Heterocyclic compounds, their using and pharmaceutical composition for treatment of states mediated by cxcr4 and ccr5

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (1): and its salts wherein X means unsubstituted monocyclic (5-6-membered) ring system comprising nitrogen atom (N); or X means condensed bicyclic (9-12-membered) ring system comprising N-atom that can be substituted with substitute -SO2-phenyl; Z represents hydrogen atom (H) or means a condensed bicyclic (9-12-membered) unsubstituted or substituted ring system comprising at least one heteroatom, N-atom; Ar represents unsubstituted phenyl ring; each among L1, L2 and L3 represents independently a bond, -CO, -SO2 or -CH2 wherein at least one among L2 and L3 must involve -CO or -SO2; L2 and L3 can represent can represent independently -CONH or -CONHCH2 also; n = 0, 1 or 2; each R1 and R2 represents independently hydrogen atom (H) or a direct (C1-C6)-alkyl chain; Y comprises at least one substituted or unsubstituted phenyl ring or 5-6-membered heteroaromatic ring comprising at least one N-atom as a heteroatom; wherein optional substituted are chosen among the group consisting of halogen atom, alkyl, -COOH, -OH or -NH2; or Y represents 6,7-dihydropyrrolo[3,4-b]pyridine-5-one; wherein ring nitrogen atom can be oxidized optionally. Also, invention relates to a pharmaceutical composition used in treatment states regulated by chemokine CXCR4 or CCR5 receptors based on these compounds. Invention provides preparing new compounds and medicinal agents based on thereof for aims in treatment of HIV- and FIV-infected patients.

EFFECT: valuable medicinal properties of compounds and composition.

15 cl, 57 ex

 

The technical field

The present invention relates to new compounds, pharmaceutical compositions and to their use. More specifically, this invention relates to new heterocyclic compounds that bind to receptors chemokines, including CXCR4 and CCR5, and a protective effect against infection of target cells by human immunodeficiency virus (HIV).

Prerequisites to the creation of inventions

In the literature about 40 chemokines person, which function, at least in part, through the regulation of many complex and overlapping biological activities, which is important for movement of lymphoid cells and extravasation and tissue infiltration of leukocytes in response to stimulating agents (see, for example: P.Ponath, Exp. Opin. Invest. Drugs, 7: 1-18, 1998; Baggiolini, M., Nature 392: 565-568 (1998); Locati, et al., Annu. Rev. Med. 50: 425-440 (1999)). Data chemotactic cytokines, or chemokines are a family of proteins with molecular masses of approximately 8-10 kDa. Chemokines, apparently, have a common structural motif, which consists of 4 conservative cysteines involved in maintaining the tertiary structure. There are two main subfamilies of chemokines: "SS" or β-chemokines and "SHS" or α-chemokines. Receptor data chemokines are classified on the basis of the chemokine, which is nature who meets the ligand receptor.

Receptors β-chemokines represent "CCR", while receptors α-chemokines represent "CXCR".

Chemokines are considered as the main intermediaries in the occurrence of inflammation and its maintenance (see Chemokines in Disease published by Humana Press (1999), Edited by C.Herbert; Murdoch, et al., Blood 95:3032-3043 (2000)). More specifically, it was found that chemokines play an important role in regulating the function of endothelial cells, including proliferation, migration, and differentiation during angiogenesis and restoration of endothelium after injury (Gupta, et al., J. Biol. Chem., 7:4282-4287 (1998); Volin et al., Biochem. Biophys. Res. Commun. 242:46-53 (1998)). Two specific chemokine involved in the etiology of infection with human immunodeficiency virus (HIV).

In most cases, HIV is initially associated through its envelope protein gp120 with the CD4 receptor of target cells. Apparently, when this happens conformational change in the protein gp120, which leads to its subsequent binding to the receptor of the chemokine, such as CCR5 (Wyatt, et al., Science, 280:1884-1888 (1998); Rizzuto, et al., Science 280:1949-1953 (1998); Berger, et al., Annu. Rev. Immunol. 17:657-700 (1999)). Isolates of HIV-1, resulting from infection, are associated with CXCR4 receptor of the chemokine.

After the initial binding of HIV to CD4 cells is the fusion of virus and cells, which is mediated by a family of receptors chemokines, various members that Slu is at as joint factors merge to macrophagecolony (M-genotype isolates of HIV-1 and genotype for the T cell lines (T-genotype isolates of HIV-1 (Carroll, et al., Science, 276:273-276 (1997); Feng, et al., Science 272:872-877 (1996); Bleul et al. Nature 382:829-833 (1996); Oberlin, et al., Nature 382:833-835 (1996); Cocchi, et al., Science 270:1811-1815 (1995): Dragic, et al., Nature 381:667-673 (1996); Deng, et al., Nature 381;661-666 (1996); Alkhatib et al., Science 272:1955-1958 (1996). In the process of infection of the patient, apparently, the majority of HIV particles undergoes a change from M genotype phenotype to a more pathogenic T genotype viral phenotype (Blaak et al., Proc. Natl. Acad, Sci. 97:1269-1274 (2000); Miedema, et al., Immune. Rev., 140:35 (1994); Simmonds, et al., J. Virol. 70:8355-8360 (1996); Tersmette et al., J. Virol. 62:2026-2032 (1988); Connor, R.I., Ho, D.D. J. Virol. 68:4400-4408 (1994); Schuitemaker et al., J. Virol. 66:1354-1360 (1992)). M-viral genotype phenotype correlates with the ability of the virus to penetrate into the cell after binding of the CCR5 receptor, while T genotype viral phenotype correlates with the entry of the virus into the cell after binding and membrane fusion with the CXCR4 receptor. Based on clinical observations, it was hypothesized that patients who have a genetic mutation in the CCR5 receptor, apparently, are resistant or less sensitive to HIV infection (Liu, et al., Cell 86:367-377 (1996); Samson, et al., Nature 382:722-725 (1996); Michael, et al., Nature Med. 3:338-340 (1997); Michael, et al., J. Virol. 72:6040-6047 (1998); Obrien, et al., Lancet 349:1219 (1997); Zhang, et al., AIDS Res. Hum. Retroviruses 13:1357-1366 (1997); Rana, et al., J. Virol. 71:3219-3227 (1997); Theodorou et al., Lancet 349:1219-1220 (1997)). Despite the number of receptors chemokines, which were reported to mediate the integration of HIV into cells, receptors CCR5 and CXCR4, what about the seemingly are the only physiologically important joint receptors for a wide range of primary clinical strains of HIV-1 (Zhang, et al., J. Virol. 72:9307-9312 (1998); Zhang, et al., J. Virol. 73:3443-3448 (1999); Simmonds, et al., J. Virol. 72:8453-8457 (1998)). Fusion and penetration T genotype variants of viruses via receptor CXCR4 inhibited natural CXC-chemokine, factor-1, produced by stromal cells, while the fusion and penetration M-genotype variants of the virus through the CCR5 receptor inhibited natural CC-chemokines, namely the regulator activation normal T-cell expression and secretion (RANTES) and macrophage inflammatory protein (MIP-1 alpha and beta).

It was suggested that in addition to functioning chemokines as a co-factor in the penetration of HIV into cells, a possible cause of CD8+T-cell apoptosis and AIDS-related dementia by induction of apoptosis of nerve cells, is a direct interaction between the viral protein gp120 with the receptor of the chemokine CXCR4 (Hesselgesser et al., Curr. Biol. 8:595-598 (1998); Hesselgesser et al., Curr. Biol. 7:112-121 (1997); Hesselgesser et al., "Chemokines and Chemokine receptors in the Brain" in Chemokines in Disease published by Humana Press (1999), Edited by Herbert C.; Herbein, et al., Nature 395:189-194 (1998); Buttini et al., Nature Med. 4:441-446 (1998); Ohagen et al., J. Virol. 73:897-906 (1999); Biard-Piechaczyk, et al., Virology 268:329-344 (2000); Sanders, et al., J. Neuroscience Res. 59:671-679 (2000); Bajetto et al., J. Neurochem. 73:2348-2357 (1999); Zheng, et al., J. Virol. 73:8256-8267 (1999)).

However, linking the recipe is the moat chemokines with their natural ligands plays, apparently, more and evolutionary important role than only mediated infection by the HIV virus. The binding of the natural ligand, catalyst pre-B-cell factor (PBSF/SDF-1), produced by stromal cells with a receptor of the chemokine CXCR4 leads to an important mechanism of signal transmission: mice subjected shock of CXCR4 or SDF-1, was found cerebellar, heart disorders and disorders of the gastrointestinal tract and intrauterine death (Zou, et al., Nature, 393:591-594 (1998); Tachibana, et al., Nature, 393:591-594 (1998); Nagasawa, et al., Nature 382:635-638 (1996)). Mice with deficiency of receptors CXCR4 was also found violations of haematopoiesis (Nagasawa, et al., Nature 382:635-638 (1996)); the migration of CXCR4-expressing cells and precursor cells of hemopoiesis to factor SDF-1 appears to be important for conservation In cell lines and localization of CD34+-precursor cells in the bone marrow (Bleul et al., Exp. Med. 187:753-762 (1998); Viardot, et al., Ann. Hematol. 77:195-197 (1998); Auiti, et al., J. Exp. Med. 185:111-120 (1997); Peled, et al., Science 283:845-848 (1999); Qing, et al., Immunity 10:463-471 (1999); Lataillade, et al., Blood 95:756-768 (1999); Ishii, et al., J. Immunol. 163:3612-3620 (1999); out by Maekawa, et al., Internal. Medicine 39:90-100 (2000); Fedyk, et al., J. Leukocyte Biol. 66:667-673 (1999); Peled, et al., Blood 95:3289-3296 (2000)).

The signal produced by the binding of factor SDF-1 receptor CXCR4, can also play an important role in the proliferation of tumor cells and the regulation of angiogenesis associated with tumor growth (with the. "Chemokines and Cancer" published by Humana Press (1999); Edited by B.J.Rollins; Arenburg, et al., J. Leukocyte Biol. 62:554-562 (1997); Moore, et al., J. Invest. Med. 46:113-120 (1998); Moore, et al., Trends cardiovasc. Med. 8:51-58 (1998); Seghal, et al., J. Surg. Oncol. 69:99-104 (1998)); the known angiogenic growth factors, VEG-F and bFGF, which increases the levels of receptor CXCR4 in endothelial cells and SDF-1 can induce revascularization in vivo (Salcedo et al., Am. J. Pathol. 154:1125-1135 (1999)). Leukemia cells expressing the receptor CXCR4, migrate to the lymph nodes and stromal cells of the bone marrow that Express factor SDF-1, and are attached to them (Burger, et al., Blood 94:3658-3667 (1999); Arai, et al., Eur. J. Haematol. 64:323-332 (2000); Bradstock et al., Leukemia 14:882-888 (2000)).

The linking factor SDF-1 receptor CXCR4 is also relevant to the pathogenesis of atherosclerosis (Abi-Younes, et al., Circ. Res. 86:131-138 (2000)), the rejection of the renal allograft (Eitner et al., Transplantation 66:1551-1557 (1998)), asthma and allergic airway inflammation (Yssel, et al., Clinical and Experimantal Allergy 28:104-109 (1998); J. Immunol. 164:5935-5943 (2000); Gonzalo, et al., J. Immunol. 165:499-508 (2000)), Alzheimer's disease (Xia, et al., J. Neurovirology 5:32-41 (1999)) and arthritis (Nanki et al., J. Immunol. 164:5010-5014 (2000)).

In an attempt to better understand the interaction between chemokines and their receptors have recently been undertaken experiments on the inhibition of fusion, penetration and replication of HIV through the receptor of the chemokine CXCR4 by using monoclonal antibodies or small molecules, which, apparently, have a useful terap ticheskoe action (Schols, et al., J. Exp. Med. 186:1383-1388 (1997); Schols, et al., Antiviral Research 35:147-156 (1997); Bridger, et al., J. Med. Chem. 42:3971-3981 (1999); Bridger, et al., "Bicyclam Derivatives as HIV Inhibitors" in Advances in Antiviral Drug Design, Vol. 3:161-229; Published by JAI press (1999); Edited by E.De Clercq). Small molecules, such as Bellamy, apparently, specifically associated with the receptor CXCR4, but not CCR5 receptor (Donzella et al., Nature Medicine, 4:72-77 (1998)). These experiments showed that Bellamy constrain the penetration of HIV and fusion with the membrane of target cells in vitro. Later it was shown that Bellamy inhibit fusion and replication of feline immunodeficiency virus (FIV), which is introduced into cells by receptor CXCR4 (Egberink et al., J. Virol. 73:6346-6352 (1999)).

Additional experiments showed that bicyclam dose-dependent manner inhibits binding125I-labeled factor SDF-1 receptor CXCR4 and signal transduction (identified by increasing calcium inside cells in response to SDF-1. Thus, bicyclam also acts as an antagonist to the signal transduction resulting from the binding of factor produced by stromal cells, or SDF-1α, natural chemokine to the receptor CXCR4. Bellamy also inhibit apoptosis induced by viral envelope protein gp120 in HIV uninfected cells (Blanco, et al., Antimicrobial Agents and Chemother. 44:51-56 (2000)).

U.S. patents Nos. 5583131; 5698546 and 5817807, which are included in the data is e description in its entirety by reference, reveal cyclic compounds exhibiting activity against HIV-1 and HIV-2 in vitro. It was subsequently discovered and shown in an interdependent applications U.S. No. 09/111895 and U.S. No. 60/172153 that these compounds exhibit activity against HIV by binding to a receptor of the chemokine CXCR4 expressed on the surface of certain cells of the immune system. Such competitive binding protects these target cells from HIV infection, which enters cells by receptor CXCR4. In addition, these compounds counteract the binding, signaling and chemotactic effects of the natural ligand for the receptor CXCR4, factor 1αproduced by stromal cells (SDF-1). It was also revealed that these new compounds exhibit a protective effect against HIV infection of target cells by binding in vitro with the CCR5 receptor.

Furthermore, in U.S. patent No. 09/495298 was revealed that these cyclic polyamine antiviral agents described in the above patents, increasing the production of white blood cells, and also have antiviral properties. Thus, these agents are used to control side effects of chemotherapy, to ensure a favorable outcome in bone marrow transplantation healing of wounds and burns, and also against bacterial infections in leukemia.

Later, in PCT international patent application PCT/SE/00321 has been disclosed a series of heterocyclic compounds that are active against HIV by binding to receptors chemokines CXCR4 and CCR5 expressed on the surface of certain cells of the immune system. Thus, such competitive binding protects target cells from HIV infection, which enters cells by receptor CXCR4 or CCR5. In addition, these compounds counteract the binding, signaling and chemotactic effects of the natural ligand for CXCR4, a chemokine, factor 1α (SDF-1), produced by stromal cells and/or natural ligand for CCR5, the chemokine RANTES.

In this description reveals new compounds that show a protective effect against HIV infection of target cells by binding to receptors chemokines CXCR4 or CCR5 in the same way as described above for macrocyclic compounds.

Quoting the above documents should not be construed as an admission that any of these documents is relevant prior art. All statements regarding the date or representations regarding the content of these documents, based on information available at the representatives, and do not imply any assumption regarding the correctness of the dates or contents of these documents. In addition, all documents that are referenced throughout the application, are included in this description in its entirety by reference.

A brief description of the invention

The present invention relates to new compounds which bind to receptors chemokines and inhibit linking them to the natural ligand. Compounds according to the present invention are used as agents exhibiting a protective effect against the target cells from HIV infection. Other aspects of the present invention are compounds that act as antagonists or agonists of the receptors, chemokines, and also possess other biological activities associated with the ability of these compounds to inhibit the binding of chemokines to their receptors.

Compounds according to the invention have the formula

and their salts and proletarienne form, where:

X means a monocyclic 5 to 6-membered) or condensed bicyclic (9-12-membered) unsubstituted or substituted ring system containing at least one heteroatom selected from N, O and S;

Z represents N or means a monocyclic 5 to 6-membered) or condensed BIC is Klionsky (9-12-membered) unsubstituted or substituted ring system, containing at least one heteroatom selected from N, O and S;

Ar, optionally, is substituted by an aromatic or heteroaromatic ring;

each of the L1L2and L3independently represents a bond, CO, SO2or CH2where at least one of L2and L3should include CO or SO2; and where L1may also mean alkylen(2-5C), where one or two atoms can optionally be replaced by N and the specified alkylene, optional, can be replaced by the bridge alkylene(3-4C); L2and L3also can independently mean SO2NH, CONH, SO2NHCH2or CONHCH2;

n is 0, 1 or 2;

each R1and R2independently represents an atom H or a straight or branched chain or cyclic alkyl(1-6C), which optionally may be substituted, and where R2may mean alkylen condensed with Y; and

Y includes at least one aromatic or heteroaromatic ring or another heterocyclic substituted or unsubstituted ring, condensed directly with L3.

The invention relates to compounds of formula 1, above, and to the use of such compounds in the treatment and preparation of drugs for the treatment of conditions associated with regulation of receptors CXCR4 and/or CCR5.

Ways of carrying out the invention

The present invention relates to compounds of formula 1, which can act as agents that regulate the activity of receptors chemokines. Such receptors chemokines include CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 and CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5, but are not limited to.

The present invention relates to new compounds of formula 1, which have a protective effect against the target cells from HIV infection by specific binding of compounds to the receptor of the chemokine, and which affect the binding of the natural ligand or chemokine to a receptor such as CXCR4 and/or CCR5 target cells.

The compounds of formula 1 are used as agents that act on receptors chemokines, such as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 and CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5, where such receptors chemokines are important mediators of many inflammatory diseases in humans, as well as immunoregulatory diseases. Thus, a compound that regulates the activity of such receptors chemokines, must be suitable for the treatment or prevention of such diseases.

The term "regulators", which is used in this description assumes values antagonist, agonist, partial antagonist and/or a partial agonist, inhibitors and activators. In one preferred embodiment n is the standing of the invention the compounds of formula 1 exhibit a protective effect against HIV infection by inhibiting the binding of HIV to the receptor of the chemokine, such as CXCR4 and/or CCR5 target cells. The invention includes a method, which is a contact target cells with the amount of compound that is effective for the implementation of inhibiting the binding of the virus to the receptor of the chemokine.

Compounds that inhibit the receptors chemokines can be used to treat diseases associated with hematopoiesis, including, but not limited to, regulation of the side effects caused by chemotherapy, ensuring a favorable outcome in bone marrow transplantation, wound healing and the treatment of burns, as well as against bacterial infections in leukemia.

Compounds that inhibit the activity and function of the receptor of the chemokine, can be used to treat diseases associated with inflammation, including, but not limited to, inflammatory or allergic diseases such as asthma, allergic rhinitis, allergic lung disease, allergic pneumonitis, eosinophilic pneumonia, allergic reaction of the delayed type, diffuse disease of connective tissue, lung (ILD) (e.g., idiopathic pneumosclerosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, xeroderma, polymyositis or dermatomyositis); systemic anaphylaxis Il is an allergic reaction, drug allergies, allergic reactions to insect bites; autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myasthenia gravis heavy psevdomatematicheskoe, juvenile diabetes; glomerulonephritis, autoimmune thyroiditis, graft rejection, including the rejection of allogeneic graft or graft versus host disease; inflammatory intestinal diseases such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including mediated by T-cells in psoriasis) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis (e.g., necrotizing, skin and allergic vasculitis); eosinophilic myositis, eosinophilic fasciitis; and malignant tumors.

Compounds that activate or support the function of the receptor of the chemokine, can be used to treat diseases associated with immunosuppression, such as, for chemotherapy of individuals, radiation therapy, for healing of wounds and burns treatment, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy), or using combinations of standard drugs in the treatment of autoimmune diseases and transpl is ncacii/graft rejection, causes immunosuppression; immunosuppression due to congenital deficiency of receptor function or other causes; and infectious diseases, such as parasitic diseases, including, but not limited to helminth infections, such worms as nematodes (round worms); trichocephalosis, enterobiasis, ascariasis, Ancylostoma, Strongyloides, trichinosis, filariasis; diseases caused by trematodes; visceral syndrome "wandering larvae" (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanema ssp.), skin syndrome "wandering larvae" (Ancylostona braziliense, Ancylostoma caninum); malaria, caused by the protozoa Plasmodium vivax, human cytomegalovirus, Herpesvirus saimiri, and Kaposi's sarcoma caused by the herpes virus, also known as virus 8 human herpes, and poxvirus Moluscum contagiosum.

It should be understood that the compounds of formula 1 can be used in combination with any other pharmaceutical composition, and such combination therapy can be applied to modulate the activity of the receptor of the chemokine and, thereby, for the prevention and treatment of inflammatory diseases and diseases associated with the immune system.

In addition, assume that the present invention can be used in combination with one or more agents used to prevent or treat HIV-infecti is. Examples of such agents include:

(1) nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, Voivodina tidoxil etc.;

(2) dinucleotides nucleoside reverse transcriptase inhibitor (including an agent having anti-oxidant activity, such as Immunocal, oltipraz etc), such as nevirapine, delavirdine, efavirenz, loviride, Immunocal, oltipraz etc.; and

(3) protease inhibitors, such as shinaver, ritonavir, indinavir, nelfinavir, APV, palinavir, latinovic etc.

The amount of combinations of the compounds of formula 1 according to this invention with agents designed for the prevention and treatment of HIV infection, is not limited to those listed in paragraphs (1), (2) or (3), but includes essentially any combination with any pharmaceutical composition used for treatment of HIV infection. In addition, combinations of compounds according to the present invention and other agents for the prevention and treatment of HIV infection, can be entered separately or together. In addition, the introduction of one element may be performed before, together or after administration of the other agent (agent).

The compounds of formula 1 according to the present invention can be administered orally, parenteral the figures (for example, intramuscular, intraperitoneal, intravenous through intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nazalnam, vaginal, rectal, sublingual, or local routes of administration and can be prepared separately or together, in suitable standard formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and binders that correspond to each method of administration.

The compounds of formula 1 are active and are used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats and monkeys. Compounds according to the present invention are also effective in applying for a person.

The compounds of formula 1 according to the present invention may form a hydrate or a solvate. When the compounds of formula 1 according to the present invention exist in the form of spatial isomers, configurational isomers, conformers, diastereoisomeric forms and their mixtures diastereoisomeric forms, you can select individual isomers, if desired, using known methods of separation and purification. When the compound of formula 1 according to the present invention is a racemate, it can be divided into (S)-compound and (R connection using an optical resolution. Individual optical isomers and mixtures thereof are included in the scope of the present invention.

This invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier or diluent and an effective amount of the compounds of formula 1. The compound of formula 1 can be entered one or in a mixture with pharmaceutically acceptable carrier (e.g., in the form of solid compositions such as tablets, capsules, granules, powders, etc.; liquid compositions, such as syrups, injections, etc.) oral and neuroretinal way. Examples separarely compositions include injections, drops, suppositories, pessaries.

The appropriate level of dose in the treatment or prevention of conditions which require modulation of the receptor of the chemokine, will mainly be about 0.01 to 500 mg per kg patient weight per day, which can be entered as a single dose or multiple doses. Preferably, the dosage level will be about from 0.1 to 250 mg/kg / day. It is clear that the specific dose level and frequency of dosage for any particular patient may vary, and the treatment regimen will depend on a number of factors, including the activity of that specific connection, resistance to metabolism and the duration of such a link is, the age of the patient, body weight, General health, sex, diet, mode and time of administration, rate of excretion, combination drugs, the severity of the condition and therapy, which is exposed to the patient.

In addition, the present invention relates to new compounds which bind to receptors chemokines and thereby prevent the binding with them the natural ligand. Compounds according to the present invention are used as agents exhibiting a protective effect against target cells from HIV infection. Compounds according to the present invention is also used as antagonists or agonists of the receptors, chemokines, and use other biological activity associated with the ability of these compounds to inhibit the binding of chemokines to their receptors.

Compounds according to the invention can be used as a "proletarienne" forms, that is, protected forms of the compounds, which release the compound after administration to the patient. For example, the connection can carry protective groups, which hatshepsuts hydrolysis in body fluids, for example, in the bloodstream, releasing, thus, an active connection, or oxidized or restored in body fluids to release the connection. Discussion data is the gadfly of prodrugs can be found in the publication "Smith and Williams Introduction to the Principles of Drug Design", H.J.Smith, Wright, Second Edition, London 1988.

Additive salts of acids which are pharmaceutically acceptable, such as a salt of an inorganic base, a salt with organic base, salt with inorganic acid, salt with organic acid, salt with basic or acidic amino acids, etc. are also considered in this invention. Examples of salts of inorganic bases include the alkali metal salt (e.g. sodium, potassium etc), alkaline earth metal (e.g. calcium, magnesium etc), aluminium, ammonium, etc. are Examples of the salt with organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenziletilendiaminom etc. Examples of salts of inorganic acids include salts of chloride-hydrogen acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. are Examples of the salt with organic acid include a salt with formic acid, oxalic acid, acetic acid, tartaric acid, methanesulfonate, benzosulfimide, malic acid, p-toluenesulfonic acid, etc. are Examples of salts of the basic amino acid include a salt with arginine, lysine, ornithine, etc. Examples of salts of acidic amino acid include a salt with aspartic acid, glutamic key is lots etc. The term "non-toxic" in this context should be considered relative to the forecast for the infected patient without treatment.

Further defining connections

X, Y and Z can be joined to the remainder of the molecule at any position in the ring.

In one series of preferred embodiments of the present invention L1means a chemical bond.

In other preferred embodiments, Z represents an optionally substituted aromatic or heteroaromatic group. In other preferred embodiments, Y is unsubstituted heteroaromatic ring.

In one preferred series of embodiments of the X or Z represents a condensed bicyclic system of the formula

where m can be 0, 1 or 2.

In another preferred embodiment of the X or Z represents a group of the formula

which may be unsubstituted or substituted, and where W stands for C, N, O, or S. Particularly preferred embodiment is a group of the formula

which may be substituted or unsubstituted, but when W = NH is preferred.

Other preferred compounds include the compounds of formula

or the formula:

where l is 0-3, and Rmeans OH, MeO, SH, SMe, CN, CO2Me, F, Cl, Br, NO2CH3CO, NH2, NHCH3N(CH3)2CH3CONH, CH3SO2NH, CONH2, CF3or Me;

each of the Z1, Z2and Z3independent means CH, CRor N, where only two of these Z1, Z2and Z3can represent N;

and L2and L3are as defined above.

Other preferred compounds are the compounds of formula

where l is 0-3, and Rmeans OH, MeO, SH, SMe, CN, CO2Me, F, Cl, Br, NO2CH3CO, NH2, NHCH3N(CH3)2CH3CONH, CH3SO2NH, CONH2, CF3or Me;

k is 0-2;

each of the Z1, Z2and Z3independent means CH, CRor N, where only two of these Z1, Z2and Z3can represent N;

and X, L2and L3are as defined above.

In formula 1, examples of optionally substituted ring system, X, or Z, are dihydroquinoline, tetrahydroquinoline, pornobilder, dihydropyrimidin, capitanerie, dihydrocapsaicin, dihydronaphthalene and tetrahydronaphthalene. Oxides of nitrogen and sulfur-containing heterocycles are also addressed in this invention. In pointed to by the th above ring any nitrogen atom in the ring may be substituted by hydrogen, substituted by alkyl, alkenyl, cycloalkyl or aryl group, or may be a nitrogen atom of the carboxamide, carbamate or sulfonamida. The preferred embodiment is tetrahydroquinolin.

In the formula 1 optional substituents in the ring system X or Z may represent halogen, nitro, cyano, carboxylic acid, optionally substituted alkyl, alkenylphenol or cycloalkyl group, optionally substituted hydroxyl group, optionally substituted Tilney group, optionally substituted by an amino group or acyl group, optionally substituted carboxylate, carbamate, carboxamide or sulfonamidnuyu group, optionally substituted aromatic or heterocyclic group.

Examples of the halogen include fluorine, chlorine, bromine, iodine, etc. and preferred are fluorine and chlorine.

Examples of optionally substituted alkyl include1-10alkyl, including methyl, ethyl, propyl, etc., examples of the optionally substituted alkenyl groups include2-10alkenyl, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc. and examples of the optionally substituted cycloalkyl groups include3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. In the above examples With1-6alkyl, alkenyl and cycloalkyl are preferred is compulsory. A possible substitute may also be optionally substituted by aralkyl (for example, panels1-4alkyl) or heteroalkyl, such as phenylmethyl (benzyl, phenethyl, pyridinylmethyl, pyridinylmethyl etc. Heterocyclic group may be a 5 - or 6-membered ring containing 1-4 heteroatom.

Examples of the optionally substituted hydroxyl and tylnej groups include optionally substituted alkyl (for example, C1-10alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl etc., preferably1-6alkyl); optionally substituted cycloalkyl (for example, C3-7cycloalkyl etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.); optionally substituted aralkyl (for example, phenyl-C1-4alkyl, for example benzyl, phenethyl, and so on). In cases where there are two adjacent hydroxyl or tylnej Deputy, the heteroatoms may be linked through alkyl group, such as O(CH2)nO, and S(CH2)nS (where n = 1-5). Examples include methylenedioxy, Ethylenedioxy etc. In the invention also addresses the oxides thioester groups, such as sulfoxidov and sulfones.

In addition, examples of the optionally substituted hydroxyl group include optionally substituted C2-4alkanoyl (EmOC is emer, acetyl, propionyl, butyryl, isobutyryl etc.)1-4alkylsulfonyl (for example, methanesulfonyl, econsultancy etc) and optionally substituted aromatic and heterocyclic carbonyl group, including benzoyl, pyridylcarbonyl etc.

The substituents at optional substituted amino group can contact each other to form a cyclic amino group (for example, 5-6-membered cyclic amino group, etc. such as tetrahydropyrrole, piperazine, piperidine, pyrrolidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.). The specified cyclic amino group may have a Deputy, and examples of the substituents include halogen (e.g. fluorine, chlorine, bromine, iodine, etc), nitro-, cyano-, hydroxy-group, Tilney group, amino group, carboxyl group, optionally halogenated1-4alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), optionally halogenated1-4alkoxy (e.g. methoxy, ethoxy, triptoreline, triptoreline etc.)2-4alkanoyl (for example, acetyl, propionyl etc.)1-4alkylsulfonyl (for example, methanesulfonyl, econsultancy etc), and the preferred number of substituents is from 1 to 3.

The amino group may also be substituted once or twice with the formation of secondary or tertiary amine) group, such as optionally substituted al the ilen group, including1-10alkyl (e.g. methyl, ethyl, propyl, etc.); optionally substituted Alchemilla group, such as allyl, crotyl, 2-pentenyl, 3-hexenyl etc., or optionally substituted cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. In these cases With1-6alkyl, alkenyl and cycloalkyl are preferred. The amino group may also be optionally substituted aromatic or heterocyclic group, aralkyl (for example, panels1-4alkyl) or heteroalkyl, such as, for example, phenyl, pyridine, phenylmethyl (benzyl, phenethyl, pyridinylmethyl, pyridinylmethyl etc. Heterocyclic group may be a 5-6-membered ring containing 1-4 heteroatoms. Possible substituents of "optionally substituted amino group" are defined above for the "optionally substituted cyclic amino group".

The amino group may be optionally substituted substituted C2-4alkanoyl (for example, acetyl, propionyl, butyryl, isobutyryl etc) or With1-4alkylsulfonyl (for example, methanesulfonyl, econsultancy etc) or carbonyl or sulfonyl, substituted aromatic or heterocyclic ring, for example, benzosulfimide, benzoyl, pyridylsulfonyl, pyridylcarbonyl etc. Heterocycles are as op is Adelino above.

Examples of the optionally substituted acyl group include as Vice-condensed ring system containing X, carbonyl group or sulfonyloxy group associated with hydrogen; optionally substituted alkyl (for example, C1-10alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (1-6)alkyl, etc.); optionally substituted cycloalkyl (for example, C3-7cycloalkyl etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.); optionally substituted of alkenyl (for example, C2-10alkenyl, such as allyl, crotyl, 2-pentenyl etc., preferably lower With2-6alkenyl etc.); optionally substituted cycloalkenyl (for example, C3-7cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentylmethyl, 2-cyclohexenylmethyl etc.); optionally substituted 5-6-membered monocyclic aromatic group (e.g. phenyl, pyridyl, and so on).

Examples of optionally substituted carboxylate group (ester group) include optionally substituted alkyl (for example, C1-10alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, reopen the sludge, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (1-6)alkyl, etc.); optionally substituted cycloalkyl (for example, C3-7cycloalkyl etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.); optionally substituted of alkenyl (for example, C2-10alkenyl, such as allyl, crotyl, 2-pentenyl, 3-hexenyl etc., preferably lower With2-6alkenyl etc.); optionally substituted cycloalkenyl (for example, C3-7cycloalkenyl, etc. such as 2-cyclohexenylmethyl etc.); optionally substituted aryl (e.g. phenyl, naphthyl, etc.) and (C1-4aryl, such as benzyl, phenethyl, etc. In the invention are also treated groups, such as methoxymethyl, methoxyethyl etc.

Examples of optionally substituted carboxamide and sulfonamidnuyu groups are identical to the preceding examples, in which the definition for amine as the "optionally substituted amino group".

Examples of optionally substituted aromatic or heterocyclic groups as possible substituents are phenyl, naphthyl, or a 5-6-membered heterocyclic ring containing 1-4 heteroatom. Possible substituents are, in the main, identical with the substituents listed above.

In the above examples, the number of substituents is 1 to 4, preferably 1-. The substituents at optional substituted groups are the same as optionally substituted group described above. Preferred substituents are halogen (fluorine, chlorine, etc.), nitro, cyano, hydroxy-group, Tolna group, amino group, carboxyl group, carboxylate group, sulphonate group, sulfonamidnuyu group, carboxamide group, optionally halogenated1-4alkyl, optionally halogenated1-4alkoxy (for example, triptoreline etc.)2-4alkanoyl (for example, acetyl, propionyl etc) or aroyl,1-4alkylsulfonyl (for example, methanesulfonyl, econsultancy etc), optionally substituted aryl or heterocyclic group. The number of substituents in the above groups is preferably from 1 to 3.

In the above formulas, W can represent CH (pyrrole), O (oxisol), S (thiazole), NH or NR(imidazole), where Rmeans1-6alkyl group or acyl or sulfonyloxy group. Examples of the condensed ring systems containing X or Z include, but are not limited to, indole, tetrahydroindole, benzimidazole, tetrahydroimidazo, azobenzenes, benzoxazol, tetrahydrobenzoic, benzothiazole, tetrahedralisation. Preferred ring systems are imidazole and benzimidazole.

In the above formula 1 Y represents optionally substituted heterocyclic group, including heteroaromatic group or an aromatic group. Examples of substituted heterocyclic groups include 5 to 6 membered, saturated, partially saturated or aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Heterocycles may include pyridine, quinoline, isoquinoline, imidazole, benzimidazole, azobenzenes, benzotriazole, furan, benzofuran, thiazole, benzothiazole, oxazole, benzoxazole, pyrrole, indole, indoline, indazole, pyrrolidine, pyrrolidone, pyrrolin, piperidine, piperazine, tetrahydropyran, tetrahydroisoquinoline, pyrazole, thiophene, isoxazol, isothiazol, triazole, tetrazole, oxadiazole, thiadiazole, morpholine, thiomorpholine, pyrazolidine, imidazolidine, imidazoline, tetrahydropyran, dihydropyran, benzopyran, dioxane, Titian, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, dihydrothiophene etc. of nitrogen Oxide and sulfur-containing heterocycles are also included in the present invention. Possible substituents for the condensed or unfused aromatic or heterocyclic rings are identical to the substituents described above.

In cases where X or Z is represented by formula a, b or C, optional substituents include complement the performance communications ring system, such as cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran, tetrahydrothiophene (tylan), tetrahydropyran, tetrahydrothiopyran (pentamethylbenzene), phenyl, oxepin, tiepin, pyrrolidine, piperidine, etc. Oxides of nitrogen, serosoderjaschei heterocycles are also addressed in this invention. Other possible substituents are identical to the substituents described above.

The new compounds of formula 1 according to the present invention can be prepared as pharmaceutical compositions, which can be entered locally; percutaneous, including intravenous; oral and other standard methods of pharmaceutical introduction mammalian subjects, as determined according to routine clinical practice.

Having now a General description of the invention, its meaning is easier to understand by reference to the following examples, aimed at illustrating the invention, and the examples do not limit the present invention unless specifically indicated.

EXPERIMENTAL PART

General procedure a: Direct reductive amination by NaBH3CN

To a stirred solution of amine (1 equivalent) in anhydrous methanol (concentration ˜0.1 M) at room temperature was added the carbonyl compound (˜1-2 equivalent) one p is the resource center. As soon as the carbonyl dissolved (˜5 minutes), was added NaBH3CN (˜2-4 equivalents) in one portion and the resulting solution was stirred at room temperature. The solvent was removed under reduced pressure and to the residue was added CH2Cl2(20 ml/mmol amine) and a saturated solution of salt or 1.0 M aqueous NaOH (10 ml/mmol amine). The phases were separated, and the aqueous phase was extracted with CH2Cl2(3 x 10 ml/mmol amine). The combined organic phases were dried (Na2SO4) and concentrated. The crude substance was purified by chromatography.

General procedure b: Direct reductive amination by NaBH(OAc)3

To a stirred solution of amine (1 equivalent) in CH2Cl2(concentration ˜0.2 M) at room temperature was added the carbonyl compound (˜1-2 equivalents), glacial acetic acid (0-2 equivalent) and NaBH(OAc)3(˜1.5-3 equivalents)and the resulting solution was stirred at room temperature. The reaction mixture was poured or in a saturated aqueous solution of NaHCO3or 1.0 M aqueous NaOH solution (10 ml/mmol amine). The phases were separated and the aqueous phase was extracted with CH2Cl2(3 x 10 ml/mmol amine). The combined organic phases were dried (Na2SO4) and concentrated. The crude substance was purified by chromatography.

General procedure C: the removal of the protection is based 2-nitrobenzenesulfonyl group (Nesil)

To mix the solution Nasil-protected amine (1 equivalent) in anhydrous CH3CN (or DMF) (concentration ˜0.05 M) at room temperature was added thiophenol (4-8 equivalents) followed by the addition of powdered K2CO3(8-12 equivalents). Received a bright yellow solution was stirred at room temperature (or 50° (C) within 1-24 hours. The solvent was removed under reduced pressure and to the residue was added CH2Cl2(10 ml/mmol amine) and water (2 ml/mmol amine). The phases were separated, and the aqueous phase was extracted with CH2Cl2(3 x 5 ml). The combined organic phases were dried (Na2SO4) and concentrated. The crude substance was purified by chromatography.

Alternative treatment: the reaction mixture was filtered and concentrated to obtain a yellow oil, which was purified by chromatography on basic alumina (eluent CH2Cl2then CH2Cl2-CH3OH, 20:1) and obtained the free base as a colourless oil.

General procedure D: the Formation of salts with the use of saturated HBr (gas) in acetic acid

To a solution of free base in glacial acetic acid or dioxane) (2 ml) was added a saturated solution of HBr (gas) in acetic acid (or dioxane) (2 ml). Then add a large amount of ether (25 ml) to precipitate solid is the first substance, which was allowed to settle on the bottom of the flask, and the supernatant decantation. The solid was washed by decantation with ether (3 x 25 ml), and the residual traces of solvent were removed in vacuum. For additional purification (where necessary), the solid can be dissolved in methanol and pereoadei large volume of ether. Washing of the solid with ether by decantation, followed by drying the solid in a vacuum of 0.1 Torr) resulted in obtaining the desired connection.

General method E: Removal SEM-protection

To a stirred solution of SEM-protected compound (1 equivalent) was added 6 N HCl (30 ml/mmol) and the resulting solution was stirred at 50°With within the specified time. The solution was diluted with water (50 ml/mmol), then neutralized NaHCO3and was extracted with EtOAc (3 x 100 ml/mmol). The combined organic phases were dried (Na2SO4) and concentrated. The crude substance was purified by chromatography.

General method F: Combination with EDCI

To a stirred solution of amine (1 equivalent), acid (1.1 equivalent), 1-hydroxybenzotriazole (1.1 equivalent), 4-methylmorpholine (1.5 equivalent) in anhydrous DMF (˜0.3 M) at room temperature under nitrogen atmosphere was added EDCI (1.1 equivalent). The resulting solution was stirred at room temperature for the specified time. Then DMF) at which alali in vacuum. The mixture was diluted with CH2Cl2(100 ml/mmol), washed with NaHCO3, dried (Na2SO4) and concentrated.

General method G: metilirovanie alcohol

To a stirred solution of alcohol (1 equivalent) and Et3N (1.2 equivalents) in anhydrous CH2Cl2(˜0.1 M) at 0°C in an atmosphere of nitrogen was added dropwise MsCl (1.1 equivalent). The resulting solution was stirred at the specified temperature for the specified time. The mixture was diluted with CH2Cl2(100 ml/mmol), washed with aqueous solution of NH4Cl, dried (Na2SO4) and concentrated.

General procedure N: substitution Reactions with mesylates

To a stirred solution of amine (1.5 equivalents) and Et33N (1.0 equivalent) in anhydrous CH2Cl2(˜0.2 M) at 0°C in an atmosphere of nitrogen was added dropwise a solution of nelfinavir (1.0 equivalent). The resulting solution was stirred at room temperature for the specified time. The mixture was diluted with CH2Cl2(100 ml/mmol), filtered through celite and concentrated. The crude substance was purified by chromatography.

EXAMPLE 1

AMD9362:Obtaining N-pyridin-2-yl-4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzamidine

4-Chloromethyl-N-pyridinyl-2-ylbenzene

To pre-cooled (bath with ice) Rast is oru 2-aminopyridine (304 mg, up 3.22 mmol) and triethylamine (0.8 ml, 5,70 mmol) in anhydrous THF (5 ml) was added a solution of 4-chlorodibenzofuran (282 mg, of 1.40 mmol) in THF (5 ml). The reaction mixture was stirred at 0°C for 3 hours in an atmosphere of N2and then was diluted with 300 ml of ethyl acetate. The resulting organic solution was washed with saturated NH4Cl, saturated salt solution, dried over Na2SO4and evaporated. The residue was purified flash chromatography on silica gel, using as eluent 10% ethyl acetate in hexane, to obtain the compound (170 mg, 49%) as a white solid.

1H NMR (CDCl3) δ 4,63 (s, 2H), 7,07 (DD, 1H, J=5,1, 7,2 Hz), 7,50 (d, 2H, J=8,1), 7,76 (DDD, 1H, J=1,5, 7,8 and 8.1 Hz), 7,92 (d, 2H, J=8,4 Hz), 8,21 (d, 1H, J=4.5 Hz), scored 8.38 (d, 1H, J=8,4 Hz), 8,89 (W, s, 1H); ES-MS m/z 247,0 (M+H).

4-{[(2-Nitrobenzenesulfonyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-pyridine-2-jbentley

8-[N-(2-nitrobenzenesulfonyl)]amino-5,6,7,8-tetrahydroquinolin (230 mg, 0.69 mmol), 4-chloromethyl-N-pyridinyl-2-ylbenzene (170 mg, 0.69 mmol) and K2CO3(285 mg, of 2.06 mmol) was boiled under reflux in CH3CN (3 ml) for 24 hours in an atmosphere of N2. The reaction mixture was diluted with 200 ml ethyl acetate and washed with saturated solution of NaHCO3then with saturated salt solution and dried over Na2SO4. Evaporation of the solvent and purification of the residue flash-HRO what ecografia on silica gel, using as eluent 6% ethyl acetate in CH2Cl2got mentioned in the title compound (344 mg, 92%) as a white foam.

1H NMR (CDCl3) δ 1,61-of 1.65 (m, 1H), 1,74 is 1.86 (m, 2H), 2,33-is 2.37 (m, 1H), 2,59-to 2.65 (m, 2H), 3,92 (d, 1H, J=16.2 Hz), to 4.87 (d, 1H, J=16.5 Hz), 5,32 (DD, 1H, J=5,8, 11.3 Hz),? 7.04 baby mortality-7,11 (m, 2H), 7,31-7,37 (m, 3H), 7,49-to 7.67 (m, 3H), 7,73-7,80 (m, 3H), of 8.15 (d, 1H, J=7.8 Hz), by 8.22 (d, 1H, J=4,2 Hz), 8,31 (d, 1H, J=4, 2 Hz), 8,35 (d, 1H, J=8,4 Hz), 8,45 (W, s, 1H); ES-MS m/z 544,1 (M+H).

The use of common methods To: Interaction of 4-{[(2-nitrobenzenesulfonyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-pyridine-2-ilasamaja (340 mg, of 0.62 mmol), thiophenol (0,12 ml of 1.24 mmol) and K2CO3(258 mg, of 1.87 mmol) in DMF (3 ml) at room temperature in an atmosphere of N2for 16 hours, followed by purification of the crude substances by radial chromatography on silica gel (2 mm plate, a mixture of CH3OH-NH3H2O-CH2Cl2, 3:3:94) resulted in a compoundAMD9362(210 mg, 93%) as a pale yellow oil.

1H NMR (CDCl3) δ 1,72-to 1.87 (m, 2H), 1,98-of 2.09 (m, 1H), 2,15-of 2.23 (m, 1H), 2,73-only 2.91 (m, 2H), 3.00 and loops, 1H), a 3.87 (DD, 1H, J=5,1, 7.5 Hz), was 4.02 (d, 1H, J=13,8 Hz), Android 4.04 (d, 1H, J=13,8 Hz), 7,06-7,10 (m, 2H), 7,38 (d, 1H, J=7.5 Hz), 7,58 (d, 2H, J=8.1 Hz), 7,76 (DDD, 1H, J=1,8, 6,9, and 8.7 Hz), 7,88 (d, 2H, J=8,4 Hz), 8,31 (d, 1H, J=4, 2 Hz), scored 8.38-to 8.41 (m, 2H), charged 8.52 (W, s, 1H);13C NMR (CDCl3) δ 20,04, 29,12, 29,22, 51,87, 58,09, 114,61, 120,20, 122,31, 127,78, 128,91, 132,87, 133,11, 137,32, 138,82, 146,04, 147,25, 148,26, 152,10, 157,63, 166,15; ES m/z 359, 2 (M+H); elemental analysis: calculated for (C22H22N4O)•0,7(H2O): C, 71,21; H, 6,36; N, 15,10. Found C, 71,16; H, Of 6.02; N, 14,79.

EXAMPLE 2

AMD9370:Getting 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-pyridine-2-ilasamaja.

N-BOC-chloromethylbenzene (115 mg, 0.43 mmol), N-pyridine-2-yl-4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzamid (AMD9362) (155 mg, 0.43 mmol) and K2CO3(179 mg, 1,29 mmol) in CH3CN (3 ml) was boiled under reflux for 24 hours in an atmosphere of N2. The reaction mixture was diluted with 200 ml ethyl acetate and washed with saturated solution of NaHCO3saturated salt solution and dried over Na2SO4.Evaporation of the solvent and purification of the residue flash-chromatography on silica gel followed by radial chromatography on silica gel (2 mm plate, a mixture of CH3OH-NH3H2O-CH2Cl2, 3:3:94) resulted in a compoundAMD9370(100 mg, 47%) as a white foam.

1H NMR (CDCl3) δ 1,68 is 1.75 (m, 1H), 1,97-of 2.08 (m, 2H), 2.26 and of-2.32 (m, 1H), 2.71 to 2,84 (m, 1H), 2,86-only 2.91 (m, 1H), 3,84 (s, 2H), 3,95 (d, 1H, J=16.5 Hz), 4,08-to 4.14 (m, 1H), 4,22 (d, 1H, J=16.0 Hz), 7.03 is-7,07 (m, 1H), 7,16-7,22 (m, 3H), 7,45 (d, 1H, J=6.9 Hz), 7,52-to 7.61 (m, 3H), of 7.65 (d, 1H, J=7.5 Hz), 7,73 (DDD, 1H, J=1,8, 7,2, to 8.7 Hz), 7,80 (d, 2H, J=8.1 Hz), 8,27-8,29 (m, 1H), 8,33 (d 1H, J=8,4 Hz), 8,44 (W, s, 1H), 8,72-8,80 (m, 1H);13C NMR (CDCl3)δ 21,72, 23,30, 29,56, 49,29, 54,16, 60,83, 111,39, 114,52, 120,17, 122,29, 122,81, 127,72, 129,28, 133,58, 135,17, 137,76, 138,77, 144,61, 147,38, 148,21, 152,00, 156,13, 157,54, 165,99; ES-MS m/z 489,2 (M+H); elemental analysis: calculated for (C30H28N6O)•0,6(H2O)•0,7(CHCl3): C, 63,25; H, TO 5.17; N, 14,42. Found: C, 63,56; H, A 5.25; N, 14,31.

EXAMPLE 3

AMD9363:Obtaining N-pyridine-2-ylmethyl-4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzamide

4-Chloromethyl-N-pyridinyl-2-ylmethylene

To pre-cooled (bath with ice) solution of 2-aminomethylpyridine (133 mg, of 1.23 mmol) and triethylamine (0.35 ml of 2.50 mmol) in anhydrous THF (3 ml) was added a solution of 4-chlorodibenzofuran (240 mg, of 1.23 mmol) in THF (3 ml). The reaction mixture was stirred at 0°C for 2 hours in an atmosphere of N2and then was diluted with 300 ml of ethyl acetate. The resulting organic solution was washed with saturated NH4Cl, saturated salt solution, dried over Na2SO4and evaporated. The residue was purified flash chromatography on silica gel, using as eluent 50% ethyl acetate in hexane, to obtain specified in the title compound (314 mg, 95%) as a pale yellow oil.

1H NMR (CDCl3) δ to 4.62 (s, 2H), amounts to 4.76 (d, 2H, J=4.5 Hz), 7,21-7,26 (m, 1H), 7,32 (d, 1H, J=7.8 Hz), 7,47 (d, 2H, J=8,4 Hz), 7,60 (W, s, 1H), 7,69 (DDD, 1H, J=1,8, to 7.5, and 7.8 Hz), 7,86 (d, 2H, J=8,4 Hz), to 8.57 (d, 1H, J=4,8 Hz); ES-MS m/z 261,0 (M+H).

4-{[(2-N is transalantic)-(5,6,7,8-tetrahydroquinolin-8-yl)amino] methyl}-N-pyridine-2-ylmethylene

8-(2-Nitrobenzenesulfonyl)amino-5,6,7,8-tetrahydroquinolin (402 mg, 1.20 mmol), 4-chloromethyl-N-pyridine-2-ylmethylene (314 mg, 1.20 mmol) and K2CO3(498 mg, of 3.60 mmol) in CH3CN (4 ml) was boiled under reflux for 24 hours in an atmosphere of N2. The reaction mixture was diluted with 200 ml ethyl acetate and washed with saturated solution of NaHCO3saturated salt solution and dried over Na2SO4.Evaporation of the solvent and purification of the residue flash-chromatography on silica gel using as eluent 50% ethyl acetate in CH2Cl2resulted in the receipt specified in the title compound (603 mg, 90%) as a white foam.

1H NMR (CDCl3) δ 1,56-to 1.61 (m, 1H), 1,74-2,05 (m, 2H), 2,32-of 2.36 (m, 1H), 2,58-of 2.64 (m, 2H), 3,95 (d, 1H, J=16.2 Hz), 4,74 (d, 2H, J=4.5 Hz), is 4.85 (d, 1H, J=15,9 Hz), and 5.30 (DD, 1H, J=11,1, to 17.4 Hz), 7,05 (DD, 1H, J=4,5, 7.5 Hz), 7,22-7,29 (m, 2H), 7,34 (DD, 2H, J=7,5, and 7.8 Hz), of 7.48-7,73 (m, 8H), 8,12-of 8.15 (m, 1H), 8,20-8,24 (m, 1H), 8,45-8,59 (m, 1H); ES-MS m/z 558,2 (M+H).

The use of common methods To: Interaction of 4-{[(2-nitrobenzenesulfonyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-pyridine-2-iletilmesine (600 mg, 1.07 mmol), thiophenol (0,22 ml, 2.14 mmol) and K2CO3(445 mg, up 3.22 mmol) in DMF (5 ml) at room temperature in an atmosphere of N2for 16 hours, followed by purification of the crude substances radially who chromatography on silica gel (2 mm plate, a mixture of CH3OH-NH3H2O-CH2Cl2, 3:3:94) resulted in a compoundAMD9363(390 mg, 93%).

1H NMR (CDCl3) δ 1,76-of 1.85 (m, 2H), 1,97-2,02 (m, 1H), 2,10-of 2.21 (m, 1H), 2,70-2,89 (m, 2H), 3,82-3,86 (m, 1H), 3,94 (d, 1H, J=13.5 Hz), was 4.02 (d, 1H, J=13,8 Hz), was 4.76 (d, 2H, J=4,8 Hz), 7,06 (DD, 1H, J=4,8, 7.5 Hz), 7,20-7,26 (m, 1H), 7,34 (DD, 2H, J=7,5, 15.6 Hz), 7,52 (d, 2H, J=8.1 Hz), 7,50-7,52 (m, 1H), 7,68 (DDD, 1H, J=1,5, and 7.5, and 7.8 Hz), 7,83 (d, 2H, J=8.1 Hz), 8,39 (d, 1H, J=3,GC), 8,56 (d, 1H);13C NMR (CDCl3) δ 20,02, 29,07, 29,21, 45,14, 51,86, 57,97, 122,26, 122,51, 122,75, 127,59, 128,65, 132,84, 133,21, 137,17, 137,28, 145,02, 147,21, 149,37, 156,78, 157,68, 167,69; ES-MS m/z 373,2 (M+H); elemental analysis: calculated for (C23H24N4O)•0,5(H2O)•0,3(CHCl3)•0,2(C4H8O2): C, 66,56; H, 6,23; N, 12,88. Found: C, 66,20; H, 6,16; N, 12,88.

EXAMPLE 4

AMD9369:Getting 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-pyridine-2-iletilmesine.

N-BOC-chloromethylbenzene (215 mg, 0.84 mmol), N-pyridine-2-ylmethyl-4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzamid (AMD9363) (300 mg, 0.84 mmol) and K2CO3(346 mg, of 2.50 mmol) in CH3CN (4 ml) was boiled under reflux for 24 hours in an atmosphere of N2. The reaction mixture was diluted with 200 ml ethyl acetate and washed with saturated solution of NaHCO3saturated salt solution and dried over Na2SO4.Evaporation of rest is rites and purification of the residue flash-chromatography on silica gel followed by radial chromatography on silica gel (1 mm plate, a mixture of CH3OH-NH3H2O-CH2Cl2, 3:3:94) led to obtain the free base specified in the title compound (120 mg, 28%) as a pale yellow oil.

Using General method D: the oil obtained above was converted to the corresponding hydrobromide Sol with gettingAMD9369.

1H NMR (D2O) δ 1,82-1,95 (t, 1H), 2,19-of 2.30 (m, 2H), 2,41 at 2.45 (m, 1H), 3,01-to 3.02 (m, 2H), 3,78 (d, 1H, J=12,6 Hz), a 3.87 (d, 1H, J=12,6 Hz), 4,43 (d, 1H, J=16.5 Hz), to 4.62 (d, 1H, J=16.2 Hz), 4.72 in (s, 2H), 4.92 in-4,95(m, 1H), 7.23 percent (d, 2H, J=8,4 Hz), 7,27-to 7.32 (m, 2H), 7,35 (d, 2H, J=8,4 Hz), 7,45-rate of 7.54 (t, 2H), 7,80 (d, 1H, J=8.1 Hz), of 7.90-of 7.96 (t, 2H), 8,39 (d, 1H, J=8.1 Hz), charged 8.52-8,59 (m, 1H), 8,67 (DD, 1H, J=0,6, 5.7 Hz), 8,76 (d, 1H);13C NMR (D2O) δ 20,43, 21,06, 27,86, 41,49, 50,28, 56,74, 63,48, 113,83, 126,15, 126,41, 127,31, 130,33, 130,51, 131,00, 139,78, 141,03, 141,34, 141,50, 147,59, 148,34, 150,62, 151,49, 153,11, 169,39; ES-MS m/z 503,14 (M+H); elemental analysis: calculated for (C31H30N6O)•3,0(HBr)•2,4(H2O): C, 47,22; H, A 4.83; N, 10,66; Br, 30,40. Found: C, 47,35; H, To 4.98; N, 10,37; Br, 30,35.

EXAMPLE 5

AMD9728:Getting [4-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)aminomethyl]-N-(2-hydroxyphenyl)benzamide (hydrobromide salt).

Getting 4-formyl-N-(2-hydroxyphenyl)benzamide

A solution of 2-NITROPHENOL (1.55 g, and 11.2 mmol) and methyl 4-chlorocarbonate (2,44 g, 12.2 mmol) in THF (14 ml) and pyridine (2.8 ml) was stirred for 2 hours at room temperature. P is a promotional mixture was diluted with saturated sodium bicarbonate (30 ml) and EtOAc (20 ml), the phases were separated and the aqueous phase was extracted with EtOAc (2 x 15 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to obtain 1-methyl ester 4-(2-nitrophenylamino)ester of terephthalic acid (3.15 g, 94%).

1H NMR (CDCl3) δ 3,98 (s, 3H), 7,43 (d, 1H, J=7.8 Hz), of 7.48 (t, 1H, J=7,8 Hz), 7,73 (t, 1H, J=7.8 Hz), to 8.20 (m, 4H), of 8.27 (m, 1H).

To a solution of 1-methyl ester 4-(2-nitrophenylamino)ester of terephthalic acid (3.13 g, 10.4 mmol) in glacial acetic acid (35 ml) was added iron powder (<5 μm mesh, 1.6 g, of 28.0 mmol)and the mixture was stirred while boiling under reflux for 1.5 hours. The mixture was cooled, stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was distributed between saturated sodium bicarbonate solution (75 ml) and ethyl acetate (75 ml), the phases were separated and the organic layer was washed with saturated solution of NaHCO3(50 ml). The organic extract was dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel (2% MeOH/CH2Cl2) to give the methyl ester (2-hydroxyphenyl)terephthalic acid (1.31 g, 46%).

1H NMR (CDCl3) δ 3,98 (s, 3H), 6,95 (t, 1H, J=7.8 Hz), 7,07 (d, 1H, J=7.8 Hz), 7,19 (t, 1H, J=7.8 Hz), 7,28 (d, 1H, J=7.8 Hz), 7,98 (d, 2H, J=8,4 Hz), to 8.20 (m, 4H).

To a solution of methyl ester (2-hydrox is phenyl)terephthalic acid (1.31 g, 4.8 mmol) in THF (50 ml) at -78°solution was added DIBAL-H (27 ml, 1.0 M in THF). The reaction mixture was left to warm to room temperature, was stirred for 1 hour, and reaction was suppressed with a saturated solution of tartrate of potassium-sodium (15 ml). A two-phase mixture was vigorously stirred for 1 hour, the phases were separated and the organic layer was dried (MgSO4), filtered, concentrated and purified column chromatography on silica gel (5% MeOH/CH2Cl2) to obtain 4-hydroxymethyl-N-(2-hydroxyphenyl)benzamide (0,58 g, 50%).

1H NMR (CDCl3) δ to 1.83 (t, 1H (OH)), 4,82 (d, 2H, J=6.0 Hz), 6,93 (t, 1H, J=7.8 Hz), was 7.08 (t, 1H, J=7.8 Hz), 7,19 (d, 2H, J=7.8 Hz), 7,53 (d, 2H, J=6.0 Hz), 7,92 (d, 2H, J=7.8 Hz), 8,07 (W, 1H), to 8.62 (s, 1H).

4-Hydroxymethyl-N-(2-hydroxyphenyl)benzamide obtained above, (0.56 g, 2.3 mmol) was dissolved in CH2Cl2(12 ml) and THF (12 ml), treated with activated MnO2(2.0 g, 23 mmol) and stirred at room temperature overnight. The mixture was filtered through celite, the residue washed with CH2Cl2and the solvent from the eluent was removed under reduced pressure. Purification of the crude substances column chromatography on silica gel (5% MeOH/CH2Cl2) gave 4-formyl-N-(2-hydroxyphenyl)benzamide (0.05 g, 10%).

1H NMR (CDCl3) δ to 6.95 (t, 1H, J=7.8 Hz), 7,05 (d, 1H, J=7.8 Hz), 7,16 (t, 1H, J=7.8 Hz), 7,42 (d, 1H, J=7.8 Hz), of 8.04 (m, 5H), 8,33 (W, 1H).

Ispolzovaniya methods: To a solution of 4-formyl-N-(2-hydroxyphenyl)benzamide (50 mg, 0.2 mmol) and (N-tert-butoxycarbonylamino-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (75 mg, 0.2 mmol) in Meon (2 ml) was added NaBH3CN (25 mg, 0.4 mmol)and the mixture was stirred at room temperature for 16 hours. Purification of the crude substances by radial chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 98:1:1) received alkilirovanny product (11 mg, 10%) as a colourless oil.

1H NMR (CDCl3) δ was 1.69 (m, 1H), of 1.97 (m, 2H), 2,17 (m, 1H), 2,80 (m, 2H), 3,70 (s, 2H), 3,92 (d, 1H, J=16,8 Hz)4,06 (m, 1H), 4,10 (d, 1H, J=17,1 Hz), at 6.84 (t, 1H, J=6.0 Hz), to 6.95 (d, 2H, J=6.0 Hz), 7,20 (m, 4H), 7,44 (m, 4H), 7,63 (W, 1H), 7,73 (d, 2H, J=7,2 Hz), 8,00 (d, 1H, J=6.0 Hz), 8,63 (d, 1H, J=3.5 Hz), 8,78 (s, 1H).

Using the common methodology D:The transformation obtained above oil (11 mg) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether resulted in the receipt of the connectionAMD9628(15 mg) as a pale yellow solid.

1H NMR (D2O) δ 1,87 (BL, 1H, in), 2.25 (m, 2H), 2,44 (BL, 1H), 3,05 (BL, 2H), 3,78 (d, 1H, J=12,6 Hz), 3,88 (d, 1H, J=12,6 Hz), of 4.45 (d, 1H, J=16.2 Hz), with 4.64 (d, 1H, J=16.2 Hz), and 4.75 (m, 1H), 7,02 (d, 2H, J=7,8 Hz), 7,22 (d, 1H, J=7.8 Hz), 7,24 (d, 2H, J=11,4 Hz), 7,34 (d, 1H, J=7.8 Hz), 7,41 (d, 2H, J=7.8 Hz), was 7.45 (d, 2H, J=9.0 Hz), 7,55 (DD, 2H, J=3,3, 6,3 Hz), of 7.96 (t, 1H, J=8,4 Hz), 8,42 (d, 1H, J=8.1 Hz), 8,79 (d, 1H, J=5.4 Hz);13C NMR (D2O) δ 20,44, 21,04, 27,86, 50,32, 56,76, 63,57, 113,82 (2C), 116,90, 121,15, of 124.8, 126,19, 126,38, 126,59, 126,81 (2C), 127,39 (2C), 128,62, 130,40 (2C), 130,47, 132,12, 139,76, 141,13 (2C), 148,34 (2C), 150,16, 150,76, 151,50; ES-MS m/z 504 (M+H); elemental analysis: calculated for C31H29N5O2•2,2HBr•2,0H2O: C, 52,05; H, 4,96; N, 9,79; Br, 24,21. Found: C, 52,07; H, Free 5.01; N, RS 9.69; Br, 24,21.

EXAMPLE 6

AMD9560:Obtaining N-pyridinyl-2-yl-3-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzamide (hydrobromide salt)

Obtaining 3-chloromethyl-N-pyridinyl-2-ilasamaja

To pre-cooled (bath with ice) solution of 2-aminopyridine (2.0 g, 21,20 mmol) in anhydrous DMF (10 ml) was added a solution of 3-chloromethylbenzene (1,51 ml, or 10.60 mmol). The reaction mixture was allowed to mix at 0°C for 1 hour and at 50°C for 0.5 hour in an atmosphere of N2. The reaction mixture was concentrated in vacuo and the resulting white solid was filtered, washing the Meon. The filtrate was concentrated in vacuo, and the crude substance was purified flash chromatography on silica gel (hexane/EtOAc, 4:1) to obtain the specified title compound (402 mg, 15%) as a colourless oil.

1H NMR (CDCl3) δ 4,63 (s, 2H), 7,63 (DD, 1H, J=5,1, 7,2 Hz), 7,49 (t, 1H, J=7,6 Hz), to 7.59 (d, 1H, J=7.8 Hz), 7,76 (DDD, 1H, J=1,8, at 9.0, 9.0 Hz), 7,78 (d, 1H, J=7.8 Hz), of 7.96 (s, 1H), they were 8.22 (d, 1H, J=4.5 Hz), 8,39 (d, 1H, J=8,4 Hz), 8,96 (SHS, 1H).

Obtaining 3- [(2-nitrobenzenesulfonyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-pyridinyl-2-ilasamaja

8-[N-(2-nitrobenzenesulfonyl)]amino-1,2,3,4-tetrahydroquinolin (248 mg, of 0.74 mmol), 3-chloromethyl-N-pyridinyl-2-ylbenzene (183 mg, of 0.74 mmol) and K2CO3(308 mg, of 2.23 mmol) in CH3CN (2.5 ml) was heated at 80°C for 4 hours in an atmosphere of N2. The reaction mixture was concentrated in vacuum, diluted with ethyl acetate and filtered through celite. Evaporation of the solvent and purification of the residue flash-chromatography on silica gel (EtOAc/CH2Cl2, 1:19) resulted in the receipt specified in the title compound (298 mg, 74%) as a yellow foam.

1H NMR (CDCl3) δ 1,21-of 1.29 (m, 2H), 1,90-2,05 (m, 1H), 2.40 a at 2.45 (m, 1H), 2,68 is 2.75 (m, 2H), 4,06 (d, 1H, J=15,0 Hz), 4,79 (d, 1H, J=15,0 Hz), lower than the 5.37 (DD, 1H, J=4,5, 12.0 Hz), 6,91-to 7.09 (m, 2H), 7,35-7,37 (m, 2H), 7,49-7,54 (m, 5H), to 7.61-7,74 (m, 2H), 8,12 (d, 1H, J=4, 2 Hz), 8,31-to 8.34 (m, 3H), 8,42 (SHS, 1H).

Using the General method of removing the protective noseley groups:The interaction of 3-{[(2-nitrobenzenesulfonyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-pyridinyl-2-ilasamaja (298 mg, 0.55 mmol), thiophenol (0.17 ml of 1.65 mmol) and K2CO3(379 mg, of 2.75 mmol) in DMF (5.5 ml) at room temperature in an atmosphere of N2within 1.5 hours, followed by purification of the crude substances by chromatography on forces is the Kagel (CH 3OH/NH3H2O/CH2Cl2, 1:1:48) resulted in obtaining the desired amide (144 mg, 73%) as a white solid.

Using the General methods of obtaining Hydrobromic salt D: The transformation of the solid product, obtained above, in hydrobromide salt resulted in the receipt of the connectionAMD9560in the form of a white powder.

1H NMR (D2O) δ 2,00-2,04 (m, 2H), 2,31 is 2.46 (m, 2H), 2,92 is 3.15 (m, 2H), 4,55 (d, 1H, J=13,2 Hz), of 4.66 (d, 1H, J=13,2 Hz), 4,86-of 4.90 (m, 1H), 7,65-7,73 (m, 3H), 7,76-7,81 (m, 2H), 7,86 (d, 1H, J=7,8gts), with 8.05 (d, 1H, J=8,1 Hz)to 8.14 (s, 1H), 8,19 (d, 1H, J=4,8 Hz), 8,43-8,49 (m, 2H), 8,63 (d, 1H, J=4,8 Hz);13C NMR (D2O) δ 17,21, 24,26, 27,02, 49,49, 55,03, 117,53, 121,88, 126,96, 129,82, 130,41, 130,51, 131,77, 132,95, 135,83, 137,86, 138,84, 143,71, 144,80, 145,75, 147,95, 148,09, 170,41; ES-MS m/z 359 (M+H); elemental analysis: calculated for (C22H22N4O)•3,0(HBr)•2,0(H2O): C, 41,47; H, 4,59; N, 8,79; Br, 37,62. Found: C, 41,70; H, 4,60; N, 8,60; Br, 37,33.

EXAMPLE 7

AMD9579:Obtaining N-pyridine-2-ylmethyl-3-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzosulfimide (hydrobromide salt).

Getting pyridine-2-yl-3-({(5,6,7,8-tetrahydroquinolin-8-yl)-[1-(2-trimethylsilylethynyl)-1H-benzimidazole-2-ylmethyl]amino}methyl)benzamide

Using the General methods of restoration amination At:The interaction of N-pyridinyl-2-yl-3-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl] benzamide(AMD9560)(80 mg, 0.22 mmol), 1-(2-trimethylsilylethynyl)-1H-benzoimidazol-2-carbaldehyde (62 mg, 0.22 mmol), NaBH(OAc)3(142 mg, 0.67 mmol) and Asón (90 ml) for 1.5 hours at room temperature, followed by purification column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 98:1:1) resulted in the receipt specified in the title compound (61 mg, 44%) as a white foam.

1H NMR (300 MHz, CDCl3) δ 0,00 (s, 9H), is 0.69 (2H, DD, J=8,4, 8.1 Hz), 1,24-1,25 (m, 1H), 2,03 with 2.14 (m, 2H), 2,25-to 2.29 (m, 1H), 2,65-is 2.88 (m, 2H), 3,21-to 3.34 (m, 2H), 3,79 (d, 1H, J=15,0 Hz), 3,90 (d, 1H, J=12.0 Hz), 4.09 to (DD, 1H, J=9,0, 6,0 Hz), 4,25 (s, 2H), 5,73 (d, 1H, J=12.0 Hz), 6,16 (d, 1H, J=12.0 Hz), 7.03 is-7,10 (m, 2H), 7,16-7,20 (m, 2H), 7,30-7,34 (m, 3H), 7,45 (d, 1H, J=7.5 Hz), of 7.64-of 7.69 (m, 2H), 7,74-7,80 (m, 1H), 8,25 (, 1H), 8,39-to 8.41 (m, 2H), 8,71 (d, 1H, J=3.3 Hz), 8,98 (s, H).

Using the General method of removing SEM-protective group E: The interaction of pyridine-2-yl-3-({(5,6,7,8-tetrahydroquinolin-8-yl)-[1-(2-trimethylsilylethynyl)-1H-benzimidazole-2-ylmethyl]amino}methyl)benzamide (61 mg, 0.10 mmol) with 6N HCl (3.5 ml) at 50°C for 3 hours and subsequent column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 98:1:1) was obtained the desired product (46 mg, 96%) as a white foam.

Using the General methodology of the HBr salt D:The transformation of the foam, obtained above, in hydrobromide salt resulted in the receipt of the connectionAMD9579in the form of a white powder is A.

1H NMR (300 MHz, D2O) δ 1,90 is 1.96 (m, 1H), 2,18 is 2.33 (t, 2H), 2,44-2,48 (m, 1H), 3,02-3,03 (t, 2H), 3,85 (d, 1H, J=12.9 Hz), of 3.94 (d, 1H, J=12.9 Hz), of 4.45 (d, 1H, J=16.5 Hz), with 4.64 (d, 1H, J=16.2 Hz), 4,67-4,78 (m, 1H), 7,26-7,40 (t, 4H), 7,43-7,50 (t, 3H), to 7.61 (s, 1H), 7,66 (d, 2H, J=8.1 Hz), to 7.93 (DD, 1H, J=7,2, 5.7 Hz), 8,40 (d, 2H, J=7.8 Hz), to 8.45 (d, 1H, J=6.0 Hz), 8,77 (d, 1H, J=5.4 Hz);13C NMR (75.5 MHz, D2O) δ 20,45, 21,05, 27,86, 50,20, 56,72, 63,37, 113,92, 117,32, 121,93, 126,19, 126,65, 127,02, 129,50, 129,65, 130,47, 130,85, 135,53, 137,80, 139,10, 139,81, 141,07, 147,13, 148,15, 148,35, 150,66, 151,62, 169,08; ES-MS m/z 489 (M+H); elemental analysis: calculated for C30H28N6O•2,7(HBr)•3,4H2O•0,2(C4H10O): C, Is 47.24; H, To 5.08; N, Of 10.73; Br, 27,55. Found: C, 47,26; H, 4,89; N, 10,51; Br, 27,41.

EXAMPLE 8

AMD9656:N-Phenyl-3-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzamid (hydrobromide salt)

Obtaining 3-chloromethyl-N-phenylbenzene

To a stirred solution of aniline (0.4 ml, 4.30 mmol) in anhydrous CH2Cl2(10 ml) was added 3-chlorodibenzofuran (360 mg, 1,90 mmol). The reaction mixture was allowed to mix at room temperature over night. The solvent was removed under reduced pressure. Purification of the residue on a column of strongly acidic ion exchange resin and elution with methanol) resulted in obtaining specified in the title compound (400 mg, 86%) as a white solid.

8-[N-(2-Nitroben alsultany)] amino-1,2,3,4-tetrahydroquinolin (332 mg, 1.00 mmol), 3-chloromethyl-N-phenylbenzene (245 mg, 1.00 mmol) and K2CO3(412 mg 2,99 mmol) was heated at 85°in CH3CN (10 ml) overnight in an atmosphere of N2. The reaction mixture was concentrated in vacuum, diluted with ethyl acetate, washed with H2O, NaCl (aqueous solution) and dried (Na2SO4). Evaporation of the solvent and purification of the residue flash-chromatography on silica gel (EtOAc-hexane, 3:7; EtOAc-CH2Cl2, 3:7) resulted in a compound (531 mg, 98%)as specified in the header, in the form of a yellow foam.

Using the General method of removing Nasil-protective group:The interaction of 3-{[(2-nitrobenzenesulfonyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-phenylbenzene (531 mg, 0.98 mmol), thiophenol (0,20 ml of 1.95 mmol) and K2CO3(404 mg, 2,90 mmol) in DMF (5 ml) at room temperature in an atmosphere of N2within 2 hours, followed by purification of the crude substances by chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 1:1:98) received the desired compound (200 mg, 57%) as a white foam.

Using the common methodology D:The transformation obtained above foam (200 mg, 0,56 mmol) in hydrobromide salt using a solution of acetic acid/HBr with the following presidenial salt of diethyl ether resulted in the receipt with the unity AMD9656in the form of a white solid.

1H NMR (CD3OD) δ 1,88-to 1.98 (m, 1H), 2,01-2,22 (m, 2H), 2,48-of 2.56 (m, 1H), 2,87 was 3.05 (m, 2H), of 4.44 (d, 1H, J=12.9 Hz), 4,55 (d, 1H, J=12.9 Hz), with 4.64 (DD, 1H, J=5,7, and 9.3 Hz), 7,16 (DD, 1H, J=7,2, 7,2 Hz), 7,37 (DD, 2H, J=8,4, and 8.4 Hz), was 7.45 (DD, 1H, J=4,8, and 7.8 Hz), to 7.64 (DD, 1H, J=7,8, and 7.8 Hz), of 7.70 (d, 2H, J=8.1 Hz), 7,81 (DD, 2H, J=7,3, 7,3 Hz), 8,01 (d, 1H, J=7.8 Hz), 8,19 (s, 1H), 8,58 (d, 1H);13C NMR (CD3OD) δ 20,97, 26,66, 28,77, 50,22 (blocked CD3OD) 58,15, 122,65, 126,21, 129,98, 130,26, 131,01, 131,06, 133,68, 134,71, 136,67, 137,70, 140,10, 141,45, 147,82, 150,43, 168,35; ES-MS m/z 358,2 (M+H); elemental analysis: calculated for (C23H23N3O)•1,7(HBr)•1,0(H2O): C, 53,85; H, A 5.25; N, 8,19; Br, 26,48. Found: C, 53,64; H, 5,23, N, 7,92, Br, 26,77.

EXAMPLE 9

AMD9657:N-(3-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)benzamide (hydrobromide salt)

Using the General methods:The interaction of 1-(2-trimethylsilylethynyl)-1H-benzimidazole-2-carbaldehyde (62 mg, 0.22 mmol), N-phenyl-3-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzamide (80 mg, 0.22 mmol) and triacetoxyborohydride sodium (46 mg, 0.29 mmol) in CH2Cl2(2 ml) at room temperature in an atmosphere of N2within 40 min, the subsequent purification of the crude substances by chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 1:1:98) resulted in obtaining specified in the header connect the deposits (127 mg, 92%) as a white foam.

Using General method F:The interaction of N-[3-({(5,6,7,8-tetrahydroquinolin-8-yl)-[1-(2-trimethylsilylethynyl)-1H-benzimidazole-2-ylmethyl]amino}methyl)phenyl]benzamide (127 mg, 0.20 mmol), 6N HCl solution (3 ml) at 50°C for 3 hours, subsequent purification of the crude substances by chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 1:1:98) resulted in obtaining specified in the title compound (70 mg, 72%) as a white foam.

Using the common methodology D:The transformation obtained above foam (70 mg, 0.14 mmol) in hydrobromide salt using a solution of acetic acid/HBr with the following presidenial salt of diethyl ether resulted in the receipt of the connectionAMD9657in the form of a white solid.

1H NMR (CD3OD) δ 1,87 is 2.01 (m, 1H), 2,24-is 2.37 (m, 2H), 2,47 is 2.51 (m, 1H), 3,05-3,10 (m, 2H), 3,88 (d, 1H, J=12.9 Hz), of 3.94 (d, 1H, J=12.9 Hz), the 4.29 (d, 1H, J=16.2 Hz), 4,63 (d, 1H, J=16.2 Hz), 4,76-4,82 (m, 1H), 7,14-7,20 (m, 2H), 7,39 (DDD, 2H, J=2,1, to 5.4, 5.4 Hz), 7,45-rate of 7.54 (m, 4H), 7,65-of 7.69 (m, 2H), to 7.77 (d, 2H, J=8.1 Hz), to 7.93 (DD, 1H, J=6,0, 7,8 Hz), of 8.04 (s, 1H), scored 8.38 (d, 1H, J=8.1 Hz), of 8.95 (d, 1H, J=5.7 Hz);13C NMR (CD3OD) δ 21,97, 22,12, 29,27, 50,79, 57,90, 63,33, 115,14, 123,04, 126,22, 127,19, 127,93, 128,72, 130,07, 130,15, 130,63, 132,33, 134,87, 136,41, 138,10, 141,86, 142,03, 148,95, 152,29, 152,96; ES-MS m/x 488,3 (M+H); elemental analysis: calculated for (C31H29N5O)•2,0(HBr)•1,7(H2O): C, 54,75; H, 5,10; N, 10.30 A.m.; Br, 3,50. Found: C, 54,81; H, 5,10, N, Of 10.21, Br, 23,41.

EXAMPLE 10

AMD9367:Obtaining N-pyridine-2-ylmethyl-4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzosulfimide

To a stirred solution of 4-bromocinnamaldehyde (500 mg, of 1.85 mmol) and Et3N (269 μl, of 1.85 mmol) in CH2Cl2(10 ml) at -78°With added aminomethylpyridine (190 μl, of 1.85 mmol) in one portion. The resulting solution was stirred at -78°C for 20 minutes. Then add the second portion of Et3N (269 μl, of 1.85 mmol) followed by addition of 8-amino-5,6,7,8-tetrahydroquinoline (274 mg, of 1.85 mmol). The solution was stirred for 18 hours at room temperature. The mixture was diluted with CH2Cl2(100 ml/mmol), filtered through celite and concentrated. The crude substance was purified by chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 48:1:1) to obtain the connectionAMD9367(150 mg, 20%) as a white foam.

1H NMR (300 MHz, CD3COCD3) δ 1,69-to 1.98 (m, 2H), 2.00 in was 2.05 (m, 1H), 2,11-to 2.18 (m, 1H), 2.71 to 2,85 (m, 3H), 3,82 (m, 1H), 3.96 points (d, 2H, J=6.0 Hz), 4,23 (CL, 2H), 6,10 (SHS, 1H), 7,05-to 7.15 (m, 3H), 7,38 (d, 1H, J=7.8 Hz), 7,49 (d, 2H, J=9.0 Hz), 7,55-7,58 (m, 1H), 7,79 (d, 2H, J=9.0 Hz), 8,39 (d, 1H, J=4,8 Hz), 8,44 (d, 1H, J=4.5 Hz),13C NMR (75.5 MHz, CD3COCD3) δ 20,05, 29,14, 29,20, 47,79, 51,70, 58,09, 122,39, 123,01, 127,68, 129,07, 132,90, 137,17, 137,40, 138,24, 146,62, 147,24, 149,38, 155,21, 157,54; ES-MS m/z 409 (M+H); elemental analysis: calculated for C 22H24N4O2S•0,2H2O: C, 64,12; H, 5,97: N, 13,59. Found: C, 64,10; H, 5,91; N, 13,71.

EXAMPLE 11

AMD9371:Getting 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-pyridine-2-ilmmilmismiliemi

Obtaining N-pyridine-2-ylmethyl-4-({(5,6,7,8-tetrahydroquinolin-8-yl)-[1-(2-trimethylsilylethynyl)-1H-benzimidazole-ylmethyl]amino}methyl)benzosulfimide.

Using the General methods:The interaction of N-pyridine-2-ylmethyl-4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzosulfimide (97 mg, 0.24 mmol), 1-(2-trimethylsilylethynyl)-1H-benzimidazole-2-carbaldehyde (72 mg, 0.26 mmol) and NaBH(OAc)3(151 mg, 0.71 mmol) for 1 hour at room temperature followed by purification column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 98:1:1) resulted in the receipt specified in the title compound (63 mg, 50%) as a white foam.

1H NMR (300 MHz, CDCl3) δ 0,00 (s, 9H), 0,77 (DD, 2H, J=7,5, 7.5 Hz), 1,73-of 1.74 (m, 1H), 1,95-to 2.06 (m, 2H), 2,20-of 2.25 (m, 1H), 2,66-of 2.86 (t, 2H), 3,29-to 3.35 (m, 2H), 3,78 (d, 1H, J=14,7 Hz), 3,98 (d, 1H, J=14,7 Hz), of 4.05 (DD, 1H, J=9,3, 6.3 Hz), 4,13 (d, 2H, J=6.0 Hz), 4,18 (CL, 2H), 5,70 (d, 1H, J=12.0 Hz), 5,98 (d, 1H, J=12.0 Hz), 7,06-7,10 (m, 2H), 7,13-to 7.18 (m, 3H), 7,31 and 7.36 (m, 2H), 7,43 (d, 2H, J=8.1 Hz), 7,52-7,66 (t, 4H), 8,42 (d, 1H, J=4,8 Hz), charged 8.52 (d, 1H, J=4.5 Hz).

Using General method E: Ot modestiam N-pyridine-2-ylmethyl-4-({ (5,6,7,8-tetrahydroquinolin-8-yl)-[1-(2-trimethylsilylethynyl)-1H-benzimidazole-2-ylmethyl]amino}methyl)benzosulfimide (63 mg, 0.09 mmol) and 6N HCl (2.5 ml) at 50°C for 3 hours and subsequent column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 48:1:1) received the connectionAMD9371(38 mg, 75%) as a white powder.

1H NMR (300 MHz, CD3OD) δ 1,68-1,71 (m, 1H), 2,01-of 2.09 (m, 2H), 2,29 (SHS, 1H), 2,73-2,89 (m, 2H), 3,68 (CL, 2H), 3,93 (SHS, 1H), 4.00 points (MS, 2H), 4,13-4,18 (m, 2H),? 7.04 baby mortality-7,30 (m, 5H), 7,50-7,54 (t, 8H), compared to 8.26 (SHS, 1H), 8,60 (SHS, 1H);13C NMR (75.5 MHz, CD3OD) δ 22,83, 24,68, 30,57, 51,69, 55,98, 63,36, 123,85, 124,14, 128,12, 130,93, 137,52, 138,92, 139,64, 140,66, 146,18, 148,46, 149,85, 155,92, 158,08, 158,74; ES-MS m/z 539 (M+H); elemental analysis: calculated for C30H30N6O2S: C, 66,89; H, 5,61; N, 15,60. Found: C, 66,65; H, The 5.65; N, 15,60.

EXAMPLE 12

AMD9577:Obtaining N-pyridine-2-ylmethyl-3-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzosulfimide (hydrobromide salt)

Obtaining 3-[(pyridine-2-ylmethyl)sulfamoyl]benzoic acid

To pre-cooled (bath with ice) solution of 2-(aminomethyl)pyridine (1,05 g, 9.7 mmol) in anhydrous CH2Cl2(15 ml) was added 3-(chlorosulfonyl)benzoic acid (714 mg, 3,23 mmol) in an atmosphere of N2after adding a bath with ice was removed. Mixing food is reaped for 18 hours at room temperature, the reaction mixture was diluted with 300 ml of CH2Cl2and filtered through celite. Evaporation of the solvent and purification of the residue flash-chromatography on silica gel, using as eluent CH3COOH-MeOH-CH2Cl2, 3:6:91, resulted in obtaining specified in the title compound (840 mg, 89%) as a white solid.

Obtaining 3-hydroxymethyl-N-pyridine-2-ilmmilmismiliemi

To a solution of 3-[(pyridine-2-ylmethyl)sulfamoyl]benzoic acid (840 mg, 2,87 mmol) in THF (5 ml) was added BH3THF (1 M, 14.4 ml, 14.4 mmol) dropwise. After the addition the reaction mixture was left to mix for 18 hours at room temperature and carefully added 5N HCl (8 ml), which led to the selection of H2. When heated at 70°C for 2 hours formed a clear solution. Then added water (30 ml)and the resulting solution was extracted with diethyl ether (3 x 20 ml). The aqueous phase was cooled to 0°neutralized solid NaOH and then solid NaHCO3and was extracted with CHCl3(6 x 20 ml). The combined organic extracts were dried over MgSO4and concentrated under reduced pressure. The crude substance was used for the next reaction without further purification.

Obtaining 3-formyl-N-pyridine-2-ilmmilmismiliemi

3-Hydroxymethyl-N-pyridine-2-ilmmilmismiliemi (crude product from the previous stage, 2,87 mmol) and MnO2(2.9 g, 28.7 mmol) in methanol (0.5 ml) and CH2Cl2(15 ml) was subjected to interaction at 50°C in an atmosphere of N2throughout the night. The mixture was concentrated and purified by chromatography on silica gel (50% ethyl acetate and CH2Cl2) obtaining specified in the title compound (600 mg, 79% over two stages) as a white foam.

Using the General methods:The interaction of 3-formyl-N-pyridine-2-ilmmilmismiliemi (317 mg, to 1.21 mmol), 5,6,7,8-tetrahydroquinolin-8-ylamine (179 mg, to 1.21 mmol), acetic acid (0.2 ml) and triacetoxyborohydride sodium (513 mg, 2.4 mmol) in THF (10 ml) at room temperature in an atmosphere of N2within 40 min, the subsequent purification of the crude substances by chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 1:1:98) resulted in obtaining specified in the title compound (284 mg, 78%) as a white foam.

Using the common methodology D:The transformation obtained above foam (30 mg, 0,073 mmol) in hydrobromide salt using a solution of acetic acid/HBr with the following presidenial salt of diethyl ether resulted in the receipt of the connectionAMD9677in the form of a white solid.

1H NMR (D2O) B4; 1,89 is 1.96 (m, 1H), 1,96-of 2.09 (m, 1H), 2,15 was 2.25 (m, 1H), 2,36-2,47 (m, 1H), 2,83-to 3.02 (m, 2H), to 4.52 (s, 2H), 4,56 (s, 2H), with 4.64-and 4.68 (m, 1H), 7,47-7,51 (m, 1H), 7,69 (t, 2H, J=7.8 Hz), 7,83-7,94 (m, 4H), 8,02 (s, 1H), 8,45-of 8.50 (m, 2H), 8,65 (d, 1H, J=6 Hz);13C NMR (D2O) δ 17,86, 24,55, 27,11, 43,69, 48,86, 55,88, 126,33, 126,66, 128,55, 128,77, 131,27, 132,77, 135,88, 137,70, 139,03, 141,53, 143,94, 144,77, 147,69, 152,17; ES-MS m/z 409,2 (M+H); elemental analysis: calculated for (C22H24N4O2S)•3,0(HBr)•4(H2O)•6(C4H10O): C, 40,06; H, 4,49; N, 8,27; Br, 35,37; S, 4,73. Found: C, 39,80; H, 4,81; Br, 35,65; S, 4,74.

EXAMPLE 13

AMD9578:Obtaining 3-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-pyridine-2-ilmmilmismiliemi (hydrobromide salt)

Using the General methods:The interaction of 1-(2-trimethylsilylethynyl)-1H-benzimidazole-2-carbaldehyde (192 mg, 0.70 mmol), N-pyridine-2-ylmethyl-3-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzosulfimide (284 mg, 0.70 mmol), acetic acid (0.2 ml) and triacetoxyborohydride sodium (442 mg, of 2.08 mmol) in THF (7 ml) at room temperature in an atmosphere of N2within 40 min, the subsequent purification of the crude substances by chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 1:1:98) resulted in obtaining specified in the title compound (177 mg, 38%) as a white foam.

Using General method E: Mutual the action of N-pyridine-2-ylmethyl-3-({ (5,6,7,8-tetrahydroquinolin-8-yl)-[1-(2-trimethylsilylethynyl)-1H-benzimidazole-2-ylmethyl]amino}methyl)benzosulfimide (177 mg, 0.26 mmol) and 6N HCl (3 ml) at 50°C for 3 hours followed by purification of the crude substances by chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 2:2:96) has been specified in the title compound (104 mg, 73%) as a white foam.

Using the common methodology D:The transformation obtained above foam (104 mg, 0,19 mmol) in hydrobromide salt using a solution of acetic acid/HBr with the following presidenial salt of diethyl ether resulted in the receipt of the connectionAMD9578.

1H NMR (CD3OD) δ 1,91 is 2.01 (m, 2H), 2,22-is 2.37 (m, 2H), 2.49 USD of $ 2.53 (m, 1H), 3.00 and-3,11 (m, 2H), 3,99 (d, 1H, J=12.9 Hz), 4,07 (d, 1H, J=13,2 Hz), 4,46 (d, 2H, J=4, 2 Hz), a 4.53 (d, 1H, J=16.5 Hz), 4,69 (d, 1H, J=16.5 Hz), 4,77-to 4.81 (m, 1H), 7,34 (DD, 1H, J=7,7, 7,7 Hz), of 7.48 (d, 1H, J=8.1 Hz), 7,52-7,56 (m, 2H), 7,72-7,76 (m, 2H), a 7.85 (d, 1H, J=7.8 Hz), 7,93 shed 8.01 (m, 2H), 8,07 (s, 1H), 8,08 (d, 1H, J=9.0 Hz), 8,40 (d, 1H, J=7.8 Hz), to 8.57 (DDD, 1H, J=1,5, and 7.8, 7.8 Hz), 8,76 (d, 1H, J=6.0 Hz), to 8.94 (d, 1H, J=5,1 Hz);13C NMR (CD3OD) δ 21,93, 29,27, 45,26, 50,48, 57,49, 62,41, 115,39, 127,31, 127,68, 128,05, 128,16, 128,24, 129,91, 130,99, 132,27, 136,64, 139,58, 140,94, 141,97, 142,15, 142,85, 148,53, 149,38, 151,97, 152,48, 155,26; ES-MS m/z to 539.3 (M+H); elemental analysis: calculated for (C30H30N6O2S)•3,0(HBr)•3,1(H2O): C, 43,04; H, 4,72; N, 10,04; Br, 28,63; S, 3,83. Found: C, 43,15; H, 4,70; N, There Is A 10.03; Br, 28,56; S, 3,80.

EXAMPLE 14

AMD9622:Obtaining 3-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N vinylbenzenesulfonic (hydrobromide salt)

Obtaining 3-phenolsulfonate acid

3-Chlorosulfonylbenzoic acid (300 mg, about 1.36 mmol) and aniline (0,30 ml, 3,29 mmol) was stirred at room temperature in anhydrous CH2Cl2(10 ml) overnight in an atmosphere of N2. The reaction mixture was concentrated in vacuum. Purification of the residue on a column of IR-120 ion exchange resin and elution with methanol) resulted in obtaining specified in the title compound (380 mg, 100%) as a white solid.

Obtaining 3-hydroxymethyl-N-vinylbenzenesulfonic

To a solution of 3-phenolsulfonate acid (380 mg, of 1.36 mmol) in THF (10 ml) was added BH3•THF (1 M, 5.4 ml, 5.4 mmol) dropwise. After the addition the reaction mixture was left to mix for 3 days at room temperature. To the reaction mixture were added methanol and the mixture was concentrated in vacuum (5 X). The compound obtained was used in the next stage without further purification.

Obtaining 3-formyl-N-vinylbenzenesulfonic

The interaction of 3-hydroxymethyl-N-vinylbenzenesulfonic (neo is ewenny from the previous stage, of 1.36 mmol), MnO2(1.40 g, 13,60 mmol) in CH2Cl2(10 ml) at 40°C in an atmosphere of N2during the night resulted in the receipt specified in the title compound (293 mg, 82%) as a white solid.

Using the General methods:Interaction tert-butyl ester 2-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzimidazole-1-carboxylic acid (172 mg, 0.46 mmol), 3-formyl-N-vinylbenzenesulfonic (119 mg, 0.46 mmol) and triacetoxyborohydride sodium (116 mg, 0.55 mmol) in THF (4 ml) at room temperature in an atmosphere of N2during the night, the subsequent purification of the crude substances by chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 2:1:97) resulted in obtaining specified in the title compound (93 mg, 33%) as a yellow foam.

Using the common methodology D:Removal of the BOC-protective group with tert-butyl methyl ether 2-{[(3-phenylsulphonyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazole-1-carboxylic acid obtained above (93 mg, 0.15 mmol), using a solution of acetic acid/HBr subsequent pereosazhdeniya salt of diethyl ether resulted in the receipt of the connectionAMD9622in the form of a white solid.

1H NMR (CD3OD) δ 1,76-of 1.85 (m, 1H), 2,15 was 2.25 (m, 2H), 2,35-2,39 (m, 1H), 2,96 was 3.05 (m, 2H), 3,85 (s, 2H), to 4.38 (d, 1H, J=16.5 Hz), 4,60 (d, 1H, J=16.5 Hz), 4,59-br4.61 (m, H), 6,90-6,93 (m, 1H), 7,00-7,10 (m, 4H), 7,22 (DD, 1H, J=7,6, 7,6 Hz), 7,34 (d, 1H, J=8.1 Hz), 7,51 (DD, 2H, J=3, and 6.3 Hz), 7,69-7,72 (m, 3H), 7,79-7,83 (m, 2H), 8,21 (d, 1H, J=7.8 Hz), cent to 8.85 (d 1H, J=4,8 Hz);13C NMR (CD3OD) δ 20,80, 21,30, 28,11, 49,24, 55,72, 61,29, 114,20, 121,15, 124,83, 125,61, 126,57, 126,74, 128,23, 129,26, 129,39, 131,49, 134,64, 137,95, 138,16, 140,09, 140,26, 141,43, 146,65, 151,71; ES-MS m/z 524,4 (M+H); elemental analysis: calculated for (C30H29N5O2S)•2,0(HBr)•1,2(H2O): C, 50,96; H, Was 4.76; N, 9,90; Br, 22,60, S, 4,53. Found: C, 51,23; Y 4,96; N, 9,80; Br, Are 22.42; S 4,45.

EXAMPLE 15

AMD9623:3-{[(H-Benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-benzenesulfonamide (hydrobromide salt)

Obtaining 3-benzisothiazole acid

3-Chlorosulfonylbenzoic acid (300 mg, about 1.36 mmol) and benzylamine (of 0.60 ml, 5,49 mmol) was stirred at room temperature in anhydrous CH2Cl2(10 ml) overnight in an atmosphere of N2. The reaction mixture was concentrated in vacuum. Purification of the residue on a column of IR-120 ion exchange resin and elution with methanol) resulted in obtaining specified in the title compound (395 mg, 100%) as a white solid.

Obtain N-benzyl-3-hydroxymethanesulfinic

To a solution of 3-phenolsulfonate acid (380 mg, of 1.36 mmol) in THF (10 ml) we use the and BH 3•THF (1 M, 5.4 ml, 5.4 mmol) dropwise. After the addition the reaction mixture was left to mix for 3 days at room temperature. To the reaction mixture were added methanol and the mixture was concentrated in vacuum (5 X). The compound obtained was used in the next stage without further purification.

Obtaining 3-formyl-N-vinylbenzenesulfonic

The interaction of N-benzyl-3-hydroxymethanesulfinic (crude from previous phase of 1.36 mmol), MnO2(1.40 g, 13,60 mmol) in CH2Cl2(10 ml) at 40°C in an atmosphere of N2during the night resulted in the receipt specified in the title compound (317 mg, 85%) as a white solid.

Using the General methods:Interaction tert-butyl ester 2-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzimidazole-1-carboxylic acid (141 mg, and 0.37 mmol), N-benzyl-3-formylbenzenesulfonic (104 mg, and 0.37 mmol) and triacetoxyborohydride sodium (95 mg, 0.45 mmol) in THF (4 ml) at room temperature in an atmosphere of N2during the night, the subsequent purification of the crude substances by chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 1:1:98) resulted in obtaining specified in the title compound (152 mg, 64%) as a yellow foam.

Using the common methodology D:Removal of the BOC-Pro is based groups with tert-butyl methyl ether 2-{ [(3-benzylaminocarbonyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazole-1-carboxylic acid (102 mg, 0.16 mmol) using a solution of acetic acid/HBr subsequent pereosazhdeniya salt of diethyl ether resulted in the receipt of the connectionAMD9623in the form of a white solid.

1H NMR (CD3OD) δ 1,86-1,89 (m, 1H), 2,19-2,31 (m, 2H), 2,41 is 2.43 (m, 1H), 3,01-3,11 (m, 2H), 3,84 (d, 1H, J=12.9 Hz), 3,90 (d, 1H, J=12.9 Hz), of 3.94 (s, 2H), 4,39 (d, 1H, J=16,2 Hz), 4,59-of 4.67 (m, 2H), 7,10 (W, 5H), 7,27 (DD, 1H, J=7,6, 7,6 Hz), 7,41 (d, 1H, J=7,8gts), 7,51 (DD, 2H, J=3, and 6.3 Hz), 7,70-7,74 (m, 3H), 7,88 (DD, 2H, J=6,4, 6.4 Hz), 8,30 (d, 1H, J=7.8 Hz), 8,88 (d, 1H);I3C NMR (CD3OD) δ 20,39, 20,90, 27,81, 46,73, 50,11, 56,29, 62,83, 114,02, 125,94, 126,16, 126,69, 127,55, 127,95, 128,08, 128,78, 129,90, 134,45, 137,85, 139,81, 140,96, 148,22, 151,28; ES-MS m/z 538,4 (M+H); elemental analysis: calculated for (C31H31N5O2S)•2,0(HBr)•1,3(H2O): C, 51,51; H, 4,96; N, RS 9.69; Br, 22,11; S, 4,43. Found: C, 51,60; H, 4,91; N, 9,63; Br, 22,07; S, 4,39.

EXAMPLE 16

AMD9397:Getting 4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzylamine pyridine-2-carboxylic acid

Getting 4-hydroxymethylbenzene pyridine-2-carboxylic acid

Using the common methodology F:Interaction (4-aminomethylphenol)methanol (200 mg, of 1.46 mmol), 1-hydroxybenzotriazole (218 mg, of 1.61 mmol), 4-methylmorpholine (241 μl, 2,19 mmol) and EDCI (309 mg, of 1.61 mmol) for 2 hours at room is the temperature resulted in the receipt specified in the title compound (335 mg, 95%) as a yellow oil.

1H NMR (300 MHz, CDCl3) δ of 4.67 (d, 2H, J=6.0 Hz), 4,69 (s, 2H), was 7.36 (CL, 4H), 7,43-7,44 (m, 1H), 7,85-7,86 (m, 1H), 8,24 (d, 1H, J=9.0 Hz), charged 8.52 (SHS, 1H), charged 8.52 (d, 1H, J=3.0 Hz); ES-MS m/z 243 (M+H).

Getting 4-{[(pyridine-2-carbonyl)amino]methyl}benzyl ether methanesulfonate

Using the common methodology G:The interaction of 4-hydroxymethylbenzene pyridine-2-carboxylic acid (200 mg, 0.83 mmol), Et3N (144 μl, 0,99 mmol) and MsCl (71 μl, of 0.91 mmol) for 10 minutes at 0°resulted in the receipt specified in the title compound (214 mg, 81%) as a white solid.

1H NMR (300 MHz, CDCl3) δ of 2.92 (s, 3H), 4,69 (d, 2H, J=3.3 Hz), 5,23 (s, 2H), 7,41-7,47 (m, 5H), the 7.85-7,87 (m, 1H), 8,24 (d, 1H, J=7,8 Hz)and 8.50 (SHS, 1H), 8,54 (d, 1H, J=3,9 Hz).

Getting 4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzylamine pyridine-2-carboxylic acid

Using General method H:The interaction of 8-amino-5,6,7,8-tetrahydroquinoline (148 mg, 1.00 mmol) with 4-{[(pyridine-2-carbonyl)amino]methyl}benzyl ether of methansulfonate (214 mg, 0.67 mmol) for 3 hours at room temperature with a subsequent column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 48:1:1) resulted in a compoundAMD9397(81 mg, 33%) as a yellow oil.

1H NMR (300 MHz, CDCl3) δ 1,72 of-1.83 (m, 2H), 2.00 in to 2.06 (m, 1H), 2,16-2.20 m, 1H), 2,75-and 2.83 (m, 2H), 3,82-a-3.84 (m, 1H), 3,88 (d, 1H, J=13,2 Hz), 3,98 (d, 1H, J=12.9 Hz)and 4.65 (d, 2H, J=6.0 Hz), 7,05-7,06 (m, 1H), 7,32-7,42 (m, 6H), a 7.85 (DDD, 1H, J=7,8, and 7.8, 1.8 Hz), 8,23 (d, 1H, J=7,8 Hz), 8.34 per (CL, 1H), of 8.37 (d, 1H, J=3.3 Hz), charged 8.52 (d, 1H, J=3,9 Hz);13C NMR (75.5 MHz, CDCl3) δ 20,05, 29,00, 29,24, 43,68, 51,85, 57,85, 122,19, 122,70, 126,56, 128,37 (2C), 129,01 (2C), 132,83, 137,07, 137,23, 137,73, 140,41, 147,20, 148,46, 150,23, 157,82, 164,57. ES-MS m/z 373 (M+H); elemental analysis: calculated for C23H24N4O•0,3H2O: C, 73,11; H, 6,56; N, 14,83. Found: C, 72,98; H, To 6.58; N, 14,63.

EXAMPLE 17

AMD9401:Getting 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]methyl}benzylamine pyridine-2-carboxylic acid.

Using the General methods:The interaction of 4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzylamine pyridine-2-carboxylic acid(AMD9397)(40 mg, 0.11 mmol), 1H-benzimidazole-2-carbaldehyde (16 mg, 0.11 mmol) and NaBH(OAc)3(68 mg, 0.32 mmol) for 2 hours at 60°With subsequent column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 98:1:1) resulted in a compoundAMD9401(28 mg, 52%) as a white foam.

1H NMR (300 MHz, CD3OD) δ 1,60-to 1.63 (m, 1H), 1,95-to 2.06 (m, 2H), 2,20-2,22 (m, 1H), 2,66-and 2.83 (m, 2H), 3,51 (d, 1H, J=13,2 Hz)to 3.58 (d, 1H, J=13,2 Hz), of 3.94 (d, 1H, J=15.3 Hz), Android 4.04-4.09 to (m, 3H), 4,42 (CL, 2H), 7,09-to 7.15 (m, 4H), 7,20 (DD, 1H, J=7,8, and 4.8 Hz), 7,20 (d, 1H, J=8.1 Hz), 7,28 (d, 2H, J=8.1 Hz), 7,41-7,47 (m, 2H), of 7.48-7,52 (m, 2H), to $ 7.91 (DDD, 1H, J=7,5, 7,5,1,8 Hz), of 8.06 (d, 1H, J=7.8 Hz), 8,55 (d, 1H, J=4.5 Hz), at 8.60 (d, 1H, J=4.5 Hz);13C NMR (75.5 MHz, CD3OD) δ 22,84, 24,33, 30,62, 44,13, 51,41, 56,15, 63,13, 123,55, 124,03, 128,13, 128,61, 130,80, 137,39, 138,95, 139,14, 139,51, 139,67, 148,35, 150,17, 151,40, 156,31, 158,31, 166,94; ES-MS m/z 503 (M+H); elemental analysis: calculated for C31H30N6O•0,8H2O•0,3CH2Cl2: C, 69,30; H, 5,98; N, 15,49. Found: C, 69,63; H, 6,14; N, 15,19.

EXAMPLE 18

AMD9927:Getting 3,5-dichloro-N-{4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzyl}isonicotinamide

Getting 3,5-dichloro-N-(4-formylmethyl)isonicotinamide

To partially dissolved 3,5-dichloro-N-(4-hydroxymethylbenzene)isonicotinamide (730 mg, 2,35 mmol) in a mixture of CH2Cl2(12 ml) and Meon (1 ml) was added to MnO2(2,43 g, 23.5 mmol)and the resulting suspension was stirred at 40°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The precipitate was washed CH2Cl2/Meon (100:3), and the filtrate was concentrated under reduced pressure to obtain white solid (630 mg). Purification of column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:1:1) resulted in obtaining the desired aldehyde (480 mg, 66%) as a white solid.

1H NMR (CDC13) δ 4,78 (d, 2H, J=6.0 Hz), to 6.19 (SHS, 1H), 7,58 (d, 2H, J=9.0 Hz), of 7.90 (d, 2H, J=9.0 Hz), 8,55 (s, 2H), 10,02 (s, 1H).

Using the General methods:actor aldehyde, obtained above (100 mg, 0.32 mmol) and 5,6,7,8-tetrahydroquinolin-8-ylamine (56 mg, 0.38 mmol) in Meon (2 ml) was stirred at room temperature overnight. Then was added NaBH4(24 mg, of 0.65 mmol)and the resulting mixture was stirred at room temperature for an additional 15 minutes. Purification of the crude brown foam (160 mg) radial chromatography on silica gel (2 mm plate, 100% EtOAc) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:2:1) resulted in a compoundAMD9927(70 mg, 50%) as a white foam.

1H NMR (CDCl3) δ 1,61-of 1.78 (m, 2H), 1,92-to 2.18 (m, 2H), 2,65-2,90 (m, 3H), of 3.73-3,81 (m, 2H), 3,89 (d, 1H, J=13,2 Hz), 4,55 (d, 2H, J=5.7 Hz), 6,97-7,06 (m, 2H), 7,25-7,28 (m, 2H), 7,31 and 7.36 (m, 3H), 8,30-8,32 (m, 1H), scored 8.38 (s, 2H);13C NMR (CDCl3) δ 20,05, 28,89, 29,18, 44,05, 51,66, 57,82, 122,27, 128,46, 128,97, 129,37, 132,84, 135,83, 137,31, 140,65, 142,70, 147,14, 147,93, 157,61, 162,36; ES-MS m/z 441,2 (M+H); elemental analysis: calculated for C23H22N4Cl2O•0,1 h2O: C, 62,34; H, Of 5.05; N, 12,64; Cl, 16,00. Found: C, 62,38; H,To 5.17; N, 12,48; Cl, 15,90.

EXAMPLE 19

AMD9960:Obtaining N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-diethylnicotinamide (hydrobromide salt)

A solution of 2,4-diethylnicotinamide acid (54 mg, 0.35 mmol) in SOCl2(˜2 ml, excess) was heated to 80°C for 4 hours. The reflux condenser in which alali, the mixture was purged with N2at 80°for ˜5 minutes and then dried in vacuum for 10 minutes. The resulting syrup was dissolved in CH2Cl2(2.4 ml) and stir the mixture was added (4-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (187 mg, 0.47 mmol), Et3N (0.33 ml, of 2.35 mmol) and catalytic amount of DMAP. The reaction mixture was stirred over night at room temperature. Purification of the crude yellow foam (240 mg) radial chromatography on silica gel (2 mm plate, CH2Cl2/MeOH/NH4OH, 100:2:1) followed by radial chromatography on silica gel (1 mm plate, EtOAc/MeOH/NH4OH, 400:3:3) yielded the desired amide (61 mg, 33%) as a white foam.

Using the common methodology D:The transformation obtained above foam in hydrobromide salt resulted in the receipt of the connectionAMD9960in the form of a white solid.

1H NMR (D2O) δ 1,80-to 1.98 (m, 1H), 2,15-of 2.38 (m, 2H), 2,39 is 2.51 (m, 4H), of 2.56 (s, 3H), 3,02 was 3.05 (m, 2H), of 3.77 (d, 1H, J=12,6 Hz), 3,84 (d, 1H, J=12,6 Hz), Android 4.04 (s, 2H), of 4.44 (d, 1H, J=16.5 Hz), 4,63 (d, 1H, J=of 16.5 Hz), 4,74-rate 4.79 (m, 1H, overlapped with HOD), 6,94 (d, 2H, J=8.1 Hz), 7,17 (d, 2H, J=8.1 Hz), 7,47-7,52 (m, 2H), EUR 7.57-to 7.61 (m, 2H), of 7.75 (d, 1H, J=6.3 Hz), 7,92 (DD, 1H, J=7,8, 5.7 Hz), 8,39 (d, 1H, J=7.8 Hz), 8,49 (d, 1H, J=6.3 Hz), 8,76 (DD, 1H, J=5,7, and 0.9 Hz);13C NMR (D2O) δ 17,56, 19,96, 20,48, 20,92, 27,85, 43,03, 50,21, 56,67, 63,20, 113,86, 126,07, 126,66, 126,98, 127,69, 130,52, 135,29, 135,93, 137,22, 139,63, 140,81, 140,93, 148,1, 150,18, 150,93, 151,87, 157,45, 166,29; ES-MS m/z 531,3 (M+H); elemental analysis: calculated for C33H33N6O•3,1HBr•1,8H2O•0,4C4H10O: C, 49,32; H, 5,23; N, Becomes 9.97; Br, 29,40. Found: C, 49,31; H, A 5.25; N, Becomes 9.97; Br, 29,39.

EXAMPLE 20

AMD9961:Obtaining N-(3-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-diethylnicotinamide (hydrobromide salt)

A solution of 2,4-diethylnicotinamide acid (56 mg, and 0.37 mmol) in SOCl2(˜3 ml, excess) was heated to 80°C for 4 hours. The reflux condenser was removed, and the mixture was purged with N2at 80°for ˜5 minutes and then dried in vacuum for 10 minutes. The resulting syrup was dissolved in CH2Cl2(2.0 ml)and stir the mixture was added (3-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (147 mg, and 0.37 mmol), Et3N (of 0.26 ml of 1.85 mmol) and catalytic amount of DMAP. The reaction mixture was stirred over night at room temperature. Purification of the crude yellow foam column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:1:1) followed by radial chromatography on silica gel (1 mm plate, EtOAc/MeOH/NH4OH, 200:1:1) yielded the desired amide (85 mg, 43%) as a pale yellow foam.

Using the common methodology D:The transformation obtained above foam in hydro is raidou salt resulted in the receipt of the connection AMD9961in the form of a beige solid.

1H NMR (D2O) δ 1,82-to 1.98 (m, 1H), 2,15 is 2.33 (m, 2H), of 2.38 (s, 3H), 2,39-of 2.50 (m, 1H), 2,53 (s, 3H), 3,01-is 3.08 (t, 2H), 3,79 (d, 1H, J=12.9 Hz), 3,86 (d, 1H, J=12,6 Hz)to 4.15 (s, 2H), 4,46 (d, 1H, J=16.5 Hz), with 4.64 (d, 1H, J=16.5 Hz), 4,79 (t, 1H, overlapped with HOD), 6,79 (d, 1H, J=7.8 Hz), 7,07 for 7.12 (m, 2H), 7,18 (d, 1H, J=7.8 Hz), 7,47-7,53 (m, 2H), EUR 7.57 to 7.62 (m, 2H), 7,74 (d, 1H, J=6.0 Hz), 7,92 (DD, 1H, J=7,8, 5.7 Hz), 8,40 (d, 1H, J=7,2 Hz), 8,48 (d, 1H, J=6.0 Hz), 8,76 (DD, 1H, J=5,7, 1.2 Hz);13C NMR (D2O) δ 17,52, 19,92, 20,49, 20,89, 27,87, 43,36, 50,14, 56,84, 62,98, 113,90, 126,10, 126,72, 127,01, 127,21, 129,39, 129,52, 129,64, 130,57, 135,27, 137,03, 137,43, 139,64, 140,78, 140,95, 148,24, 150,17, 150,88, 151,79, 157,50, 166,29; ES-MS m/z 531,3 (M+H); elemental analysis: calculated for C33H33N6O•3,2HBr•1,4H2O•0,5C4H10O: C, 49,41; H, To 5.21; N, 9,88; Br, 30,05. Found: C, 49,43; H, A 5.25; N, 9,85; Br, 29,94.

EXAMPLE 21

AMD11036:N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-dimethyl-1-oxycotine (hydrobromide salt)

Obtaining the ethyl ester of 2,4-dimethyl-1-oxycodonebuy acid

To a solution of ethyl 2,4-dimethylpyridin-3-carboxylate (2.0 g, and 11.2 mmol) in Asón (28 ml) was added N2About2(34-37%, 1.1 ml, and 11.2 mmol)and the resulting mixture was heated to 70°C for 3 hours. A second aliquot of N2About2(34-37%, 1.1 ml, and 11.2 mmol) was added, and the mixture was heated to 70°With during the night. The reaction mixture was concentrated under reduced pressure, obrazovalis the syrup was dissolved in CH 2Cl2(150 ml) and washed with saturated solution of NaHCO3(2 x 25 ml). The aqueous layer was extracted with CH2Cl2(2 x 100 ml), the combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to obtain the desired N-oxide (2,07 g, 95%).

1H NMR (CDCl3) δ of 1.41 (t, 3H, J=7.2 Hz), is 2.30 (s, 3H), 2.49 USD (s, 3H), of 4.44 (q, 2H, J=7,2 Hz), of 6.99 (d, 1H, J=6.6 Hz), 8,19 (d, 1H, J=6,6 Hz).

To a solution of N-oxide obtained above, from 2.06 g, 10,55 mmol) in EtOH (25 ml) was added NaOH solution (844 mg, 21.1 mmol) in N2O (5 ml). The resulting mixture was stirred at 40°C for 3 days. The solution was concentrated under reduced pressure. Then was added a saturated solution of NaHCO3(10 ml)and the aqueous layer was extracted with CH2Cl2(2 x 100 ml). The aqueous phase was acidified with 10% HCl and concentrated in vacuum. The obtained solid was partially dissolved in CH2Cl2/Meon (10:1), filtered and concentrated. Acid N-oxide (1.40 g) was used for the next reaction without further purification.

Using the common methodology F:Through a solution of the acid obtained above (46 mg, 0.28 mmol), (4-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (100 mg, 0.25 mmol), NOT (37 mg, 0.28 mmol) and 4-methylmorpholine (40 μl, 0.38 mmol) in DMF (0.8 ml) was miss N2.Then was added EDCI (53 mg, 0.28 mmol)and the mixture peremeci the Ali at room temperature over night. Clean yellow syrup (140 mg) radial chromatography on silica gel (EtOAc/MeOH/NH4OH, 100:4:1) yielded the desired amide (75 mg, 55%) as a yellow foam.

Using the common methodology D:The transformation obtained above foam in hydrobromide salt resulted in the receipt of the connectionAMD11036in the form of a pale yellow solid.

1H NMR (D2O) δ 1,80-to 1.98 (m, 1H), 2,13-of 2.28 (m, 5H), was 2.34 (s, 3H), 2,36-2,48 (m, 1H), 2,97-of 3.07 (m, 2H), and 3.72 (d, 1H, J=12.3 Hz), 3,81 (d, 1H, J=12.3 Hz), to 4.01 (s, 2H), 4,43 (d, 1H, J=16.5 Hz), br4.61 (d, 1H, J=is 16.8 Hz), 4,72-rate 4.79 (m, 1H, overlapped with HOD), 6,91 (d, 2H, J=8.1 Hz), 7,14 (d, 2H, J=8.1 Hz), 7,39-7,46 (m, 3H), 7,54-7,58 (m, 2H), to $ 7.91 (DD, 1H, J=7,8, 6,0 Hz), 8,29 (d, 1H, J=6.9 Hz), scored 8.38 (d, 1H, J=8.1 Hz), the rate of 8.75 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 14,97, 18,51, 20,49, 20,92, 27,86, 42,94, 50,21, 56,65, 63,16, 113,84, 126,08, 126,63, 126,90, 127,64, 130,50, 135,53, 135,82, 137,28, 139,63, 139,74, 140,92, 143,06, 146,82, 148,23, 150,90, 151,87, 167,37; ES-MS m/z 547,4 (M+H); elemental analysis: calculated for C33H34N6O2•3,0HBr•2,1H2O•0,3C4H10O: C, 48,36; H, 5,24; N, 9,89; Br, 28,22. Found: C, 48,17; H, 5,41; N, 9,98; Br, 28,48.

EXAMPLE 22

AMD11037:Obtaining N-(3-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-dimethyl-1-oxycotine (hydrobromide salt)

Using the common methodology F:Through a solution of 2,4-dimethyl-1-oxycodonebuy acid (46 mg, 0.28 mmol), (3-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroxy the Lin-8-yl)amine (100 mg, 0.25 mmol), NOT (37 mg, 0.28 mmol) and 4-methylmorpholine (40 μl, 0.38 mmol) in DMF (0.8 ml) was miss N2.Then was added EDCI (53 mg, 0.28 mmol)and the mixture was stirred at room temperature for 3 days. Clean yellow syrup (130 mg) column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:5:1) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:5:1) yielded the desired amide (81 mg, 59%) as a white foam.

Using the common methodology D:The transformation obtained above foam in hydrobromide salt resulted in the receipt of the connectionAMD11037in the form of a white solid.

1H NMR (D2O) δ 1,80-to 1.98 (m, 1H), 2.13 and to 2.35 (m, 8H), 2,36 is 2.51 (m, 1H), 2,99-of 3.07 (m, 2H), of 3.77 (d, 1H, J=12,6 Hz), 3,84 (d, 1H, J=12.9 Hz), of 4.12 (s, 2H), 4,45 (d, 1H, J=16.5 Hz), 4,63 (d, 1H, J=16.5 Hz), 4,79 (m, 1H, overlapped with HOD), 6,77 (d, 1H, J=7.5 Hz), 7,05-7,10 (m, 2H), 7,16 (d, 1H, J=7.8 Hz), was 7.36 (d, 1H, J=6.9 Hz), 7,47-7,51 (m, 2H), 7,56-of 7.60 (m, 2H), to $ 7.91 (DD, 1H, J=8,1, 6,0 Hz), compared to 8.26 (d, 1H, J=6.9 Hz), 8,39 (d, 1H, J=7.8 Hz), a total of 8.74 (d, 1H, J=4.5 Hz);13C NMR (D2O) δ 14,87, 18,35, 20,48, 20,87, 27,85, 43,25, 50,13, 56,80, 62,95, 113,87, 126,10, 126,72, 126,80, 127,21, 129,29, 129,48, 129,57, 130,54, 135,38, 136,97, 137,53, 139,61, 139,67, 140,94, 142,35, 146,65, 148,24, 150,88, 151,78, 167,58; ES-MS m/z 547,4 (M+H); elemental analysis: calculated for C33H34N6O2•2,9HBr•2,2H2O•0,2C4H10O: C, 48,57; H, 5,22; N, 10,06; Br, 27,73. Found: C, 48,65; H, 5,46; N, 10,26; Br, 27,60.

EXAMPLE 23

AMD1084: Obtaining 3-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylamine 4,6-dimethylpyrimidin-5-carboxylic acid

Obtaining the ethyl ester of 4,6-dimethylpyrimidin-5-carboxylic acid

The solution ethyldiazoacetate (8,04 g, to 46.7 mmol) and Cs2CO3(15,93 g, for 48.9 mmol) in CH3CN (82 ml) was cooled to 0°C. Then was added dropwise methyltrichlorosilane (5,3 ml, 46.8 mmol), after adding a bath with ice was removed and the mixture was stirred at room temperature for 3 hours. The mixture was filtered and the salts washed with Et2O (2 x 20 ml). To the filtrate was added Et2O (30 ml), the mixture was filtered and the salts washed with Et2O (2 x 40 ml). The combined filtrate was concentrated to half volume, cooled to 0°in a bath with ice, washed with chilled 2N NaOH solution (pH 11). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure before formation of a yellow suspension. Then added CH2Cl2(100 ml)and the mixture was placed overnight in a refrigerator. The resulting mixture was filtered, and the solid is washed with chilled CH2Cl2. The filtrate was concentrated under reduced pressure to obtain product as a yellow liquid (9.6 g), which was used in the next reaction without further purification.

The solution obtained in the above ethyl ester (3,19 g, 17,13 mmol), ethoxide sodium (21% of the mass. solution in EtOH, 6.4 ml, 17,14 mmol) and formamidine (1.78 g, 17,09 mmol) in EtOH (30 ml) was boiled under reflux for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. Then added CH2Cl2(200 ml) and N2About (15 ml), the phases were separated and the aqueous layer was extracted with CH2Cl2(2 x 50 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification of the crude product as an orange syrup column chromatography on silica gel (hexane/EtOAc, 6:1) resulted in obtaining the desired pyrimidine (2,23 g, 30% two steps) as a yellow syrup.

1H NMR (CDCl3) δ of 1.41 (t, 3H, J=7.2 Hz), to 2.55 (s, 6H), of 4.44 (q, 2H, J=7,2 Hz), 8,96 (s, 1H).

To a solution of ethyl ester of 4,6-dimethylpyrimidin-5-carboxylic acid (2.65 g, 14.7 mmol) in EtOH (20 ml) was added NaOH solution (991 mg, of 24.8 mmol) in N2About (10 ml)and the mixture was stirred at 40°C for 2 hours. The mixture was concentrated under reduced pressure, was added N2O (5 ml)and the mixture was cooled to 0°in a bath with ice. Then was added concentrated HCl (1.3 ml) dropwise with constant stirring. The precipitate was filtered, washed with ice water (2 x 3 ml) and dried on the filter by sucking air is within 20 minutes to obtain a white solid (600 mg), which was used in the next reaction without further purification.

Using the common methodology F:Through a solution of 4,6-dimethylpyrimidin-5-carboxylic acid obtained above (according to the method described in patent application PCT/US00/11632) (42 mg, 0.28 mmol), (3-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (100 mg, 0.25 mmol), NOT (38 mg, 0.28 mmol) and 4-methylmorpholine (40 μl, 0.38 mmol) in DMF (0.8 ml) was miss N2.Then was added EDCI (54 mg, 0.28 mmol)and the mixture was stirred at room temperature overnight. Cleaning colorless syrup (150 mg) column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:2:1) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:2:1) resulted in a compoundAMD11084(80 mg, 60%) as a white foam.

1H NMR (CDCl3) δ 1,64-to 1.77 (m, 1H), 1,91-of 2.08 (m, 2H), 2,18-of 2.34 (m, 1H), is 2.37 (s, 6H), 2,69-only 2.91 (m, 2H), of 3.73 (s, 2H), 3,80 (d, 1H, J=16.5 Hz), 4.00 points (d, 1H, J=16.5 Hz), 4,07 is 4.13 (m, 1H), 4,69 (d, 2H, J=5.7 Hz), 6,53 (t, 1H, J=5.7 Hz), of 6.96-7,10 (m, 3H), 7,16-7,22 (m, 2H), 7,29-7,31 (m, 2H), 7,40 was 7.45 (m, 3H), 8,64 (d, 1H, J=3.6 Hz), 8,81 (s, 1H);I3C NMR (CDCl3) δ 21,71, 22,28, 24,38, 29,55, 44,29, 49,22, 55,11, 61,90, 111,12, 118,82, 121,68, 122,78, 127,32, 128,67, 129,09, 129,24, 130,48, 135,22, 137,66, 137,83, 140,30, 147,22, 156,42, 157,60, 157,91, 163,43, 166,96; ES-MS m/z 532,4 (M+H); elemental analysis: calculated for C32H33N7O•0,4CH2Cl2: C, 68,80; H, OF 6.02; N, 17,33. Nage is about: C 68,56; H, 6,09; N, 17,34.

EXAMPLE 24

AMD9794:Obtaining N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,6-dimethylbenzamide

Using the General technique combination using EDCI F:Interaction (4-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (120 mg, 0.30 mmol), 2,6-dimethylbenzoic acid (50 mg, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), 4-methylmorpholine (49 μl, 0.45 mmol) and EDCI (63 mg, 0.33 mmol) for 4 hours at room temperature with a subsequent column chromatography on silica gel (EtOAc/MeOH/NH4OH, 199:1:1) yielded the desired product (120 mg, 77%) as a white foam.

Using the General methods of education HBr salt D:The transformation obtained above foam in hydrobromide salt resulted in the receipt of the connectionAMD9794in the form of a white powder.

1H NMR (300 MHz, D2O) δ 1,90-of 1.94 (m, 1H), 2,15 (s, 6H), 2,18-of 2.26 (m, 2H), 2,41 (CL, 2H), 3.00 and was 3.05 (m, 2H), 3,66 (d, 1H, J=12.3 Hz), of 3.77 (d, 1H, J=12,6 Hz), 4,01-4,07 (m, 2H), to 4.41 (d, 1H, J=16.5 Hz), 4,50 (d, 1H, J=is 16.8 Hz), 4,72-of 4.75 (m, 1H), 6,92 (d, 2H, J=7.5 Hz), 7,09-7,14 (m, 4H), 7.23 percent-7,28 (m, 3H), 7,52 (DD, 1H, J=5,7, and 3.3 Hz), to $ 7.91-of 7.96 (t, 1H), 8,40 (d, 1H, J=7.8 Hz), 8,76 (d, 1H, J=5.4 Hz);13C NMR (75.5 MHz, D2O) δ 18,68 (2C), 20,47, 20,94, 27,85, 42,75, 50,20, 56,63, 63,17, 113,79, 126,11, 126,48, 127,87, 129,83, 130,45, 134,60, 135,61, 136,34, 137,74, 139,63, 140,90, 148,25, 150,83, 151,89, 173,13; ES-MS m/z 530 (M+H); cell battery (included) the fair analysis: calculated for C 34H35N5O•0,1C4H10O•1,5H2O•2,1HBr: C, 56,29; H, 5,64; N, 9,54; Br, 22,86. Found: C, 56,47; H, 5,62; N, 9,52; Br, 22,68.

EXAMPLE 25

AMD9842:Obtaining N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

Using General method for the reaction combination with EDCI F:Interaction (4-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (105 mg, 0.26 mmol), 3,5-dichlorophenylamino acid (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (36 mg, 0.26 mmol), 4-methylmorpholine (100 μl, 0.89 mmol) and EDCI (51 mg, 0.26 mmol) for 2 days at room temperature with a subsequent column chromatography on silica gel (MeOH-NH4OH-CH2Cl2, 1:1:98) resulted in a compoundAMD9842(42 mg, 28%) as a white foam.

1H NMR (CDCl3) δ 1,68-of 1.74 (m, 1H), 1,94-2,05 (m, 2H), 2,16 was 2.25 (m, 1H), 2,69 is 2.75 (m, 1H), 2,81-is 2.88 (m, 1H), 3,70 (s, 2H), 3,78-a 3.83 (m, 1H), a 4.03-4.09 to (m, 2H), 5,54 (DD, 2H, J=4,5, 4,5 Hz), 7,02 for 7.12 (m, 3H), 7,17-7,21 (m, 3H), 7,34 (d, 2H, J=8.1 Hz), 7,44 (d, 2H, J=7.5 Hz), 7,50 (d, 1H, J=7.8 Hz), 8,31-8,35 (m, 2H), 8,68 (d, 1H, J=3,9 Hz);13C NMR (CDCl3) δ 21,76, 23,87, 29,59, 44,13, 48,78, 54,26, 61,05, 111,30, 118,84, 121,62, 122,06, 122,74, 128,61, 129,43, 133,96, 135,16, 136,24, 137,72, 139,41, 142,90, 144,35, 147,31, 147,72, 156,49, 157,64, 162,39; ES-MS m/z 571,6 (M+H); elemental analysis: calculated for (C31H28N6Cl2O)&x02022; 0,5(CH2Cl2)•0,5(H2O): C, 60,73; H, Is 4.85; N, 13,49; Cl, 17,07. Found: C, 60,60; H, 4,96; N, 13,13; Cl, 17,46.

EXAMPLE 26

AMD11034:Obtaining N-(3,5-dichlorosalicylic)-N-(1H-benzimidazole-2-ylmethyl)-N-(S)-5,6,7,8-tetrahydroquinolin-8-yl-1,4-benzilpenetsillina (cleaners containing hydrochloride salt)

Getting 3,5-dichloro-N-(4-formylmethyl)isonicotinamide

To a stirred, cooled (0° (C) to a solution of 4-cyanobenzaldehyde (3,47 g of 26.5 mmol) in anhydrous THF (150 ml) portions was added LAH (6.0 g, 160 mmol). The suspension was stirred in an atmosphere of N2at 60°C for 24 hours. After cooling to room temperature, the reaction gradually extinguished with distilled water (6 ml), then 15% (wt./about.) NaOH (6 ml), then with distilled water (18 ml). The mixture was stirred for 20 minutes, diluted with diethyl ether (200 ml), and white flocculent precipitate was removed by filtration. The filtrate was dried (MgSO4) and concentrated in vacuum. The resulting aminoplast (2,78 g) was used in the next reaction without further purification.

To the solution obtained above amine (1.75 g, 12.8 mmol) in DMF (13 ml) was added 3,5-dichlorophenylamino acid (2,04 g, 10.6 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (a 4.03 g, 21,0 mmol), 1-hydroxybenzotriazole (2,84 g, 21,0 mmol), 4-methylmorpholine (7.9 ml, 71,8 mmol). The reaction mixture was stirred at 50°C ATA is osphere N 2for 65 hours, then concentrated in vacuo. The residue was distributed between chloroform (100 ml) and a saturated solution of NH4Cl (100 ml). The aqueous layer was extracted with chloroform (2 x 100 ml), the combined organic extracts were dried (MgSO4) and concentrated in vacuum. The obtained orange oil (6,84 g) was purified on a flash chromatography column on silica gel (5 cm inner diameter, 140 g of silica gel, 5% Meon/CH2Cl2) to give the desired alcohol (1,33 g, 30% two steps).

The above alcohol (1,33 g, 68 mmol) in 10% Meon/CH2Cl2(50 ml) was treated with MnO2(5.9 g, 68 mmol) and boiled under reflux in an atmosphere of N2within 32 hours. The resulting suspension was cooled, filtered and concentrated in vacuum to obtain pure indicated in the title compound (1.20 g, 91%).

1H NMR (CDCl3) δ 4,79 (d, 2H, J=6,1 Hz), 6,13 (SHS, 1H), to 7.59 (d, 2H, J=8,3 Hz), of 7.90 (d, 2H, J=8,3 Hz), 8,56 (s, 2H), there is a 10.03 (s, 1H).

Using the General methods:Obtained above 3,5-dichloro-N-(4-formylmethyl)isonicotinamide (1.28 g, 4.1 mmol) was subjected to interaction with S-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,80 g, 5.4 mmol) and NaBH(OAc)3(2.65 g, 12.5 mmol) in dichloromethane (80 ml). Flash chromatography (5 cm inner diameter column, 80 g silica gel, 5% Meon/CH2Cl2) resulted in obtaining pure solid pale yellow what about the color (1,74 g, 95%).

To the solution obtained above amine (1,74 g, 3.9 mmol) in a mixture of acetonitrile (40 ml) and chloroform (10 ml) was added diisopropylethylamine (1 ml, 5.8 mmol), 1-boc-2-chloromethylbenzene (1.35 g, 5.0 mmol) and potassium iodide (66 mg, 0.40 mmol). The mixture was stirred in an atmosphere of N2at 60°C for 16 hours, cooled to room temperature and concentrated in vacuum. The residue was distributed between dichloromethane (100 ml) and saturated salt solution (100 ml). The separated organic layer was dried (MgSO4), was concentrated to the formation of the product as a brown oil (3.5 g) and purified flash chromatography (column, 5 cm internal diameter, 100 g of silica gel, elution CH2Cl2to remove unreacted chloride, then 5% MeOH/CH2Cl2to scroll to the desired product) to give the pure desired boc-protected amine in the form of a frothy pale yellow solid (2,36 g, 89%).

The result of the above amine (2,32 g of 3.45 mmol) was dissolved in glacial acetic acid (10 ml) and stir the solution was passed gaseous HCl for 10 minutes. The solution was left to mix at room temperature for an additional 30 minutes, then diluted glacial acetic acid (10 ml) and slowly added dropwise was poured into diethyl ether (500 ml) with vigorous stirring. The resulting suspension f is literaly through a filter with a porous glass plate with suction, the filter cake was washed with diethyl ether (100 ml) and dried in a vacuum Cabinet at 40°C for 65 hours with obtaining connectionAMD11034in the form of a white solid(2,05 g, 88%).

1H NMR (D2O) δ 1,81-of 1.95 (m, 1H), 2,19-of 2.36 (m, 2H), 2,41-2,49 (m, 1H), 2,97-3,11 (m, 2H), of 3.77-a-3.84 (m, 2H), 4,10 (s, 2H), 4,43 (d, 1H, J=16,3 Hz), 4,60 (d, 1H, J=16,3 Hz), 4,68-4,78 (m, 1H), 6,95 (d, 2H, J=7,8 Hz), 7,14 (d, 2H, J=7.8 Hz), 7,42-7,46 (m, 2H), 7,56-to 7.59 (m, 2H), of 7.90 (t, 1H, J=5.7 Hz), of 8.37 (d, 1H, J=7.8 Hz), 8,58 (s, 2H), 8,72 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,48, 20,87, 27,83, 42,74, 50,26, 56,61, 63,18, 113,85 (2 carbon), 126,02, 126,60 (2 carbon), 127,46 (2 carbon), 129,12, 130,35 (2 carbon), 130,64, 135,74, 137,15, 139,60, 10 140,86, 147,79 (2 carbon), 148,12, 150,98, 151,91; ES-MS m/z 571 (M+H); elemental analysis: calculated for C31H28N6Cl2O•2,0HCl•1,8H2O: C, 55,01; H; 5,00; N, 12,42; Cl, 20,95. Found: C, 55,11; H, The 4.90; N, 12,36; Cl, 20,86.

The enantiomeric purity of theAMD11034was defined as 100% by chiral chromatography using the following conditions: Equipment: Hewlett Packard 1100 HPLC (VWD2); Column: Chiralpak AD, and 0.46 cm x 25 cm; Mobile phase: a: 90:10 hexane/isopropanol with 0.1%DEA, b: isopropanol; Trim: 97% A, 3% B; Total time: 25 min; flow Rate: 2.0 ml/min; Temperature: 5°C; Detector: UV @ 254 nm; Injected volume: 10 μl.

Retention time for the S enantiomer = 13,0 minutes

Retention time for the R enantiomer = 15,5 minutes

EXAMPLE 27

AMD9853:N-(4-{[ (1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)for 3,5-dibromosalicylic (hydrobromide salt)

The interaction of 3,5-dibromosalicylic acid (73 mg, 0.26 mmol), thionyl chloride (2 ml) by boiling under reflux for 1 hour, followed by the interaction of the corresponding acylchlorides, (4-aminomethylbenzoic)-(1H-benzimidazole)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (103 mg, 0.26 mmol), Et33N (0,50 ml, 3.46 mmol) and catalytic amount of DMAP for 3 hours at room temperature resulted in the receipt of crude product as a yellow oil. The crude substance was purified column chromatography on silica gel (CH2Cl2-MeOH-NH4OH, 98:1:1) to obtain the specified title compound (67 mg, 39%) as a white foam.

Using the common methodology D:The transformation obtained above foam (67 mg, 0.10 mmol) in hydrobromide salt using a solution of acetic acid/HBr with the following presidenial salt of diethyl ether resulted in the receipt of the connectionAMD9853in the form of a white solid.

1H NMR (CD3OD) δ 1,96 (SHS, 1H), 2,25-is 2.37 (m, 2H), 2,45 (SHS, 1H), 3,06 (CL, 2H), 3,80-of 3.85 (m, 2H), 4,18 (CL, 2H), 4,47 (d, 1H, J=16.2 Hz), and 4.68 (d, 1H, J=16.2 Hz), 4,77-4,82 (m, 1H), 7,13 (d, 2H, J=7.5 Hz), 7,45 (d, 2H, J=7.8 Hz), 7,55-7,58 (t, 2H), 7,76-7,79 (m, 2H), 7,93-of 7.97 (m, 1H), 8,40 (d, 1H, J=7.8 Hz), to 8.70 (s, 2H), to 8.94 (d, 1H, J=5.4 Hz);13C NMR (CD 3OD) δ 21,97, 29,24, 43,94, 50,85, 57,71, 62,75, 115,28, 119,66, 127,21, 128,02, 129,16, 131,94, 132,28, 136,55, 139,46, 141,64, 141,89, 148,53, 149,24, 151,84, 152,19, 152,93, 166,75; ES-MS m/z 661,3 (M+H); elemental analysis: calculated for (C31H28Br2N6O)•2,0(HBr)•1,3H2O: C, 43,61; H, 3,86; N, 9,84; Br, 38,37. Found: C, 43,69; H, Of 3.80; N, 9,70; Br, 38,22.

EXAMPLE 28

AMD9862:Obtaining 2-amino-N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-6-chlorobenzamide

Using the General technique combination using EDCI F:Interaction (4-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (100 mg, 0.25 mmol), 2-chloro-6-aminobenzoic acid (43 mg, 0.25 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), 4-methylmorpholine (38 μl, 0.35 mmol) and EDCI (48 mg, 0.25 mmol) for 4 hours at room temperature with a subsequent column chromatography on silica gel (EtOAc/MeOH/NH4OH, 199:1:1) resulted in a compoundAMD9862(90 mg, 65%) as a white foam.

1H NMR (300 MHz, CD3OD) δ 1,66 was 1.69 (m, 1H), 2,01-of 2.09 (m, 2H), 2,25 (SHS, 1H), 2,78-2,89 (m, 2H), 3,55-the 3.65 (m, 2H), 3,97 (d, 1H, J=15.3 Hz), 4,08 is 4.13 (m, 2H), 4,37 (s, 2H), 6,85 (d, 2H, J=7.8 Hz), 7,22-7,29 (m, 3H), of 7.36 (d, 2H, J=8.1 Hz), 7,43-7,47 (m, 1H), 7,50 (d, 2H, J=8.1 Hz), 7,62-the 7.65 (m, 2H), of 7.75 (d, 1H, J=7.8 Hz), 8,79-8,81 (m, 1H);13C NMR (75.5 MHz, CD3OD) δ 22,83, 24,34, 30,62, 44,55, 51,36, 56,17, 63,17, 115,72, 119,07, 123,04, 123,51, 124,05, 128,92, 130,79, 132,13, 132,70, 137,39, 138,62, 139,54, 13963, 148,36, 148,76, 156,41, 158,27, 169,43; ES-MS m/z 551 (M+H); elemental analysis: calculated for C32H31ClN6O•0,8(H2O): C, 67,97; H, Of 5.81; N, 14,86; Cl, 6,27. Found: C, 68,07; H, By 5.87; N, 14,87; Cl, 6.42 Per.

EXAMPLE 29

AMD11028:Getting 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylamine 4,6-dimethylpyrimidin-5-carboxylic acid

Using General method for the reaction combination with EDCI F:Interaction (4-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (100 mg, 0.25 mmol), 4,6-dimethylpyrimidin-5-carboxylic acid (42 mg, 0.28 mmol), 1-hydroxybenzotriazole (38 mg, 0.28 mmol), 4-methylmorpholine (39 μl, 0.35 mmol) and EDCI (54 mg, 0.28 mmol) for 24 hours at room temperature with a subsequent column chromatography on silica gel (EtOAc/MeOH/NH4OH, 98:1:1) resulted in a compoundAMD11028(101 mg, 76%) as a white foam.

1H NMR (300 MHz, CDCl3) δ 1,71-to 1.98 (m, 1H), 2,02-2,05 (m, 2H), 2,24 to 2.35 (m, 1H), 2,41 (s, 6H), 2,70-of 2.86 (m, 2H), 3,70 (s, 2H), 3,84 (d, 1H, J=16.5 Hz), a 4.03-4,11 (m, 2H), 4,47-4,50 (m, 2H), 6,54-to 6.57 (m, 1H), 7,07 (SHS 2H), 7,14 (d, 2H, J=7.8 Hz), 7,17-7,27 (m, 1H), 7,35 (d, 2H, J=7.8 Hz), 7,43-7,46 (m, 3H), 8,68 (d, 1H, J=3.0 Hz), 8,83 (c, 1H);13C NMR (75.5 MHz, CDCl3) δ 21,74, 22,36, 23,99, 29,59, 44,18, 48,97, 54,36, 61,36, 111,30, 118,85, 121,85, 122,77, 128,48, 129,67, 130,48, 135,22, 136,42, 137,79, 139,51, 147,28, 156,48, 157,60, 157,93, 163,47, 167,01; ES-MS m/z 532 (M+H); elemental and the Alize: calculated for C32H33N7O•1,6H2O: C, 68,58; H, 6,51; N, 17,49. Found: C, 68,64; H, 6,44; N, 17,64.

EXAMPLE 30

AMD9593:Obtaining 1-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-3-phenylacetone (hydrobromide salt)

To a cooled (0° (C) the solution of (4-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,136 g, 0.34 mmol) in CH2Cl2(3.5 ml) was added phenylisocyanate (41 μl, 0.38 mmol)and the resulting solution was stirred for 50 minutes. Bath for cooling was removed and the mixture was concentrated under reduced pressure. Purification of the crude substances column chromatography on silica gel (CH2Cl2-CH3OH-NH4OH, 25:1:1) resulted in the receipt of free base specified in the connection header (to 0.127 g, 72%) as a white solid.

Using the common methodology D:Conversion of the free base (127 mg) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether resulted in the receipt of the connectionAMD9593(139 mg) as a white solid.

1H NMR (D2O) δ 1,79-of 1.93 (m, 1H), 2,16-of 2.28 (m, 2H), 2,35-to 2.42 (m, 1H), 3.00 and (CL, 2H), 3,65 (d, 1H, J=12.3 Hz), to 3.73 (d, 1H, J=12.3 Hz), 3,79 (s, 2H) to 4.38 (d, 1H, J=16.5 Hz), to 4.62 (d, 1H, J=16.5 Hz), 4,66-4,71 (m, 1H), at 6.84 (d, 2H, J=7.8 Hz), 7,05 (d 2H, J=7.8 Hz), 7,09-7,14 (t, 1H), 7,25 (d, 2H, J=7.8 Hz), 7,32-7,40 (m, 4H), 7,50 (CL, 2H), 7,87 (DD, 2H, J=6,6 and 6.9 Hz), a 8.34 (d, 1H, J=7.8 Hz), 8,69 (d, 1H, J=5.4 Hz);13C NMR (D2O) δ 20,44, 20,80, 27,79, 42,77, 50,25, 56,49, 63,07, 113,68, 121,31, 124,32, 126,00, 126,56, 127,33, 129,70, 130,22, 130,45, 135,09, 138,56, 139,51, 140,81, 148,14, 150,91, 151,74, 158,00; ES-MS m/z 517 (M+H); elemental analysis: calculated forC32H32N6O•2,3HBr•1,4H2O: C, 52,80; H, 5,14; N, 11,54; Br, 25,25. Found: C, 52,76; H, 5,19; N, 11,30; Br, 25,30.

EXAMPLE 31

AMD9594:Obtaining 1-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-3-benzyladenine (hydrobromide salt)

To a cooled (0° (C) the solution of (4-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,130 g, 0.33 mmol) in CH2Cl2(3.5 ml) was added benzylsuccinic (45 μl, 0.36 mmol)and the resulting solution was stirred for 100 minutes. Bath for cooling was removed and the mixture was concentrated under reduced pressure. Purification of the crude substances column chromatography on silica gel (CH2Cl2-CH3OH-NH4OH, 25:1:1) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2-CH3OH-NH4OH, 25:1:1) resulted in the receipt of free base specified in the connection header (0,047 g, 28%) as a white solid.

Use common IU Tiki D: Conversion of the free base (47 mg) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether resulted in the receipt of the connectionAMD9594(49 mg) as a white solid.

1H NMR (D2O) δ 1,79 is 1.96 (m, 1H), 2,18-of 2.30 (m, 2H), 2,38 (SHS, 1H), 3.00 and (CL, 2H), 3,66 of 3.75 (m, 4H), 4,25 (s, 2H), and 4.40 (d, 1H, J=16.5 Hz), of 4.57 (d, 1H, J=16.5 Hz), 4,68-to 4.73 (m, 1H), 6,76 (d, 2H, J=7.5 Hz), 7.03 is (d, 2H, J=7.5 Hz), 7.24 to 7,51 (m, 9H), 7,87 (DD, 1H, J=7,2, 6.3 Hz), a 8.34 (d, 1H, J=7.8 Hz), 8,67 (d, 1H, J=5.4 Hz);I3C NMR (D2O) δ 20,45, 20,78, 27,98, 42,92, 43,78, 50,24, 56,48, 63,01, 113,75, 125,98, 126,58, 127,00, 127,26, 127,62, 129,13, 130,15, 130,48, 135,02, 139,50, 139,70, 139,90, 140,80, 148,11, 150,93, 151,76, 160,44; ES-MS m/z 531 (M+H); elemental analysis: calculated forC32H34N6O•2,5HBr•3,0H2O: C, 50,36; H, 5,44; N Is 10.68; Br, 25,38. Found: C, 50,19; H, 5,26; N, 10,41; Br, 25,56.

EXAMPLE 32

AMD9547:Getting 6-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-6,7-dihydropyrrolo[3,4-b]pyridine-5-it (hydrobromide salt)

Obtaining 3-carboethoxy-2-pyridinecarboxamide

To a stirred solution of 2-methylnicotinate (1,657 g, 10.0 mmol) in a mixture of 1,4-dioxane (10 ml) and water (1 ml) was added selenium dioxide (while 1,568 g, 14.1 mmol)and the resulting mixture is boiled under reflux during the night. The reaction mixture was cooled to room temperature and the concentration of Aravali under reduced pressure. The residue was purified column chromatography on silica gel (hexane/ethyl acetate, 3:1) and has been specified in the header connection (0,90 g, 50%) as a yellow oil.

1H NMR (CDCl3) δ of 1.41 (t, 3H, J=7.5 Hz), of 4.45 (q, 2H; J=7.5 Hz), 7,56 (DD, 1H, J=6,0, 6,0 Hz), 8,11 (DD, 1H, J=6,0, 1.0 Hz), 8,87 (DD, 1H, J=6,0, 1.0 Hz), 10,34 (s, 1H).

Using the General methods:The interaction of 3-carboethoxy-2-pyridinecarboxamide (0,210 g at 1.17 mmol) and (4-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,472 g, 1.18 mmol) with NaBH(OAc)3(0,507 g, 2,39 mmol) in CH2Cl2(12 ml) for 75 minutes, followed by purification of the crude substances column chromatography on silica gel (CH2Cl2-CH3OH-NH4OH, 40:1:1) and then by radial chromatography on silica gel (2 mm plate, CH2Cl2-CH3OH-NH4OH, 100:1:1) resulted in the receipt of free base specified in the connection header (0,396 g, 65%) as a white solid.

Using the common methodology D:Conversion of the free base (56 mg) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether resulted in the receipt of the connectionAMD9547(61 mg) as a white solid.

1H NMR (D2O) δ 1,81-of 1.95 (m, 1H), 2,19 of-2.32 (m, 2H), 2.40 a is 2.46 (m, 1H), 3,03 (CL, 2H), 3,70 (d, 1H, J=12,6 Hz), 3,80 (d, 1H, J=12,6 Hz) to 4.14 (d, 2H, J=3.3 Hz) or 4.31 (s, 2H), of 4.44 (d, 1H, J=16,8 Hz), to 4.62 (d, 1H, J=16,8 Hz), 4,73-4,80 (m, 1H, overlapped with HOD), 6,92-6,98 (m, 4H), 7,16 (d, 2H, J=8.1 Hz), 7,39 (DD, 2H, J=of 3.0, 6.0 Hz), to 7.77 (DD, 1H, J=5,4, and 7.8 Hz), 7,92 (DD, 1H, J=5,4, 7,8 Hz), 8,32 (d, 1H, J=7.8 Hz), 8,39 (d, 1H, J=7.8 Hz), 8,76 (d, 1H, J=5.7 Hz), 8,82 (d, 1H, J=5,1 Hz);13C NMR (D2O) δ 20,44, 20,97, 27,85, 45,99, 50,42, 51,23, 56,73, 63,50, 113,41, 125,30, 126,10, 127,59, 128,66, 130,23, 130,68, 135,30, 135,83, 136,11, 139,65, 141,02, 148,28, 150,66, 150,84, 152,02, 160,43, 167,55; ES-MS m/z 515 (M+H); elemental analysis: calculated for C32H30N6O • 3,1HBr • 2,8H2O: C, 47,11; H, 4,78; N, 10.30 A.m.; Br, 30,36. Found: C, 46,98; H, 4,60; N, 10,07; Br, 30,65.

EXAMPLE 33

AMD9933:Obtaining N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-7-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

Obtain tert-butyl ether {4-[(5,6,7,8-tetrahydroquinolin-7-ylamino)methyl]benzyl}carbamino acid

Using the General methods:Interaction tert-butyl ester (4-formylmethyl)carbamino acid (356 mg and 1.51 mmol), 5,6,7,8-tetrahydroquinolin-7-ylamine (224 mg and 1.51 mmol) in anhydrous Meon (5 ml) at room temperature overnight in an atmosphere of N2and stirring for 2 minutes after the addition of sodium borohydride (115 mg, 3.00 mmol), and subsequent purification of the crude substances by chromatography on silica gel (CH3OH-NH3H2O-CH2 Cl2, 2:2:96) resulted in obtaining specified in the header of the compound (556 mg, 100%) as a white foam.

Obtain tert-butyl ester 2-{[[4-(tert-butoxycarbonylamino)benzyl]-(5,6,7,8-tetrahydroquinolin-7-yl)amino]methyl}benzimidazole-1-carboxylic acid

Tert-butyl ether {4-[(5,6,7,8-tetrahydroquinolin-7-ylamino)methyl]benzyl}carbamino acid (88 mg, 0.24 mmol), tert-butyl ester 2-chloromethylbenzene-1-carboxylic acid (80 mg, 0.30 mmol), DIPEA (0.10 ml, 0.54 mmol) and KI (19 mg, 0.11 mmol) was heated at 80°in CH3CN (1.5 ml) for 2 hours in an atmosphere of N2then the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuum, diluted with ethyl acetate, washed with NH4Cl (aqueous solution), NaCl (aqueous solution) and dried (MgSO4). Evaporation of the solvent and purification of the residue flash-chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 1:1:98) resulted in obtaining specified in the title compound (80 mg, 56%) as a white foam.

Receive (4-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-7-yl)amine

To a stirred solution of tert-butyl methyl ether 2-{[[4-(tert-butoxy erboneliner)benzyl] -(5,6,7,8-tetrahydroquinolin-7-yl)amino]methyl}benzimidazole-1-carboxylic acid (120 mg, 0.20 mmol) in anhydrous CH2Cl2(1 ml) was added TFU (1 ml). The solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, dissolved using Meon and added NaHCO3. The mixture was stirred for 20 minutes, diluted with CH2Cl2was filtered through celite. The crude product was purified flash chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 2:2:96), which resulted in the receipt specified in the title compound (71 mg, 89%) as a white foam.

Using the General technique combination using EDCI F:Interaction (4-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-7-yl)amine (71 mg, 0.18 mmol), 3,5-dichlorophenylamino acid (75%, 48 mg, 0.18 mmol), 1-hydroxybenzotriazole (25 mg, 0.18 mmol), 4-methylmorpholine (60 μl, of 0.53 mmol) and EDCI (34 mg, 0.18 mmol) for 2 days at 50°and subsequent column chromatography on silica gel (MeOH-NH4OH-CH2Cl2, 1:1:98) resulted in a compoundAMD9933(29 mg, 28%) as a white powder.

1H NMR (CDCl3) δ 1,72 (SHS, 1H), 2,18-of 2.24 (m, 1H), 2,74 of 2.92 (t, 2H), 3,02-3,19 (t, 3H), 3,70 (d, 1H, J=13.5 Hz), 3,83 (d, 1H, J=13.5 Hz), 3,94-of 4.05 (t, 2H), 4,57 (d, 2H, J=5.4 Hz), 6,47 (SHS, 1H), 7,00-7,08 (t, 3H), 7,21 was 7.36 (t, 6N), 7,56-to 7.59 (t, 1H), 8,31 (d, 1H, J=3.3 Hz), 8,48 (who, 2H), 9,59 (s, 1H);13C NMR (CDCl3) δ 24,73, 28,40, 35,98, 43,92, 49,16, 55,11, 57,07, 110,99, 119,39, 121,76, 122,20, 122,85, 128,55, 129,41, 131,78, 133,85, 136,51, 136,95, 139,03, 142,88, 143,55, 147,26, 147,91, 154,08, 156,03, 162,48; ES-MS m/z 571,2 (M+H); elemental analysis: calculated for (C31H28N6Cl2O)•0,1(CH2Cl2)•0,3(H2O): C, Expenses 63.81; H, 4,96; N, 14,36; Cl, 13,32. Found: C, 63,85; H, 5,02; N, 14.24 From; Cl, 13,47.

EXAMPLE 34

AMD9958:3,5-Dichloro-N-{4-[(5,6,7,8-tetrahydroquinolin-7-ylamino)methyl]benzyl}isonicotinamide

Obtain tert-butyl ester (4-{[(2-nitrobenzenesulfonyl)-(5,6,7,8-tetrahydroquinolin-7-yl)amino]methyl}benzil)carbamino acid

Interaction tert-butyl ether {4-[(5,6,7,8-tetrahydroquinolin-7-ylamino)methyl]benzyl}carbamino acid (98 mg, 0.27 mmol), NsCl (67 mg, 0.29 mmol), DIPEA (0.10 ml, 0.54 mmol) in anhydrous CH2Cl2for 3 hours at room temperature with a subsequent column chromatography on silica gel (MeOH-NH4OH-CH2Cl2, 1:1:98) resulted in obtaining specified in the title compound (70 mg, 47%) as a yellow foam.

Obtain N-(4-aminomethylbenzoic)-2-nitro-N-(5,6,7,8-tetrahydroquinolin-7-yl)benzosulfimide

To a stirred solution of tert-butyl methyl ether (4-{[(2-nitro is endolsulfan)-(5,6,7,8-tetrahydroquinolin-7-yl)amino] methyl}benzil)carbamino acid (160 mg, 0.29 mmol) in anhydrous CH2Cl2(2 ml) was added TFU (2 ml). The solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, dissolved Meon and added NaHCO3. The mixture was stirred for 20 minutes, diluted with CH2Cl2was filtered through celite. The crude product was purified flash chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 1:1:98), which resulted in the receipt specified in the title compound (75 mg, 57%) as a white foam.

Getting 3,5-dichloro-N-(4-{[(2-nitrobenzenesulfonyl)-(5,6,7,8-tetrahydroquinolin-7-yl)amino]methyl}benzyl)isonicotinamide

Using General method for the reaction combination with EDCI F:The interaction of N-(4-aminomethylbenzoic)-2-nitro-N-(5,6,7,8-tetrahydroquinolin-7-yl)benzosulfimide (75 mg, 0,17 mmol), 3,5-dichlorophenylamino acid (75%, 55 mg, 0.22 mmol), 1-hydroxybenzotriazole (23 mg, 0,17 mmol), 4-methylmorpholine (100 μl, 0.89 mmol) and EDCI (32 mg, 0,17 mmol) for two days at 50°and subsequent column chromatography on silica gel (MeOH-NH4OH-CH2Cl2, 1:1:98) resulted in obtaining specified in the title compound (42 mg, 40%) as a yellow foam.

Using the General method of removing nasilsin groups: The interaction of 3,5-dichloro-N-(4-{[(2-nitrobenzenesulfonyl)-(5,6,7,8-tetrahydroquinolin-7-yl)amino]methyl}benzyl)isonicotinamide (42 mg, 0.07 mmol), thiophenol (0.10 ml, 0.97 mmol) and K2CO3(269 mg, of 1.95 mmol) in DMF (2 ml) at room temperature in an atmosphere of N2followed by purification of the crude substances by chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 2:2:96) resulted in a compoundAMD9958(15 mg, 51%) as a white foam.

1H NMR (CDCl3) δ 1,57 is 1.70 (m, 2H), 2,01-to 2.06 (m, 1H), 2,60-2,89 (m, 3H), 3.00 and-3,13 (m, 2H), 3,83 (s, 2H), of 4.66 (d, 2H, J=5.7 Hz), 7,00 (DD, 2H, J=4,8, 7.5 Hz), 7,30-7,37 (m, 5H), 8,23 (d, 1H, J=3,9 Hz), 8,46 (s, 2H,);13C NMR (CDCl3) δ 26,48, 28,80, 39,42, 43,70, 50,69, 52,39, 121,16, 127,68, 128,27, 128,55, 129,02, 131,47, 135,75, 136,46, 140,19, 142,35, 146,79, 147,65, 155,51, 162,04; ES-MS m/z 441,5 (M+H); elemental analysis: calculated for (C23H22N4Cl2O)•0,5(CH4O): C, 61,71; H, FROM 5.29; N, 12,25. Found: C, 61,71; H, 5,24; N, 12,24.

EXAMPLE 35

AMD11072:N-(4-{2-[(1H-Benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]ethyl}benzyl)3,5-dichlorosalicylic

Obtaining 2-(4-aminomethylphenol)ethanol

To a stirred solution of NH3/EtOH (170 ml) was added (4-bromomethylphenyl)acetic acid (1,61 g, 7,01 mmol). The solution was stirred at room temperature for 2 h the owls. The mixture was concentrated in vacuo and re-dissolved in anhydrous THF (10 ml). To the solution was added BH3.Me2S and the mixture was stirred for 1 hour at 70°and at room temperature for 2 days. The reaction mixture was concentrated under vacuum, was added 6N HCl (10 ml) and the mixture was stirred at 70°C for 1 hour. Then added water (20 ml)and the solution was neutralized 1N NaOH to pH ˜7. The solution was concentrated to dryness in high vacuum, washed with MeOH/CH2Cl2and filtered. The crude product was purified flash chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 5:3:92) to obtain the specified title compound (820 mg, 77%) as a white foam.

Getting 3,5-dichloro-N-[4-(2-hydroxyethyl)benzyl]isonicotinamide

Using the General technique combination using EDCI F:The interaction of 2-(4-aminomethylphenol)ethanol (306 mg, 2.03 mmol), 3,5-dichlorophenylamino acid (385 mg, 2.03 mmol), 1-hydroxybenzotriazole (301 mg, 2.22 mmol), 4-methylmorpholine (0,50 ml of 4.45 mmol) and EDCI (426 mg, 2.22 mmol) in anhydrous DMF (5 ml) over night at room temperature and overnight at 40°and subsequent column chromatography on silica gel (MeOH-NH4OH-CH2Cl2, 2:2:96) resulted in obtaining specified in the title compound (291 mg, 44%) as white is th foam.

Getting 3,5-dichloro-N-[4-(2-oxoethyl)benzyl]isonicotinamide

To a stirred solution of 3,5-dichloro-N-[4-(2-hydroxyethyl)benzyl]isonicotinamide (105 mg, 0.32 mmol) in anhydrous CHCl2(2.4 ml) was added periodan dess-Martin (206 mg, 0.48 mmol). The solution was stirred at room temperature for 1 hour. The mixture was diluted with 100 ml of CH2Cl2was filtered through celite and concentrated in vacuum. The crude product (74 mg, 71%) was used in the next stage without further purification.

Obtain tert-butyl ester 2-{[[2-(4-{[(3,5-dichloropyridine-4-carbonyl)amino]methyl}phenyl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazole-1-carboxylic acid

Using the General methods of restoration amination At:Interaction tert-butyl ester 2-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzimidazole-1-carboxylic acid (74 mg, 0.20 mmol), 3,5-dichloro-N-[4-(2-oxoethyl)benzyl]isonicotinamide (53 mg, 0.16 mmol) and NaBH(OAc)3(44 mg, 0.20 mmol) overnight at room temperature with a subsequent column chromatography on silica gel (CH2Cl2-MeOH-NH4OH, 98:1:1) resulted in the receipt specified in the title compound (99 mg, 88%) in view of the white foam.

To a stirred solution of tert-butyl methyl ether 2-{[[2-(4-{[(3,5-dichloropyridine-4-carbonyl)amino]methyl}phenyl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazole-1-carboxylic acid (99 mg, 0.14 mmol) in anhydrous CH2Cl2(1 ml) was added TFU (1 ml). The solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, dissolved in Meon and added NaHCO3. The mixture was stirred for 20 minutes, diluted with CH2Cl2was filtered through celite. The crude product was purified flash chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 2:2:96) to obtain the connectionAMD11072(50 mg, 59%) as a pale yellow foam.

1H NMR (CDCl3) δ 1,67-of 1.73 (m, 1H), 1,84-of 1.95 (m, 1H), 2,01-2,05 (m, 1H), 2,17-of 2.24 (m, 1H), 2,65-to 3.02 (m, 6H), 3,99-to 4.14 (m, 3H), br4.61 (d, 2H, J=5.7 Hz), 6,13 (SHS, 1H), 6,99 (d, 2H, J=7.8 Hz), 7,06-7,17 (m, 5H), 7,38-7,44 (m, 2H), to 7.61 (d, 1H, J=8.1 Hz), charged 8.52 (MS, 3H);13C NMR (CDCl3) δ 21,79, 24,64, 29,51, 35,64, 43,87, 49,72, 52,89, 62,70, 114,04, 118,22, 121,99, 122,67, 127,78, 128,29, 129,43, 134,98, 135,34, 137,87, 139,86, 142,94, 146,89, 147,84, 156,88, 157,54, 162,54; ES-MS m/z 585,5 (M+H); elemental analysis: calculated for (C32H30N6Cl2O)•0,3(CH2Cl2)•0,3(H2O): C, 62,94; H, 5,10; N, 13,63; Cl, 14,95. Found: C, 63,17; H, 5,14; N, 13,68; Cl, 14,64.

EXAMPLE 36

AMD9702:3-{[(1H-Benzimidazole-2-ylmethyl)-(5,67,8-tetrahydroquinolin-8-yl)amino] methyl}benzylated pyridine-2-carboxylic acid (hydrobromide salt)

Using the General technique combination using EDCI F:Interaction (3-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (133 mg, 0.33 mmol), pikolinos acid (40 mg, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), DIPEA (100 μl, or 0.57 mmol) and EDCI (64 mg, 0.33 mmol) in anhydrous DMF (3 ml) for 3 days at room temperature followed by purification of the crude substances by chromatography on silica gel (CH3OH-NH3H2O-CH2Cl2, 2:2:96) resulted in obtaining specified in the title compound (158 mg, 94%) as a white foam.

Using the common methodology D:The transformation obtained above foam (158 mg, 0.31 mmol) in hydrobromide salt using a solution of acetic acid/HBr with the following presidenial salt of diethyl ether resulted in the receipt to joinAMD9702in the form of a white solid.

1H NMR (D2O) δ 1,75-1,89 (m, 1H), 2,14 was 2.25 (m, 2H), 2,36 (W, 1H), 2,97 totaling 3.04 (m, 2H), 3,67 of 3.75 (m, 2H), 4,18 (s, 2H), 4,37 (d, 1H, J=16.2 Hz), 4,55 (d, 1H, J=16.2 Hz), of 4.67-4.72 in (m, 1H), 6.73 x (d, 1H, J=7,2 Hz), 6,94-was 7.08 (m, 3H), of 7.36-7,39 (m, 2H), 7,47-to 7.50 (m, 2H), 7,82-of 7.90 (m, 2H), 8,16 (d, 1H, J=7.8 Hz), 8,29-to 8.34 (m, 2H), 8,65 (d, 1H, J=5.7 Hz), 8,73 (d, 1H);13C NMR (D2O) δ 18,36, 18,74, 25,75, 41,20, 48,00, 54,57, 60,66, 111,72, 122,17, 123,99, 124,53, 125,21, 126,79, 127,13, 127,31, 128,32, 134,67, 135,79, 137,49, 138,72, 141,85, 143,48, 144,06, 146,11, 148,69, 149,54, 16,17; ES-MS m/z 503,3 (M+H); elemental analysis: calculated for (C31H29N5O)•2,7(HBr)•1,7(H2O)•0,2(C4H10O): C, 49,83; H, Free 5.01; N, 10,96; Br, 28,15. Found: C, 49,75; H, Of 4.77; N, 10,89; Br, 28,30.

EXAMPLE 37

AMD9788:Obtaining N-(3-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,6-dichlorosalicylic

Using General method for the reaction combination with EDCI F:Interaction (3-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (94 mg, 0.24 mmol), 2,6-dichlorophenylamino acid (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol), 4-methylmorpholine (40 μl, 0.36 mmol) and EDCI (50 mg, 0.26 mmol) for 24 hours at room temperature with a subsequent column chromatography on silica gel (EtOAc/MeOH/NH4OH, 199:1:1) resulted in a compoundAMD9788(87 mg, 59%) as a white foam.

1H NMR (300 MHz, CDCl3) δ 1,74 of-1.83 (m, 1H), 1,98-to 2.06 (m, 2H), 2,27-of 2.28 (m, 1H), 2,72-2,84 (m, 2H), 3,74 (s, 2H), 3,88 (d, 1H, J=18,0 Hz), 4,08 (d, 1H, J=18,0 Hz), 4,13-4,16 (m, 1H), 4,43 (DD, 1H, J=15,0, 3.0 Hz), 4,56 (DD, 1H, J=to 15.0, 6.0 Hz), 7.03 is-7,37 (m, 10H), 7,44 (s, 1H), 7,65 (s, 2H), 8,60-to 8.62 (m, 1H);13C NMR (75.5 MHz, CDCl3) δ 14,85, 21,94, 24,35, 37,14, 44,78, 49,25, 54,67, 61,32, 112,37, 118,95, 121,89, 122,34, 123,01, 127,43, 128,45, 128,97, 129,19, 135,48, 138,08, 138,14, 140,43, 147,42, 147,69, 151,66, 156,54, 157,73, 163,68; ES-MS m/z 573 (M+H); elemental analysis: calculated for C1 H28N6Cl2O•1,0CH2Cl2•0,4H2O: C, 57,92; H, To 4.68; N, 12,66; Cl, 21,37. Found: C, 58,08; H, 4,60; N, 12,63; Cl, 21,20.

EXAMPLE 38

AMD9795:Obtaining N-(3-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,6-dimethylbenzamide

Using the General technique combination using EDCI F:Interaction (3-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (120 mg, 0.30 mmol), 2,6-dimethylbenzoic acid (50 mg, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), 4-methylmorpholine (49 μl, 0.45 mmol) and EDCI (63 mg, 0.33 mmol) for 4 hours at room temperature with a subsequent column chromatography on silica gel (EtOAc/MeOH/NH4OH, 199:1:1) yielded the desired product (89 mg, 56%) as a white foam.

Using the General methods of education HBr salt D:The transformation of the obtained foam in hydrobromide salt resulted in the receipt of the connectionAMD9795in the form of a white powder.

1H NMR (300 MHz, D2O) δ 1,92-of 2.09 (m, 1H), 2,13 (s, 6H), 2,20-of 2.33 (t, 2H), 2,46-2,49 (t, 1H), 3,02-is 3.08 (m, 2H), of 3.77-3,88 (m, 2H), 4,14 (s, 2H), 4,47 (d, 1H, J=16.5 Hz), of 4.66 (d, 1H, 7=16.2 Hz), 4,76-to 4.81 (t, 1H), 6,92 (d, 1H, J=7.5 Hz), 7,09 for 7.12 (t, 4H), 7,16-7,19 (t, 1H), 7.24 to 7,29 (m, 1H), 7,42-to 7.50 (m, 2H), 7,58-7,63 (m, 2H), 7,94 (DD, 1H, J=7,5, 6,0 Hz), 8,42 (d, 1H, J=7.8 Hz), the rate of 8.75 (d, 1H, J=5.4 Hz);13C NMR (75.5 MHz, D2O) 18,55 (2C), 20,47, 20,85, 27,84, 43,00, 5016, 56,80, 62,94, 113,83, 126,11, 126,76, 127,37, 127,84, 129,17, 129,38, 129,79, 130,55, 134,59, 136,85, 138,12, 139,58, 140,96, 148,24, 150,92, 151,81; ES-MS m/z 530 (M+H); elemental analysis: calculated for C34H35N5O•2,2HBr•1,2H2O: C, 55,99; H, Vs. 5.47; N, 9,60; Br, 24,10. Found: C, 55,80; H, 5,50; N, At 9.53; Br, 24,26.

EXAMPLE 39

AMD9836:Obtaining N-(3-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)for 3,5-dibromosalicylic (hydrobromide salt)

The interaction of 3,5-dibromosalicylic acid (73 mg, 0.26 mmol), oxalicacid (1 ml) by boiling under reflux for 1 hour, followed by the interaction of the corresponding acylchlorides, (3-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (103 mg, 0.26 mmol), DIPEA (0,30 ml, 1.70 mmol) and catalytic amount of DMAP for 3 hours at room temperature resulted in the receipt of crude yellow oil. The crude product was purified column chromatography on silica gel (EtOAc-MeOH-NH4OH, 199:1:1) to obtain the specified title compound (60 mg, 35%) as a white foam.

Using the common methodology D:The transformation of the obtained foam (60 mg, 0.09 mmol) in hydrobromide salt using a solution of acetic acid/HBr with the following presidenial salt of diethyl ether resulted in the receipt of the connectionAMD9836the form of a white foam.

1H NMR (CD3OD) δ 1,88-of 1.93 (m, 1H), 2,22 to 2.35 (m, 2H), 2,44-2,48 (m, 1H), 3,05-to 3.09 (m, 2H), 3,80-to 3.89 (m, 2H), 4,40-to 4.46 (m, 3H), with 4.64 (d, 1H, J=16.5 Hz), 4,72-of 4.77 (m, 1H), 6,99-7,07 (m, 2H), 7,28 (d, 1H, J=6,9 Hz), at 7.55 (DD, 2H, J=3,3, 6,3 Hz), the 7.65 (s, 1H), 7,73-to 7.77 (m, 2H), 7,94 (DD, 1H, J=6,0, 7,8 Hz), 8,40 (d, 1H, J=7.8 Hz), 8,67 (s, 2H), 8,93 (d, 1H, J=5.7 Hz);13C NMR (CD3OD) δ 25,22, 25,31, 32,59, 47,62, 54,07, 61,33, 66,00, 118,63, 122,98, 130,57, 131,39, 132,35, 133,36, 133,90, 134,59, 135,71, 141,05, 143,19, 145,09, 145,38, 151,80, 152,66, 155,26, 155,55, 156,18; ES-MS m/z 661,3 (M+H); elemental analysis: calculated for (C31H28Br2N6O)•0,4(C2H4O2)•0,7(H2O)•2,1(HBr): C, 44,06; H, of 3.85; N, RS 9.69; Br, 37,79. Found: C, 44,22; H, A 3.87; N, 9,75; Br, 37,77.

EXAMPLE 40

AMD9874:Obtaining 2-amino-N-(3-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-6-chlorobenzamide

Using the General technique combination using EDCI F:Interaction (3-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (100 mg, 0.25 mmol), 2-chloro-6-aminobenzoic acid (43 mg, 0.25 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), 4-methylmorpholine (38 μl, 0.35 mmol) and EDCI (48 mg, 0.25 mmol) for 4 hours at room temperature with a subsequent column chromatography on silica gel (EtOAc/MeOH/NH4OH, 199:1:1) resulted in a compoundAMD9874(108 mg, 79%) as a white foam.

1H NMR (300 MHz, CD3OD) δ 1,58-175 (m, 1H), 2,01-2,12 (t, 2H), 2,18-to 2.67 (t, 1H), 2,73-to 2.94 (t, 2H), 3,56 (d, 1H, J=12.9 Hz), to 3.64 (d, 1H, J=13,2 Hz), 3,97-4,15 (t, 3H), 4,20 (s, 2H), 6,64-6,69 (m, 2H), 7.03 is-was 7.08 (m, 3H), 7,13 (DD, 2H, J=6,0, 3,3 Hz), 7,20-7,28 (m, 2H), 7,37 (SHS, 1H), 7,42 was 7.45 (m, 2H), EUR 7.57 (d, 1H, J=7.8 Hz), 8,58 (d, 1H, J=5.4 Hz);13C NMR (75.5 MHz, CD3OD) δ 22,81, 24,38, 30,60, 44,81, 51,53, 56,52, 63,34, 115,78, 115,95, 119,12, 123,06, 123,65, 124,07, 127,93, 129,57, 129,86, 130,05, 132,16, 132,75, 137,41, 139,49, 139,62, 140,88, 148,34, 148,85, 156,26, 158,17, 169,44; ES-MS m/z 551 (M+H); elemental analysis: calculated for C32H31ClN6O•0,8H2O•0,7(C4H8O2): C, 66,65; H, 6,14; N, 13,40; Cl, 5,65. Found: C, 66,62; H, Equal To 6.05; N, 13,28; Cl, 5,76.

EXAMPLE 41

AMD9843:Obtaining N-(3-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

Using the General technique combination using EDCI F:Interaction (3-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (105 mg, 0.26 mmol), 3,5-dichlorophenylamino acid (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (36 mg, 0.26 mmol), 4-methylmorpholine (100 μl, 0.89 mmol) and EDCI (51 mg, 0.26 mmol) for 2 days at room temperature with a subsequent column chromatography on silica gel (MeOH-NH4OH-CH2Cl2, 1:1:98) resulted in a compoundAMD9843(62 mg, 41%) as a white foam.

1H NMR (CDCl3) δ of 1.65-1.77 in (m, 1H), 1.91 a-2,07 (t, 2H), 2,23-of 2.28 (m, 1H), 2,70-only 2.91 (m, 1H), 3,71 (2H), 3,81 (d, 1H, J=16.5 Hz), 4,01 (d, 1H, J=16.5 Hz), 4,05-4,10 (m, 1H), 4.53-in (d, 2H, J=5.7 Hz), 7,02? 7.04 baby mortality (t, 3H), 7,12-7,21 (t, 3H), 7,29-7,35 (m, 2H), 7,42 was 7.45 (m, 3H), 7,50 (d, 1H, J=7.8 Hz), 8,29 (s, 2H), 8,65-8,67 (m, 1H);13With NMR (CDCl3) δ 21,72, 24,12, 29,56, 44,23, 49,04, 54,87, 61,48, 121,93, 122,80, 127,50, 128,54, 129,06, 129,13, 129,40, 135,27, 137,46, 137,92, 140,10, 142,89, 147,17, 147,73, 156,27, 157,48, 162,47; ES-MS m/z 571,6 (M+H); elemental analysis: calculated for (C31H28N6Cl2O)•0,2(CH2Cl2)•0,7(H2O): C, 62,34; H; 5,00; N, 13,98; Cl, 14,16. Found: C, 62,28; H, To 4.98; N, Of 13.58; Cl, 14,20.

EXAMPLE 42

AMD9849:Obtaining N-(2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,6-dimethylbenzamide

Using the General technique combination using EDCI F:Interaction (2-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (70 mg, 0.18 mmol), 2,6-dimethylbenzoic acid (29 mg, 0,19 mmol), 1-hydroxybenzotriazole (26 mg, 0,19 mmol), 4-methylmorpholine (27 μl, 0.25 mmol) and EDCI (37 mg, 0,19 mmol) for 18 hours at room temperature with a subsequent column chromatography on silica gel (EtOAc/MeOH/NH4OH, 199:1:1) yielded the desired product (34 mg, 37%) as a white foam.

Using the General methods of education HBr salt D:The transformation of the obtained foam in hydrobromide salt resulted in the receipt of the connectionAMD9849in the form of a white powder.

1H NMR (300 MHz, D2O) δ 1,94-to 1.98 (m, 1H), 2,08 (s, 6H), 2,23-of 2.28 (m, 1H), 2.40 a-2,48 (t, 2H), 3,06 (CL, 2H), 3,94 (d, 1H, J=12.9 Hz), 4,17 (d, 1H, J=12.9 Hz), of 4.44-4,51 (t, 2H), 4,58-of 4.66 (m, 2H), 4,81-to 4.87 (m, 1H), 6.87 in-6,92 (m, 1H), 6,97-7,01 (m, 1H),? 7.04 baby mortality-was 7.08 (t, 3H), 7,21-7,26 (m, 1H), 7,34 (d, 1H, J=7.5 Hz), 7,53-EUR 7.57 (t, 2H), 7,60-the 7.65 (t, 2H), to $ 7.91 (DD, 1H, J=7,8, 6,0 Hz), to 8.41 (d, 1H, J=7.8 Hz), 8,73 (d, 1H, J=5.7 Hz);13C NMR (75.5 MHz, D2O) δ a 18.57 (2C), 20,46, 20,73, 27,93, 43,93, 49,60, 53,83, 62,04, 113,94, 126,19, 126,82, 127,76, 128,30, 129,24, 129,31, 129,75, 130,59, 131,89, 133,93, 134,50, 136,01, 136,34, 139,87, 141,06, 148,29, 150,67, 151,32, 173,34; ES-MS m/z 530 (M+H); elemental analysis: calculated for C34H35N5O•2,1HBr•1,4H2O: C, 56,34; H, To 5.55; N, 9,66; Br, 23,15. Found: C, 56,48; H, 5,73; N, Of 9.30; Br, 23,18.

EXAMPLE 43

AMD9981:Obtaining N-(2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

Using the General technique combination using EDCI F:Interaction (2-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (70 mg, 0.18 mmol), 3,5-dichlorophenylamino acid (75%, 67 mg, 0.26 mmol), 1-hydroxybenzotriazole (24 mg, 0.18 mmol), 4-methylmorpholine (100 μl, 0.89 mmol) and EDCI (37 mg, 0,19 mmol) for 2 days at room temperature with a subsequent column chromatography on silica gel (MeOH-NH4OH-CH2Cl2, 1:1:98) resulted in a compoundAMD9981(40 mg, 40%) as a white foam.

1NAMR (CDCl 3) δ 1,53-to 1.77 (m, 2H), 2,02-of 2.08 (m, 1H), 2,35-2,39 (m, 1H), 2,68-is 2.88 (m, 2H), 3,56-of 3.85 (m, 5H), 4,20 (d, 1H, J=12,6 Hz), free 5.01 (DD, 1H, J=9,6, 13,2 Hz), 6.75 in-6,79 (m, 1H), 7.18 in-7,33 (m, 8H), 7,47 (SHS, 1H), 7,66 (d, 2H, J=7.5 Hz), 8,32 (s, 2H), 9,81 (m, 1H);13C NMR (CDCl3) δ 20,86, 21,16, 28,87, 40,32, 49,16, 55,17, 58,51, 110,68, 119,37, 122,04, 122,38, 123,07, 127,85, 128,82, 129,15, 130,47, 132,07, 134,95, 135,39, 138,01, 138,23, 143,38, 145,30, 147,33, 153,38, 157,32, 162,39; ES-MS m/z 571,2 (M+H); elemental analysis: calculated for (C31H28N6Cl2O)•0,2(CH2Cl2): C, 63,68; H, A 4.86; N, Of 14.28; Cl, Of 14.46. Found: C, PHP 64.00; H, To 4.87; N, 14,10; Cl, 14,36.

EXAMPLE 44

AMD9981:Getting {4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]phenyl}amide pyridine-2-carboxylic acid

Receive (4-hydroxymethylene)amide pyridine-2-carboxylic acid

Using the common methodology F:Interaction (4-AMINOPHENYL)methanol (200 mg, and 1.63 mmol), pikolinos acid (217 mg, to 1.79 mmol), 1-hydroxybenzotriazole (242 mg, to 1.79 mmol), 4-methylmorpholine (269 μl, 2.45 mmol) and EDCI (343 mg, to 1.79 mmol) for 24 hours at room temperature resulted in the receipt specified in the title compound (342 mg, 92%) as a red solid.

1H NMR (300 MHz, CDCl3) δ 4,70 (d, 2H, J=3,9 Hz), 7,41 (d, 2H, J=8,4 Hz)to 7.50 (DDD, 1H, J=7,5, to 4.8, 1.3 Hz), 7,79 (d, 2H, J=8,4 Hz), 7,92 (DDD, 1H, J=7,5, to 7.5, 4.5 Hz), 8,31 (d, 1H, J=6.0 Hz), 10,06 (SHS, 1H).

Receive (4-chloromethylene)amide pyridine-2-carboxylic acid

Interaction (4-hydroxymethylene)amide pyridine-2-carboxylic acid (342 mg, 1.50 mmol), Et3N (262 μl, of 1.80 mmol) and methanesulfonamide (128 μl, of 1.65 mmol) for 2 hours at boiling under reflux resulted in the receipt specified in the title compound (352 mg, 95%) as a red solid.

1H NMR (300 MHz, CDCl3) δ br4.61 (s, 2H), 7,45 (d, 2H, J=8,4 Hz)to 7.50 (DDD, 1H, J=7,5, to 4.8, 0.9 Hz), 7,80 (d, 2H, J=8.7 Hz), 7,92 (DDD, 1H, J=7,8, and 7.8, 1.6 Hz), 8,63 (d, 1H, J=6.0 Hz), 10,08 (SHS, 1H).

Getting {4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]phenyl}amide pyridine-2-carboxylic acid

General methodology for substitution reactions chlorides (I):

To a stirred solution of amine (˜1.5 equivalents) and a base Janiga (1.0 equivalent) in anhydrous MeCN (˜0.2 M) at room temperature under nitrogen atmosphere was added dropwise a solution of chloride (1.0 equivalent). The resulting solution was stirred at the same temperature (˜80° (C) during a specified period of time. The mixture was diluted with CH2Cl2(100 ml/mmol), filtered through celite and concentrated. The crude substance was purified by chromatography.

Using the above methods I:The interaction of 8-amino-5,6,7,8-tetrahydroquinoline (181 mg, 1,22 mmol), N,N-diisopropylethylamine (142 μl, 0.81 mmol) and (4-chloromethylene)amide pyridine-2-carboxylic KIS is the notes (200 mg, 0.81 mmol) for 3 hours at 80°and subsequent column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 198:1:1) resulted in a compoundAMD9409(106 mg, 36%) as a yellow oil.

1H NMR (300 MHz, CDCl3) δ 1,75-of 1.85 (m, 2H), 2.00 in 2,04 (m, 1H), 2,16-of 2.20 (m, 1H), 2,73-of 2.81 (m, 3H), 3,82-3,86 (m, 1H), a 3.87 (d, 1H, J=12.0 Hz), 3,98 (d, 1H, J=15,0 Hz), 7,03 (DD, 1H, J=7,4, a 4.7 Hz), 7,34 (d, 1H, J=7.5 Hz), 7,41-7,46 (m, 3H), 7,43 (d, 2H, J=8,4 Hz), 7,87 (DDD, 1H, J=7,8, and 7.8, 1.7 Hz), of 8.27 (d, 1H, J=7.8 Hz), of 8.37 (d, 1H, J=7.8 Hz), 8,58 (d, 1H, J=3.3 Hz), 10,00 (SHS, 1H);13C NMR (75.5 MHz, CDCl3) δ 20,09, 29,08, 29,28, 51,86, 57,98, 120,06 (2C), 122,20, 122,75, 126,79, 129,37 (2C), 132,85, 136,85, 137,25, 138,05, 147,23, 148,34, 150,25, 157,90, 162,28; ES-MS m/z 359 (M+H); elemental analysis: calculated for C22H22N4O•0,2H2O: C, 72,99; H, 6,24; N, 15,48. Found: C, 72,98; H, 6,20; N, 15,48.

EXAMPLE 45

AMD9413:Receive (4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)amide pyridine-2-carboxylic acid

Using the General methods:Interaction (4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]phenyl}amide pyridine-2-carboxylic acid(AMD9409)(67 mg, 0,19 mmol), 1H-benzimidazole-2-carbaldehyde (30 mg, 0.21 mmol) and NaBH(OAc)3(119 mg, 0.50 mmol) for 0.5 hour at 60°followed by purification of the crude product column chromatography on silica gel (CH2Cl2/MeOH/NH4 OH, 198:1:1) resulted in a compoundAMD9413(48 mg, 53%) as a white foam.

1H NMR (300 MHz, CDCl3) δ of 1.62 and 1.75 (m, 1H), 1,96-2,07 (m, 2H), 2,23-of 2.30 (m, 1H), 2,68-only 2.91 (m, 2H), 3,74 (CL, 2H), 3,98 (d, 1H, J=16,8 Hz), 4.09 to (m, 1H), 4,19 (d, 1H, J=16.5 Hz), 7,16-7,20 (m, 3H), 7,41-7,46 (m, 4H), 7,53 (d, 1H, J=6.0 Hz), of 7.64-to 7.67 (m, 3H), 7,87 (DDD, 1H, J=7,5, to 7.5, 1.5 Hz), compared to 8.26 (d, 1H, J=7.8 Hz), 8,58 (d, 1H, J=3,9 Hz), to 8.70 (d, 1H, J=3.3 Hz), 9,94 (SHS, 1H);13C NMR (75.5 MHz, CDCl3) δ 21,39, 23,41, 29,22, 48,54, 53,54, 60,11, 119,57, 121,50, 122,25, 122,36, 126,37, 129,28, 134,71, 135,33, 136,73, 137,21, 137,62, 146,93, 147,93, 149,80, 157,47, 161,84; ES-MS m/z 489 (M+H); elemental analysis: calculated for C30H28N6O•0,5H2O•0,3CHCl3: C, 68,23; H, 5,54; N, 15,76. Found: C, 68,06; H, 5,54; N, 15,46.

EXAMPLE 46

AMD9982:Obtaining N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl) - for 3,5-dichlorosalicylic

Getting 3,5-dichloro-N-(4-hydroxymethylene)isonicotinamide

A suspension of 3,5-dichlorophenylamino acid (128 mg, 0,667 mmol) in thionyl chloride (2 ml) was boiled under reflux for 2 hours, then concentrated. To the residue was added 4-aminobenzoyl alcohol (123 mg, 0,999 mmol) and THF (2.2 ml)and the mixture was stirred at room temperature for 19 hours. The mixture was filtered and the filtrate was concentrated to obtain a yellow foam.

1H NMR (CD3OD) δ 4,60 (s, 2H),and 7.3 (d, 2H, J=8.7 Hz), 7,63 (d, 2H, J=8,4 Hz), 8,66 (s, 2H).

Getting 3,5-dichloro-N-(4-formylphenyl)isonicotinamide

A solution of 3,5-dichloro-N-(4-hydroxymethylene)isonicotinamide (125 mg, 0,421 mmol) in CH2Cl2(4,2 ml) was boiled under reflux with a suspension of 85% MnO2(430 mg, 4.20 mmol) for 3 hours. The mixture was filtered, and the filtrate was concentrated to obtain a brown solid.

1H NMR (CDCl3) δ for 7.78 (s, 1H), 7,83 (d, 2H, J=8.7 Hz), 7,94 (d, 2H, J=8,4 Hz), 8,61 (s, 2H), 9,98 (s, 1H).

Using the General methods:To a stirred solution of (1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (76 mg, 0.27 mmol), 3,5-dichloro-N-(4-formylphenyl)isonicotinamide (81 mg, 0.27 mmol) and Asón (0,016 ml, 0.28 mmol) in THF (3 ml) was added NaBH(OAc)3(175 mg, 0,826 mmol)and the mixture was stirred at room temperature for 17.5 hours. The crude substance was dissolved in a saturated solution of HBr/AcOH (2 ml) and stirred at room temperature for 15 minutes. The solution was podslushivaet 10N NaOH (aqueous solution) and was extracted with CH2Cl2(3 x 15 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuum. Purification of the crude substances column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 400:5:1-200:5:1) resulted in a compoundAMD9982(69 mg, 42%) as a yellow foam.

1H NMR (CDCl3) δ by 1.68 (m, 1H), up to 1.98 (m, 2H), 2,17 (m, 1H), 2,69-only 2.91 (m, 2H), 3,63 (d, 1H, J=17 Hz), to 3.67 (d, 1H, J=17 Hz), a 3.87 (d, 1H, J=17 Hz), a 4.03 (m, 1H), 4.09 to (d, 1H, J=17 Hz), 7,19 (m, 3H), 7,29 (d, 2H, J=8,4 Hz), 7,49 (m, 5H), 8,30 (s, 2H), 8,69 (d, 1H, J=3 Hz), 10,29 (s, 1H);13C NMR (CDCl3) δ 21,31, 24,10, 29,15, 48,10, 53,17, 60,55, 111,13, 118,26, 120,20, 121,50, 121,81, 122,40, 128,94, 129,13, 134,84, 136,13, 136,61, 137,42, 142,42, 146,79, 147,39, 156,23, 157,24, 160,31; ES-MS m/z 557 (M+H)(35Cl), 559 (M+H) (37Cl); elemental analysis: calculated for C30H26N6Cl2O•0,2H2O•0,4CH2Cl2: C, 61,36; H, Br4.61; N, 14,12; Cl, 16,68. Found: C, 61,22; H, To 4.62; N, 13,86; Cl, Ls 16.80.

EXAMPLE 47

AMD9426:Getting 4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzylamine pyridine-2-sulfonic

Getting 4-hydroxymethylbenzene pyridine-2-sulfonic

A General method of carrying out the reaction of amines with sulphonylchloride J:

To a stirred solution of amine (1.1 equivalents) and a base Janiga (1.0 equivalent) in anhydrous CH2Cl2(˜0.2 M) at room temperature under nitrogen atmosphere was added dropwise a solution of sulphonylchloride (1.0 equivalent). The resulting solution was stirred at room temperature for the specified time. The mixture was diluted with CH2Cl2(100 ml/mmol), washed with aqueous solution of NaHCO3, dried (Na2SO4) and concentrated. The crude product is t was purified by chromatography.

Using the above methods J:Interaction (4-aminomethylphenol)methanol (255 mg, of 1.86 mmol), N,N-diisopropylethylamine (294 μl, was 1.69 mmol) and pyridine-2-sulphonylchloride (300 mg, was 1.69 mmol) for 10 minutes at room temperature resulted in the receipt specified in the title compound (400 mg, 85%) as a white solid.

1H NMR (300 MHz, CDCl3) δ 4.26 deaths (CL, 2H), 4,66 (CL, 2H), 5,28 (SHS, 1H), 7.23 percent-7,30 (m, 4H), 7,49-7,51 (m, 1H), of 7.90-a 7.92 (m, 1H), to 7.99 (d, 1H, J=4,8 Hz), 8,68 (d, 1H, J=4.5 Hz).

Getting 4-chloromethylbenzene pyridine-2-sulfonic

The interaction of 4-hydroxymethylbenzene pyridine-2-sulfonic acids (140 mg, 0.50 mmol), Et3N (88 μl, of 0.60 mmol) and MsCl (47 μl, of 0.60 mmol) for 2 hours at boiling under reflux and subsequent column chromatography on silica gel (CHCl2/MeOH, 99:1) resulted in the receipt specified in the title compound (67 mg, 45%) as a white solid.

1H NMR (300 MHz, CDCl3) δ to 4.28 (d, 2H, J=6.0 Hz), of 4.54 (s, 2H), 5,17 (SHS, 1H), 7.23 percent-7,49 (m, 4H), 7,47-7,52 (m, 1H), 7,88 (DDD, 1H, J=7,5, of 7.5 and 1.7 Hz), of 7.97 (d, 2H, J=7.5 Hz), 8,69 (d, 1H, J=4,8 Hz); ES-MS m/z 319 (M+Na).

Getting 4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzylamine pyridine-2-sulfonic

The interaction of 8-amino-5,6,7,8-tetrahydroquinoline (200 mg, 1.35 mmol), N,N-diisopropylethylamine (157 μl, 0.90 mmol) and 4-chloromethylbenzene pyridine-2-sulfat the slots (266 mg, 0.90 mmol) for 3 hours at 500With subsequent column chromatography on silica gel resulted in the receipt of the connectionAMD9426(150 mg, 41%) as a yellow oil.

1H NMR (300 MHz, CDCl3) δ 1,68-to 1.79 (m, 2H), 1,97-2,03 (m, 1H), 2,12-of 2.20 (m, 1H), 2,69-2,84 (m, 3H), of 3.77-3,81 (m, 2H), 3,92 (d, 1H, J=12.0 Hz), 4,20 (CL, 2H), 7,05 (DD, 1H, J=7,5, 4,8 Hz), to 7.15 (d, 2H, J=7.8 Hz), 7,25 (d, 2H, J=7.8 Hz), was 7.36 (d, 1H, J=7.5 Hz), 7,39-7,44 (m, 1H), 7,82 (DDD, 1H, J=7,8, and 7.8, 1.5 Hz), 7,92 (d, 1H, J=7.8 Hz), at 8.36 (d, 1H, J=3,9 Hz), 8,59 (d, 1H, J=4, 2 Hz);13C NMR (75.5 MHz, CDCl3) δ 20,09, 28,94, 29,23, 47,80, 51,75, 57,87, 122,25, 122,63, 126,94, 128,45 (2C), 128,88 (2C), 132,88, 135,25, 137,30, 138,35, 147,68, 147,15, 150,34, 157,75, 157,95, ES-MS m/z 409 (M+H); elemental analysis: calculated for C22H24N4O2S•0,2H2O•0,3CH2Cl2: C, 61,21; H, USD 5.76; N, 12,80; S, 7,33, O, 8,04. Found: C, 60,82; H, 5,73; N, 12,42; S, 7,30; O, 8,14.

EXAMPLE 48

AMD9429:Getting 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylamine pyridine-2-sulfonic acids (hydrobromide salt)

Getting 4-({(5,6,7,8-tetrahydroquinolin-8-yl)-[1-(2-trimethylsilylethynyl)-1H-benzimidazole-2-ylmethyl]amino}methyl)benzylamine pyridine-2-sulfonic

Using the General methods:The interaction of 4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzylamine pyridine-2-sulfonic acids (AMD9426)(150 mg, and 0.37 mmol), 1-(2-trimethylsilyl methoxymethyl)-1H-benzimidazole-2-carbaldehyde (102 mg, of 0.37 mmol) and NaBH(OAc)3(233 mg, 1.10 mmol) for 1 hour at room temperature with a subsequent column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 198:1:1) resulted in the receipt specified in the title compound (101 mg, 41%) as a yellow foam.

1H NMR (300 MHz, CD3OD) δ 0,00 (s, 9H), 0.75 in (DD, 2H, J=8,1, 8.1 Hz), 1,58 is 1.75 (m, 2H), 2,22 (CL, 2H), 2,66-to 2.85 (t, 2H), 3,25 (DD, 2H, J=8,1, 8.1 Hz), 3,66 (d, 1H, J=14.1 Hz), of 3.78 (d, 1H, J=14.1 Hz), was 4.02 (d, 1H, J=6.0 Hz), 4,06-4,16 (m, 1H) 4,20 (CL, 2H), 4,81 (SHS, 1H), of 5.68 (d, 1H, J=12.0 Hz), 5,91 (d, 1H, J=12.0 Hz), 6,92 (d, 2H, J=7.8 Hz), 7,06 (DD, 1H, J=7,5, 4,8 Hz), 7,17-of 7.23 (m, 4H), 7,30-7,35 (m, 2H), 7,45 (DDD, 1H, J=7,5, 4,5, 1.1 Hz), to 7.61-to 7.64 (t, 1H), 7,87 (DDD, 1H, J=7,8, and 7.8, 1.7 Hz), 7,98 (d, 1H, J=7.8 Hz), 8,55 (d, 1H, J=3.6 Hz), 8,68 (d, 1H, J=3,9 Hz). ES-MS m/z 669 (M+H).

Getting 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylamine pyridine-2-sulfonic

Using General method F:The interaction of 4-({(5,6,7,8-tetrahydroquinolin-8-yl)-[1-(2-trimethylsilylethynyl)-1H-benzimidazole-2-ylmethyl]amino}methyl)benzylamine pyridine-2-sulfonic acids (100 mg, 0.15 mmol) and 6N HCl (3,9 ml) for 3 hours at 50°and subsequent column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 94:3:3) resulted in the receipt specified in the title compound (68 mg, 85%) as a white foam.

Using the common methodology D:The obtained product was transformed in soo is relevant hydrobromide Sol with getting AMD9429in the form of a white solid.

1H NMR (300 MHz, CD3OD) δ 1,92-2,02 (m, 1H), 2,22-to 2.41 (m, 3H), 3.04 from was 3.05 (m, 2H), 3,68 (CL, 4H), 4,42 (d, 1H, J=16.2 Hz), with 4.64 (d, 1H, J=16.5 Hz), of 4.77 (DD, 1H, J=10,2, 6.3 Hz), 6,93 (d, 2H, J=8,4 Hz), 7,33 (d, 2H, J=8,1 Hz), 7,53 (DD, 2H, J=6,3, and 3.3 Hz), 7,60 (DDD, 1H, J=7,5, to 4.8, 1.2 Hz), 7,73 (DD, 2H, J=6.3, in the 3.2 Hz), to $ 7.91-of 7.97 (m, 2H), 8,01-8,07 (m, 1H), 8,39 (d, 1H, J=7.8 Hz), 8,65-8,67 (m, 1H), of 8.92 (d, 1H, J=5.7 Hz);13C NMR (75.5 MHz, CD3OD) δ 15,86, 21,94, 29,21, 47,78, 57,69, 62,82, 67,31, 115,22 (2C), 123,70, 127,23, 128,03 (2C), 128,65, 129,10 (2C), 131,80 (2C), 132,24, 136,53, 139,56, 140,73, 141,58, 141,92, 149,29, 151,08 (2C), 152,21, 152,92, 159,36. ES-MS m/z 539 (M+H). Elemental analysis: calculated for C30H30N6O2S•2,2HBr•1,9H2O: C, 47,99; H, A 4.83; N, 11,19; O, 8,31; Br, 23,41; S, 4,27. Found: C, 43,35; H, To 4.92; N, 11,13; O, 8,35; Br, 23,27; S, 4,22.

EXAMPLE 49

AMD9830:Obtaining N-(4-{[(1-benzazolyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)benzosulfimide

A solution of N-(1H-benzimidazole-2-ylmethyl)-N-(5,6,7,8-tetrahydro-8-chinoline)-1,4-benzilpenetsillina (302 mg, 0,760 mmol), benzosulfimide (0,12 ml of 0.94 mmol) and Et3N (0.15 ml, 1.1 mmol) in CH2Cl2(7.5 ml) was boiled under reflux for 17 hours, then concentrated in vacuo. The residue was distributed between saturated NaHCO3(aqueous solution) (15 ml) and EtOAc (20 ml). The aqueous phase was extracted with EtOAc (20 ml), United organic the ski phase was dried (MgSO 4), filtered and concentrated in vacuum. Purification of the crude product column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 400:5:1) received the connectionAMD9830(229 mg, 71%) as a yellow foam.

1H NMR (CDCl3) δ 1,64-2,03 (m, 3H), is 2.37 (m, 1H), 2,66-2,84 (m, 2H), 3,76-to 3.89 (m, 4H), 4,06 (m, 1H), to 4.41 (DD, 1H, J=9,6, 6,0 Hz), of 4.66 (d, 1H, J=15 Hz), 4,79 (d, 1H, J=15 Hz), 6,76 (d, 2H, J=8.1 Hz), 7,07 (m, 1H), 7,18 (d, 2H, J=8.1 Hz), 7,27 (m, 2H), 7,41 (m, 3H), at 7.55 (m, 5H), to 7.84 (m, 3H), of 7.96 (m, 2H), 8,48 (m, 1H);13C NMR (CDCl3) δ 20,15, 27,15, 27,55, 45,30, 51,78, 53,32, 61,49, 111,81, 118,60, 119,84, 122,59, 123,06, 125,43, 125,60, 127,06, 127,47, 127,76, 131,01, 131,24, 131,92, 132,55, 132,69, 134,81, 136,75, 138,13, 139,21, 140,14, 145,11, 151,74, 156,99; ES-MS m/z 678 (M+H); elemental analysis: calculated for C37H35N5S2O4•0,5H2O: C, 64,70; H, 5,28; N, 10,20. Found: C, 64,65; H, 5,11; N, 10,08.

EXAMPLE 50

AMD9831:Obtaining N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-N-methylbenzenesulfonamide

Obtaining methyl ester 4-methylaminoethanol acid

A mixture of methyl (4-(methyl bromide)benzoate (600 mg, 2,62 mmol), methylamine (2.0 M/Meon, 6.5 ml, 13 mmol), potassium iodide (cat.) and N,N-diisopropylethylamine (and 0.46 ml of 2.64 mmol) was heated to 40°in CH3CN in a tightly closed vessel for 17 hours, then concentrated in vacuo. The remainder of the distribution is elali between saturated NaHCO 3(aqueous solution) and CH2Cl2(20 ml)and the aqueous phase was extracted with CH2Cl2(20 ml). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuum. Purification of the crude product column chromatography on silica gel (20% EtOAc/hexane, then CH2Cl2/MeOH/NH4OH, 100:5:1) was obtained colorless oil (262 mg, 56%).

1H NMR (CDCl3) δ the 2.46 (s, 3H), 3,81 (s, 2H), 3,91 (s, 3H), 7,39 (d, 2H, J=8.1 Hz), 8,00 (d, 2H, J=8.1 Hz).

N-(4-hydroxymethylbenzene)-N-methylbenzenesulfonic

A solution of methyl ester 4-methylaminoethanol acid (262 mg, of 1.46 mmol), benzosulfimide (to 0.22 ml, 1.7 mmol) and Et3N (to 0.29 ml, 2.1 mmol) in CH2Cl2(15 ml) was boiled under reflux for 15 hours, then concentrated in vacuo. The residue was distributed between saturated NaHCO3(aqueous solution) (20 ml) and EtOAc (20 ml)and the aqueous phase was extracted with EtOAc (20 ml). The combined organic phases were washed with saturated NaHCO3(aqueous solution) (15 ml) and saturated salt solution (10 ml), then dried (MgSO4), filtered and concentrated in vacuo to obtain a yellow-brown crystals (672 mg).

To the solution obtained above ester (672 mg) in THF (2.9 ml) was added diisobutylaluminium (1.0 M/THF, and 8.8 ml of 8.8 mmol) at 0°and the solution stirred the ri room temperature for 30 minutes. To the solution was added Meon (4 ml)and the solution was acidified (pH 2) 10% HCl (aqueous solution). The mixture was podslushivaet 1 N NaOH (aqueous solution) and was extracted with EtOAc (2 x 20 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuum. Purification of the crude product column chromatography on silica gel (40% EtOAc/hexane) was obtained colorless crystals (258 mg, 61%).

1H NMR (CDCl3) δ of 1.66 (t, 1H, J=6.0 Hz), 2,60 (s, 3H), 4,15 (s, 2H), 4,70 (d, 2H, J=6.0 Hz), 7,33 (m, 4H), 7,54-7,66 (m, 3H), a 7.85 (m, 2H).

N-(4-formylmethyl)-N-methylbenzenesulfonic

A solution of N-(4-hydroxymethylbenzene)-N-methylbenzenesulfonamide (258 mg, 0,885 mmol) in CH2Cl2(9 ml) was stirred at room temperature with a suspension of 85% MnO2(900 mg, 8,8 mmol) for 63 hours. The mixture was filtered through celite, and the solvent of the filtrate was removed under reduced pressure to obtain a colorless solid.

1H NMR (CDCl3) δ to 2.65 (s, 3H), 4,24 (s, 2H), 7,50 (d, 2H, J=8.1 Hz), 7,56-to 7.68 (m, 3H), 7,87 (m, 4H), 10,02 (s, 1H).

Using the General methods:To a stirred solution of (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (130 mg, 0,343 mmol), N-(4-formylmethyl)-N-methylbenzenesulfonamide (109 mg, 0,377 mmol) and Asón (0,020 ml, 0.35 mmol) in THF (3.5 ml) was added NaBH(OAc)3(218 mg, of 1.03 mmol)and the mixture per Merivale at room temperature for 20 hours. Purification of the crude substances column chromatography on silica gel (40% EtOAc/hexane) received the product as a colourless oil (41 mg).

The solution obtained above oil (41 mg, 0,063 mmol) in a mixture of TFU/CH2Cl2, 3:1 (4 ml) was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was distributed between CH2Cl2(10 ml) and 1 N NaOH (aqueous solution) (15 ml)and the aqueous phase was extracted with CH2Cl2(2 x 10 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuum to obtain compoundAMD9831(33 mg, 16%) as a colourless foam.

1H NMR (CDCl3) δ was 1.69 (m, 1H), 2,02 (m, 2H), and 2.26 (m, 1H), of 2.51 (s, 3H), 2,69-only 2.91 (m, 2H), of 3.73 (s, 2H), 3,95 (d, 1H, J=17 Hz), of 4.05 (s, 2H), 4.09 to (m, 1H), 4,18 (d, 1H, J=17 Hz), 7,17 (m, 5H), 7,37 (d, 2H, J=8.1 Hz), the 7.43 (d, 1H, J=6.6 Hz), 7,49-to 7.61 (m, 5H), 7,80 (m, 2H), 8,69 (m, 1H);13C NMR (CDCl3) δ 21,77, 23,84, 29,61, 34,71, 49,05, 54,15, 60,81, 121,87, 122,69, 127,79, 128,68, 129,25, 129,48, 133,00, 134,85, 135,14, 137,66, 137,86, 139,57, 147,33, 156,54, 157,75; ES-MS m/z 552 (M+H); elemental analysis: calculated for C32H33N5SO2•0,2H2O•0,4C4H8O2: C, 68,34; H, 6,25; N, UP 11,86. Found: C, 68,31; H, 6,33: N, Up 11,86.

EXAMPLE 51

AMD9845:Obtaining N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)benzosulfimide

A solution of N-(4-{[(1-be solarpanel-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino] methyl}benzyl)benzosulfimide(AMD9830)(161 mg, 0,234 mmol) in a saturated solution of HBr/AcOH (3 ml) was stirred at room temperature for 3.5 hours, then was added diethyl ether (20 ml) to give a colorless precipitate. The supernatant decantation, and the residue was distributed between CH2Cl2(10 ml)and saturated NaHCO3(aqueous solution) (15 ml). The basic aqueous phase was extracted with CH2Cl2(10 ml)and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuum. Purification of the crude substances column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 500:5:1) received the connectionAMD9845(59 mg, 44%) as a yellow foam.

1H NMR (CDCl3) δ by 1.68 (m, 1H), 1,99 (m, 2H), 2,24 (m, 1H), 2,67-only 2.91 (m, 2H), 3,68 (s, 2H), 3,86 (d, 1H, J=17 Hz), of 4.05 (m, 3H), 4,14 (d, 1H, J=17 Hz), to 4.87 (m, 1H), 7,01 (d, 2H, J=7.8 Hz), 7,18 (t, 3H), 7,28 (t, 2H), 7,37-7,60 (t, 6N), 7,80 (t, 2H), 8,68 (t, 1H);13C NMR (CDCl3) δ 22,08, 24,18, 29,90, 47,66, 49,21, 54,47, 61,26, 122,30, 123,03, 127,75, 128,54, 129,65, 129,73, 133,29, 135,47, 135,74, 138,01, 139,87, 140,65, 147,63, 156,87, 158,03; ES-MS m/z 538 (M+H); elemental analysis: calculated for C31H31N5SO2•0,46CH2Cl2: C, 65,52; H, TO 5.58; N, 12,14. Found: C, 65,56; H, The Ceiling Of 5.60; N, 12,09.

EXAMPLE 52

AMD9436:Getting {4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]phenyl}amide pyridine-2-sulfonic acids (hydrobromide with the l)

Receive (4-hydroxymethylene)amide pyridine-2-sulfonic

Interaction (4-AMINOPHENYL)methanol (249 mg, 2.03 mmol), N,N-diisopropylethylamine (294 μl, was 1.69 mmol) and pyridine-2-sulphonylchloride (300 mg, was 1.69 mmol) for 1 hour at room temperature with a subsequent column chromatography on silica gel (CH2Cl2/MeOH, 194:3) resulted in the receipt specified in the title compound (210 mg, 47%) as a red solid.

1H NMR (300 MHz, CDCl3) δ 4,60 (d, 2H, J=6.0 Hz), 7,07 (SHS, 1H), 7,15 (d, 2H, J=8,4 Hz), of 7.23 (d, 2H, J=8.7 Hz), 7,44-of 7.48 (m, 1H), 7,83 (DDD, 1H, J=7,5, to 7.5, 1.8 Hz), 7,89 (d, 1H, J=7.8 Hz), 8,72 (d, 1H, J=4.5 Hz).

Receive (4-formylphenyl)amide pyridine-2-sulfonic

To a stirred solution of (4-hydroxymethylene)amide pyridine-2-sulfonic acids (200 mg, from 0.76 mmol) and pyridine (612 μl) in anhydrous CH2Cl2(3 ml) was added periodan dess-Martin (450 mg, 1.06 mmol). The resulting solution was stirred at room temperature for 1 hour. The mixture was diluted with 100 ml of CH2Cl2was filtered through celite and concentrated. The crude substance was purified by recrystallization from chilled CH2Cl2obtaining specified in the title compound (120 mg, 60%) as a yellow powder.

1H NMR (300 MHz, CDCl3) δ 7,34 (d, 2H, J=8,4 Hz), 7,49-to 7.50 (m, 1H), 7,74 (SHS, 1H), of 7.75 (d, 2H, J=8,4 Hz), 7,89-of 7.70 (m, 1H), 8,03 (d, 1H, J=8.1 Hz), 8,70 (who, 1H, J=4, 2 Hz), 9,87 (s, 1H).

Getting {4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]phenyl}amide pyridine-2-sulfonic

Using the General methods:Interaction 5,6,7,8-tetrahydroquinolin-8-ylamine (68 mg, 0.46 mmol), (4-formylphenyl)amide (120 mg, 0.46 mmol) and NaBH(OAc)3(291 mg, 1.37 mmol) for 1 hour at room temperature followed by purification of the crude product column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 98:1:1) resulted in the receipt specified in the title compound (121 mg, 67%) as a white foam.

Using the common methodology D:The above foam was converted to the corresponding hydrobromide Sol with getting connectionAMD9436in the form of a white solid.

1H NMR (300 MHz, CD3OD) δ 1,86 is 2.00 (m, 2H), 2,11-of 2.15 (m, 1H), 2,43-2,49 (m, 1H), 2,88-2,90 (m, 2H), 4,20 (d, 1H, J=13,2 Hz), 4,32 (d, 1H, J=12.9 Hz), and 4.40 (DD, 1H, J=of 9.6, 4.8 Hz), 7,29 (d, 2H, J=8,4 Hz), 7,35 (DD, 1H, J=of 7.8, 4.8 Hz), 7,42 (d, 2H, J=8.7 Hz), 7,53-to 7.59 (m, 1H), to 7.67 (d, 1H, J=7.5 Hz), 7.95 is-to 7.99 (m, 2H), and 8.50 (d, 1H, J=4.5 Hz), to 8.62 (d, 1H, J=3,9 Hz);13C NMR (75.5 MHz, CD3OD) δ 20,34, 26,35, 28,67, 57,32, 122,43 (2C), 124,35, 126,69, 128,64, 128,89, 132,57 (2C), 137,67, 140,17, 140,73, 143,04, 146,85, 149,31, 151,52, 158,47; ES-MS m/z 395 (M+H); elemental analysis: calculated for C21H22N4O2S•2,0HBr•1,5H2O: C, 43,24; H, Of 4.67; N, 9,60; O, 9,60; S, 5,50; Br 27,40. Found: C, 42,89; H, Of 4.77; N, 9,63; O, Was 9.33; S, 5,42; Br, Of 27.50.

EXAMPLE 53

AMD9444:Receive (4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)amide pyridine-2-sulfonic

Using the General methods:Interaction {4-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]phenyl}amide pyridine-2-sulfonic acids (hydrobromide salt)(AMD9436)(82 mg, 0.21 mmol), 1-(2-trimethylsilylethynyl)-1H-benzimidazole-2-carbaldehyde (57 mg, 0.21 mmol) and NaBH(OAc)3(132 mg, of 0.62 mmol) for 1 hour at room temperature followed by purification of the crude product column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 198:1:1) resulted in obtaining [4-({(5,6,7,8-tetrahydroquinolin-8-yl)-[1-(2-trimethylsilylethynyl)-1H-benzimidazole-2-ylmethyl]amino}methyl)phenyl]amide pyridine-2-sulfonic acids (72 mg, 41%) as a yellow foam.

Using General method F:The interaction of the above compound (72 mg, 0.11 mmol) and 6 N HCl (2.0 ml) for 3 hours at 50°and subsequent column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 194:3:3) resulted in the receipt specified in the title compound (41 mg, 71%) as a white foam.

Using the common methodology D:The transformation product obtained above in an appropriate hydrobromide salt resulted in the receipt of the connectionAM9444 in the form of a white solid.

1H NMR (300 MHz, CD3OD) δ 1,88-1,90 (m, 1H), 2,18-of 2.24 (t, 2H), 2,35-of 2.36 (m, 1H), 3.00 and-a 3.01 (t, 2H), 3,70 (d, 1H, J=12.9 Hz), 3,76 (d, 1H, J=12.9 Hz), to 4.38 (d, 1H, J=16.2 Hz), 4,59 (d, 1H, J=16.2 Hz), with 4.64-to 4.73 (m, 1H), 6.87 in (d, 2H, J=8,4 Hz), 7,30 (d, 2H, J=8,4 Hz), 7,51-7,56 (t, 3H), 7,72 (DD, 2H, J=6,0, 3.0 Hz), 7,84-to $ 7.91 (t, 2H), 7,92-7,98 (m, 1H), with 8.33 (d, 1H, J=7.8 Hz), 8,59 (d, 1H, J=4.5 Hz), 8,86 (d, 1H, J=4.5 Hz);13C NMR (75.5 MHz, CD3OD) δ 15,84, 21,90, 29,17, 50,61, 57,21, 62,46, 115,19 (2C), 121,77 (2C), 124,09, 127,11, 128,09 (2C), 128,77, 132,28 (2C), 133,15, 139,16, 140,07, 141,57, 141,81, 149,10, 151,46, 152,87; ES-MS m/z 525 (M+H); elemental analysis: calculated for C29H28N6O2S•2,2HBr•1,5H2O•0,3C4H10O: C, 48,24; H, Is 4.85; N, 11,18; O 8,09; Br, 23,38; S, 4.26 Deaths. Found: C, 48,44; H, Is 4.85; N, 11,18; O, By 8.22; Br, Results Were 23.08; S, 4,34.

EXAMPLE 54

AMD 9541:Getting 4-{[CIS-2-[(N-pyridine-2-ylmethyl)amino]cyclohexyl]aminomethyl}benzylamine pyridine-2-carboxylic acid (hydrobromide salt)

Getting 4-hydroxymethylbenzene pyridine-2-carboxylic acid

Using the common methodology F:To a stirred solution of 4-aminomethylbenzoic alcohol (203 mg, 1.48 mmol) in DMF (3 ml) was added Pikalyovo acid (198 mg, of 1.61 mmol), 1-hydroxybenzotriazole (213 mg, was 1.58 mmol), N,N-diisopropylethylamine (of 0.39 ml, 2,24 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDC) (315 mg, of 1.64 mmol)and the mixture was stirred over night at room the Oh temperature. Standard processing resulted in the receipt specified in the title compound (340 mg, 95%) as a yellow oil.

1H NMR (300 MHz, CDCl3) δ of 4.67 (d, 2H, J=6.0 Hz), 4,69 (s, 2H), was 7.36 (CL, 4H), 7,43-7,44 (m, 1H), 7,85-7,86 (m, 1H), 8,24 (d, 1H, J=9.0 Hz), charged 8.52 (SHS, 1H), charged 8.52 (d, 1H, J=3.0 Hz); ES-MS m/z 243 (M+H).

Getting 4-formylbenzoate pyridine-2-carboxylic acid

To a stirred solution of 4-hydroxymethylbenzene pyridine-2-carboxylic acid (360 mg, 1.48 mmol) in anhydrous CH2Cl2(10 ml) was added periodan dess-Martin (690 mg, and 1.63 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with diethyl ether (25 ml), ethyl acetate (25 ml), saturated aqueous sodium bicarbonate (15 ml) and saturated aqueous sodium thiosulfate (15 ml) and was stirred for 30 minutes. The phases were separated, and the aqueous phase washed with ethyl acetate (1 x 15 ml). The combined organic layers were washed with saturated salt solution (1 x 20 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the crude product in the form of oil column chromatography on silica gel (CH2Cl2) resulted in obtaining the desired aldehyde as a pale yellow oil (300 mg, 85%).

1H NMR (300 MHz, CDCl3) δ was 4.76 (d, 2H, J=6.0 Hz), 7,42-7,44 (m, 1H), 7,53 (d, 2H, J=6.0 Hz), 7,87 (d, 2H, J=6.0 Hz), the 7.85-7,88 (m, 1H), 8,24 (d, 1H, J=6.0 G is), 8,55 (SHS, 1H), to 8.57 (d, 1H, J=3.0 Hz), 10,00 (s, 1H).

Using the General methods:To a solution of CIS-1-[N-(tert-butoxycarbonyl)]cyclohexane-1,2-diamine (0,79 g of 3.69 mmol) and 2-pyridinecarboxamide (0.35 ml, 3,68 mmol) in CH2Cl2(20 ml) was added NaBH(OAc)3(0.036 g, or 0.57 mmol)and the mixture was stirred at room temperature overnight. The crude oil used in the next stage without further purification.

1H NMR (CDCl3) δ 1,35-is 1.51 (m, 4H), of 1.44 (s, 9H), 1,54-of 1.64 (m, 3H), 2,01-2,04 (m, 2H), 2,75-and 2.79 (m, 1H), 3,66-3,70 (m, 1H), a 3.87 (d, 1H, J=15 Hz), 3.96 points (d, 1H, J=15 Hz), 5,42 (SHS, 1H, NH), 7,16 (DD, 1H, J=9.6 Hz), 7,30 (d, 1H, J=9 Hz), to 7.61 (TD, 1H, J=9.3 Hz), 8,56 (d, 1H, J=3 Hz).

To the solution obtained above oil and N,N-diisopropylethylamine (of 0.96 ml, 5,52 mmol) in CH2Cl2(10 ml) was added benzylchloride (of 0.64 ml, 4,48 mmol)and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with CH2Cl2(15 ml) and saturated salt solution (25 ml)and the phases were separated. The aqueous phase was washed CH2Cl2(2 x 20 ml)and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the crude product flash chromatography on silica gel (CH2Cl2/Meon, 97:3) yielded di-protected diamine (1.44 g, 89% two steps) as an orange oil.

Destruction In the s-protective groups: the above oil (1.44 g, of 3.28 mmol) was dissolved in CH2Cl2(2 ml), treated triperoxonane acid (2 ml) and the mixture was stirred over night. Conventional treatment has resulted in an orange oil (1,17 g), which was used in the next reaction without further purification.

Using the General methods:To the solution obtained above oil (187 mg) and 4-hydroxymethylbenzene pyridine-2-carboxylic acid (127 mg, of 0.53 mmol) in CH2Cl2(6 ml) was added NaBH(OAc)3(170 mg, 0.80 mmol)and the mixture was stirred at room temperature overnight. Purification of the crude substance flash chromatography on silica gel (CH2Cl2/Meon, 96:4, then 90:10) resulted in obtaining the desired protected amine (150 mg, 50% two steps) as a pale yellow foam.

The removal of the Cbz-group: To a solution of the foam obtained above (150 mg, 0.27 mmol), Meon (5 ml) was added palladium on charcoal (10%, 34 mg), and the mixture was first made (1 atmosphere) at room temperature over night. The reaction mixture was filtered through celite, and pressed the precipitate was washed with methanol. The combined filtrates evaporated under reduced pressure, and the resulting clear oil was purified by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:2:1) to give the free amine (45 mg, 39%) as a clear oil.

Use their total techniques D: The above free base (33 mg, 0,077 mmol) was converted into hydrobromide Sol with getting connectionAMD9541(70 mg) as a white solid.

1H NMR (D2O) δ 1,39-of 1.56 (m, 4H), of 1.62 and 1.75 (m, 2H), 1,92-of 1.97 (m, 2H), 3.27 to and 3.31 (m, 1H), 3,42-of 3.46 (m, 1H), 3,90 (d, 1H, J=17,4 Hz), 4,20 (d, 1H, J=13.5 Hz), 4,33 (d, 1H, J=13.5 Hz), to 4.41 (d, 1H, J=17,4 Hz), 4,59 (s, 2H), 7,35 (d, 2H, J=8.1 Hz), 7,42 (d, 2H, J=8.1 Hz), the 7.85-of 7.90 (m, 2H), 8,11-8,13 (BL, 1H), 8,40-of 8.47 (m, 2H), 8,56-8,63 (m, 2H), 8,82-8,87 (BL, 1H);13C NMR (D2O) δ 19,63, 23,45, 24,83, 27,17, 44,41, 48,33, 49,12, 54,52, 58,88, 125,63, 126,66, 126,85, 129,15 (2 carbon), 130,42, 131,33 (2 carbon), 139,69, 141,47, 144,55, 145,00, 147,16, 147,45 (2 carbon), 155,72, 162,53; ES-MS m/z 430 (M+H).

EXAMPLE 55

The inhibition induced chemokine receipt of Sa measured by FLIPR (molecular devices)

Reagents:

Used dye: Fluo-3, AM (Molecular Probes F-1241) was dissolved in anhydrous DMSO and stored frozen in the form of an aliquot. To increase the solubility of the dye in your environment to the basic solution of Fluo-3 was added to 10% (wt./about.) plutonomy acid (Molecular Probes F-127) immediately before use.

Buffer returns:

HBSS + 20 mm Hepes

Buffer + 0.2% BSA, pH 7.4. HBSS 10x [(wt./about. Phenol red and sodium bicarbonate (Gibco 14065-049)]; Hepes buffer 1 M (Gibco 15630-056), BSA (Sigma A). Buffer revenues were subjected to vacuum filtration and stored in the refrigerator for up to 5 days. Before applying the experience of the buffer was heated at 37° C in a water bath.

Antagonists:

Test compounds were diluted in buffer receipts at the desired concentration and added to 4 wells of a black microplate (4 parallel measurements of the connection). Used the following control wells: 100% response control (without inhibition)was added to the buffer for admission; control 100% of inhibition: chemokine was added at a concentration which is 5 times the concentration that is required for the induction of Sa receipt.

Preparation of tablet experience with agonist (chemokine)

Chemokines were diluted in buffer receipts up to concentrations that are 4 times higher than the required concentrations for stimulation of the cells (i.e. 2.5 nm for SDF-1α and 0.6 nm for RANTES). Chemokines were added to untreated 96-well tablets Sero well compound plates (International Medical, Sterilin code 611F96). In wells with a negative control (monitoring baseline) was added to the buffer receipts instead of the chemokine. As a positive control to test the effectiveness staining, 20 μm of digitonin (final concentration) was also included. Tablet agonist incubated in a FLIPR (37°C) for 15-30 minutes.

Protocol for the measurement of inhibition of SDF-1α-induced receipt of CA in SUP-T1 cells load cells.

SUP-T1 cells were centrifuged at room temp is the temperature (RT) and resuspendable used in medium (RPMI-1640, containing 2% FBS and 4 μm Fluo-3, AM). Cells were incubated at room temperature for 45 minutes, then washed twice in buffer a receipt, and then incubated in buffer revenues at room temperature for 10 minutes. Cells were centrifuged and resuspendable buffer receipts at a density of 3x106cells / ml. Aliquot of 100 μl of cell suspension (3x105cells) was added to each well black microplate (Costar 3603), which already contained 50 μl of a solution of test compounds (at concentrations that are 3 times higher than the desired final concentration of the compound). Then the microplate gently centrifuged at room temperature. A homogeneous distribution of cells on the bottom of the wells of the microplate was then confirmed using a microscope and the microplate was incubated in FLIPR (37°C) for 10 minutes before testing.

Measurement of fluorescence as a function of time on FLIPR

The settings FLIPR (the camera exposure time and laser power) was summed to obtain the original value of fluorescence between 8000 and 10,000 units. After checking 20-second baseline agonist (chemokine) (50 ml) was added using pipettor with black pipette tips. Fluorescence was measured simultaneously in all the wells of the microplate every 2 seconds (the first is e 2 minutes) and after that every 6 seconds (2 minutes). The average income of Sa measured in each of a series of 4 identical holes (one test connection), was calculated using FLIPR.

Compounds according to the present invention was tested in relation to inhibition of SDF-1α-induced receipt of CA in SUP-T1 cells using the above method. Illustrated compounds showed inhibition. The following compounds inhibited SDF-1α-induced Sa receipt of more than 20% at 20 μg/ml:

Numbers examples: 2, 4, 11, 17, 45, 48.

EXAMPLE 56

The study of inhibition of HIV-1 (NL4.3) replication in MT-4 cells.

The study of inhibition of HIV-1 NL4.3 (or IIIBthe use CXCR4) replication was performed as described previously (Bridger et al. J.Med.Chem. 1999, 42, 3971-3981; De Clercq et al. Proc. Natl. Acad. Sci, 1992, 89, 5286-5290; De Clercq et al. Antimicrob. Agents Chemother. 1994, 38, 668-674; Bridger et al, J. Med. Chem. 1995, 38, 366-378; Schols et al, J. Exp. Med., 1997, 186, 1383-1388). In parallel was performed by measuring anti-HIV activity and cytotoxicity. They were based on the degree of survival of MT-4 cells, which were infected with HIV in the presence of various concentrations of test compounds. After MT-4 cells proliferated within 5 days, the number of viable cells was quantified using based on tetrazolium colorimetric method using 3-(4,5-di is utilitiesa-2-yl)-2,5-diphenyltetrazolium (MTT) in 96-well plates. In all experiments, the introduction of the virus (multiplicity of infection, MOI) was 0.01 or 100 times more infective dose 50% cell culture (CCID50). An EC50was defined as the concentration required to protect 50% of virus-infected cells against viral cytopathology.

When the compounds according to the present invention was tested on inhibition of HIV-1 NL4.3 or IIIBreplication in MT-4 cells, all compounds showed inhibitory activity. The following compounds showed values EU50less than 20 mcg/ml:

Numbers examples: 2, 4, 11, 17, 45, 48, 53.

EXAMPLE 57

The study of inhibition of HIV-1 (BaL) replication in PBMC

When the compounds according to the present invention was tested on inhibition of HIV-1 Bal (using CCR5) replication in RNA-stimulated cells RVMS (mononuclear cells peripheral blood), using the expression of the viral P24 antigen (De Clercq et al. Antimicrob. Agents Chemother., 1994, 38, 668-674; Schols et al. J. Exp. Med., 1997, 186, 1383-1388), all showed inhibitory activity. The following compounds showed values EU50less than 20 mcg/ml:

Numbers examples: 2, 4, 11, 16, 17, 48, 53.

According to the above methods were also obtained following connections:

1.

3,5-dichloro-N-(4-{[(1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydro the quinoline-8-yl)amino] methyl}benzyl)isonicotinate

2.

3,5-dichloro-N-(3-{[(1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3.

3,5-dichloro-N-(4-{[(2-methyl-1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

4.

3,5-dichloro-N-(3-{[(2-methyl-1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

5.

3,5-dichloro-N-(4-{[(5-methyl-1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

6.

3,5-dichloro-N-(3-{[(5-methyl-1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

7.

3,5-dichloro-N-(4-{[(2,5-dimethyl-1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

8.

3,5-dichloro-N-(3-{[(2,5-dimethyl-1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

9.

3,5-dichloro-N-(4-{[(1-methyl-1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl&x0007D; benzyl)isonicotinamide

10.

3,5-dichloro-N-(3-{[(1-methyl-1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

11.

3,5-dichloro-N-(4-{[(1,2-dimethyl-1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

12.

3,5-dichloro-N-(3-{[(1,2-dimethyl-1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

13.

3,5-dichloro-N-(4-{[(1,5-dimethyl-1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

14.

3,5-dichloro-N-(3-{[(1,5-dimethyl-1H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

15.

3,5-dichloro-N-(4-{[(1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

16.

3,5-dichloro-N-(3-{[(1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

17.

3,5-dichloro-N-(4-{[(4-methyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}b is nil)isonicotinamide

18.

3,5-dichloro-N-(3-{[(4-methyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

19.

3,5-dichloro-N-(4-{[[4-(2-forfinal)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(4-{[[4-(3-forfinal)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(4-{[[4-(4-forfinal)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

20.

3,5-dichloro-N-(3-{[[4-(2-forfinal)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(3-{[[4-(3-forfinal)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(3-{[[4-(4-forfinal)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

21.

3,5-dichloro-N-(4-{[(4-phenyl-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

22.

3,5-dichloro-N-(3-&x0007B; [(4-phenyl-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

23.

3,5-dichloro-N-(4-{[(2-phenyl-3H-imidazol-4-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

24.

3,5-dichloro-N-(4-{[[2-(2-methoxyphenyl)-3H-imidazol-4-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(4-{[[2-(3-methoxyphenyl)-3H-imidazol-4-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(4-{[[2-(4-methoxyphenyl)-3H-imidazol-4-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

25.

3,5-dichloro-N-(3-{[[2-(2-methoxyphenyl)-3H-imidazol-4-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(3-{[[2-(3-methoxyphenyl)-3H-imidazol-4-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(3-{[[2-(4-methoxyphenyl)-3H-imidazol-4-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

26.

3,5-dichloro-N-(4-{[[4-(2-methoxyphenyl)-niridazole-2-ylmethyl] -(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(4-{[[4-(3-methoxyphenyl)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(4-{[[4-(4-methoxyphenyl)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

27.

3,5-dichloro-N-(3-{[[4-(2-methoxyphenyl)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(3-{[[4-(3-methoxyphenyl)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(3-{[[4-(4-methoxyphenyl)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

28.

3,5-dichloro-N-(4-{[(3H-pyrrol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

29.

3,5-dichloro-N-(3-{[(3H-pyrrol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

30.

3,5-dichloro-N-(4-{[(5-methyl-3H-pyrrol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

,5-dichloro-N-(4-{ [(4-methyl-3H-pyrrol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

31.

3,5-dichloro-N-(3-{[(5-methyl-3H-pyrrol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(3-{[(4-methyl-3H-pyrrol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

32.

3,5-dichloro-N-(4-{[oxazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

33.

3,5-dichloro-N-(4-{[(4-methoxazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(4-{[(5-methoxazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

34.

3,5-dichloro-N-(4-{[oxazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

35.

3,5-dichloro-N-(4-{[(2 methoxazole-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

36.

3,5-dichloro-N-(3-{[oxazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

37.

3,5-dichloro-N-(3-{[(4-methoxazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(3-{[(5-methoxazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

38.

3,5-dichloro-N-(3-{[oxazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

39.

3,5-dichloro-N-(3-{[(2 methoxazole-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

40.

3,5-dichloro-N-(4-{[(5,6,7,8-tetrahydroquinolin-8-yl)thiazol-2-ylmethylamino]methyl}benzyl)isonicotinamide

41.

3,5-dichloro-N-(4-{[(4-methylthiazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(4-{[(5-methylthiazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

42.

3,5-dichloro-N-(4-{[(5,6,7,8-tetrahydroquinolin-8-yl)thiazole-4-ylmethylamino]methyl}benzyl)isonicotinamide

43.

3,5-dichloro-N-(4-{[(2 methylthiazole-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

44.

3,5-dichloro-N-(3-{[(5,6,7,8-tetrahydroquinolin-8-yl)thiazol-2-ylmethylamino]methyl}benzyl)isonicotinamide

45.

3,5-dichloro-N-(3-{[(4-methylthiazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(3-{[(5-methylthiazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

46.

3,5-dichloro-N-(3-{[(5,6,7,8-tetrahydroquinolin-8-yl)thiazole-4-ylmethylamino]methyl}benzyl)isonicotinamide

47.

3,5-dichloro-N-(3-{[(2 methylthiazole-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

48.

3,5-dichloro-N-(4-{[(1H-indol-3-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

49.

3,5-dichloro-N-(4-{[(1-methyl-1H-indol-3-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

50.

3,5-dichloro-N-(4-{[(1H-indol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

51.

3,5-dichloro-N-(4-{[(1-methyl-1H-indole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl} benzyl)isonicotinamide

52.

3,5-dichloro-N-(3-{[(1H-indol-3-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

53.

3,5-dichloro-N-(3-{[(1-methyl-1H-indol-3-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

54.

3,5-dichloro-N-(3-{[(1H-indol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

55.

3,5-dichloro-N-(3-{[(1-methyl-1H-indole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

56.

N-(4-{[[2-(1H-benzimidazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

57.

N-(3-{[[2-(1H-benzimidazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

58.

3,5-dichloro-N-(4-{[[2-(1-methyl-1H-benzimidazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

59.

3,5-dichloro-N-(3-{[[2-(1-methyl-1H-benzimidazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin--yl)amino] methyl}benzyl)for 3,5-dichlorosalicylic

60.

3,5-dichloro-N-(4-{[[2-(1H-imidazol-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

61.

3,5-dichloro-N-(3-{[[2-(1H-imidazol-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

62.

3,5-dichloro-N-(4-{[[2-(1-methyl-1H-imidazol-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

63.

3,5-dichloro-N-(3-{[[2-(1-methyl-1H-imidazol-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

64.

3,5-dichloro-N-(4-{[[2-(3H-imidazol-4-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

65.

3,5-dichloro-N-(3-{[[2-(3H-imidazol-4-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

66.

3,5-dichloro-N-(4-{[[2-(3-methyl-3H-imidazol-4-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

67.

3,5-dichloro-N-(3-{[[2-(3-methyl-3H-and idazole-4-yl)ethyl] -(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

68.

3,5-dichloro-N-(4-{[(2 oxazol-5-retil)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

69.

3,5-dichloro-N-(4-{[[2-(2-methoxazole-5-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

70.

3,5-dichloro-N-(3-{[(2 oxazol-5-retil)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

71.

3,5-dichloro-N-(3-{[[2-(2-methoxazole-5-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

72.

3,5-dichloro-N-(4-{[(2 oxazol-2-retil)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

73.

3,5-dichloro-N-(3-{[(2 oxazol-2-retil)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

74.

3,5-dichloro-N-(4-{[[2-(4-methoxazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(4-{[[2-(5-methoxazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}gasoline is)isonicotinamide

75.

3,5-dichloro-N-(3-{[[2-(4-methoxazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

3,5-dichloro-N-(3-{[[2-(5-methoxazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

76.

N-(4-{[{2-[(1H-benzimidazole-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

77.

N-(3-{[{2-[(1H-benzimidazole-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

78.

3,5-dichloro-N-(4-{[{2-[(1-methyl-1H-benzimidazole-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

79.

3,5-dichloro-N-(3-{[{2-[(1-methyl-1H-benzimidazole-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

80.

3,5-dichloro-N-(4-{[{2-[(1-methyl-1H-imidazol-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

81.

3,5-dichloro-N-(3-{[{2-[(1-methyl-1H-imidazol-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

82.

3,5-dichloro-N-(4-{[{2-[(1H-imidazol-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

83.

3,5-dichloro-N-(3-{[{2-[(1H-imidazol-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

84.

3,5-dichloro-N-(4-{[{2-[(3H-imidazol-4-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

85.

3,5-dichloro-N-(3-{[{2-[(3H-imidazol-4-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

86.

3,5-dichloro-N-(4-{[{2-[(2-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

87.

3,5-dichloro-N-(3-{[{2-[(2-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

88.

3,5-dichloro-N-(4-{[{2-[(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

89.

3,5-dichloro-N-(3-{[{2-[(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

90.

3,5-dichloro-N-(4-{[piperidine-4-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

91.

3,5-dichloro-N-(3-{[piperidine-4-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

92.

3,5-dichloro-N-(4-{[pyrrolidin-3-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

93.

3,5-dichloro-N-(3-{[pyrrolidin-3-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)isonicotinamide

94.

N-(4-{[(3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-diethylnicotinamide

95.

N-(3-{[(3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-diethylnicotinamide

96.

2,4-dim the Teal-N-(4-{ [(3-methyl-3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

97.

2,4-dimethyl-N-(3-{[(3-methyl-3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

98.

2,4,N-trimethyl-N-(4-{[(3-methyl-3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

99.

2,4,N-trimethyl-N-(3-{[(3-methyl-3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

100.

N-(4-{[(1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-diethylnicotinamide

101.

N-(3-{[(1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-diethylnicotinamide

102.

2,4-dimethyl-N-(4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

103.

2,4-dimethyl-N-(3-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

104.

2,4-dimethyl-N-(4-{[oxazol-2-ylmethyl-(5,67,8-tetrahydroquinolin-8-yl)amino] methyl}benzyl)nicotinamide

105.

2,4-dimethyl-N-(3-{[oxazol-2-ylmethyl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

106.

2,4-dimethyl-N-(4-{[oxazol-5-ylmethyl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

107.

2,4-dimethyl-N-(3-{[oxazol-5-ylmethyl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

108.

2,4-dimethyl-N-(4-{[(5,6,7,8-tetrahydroquinolin-8-yl)thiazole-5-ylmethylamino]methyl}benzyl)nicotinamide

109.

2,4-dimethyl-N-(3-{[(5,6,7,8-tetrahydroquinolin-8-yl)thiazole-5-ylmethylamino]methyl}benzyl)nicotinamide

110.

2,4-dimethyl-N-(4-{[(5,6,7,8-tetrahydroquinolin-8-yl)thiazol-2-ylmethylamino]methyl}benzyl)nicotinamide

111.

2,4-dimethyl-N-(3-{[(5,6,7,8-tetrahydroquinolin-8-yl)thiazol-2-ylmethylamino]methyl}benzyl)nicotinamide

112.

2,4-dimethyl-N-(4-{[piperidine-4-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

113.

2,4-dimethyl-N-(3-{[piperidine-4-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino] methyl}benzyl)nicotinamide

114.

2,4-dimethyl-N-(4-{[piperidine-3-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

115.

2,4-dimethyl-N-(3-{[piperidine-3-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

116.

2,4-dimethyl-N-(4-{[pyrrolidin-3-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

117

2,4-dimethyl-N-(3-{[pyrrolidin-3-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

118.

N-(4-{[[2-(1H-benzimidazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-diethylnicotinamide

119.

N-(3-{[[2-(1H-benzimidazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-diethylnicotinamide

120.

2,4-dimethyl-N-(4-{[[2-(1-methyl-1H-benzimidazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

121.

2,4-dimethyl-N-(3-{[[2-(1-methyl-1H-benzimidazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotina is d

122.

N-(4-{[[2-(1H-imidazol-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-diethylnicotinamide

123.

N-(3-{[[2-(1H-imidazol-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-diethylnicotinamide

124.

N-(4-{[[2-(3H-imidazol-4-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-diethylnicotinamide

125.

N-(3-{[[2-(3H-imidazol-4-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-2,4-diethylnicotinamide

126.

2,4-dimethyl-N-(4-{[[2-(3-methyl-3H-imidazol-4-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

127.

2,4-dimethyl-N-(3-{[[2-(3-methyl-3H-imidazol-4-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

128.

2,4-dimethyl-N-(4-{[(2 oxazol-5-retil)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

129.

2,4-dimethyl-N-(3-{[(2 oxazol-5-retil)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)nicotinamide

10.

2,4-dimethyl-N-(4-{[(5,6,7,8-tetrahydroquinolin-8-yl)-(2-thiazole-5-retil)amino]methyl}benzyl)nicotinamide

131.

2,4-dimethyl-N-(3-{[(5,6,7,8-tetrahydroquinolin-8-yl)-(2-thiazole-5-retil)amino]methyl}benzyl)nicotinamide

132.

2,4-dimethyl-N-(4-{[(5,6,7,8-tetrahydroquinolin-8-yl)-(2-thiazol-2-retil)amino]methyl}benzyl)nicotinamide

133.

2,4-dimethyl-N-(3-{[(5,6,7,8-tetrahydroquinolin-8-yl)-(2-thiazol-2-retil)amino]methyl}benzyl)nicotinamide

134.

4-{[(3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

135.

3-{[(3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

136.

4-{[(2-methyl-3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

137.

3-{[(2-methyl-3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

138.

4-{[(3-methyl-3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

139.

3-{[(3-methyl-3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

140.

4-{[oxazol-5-ylmethyl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

141.

3-{[oxazol-5-ylmethyl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

142.

4-{[(5,6,7,8-tetrahydroquinolin-8-yl)thiazole-5-ylmethylamino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

143.

3-{[(5,6,7,8-tetrahydroquinolin-8-yl)thiazole-5-ylmethylamino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

144.

4-{[(1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

145.

3-{[(1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methylD; benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

146.

4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

147.

3-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

148.

4-{[oxazol-2-ylmethyl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

149.

3-{[oxazol-2-ylmethyl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

150.

4-{[(5,6,7,8-tetrahydroquinolin-8-yl)thiazol-2-ylmethylamino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

151.

3-{[(5,6,7,8-tetrahydroquinolin-8-yl)thiazol-2-ylmethylamino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

152.

4-{[piperidine-4-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

153.

3-{ [piperidine-4-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

154.

4-{[piperidine-3-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

155.

3-{[piperidine-3-yl-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

156.

4-{[[2-(1H-benzimidazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

157.

3-{[[2-(1H-benzimidazole-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

158.

4-{[[2-(1H-imidazol-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

159.

3-{[[2-(1H-imidazol-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

160.

4-{[[2-(1-methyl-1H-imidazol-2-yl)ethyl]-(5,6,7,8-Tetra is hydrochinon-8-yl)amino] methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

161.

3-{[[2-(1-methyl-1H-imidazol-2-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

162.

4-{[(2 oxazol-2-retil)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

163.

3-{[(2 oxazol-2-retil)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

164.

4-{[(5,6,7,8-tetrahydroquinolin-8-yl)-(2-thiazol-2-retil)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

165.

3-{[(5,6,7,8-tetrahydroquinolin-8-yl)-(2-thiazol-2-retil)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

166.

4-{[[2-(3H-imidazol-4-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

167.

3-{[[2-(3H-imidazol-4-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic KIS is the notes

168.

4-{[[2-(3-methyl-3H-imidazol-4-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

169.

3-{[[2-(3-methyl-3H-imidazol-4-yl)ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

170.

4-{[(2 oxazol-5-ileti]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

171.

3-{[(2 oxazol-5-ileti]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

172.

4-{[(5,6,7,8-tetrahydroquinolin-8-yl)-(2-thiazole-5-retil)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

173.

3-{[(5,6,7,8-tetrahydroquinolin-8-yl)-(2-thiazole-5-retil)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

174.

4-{[{2-[(1H-benzimidazole-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

175.

3-{[{2-[(1H-benzimidazole-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

176.

4-{[{2-[(1H-imidazol-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

177.

3-{[{2-[(1H-imidazol-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

178.

4-[((5,6,7,8-tetrahydroquinolin-8-yl)-{2-[(thiazol-2-ylmethyl)amino]ethyl}amino)methyl]benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

179.

3-[((5,6,7,8-tetrahydroquinolin-8-yl)-{2-[(thiazol-2-ylmethyl)amino]ethyl}amino)methyl]benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

180.

4-{[{2-[(oxazol-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

181.

3-{[{2-[(oxazol-2-ylmethyl)amino]ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl)the Mino] methyl}benzylated 4,6-dimethylpyrimidin-5-carboxylic acid

182.

3,5-dichloro-N-{4-[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-ylamino)methyl]benzyl}isonicotinamide

183.

3,5-dichloro-N-{3-[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-ylamino)methyl]benzyl}isonicotinamide

184.

N-(4-{[(1H-benzimidazole-2-ylmethyl)-(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

185.

N-(3-{[(1H-benzimidazole-2-ylmethyl)-(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

186.

3,5-dichloro-N-(4-{[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)isonicotinamide

187.

3,5-dichloro-N-(3-{[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)isonicotinamide

188.

3,5-dichloro-N-(4-{[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-(3H-imidazol-4-ylmethyl)amino]methyl}benzyl)isonicotinamide

189.

3,5-dichloro-N-(3-{[(3,4-di is Idro-2H-pyrano[ 3,2-b]pyridine-4-yl)-(3H-imidazol-4-ylmethyl)amino]methyl}benzyl)isonicotinamide

190.

3,5-dichloro-N-(4-{[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]methyl}benzyl)isonicotinamide

191.

3,5-dichloro-N-(3-{[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]methyl}benzyl)isonicotinamide

192.

3,5-dichloro-N-(4-{[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)piperidine-4-ylamino]methyl}benzyl)isonicotinamide

193.

3,5-dichloro-N-(3-{[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)piperidine-4-ylamino]methyl}benzyl)isonicotinamide

194.

3,5-dichloro-N-(4-{[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)piperidine-3-ylamino]methyl}benzyl)isonicotinamide

195.

3,5-dichloro-N-(3-{[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)piperidine-3-ylamino]methyl}benzyl)isonicotinamide

196.

3,5-dichloro-N-(4-{[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)pyrrolidin-3-ylamino]methyl}benzyl)isonicotinamide

197.

3,5-dichloro-N-(3-{[(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)pyrrolidin-3-ylamino]methyl}benzyl)isonicotinamide

198.

N-(4-{[[2-(1H-benzimidazole-2-yl)ethyl]-(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

199.

N-(3-{[[2-(1H-benzimidazole-2-yl)ethyl]-(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

200.

3,5-dichloro-N-[4-({(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-[2-(1-methyl-1H-benzimidazole-2-yl)ethyl]amino}methyl)benzyl]isonicotinamide

201.

3,5-dichloro-N-[3-({(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-[2-(1-methyl-1H-benzimidazole-2-yl)ethyl]amino}methyl)benzyl]isonicotinamide

202.

3,5-dichloro-N-[4-({(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)ethyl]amino}methyl)benzyl]isonicotinamide

203.

3,5-dichloro-N-[3-({(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)ethyl]amino}methyl)benzyl]isonicotinamide

204.

3,5-dichloro-N-[4-({(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-[2-(3H-imidazol-4-yl)ethyl]amino}methyl)benzyl]isonicotinamide

205.

3,5-dichloro-N-[3-({(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-[2-(3H-imidazol-4-yl)ethyl]amino}methyl)benzyl]isonicotinamide

206.

N-(4-{[{2-[(1H-benzimidazole-2-ylmethyl)amino]ethyl}-(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

207.

N-(3-{[{2-[(1H-benzimidazole-2-ylmethyl)amino]ethyl}-(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)amino]methyl}benzyl)for 3,5-dichlorosalicylic

208.

3,5-dichloro-N-{4-[((3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-{2-[(3H-imidazol-4-ylmethyl)amino]ethyl}amino)methyl]benzyl}isonicotinamide

209.

3,5-dichloro-N-{3-[((3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-{2-[(3H-imidazol-4-ylmethyl)amino]ethyl}amino)methyl]benzyl}isonicotinamide

1. The compound of formula (1)

and its salt,

where X is unsubstituted monocyclic 5 to 6-membered) ring C is a topic containing N; or

X means a condensed bicyclic (9-12-membered) ring system containing N, which can be substituted by the Deputy-SO2is phenyl;

Z represents N or means of condensed bicyclic (9-12-membered) unsubstituted or substituted ring system containing at least one heteroatom, N;

Ar is unsubstituted phenyl ring;

each of the L1L2and L3independently represents a bond, CO, SO2or CH2where at least one of L2and L3must include WITH or SO2;

L2and L3also independently can represent CONH or CONHCH2;

n is 0, 1 or 2;

each R1and R2independently represents an atom H or a straight chain (1-6C)alkyl; and

Y includes at least one substituted or unsubstituted phenyl ring or a 5-6-membered heteroaromatic ring containing at least one heteroatom N;

where the optional substituents selected from the group consisting of halogen,

of alkyl, -COOH, -HE-NH2; or

Y represents 6,7-dihydro-pyrrolo[3,4-b]pyridine-5-he;

where the nitrogen in the ring, optionally, can be oxidized;

provided that excluded

N-(2-pyridylmethyl)-4-(2-what AMINOPHENYL)aminocarbonylmethyl and

N-(3-pyridylmethyl)-4-(2-AMINOPHENYL)aminocarbonylmethyl.

2. The compound according to claim 1, where Z means tetrahydroquinolin.

3. The compound according to claim 1, where L1means alkylene as defined in claim 1, WITH or SO2and X means a benzimidazole or unsubstituted monocyclic 5 to 6-membered) ring system containing at least one heteroatom selected from n

4. The compound according to claim 3, where X represents an optionally substituted imidazole.

5. The compound according to claim 1, where Z denotes hydrogen.

6. The compound according to claim 1, where Y represents optionally substituted imidazole, pyridine, pyrimidine or phenyl, where the nitrogen in the ring, optionally, can be oxidized.

7. The compound according to claim 1, having the formula

or the formula

where l is 0-3, and R' is HE, F, Cl, Br, NH2or Me;

each of the Z1, Z2and Z3independent means SN, CR' or N, where only two of these Z1, Z2and Z3can mean N;

and L2and L3are as defined in claim 1.

8. The connection according to claim 7, where all of the Z1, Z2and Z3represent CH or CR'.

9. The connection according to claim 7, where Z3mean N and L3means.

10. The compound of claim 8 or 9, where one of L2and L3means SO2and the other is a bond or CH 2.

11. The compound of claim 8 or 9, where one of L2and L3means and the other represents a bond or CH2.

12. Pharmaceutical composition for treating conditions which are regulated by the receptor of the chemokine CXCR4 or CCR5, containing an effective amount of at least one compound according to claims 1-11.

13. The use of compounds according to any one of claims 1 to 11 for the manufacture of a medicinal product for treating conditions which are regulated by the receptor of the chemokine CXCR4 or CCR5.

14. The use of compounds according to any one of claims 1 to 11 for the manufacture of a medicinal product for the treatment of HIV or FIV-infected patients.

15. The use of compounds according to any one of claims 1 to 11 for the manufacture of a medicinal product for treating conditions regulated by the receptor of the chemokine in a mammal subject.

Post priorities:

15.09.2000 according to claim 1 according to all signs, except X, means a condensed bicyclic (9-12-membered) ring system containing N, which can be substituted by the Deputy-SO2is phenyl; L2and L3independently represent CONH or CONHCH2; Y represents 6,7-dihydro-pyrrolo[3,4-b]pyridine-5-he;

Fig.6 all signs, except Y denotes a pyrimidine;

7 for all signs, except for the Z1, Z2and Z3every means independently CH or CR'; two of the Z1, Z2 and Z3can mean N;

claim 2, 3, 5, 12-15 by all indications;

17.09.2001 according to claim 1, when X is condensed bicyclic (9-12-membered) ring system containing N, which can be substituted by the Deputy-SO2is phenyl; L2and L3independently represent CONH or CONHCH2; Y represents 6,7-dihydro-pyrrolo[3,4-b]pyridine-5-he;

claim 6, wherein Y denotes a pyrimidine;

7, when Z1, Z2and Z3every means independently CH or CR';

two of the Z1, Z2and Z3can mean N;

claims 4, 8-11, by all indications.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

11 cl, 2 tbl, 27 ex

FIELD: organic chemistry, biochemistry, pharmacy.

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

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FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes phenyl-substituted heterocyclic 1,3-ketoenols of the formula (I): wherein R1 and R3 mean independently of one another ethyl or (C1-C2)-alkoxy-group; Q means the group of the formula (Q1): or (Q2): wherein R4 and R5 in common with atoms to which they are joined form 5-7-membered cycle that can comprise additionally anellated alkylene chain consisting of 2-6 carbon atoms that, in turn, can comprise two heteroatoms taken among oxygen atom, and indicated cycle can be substituted with halogen atom, hydroxy-group, (C1-C6)-alkoxy-group, (C1-C6)-alkoxy-(C1-C6)-alkoxy-group, (C1-C4)-alkylcarbonyloxy-group, hydroxy-(C1-C4)-alkoxy-group, hydroxycarbonyl-(C1-C2)-alkoxy-group, methoxycarbonyl-(C1-C2)-alkoxy-group, methoxyimino-, methoxyethoxyethoxy-group; R6 and R7 means (C1-C10)-alkyl; R8 means hydrogen atom; X means oxygen atom; R20 means (C1-C10)-alkyl, and also agronomically acceptable salts and isomers of these compounds. Also, invention describes a method for preparing compounds of the formula (I), herbicide agent and a method for control of weed growth based on compounds of the formula (I). Invention provides preparing compounds possessing the herbicide activity.

EFFECT: improved preparing method, valuable properties of compounds and agents.

5 cl, 28 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, amino acids, medicine, pharmacy.

SUBSTANCE: invention relates to using derivatives of cysteine for preparing a medicinal agent. The proposed agent is designated for treatment of diseases arising as a result of formation of heterotrimeric protein G, and to new derivatives of cysteine, and pharmaceutical composition based on thereof. Derivatives of cysteine, in particular, involve the following compounds: bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[2,2a]-pyrazine]-disulfide and bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-2-91-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo-[1,2a]-pyrazine-7-yl]-disulfide. Invention provides high effectiveness of treatment.

EFFECT: valuable medicinal properties of compounds.

6 cl, 7 dwg, 2 tbl, 7 ex

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

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

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

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)

or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).

EFFECT: improved preparing methods.

10 cl, 2 sch, 25 tbl, 7 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes using 2-pyrrolidine-6-diphenylamino-4-[(4'-ethoxycarbonyl-5'-methyl-1',2',3'-triazol)-1'-yl]-1,3,5-triazine of the formula: as an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyaxetic acid on sunflower germinated seeds. The proposed compound allows significant increasing roots and hypocotyls length of seedlings and to expand assortment of the known antidotes.

EFFECT: valuable properties of antidote.

2 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to maleic acid substituted bis-indolylimides of the formula (I):

wherein R means -PO3R1R2, -CHR3OCOR4, -CHR3OCO2R4, -CHR3OCONHR4, -COR4; R1 and R2 are taken among the group consisting of H, Na being they are similar but if one among R1 or R2 means H then other means sodium atom (Na); R3 means H or methyl; R4 is taken among the group including (lower)-alkyl that can be substituted optionally with one substitute taken among the group including -CO2R5, -NR6R7, polyethtylene glycol of the formula R9(OCH2CH2)nOH wherein n means an average number from 2 to 1500 with average molecular mass from 500 to 5000 Da and wherein R9 means carboxyl or lower alkyl, (C1-C10)-alkenyl, piperidine, phenyl that can be substituted optionally with one or two substitutes taken among the group including alkoxy-group, alkyl that in turn can be substituted with dialkylamino-group under condition that R4 can not mean (lower)-alkyl in the group -COR4; R5 means H, lower alkyl; R6 and R7 mean H, lower alkyl; or their pharmaceutically acceptable salts. Compounds of the formula (I) possess anti-proliferative effect and can be used in pharmaceutical composition for parenteral administration.

EFFECT: valuable biological and medicinal properties of compounds.

16 cl, 1 tbl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to organic chemistry and can find application in medicine

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

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