what about the application. As examples of the types of auxiliary substances or additives that may be contained in the pharmaceutical compositions and medicines, mention can be made of lubricants, preservatives, thickeners, stabilizers, leavening agents, wetting agents, agents for achieving a depot effect, emulsifiers, salts of, for example, for influencing the osmotic pressure, buffer substances, dyes and fragrances. Pharmaceutical compositions and medicaments can also contain one or more other active ingredients and/or, for example, one or more vitamins.

As usual, the dose of the compounds of the formula I depends on the circumstances of the particular case and installed by the attending physician according to accepted rules and procedures. It depends, for example, input from the compounds of formula I and its activity and duration, nature and severity of the individual syndrome, gender, age, weight and individual responsiveness of the human or animal, which will be treated, whether the treatment of immediate or protracted or prophylactic, or on whether to impose any additional pharmaceutical active compounds in addition to the compound of formula I. Typically, in the case of the introduction of an adult weighing about 75 kg, the dose from about 0.1 mg to about 10 mg per kg per day, preferably from about 1 mg to about 10 mg per kg per day (in each case in mg per kg of body weight) is sufficient. The daily dose can be administered in the form of a single dose or divided into several individual doses, for example two, three or four separate doses. The introduction can also be done continuously, for example, by continuous injection or infusion. Depending on the circumstances of the particular case, it may be necessary to increase or decrease the dose in comparison with these doses.

In addition to the use of pharmaceutically active compounds in medicinal products for human and animals, the compounds of formula I can also be used as additives in biochemical research or as a research tool or for diagnostic purposes, for example, in in vitro diagnosis of biological samples, assuming the inhibition of renin. The compounds of formula I and their salts can also be used as intermediates, for example, for more pharmaceutically active substances.

The following examples illustrate the present invention.

Abbreviations:

ACN acetonitrile

B-OM-9-BBN B-methoxy-9-borabicyclo[3.3.1]nonan

DCM dichloromethane

DMF dimethylformamide

DMSO dimethyl sulfoxide

EA acetate

HEP n-heptane

MOH methanol

NMM N-methylmorpholin the

NMP N-methylpyrrolidine-2-he

S-PHOS 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl

TFA triperoxonane acid

THF tetrahydrofuran

When compounds containing main group, clear preparative liquid chromatography high pressure (HPLC) on reversed-phase (RP) column material and, as is common, the eluent is a mixture of water and acetonitrile containing triperoxonane acid, they are usually obtained in the form of salt accession acid triperoxonane acid, depending on the treatment conditions, such as conditions of lyophilization. Content triperoxonane acid, whose number can vary and can be up to about two equivalents of acid in the case of compounds containing two basic groups, for example, are not indicated in the headings of examples and is not depicted in the structural formula, but indicate in the description of the examples. This applies correspondingly to the compounds which are in the form of another salt accession acid, such as salt accession acid chloroethanol acid, whose number may also vary and be up to about two equivalents of acid in the case of compounds containing, for example, two main groups, which are not indicated in the headings of examples and do not represent in traktornyh formulas, but is indicated in the description of examples. Data method preparative HPLC were as follows. Column: Waters Atlantis dC18 OBD, 30x100 mm, 5 μm. Flow rate: 60 ml/min Eluent A: ACN. Eluent B: water + 0.1% of TFA. Gradient: 10% A + 90% B to 90% A + 10% B for 10 minutes

Obtaining characteristics of connections

The compounds obtained in General okharakterizovali spectroscopic data and chromatographic data, in particular the mass spectra (MS) and HPLC retention time (Rt; in minutes), which received a combined analytical HPLC/MS receiving characteristics (LC/MS), and/or spectra of nuclear magnetic resonance (NMR). If not specified,1H-NMR spectra were recorded at 500 MHz in DMSO-d6as a solvent. When receiving the NMR characteristics give the chemical shift δ (ppm, ppm), the number of hydrogen atoms and multipletness (s: singlet, d: doublet, DD: doublet of doublet, t: triplet, dt: doublet of triplets, q: Quartet, m: multiplet; ush.: extended) peaks. When receiving MS characteristics given in the General mass number (m/z molecular ion peak (M, e.g. M+or associated ion, such as ion M+1 (e.g., M+1+; protonated molecular ion M+H+or ion M-17 (for example, M-17+; protonated molecular ion minus H2O), which were formed depending on the applied method of ionization. Oba is but a way of ionization was way electrospray ionization (ESI). The data used LC/MS methods were as follows.

The way LC1

Column: YMC J sphere H80, 33×2.1 mm, 4 μm; flow rate: 1.3 ml/min; eluent A: ACN + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: from 5% A + 95% B to 95% A + 5% B for 2.5 min, then 95% A + 5% B for 0.5 min; MS method ionization: ESI+

The way LC2

Column: YMC J sphere H80, 33×2.1 mm, 4 μm; flow rate: 1.0 ml/min; eluent A: ACN + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: from 5% A + 95% B to 95% A + 5% B for 3.4 min, then 95% A + 5% B within 1,0 min; MS method ionization: ESI+

The way LC3

Column: YMC J sphere H80, 33×2.1 mm, 4 μm; flow rate: 1.3 ml/min; eluent A: ACN + 0,08% formic acid; eluent B: water + 0.1% of formic acid; gradient: from 5% A + 95% B to 95% A + 5% B for 2.5 min, then 95% A + 5% B for 0.5 min; MS method ionization: ESI+

The way LC4

Column: YMC J ' sphere ODS H80, 20×2.1 mm, 4 μm; flow rate: 1.0 ml/min; eluent A: ACN; eluent B: water + 0.05% of TFA; gradient: from 4% A + 96% B to 95% A + 5% B within a 2.0 min, then 95% A + 5% B for 0.4 min, then up to 96% A + 4% B within 0,05 min; MS method ionization: ESI+

The way LC5

Column: YMC J sphere H80, 33×2.1 mm, 4 μm; flow rate: 1.3 ml/min; eluent A: ACN + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: 5% A + 95% B for 0.5 min, then to 95% A + 5% B within a 3.0 min, then 95% A + 5% B for 0.5 min; MS method ionization: ESI+

The way LC6

Column: YMC J sphere H80, 33×2.1 mm, 4 μm; flow rate: 1.0 ml/min; alwen is A: ACN + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: 2% A + 98% B for 1 min, then to 95% A + 5% B for 4 min, then 95% A + 5% B for 1.25 min; MS method ionization: ESI+

The way LC7

Column: YMC Pack Pro C18 RS, 33×2.1 mm, 4 μm; flow rate: 1.0 ml/min; eluent A: ACN + 0.1% of TFA; eluent B: water + 0.1% of TFA; gradient: from 5% A + 95% B to 95% A + 5% B for 2.5 min, then 95% A + 5% B for 0.5 min; MS method ionization: ESI+

The way LC8

Column: Waters XBridge C18, 33×2.1 mm, 4 μm; flow rate: 1.0 ml/min; eluent A: ACN + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: 5% A + 95% B within 0.3 min, then to 95% A + 5% B within 3.2 min, then 95% A + 5% B for 0.5 min; MS method ionization: ESI+

The way LC9

Column: YMC J sphere H80, 33×2.1 mm, 4 μm; flow rate: 1.0 ml/min; eluent A: ACN + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: 5% A + 95% B for 0.5 min, then to 95% A + 5% B within a 3.0 min, then 95% A + 5% B for 0.5 min; MS method ionization: ESI+

The way LC10

Column: Luna C18, 10×2 mm, 3 μm; flow rate: 1.1 ml/min; eluent A: ACN + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: from 7% A + 93% B to 95% A + 5% B within 1,2 min, then 95% A + 5% B for 0.2 min; MS method ionization: ESI+

The way LC11

Column: Waters XBridge C18, 33×2.1 mm, 4 μm; flow rate: 1.0 ml/min; eluent A: ACN + 0.1% of TFA; eluent B: water + 0,08% TFA; gradient: from 3% A + 97% B to 60% A + 40% B within 3.5 min, then to 98% A + 2% B for 1.5 min; MS method ionization: ESI+

Example 1

[1-Phenyl-2-(2-m is tolfanate)-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 1-Phenyl-1H-pyrrolo[3,2-b]pyridine

To a mixture of 4-azaindole (1.20 g, 10.2 mmol), copper iodide(I) (290 mg, 1.53 mmol), 8-hydroxyquinoline solution (221 mg, 1.53 mmol) and potassium carbonate (1.55 g, and 11.2 mmol) in DMSO (24 ml) was added iadanza (1.25 ml, and 11.2 mmol). The reaction mixture was stirred at 130°C for 3 hours. Then the mixture was cooled to room temperature, and the solution was added ammonium hydroxide (10% in water) and EA. The organic layer was separated, washed twice with saturated saline solution, dried over sodium sulfate, filtered and evaporated under reduced pressure. Column chromatography on silica gel (EA/HEP) to give 560 mg stated in the connection header.

LC/MS (method LC4): m/z=195

Stage 2: 1-Phenyl-1,3-dihydropyrrolo[3,2-b]pyridine-2-he

To a stirred solution of 610 mg (3.14 mmol) of compound of stage 1 in tert-butanol (23 ml) and water (23 ml) was added dropwise over 20 min bromine (676 μl, 13,2 mmol). Then the reaction mixture was treated with a saturated solution of sodium bicarbonate until a pH of approximately 6.5 to 7, and then added EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The resulting solid residue was dissolved in ethanol (45 ml), was added palladium on charcoal (668 mg, 628 mmol, 10%), and the reaction mixture was first made(6 bar H 2) at room temperature over night. The mixture was filtered through celite, and the solvent was removed under reduced pressure to obtain 660 mg of the crude stated in the connection header.

LC/MS (method LC4): m/z=211

Stage 3: 2-Chloro-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde

A solution of DMF (1,36 ml) in DCM (3.5 ml) was cooled to 0°C and stirred under argon. Within 15 min was added phosphorus oxychloride (1,32 ml, 14.1 mmol)and the mixture was stirred for 30 min at 0°C. the Connection stage 2 (660 mg, 3.14 mmol) was dissolved in DCM (10 ml) and then added to a cooled solution of pyridine (864 μl, of 10.7 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was slowly poured into 300 ml of ice, and in a few minutes was added DCM. The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The resulting solid residue was dissolved in DCM (10 ml) and phosphorus oxychloride (1,32 ml, 14.1 mmol) and was heated at 100°C for 2 hours. After cooling, the mixture was slowly poured into 300 ml of ice, and in a few minutes was added DCM. The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. Column chromatography on silica gel (EA/HEP) to give 508 mg stated in the connection header.

LC/MS (method LC4): m/z=257

Stud is I 4: 2-Chloro-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid

Connection stage 3 (508 mg, to 1.98 mmol) was dissolved in tert-butanol (25 ml) and 2-methyl-2-butene (5 ml), was added a solution of sodium chlorite (1.07 g, to 11.9 mmol) and sodium dihydrophosphate (950 mg, a 7.92 mmol) in water (10 ml). The reaction mixture was stirred at room temperature for 48 hours. The mixture was diluted with water and was extracted with EA. The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 474 mg of the crude stated in the connection header.

LC/MS (method LC4): m/z=273

Step 5: tert-Butyl ether 4-(2-chloro-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl)piperazine-1-carboxylic acid

To a solution of 460 mg (1,69 mmol) of compound of stage 4 in DMF (24 ml) and NMM (478 μl, 4.35 mmol) was added tetrafluoroboric O-(cyano(etoxycarbonyl)methylamino)-N,N,N',N'-tetramethylurea (627 mg, at 1.91 mmol)and the mixture was stirred at room temperature for 30 minutes Then added tert-butyl 1-piperidinecarboxylate (356 mg, at 1.91 mmol)and the reaction mixture was stirred over night. The mixture is extinguished with water and was extracted with EA. The organic layer was separated, washed with a saturated solution of sodium bicarbonate, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (EA (70-95%)/HEP). Received 390 mg stated in the connection header.

LC/MS (method LC4): m/z=441

To a solution of 2-METHYLPHENOL cases (36.8 mg, 133 μmol) in NMP (2 ml) was added sodium hydride (15,0 mg, 375 μmol, 60% dispersion in mineral oil), and the suspension was stirred at room temperature under argon for 20 minutes After addition of 50.0 mg (113 mmol) of the compound stage 5 the reaction mixture was stirred for 2 hours at 140°C in a microwave reactor. The mixture is extinguished with water and was extracted with EA. Stated in the title compound was purified by chromatography on silica gel (EA (70-95%)/HEP) and directly used in the next stage.

LC/MS (method LC4): m/z=513

Stage 7: [1-Phenyl-2-(2-methylphenoxy)-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

A solution of compound of stage 6 in DCM (12 ml) and TFA (3 ml) was stirred at room temperature for 2 hours. The solvent was evaporated, and the resulting solid residue was purified preparative HPLC. The fractions containing the stated in the title compound were combined and were liofilizovane during the night. Stated in the title compound was obtained in the form of bissoli triperoxonane acid [1-phenyl-2-(2-methylphenoxy)-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone in the form of a solid residue of white. Output: 26,5 mg

LC/MS (method LC1): m/z=412,18; Rt=1,06 min

1H-NMR: δ (ppm)=to 2.18 (s, 3H), 2,98 (ush. d, 4H), 3,60 (ush. d, 4H), 7,01? 7.04 baby mortality (m, 1H), 7,10-7,11 (m, 2H), 7,19 (d, 1H), 7,28 (kV, 1H), 7,50-rate of 7.54 (m, 1H), 7,56-to 7.61 (m, 4H), to 7.67 (d, 1H), 8,46 (DD, 1H), 8,75 (the sh. s, 2H).

Example 2

(2-Benzyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl)piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-(2-benzyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl)piperazine-1-carboxylic acid

To a solution of palladium(II) acetate (1,27 mg, the 5.65 mmol) and S-PHOS (with 4.64 mg, 11.3 μmol) in DMF (1.5 ml) was added potassium phosphate (71,9 mg, 339 μmol), compound of example 1, stage 5 (of 49.8 mg, 113 μmol) and (B-benzyl-9-borabicyclo[3,3,1]nonan (452 μl, 226 mmol, 0.5 M in THF). The reaction mixture was heated at 100°C for 1 hour and then was added 2 n sodium hydroxide solution. The mixture was extracted with EA, the organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (EA (75-99%)/HEP). Received 56,0 mg stated in the connection header.

LC/MS (method LC4): m/z=497

Stage 2: (2-Benzyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl)piperazine-1-ylmethanone

From the connection phase 1 (56,0 mg, 113 μmol) mentioned in the title compound were obtained analogously as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid (2-benzyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl)piperazine-1-ylmethanone. Output: 35,7 mg.

LC/MS (method LC1): m/z=396,20; Rt=min 1,05

1H-NMR: δ (ppm)=3,11 (ush. d, 4H), 3,60 (ush. s, 2H), 3,83 (ush. s, 2H), 4,22 (s, 2H), 6,86-to 6.88 (m, 2H), 7,10-7,14 (m, 3H), 7,24 (kV, 1H), 7,31-7,33 (m, 2H), 7,47 (d, 1H), 7,54-7,56 (m, 3H), 8,49 (DD, 1H), 882 (ush. s, 2H).

Example 3

[2-(2-Methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(2-methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

A solution of 2-methylbenzylamine (454 μl, 227 mmol, 0.5 M in THF) was added dropwise at -78°C to a solution of B-OM-9-BBN (1.13 ml, 1.13 mmol, 1 M in hexane). The cooling bath was removed and the mixture was stirred at room temperature for 30 minutes was Added DMF (2 ml), followed by the addition of the compound of example 1, step 5, (50.0 mg, 113 μmol), palladium(II) acetate (2.55 mg, 11.3 mmol) and S-PHOS (9,31 mg, 22.7 μmol). The reaction mixture was heated at 100°C with stirring for 3.5 hours. After cooling, the mixture was diluted with water and was extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (EA/HEP). The fractions containing the stated in the title compound were combined and evaporated to obtain 38 mg stated in the connection header.

LC/MS (method LC4): m/z=511

Stage 2: [2-(2-Methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

From the connection phase 1 (38,0 mg of 74.4 mmol) mentioned in the title compound were obtained analogously as described in example 1, step 7, and obtained forme bissoli triperoxonane acid [2-(2-methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone. Output: 26,2 mg.

LC/MS (method LC1): m/z=410,21 ; Rt=1,09 min

1H-NMR: δ (ppm)=1,94 (s, 3H), 3,05 (ush. s, 4H), 3,56 (ush. s, 2H), 3,74 (ush. s, 2H), 4,15 (ush. s, 2H), 6,83 (d, 1H), of 6.96-7,05 (m, 3H), 7,24 (kV, 1H), 7,32-7,34 (m, 2H), 7,47 (d, 1H), 7,51-rate of 7.54 (m, 3H), 8,49 (DD, 1H), 8,77 (ush. s, 2H).

Example 4

[2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

To zinc (29,7 mg, 454 mmol) in dry THF (300 ml) in a dry flask in an argon atmosphere was added 1,2-dibromoethane (0,49 μl, 5,67 Microm). The mixture was heated three times to boil a hot air gun. After 5 min the flask was placed in an ice bath and slowly added the solution of 3-fluoro-2-methylbenzylamine (23,0 mg, 227 μmol) in dry THF (700 μl) so that the temperature was maintained equal to 0°C. the Mixture was stirred at 0°C for 3 hours. Then the cooled suspension was added dropwise to a pre-cooled solution (-78°C) B-OM-9-BBN (1.13 ml, 1.13 mmol, 1 M in hexane). The mixture was stirred at room temperature for 30 minutes Then added DMF (4 ml), followed by the addition of the compound of example 1, step 5, (50.0 mg, 113 μmol), palladium(II) acetate (2.55 mg, 11.3 mmol) and S-PHOS (9,31 mg, 22.7 μmol). The reaction mixture was stirred at 100°C for 3.5 hours. After cooling, the mixture was extinguished with water and extragere the Ali EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography to obtain 44 mg stated in the connection header.

LC/MS (method LC4): m/z=529

Stage 2: [2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

From the connection phase 1 (43,0 mg, 81,3 µmol) mentioned in the title compound were obtained analogously as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid [2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone. Output: 30 mg

LC/MS (method LC1): m/z=428,20; Rt=1,13 min

1H-NMR: δ (ppm)=1,85 (s, 3H), 3,10 (ush. s, 4H), 3,59 (ush. s, 2H), 3,76 (ush. s, 2H), is 4.21 (s, 2H), 6,69 (d, 1H), 6,92 (t, 1H), 7,00 (kV, 1H), 7,25 (kV, 1H), 7,31-7,33 (m, 2H), of 7.48 (d, 1H), 7,51-7,53 (m, 3H), and 8.50 (DD, 1H), 8,82 (ush. s, 2H).

Example 5

[2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

From the compound of example 1, step 5, (50.0 mg, 113 μmol) and 5-fluoro-2-METHYLPHENOL untreated mentioned in the title compound were obtained analogously as described in example 1, step 6.

LC/MS (method LC4): m/z=531

Stage 2: [2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridin-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from untreated connection stage 1 similarly as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid [2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone. Output: 30,6 mg.

LC/MS (method LC1): m/z=430,18; Rt=1,10 min

1H-NMR: δ (ppm)=a 2.13 (s, 3H), 3.04 from (ush. d, 4H), 3,66 (ush. d, 4H), to 6.88 (dt, 1H), 7,14 (DD, 1H), 7,22 (m, 1H), 7,28 (kV, 1H), 7,50-rate of 7.54 (m, 1H), EUR 7.57 to 7.62 (m, 4H), of 7.65 (d, 1H), of 8.47 (DD, 1H), 8,81 (ush. s, 2H).

Example 6

[2-(3-Fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(3-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

From the compound of example 1, step 5, (50.0 mg, 113 μmol) and 3-fluoro-2-METHYLPHENOL untreated mentioned in the title compound were obtained analogously as described in example 1, step 6.

LC/MS (method LC4): m/z=531

Stage 2: [2-(3-Fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from untreated connection stage 1 similarly as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid [2-(3-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone. Output: 29,9 mg.

LC/MS (method LC1): m/z=430,18; Rt=1,11 is in

1H-NMR: δ (ppm)=2,09 (s, 3H), 3,02 (ush. d, 4H), 3,63 (ush. d, 4H), to 6.95 (t, 1H), 7,00 (d, 1H), 7,13 (kV, 1H), 7,28 (kV, 1H), 7,50-rate of 7.54 (m, 1H), 7,56-to 7.61 (m, 4H), of 7.65 (d, 1H), of 8.47 (DD, 1H), 8,73 (ush. s, 2H).

Example 7

[2-(2-Fluoro-6-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(2-fluoro-6-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

From the compound of example 1, step 5, (30.0 mg, 68 μmol) and 2-fluoro-6-METHYLPHENOL untreated mentioned in the title compound were obtained analogously as described in example 1, step 6.

LC/MS (method LC4): m/z=531

Stage 2: [2-(2-Fluoro-6-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from untreated connection stage 1 similarly as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid [2-(2-fluoro-6-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone. Output: 6,1 mg

LC/MS (method LC4): m/z=431,1; Rt=0,934 min

1H-NMR (500 MHz, CDCl3): δ (ppm)=of 2.16 (s, 3H), 3,19 (ush. s, 4H), 3,70 (ush. s, 4H), 6,79 (d, 1H), 6.90 to (t, 1H), 7,13 (kV, 1H), 7,40 (kV, 1H), 7,46 (DD, 2H), 7,56-to 7.61 (m, 3H), 7,83 (d, 1H), 8,58 (d, 1H), 9,90 (ush. s, 2H).

Example 8

[2-(3-fluoro-2-methylbenzyl)-5-methoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 5-Methoxy-1-f the Nile-1H-pyrrolo[3,2-b]pyridine

Stated in the title compound was obtained from 5-methoxy-1H-pyrrolo[3,2-b]pyridine (1,59 g of 10.7 mmol; see, D. Mazeas et al., Heterocycles 50 (1999), 1065) similarly as described in example 1, stage 1. Output: 1,83,

LC/MS (method LC4): m/z=225

Stage 2: 5-Methoxy-1-phenyl-1,3-dihydropyrrolo[3,2-b]pyridine-2-he

Stated in the title compound was obtained from the compound of stage 1 (1.70 g, 7,58 mmol) analogously as described in example 1, step 2. Output: 2,30,

LC/MS (method LC4): m/z=241

Stage 3: 2-Chloro-5-methoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde

Stated in the title compound was obtained from compound stage 2 (790 mg, 3,29 mmol) analogously as described in example 1, stage 3. Yield: 820 mg

LC/MS (method LC4): m/z=287

Stage 4: 2-Chloro-5-methoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid

Stated in the title compound was obtained from compound stage 3 (920 mg, is 3.21 mmol) analogously as described in example 1, stage 4, except that the reaction mixture was stirred at 100°C for 2 hours. Output: 1,09,

LC/MS (method LC4): m/z=303

Step 5: tert-Butyl ether 4-(2-chloro-5-methoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl)piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 4 (658 mg, of 3.53 mmol) analogously as described in example 1, stage 5. Output: 1,12,

LC/MS (method LC4): m/z=471

Step 6: tert-Butyl EPE is 4-[2-(3-fluoro-2-methylbenzyl)-5-methoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 5 (100 mg, 212 μmol) analogously as described in example 4, stage 1. Yield: 83 mg

LC/MS (method LC4): m/z=559

Stage 7: [2-(3-fluoro-2-methylbenzyl)-5-methoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 6 (23 mg, 41.2 mmol) was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave to 15.9 mg stated in the title compound in the form of a dihydrochloride [2-(3-fluoro-2-methylbenzyl)-5-methoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC3): m/z=458,21; Rt=1,55 min

1H-NMR: δ (ppm)=1,84 (s, 3H), 3,11 (ush. s, 4H), 3,70 (ush. d, 4H), 3,93 (s, 3H), of 4.16 (s, 2H), 6,63 (d, 1H), 6,66 (d, 1H), 6,91 (t, 1H), 7,00 (kV, 1H), 7,28-7,30 (m, 2H), 7,35 (d, 1H), 7,49-7,52 (m, 3H), 9,04 (ush. s, 2H).

Example 9

[2-(3-fluoro-2-methylbenzyl)-5-hydroxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

The solution tribromide boron (537 μl, 537 mmol, 1 M in DCM) was added dropwise at -78°C to a solution of compound of example 8, step 6, (50.0 mg, or 89.5 mmol) in DCM (2 ml). The cooling bath was removed and the mixture was stirred at room temperature overnight. The mixture was again cooled to -78°C and slowly added tribromide boron (to 3.58 ml, 3.58 mmol, 1 M in DCM). Ohla is giving bath was removed, and the mixture was stirred at 65°C for 8 days. The mixture was slowly poured into ice, and in a few minutes was added DCM. The aqueous layer was separated and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (7 M ammonia in MOH (1,5-15%)/DCM). The obtained solid residue was dissolved in a small quantity of MOH, added chloroethanol acid (0.1 M), and the mixture was liofilizovane during the night in order to get 21,3 mg stated in the title compound in the form of a dihydrochloride [2-(3-fluoro-2-methylbenzyl)-5-hydroxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC1): m/z=444,20; Rt=1,17 min

1H-NMR (400 MHz, DMSO-d6): δ (ppm)=1,84 (s, 3H), 2,98 (ush. s, 4H), Android 4.04 (s, 2H), 6,29 (d, 1H), to 6.67 (d, 1H), 6,91 (t, 1H), 7,01 (kV, 1H), 7,31-7,33 (m, 3H), 7,50-7,53 (m, 3H), 9,29 (ush. s, 2H).

Example 10

[2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 1-Phenyl-1H-pyrrolo[3,2-c]pyridine

To a mixture of 5-azaindole (780 mg, 6,60 mmol), copper iodide(I) (25.1 mg, 132 μmol), (1S,2S)-(+)-1,2-diaminocyclohexane (162 μl, 1.35 mmol) and potassium phosphate (2,52 g, to 11.9 mmol) in dioxane (24 ml) was added iadanza (739 μl, 6,60 mmol). The reaction mixture was stirred overnight at 110°C. Then the mixture was cooled to room temperature, filtered through silica gel and the silica gel was washed with EA. The combined filtrates were evaporated when pony is hinnon pressure, and the resulting solid residue was purified preparative HPLC. The fractions containing the stated in the title compound were combined and were liofilizovane during the night. Output: 1,28,

LC/MS (method LC4): m/z=195

Stage 2: 1-Phenyl-1,3-dihydropyrrolo[3,2-c]pyridine-2-he

Untreated mentioned in the title compound was obtained from the compound of stage 1 (1.28 g, 6,60 mmol) analogously as described in example 1, step 2.

LC/MS (method LC4): m/z=211

Stage 3: 2-Chloro-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde

Stated in the title compound was obtained from untreated connection stage 2 analogously as described in example 1, stage 3. Output: 480 mg

LC/MS (method LC4): m/z=257

Stage 4: 2-Chloro-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid

Stated in the title compound was obtained from compound stage 3 (480 mg, of 1.87 mmol) analogously as described in example 1, stage 4, except that the reaction mixture was stirred at 100°C for 90 min Output: 1,14,

LC/MS (method LC4): m/z=273

Step 5: tert-Butyl ether 4-(2-chloro-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-carbonyl)piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 4 (460 mg, 1,69 mmol) analogously as described in example 1, stage 5. Output: 325 mg.

LC/MS (method LC4): m/z=441

Step 6: tert-Butyl ether 4-[2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-Pierre is lo[3,2-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 5 (187 mg, 424 μmol) and 5-fluoro-2-METHYLPHENOL similarly as described in example 1, step 6. Yield: 173 mg

LC/MS (method LC4): m/z=531

Stage 7: [2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 6 (173 mg, 327 μmol) was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 66 mg stated in the title compound in the form of a dihydrochloride [2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC3): m/z=430,18; Rt=0,93 min

1H-NMR (400 MHz, DMSO-d6): δ (ppm)=and 2.14 (s, 3H), 3,01 (ush. s, 4H), 3,70 (ush. s, 4H), 6,92 (dt, 1H), 7,12 (DD, 1H), 7,24 (t, 1H), EUR 7.57-7,72 (m, 6H), 8,54 (d, 1H), to 9.32 (s, 1H), 9,45 (ush. s, 2H).

Example 11

(2-Benzyl-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl)piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-(2-benzyl-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-carbonyl)piperazine-1-carboxylic acid

From the compound of example 10, step 5, (49,8 mg, 113 μmol) mentioned in the title compound were obtained analogously as described in example 2, stage 1. Yield: 37 mg

LC/MS (method LC4): m/z=497

Stage 2: (2-Benzyl-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl)piperazine-1-and metano

From the connection phase 1 (37,0 mg, to 74.5 mmol) mentioned in the title compound were obtained analogously as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid (2-benzyl-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl)-piperazine-1-ylmethanone. Output: 10,9 mg

LC/MS (method LC1): m/z=396,20; Rt=1,07 min

1H-NMR: δ (ppm)=3,72 (ush. s, 4H), 4,19 (s, 2H), 6,82-6,84 (m, 2H), 7,11-7,13 (m, 3H), 7,39 (ush. s, 2H), 7,49 (d, 1H), EUR 7.57-7,63 (m, 3H), of 8.47 (d, 1H), 8,91 (ush. s, 2H), was 9.33 (s, 1H).

Example 12

[2-(2-Methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(2-methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

From the compound of example 10, step 5, (49,8 mg, 113 μmol) mentioned in the title compound were obtained analogously as described in example 3, stage 1. Output: 44 .LC/MS (method LC4): m/z=511

Stage 2: [2-(2-Methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

From the connection phase 1 (to 44.0 mg, 86,2 µmol) mentioned in the title compound were obtained analogously as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid [2-(2-methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone. Output: 17,7 mg.

LC/MS (method LC1): m/z=410,21; Rt=1,08 min

1H-NMR: δ (ppm)=1,92 (s, 3H), 2.95 and (ush. s, 2H), and 3.16 (ush. s, 2H), 4,13 (s, 2H), for 6.81 (d, 1H), of 6.96-7,06 (m, 3H), 7,40 (ush. s, 2H), of 7.48 (ush. d, 1H), 7,55-of 7.60 (m, 3H), of 8.47 (d, 1H), 8,89 (ush. s, 2H), 9,31 (s, 1H).

Example 13

[2-(2-Chloro-6-terbisil)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(2-chloro-6-terbisil)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

From the compound of example 10, step 5, (49,8 mg, 113 μmol) mentioned in the title compound were obtained analogously as described in example 4, stage 1. Yield: 26 mg

LC/MS (method LC4): m/z=550

Stage 2: [2-(2-Chloro-6-terbisil)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

From the connection phase 1 (26,0 mg, with 47.4 mmol) mentioned in the title compound were obtained analogously as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid [2-(2-chloro-6-terbisil)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone. Output: 2,7 mg

LC/MS (method LC4): m/z=449,10; Rt=0,865 min

1H-NMR (400 MHz, MOH-D4): δ (ppm)=3,12 (ush. s, 2H), 3,65 (ush. s, 2H), 3,92 (ush. s, 2H), 4,39 (s, 2H), 7,00 (dt, 1H), 7,15 (d, 1H), 7.24 to 7,30 (m, 1H), 7,45-of 7.48 (m, 2H), 7,56 (ush. s, 1H), to 7.61-7,66 (m, 3H), to 8.41 (ush. s, 1H), of 9.21 (ush. s, 1H).

Example 14

[2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-carbonyl]piperazine-1-carboxylic KIS is the notes

From the compound of example 10, step 5, (97 mg, 220 μmol) mentioned in the title compound were obtained analogously as described in example 4, stage 1. Output: 30 mg

LC/MS (method LC4): m/z=529

Stage 2: [2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

The connection phase 1 (to 28.3 mg of 53.5 mmol) was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 20,1 mg stated in the title compound in the form of a dihydrochloride [2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC1): m/z=428,20; Rt=1,04 min

1H-NMR: δ (ppm)=1,82 (s, 3H), is 3.08 (ush. d, 4H), 3,71 (ush. d, 4H), 4,20 (s, 2H), to 6.67 (d, 1H), 6,93 (t, 1H), 7,00 (kV, 1H), 7,41 (ush. s, 2H), 7,52 (d, 1H), 7,55-of 7.60 (m, 3H), of 8.47 (d, 1H), 9,43 (s, 1H).

Example 15

[2-(5-fluoro-2-methylphenoxy)-1-(4-forfinal)-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 1-(4-Forfinal)-1H-pyrrolo[3,2-c]pyridine

Stated in the title compound was obtained from 5-azaindole (1,00 g of 8.47 mmol) and 1-fluoro-4-yogashala similarly as described in example 1, stage 1. Output: 1,23,

LC/MS (method LC4): m/z=213

Stage 2: 1-(4-Forfinal)-1,3-dihydropyrrolo[3,2-c]pyridine-2-he

Stated in the title compound was obtained from compound a hundred is AI 1 (1.23 g, 5,79 mmol) analogously as described in example 1, step 2. Output: 1,27,

LC/MS (method LC4): m/z=229

Stage 3: 2-Chloro-1-(4-forfinal)-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde

Stated in the title compound was obtained from compound stage 2 (1.27 g, to 5.56 mmol) analogously as described in example 1, stage 3. Output: 278 mg.

LC/MS (method LC4): m/z=275

Stage 4: 2-Chloro-1-(4-forfinal)-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid

Untreated mentioned in the title compound was obtained from compound stage 3 (278 mg, 1.01 mmol) analogously as described in example 1, stage 4, except that the reaction mixture was stirred at 100°C for 2 hours.

LC/MS (method LC4): m/z=291

Step 5: tert-Butyl ether 4-[2-chloro-1-(4-forfinal)-1H-pyrrolo[3,2-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from untreated connection stage 4 similarly as described in example 1, stage 5. Output: 386 mg

LC/MS (method LC4): m/z=459

Step 6: tert-Butyl ether 4-[2-(5-fluoro-2-methylphenoxy)-1-(4-forfinal)-1H-pyrrolo[3,2-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Untreated mentioned in the title compound was obtained from compound stage 5 (50.0 mg, 109 μmol) and 5-fluoro-2-METHYLPHENOL similarly as described in example 1, step 6.

LC/MS (method LC4): m/z=549

Stage 7: [2-(5-fluoro-2-methylphenoxy)-1-(4-forfinal)-1H-pyrrolo[3,2-a]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from untreated connection stage 6 in the same manner as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid [2-(5-fluoro-2-methylphenoxy)-1-(4-forfinal)-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone. Output: to 25.3 mg

LC/MS (method LC1): m/z=448,17; Rt=1,10 min

1H-NMR: δ (ppm)=and 2.14 (s, 3H), 3.04 from (ush. s, 4H), 3,66 (ush. s, 4H), 6,93 (dt, 1H), 7,11 (DD, 1H), 7,26 (t, 1H), of 7.48-7,52 (m, 2H), 7,74-to 7.77 (m, 3H), 8,59 (d, 1H), 9,04 (ush. s, 2H), 9,29 (s, 1H).

Example 16

[1-Phenyl-2-(2-methylphenoxy)-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 1-Phenyl-1H-pyrrolo[2,3-c]pyridine

Stated in the title compound was obtained from 6-azaindole (1,00 g of 8.47 mmol) analogously as described in example 10, step 1. Output: 1,20,

LC/MS (method LC4): m/z=195

Stage 2: 1-Phenyl-1,3-dihydropyrrolo[2,3-c]pyridine-2-he

Untreated mentioned in the title compound was obtained from the compound of stage 1 (400 mg, to 2.06 mmol) analogously as described in example 1, step 2.

LC/MS (method LC4): m/z=211

Stage 3: 2-Chloro-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde

Stated in the title compound was obtained from untreated connection stage 2 analogously as described in example 1, stage 3. Yield: 111 mg

LC/MS (method LC4): m/z=257

Stage 4: 2-Chloro-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid

Declared in the header is the connection received from the connection stage 3 (218 mg, 0.85 mmol) analogously as described in example 1, stage 4, except that the reaction mixture was stirred at 100°C for 2 hours. Output: 217 mg

LC/MS (method LC4): m/z=272

Step 5: tert-Butyl ether 4-(2-chloro-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 4 (217 mg, 796 mmol) analogously as described in example 1, stage 5. Yield: 191 mg

LC/MS (method LC4): m/z=441

Step 6: tert-Butyl ether 4-[1-phenyl-2-(2-methylphenoxy)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 5 (43,0 mg, 97.5 mmol) analogously as described in example 1, step 6, and purification preparative HPLC. Yield: 27 mg

LC/MS (method LC4): m/z=513

Stage 7: [1-Phenyl-2-(2-methylphenoxy)-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-yl-metano

Stated in the title compound was obtained from compound stage 6 (27.0 mg, 52,7 μmol) analogously as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid [1-phenyl-2-(2-methylphenoxy)-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone. Output: 24 mg.

LC/MS (method LC1): m/z=412,19; Rt=0,98 min

1H-NMR: δ (ppm)=of 2.21 (s, 3H), 2,96 (ush. s, 4H), 7,11-7,19 (m, 2H), 7.23 percent (d, 1H), 7,27 (d, 1H), to 7.61-to 7.64 (m, 1H), 7,66-of 7.70 (m, 2H), 7,73-7,76 (m, 2H), with 8.05 (d, 1H), 8,46 (d, 1H), 8,88 (ush. s, 3H).

Example 17

(2-Benzyl-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl)piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-(2-benzyl-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperazine-1-carboxylic acid

Untreated mentioned in the title compound was obtained from the compound of example 16, step 5, (50.0 mg, 113 μmol) analogously as described in example 2, stage 1. Yield: 105 mg

LC/MS (method LC4): m/z=497

Stage 2: (2-Benzyl-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl)piperazine-1-ylmethanone

Stated in the title compound was obtained from the compound of stage 1 (56,3 mg, 113 μmol) analogously as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid (2-benzyl-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl)piperazine-1-ylmethanone. Yield: 25 mg

LC/MS (method LC1): m/z=396,20; Rt=0,93 min

1H-NMR: δ (ppm)=2,90 (ush. s, 2H), 3,21 (ush. s, 2H), 4,25 (s, 2H), 6.87 in-6,89 (m, 2H), 7,13-7,16 (m, 3H), 7,51 (ush. s, 2H), to 7.61-to 7.64 (m, 3H), 8,13 (d, 1H), 8,45 (d, 1H), 8,77 (s, 1H), 8,99 (ush. d, 2H).

Example 18

[2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from the compound of example 16, step 5, (100 mg, 227 μmol) analogously as described in example 4, stage 1. Yield: 180 mg

LC/MS (method LC4): m/z=529

Stage 2: [2-(3-fluoro-2-methylbenzyl)1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 1 (120 mg, 226 μmol) was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 36,1 mg stated in the title compound in the form of a dihydrochloride [2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC3): m/z=428,20; Rt=1,06 min

1H-NMR: δ (ppm)=1,85 (s, 3H), 2,90 (ush. s, 2H), 3,18 (ush. s, 2H), 3,74 (ush. s, 2H), 4,28 (ush. s, 2H), 6,70 (d, 1H), 6,95 (t, 1H), 7,01 (kV, 1H), 7,51 (ush. s, 2H), 7,58-to 7.61 (m, 3H), by 8.22 (d, 1H), of 8.47 (d, 1H), 8,77 (s, 1H), 9,41 (ush. s, 1H), 9,60 (ush. s, 1H).

Example 19

[2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Untreated mentioned in the title compound was obtained from the compound of example 16, step 5, (100 mg, 227 μmol) and 5-fluoro-2-METHYLPHENOL similarly as described in example 1, step 6.

LC/MS (method LC4): m/z=531

Stage 2: [2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

The crude compound stage 1 was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, relax is chloroethanol acid (0.1 M) and lyophilization overnight gave 25,9 mg stated in the title compound in the form of a dihydrochloride [2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC3): m/z=430,18; Rt=1,04 min

1H-NMR: δ (ppm)=2,17 (s, 3H), 2,98 (ush. s, 4H), 3,62 (ush. s, 4H), of 6.99 (dt, 1H), 7,30 (m, 2H), a 7.62 (t, 1H), 7,68 (t, 2H), of 7.75 (d, 2H), 8,10 (d, 1H), of 8.47 (d, 1H), 8,87 (s, 1H), 9,40 (ush. s, 2H).

Example 20

[2-(5-fluoro-2-methylphenoxy)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 5-Methoxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine

To a mixture of 5-methoxy-1H-pyrrolo[2,3-c]pyridine (6,00 g, 40,5 mmol; see, D. Mazeas et al., Heterocycles 50 (1999), 1065), acetylacetonate, copper(II) (1.06 g, of 4.05 mmol) and potassium carbonate (11.2 g, 81.0 mmol) in DMSO (63 ml) was added iadanza (4,99 ml and 44.6 mmol). The reaction mixture was stirred at 130°C for 10 hours. Then the mixture was cooled to room temperature, and the solution was added ammonium chloride (20% in water). The mixture was filtered through celite, and the filtrate was extracted three times with EA. The organic layers were combined, dried over sodium sulfate, filtered and evaporated under reduced pressure. Column chromatography of the residue on silica gel (EA/HEP) gave 8,43 g declared in the header connection.

LC/MS (method LC4): m/z=225

Stage 2: 5-Methoxy-1-phenyl-1,3-dihydropyrrolo[2,3-c]pyridine-2-he

Stated in the title compound was obtained from the compound of stage 1 (of 7.68 g, to 34.3 mmol) analogously as described in example 1, step 2. Yield: 2.28,

LC/MS (method LC4): m/z=241

Stage 3: 2-Chloro-5-methoxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carb is legid

Stated in the title compound was obtained from compound stage 2 (2,23 g, 9,29 mmol) analogously as described in example 1, stage 3. Output: 914 mg

LC/MS (method LC4): m/z=287

Stage 4: 2-Chloro-5-methoxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid

Untreated mentioned in the title compound was obtained from compound stage 3 (790 mg, was 2.76 mmol) analogously as described in example 1, stage 4, except that the reaction mixture was stirred at 60°C for 2 hours.

LC/MS (method LC4): m/z=303

Step 5: tert-Butyl ether 4-(2-chloro-5-methoxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperazine-1-carboxylic acid

To a solution of the crude compound of stage 4, tert-butile 1 piperidinecarboxylate (565 mg, 3.03 mmol), the hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (581 mg, 3.03 mmol) and hydrate of 1-hydroxybenzotriazole (312 mg, to 2.29 mmol) in DMF (20 ml) was added NMM (911 µl of 8.27 mmol)and the reaction mixture was stirred at room temperature overnight. The mixture is extinguished with water and was extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (EA (5-35%)/HEP) to obtain 653 mg stated in the connection header.

LC/MS (method LC4): m/z=471

Step 6: tert-Butyl ether 4-[2-(5-fluoro-2-methylphenoxy)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-to rbony]piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 5 (100 mg, 212 μmol) and 5-fluoro-2-METHYLPHENOL similarly as described in example 1, step 6. Output: 98,0 mg.

LC/MS (method LC4): m/z=561

Stage 7: [2-(5-fluoro-2-methylphenoxy)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 6 (27.0 mg, 48.2 mmol) was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave to 21.9 mg stated in the title compound in the form of a dihydrochloride [2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC1): m/z=460,19; Rt=1,06 min

1H-NMR: δ (ppm)=a 2.13 (s, 3H), 2,98 (ush. s, 4H), to 3.89 (s, 3H), 6.89 in (dt, 1H), of 6.96 (s, 1H),? 7.04 baby mortality (DD, 1H), 7.23 percent (t, 1H), 7,50 (t, 1H), EUR 7.57-7,63 (m, 4H), to 8.14 (s, 1H), 9,06 (ush. s, 2H).

Example 21

[2-(5-fluoro-2-methylphenoxy)-5-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from the compound of example 20, step 6, (67,0 mg, 119 μmol) analogously as described in example 9 and was obtained in the form of a dihydrochloride [2-(5-fluoro-2-methylphenoxy)-5-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone. Output: 35,5 mg.

LC/MS (method LC1): m/z=446,18; Rt=1,07 min

1H-NMR: δ (ppm)=215 (, 3H), 2,99 (ush. s, 4H), 3,61 (ush. s, 4H), to 6.95 (dt, 1H), 7,03 (s, 1H), 7,21 (d, 1H), 7,27 (t, 1H), 7,54 (t, 1H), 7,60-to 7.67 (m, 4H), 8,10 (s, 1H), 9,27 (ush. s, 2H).

Example 22

[2-(3-fluoro-2-methylbenzyl)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(3-fluoro-2-methylbenzyl)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from the compound of example 20, step 5, (104 mg, 220 μmol) analogously as described in example 4, stage 1. Yield: 89 mg

LC/MS (method LC4): m/z=559

Stage 2: [2-(3-fluoro-2-methylbenzyl)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

The connection phase 1 ((25.0 mg, to 44.7 mmol) was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave to 18.4 mg stated in the title compound in the form of a dihydrochloride [2-(3-fluoro-2-methylbenzyl)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC1): m/z=458,21 ; Rt=1,08 min

1H-NMR: δ (ppm)=1,85 (s, 3H), 2,86 (ush. s, 2H), 3,18 (ush. s, 2H), 3,90 (s, 3H), 4,15 (s, 2H), to 6.67 (d, 1H), 6,92 (t, 1H), 6,98-7,02 (m, 2H), 7,37-7,39 (m, 2H), 7,51-rate of 7.54 (m, 3H), to 7.99 (s, 1H), 9,19 (ush. s, 2H).

Example 23

[2-(3-fluoro-2-methylbenzyl)-5-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]Pieper is Zin-1-ylmethanone

Stated in the title compound was obtained from the compound of example 22, step 1, (60,0 mg, 107 μmol) analogously as described in example 9. and received in the form of a dihydrochloride [2-(3-fluoro-2-methylbenzyl)-5-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone. Output: 29,3 mg.

LC/MS (method LC1): m/z=444,20; Rt=1,09 min

1H-NMR: δ (ppm)=1,84 (s, 3H), 2,93 (ush. s, 2H), 3,17 (ush. s, 2H), 3,56 (ush. s, 2H), 3,37 (ush. s, 2H), 4,20 (s, 2H), of 6.68 (d, 1H), 6,94 (t, 1H), 7,01 (kV, 1H), 7,17 (s, 1H), 7,41-the 7.43 (m, 2H), 7,53-of 7.55 (m, 3H), 8,01 (s, 1H), 9.28 are (ush. s, 1H), 9,56 (ush. s, 1H).

Example 24

[2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 1-Phenyl-1H-pyrrolo[2,3-b]pyridine

Stated in the title compound was obtained from 7-azaindole (1.18 g, 10.0 mmol) analogously as described in example 10, step 1. Output: 960 mg

LC/MS (method LC4): m/z=195

Stage 2: 3,3-Dibromo-1-phenyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-he

To a stirred solution of compound of stage 1 (960 mg, 4,94 mmol) in tert-butanol (36 ml) under argon was added broederbond pyridinium (6,32 g of 19.8 mmol) for 2 hours in small portions at a temperature between 30°C and 35°C. the Suspension was stirred at room temperature overnight. The solvent was evaporated, and the resulting solid residue was dissolved in EA and water. The organic layer was separated, sushi is over sodium sulfate, was filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (EA (15-40%)/HEP). The fractions containing the stated in the title compound were combined and evaporated. Output: 1,46,

LC/MS (method LC4): m/z=369

Stage 3: 1-Phenyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-he

Connection stage 2 (1.40 g, of 3.80 mmol) was dissolved in ethanol (160 ml), was added palladium on activated carbon (700 mg, 658 mmol, 10%). The reaction mixture was first made (1 bar H2) at room temperature over night. The mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. Column chromatography of the residue on silica gel (EA (50%)/HEP) gave 1.10 g declared in the header connection.

LC/MS (method LC4): m/z=211

Stage 4: 2-Chloro-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

Stated in the title compound was obtained from compound stage 3 (799 mg, of 3.80 mmol) analogously as described in example 1, stage 3. Yield: 290 mg

LC/MS (method LC4): m/z=257

Stage 5: 2-Chloro-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

Stated in the title compound was obtained from compound stage 4 (280 mg, of 1.09 mmol) analogously as described in example 1, stage 4, except that the reaction mixture was stirred at 100°C for 2 hours. Yield: 220 mg

LC/MS (method LC4): m/z=273

Step 6: tert-Butyl ether 4-(2-chloro-1-phenyl-1H-pyrrolo[2,3-b]pyridine-carbonyl)piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 5 (220 mg, 807 μmol) analogously as described in example 1, stage 5. Output: 292 mg.

LC/MS (method LC4): m/z=441

Step 7: tert-Butyl ether 4-[2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 6 (50.0 mg, 113 μmol) and 5-fluoro-2-METHYLPHENOL similarly as described in example 1, step 6, and purification preparative HPLC. Yield: 28 mg

LC/MS (method LC4): m/z=531

Stage 8: [2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from compound stage 6 (28,0 mg, 52,7 μmol) analogously as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid [2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone. Output: 30 mg

LC/MS (method LC1): m/z=430,18; Rt=1,23 min

1H-NMR: δ (ppm)=a 2.13 (s, 3H), 3,01 (ush. s, 4H), 3,67 (ush. s, 4H), 6,85 (dt, 1H), 6,93 (DD, 1H), 7,21 (t, 1H), 7,32 (kV, 1H), 7,42-7,46 (m, 1H), 7,50-EUR 7.57 (m, 4H), of 8.06 (d, 1H), 8,27 (d, 1H), 8,82 (ush. s, 2H).

Example 25

(2-Benzyl-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl)piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-(2-benzyl-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)piperazine-1-carboxylic acid

Declared in the header the connection was obtained from the compound of example 24, stage 6, (49,8 mg, 113 μmol) analogously as described in example 2, stage 1. Yield: 45 mg

LC/MS (method LC4): m/z=497

Stage 2: (2-Benzyl-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl)piperazine-1-ylmethanone

Stated in the title compound was obtained from the compound of stage 1 (40,0 mg, 80,5 μmol) analogously as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid (2-benzyl-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl)piperazine-1-ylmethanone. Yield: 19 mg

LC/MS (method LC1): m/z=396,20; Rt=1,17 min

1H-NMR: δ (ppm)=2,93 (ush. s, 2H), 3,17 (ush. s, 2H), 4,18 (s, 2H), 6,83-6,85 (m, 2H), 7,10 for 7.12 (m, 3H), 7,26-7,29 (m, 3H), of 7.48-to 7.50 (m, 3H), with 8.05 (DD, 1H), 8,21 (DD, 1H), 8,93 (ush. s, 2H).

Example 26

[2-(2-Methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from the compound of example 24, step 6, (66,0 mg, 150 μmol) analogously as described in example 3, stage 1, and purification preparative HPLC in the form of a white powder. Yield: 32 mg

LC/MS (method LC4): m/z=511

Stage 2: [2-(2-Methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from the compound of stage 1 (30.0 mg, 58.8 mmol) analogously as described in example 1, step 7, and received is in the form of bissoli triperoxonane acid [2-(2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone. Output: 29,4 mg.

LC/MS (method LC1): m/z=410,21 ; Rt=1,17 min

1H-NMR: δ (ppm)=1,93 (s, 3H), 2,86 (ush. s, 2H), 3.15 in (ush. s, 2H), 4,12 (s, 2H), PC 6.82 (d, 1H), 6,95? 7.04 baby mortality (m, 3H), 7,26-7,29 (m, 3H), 7,45-of 7.48 (m, 3H), of 8.04 (DD, 1H), they were 8.22 (DD, 1H), 8,84 (ush. s, 2H).

Example 27

[2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from the compound of example 24, step 6, (66,0 mg, 150 μmol) analogously as described in example 4, stage 1. Yield: 20 mg

LC/MS (method LC4): m/z=529

Stage 2: [2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from the compound of stage 1 (20.0 mg, 37.8 mmol) analogously as described in example 1, step 7, and obtained in the form of bissoli triperoxonane acid [2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone. Yield: 15 mg

LC/MS (method LC1): m/z=428,20; Rt=1,23 min

1H-NMR: δ (ppm)=1,84 (s, 3H), 2.95 and (ush. s, 2H), and 3.16 (ush. s, 2H), 3,62 (ush. s, 4H), 4,17 (s, 2H), to 6.67 (d, 1H), 6,91 (t, 1H), 6,99 (kV, 1H), 7,26-7,29 (m, 3H), 7,45-7,47 (m, 3H), of 8.06 (DD, 1H), they were 8.22 (DD, 1H), 8,80 (ush. s, 2H).

Example 28

[2-(5-fluoro-2-methylphenoxy)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 5-Methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine

Stated in the title compound was obtained from 5-methoxy-1H-pyrrolo[2,3-b]pyridine (6,00 g, 40,5 mmol) analogously as described in example 20, step 1. Output: 5,69,

LC/MS (method LC4): m/z=225

Stage 2: 5-Methoxy-1-phenyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-he

Stated in the title compound was obtained from the compound of stage 1 (of 5.68 g, to 25.3 mmol) analogously as described in example 1, step 2. Output: 1,71,

LC/MS (method LC4): m/z=241

Stage 3: 2-Chloro-5-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

Stated in the title compound was obtained from compound stage 2 (1.56 g, of 6.49 mmol) analogously as described in example 1, stage 3. Output: 475 mg.

LC/MS (method LC4): m/z=287

Stage 4: 2-Chloro-5-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

Stated in the title compound was obtained from compound stage 3 (500 mg, of 1.74 mmol) analogously as described in example 1, stage 4, except that the reaction mixture was stirred at 45°C for 5 hours. Yield: 490 mg

LC/MS (method LC4): m/z=303

Step 5: tert-Butyl ether 4-(2-chloro-5-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 4 (490 mg, of 1.62 mmol) analogously as described in example 20, step 5. Yield: 580 mg

LC/MS (method LC4): m/z=471

Step 6:tert-Butyl ether 4-[2-(5-fluoro-2-methylphenoxy)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 5 (100 mg, 212 μmol) and 5-fluoro-2-METHYLPHENOL similarly as described in example 1, step 6. Output: 99,0 mg.

LC/MS (method LC4): m/z=561

Stage 7: [2-(5-fluoro-2-methylphenoxy)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 6 (30.0 mg, of 53.5 mmol) was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave to 20.4 mg stated in the title compound in the form of a dihydrochloride [2-(5-fluoro-2-methylphenoxy)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC1): m/z=460,19; Rt=1,31 min

1H-NMR: δ (ppm)=a 2.13 (s, 3H), 2,99 (ush. s, 4H), 3,70 (ush. s, 4H), 3,88 (s, 3H), for 6.81-6.87 in (m, 2H), 7,20 (m, 1H), 7,42 (m, 1H), of 7.48-of 7.55 (m, 4H), 7,60 (d, 1H), 8,02 (d, 1H), 9,13 (ush. s, 2H).

Example 29

[2-(5-fluoro-2-methylphenoxy)-5-hydroxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from the compound of example 28, step 6, (70.0 mg, 125 μmol) analogously as described in example 9 and was obtained in the form of a dihydrochloride [2-(5-fluoro-2-methylphenoxy)-5-hydroxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]-piperazine-1-ylmethanone. Output: 32,0 mg.

LC/MS (LC method 1): m/z=446,18; Rt=1,26 min

1 H-NMR: δ (ppm)=2,12 (s, 3H), 2,98 (ush. s, 4H), 3,69 (ush. s, 4H), 6,80-6,84 (m, 2H)17,19 (kV, 1H), 7,38-7,42 (m, 2H), 7,47-rate of 7.54 (m, 4H), 7,88 (d, 1H), 9,20 (ush. s, 2H), 9,65 (ush. s, 1H).

Example 30

[2-(3-fluoro-2-methylbenzyl)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(3-fluoro-2-methylbenzyl)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from the compound of example 28, step 5, (100 mg, 212 μmol) analogously as described in example 4, stage 1. Output: 110 mg.

LC/MS (method LC4): m/z=559

Stage 2: [2-(3-fluoro-2-methylbenzyl)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

The connection phase 1 (35,0 mg, and 62.6 mmol) was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave to 17.6 mg stated in the title compound in the form of a dihydrochloride [2-(3-fluoro-2-methylbenzyl)-5-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC2): m/z=458,21 ; Rt=2,68 min

1H-NMR: δ (ppm)=1,84 (s, 3H), 2,90 (ush. s, 2H), 3,19 (ush. s, 2H), 3.72 points ush. s, 2H), a 3.87 (s, 3H), 4,15 (s, 2H), of 6.65 (d, 1H), 6.90 to (t, 1H), 6,99 (kV, 1H), 7,25-7,27 (m, 2H), 7,44-7,46 (m, 3H), 7,56 (d, 1H), of 7.97 (d, 1H), 9,05 (ush. s, 2H).

Example 31

[2-(3-fluoro-2-methylbenzyl)-5-hydro is C-1-phenyl-1H-pyrrolo[2, 3-b]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from the compound of example 22, step 1, (72,0 mg, 129 μmol) analogously as described in example 9 and was obtained in the form of a dihydrochloride [2-(3-fluoro-2-methylbenzyl)-5-hydroxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone. Output: 11,2 mg

LC/MS (method LC1): m/z=444,20; Rt=1,21 min

1H-NMR: δ (ppm)=1,83 (s, 3H), 2,92 (ush. s, 2H), 3,14 (ush. s, 2H), 4,15 (s, 2H), only 6.64 (d, 1H), 6.90 to (t, 1H), 6,99 (kV, 1H), 7.23 percent-of 7.25 (m, 2H), 7,35 (m, 1H), 7,42 was 7.45 (m, 3H), at 6.84 (d, 1H), 9,05 (ush. d, 2H), to 9.57 (ush. s, 1H).

Example 32

[2-(3-fluoro-2-methylbenzyl)-6-methoxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 6-Methoxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine

6-Methoxy-1H-pyrrolo[3,2-c]pyridine (4,25 g, 28.6 mmol) was reacted analogously as described in example 1, stage 1, in order to get to 4.92 g declared in the header connection.

LC/MS (method LC4): m/z=225

Stage 2: 3,3-Dibromo-6-methoxy-1-phenyl-1,3-dihydropyrrolo[3,2-c]pyridine-2-he

To stir the solution to 4.92 g (21.9 mmol) of the compound of stage 1 in tert-butanol (177 ml) and water (177 ml) was added dropwise within 10 min bromine (of 5.06 ml, 98,7 mmol). The reaction mixture was stirred at room temperature for 30 minutes the Mixture was treated with a saturated solution of sodium bicarbonate until, as the pH of the camp is wound approximately 6.5-7, and then added EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain 9,40 g of the crude stated in the connection header.

LC/MS (method LC4): m/z=398

Stage 3: 6-Methoxy-1-phenyl-1,3-dihydropyrrolo[3,2-c]pyridine-2-he

To a solution of 8,73 g connection stage 2 in acetic acid (180 ml) was added zinc, and the suspension was stirred at room temperature overnight. The mixture was extracted with EA, the organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The resulting solid residue was dissolved in ethanol (245 ml)was added palladium on charcoal (1,75 g of 1.64 mmol, 10%). The reaction mixture was first made (5,2 bar H2) at room temperature over night. The mixture was filtered through celite, the solvent was removed under reduced pressure and the solid residue was purified by chromatography on silica gel (EA (10-70%)/HEP). Received 870 mg stated in the connection header.

LC/MS (method LC4): m/z=241

Stage 4: 2-Chloro-6-methoxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde

From the connection stage 3 (870 mg, 3.62 mmol) mentioned in the title compound were obtained analogously as described in example 1, stage 3. Yield: 300 mg

LC/MS (method LC4): m/z=287

Stage 5: 2-Chloro-6-methoxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-Carbo the OIC acid

Connection stage 4 (300 mg, 1.05 mmol) was reacted analogously as described in example 1, stage 4. The reaction mixture was stirred for 3 hours at 45°C. was Obtained 304 mg stated in the connection header.

LC/MS (method LC4): m/z=303

Step 6: tert-Butyl ether 4-(2-chloro-6-methoxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-carbonyl)piperazine-1-carboxylic acid

From the connection stage 5 (304 mg, 1.00 mmol) mentioned in the title compound were obtained analogously as described in example 20, step 5. Yield: 300 mg

LC/MS (method LC4): m/z=471

Step 7: tert-Butyl ether 4-[2-(3-fluoro-2-methylbenzyl)-6-methoxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

To zinc (167 mg, 2.55 mmol) in dry THF (500 ml) in a dry flask in an argon atmosphere was added 1,2-dibromoethane (5,49 µl of 63.7 μmol). The mixture was heated three times to boil a hot air gun and cooled to room temperature. Then add chlorotrimethylsilane (0,27 μl, 2,12 mmol)and the mixture was stirred at room temperature for 20 minutes and Then the flask was placed in an ice bath, was added slowly a solution of 3-fluoro-2-methylbenzylamine (259 mg, of 1.27 mmol) in dry THF (1 ml), so that the temperature was maintained equal to 0°C. the Mixture was stirred at 0°C for 4.5 hours and kept in the refrigerator over night. The cooled mixture was added dropwise to a pre-cooled process is at (-78°C) B-OM-9-BBN (2,12 ml, 2,12 mmol, 1 M) in hexane. The mixture was stirred at room temperature for 30 minutes was Added DMF (5 ml), followed by the addition of the connection stage 6 (100 mg, 212 μmol), palladium(II) acetate (4,77 mg of 21.2 mmol) and S-PHOS (17,4 mg, 42,5 Microm). The reaction mixture was stirred at 100°C for 3 hours. After cooling, the mixture was extinguished with water and was extracted with EA. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (EA (10-60%)HEP) to obtain 90 mg stated in the connection header.

LC/MS (method LC4): m/z=559

Stage 8: [2-(3-fluoro-2-methylbenzyl)-6-methoxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 7 (33 mg, 59,1 µmol) was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave to 22.3 mg stated in the title compound in the form of a dihydrochloride [2-(3-fluoro-2-methylbenzyl)-6-methoxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC6): m/z=458,21; Rt=2,45 min

1H-NMR (400 MHz, DMSO-D6): δ (ppm)=is 1.81 (d, 3H), is 3.08 (ush. s, 4H), 3,88 (s, 3H), 4.09 to (s, 2H), 6,37 (s, 1H), 6,66 (d, 1H), 6,91 (t, 1H), 6,99 (kV, 1H), 7,28-7,31 (m, 2H), 7,49-7,51 (m, 3H), 8,64 (s, 1H), 9.28 are (ush. s, 2H).

Example 33

[2-(3-fluoro-2-methylbenzyl)-6-g is droxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from the compound of example 32, step 7, (of 60.8 mg, 109 μmol) analogously as described in example 9 and was obtained in the form of a dihydrochloride [2-(3-fluoro-2-methylbenzyl)-6-hydroxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone. Output: 18,7 mg.

LC/MS (method LC5): m/z=444,20; Rt=1,67 min

1H-NMR: δ (ppm)=1,80 (d, 1H), of 4.05 (s, 2H), 6,27 (s, 1H), of 6.68 (d, 1H), 6,91 (t, 1H), 7,00 (kV, 1H), 7,31 (s, 2H), 7,50-7,53 (m, 3H), 8,53 (s, 1H), 9.28 are (ush. s, 2H).

Example 34 [2-(5-fluoro-2-methylphenoxy)-6-methoxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(5-fluoro-2-methylphenoxy)-6-methoxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound were obtained analogously as described in example 1, step 6, from the compound of example 32, step 6, (100 mg, 212 μmol) and 5-fluoro-2-METHYLPHENOL. Yield: 88 mg

LC/MS (method LC4): m/z=561

Stage 2: [2-(5-fluoro-2-methylphenoxy)-6-methoxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

The connection phase 1 (27.0 mg, 48.1 mmol) was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 15,5 mg stated in the title compound in the form of the e dihydrochloride [2-(5-fluoro-2-methylphenoxy)-6-methoxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC4): m/z=461,20; Rt=0,95 min

1H-NMR: δ (ppm)=2,11 (s, 3H), 3,14 (m, 4H), 3,19 (m, 4H), 3,90 (m, 3H), 6,51 (m, 1H), 6,86 (m, 2H), 7,28 (m, 1H), of 7.48 (m, 1H), 7,53 (m, 4H), 8,56 (m, 1H), 9,17 (m, 2H).

Example 35

[2-(5-fluoro-2-methylphenoxy)-6-hydroxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from the compound of example 34, step 1, (61 mg, 108 μmol) analogously as described in example 9 and was obtained in the form of a dihydrochloride [2-(5-fluoro-2-methylphenoxy)-6-hydroxy-1-phenyl-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone. Output: 25,9 mg.

LC/MS (method LC6): m/z=446,18; Rt=2,37 min

1H-NMR: δ (ppm)=2,10 (s, 3H), of 3.00 (m, 4H), 3,68 (m, 4H), 6.48 in (m, 1H), to 6.88 (m, 1H), 6,97 (m, 1H), 7,22 (m, 1H), 7,51 (m, 1H), 7,54 (m, 4H), 8,40 (m, 1H), 9.28 are (m, 2H).

Example 36

[2-(2,6-Dimethylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(2,6-dimethylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound were obtained analogously as described in example 1, step 6, from the compound of example 1, step 5, (100.0 mg, 227 μmol) and 2,6-dimethylphenol. Yield: 96 mg

LC/MS (method LC4): m/z=500

Stage 2: [2-(2,6-Dimethylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from compound article is Hai 1 similarly, as described in example 1, step 7, and obtained in the form of a dihydrochloride [2-(2,6-dimethylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone. Yield: 51 mg

LC/MS (method LC5): m/z=426,21; Rt=1,71 min

1H-NMR: δ (ppm) =of 2.16 (s, 6H), to 2.94 (m, 4H), to 3.38 (m, 2H), 3,50 (m, 2H), 7,10 (m, 3H), 7,44 (m, 1H), to 7.64 (m, 1H), 7,72 (m, 4H), 7,92 (m, 1H), 8,48 (m, 1H), 9,24 (m, 2H).

Example 37

[2-(3-Fluoro-2,6-dimethylphenoxy]-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(3-Fluoro-2,6-dimethylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound were obtained analogously as described in example 1, step 6, from the compound of example 16, step 5, (100 mg, 227 μmol) and 3-fluoro-2,6-dimethylphenol.

LC/MS (method LC4): m/z=545

Stage 2: [2-(3-Fluoro-2,6-dimethylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

The crude compound stage 1 was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 42 mg stated in the title compound in the form of a dihydrochloride [2-(3-fluoro-2,6-dimethylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC8): m/z=445,30; Rt=2,43 min

1H-NMR: δ (ppm)=2,10 (m, 6H),to 2.94 (m, 4H), of 3.45 (m, 4H), to 7.09 (m, 1H), 7,16 (m, 1H), to 7.59 (m, 1H), 7,63 (m, 2H), 7,31 (m, 2H), with 8.05 (m, 1H), 8,43 (m, 1H), 8,81 (m, 1H), 9,41 (m, 2H).

Example 38 [7-Chloro-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 7-Methoxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine

Stated in the title compound was obtained from 7-methoxy-1H-pyrrolo[2,3-c]pyridine (1 g, of 6.75 mmol) analogously as described in example 1, stage 1. Output: 1,27,

LC/MS (method LC4): m/z=225

Stage 2: 7-Methoxy-1-phenyl-1,3-dihydropyrrolo[2,3-c]pyridine-2-he

Stated in the title compound was obtained from the compound of stage 1 (1.19 g, 5,31 mmol) analogously as described in example 1, step 2. Output: 0,74,

LC/MS (method LC4): m/z=241

Stage 3: 2,7-Dichloro-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde

Stated in the title compound was obtained from compound stage 2 (639 mg, of 2.66 mmol) analogously as described in example 1, stage 3. Yield: 490 mg

LC/MS (method LC4): m/z=291

Stage 4: 2,7-Dichloro-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid

Connection stage 3 (691 mg, is 2.37 mmol) was reacted analogously as described in example 1, stage 4. The reaction mixture was stirred at 40°C for 2 hours. Received 1,11 g of the crude stated in the connection header.

LC/MS (method LC4): m/z=273

Step 5: tert-Butyl ether 4-(2,7-dichloro-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperazine-1-carbon is Oh acid

The crude compound stage 4 (1,11 g) was reacted analogously as described in example 1, stage 5. Received 587 mg stated in the connection header.

LC/MS (method LC4): m/z=475

Step 6: tert-Butyl ether 4-[7-chloro-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 5 (160 mg, 336 μmol) analogously as described in example 5, stage 1. Yield: 102 mg

LC/MS (method LC4): m/z=566

Stage 7: [7-Chloro-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 6 (35 mg, 62 μmol) was reacted analogously as described in example 5, stage 2. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 32 mg stated in the title compound in the form of a dihydrochloride [7-chloro-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC5): m/z=464,14; Rt=1,92 min

1H-NMR: δ (ppm)=2,02 (s, 3H), 2,98 (m, 4H), 3,66 (m, 4H), to 6.88 (m, 1H), 7,05 (m, 1H), 7,20 (m, 1H), 7,52 (m, 3H), 7,58 (m, 2H), 7,68 (m, 1H), 8,13 (m, 1H), 9,20 (m, 2H).

Example 39

[7-Chloro-2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[7-chloro-2-(3-fluoro-2-methylbenzyl)-1-Fe is Il-1H-pyrrolo[2,3-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

The compound of example 38, step 5, (100 mg, 210 μmol) was reacted analogously as described in example 4, step 1, to obtain a mixture mentioned in the title compound and tert-butyl ester 4-[2,7-bis-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid, which was separated by preparative HPLC. Received 30 mg stated in the connection header.

LC/MS (method LC4): m/z=564

Stage 2: [7-Chloro-2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

The connection phase 1 (30 mg, 53 μmol) was reacted analogously as described in example 4, stage 2. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 8.6 mg stated in the title compound in the form of a dihydrochloride [7-chloro-2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC8): m/z=462,16; Rt=1,99 min

1H-NMR: δ (ppm)=1,68 (s, 3H), 3,19 (m, 4H), of 3.84 (m, 4H), 3,98 (m, 2H), 6,17 (m, 1H), 7,00 (m, 2H), was 7.36 (m, 2H), 7,40 (m, 2H), 7,56 (m, 1H), 8,10 (m, 1H), 8,48 (m, 1H).

Example 40

[2,7-Bis-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2,7-bis(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

The compound of example 38, step 5, (100 mg, 210 μmol) was reacted analogously as described in example 4, step 1, to obtain a mixture mentioned in the title compound and tert-butyl ester 4-[7-chloro-2-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid, which was separated by preparative HPLC. Received 40 mg stated in the connection header.

LC/MS (method LC4): m/z=651

Stage 2: [2,7-Bis-(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

The connection phase 1 (40 mg, 61 μmol) was reacted analogously as described in example 4, stage 2. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 30 mg stated in the title compound in the form of a dihydrochloride [2,7-bis(3-fluoro-2-methylbenzyl)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC7): m/z=550,25; Rt=min 1,35

1H-NMR: δ (ppm)=1,16 (s, 3H), 1,25 (s, 3H), 2,98 (m, 2H), 3,23 (m, 2H), 3,62 (m, 2H), 3,79 (m, 2H), 3,98 (m, 2H), 4,01 (m, 2H), 6,12 (m, 1H), 6,70 (m, 1H), 6,95 (m, 1H), 7,03 (m, 4H), 7,18 (m, 2H), of 7.48 (m, 1H), 8,21 (m, 1H), and 8.50 (m, 1H), 9,37 (m, 1H).

Example 41 [7-Benzyl-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[7-benzyl-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]p is ridin-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from the compound of example 38, step 6, (45 mg, 80 μmol) analogously as described in example 4, stage 1. Yield: 37 mg

LC/MS (method LC4): m/z=621

Stage 2: [7-Benzyl-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 1 (37 mg, 60 µmol) was reacted analogously as described in example 4, stage 2. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 35 mg stated in the title compound in the form of a dihydrochloride [7-benzyl-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC6): m/z=520,23; Rt=2,59 min

1H-NMR: δ (ppm)=e 2.06 (s, 3H), of 2.97 (m, 4H), 3,61 (m, 4H), of 4.12 (s, 2H), of 6.68 (m, 2H), 6,98 (m, 1H), 7,18 (m, 3H), 7,25 (m, 2H), of 7.48 (m, 2H), 7,58 (m, 3H), 8,08 (m, 1H), 8,46 (m, 1H), was 9.33 (m, 2H).

Example 42

[7-Ethyl-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[7-ethyl-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

A mixture of compound of example 38, step 6, (65 mg, 115 μmol), iron acetylacetonate(III) (2,03 mg, 5.7 mmol) and NMP (102,6 mg, 1.04 mmol) in THF (5 ml) was cooled to 0°C. was Added ethylmagnesium (115 μl, 230 mmol, 2 M in THF), and polucen the th resulting solution was stirred for 5 minutes Mix brown extinguished with water and was extracted with EA. The organic layers were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (EA/HEP) to obtain 29 mg stated in the connection header.

LC/MS (method LC4): m/z=558,66

Stage 2: [7-Ethyl-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

The connection phase 1 (29 mg, 52 μmol) was reacted analogously as described in example 4, stage 2. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 12 mg stated in the title compound in the form of a dihydrochloride [7-ethyl-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC6): m/z =458,21; Rt=2,38 min

1H-NMR: δ (ppm)=1.06 a (t, 3H), of 2.08 (s, 3H), 2,58 (kV, 2H), 2,98 (m, 4H), 3,61 (m, 4H), 6,98 (m, 1H), 7,25 (m, 2H), 7,68 (m, 3H), 7,80 (m, 2H), 8,00 (m, 1H), scored 8.38 (m, 1H), 9,42 (m, 1H).

Example 43

[2-(5-fluoro-2-methylphenoxy)-6-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 6-Methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine

6-Methoxy-1H-pyrrolo[2,3-b]pyridine (1 g, of 6.75 mmol) was reacted analogously as described in example 20, step 1, to obtain for 9.64 g declared in the header connection.

LC/MS (method LC4): m/z=225

Stage 2: 6-who, ethoxy-1-phenyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-he

To stir the solution for 9.64 g (43 mmol) of compound of stage 1 in DCM (250 ml) was added N-chlorosuccinimide (of 6.02 g, 45 mmol) in one portion at room temperature. The reaction mixture was stirred for 12 hours, and the solvent was evaporated. The remaining residue was dissolved in a mixture of acetic acid (180 ml) and phosphoric acid (31 ml) and was heated at 125°C for 1 hour. The solution was cooled to room temperature and concentrated in vacuum. The remaining residue was poured on ice, and the aqueous phase was extracted with EA. The combined organic phase was washed with saturated saline solution, dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The remaining oil was purified column chromatography on silica gel (EA/HEP) to get 4,80 g declared in the header connection.

LC/MS (method LC4): m/z=241

Stage 3: 2-Chloro-6-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

Stated in the title compound was obtained from compound stage 2 (4,32 g, 18.0 mmol) analogously as described in example 1, stage 3. Output: 1,77,

LC/MS (method LC4): m/z=287

Stage 4: 2-Chloro-6-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

Connection stage 3 (1.77 g, 6,17 mmol) was reacted analogously as described in example 1, stage 4. The reaction mixture was stirred at 40°C for 2 hours. Received 2,62 g neocidin the th stated in the connection header.

LC/MS (method LC4): m/z=303

Step 5: tert-Butyl ether 4-(6-chloro-2-methoxy-7-phenyl-7H-pyrrolo[2,3-c]pyridazin-5-carbonyl)piperazine-1-carboxylic acid

The crude compound stage 4 (2,62 g) was reacted analogously as described in example 20, step 5. Got a 2.71 g declared in the header connection.

LC/MS (method LC4): m/z=471

Step 6: tert-Butyl ether 4-[2-(5-fluoro-2-methylphenoxy)-6-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 5 (153 mg, 325 μmol) analogously as described in example 5, stage 1. Yield: 80 mg

LC/MS (method LC4): m/z=562

Stage 7: [2-(5-fluoro-2-methylphenoxy)-6-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 6 (30 mg, 54 μmol) was reacted analogously as described in example 5, stage 2. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 16 mg stated in the title compound in the form of a dihydrochloride [2-(5-fluoro-2-methylphenoxy)-6-methoxy-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC6): m/z=460,19; Rt=2,92 min

1H-NMR: δ (ppm)=2,12 (s, 3H), of 3.00 (m, 4H), and 3.72 (m, 4H), of 3.78 (s, 3H), 6,69 (m, 1H), 6,80 (m, 2H), 7,19 (m, 1H), 7,40 (m, 1H), 7,51 (m, 2H), to 7.59 (m, 2H), 8,00 (m, 1H), 9.15, with (m, 1H).

Example 44

[2-(2,6-Dimethylphenoxy is)-1-phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 4-Chloro-1-phenyl-1H-pyrrolo[2,3-b]pyridine

4-Chloro-1H-pyrrolo[2,3-b]pyridine (10 g, 65,5 mmol) was reacted analogously as described in example 20, step 1, to obtain 9.81 g declared in the header connection.

LC/MS (method LC4): m/z=229

Stage 2: 1-Phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridine

Stated in the title compound was obtained from the compound of stage 1 (4,69 g of 20.5 mmol) and chloride propylene similarly as described in example 42, step 1. Output: 3,57,

LC/MS (method LC4): m/z=237

Stage 3: 3,3-Dibromo-1-phenyl-4-propyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-he

Stated in the title compound was obtained from compound stage 2 (3.57 g, 15.1 mmol) analogously as described in example 32, step 2. Output: 8,5,

LC/MS (method LC4): m/z=410

Stage 4: 1-Phenyl-4-propyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-he

Stated in the title compound was obtained from compound stage 3 (8.5 g) in the same way as described in example 32, step 3. Output: 3,53,

LC/MS (method LC4): m/z=253

Stage 5: 2-Chloro-1-phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

Stated in the title compound was obtained from compound stage 4 (3,53 g, 14.0 mmol) analogously as described in example 1, stage 3. Output: 2,59,

LC/MS (method LC4): m/z=299

Step 6: 2-Chloro-1-phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

Connection stage 5 (1,59 g, 5,32 mmol) re who was Garofalo similarly, as described in example 1, stage 4. The reaction mixture was stirred at 40°C for 2 hours. Received 1.73 g of the crude stated in the connection header.

LC/MS (method LC4): m/z=315

Step 7: tert-Butyl ether 4-(2-Chloro-1-phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)piperazine-1-carboxylic acid

The crude compound stage 6 (1.73 g) was reacted analogously as described in example 1, stage 5. Received 1.28 g declared in the header connection.

LC/MS (method LC4): m/z=483

Stage 8: [2-(2,6-Dimethylphenoxy)-1-phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

To a solution of 2,6-dimethylphenol (152 mg, 1,24 mmol) in NMP (3 ml) was added sodium hydride (50 mg, 1,24 mmol, 60% dispersion in mineral oil), and the suspension was stirred at room temperature in an argon atmosphere for 20 minutes After adding 100 mg, 207 μmol) of compound of stage 7, the reaction mixture was stirred for 2 hours at 140°C. After cooling, the reaction mixture was extinguished with water and was extracted with EA. The organic phase was concentrated and the remaining residue was dissolved in DCM (12 ml) and TFA (3 ml) and stirred at room temperature for 2 hours. The solvent was evaporated, and the resulting solid residue was purified preparative HPLC. The fractions containing the stated in the title compound were combined and were liofilizovane during the night. Received the solid residue was dissolved in a small quantity of MOH, mixed with chloroethanol acid (0.1 M) and liofilizovane during the night in order to obtain 34 mg stated in the title compound in the form of a dihydrochloride [2-(2,6-dimethylphenoxy)-1-phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC8): m/z=468,25; Rt=2,60 min

1H-NMR: δ (ppm)=of 0.91 (t, 3H), 1,58 (m, 2H), 2.05 is (m, 3H), 2,19 (m, 3H), by 2.55 (m, 1H), 2,62 (m, 2H), 2,75 (m, 1H), 2,88 (m, 2H), up 3.22 (m, 1H), 3,35 (m, 1H), 3,50 (m, 2H),? 7.04 baby mortality (m, 4H), to 7.50 (m, 1H), to 7.59 (m, 4H), of 8.06 (m, 1H), 9,13 (m, 2H).

Example 45

[2-(3-fluoro-2-methylbenzyl)-1-phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(3-fluoro-2-methylbenzyl)-1-phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from the compound of example 44, step 7, (150 mg, 310 μmol) analogously as described in example 4, stage 1. Yield: 175 mg

LC/MS (method LC4): m/z=572

Stage 2: [2-(3-fluoro-2-methylbenzyl)-1-phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone

The connection phase 1 (175 mg, 307 mmol) was reacted analogously as described in example 4, stage 2. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 90 mg stated in the title compound in the form of a dihydrochloride [2-(3-fluoro-2-methylben who yl)-1-phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC8): m/z=470,25; Rt=2,61 min

1H-NMR: δ (ppm)=0,95 (t, 3H), of 1.62 (m, 2H), 1,71 (s, 3H), 2,70 (m, 1H), and 2.83 (m, 2H), 2,96 (m, 1H), 3,14 (m, 2H), Android 4.04 (m, 3H), of 6.65 (m, 1H), to 6.88 (m, 1H), 7,07 (m, 1H), 7,25 (m, 2H), 7,42 (m, 3H), 8,10 (m, 1H), 9,23 (m, 2H).

Example 46

[1-Cyclohexyl-2-(3-fluoro-2-methylbenzyl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 1-Cyclohex-2-enyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine

Dimer chloride allylpalladium(II) (558 mg, of 1.52 mmol) and triphenylphosphine (1.75 g, of 6.68 mmol) was dissolved in dry DMF (210 ml) and stirred at room temperature for 30 minutes was Added methyl ether cyclohex-2-enrobage ester of carbonic acid (for 9.47 g, 60,74 mmol)and the mixture was stirred for an additional 30 minutes was Added 6-methoxy-1H-pyrrolo[3,2-c]pyridine (4.5 g, 30.37 per mmol) and cesium carbonate (19,79 g, 60,74 mmol)and the reaction the mixture was stirred at room temperature for 16 hours. The mixture is then distributed between water and EA, the aqueous phase was extracted with EA and the combined organic phases were dried over sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (EA/HEP) to obtain 5.6 g declared in the header connection.

LC/MS (method LC4): m/z=229

Stage 2: 1-Cyclohexyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine

The connection phase 1 (5.6 g, 24.5 mmol) and palladium on coal (1.12 g, 10%) was stirred in etano is e (160 ml) in an atmosphere of hydrogen for 3 hours. The catalyst was filtered, and the solvent was removed in vacuum to obtain 5.34 g declared in the header connection.

LC/MS (method LC4): m/z=231

Stage 3: 3,3-Dibromo-1-cyclohexyl-6-methoxy-1,3-dihydropyrrolo[3,2-c]pyridine-2-he

Connection stage 2 (5.34 g, 23.2 mmol) was reacted analogously as described in example 32, step 2, in order to get to 34.5 g of the crude stated in the connection header.

LC/MS (method LC4): m/z=405

Stage 4: 1-Cyclohexyl-6-methoxy-1,3-dihydropyrrolo[3,2-c]pyridine-2-he

The crude compound stage 3 (34.4 g) was reacted analogously as described in example 32, step 3, to obtain 8,68 g of the crude stated in the connection header.

LC/MS (method LC4): m/z=247

Stage 5: 2-Chloro-1-cyclohexyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde

Stated in the title compound was obtained from untreated connection stage 4 (8,68 g) analogously as described in example 1, stage 3. Output: 3,60,

LC/MS (method LC4): m/z=294

Step 6: 2-Chloro-1-cyclohexyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid

Connection stage 5 (1.60 g, vs. 5.47 mmol) was reacted analogously as described in example 1, stage 4. The reaction mixture was stirred at 40°C for 2 hours. Got to 1.60 g of the crude stated in the connection header.

LC/MS (method LC4): m/z=310

Step 7: tert-Butyl ether 4-(2-chloro-cyclohexyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbonyl)piperazine-1-carboxylic acid

The crude compound stage 6 (1.60 g) was reacted analogously as described in example 1, stage 5. Received 540 mg stated in the connection header.

LC/MS (method LC4): m/z=478

Step 8: tert-Butyl ether 4-[1-cyclohexyl-2-(3-fluoro-2-methylbenzyl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from compound stage 7 (180 mg, 377 μmol) analogously as described in example 4, stage 1. Yield: 86 mg

LC/MS (method LC4): m/z=566

Stage 9: [1-Cyclohexyl-2-(3-fluoro-2-methylbenzyl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 8 (38 mg, 67 μmol) was reacted analogously as described in example 4, stage 2. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 21 mg stated in the title compound in the form of a dihydrochloride [1-cyclohexyl-2-(3-fluoro-2-methylbenzyl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC8): m/z=464,26; Rt=2,55 min

1H-NMR: δ (ppm)=1,05 (m, 2H), 1,32 (m, 1H), 1,42 (m, 2H), 1,53 (m, 1H), 1,70 (m, 2H), 2,08 (m, 2H), 2,30 (s, 3H), of 2.97 (m, 2H), 3,18 (m, 2H), only 3.57 (m, 2H), 3,71 (m, 2H), 3,97 (m, 3H), 4,28 (m, 2H), 6,63 (m, 1H), 7,19 (m, 3H), 8,58 (m, 1H), 9,20 (m, 1H), of 9.30 (m, 1H).

Example 47

[1-Cyclohexyl-2-(3-fluoro-2-methylbenzyl)-6-hydroxy-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from the compound of example 46, step 8, (42 mg, 74 μmol) analogously as described in example 9 and was obtained in the form of a dihydrochloride [1-cyclohexyl-2-(3-fluoro-2-methylbenzyl)-6-hydroxy-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone. Yield: 8 mg

LC/MS (method LC4): m/z=451,20; Rt=min 1,05

1H-NMR (400 MHz, MOH-D4): δ (ppm)=1,21 (m, 4H), by 1.68 (m, 3H), of 1.84 (m, 2H), 2,08 (m, 2H), 2,34 (m, 3H), 3,10 (m, 2H), 3,32 (m, 2H), 3,88 (m, 4H), of 3.96 (m, 1H), 6,72 (m, 1H), 6,98 (m, 1H), 7,10 (m, 2H), 8,51 (m, 1H).

Example 48

[1-Cyclohexyl-2-(2,6-dimethylphenoxy)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[1-cyclohexyl-2-(2,6-dimethylphenoxy)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from the compound of example 46, step 7, (180 mg, 377 mmol) and 2,6-dimethylphenol similarly as described in example 1, step 6. Yield: 117 mg

LC/MS (method LC4): m/z=564

Stage 2: [1-Cyclohexyl-2-(2,6-dimethylphenoxy)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

The connection phase 1 (52 mg, 92 μmol) was reacted analogously as described in example 1, step 7. Dissolving the obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 33 mg claimed in reception the e connection in the form of a dihydrochloride [1-cyclohexyl-2-(2,6-dimethylphenoxy)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC8): m/z=464,26; Rt=2,55 min

1H-NMR: δ (ppm)=1,33 (m, 1H), and 1.54 (m, 2H), 1.69 in (m, 1H), 1.93 and (m, 4H), 2,17 (s, 6H), 2,28 (m, 2H), 2,85 (m, 4H), 3,29 (m, 4H), was 4.02 (m, 3H), and 4.68 (m, 1H), 7,11 (m, 3H), 7,39 (m, 1H), of 8.37 (m, 1H), 9,18 (m, 1H).

Example 49

[1-Cyclohexyl-2-(2,6-dimethylphenoxy)-6-hydroxy-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from the compound of example 48, step 1, (63 mg, 112 μmol) analogously as described in example 9 and was obtained in the form of a dihydrochloride [1-cyclohexyl-2-(2,6-dimethylphenoxy)-6-hydroxy-1H-pyrrolo[3,2-c]pyridine-3-yl]-piperazine-1-ylmethanone. Yield: 10 mg

LC/MS (method LC4): m/z=449,20; Rt=1,08 min

1H-NMR (400 MHz, MOH-D4): δ (ppm)=1,35 (m, 2H), 1.61 of (m, 2H), equal to 1.82 (m, 1H), 2.06 to (m, 4H), to 2.29 (s, 6H), a 2.36 (m, 2H), 2,98 (m, 4H), of 3.48 (m, 4H), br4.61 (m, 1H), 7,12 (m, 1H), 7,18 (m, 3H), by 8.22 (m, 1H).

Example 50

[1-Phenyl-2-(1-phenylethyl)-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

A solution of compound of example 1, step 5, (120 mg, 27 μmol), bromide α-methylbenzidine (820 μl, 408 mmol, 0.5 M in THF), tetrafluoroborate three(tert-butyl)phosphonium (15.6 mg, 54 μmol) and bis(dibenzylideneacetone)palladium (15.6 mg, 27 μmol) in THF (5 ml) was stirred for 12 hours at 80°C. the Reaction mixture was diluted with water and was extracted with EA. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. About eroticne compound was purified preparative HPLC, and it reacted analogously as described in example 1, step 7. The obtained solid residue was dissolved in a small quantity of MOH, mixed with chloroethanol acid (0.1 M) and liofilizovane during the night in order to obtain 20 mg stated in the title compound in the form of a dihydrochloride [1-phenyl-2-(1-phenylethyl)-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC5): m/z=410,21; Rt=1,65 min

1H-NMR: δ (ppm)=1,65 (m, 3H), 2,99 (m, 2H), 3,20 (m, 2H), 3,82 (m, 4H), 4,28 (m, 1H), 7,13 (m, 2H), 7,22 (m, 3H), 7,41 (m, 1H), 7,52 (m, 1H), 7,66 (m, 4H), 8,54 (m, 1H), 9,23 (m, 2H).

Example 51

[2-(3-fluoro-2-methylbenzyl)-6-methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 5-Methyl-2-trimethylsilylethynyl-3-ylamine

2-Chloro-5-methylpyridin-3-ylamine (10 g, 70,13 mmol), trimethylsilylacetamide (13.8 g, 140,3 mmol), copper iodide(I) (534 mg, of 2.81 mmol) and chloride bis(triphenylphosphine)palladium(II) (1.97 g, of 2.81 mmol) was dissolved in triethylamine (140 ml) and stirred at 80°C for 5 hours. After cooling to room temperature the reaction mixture was filtered through a layer of celite, and the solvent was removed in vacuum. The residue was purified column chromatography (silica gel, EA/HEP) to get 5,12 g declared in the header connection.

LC/MS (method LC4): m/z=205

Stage 2: 6-Methyl-1H-pyrrolo[3,2-b]pyridine

A solution of compound of stage 1 (5,12 is, a 25.1 mmol) in NMP (125 ml) was added dropwise at room temperature to tert-butyl potassium (5,91 g, for 52.6 mmol) in NMP (125 ml). The reaction mixture was stirred for 4 hours at room temperature, then added water, and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated to obtain 2.5 g declared in the header connection.

LC/MS (method LC4): m/z=133

Stage 3: 6-Methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine

Connection stage 2 (2.50 g, to 18.9 mmol) was reacted analogously as described in example 20, step 1, to obtain 966 mg stated in the connection header.

LC/MS (method LC4): m/z=209

Stage 4: 3,3-Dibromo-6-methyl-1-phenyl-1,3-dihydropyrrolo[3,2-b]pyridine-2-he

Connection stage 3 (800 mg, of 3.84 mmol) was reacted analogously as described in example 24, step 2. Received of 1.97 g of the crude stated in the connection header.

LC/MS (method LC4): m/z=383

Stage 5: 6-Methyl-1-phenyl-1,3-dihydropyrrolo[3,2-b]pyridine-2-he

Stated in the title compound was obtained from untreated connection stage 4 (1.97 g) in the same way as described in example 32, step 3. Output: 770 mg.

LC/MS (method LC4): m/z=224

Step 6: 2-Chloro-6-methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde

Stated in the title compound was obtained from compound stage 5 (760 mg, 3,39 IMO the b) similarly, as described in example 1, stage 3. Output: 910 mg.

LC/MS (method LC4): m/z=271

Stage 7: 2-(3-fluoro-2-methylbenzyl)-6-methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde

Stated in the title compound was obtained from compound stage 6 (150 mg, 554 μmol) analogously as described in example 4, stage 1. Yield: 22 mg

LC/MS (method LC4): m/z=359

Step 8: 2-(3-fluoro-2-methylbenzyl)-6-methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid

Connection stage 7 (20 mg, 56 μmol) was reacted analogously as described in example 1, stage 4. The reaction mixture was stirred at 40°C for 2 hours. Received 60 mg of the crude stated in the connection header.

LC/MS (method LC4): m/z=375

Stage 9: [2-(3-fluoro-2-methylbenzyl)-6-methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

The crude compound stage 8 (60 mg) was reacted analogously as described in example 1, step 5, and then, as described in example 4, stage 2. The obtained solid residue was dissolved in a small quantity of MOH, mixed with chloroethanol acid (0.1 M) and liofilizovane during the night in order to obtain 6.4 mg stated in the title compound in the form of a dihydrochloride [2-(3-fluoro-2-methylbenzyl)-6-methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC4): m/z=443,20; Rt=0,98 min

1H-NMR (400 MHz, MOH-D4): δ (ppm)=1,96 (s, 3H), 2,61 (s, 3H), up 3.22 (m, 4H), was 4.02 (m, 4H) 4,35 (m, 2H), 6,83 (m, 1H), 6,98 (m, 1H), 7,11 (m, 1H), of 7.48 (m, 2H), 7,66 (m, 3H), of 8.09 (m, 1H), 8,53 (m, 1H).

Example 52

[2-(5-fluoro-2-methylphenoxy)-6-methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 2-(5-fluoro-2-methylphenoxy)-6-methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde

Stated in the title compound were obtained analogously as described in example 1, step 6, from the compound of example 51, step 6, (150 mg, 554 mmol) and 5-fluoro-2-METHYLPHENOL. Yield: 25 mg

LC/MS (method LC4): m/z=361

Stage 2: 2-(5-fluoro-2-methylphenoxy)-6-methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid

The connection phase 1 (25 mg, 69 μmol) was reacted analogously as described in example 1, stage 4. The reaction mixture was stirred at 40°C for 2 hours. Received 17 mg of the crude stated in the connection header.

LC/MS (method LC4): m/z=377

Step 3: tert-Butyl ether 4-[2-(5-fluoro-2-methylphenoxy)-6-methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

The crude compound stage 2 (17 mg) was reacted analogously as described in example 1, stage 5. Received 19 mg stated in the connection header.

LC/MS (method LC4): m/z=545

Stage 4: [2-(5-fluoro-2-methylphenoxy)-6-methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 3 (19 mg, 35 µmol) was reacted analogously as described in example 1, step 7. astorina obtained solid residue in a small quantity of MOH, adding chloroethanol acid (0.1 M) and lyophilization overnight gave 2.4 mg stated in the title compound in the form of a dihydrochloride [2-(5-fluoro-2-methylphenoxy)-6-methyl-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC4): m/z=445,20; Rt=1,01 min

1H-NMR (400 MHz, MOH-D4): δ (ppm)=R $ 2.20 (s, 3H), 2,58 (s, 3H), 3,21 (m, 4H), of 3.84 (m, 4H), 6.89 in (m, 2H), 7.23 percent (m, 1H), 7,60 (m, 5H), of 8.09 (m, 1H), 8,48 (m, 1H).

Example 53

[1-Cyclohexyl-2-(2,6-dimethylphenoxy)-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 1-Cyclohex-2-enyl-1H-pyrrolo[3,2-b]pyridine

Stated in the title compound was obtained from 1H-pyrrolo[3,2-b]pyridine (5.7 g, 48.2 mmol) analogously as described in example 46, step 1. Output: 7,3,

LC/MS (method LC4): m/z=199

Stage 2: 1-Cyclohexyl-1H-pyrrolo[3,2-b]pyridine

Stated in the title compound was obtained from the compound of stage 1 (7.30 g, to 36.8 mmol) analogously as described in example 46, step 2. Output: of 7.36,

LC/MS (method LC4): m/z=201

Stage 3: 3,3-Dibromo-1-cyclohexyl-1,3-dihydropyrrolo[3,2-b]pyridine-2-he

Connection stage 2 (7,63 g of 38.1 mmol) was reacted analogously as described in example 24, step 2. Received 20 g of the crude stated in the connection header.

LC/MS (method LC4): m/z=375

Stage 4: 1-Cyclohexyl-1,3-dihydropyrrolo[3,2-b]pyridine-2-he

Stated in the title compound was obtained from n is cleared connections stage 3 (20 g) similarly, as described in example 32, step 3. Output: 2,1,

LC/MS (method LC4): m/z=217

Stage 5: 2-Chloro-1-cyclohexyl-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde

Stated in the title compound was obtained from compound stage 4 (1.60 g, 7.40 mmol) analogously as described in example 1, stage 3. Output: 1,20,

LC/MS (method LC4): m/z=263

Step 6: 2-Chloro-1-cyclohexyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid

Connection stage 5 (700 mg, of 2.66 mmol) was reacted analogously as described in example 1, stage 4. The reaction mixture was stirred at 40°C for 2 hours. Received 740 mg of the crude stated in the connection header.

LC/MS (method LC4): m/z=279

Step 7: tert-Butyl ether 4-(2-chloro-1-cyclohexyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl)piperazine-1-carboxylic acid

The crude compound stage 6 (740 mg) was reacted analogously as described in example 1, stage 5. Received 660 mg stated in the connection header.

LC/MS (method LC4): m/z=448

Stage 8: [1-Cyclohexyl-2-(2,6-dimethylphenoxy)-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 7 (200 mg, 447 mmol) and 2,6-dimethylphenol reacted analogously as described in example 1, step 6, and the product is then reacted as described in example 1, step 7. The obtained solid residue was dissolved in a small quantity of MOH, mixed with chloroethanol acid (0.1 M) and liofilizovane within but is also to obtain 32 mg stated in the title compound in the form of a dihydrochloride [1-cyclohexyl-2-(2,6-dimethylphenoxy)-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC8): m/z=432,25; Rt=2,43 min

1H-NMR: δ (ppm)=1,47 (m, 1H), 1,58 (m, 2H), 1,72 (m, 1H), 1,92 (m, 2H), 2,04 (m, 2H), measuring 2.20 (s, 6H), is 2.41 (m, 2H), 2.91 in (m, 4H), 3,49 (m, 4H), 4,80 (m, 1H), 7,16 (m, 3H), 7,55 (m, 1H), to 8.41 (m, 1H), 8,76 (m, 1H), 9,26 (m, 2H).

Example 54

[2-(2,6-Dimethylphenoxy)-6-ethoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Stage 1: 5-Ethoxy-2-trimethylsilylethynyl-3-ylamine

Stated in the title compound was obtained from 2-bromo-5-ethoxypyridine-3-ylamine (20 g, of 92.1 mmol) analogously as described in example 51, step 1. Yield: 15.9 g

LC/MS (method LC4): m/z=235

Stage 2: 6-Ethoxy-1H-pyrrolo[3,2-b]pyridine

Stated in the title compound was obtained from the compound of stage 1 (12.5 g, 53.3 per mmol) analogously as described in example 52, step 2. Output: 6.0V,

LC/MS (method LC4): m/z=163

Stage 3: 6 Ethoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine

Iadanza (5,85 ml, 28.7 mmol) was added to a mixture of compound stage 2 (3 g, 18.5 mmol), copper iodide(I) (387,6 mg, 2.04 mmol), lithium chloride (941,1 mg of 22.2 mmol), N,N'-dimethylethylenediamine (505,5 mg, 5,74 mmol) and potassium carbonate (9,10 g, 65,9 mmol) in DMF (50 ml). The reaction mixture was stirred at 120°C for 6 hours. After cooling to room temperature, we use the solution of ammonium hydroxide (10% in water) and EA. The organic layer was separated, washed twice with saturated saline solution, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified column chromatography on silica gel (EA/HEP) to get 3,40 g declared in the header connection.

LC/MS (method LC4): m/z=239

Stage 4: 6 Ethoxy-1-phenyl-1,3-dihydropyrrolo[3,2-b]pyridine-2-he

Connection stage 3 (2,05 g, 8.60 mmol) was dissolved in DCM (30 ml) was added N-chlorosuccinimide (1.26 g, 9,46 mmol). The reaction mixture was stirred at room temperature for 3 days. The solvent was removed and the resulting solid residue was dissolved in acetic acid (10 ml) and heated at 70°C. After the addition of phosphoric acid (7,31 ml, 107 mmol, 85%), the reaction mixture was heated at 120°C for 3 days. After cooling, the mixture was diluted with water and was extracted with EA. The extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (EA/HEP 1:6). Received 650 mg stated in the connection header.

LC/MS (method LC4): m/z=255

Stage 5: 2-Chloro-6-ethoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde

Stated in the title compound was obtained from compound stage 4 (80 mg, 317 μmol) analogously as described in example 1, stage 3. Yield: 50 mg

LC/MS (method LC4): m/z=201

Step 6: 2-Chloro-6-ethoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-CT is about acid

Connection stage 5 (50 mg, 166,3 µmol) was reacted analogously as described in example 1, stage 4. The reaction mixture was stirred at 40°C for 2 hours. Received 47 mg of the crude stated in the connection header.

LC/MS (method LC4): m/z=317

Step 7: tert-Butyl ether 4-(2-chloro-6-ethoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl)piperazine-1-carboxylic acid

The crude compound stage 6 (47 mg) was reacted analogously as described in example 1, stage 5. Received 31 mg stated in the connection header.

LC/MS (method LC4): m/z=486

Stage 8: [2-(2,6-Dimethylphenoxy)-6-ethoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Connection stage 7 (28 mg, 57,7 mmol) and 2,6-dimethylphenol reacted analogously as described in example 1, step 6, and the product is then reacted as described in example 1, step 7. The obtained solid residue was dissolved in a small quantity of MOH, mixed with chloroethanol acid (0.1 M) and liofilizovane during the night in order to obtain 15 mg stated in the title compound in the form of a dihydrochloride [2-(2,6-dimethylphenoxy)-6-ethoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC4): m/z=471,20; Rt=min 0,75

1H-NMR: δ (ppm)=1,32 (t, 3H), 2.13 and (s, 3H), 2,87 (m, 4H), 3.43 points (m, 4H), 4,10 (kV, 2H), was 7.08 (m, 3H), 7,29 (m, 1H), to 7.59 (m, 1H), 7,68 (m, 4H), 8,18 (m, 1H), of 9.21 (m, 2H).

Example 55

[2-(2,6-Dimethylphenoxy)-6-HYDR the XI-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Step 1: tert-Butyl ether 4-[2-(2,6-dimethylphenoxy)-6-ethoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

Stated in the title compound was obtained from the compound of example 54, step 7, (290 mg, 598 μmol) and 2,6-dimethylphenol similarly as described in example 1, step 6. Yield: 170 mg

LC/MS (method LC10): m/z=571

Stage 2: [2-(2,6-Dimethylphenoxy)-6-hydroxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained from the compound of stage 1 (170 mg, 298 μmol) analogously as described in example 9 and was obtained in the form of a dihydrochloride [2-(2,6-dimethylphenoxy)-6-hydroxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone. Output: 25,9 mg.

LC/MS (method LC9): m/z=442,20; Rt=2,47 min

1H-NMR: δ (ppm)=a 2.13 (s, 6H), of 2.86 (m, 2H), equal to 2.94 (m, 2H), 3,38 (m, 2H), 3,48 (m, 2H), between 6.08 (s, 3H), 7,30 (m, 1H), 7.62mm (m, 1H), of 7.70 (m, 4H), 8,11 (m, 1H), 9,25 (m, 2H).

Example 56

tert-Butyl ester 4-[2-(2,6-dimethylphenoxy)-6-hydroxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-1-carboxylic acid

To a solution of 80 mg (181 mmol) of the compound of example 55, step 2, MOH (1.0 ml) and THF (2.0 ml) was added sodium bicarbonate (to 45.6 mg, 542 μmol) and a solution of di-tert-BUTYLCARBAMATE (43,4 mg, 199 μmol) in THF (2 ml). The reaction mixture was stirred at room temperature overnight. Dissolve Italy was evaporated, and the obtained solid residue was dissolved in water and EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. Received 90 mg stated in the connection header.

LC/MS (method LC10): m/z=543

Example 57

[2-(2,6-Dimethylphenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-pyrrolo[3,2-b]pyridine-6-yloxy]acetic acid

Step 1: tert-Butyl ether 4-[6-tert-butoxycarbonylmethyl-2-(2,6-dimethylphenoxy)-1-phenyl-1H-indole-3-carbonyl]piperazine-1-carboxylic acid

The compound of example 56 (60 mg, 111 μmol), cesium carbonate (108 mg, 332 μmol) and tert-butylbromide (17,9 µl, with 23.7 mmol) was stirred in DMF at room temperature for 2 hours. The mixture was diluted with water and was extracted with EA. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (EA/HEP). Yield: 67 mg

LC/MS (method LC10): m/z=657

Stage 2: [2-(2,6-Dimethylphenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-pyrrolo[3,2-b]pyridine-6-yloxy]acetic acid

The connection phase 1 (67 mg, 102 μmol) was reacted analogously as described in example 1, stage 3, the obtained solid residue was purified by chromatography on silica gel (EA/HEP), was dissolved in a small quantity of MOH, mixed with chloroethanol acid (0.1 M) and liofilizovane within n the Chi, to obtain 44 mg stated in the title compound in the form of a dihydrochloride [2-(2,6-dimethylphenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-pyrrolo[3,2-b]pyridine-6-yloxy]acetic acid.

LC/MS (method LC8): m/z=500,21; Rt=2,55 min

1H-NMR (400 MHz, DMSO-D6): δ (ppm)=2,12 (s, 6H), of 2.81 (m, 2H), 2.91 in (m, 2H), 3,38 (m, 2H), 3,47 (m, 2H), 4,70 (s, 2H), 7,05 (s, 3H), 7,28 (m, 1H), to 7.59 (m, 1H), 7,68 (m, 4H), to 8.20 (m, 1H), 9.15, with (m, 2H).

Example 58

Methyl ester {4-[2-(2,6-dimethylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-2-yl}acetic acid

Step 1: tert-Butyl ether 4-(2-chloro-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl)-2-methoxycarbonylmethylene-1-carboxylic acid

Stated in the title compound was obtained from the compound of example 1, stage 4, (of 199, 9 mg, 737 μmol) and tert-butyl methyl ether 2-methoxycarbonylmethylene-1-carboxylic acid (189,3 mg, 737 μmol) analogously as described in example 1, stage 5. Output: 254 mg.

LC/MS (method LC10): m/z=512,9

Step 2: tert-Butyl ether 4-[2-(2,6-dimethylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]-2-methoxycarbonylmethylene-1-carboxylic acid

The connection phase 1 (254 mg, 507 mmol) and 2,6-dimethylphenol reacted analogously as described in example 1, step 6. Received 340 mg of the crude stated in the connection header.

LC/MS (method LC10): m/z=598,9

Stage 3: Methyl ester {4-[2-(2,6-is immiltenali)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-2-yl}acetic acid

The crude compound stage 2 (40 mg) was reacted analogously as described in example 1, stage 7, the obtained product was dissolved in a small quantity of MOH, mixed with chloroethanol acid (0.1 M) and liofilizovane during the night in order to obtain 13 mg stated in the title compound in the form of a dihydrochloride methyl ester {4-[2-(2,6-dimethylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-2-yl}acetic acid.

LC/MS (method LC10): m/z=498,9; Rt=0,66 min

1H-NMR: δ (ppm)=2,16 (m, 6H), 2,64-of 2.97 (m, 4H), 3,11-to 3.35 (m, 3H), 3,70 (s, 3H), of 3.84 (m, 1H), Android 4.04 (m, 1H), to 7.09 (m, 3H), 7,38 (m, 1H), 7,63 (m, 1H), 7,71 (m, 4H), 7,87 (m, 1H), 8,45 (m, 1H).

Example 59

2-{4-[2-(2,6-Dimethylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-2-yl}-N-methylacetamide

Step 1: tert-Butyl ether 4-[2-(2,6-dimethylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]-2-methylcarbamoylmethyl-1-carboxylic acid

A solution of the crude compound of example 58, step 2, (140 mg, 234 μmol) in MOH (1 ml) was mixed with 2 M methanolic solution of methylamine (2,60 ml, 5,19 mmol). The reaction mixture was stirred at 40°C for 7 days. After cooling to room temperature the mixture was neutralized with an aqueous solution of citric acid and was extracted with EA. The combined organic phases were dried over sodium sulfate and evaporated. Received 45 mg of the crude allow the military in the connection header.

LC/MS (method LC10): m/z=598,0

Stage 2: 2-{4-[2-(2,6-Dimethylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-2-yl}-N-methylacetamide

The crude compound stage 1 was reacted analogously as described in example 1, stage 7, the obtained product was dissolved in a small quantity of MOH, mixed with chloroethanol acid (0.1 M) and liofilizovane during the night in order to get a 27.6 mg stated in the title compound in the form of the dihydrochloride of 2-{4-[2-(2,6-dimethylphenoxy)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-carbonyl]piperazine-2-yl}-N-methylacetamide.

LC/MS (method LC10): m/z=498,0; Rt=0,67 min

1H-NMR: δ (ppm)=2,09-2,22 (m, 6H), of 2.64 (m, 2H), 2,90 (m, 1H), 3,11-3,24 (m, 3H), of 3.48 (m, 3H), of 3.75 (m, 1H), 3,34 (m, 1H), 4,08 (m, 1H), to 7.09 (m, 3H), 7,42 (m, 1H), 7,63 (m, 1H), 7,72 (m, 4H), to $ 7.91 (m, 1H), 8,13 (m, 1H), 8,49 (m, 1H).

Similarly, as described in the above examples, were obtained the compounds of formula Ip, listed in table 1, and they were received in the form of bissoli triperoxonane acid or in the form of the dihydrochloride, respectively. The compounds can be named as [2-(R20-oxy)-1-R30-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone, in the case when group A represents O, or [2-(R20-sulfanyl)-1-R30-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone, in the case when the group A is an S, or [2-(R20-methyl)-1-R30-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone, in the case when group A is predstavljaet a CH 2allowing modifications in connection with the rules of nomenclature, such as the designation R20-methyl in the form of a benzyl group.

Table 1
Exemplary compounds of formula 1p
Example No.AR20R30Rt(min)MS (m/z)LC/MS method
60 (1)O3,5-debtor-2-werephenyl1,17448,17LC1
61 (2)O5-fluoro-2-were4-forfinal1,20448,17LC2
62 (2)O5-fluoro-2-werephenyl0,95431 LC4
63 (2)CH22,3-differenlphenyl1,71432,18LC5
64 (2)CH22.5-differenlphenyl1,64432,18LC5
65 (2)CH22,6-dichlorophenylphenyl1,70464,12LC5
66 (2)CH22-chloro-6-forfinalphenyl2,23448,15LC8
67 (2)CH24-fluoro-2,6-dimetilfenilphenyl2,33442,22LC8
CH22,6-dimetilfenilphenyl2,27424,23LC8
69 (1)CH22-fluoro-6-werephenyl2,23428,20LC5
70 (1)CH22-chloro-6-werephenyl2,55444,17LC6
71 (2)O2-forfinalphenyl1,60416,16LC5
72 (2)O2.5-differenlphenyl1,70434,16LC5
73 (2)O 2,3-differenlphenyl1,74434,16LC5
74 (2)O2-chloro-5-forfinalphenyl1,70450,13LC5
75 (2)O2,5-dimetilfenilphenyl2,28426,21LC8
76 (1)O2-chloro-6-werephenyl2,48446,15LC6
77 (1)CH23-fluoro-2-were3-forfinal2,47446,19LC6
78 (1)CH23-fluoro-2-were2,43446,19LC6
79 (2)CH22,6-differenlcyclohexyl2,43438,22LC8
80 (2)O2,6-dimetilfenil4-forfinal1,01445,20LC4
81 (1)O2,6-dimetilfenil3-forfinal2,47444,20LC6
82 (1)O2,6-dimetilfenil2-forfinal2,37444,20LC8
83 (1)O2,6-dimetilfenilcyclopentyl2,73 418,24LC11
84 (2)O3-fluoro-2,6-dimetilfenilphenyl2,99444,20LC8
85 (2)O3-fluoro-2,6-dimetilfenilcyclohexyl3,01450,24LC8
86 (2)O4,5-debtor-2-werephenyl2,34448,17LC8
87 (2)S2,6-dimetilfenilphenyl0,69byr442.9LC10
(1) is Obtained in the form of bissoli triperoxonane acid
(2) is Obtained in the form of a dihydrochloride

In the same way. as described in the above examples, were obtained the compounds of formula Iq, listed the table 2, and they were received in the form of the dihydrochloride. The compounds can be named as [2-(R20-oxy)-1-R30-1H-pyrrolo[3,2-b]pyridine-3-yl]-R100-methanon, allowing modifications in connection with the rules of nomenclature.

(S)-3-ethyl-piperazine-1-Il
Table 2
Exemplary compounds of formula Iq
Example No.R20R30R100Rt(min)MS (m/z)LC/MS method
882,6-
dimethyl-phenyl
phenyl(R)-3-hydroxy-methylpiperid-Zin-1-yl2,42456,22LC9
892,6-
dimethyl-phenyl
phenyl(R)-3-methoxy-methyl-piperazine-1-Il2,47470,23LC9
902,6-
dimethyl-phenyl
phenyl(S)-3-methyl-Pipera the Jn-1-yl 0,99441,20LC4
912,6-
dimethyl-phenyl
cyclo-hexyl(R)-3-
methoxy-mailpipe-Razin-1-yl
2,50476,28LC9
922,6-
dimethyl-phenyl
cyclo-hexyl(R)-3-hydroxy-methyl-piperazine-1-Il2,47462,26LC9
932,6-
dimethyl-phenyl
cyclo-hexyl(S)-3-methyl-piperazine-1-Il2,94446,27LC8
943-fluoro-
2,6-
dimethyl-phenyl
cyclo-hexyl(S)-3-methyl-piperazine-1-Il2,59464,26LC9
953-fluoro-
2,6-
dimethyl-phenyl
cyclo-hexyl (R)-3-methoxy-methyl-piperazine-1-Ilto 2.57494,27LC9
963-fluoro-
2,6-
dimethyl-
phenyl
cyclo-hexyl(R)-3-hydroxy-methyl-piperazine-1-Il3,16480,25LC8
972,6-
dimethyl-
phenyl
phenyl(S)-3-isobutyl-piperazine-1-Il2,53482,27LC8
982,6-
dimethyl-
phenyl
phenyl(S)-3-isopropyl-piperazine-1-Il2,44468,25LC8
992,6-
dimethyl-phenyl
phenyl(S)-3-propyl-piperazine-1-Il2,92468,25LC8
1002,6-
dimethyl-phenyl
phenyl2,39454,24LC8
1013-fluoro-
2,6-
dimethyl-
phenyl
phenyl(S)-3-methyl-piperazine-1-Il3,14458,21LC8
1022,6-
dimethyl-
phenyl
phenyl2,2-dimethyl-piperazine-1-Il0,96455,20LC4
1032,6-
dimethyl-
phenyl
phenyl3,3-dimethyl-piperazine-1-Il0,96455,20LC4
1042,6-
dimethyl-phenyl
phenyl(2R,5S)-2,5-dimethyl-piperazine-1-Il0,96455,20LC4
1052,6-
dimethyl-phenyl
phenyl 0,76483,00LC10
1062,6-
dimethyl-phenyl
phenyl2-benzyl-piperazine-1-Il1,07517,20LC4
1072,6-
dimethyl-
phenyl
phenyl(S)-2-benzyl-piperazine-1-Il0,75516,9LC10
1082,6-dimethyl-phenyl3-[(2-carbarnoyl-2-0,67583,0LC10
phenylmethylpropyl-carbarnoyl)-methyl]-piperazine-1-Il

In the same way. as described in the above examples, were obtained the compounds of formula Ir, listed in table 3, and they were received in the form of bissoli triperoxonane acid. The connection can be described as [1-phenyl-2-(R20/sup> -oxy)-1H-pyrrolo[3,2-c]pyridine-3-yl]piperazine-1-ylmethanone.

Table 3
Exemplary compounds of formula Ir
Example No.R20Rt(min)MS (m/z)LC/MS method
1092-were1,02412,19LC1
1103-fluoro-2-were1,06430,18LC1
1113,5-debtor-2-were1,09448,17LC1

Similarly, as described in the above examples, were obtained the compounds of formula Is listed in table 4, and they were received in the form of the dihydrochloride. The connection can be described as [1-cyclohexyl-2-(R20-oxy)-6-R40-1H-pyrrolo[3,2-c]pyridine-3-yl]-R100-methanon, in the case when group A represents O, or [1-cyclohexyl-2-(R20-methyl)-6-R40-1H-pyrrolo[3,2-c]pyridine-3-yl]-R100mechanon, in the case when group A represents CH2allowing modifications in connection with the rules of nomenclature, such as the designation R20-methyl in the form of a benzyl group.

3-fluoro-2-methyl-phenyl
Table 4
Exemplary compounds of formula Is
When Mer No.AR20R40R100Rt(min)MS (m/z)LC/MS method
112CH23-fluoro-2-methyl-phenylmethoxy(R)-3-
methoxy-methyl-piperazine-1-Il
2,62508,29LC9
113CH23-fluoro-2-methyl-phenylmethoxy(S)-3-methyl-piperazine-1-Ilto 2.57478,27LC9
114CH2methoxy(R)-3-hydroxy-methyl-piperazine-1-Il3,17494,27LC8
115CH23-fluoro-2-methyl-phenylhydroxy(S)-3-mailpipe-Razin-1-yl2,97464,26LC8
116CH23-fluoro-2-methyl-phenylhydroxy(R)-3-hydroxy-methyl-piperazine-1-Il2,95480,25LC8
117O5-fluoro-2-methyl-phenylhydroxy(S)-3-methyl-piperazine-1-Il2,50466,24LC9
118O3-fluoro-2,6-dimethyl-phenylhydroxy(S)-3-methyl-piperazine-1-Il 0,69481,15LC10
119O3-fluoro-2,6-dimethyl-phenylhydroxypiperazine-
1-Il
1,09467,20LC4

Similarly, as described in the above examples, were obtained the compounds of formula It, listed in table 5, and they were received in the form of bissoli triperoxonane acid or dihydrochloride, respectively. The compounds can be named as [2-(R20-oxy)-1-R30-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone.

Table 5
Exemplary compounds of formula It
Example No.R20R30Rt(min)MS (m/z)LC/MS method
120 (1)phenylphenyl0,77399,20LC4
121 (1)2-forfinalphenyl0,94416,16LC1
122 (1)3-fluoro-2-were4-forfinal1,04448,17LC1
123 (1)5-fluoro-2-were4-forfinal1,03448,17LC1
124 (1)2-fluoro-6-were4-forfinal1,06448,17LC1
125 (2)2,6-dimetilfenilphenyl0,95427,20LC4
(1) is Obtained in the form of bissoli triperoxonane acid
(2) is Obtained in the form of a dihydrochloride

Similarly, as described in the above examples, were obtained the compounds of formula Iu, listed in table 6, and they were received in the form is bissoli triperoxonane acid. The connection can be described as [1-phenyl-2-(R20-oxy)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone.

Table 6
Exemplary compounds of formula Iu
Example No.R20Rt(min)MS (m/z)LC/MS method
126phenyl1,18398,17LC2
1272-were1,28412,19LC2
1282-forfinal1,23416,16LC1
1293-fluoro-2-were1,22430,18LC1
1303,5-debtor-2-were1,31448,17LC1
1312-fluoro-6-were1,00431,10LC4

Similarly, as described in the above examples, were obtained the compounds of formula Iw, listed in table 7, and they were received in the form of the dihydrochloride. The connection can be described as [1-phenyl-2-(R20-oxy)-((4 - or 5 - or 6)-R40)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone, in the case when group A represents O, or [1-phenyl-2-(R20-methyl)-((4 - or 5 - or 6)-R40)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperazine-1-ylmethanone, in the case when group A represents CH2allowing modifications in connection with the rules of nomenclature, such as the designation R20-methyl in the form of a benzyl group.

Table 7
Exemplary compounds of formula Iw
Example No.AR20Deputy R40and its positionRt(min)MS (m/z)LC/MS method
132CH23-fluoro-2-were 4-ethylto 2.57456,23LC8
133O5-fluoro-2-were4-propyl2,70472,23LC8
134O2,6-dimetilfenil6-methoxy2,85456,22LC8
135O5-fluoro-2-were4-ethyl2,58458,21LC8

Example 136

[2-(5-fluoro-2-methylphenoxy)-5-methoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained similarly as described in the examples above, and received in the form of a dihydrochloride [2-(5-fluoro-2-methylphenoxy)-5-methoxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC3): m/z=460,19; Rt=1,52 min

Example 137

[2-(5-fluoro-2-methylphenoxy)-5-hydroxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained similarly as described in the examples above, and received in the form of a dihydrochloride [2-(5-fluoro-2-methylphenoxy)-5-hydroxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC1): m/z=446,18; Rt=1,18 min

Example 138

[2-(2,6-Dimethylphenoxy)-6-hydroxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]-((S)-3-methylpiperazin-1-yl)methanon

Stated in the title compound were obtained analogously as described in examples above and received in the form of a dihydrochloride [2-(2,6-dimethylphenoxy)-6-hydroxy-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]-((S)-3-methylpiperazin-1-yl)methanone.

LC/MS (method LC10): m/z=456,22; Rt=2,45 min

Example 139

[2-(5-fluoro-2-methylphenylsulfonyl)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]-((S)-3-methylpiperazin-1-yl)methanon

Stated in the title compound was obtained similarly as described in the examples above, and received in the form of a dihydrochloride [2-(5-fluoro-2-methylphenylsulfonyl)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]-((S)-3-methylpiperazin-1-yl)methanone.

LC/MS (method LC4): m/z=461,2; Rt=min 1,05

Example 140

[2-(2,6-Dimethylbenzenesulfonyl)-1-phenyl-1H-pyrrolo[3,2-b]pyridine-3-yl]-((S)-3-methylpiperazin-1-yl)methanon

Stated in the title compound was obtained similarly as described in the examples above, and received the form of the dihydrochloride [2-(2,6-dimethylbenzenesulfonyl)-1-phenyl-1H - pyrrolo[2,3-b]pyridine-3-yl]-((S)-3-methylpiperazin-1-yl)methanone.

LC/MS (method LC4): m/z=457,2; Rt=1,13 min

Example 141

[7-Chloro-2-(2,6-dimethylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone

Stated in the title compound was obtained similarly as described in the examples above, and received in the form of a dihydrochloride [7-chloro-2-(2,6-dimethylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridine-3-yl]piperazine-1-ylmethanone.

LC/MS (method LC5): m/z=460,17; Rt=1,94 min

Pharmacological tests

A) Inhibition of renin

Renin inhibitory activity of the compounds of the present invention was demonstrated in in vitro test, in which endogeny fluorogenic peptide substrate was digested with renin specific in Leu-Val connection, which corresponds to the cleavage site of angiotensinogen.

Recombinant human renin (Cayman, No. 10006217) with a concentration of 5 nm were incubated with test compounds at various concentrations and synthetic substrate Dabcyl-γ-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS (Bachem, No. M-2050; Dabcyl refers to 4-(4-dimethylaminophenyl)bentilee group and EDANS relates to amide 5-[(2-amino-ethyl)amino]naphthalene-1-sulfonic acid) at a concentration of 10 μm for 2 hours at room temperature in 0.05 M Tris buffer (pH 8)containing 0.1 M NaCl, 2.5 mm EDTA and 1.25 mg/ml bovine serum albumin. The enhancement of fluorescence, which is the result the ω resonance energy transfer fluorescence, recorded at the wavelength of excitation equal to 330 nm, and the wavelength equal to 485 nm in a microplate spectrophotometer. Inhibiting concentration IC50was calculated from the percentage inhibition of renin activity as a function of the concentration of the test compounds. In this test a sample of connection is usually inhibited renin with IC50a value of less than about 10 micromoles/l (10 μm). Typical IC50the values that have been defined with compounds in the form of the salts shown in the examples above, are listed in table 8.

B) Inhibition of renin in the plasma of man

Renin inhibitory activity of the compounds of the present invention is also demonstrated in in vitro testing in the presence of human plasma. The technique is similar to the method described in pharmacological test A, except that recombinant human renin at a concentration of 30 nm were incubated with test compounds at various concentrations and fluorogenic substrate Dabcyl-γ-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS at a concentration of 25 μm for 30 min at 37°C and 30 min at room temperature in plasma (Innovative Research, the joint normal human plasma collected in EDTA K3 as an anticoagulant, No. IPLA-5).

C) Antihypertensive shall aktivnosti

Antihypertensive activity in vivo of the compounds of the present invention can be demonstrated in double-transgenic mice, sverkhekspressiya genes and human renin and angiotensinogen (dTghRenhAgt mouse; see, D. C. Merrill et al., J. Clin. Invest. 97 (1996), 1047; R. L. Davisson et al., J. Clin. Invest. 99 (1997), 1258; J. L. Lavoie et al., Acta Physiol. Scand. 81 (2004), 571; obtained by crossing strains carrying the transgene, human renin and angiotensinogen transgene person, respectively). Briefly, in this test blood pressure in freely moving dTghRenhAgT mice was determined by telemetry monitoring. For this purpose, the catheter transmitter (model TA11 PA-10, DSI) implanted in the left carotid artery dTghRenhAgT mice under anesthesia. The animals were kept under a 12-hour cycle of day/night and gave them free access to food and water. After one week recovery period monitored blood pressure and heart rate within 24 hours to determine the basic units. Then, the animals were injected orally through a feeding tube or a daily dose of the test compounds in the environment (water containing 0.6% methylcellulose and 0.5% Tween®80), or as a control-only environment. Hemodynamic parameters were recorded continuously for an additional 24 hours, and determine the maximum decrease mean arterial pressure effect and will continue lnost antihypertensive activity (mean arterial pressure=diastolic pressure + 1/3·(systolic pressure - diastolic pressure)). The connection was skanirovali at different doses such as 3 mg/kg body weight and 10 mg/kg of body weight per day.

1. The compound of formula I in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt or physiologically acceptable MES any of them:

in which And are selected from O, S and C(Ra)2;
Raselected from hydrogen and (C1-C4)-alkyl, where two groups Raare independent from each other and can be identical or different;
R is selected from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, phenyl-(C1-C4)-alkyl, (C1-C4)-alkyl-O-CO-CuH2uand R1-NH-CO-CuH2u-where all groups R are independent of each other and can be identical or different;
R1selected from hydrogen, (C1-C4)-alkyl and H2N-CO-(C1-C4)-alkyl-;
R10selected from hydrogen and (C1-C6)-alkyl-O-CO-;
R20selected from phenyl, which is optionally substituted by one or more identical or different substituents selected from halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O-;
R30 choose from (C3-C7)-cycloalkyl and phenyl, where phenyl optionally substituted by one or more identical or different substituents selected from halogen and (C1-C6)-alkyl;
R40selected from halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O - and (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, where all substituents R40are independent from each other and can be identical or different;
one of the groups Y1, Y2, Y3and Y4represents N and the others are the same or different groups CH or CR40;
n is chosen from 0, 1, 2, and 3;
p and q, which are independent from each other and can be identical or different, chosen from 2 and 3;
u is chosen from 0, 1 and 2, where all values of u are independent of each other and can be identical or different;
where all alkyl groups, independently of each other optionally substituted by one or more fluorine atoms;
where all of the phenyl groups present in R and R40, independently of each other optionally substituted by one or more identical or different substituents selected from halogen and (C1-C4)-alkyl.

2. The compound of formula I according to claim 1 in any of its stereoid the dimensional form or in the form of a mixture of stereoisomeric forms in any ratio, or its physiologically acceptable salt or physiologically acceptable MES any of them, where p is 2 and q is chosen from 2 and 3.

3. The compound of formula I according to claim 1 in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt or physiologically acceptable MES any of them, where
And are selected from O, S and C(Ra)2;
Raselected from hydrogen and methyl, where two groups Raare independent from each other and can be identical or different;
R is selected from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, phenyl-(C1-C4)-alkyl, (C1-C4)-alkyl-O-CO-CuH2uand R1-NH-CO-CuH2u-where all groups R are independent of each other and can be identical or different;
R1choose from (C1-C4)-alkyl and H2N-CO-(C1-C4)-alkyl-;
R10selected from hydrogen and (C1-C6)-alkyl-O-CO-;
R20represents phenyl which is optionally substituted by one or more identical or different substituents selected from halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O;
R30choose from (C3-C7)-cycloalkyl and FeNi is a, where phenyl optionally substituted by one or more identical or different substituents selected from halogen and (C1-C6)-alkyl;
R40selected from halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl, hydroxy, (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O - and (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, where all substituents R40are independent from each other and can be identical or different;
one of the groups Y1, Y2, Y3and Y4represents N and the others are the same or different groups CH or CR40;
n is chosen from 0, 1 and 2;
p and q are equal to 2;
u is chosen from 0, 1 and 2, where all values of u are independent of each other and can be identical or different;
where all alkyl groups, independently of each other optionally substituted by one or more fluorine atoms;
where all of the phenyl groups present in R and R40, independently of each other optionally substituted by one or more identical or different substituents selected from halogen and (C1-C4)-alkyl.

4. The method of obtaining the compounds of formula I or its salts or its MES according to any one of claims 1 to 3, including the interaction of the compounds of formula XIV with a compound of formula X to obtain a compound of formula XIII:

where A, R, R20, R30, R40, Y1, Y2, Y3, Y4n, p and q are determined as in claims 1 to 3, and when this functional group can be present in protected form or in the form of a group, which is the predecessor, and R50defined as R10in claims 1 to 3, with the exception of hydrogen, or a protective group, and removing the protective group R50in the case of obtaining the compounds of formula I in which R10represents hydrogen.

5. The compound of formula I according to any one of claims 1 to 3 or a physiologically acceptable salt or physiologically acceptable MES any of them, intended for use as pharmaceutical agents having renin inhibitory activity.

6. Pharmaceutical composition having renin inhibitory activity, which contains at least one compound of formula I according to any one of claims 1 to 3 or a physiologically acceptable salt or physiologically acceptable MES any of them and a pharmaceutically acceptable carrier.

7. The use of the compounds of formula I according to any one of claims 1 to 3 or a physiologically acceptable salt or physiologically acceptable MES any of them to obtain drugs for the treatment of hypertension, heart disease, myocardial infarction, angina, heart failure, hypertrophy of the heart, fibrosis with whom rdca, vascular hypertrophy, dysfunction of the left ventricle, restenosis, renal fibrosis, renal ischemia, renal failure, weakness of the kidney, nephropathy, retinopathy, ischemic disorders or obstructive disorders of the peripheral circulation, glaucoma or damage to the target organ.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmacy and medicine, and concerns using the pyridopyrazine derivatives for preparing a drug for treating or preventing the physiological and/or pathophysiological conditions associated withPI3K kinase inhibition in mammals.

EFFECT: invention provides high clinical effectiveness.

7 cl, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a compound having chemical formula or a salt thereof, where: Ar is an optionally substituted heteroaryl; R1 in each case is independently selected from a group which includes halogen, lower alkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, monoalkylamino, dialkylamino, -O-R5, -N(R5)-R6 and -N(R5)-C(X)-R7; m equals 0 or 1; n equals 0, 1 or 2; R2 is hydrogen or a halogen; L2 is -S(O)2-; R3 is a lower alkyl, optionally substituted with fluorine, C3-6 cycloalkyl, optionally substituted with a lower alkyl, a 5- or 6-member nitrogen-containing heterocycloalkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio or fluorine-substituted lower alkylthio, aryl, optionally substituted with a halogen, lower alkyl, optionally substituted with a halogen or lower alkoxy, optionally substituted with a halogen, or a heteroaryl, optionally substituted with a halogen or a lower alkyl; L1 is selected from a group which includes -O-, -C(R12R13)-X-, -X-C(R12R13)-, -C(R12R13)-N(R11)-, -(R11)-C(R12R13)-, -C(X)-N(R11)-, -N(R11)-C(X)-; X is O; R11 is hydrogen; R4 is hydrogen or a lower alkyl; R5 and R6 in each case are independently selected from a group which includes hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where each is optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio, fluorine-substituted lower alkylthio, monoalkylamino, dialkylamino; R7 in each case is independently selected from a group which includes lower alkyl; where the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "monoalkylamino", "dialkylamino", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", are as described in the claim. The invention also discloses a pharmaceutical composition for treating Raf kinase mediated diseases which is based on a compound of formula I; use of the compound of formula I to produce a medicinal agent is also disclosed.

EFFECT: novel compound which can be useful in treating diseases and conditions associated with aberrant activity of protein kinases is obtained and described.

9 cl, 13 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new polycyclic compounds, pharmaceutically acceptable salts thereof of general formula wherein R1 -phenyl, pyridyl, optionally substituted, or C3-7-cycloalkyl; R2 -H, -CH2R3, -C(=O)R3, -C(=O)N(R4)R3, and -SO2-pyridyl, wherein R3-H, C1-6 alkyl, C2-6 alkenyl, C3-7-cycloalkyl, -(CH2)m-phenyl -(CH2)m-(5-, 6- or 9-member heterocyclyl with 1-3 heteroatoms N, O or S); m is equal to 0-6; R4 -H; X represents O or S; the alkyl, alkenyl, cycloalkyl, phenyl and heterocyclyl groups may be substituted by one or more substitutes. A together with atoms whereto attached forms phenyl or heteroaryl with 1 or 2 nitrogen atoms, optionally substituted; B-C means -CH2-(CH2)z-, wherein z is equal to 1 or 2; D represents -CRIIIRIV-, wherein RIII and RIV are identical, and mean CH3 or H; or RIII and RIV together with the atom C whereto attached form a 3-member cycloalkyl ring, a pharmaceutical composition containing them, and the use of the above compounds for treating viral RSV infections.

EFFECT: new polycyclic compounds are described.

24 cl, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to azaindole-indole derivatives and pharmaceutically acceptable salts thereof of general formula: Y=Z (G), wherein Y means a group of azaindole of formula (Yl) Z means a group of indole of formula (Z1) or (Z2) wherein the values "=", R, R1, R1', R2, R3, R4, R2', R3, R4', R5' are presented in cl. 1 of the patent claim.

EFFECT: compounds inhibit cycline-dependent kinase that enables using them in a pharmaceutical composition.

6 cl, 3 dwg, 9 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of formula I or pharmaceutically acceptable salts thereof, wherein R1 represents H; R2 represents (C1-3)alkyl; R3 represents (C1-4)alkyl optionally substituted by three halogen atoms; R4 represents H; X represents O; n is equal to 1 or 2 or 3; Y is specified in OH, NR5R6 and Z, wherein Z represents a saturated 5- or 6-member heterocyclic ring containing 1 heteroatom specified in NR7, wherein the ring can be substituted by oxo(C1-3)alkyl, hydroxy(C1-3)alkyl; or wherein Z represents an aromatic 5- or 6-member heterocyclic ring containing 1-2 heretoatoms specified in N wherein the ring can be substituted by (C1-3)alkyl; R5 and R6 optionally represent H, (C3-8)cycloalkyl or (C1-6)alkyl optionally substituted 1-2 times by halogen, OH, (C1-6)alkyloxy, CONR14R15, NR14R15 or a 6-member saturated heterocyclic group containing a heteroatom specified in NR8; or R5 and R6 together with a nitrogen atom whereto attached form a 5-10-member saturated heterocyclic ring optionally additionally containing 1, 3 heteroatoms specified in NR9, with the ring optionally substituted by OH, oxo, (C1-4)alkyl, hydroxy(C1-3)alkyl, CONR10R11 or NR10R11; R7 represents H; R8 represents (C1-3)alkyl; R9 represents H, (C1-3)alkyl, hydroxy(C1-3)alkyl, (C1-3)alkoxy(C1-3)alykl, (C1-6)alkylcarbonyl, (C1-6)alkyloxycarbonyl, CONR12R13 or a 6-member heteroaryl group containing 1-2 heteroatoms specified in N; R10 and R11 optionally represent H or (C1-3)alkyl; R12 and R13 optionally represent (C1-3)alkyl; or R14 and R15 optionally represent (C1-3)alkyl. Also, the invention refers to the use of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of formula I and a pharmaceutical composition thereof.

EFFECT: there are prepared new 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives effective for treating osteoporosis, atherosclerosis, inflammation and immune disorders, such as rheumatoid arthritis, psoriasis and chronic pain, such as neuropathic pain .

9 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline compounds of formula (I) and physiologically acceptable acid addition salts and N oxides thereof, wherein R denotes a polycyclic group of formula (R) wherein * indicates the quinolinyl radical binding site; A denotes (CH2)a, where a equals 0, 1, 2 or 3; B denotes (CH2)b, where b equals 0, 1, 2 or 3; X' denotes (CH2)x where x equals 0, 1, 2 or 3; Y denotes (CH2)y where y equals 0, 1, 2 or 3; provided that a+b=1, 2, 3 or 4, x+y=1, 2, 3 or 4, and a+b+x+y=3, 4, 5, 6 or 7; Q denotes N; R1 denotes hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, phenyl-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where phenyl rings in last two said groups are unsubstituted or carry 1, 2 or 3 substitutes selected from halogen, C1-C4-alkyl or C1-C4-halogenalkyl; R2 denotes hydrogen; R3 denotes hydrogen; p=0, 1 or 2; R4, if present, denotes C1-C4-alkyl and is bonded with X and/or Y, if p=2, two radicals R4, which are bonded with adjacent carbon atoms of X or Y, together can also denote a straight C2-C5-alkylene; q=0; n=0; m=0; X denotes S(O)2; which is located in position 3 of quinoline; Ar denotes a radical Ar1, wherein Ar1 is a phenyl, wherein the phenyl can be unsubstituted or can carry 1 substitute Rx wherein Rx denotes halogen, CN, C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogenalkoxy, C1-C6-alkylthio, C1-C6-halogenalkylthio, NRx1 Rx2, wherein Rx1 and Rx2 independently denote hydrogen, C1-C6-alkyl, or Rx1 and Rx2 together with a nitrogen atom form an N-bonded 5-, 6- or 7-member saturated heteromonocyclic ring or an N-boned 7-, 8-, 9- or 10-member saturated heterobicyclic ring, which are unsubstituted or carry 1, 2, 3 or 4 radicals selected from C1-C4-alkyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treatment using the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel quinoline derivatives are obtained, which respond to modulation of the serotonin 5-HT6 receptor.

23 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(5-isopropoxy-1H-pyarazol-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine or pharmaceutically acceptable salt thereof, having inhibiting activity with respect to Trk (tropomyosin-related kinase). The compounds can be used as a medicinal agent for treating cancer. The invention also relates to use of said compound of pharmaceutically acceptable salt thereof to produce a medicinal agent for treating cancer in a warm-blooded animal and a pharmaceutical composition containing said compound or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, a solvent or an inert filler.

EFFECT: high efficiency of using the compound.

4 cl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to a compound of formula I, wherein W and Z represent CH; Y represents CH2; wherein R1 and R2 independently represent H, halogen, CH2F, CHF2, CF3, CF2CF3, or C1-C6alkyl; R' represents H; R3 and R4 independently represent H, or C1-C3alkyl, all mentioned C1-C3alkyl groups and mentioned C1-C6alkyl groups are independently substituted by one or two groups independently substituted by one or two groups independently specified in OH, halogen, C1-C3alkyl, OC1-C3alkyl or trifluoromethyl; q=1 or 0; R5 represents C1-C6alkyl; and to pharmaceutically acceptable salts thereof. Furthermore, the invention refers to a composition, a tablet and pharmaceutical syrup having potassium channel modulation activity and containing the compound of formula I, to a method of preventing and treating diseases that are affected by the activation of potentially opened potassium channels.

EFFECT: there are prepared and described the new biologically active compounds which may be effective in the prevention or treatment of diseases or disorders that are affected by potassium channel activity.

21 cl, 2 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where A is C-R1b; R1a, R1b, R1c, R1d, R1e, R2, R3, R4, R5 and n are as described in claim 1 of the invention, as well as pharmaceutically acceptable salts thereof. Described also is a pharmaceutical composition having activity as glucocorticoid receptor modulators.

EFFECT: novel compounds are obtained and described, which are glucocorticoid receptor antagonists and useful for treating and/or preventing diseases such as diabetes, dyslipidaemia, obesity, hyptension, cardiovascular diseases, adrenal gland malfunction or depression.

24 cl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition the form of an oral suspension consisting of valsartan or a pharmaceutically acceptable salt thereof and at least one or two or more ingredients specified in glycerol or a syrup or a mixture thereof, a preserving agent, a buffer system, a suspending/stabilising agent and anti-foaming agent. The buffer system is specified in sodium citrate, potassium citrate, sodium bicarbonate, sodium dihydrophosphate and potassium dihydrophosphate, and maintains pH of the composition within the range of 3.0 to 5.0. Further, the present invention refers to using the pharmaceutical composition for preparing a drug.

EFFECT: orally administered valsartan suspension provides high bioavailability and reduced variability of response to the administered dose when administered to different subjects or one subject.

10 cl, 4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a selective thiazolidinedione analogue to be used in treating and preventing diabetes and dyslipidemia, representing 5-(4-(2-(3-methoxyphenyl)-2-oxoethoxy)benzyl)thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof. Also, the invention refers to a pharmaceutical composition for diabetes and dyslipidemia, containing an effective amount of 5-(4-(2-(3-methoxyphenyl)-2-oxoethoxy)benzyl)thiazolidine-2,4-dione or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. .

EFFECT: what is produced is the selective thiazolidinedione analogue decreasing binding and activating of the PPARγ nuclear transcription factor.

4 cl, 2 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cyclic indole-3-carboxamide of formula (I) or physiologically acceptable salts thereof of formula (I): wherein the values A, R, R10, R20, R30, R40, n, p and q are specified in clause 1 of the patent claim. A method for preparing them is described.

EFFECT: compounds have renin-inhibitory activity that allows using them for preparing a pharmaceutical composition and a drug preparation for treating the diseases associated with renin activity.

11 cl, 4 tbl, 127 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combined antihypertensive drug containing an agent presented by Amlodipine besilate and Lisinopril dehydrate mixed with an excipient. As the excipient, the specified antihypertensive drug contains microcrystalline cellulose of an average particle size of 90-100 mcm and a bulk density of 0.28-0.33 g/ml; as additives, it contains colloidal silicon dioxide, magnesium stearate and sodium carboxymethyl starch. The invention also refers to a method for preparing the mentioned antihypertensive drug by direct compression.

EFFECT: providing a stable drug preparation, more storage-stable, having high producibility, active substance distribution uniformity and bioavailability.

8 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to medicine, namely to solid peroral dosage form, obtained by rotation pressing, which includes therapeutically effective quantity of aliskiren or its pharmaceutically acceptable salt, and active ingredient is present in said dosage form in amount higher than 38% by weight of peroral dosage form, as well as to method of obtaining said solid peroral dosage form.

EFFECT: method with application of rotational pressing makes it possible to exclude application of solvent, requires for wet granulation, method ensures high content of drug agent in composition.

23 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using a compound of formula (I):

wherein R represents a hydrogen atom or CH3, and X represents a physiologically acceptable counter ion for preparing a hepatoprotective agent for treating or preventing a liver injury. The invention also refers to a method for treating or preventing the liver injury which involves a therapeutically or preventive effective amount of said compound of formula (I).

EFFECT: declared group of inventions provides hepatoprotective activity ensured by an ability of the compounds of formula (I) to improve an endothelium function to release endogenic prostacyclin.

14 cl, 7 dwg, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a drug preparation for preventing the development of cardiovascular diseases in individuals of a high-risk group. A capsule for preventing the development of cardiovascular diseases in individuals of a high-risk group which contains acetylsalicylic acid tablets coated by partially hydrolised polyvinyl alcohol (PVA), tablets of simvastatin and pravastatin coated by hydroxypropyl methylcellulose (HPMC) and tablets of lisinopril, ramipril or perindopril coated by partially hydrolised polyvinyl chloride. Using the capsule in producing the drug preparation for preventing the development of cardiovascular diseases in individuals of a high-risk group.

EFFECT: capsule is stable at variable temperature and relative humidity, as well as resistant to decomposition of the active ingredients under exposure to light.

8 cl, 29 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: disclosed are novel 4-dimethyl aminobutyric acid derivatives of formula (I) (pharmaceutically acceptable salts thereof), where values of A1, A2, R1, m and n are given in the claim, which inhibit activity of carnitine palmitoyltransferase (CPT), and more specifically CPT2.

EFFECT: compounds are an agent of pharmaceutical compositions, having CPT2 inhibiting activity.

18 cl, 71 ex, 1 tbl

FIELD: chemistry.

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

EFFECT: improved method.

11 cl, 9 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to 6-substituted isoquinoline and isoquinolinone derivatives of formula or stereoisomer and/or tautomer forms thereof, and/or pharmaceutically acceptable salts thereof, where R1 is H or OH; R2 is R', (C7-C8)alkyl, (C1-C6)alkylene-R', (C2-C6)alkenyl; or R2 is (C1-C6)alkyl, under the condition that in said alkyl residue, at least one hydrogen is substituted with OH or OCH3; or R2 is (C1-C6)alkylene, bonded with cycloalkylamine, where (C1-C4)alkylene forms a second bond with another carbon atom of the cycloalkylamine ring and, together with carbon atoms of the cycloalkyalmine, forms a second 5-8-member ring; R3, R5 and R8 denote H; R4 is H, (C1-C6)alkyl or (C1-C6)alkylene-R'; R6 and R6' independently denote H, (C1-C8)alkyl, (C1-C6)alkylene-R' or C(O)O-(C1-C6)alkyl; R7 is H, halogen or (C1-C6)alkyl; n equals 1; m equals 3 or 5; r equals 0 or 1 and L is O(CH2)p, where p=0; where R' is (C3-C8)cycloalkyl, (C6)aryl; where in residues R2-R8 (C6)aryl is unsubstituted or substituted with one or more suitable groups independently selected from halogen, (C1-C6)alkyl, O-(C1-C6)alkyl, where the alkyl group can be substituted with 1-3 halogen atoms. The invention also relates to use of the compound of formula (I) and a medicinal agent based on the compound of formula (I).

EFFECT: obtaining novel 6-substituted isoquinoline and isoquinolinone derivatives suitable for treating and/or preventing diseases associated with Rho-kinase and/or Rho-kinase-mediated myosin light chain phosphatase phosphorylation.

36 cl, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

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