Heterocyclic compounds modulating activity of chemokine receptor, their using and pharmaceutical composition containing thereof

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

 

This application claims priority under 35 U.S.C. 119(e) upon request 60/232891, filed September 15, 2000; 60/234510, filed September 22, 2000; the application 0/233087, filed September 15, 2000; and the application 60/234816, filed September 22, 2000. The contents of these applications are included in the present description as a reference.

The technical field

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

Background of invention

Described about 40 chemokines person, which function, at least in part, by modulation of the complex and overlapping sequence of the biological activities that are important for the 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 393, 565-568 (1998); Locati et al., Annu. Rev. Med. 50, 425-40 (1999)). These chemotactic cytokines, or chemokines constitute a family of proteins approximately 8-10 kDa. Chemokines have, obviously, part of the General structural motif, which faced the t 4 saved cysteine, included in the maintenance of 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 a chemokine, which creates a natural ligand of the receptor. Receptors β-chemokines represent "CCR", whereas receptors α-chemokines represent "CXCR".

Chemokines are considered as key mediators in the initiation and maintenance of inflammation (see, "Chemokines in Disease", published by Humana Press (1999), edited by C.Herbert; Murdoch et al., Blood 95, 3032-3042 (2000)). More specifically, it is established that chemokines play an important role in regulating the function of endothelial cells, including proliferation, migration, and differentiation during angiogenesis and re-endothelialization 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 gp120 envelope protein to the CD4 receptor of target cells. Apparently, in gp120 occurs conformational change, which leads to subsequent binding to the chemokine receptor, 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)). HIV-1 isolate (strain) occurs, consequently the AI in infectious binding to the CXCR4 chemokine receptor.

After the initial binding of HIV to CD4 is the fusion of virus-cell, which is mediated by members of the family of chemokine receptors, where various members serve as cofactors merge for Mariah genotype (M genotype) and T-cell line genotype (T genotype) strains 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)). During the process of infection within the body of the patient, it appears that the majority of HIV particles pass from M genotype in 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, 2022-2032, (1988); R.I. Connor, 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 to the CCR5 receptor, whereas T genotype viral phenotype correlates with the ability of the penetration of the virus into the cell after binding and membrane fusion with the CXCR4 receptor. On the basis of clinical observations suggest that patients with genetic mutations in CCR5 are resistant or less susceptible 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)). Although it was reported several chemokine receptors, mediating the integration of HIV into cells, CCR5 and CXCR4 are the only physiologically relevant coreceptors used a wide range of primary clinical HIV-1 strains (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 (1988)). Fusion and penetration T genotype viruses that use CXCR4, inhibited natural ESS-chemokine stromal cell-derived factor-1, whereas the fusion and penetration M-genotype viruses that use CCR5, inhibited natural CC-chemokines, namely regulated when ekspressirovannoj and the normal secretion of the activated T-cell (RANTES) and microwaveability protein (MIP-1 alpha and beta).

Recently it has been suggested that, in addition to the fact that it serves as a cofactor for penetration of HIV, direct interaction between virus-associated gp-120 with CXCR4 as a possible cause of CD8+T-cell apoptosis and related to AIDS dementia due to induction of apoptosis of neural cells (Hesselgesser et al., Curr.Biol., 8, 595-598 (1998); Hesselgesser et al., Curr.Biol., 7, 112-121 (1997); Heddelgesser et al., "Chemokines and Chemokine receptors in the Brain" in "Chemokines in Disease", on oblikovanje Humana Press (1999), edited C.Herbert; 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, the binding of chemokine receptors and their natural ligands, it turns out, plays a more evolutionary and Central role than only as mediators of HIV infection. The binding of the natural ligand, pre-b-cell stimulating growth factor/factor derived stromal cells (PBSF/SDF-1), with the CXCR4 chemokine receptor provides an important signaling mechanism: mouse damage CXCR4 or SDF-1 are cerebral, cardiac anomalies and anomalies of the gastrointestinal tract and die in utero (Zou et al., Nature, 393: 591-594 (1998); Tachibana et al., Nature, 393: 591-594 (1998); Nagasawa et al., Nature 382, 635-638 (1996)). CXCR4-deficient mice also exhibit hematopoietic defects (Nagasawa et al., Nature 382, 635-638 (1996)); the migration of CXCR4-expressing leukocytes and hematopoietic precursors to SDF-1 was important for maintaining b-cell lines and localization of CD34+precursor cells in the bone marrow (Bleul et al., J.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.Leukocte Biol., 66, 667-673 (1999); Peled et al., Blood 95, 3289-3296 (2000)).

The signal provided by SDF-1 upon binding to CXCR4, can also play an important role in the proliferation of tumor cells and the regulation of angiogenesis associated with tumor growth (see, "Chemokines and Cancer", published by Humana press (1999); edited by B.J.Rollins; Arenburg et al., J.Leucocyte 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 adjust to increased levels of CXCR4 in endothelial cells and SDF-1 can induce neovascularization in vivo (Salcedo et al., Am.J.Pathol. 154, 1125-1135 (1999)); leukemia cells that Express CXCR4, migrate together with the lymph nodes and stromal bone marrow cells, which Express SDF-1 (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 binding of SDF-1 with CXCR4 is also involved in the pathogenesis of atherosclerosis (Abi-Yones et al., Circ. Res., 86, 131-138 (2000)), the rejection of the renal allograft (Eitner et al., Transplantation 66, 1551-1557 (1998)), asthmatic and allergic airway inflammation (Yssel et al., Clinical and Experimental 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.Immunl., 164, 5010-5014 (2000)).

For a better understanding of the relationship between chemokines and their receptors have recently been made of the experimental the options to block the merger, penetration and replication of HIV through CXCR4 chemokinesis receptor through the use of monoclonal antibodies or small molecules, which are supposed to offer a useful therapeutic strategy (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, Volume 3, 161-229; published by JAI press (1999); edited by E.De.Clereq). Small molecules, such as Bellamy, show specific binding to CXCR4, but not CCR5 (Donzella et al., Nature Medicine, 4: 72-77 (1998)). These experiments demonstrated the interference of HIV penetration and membrane fusion in a target cell in vitro. Later it was also shown that Bellamy inhibit fusion and replication of Feline Immunodeficiency Virus (FIV), which uses CXCR4 for penetration (Egberink et al., J.Virol., 73, 6346-6352 (1999)).

Additional experiments showed that bicyclam dose-dependently inhibits binding121I-labeled SDF-1 with CXCR4 and signal transduction (revealed by the increase of intracellular calcium in response to SDF-1. Thus, bicyclam also acts as an antagonist of signal transduction resulting from the binding of stromal derived factor or SDF-1α, natural chemokine, with CXCR4. Bellamy also inhibit HIV gp120 (shell)-induced apoptosis in non-the ICH infected cells (Blanco et al., Antimicrobial Agents and Chemother., 44, 51-56 (2000)).

In U.S. patent No. 5583131, 5698546, 5817807, 5021409 and 6001826, which are included in this description in its entirety by reference, describes cyclic compounds that are active against HIV-1 and HIV-2 in in vitro tests. It was subsequently established and additionally described in concurrently pending applications U.S. patent number 09/111895 and 60/172153 that these compounds exhibit anti-HIV activity by binding the chemokine receptor CXCR4 expressed on the surface of certain cells of the immune system. Such competitive binding thus protects such target cells from HIV infection, which uses the receptor CXCR4 for the invasion. In addition these compounds antagonizing binding, signaling and chemotactic action of the natural ligand for XCR4, chemokine factor 1αderived stromal cells (SDF-1). In the future, the authors of this invention, it was found that these new compounds exhibit a protective effect against HIV infection of target cells by binding in vitro with the CCR5 receptor.

In addition, the authors of this invention in the application for U.S. patent number 09/495298 was revealed that such cyclic polyamine antiviral agents described in the above patents, have there is quality, enhancing production of white blood cells, and also have antiviral properties. Thus, these agents can be used to control side effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and the treatment of burns, as well as combating bacterial infections in leukemia.

Later the authors of the present invention in the application for U.S. patent number 09/535314 was discovered a number of heterocyclic compounds, which have anti-HIV activity by binding to chemokine receptors XCR4 and CCR5 expressed on the surface of certain cells of the immune system. Such competitive binding thus protects these target cells from HIV infection, which uses CXCR4 or CCR5 receptors for invasion. In addition these compounds antagonizing binding, signaling and chemotactic action of the natural ligand for XCR4, chemokine factor 1αderived stromal cells (SDF-1), and/or natural ligand for CCR5, the chemokine RANTES.

The present invention describes novel compounds having a protective effect against HIV infection of target cells by binding to the chemokine receptor CXCR4 or CCR5 similar manner as previously described macrocyclic compounds. In addition, danyushevsky antagonizing linking, signaling and chemotactic action of the natural ligand for XCR4, chemokine factor 1αderived stromal cells (SDF-1), and/or natural ligand for CCR5, the chemokine RANTES.

Quoting the above publications should not be construed as an admission that any of the above is a relevant prior development of this area. All provisions regarding the date or claims regarding the content of these publications is based on information available to the applicant, and do not constitute any admission as to the correctness of the dates or contents of these publications. In addition, all publications cited in the text of the application included in this description in its entirety by reference.

Summary of the invention

The present invention relates to new compounds that bind chemokine receptors and prevent their binding to natural ligands. Compounds of the present invention can be used as agents, demonstrating a protective effect for target cells against HIV infection. Other variants of implementation of the present invention are compounds that act as antagonists or agonists of chemokine receptors, and also have other kinds of biological activity which, related to the ability of these compounds to inhibit the binding of chemokines to their receptors.

Compounds according to the invention have the formula (1), including their pharmaceutically acceptable salts and proletarienne form. The compounds of formula (1) have the formula:

where

ring And optionally includes a heteroatom selected from N, O and S;

dotted lines represent optional unsaturation;

R1, R2and R3represent substituents that do not create obstacles;

k is 0-4;

l is 0, 1 or 2;

X is unsubstituted or substituted With, or N, or represents O or S;

Ar represents a residue of an aromatic or heteroaromatic fragment;

each n independently equals 0-2;

each R independently represents H or alkyl(1-6C);

j equal to 0 to 3; and

each Y independently is an optional Deputy, not creating obstacles, as defined herein, is different from CR2NR(CR2)nB, where a is aromatic or heteroaromatic, or another heterocycle.

Preferably, each Y independently represents halogen, HE, SH, SO, SO2or organic fragment from 1 to 20 C atoms, which does not contain N, where two such Y can be associated with the formation of a condensed ring with Ar, or selected from the group status is the present of

and those where Y includes guanidino or NHNHR, or amidino;

where Z represents an optionally substituted aromatic or heteroaromatic fragment containing 5-12 ring members; and

where R is as defined above, each m is independently equal to 0-4, and R4and each R5independently represents H, alkyl (1-6C), alkenyl (1-6C), quinil (1-6C) or acyl (1-6C), each of which is optionally substituted by one or more nonaromatic(and), vegetarianism(and) substituent(s), and where two R5may be associated with the formation of a cyclic amine, optionally containing one or more additional heteroatoms selected from N, O and S.

Compounds of the invention specifically exclude options for implementation, where Y represents CR2NR(CR2)nB, where a is aromatic or heteroaromatic, or another heterocycle.

Optional substituents defined below.

The invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of the compounds of formula (1); methods of treatment of diseases of the human organism or organisms other mammals, including the introduction of such pharmaceutical compositions, and method for blocking or preventing the binding of the chemokine receptor with its natural Li gang is om, including contacting the indicated chemokine receptor with an effective amount of the compounds of formula (1).

This invention also relates to the use of compounds of formula (1) to obtain drugs for the treatment of diseases in which the blocking or preventing the binding of the chemokine receptor with its natural ligand is favorable, and this method may include the preparation of(getting) a composition comprising a therapeutically effective amount of the compounds of formula (1). The invention is also a method of protection of target cells with chemokine receptors, binding with which the pathogenic agent causes disease or pathology, comprising the administration to a mammal a pharmaceutical composition comprising a therapeutically effective amount of the compounds of formula (1).

The compounds according to the invention can be moulded into the form of a prodrug, that is, protected forms of the compounds, which release the compound after administration to the patient. For example, the connection may have a protective group, which hatshepsuts hydrolysis in body fluids, for example in the circulation, thus releasing the active compound, or oxidized, or restored in body fluids, releasing the connection. Discussion p is lekarstv can be found in "Smith and Williams' Introduction to the Principles of Drug Design", H.J.Smith, Wright, Second Edition, London, 1988.

Acid additive salts which are pharmaceutically acceptable, such as a salt with inorganic base, a salt with organic base, salt with inorganic acid, salt with organic acid, salt with basic or acidic amino acid, etc. are also covered by the present invention. Examples of the salt with inorganic base include a salt with alkali metal (e.g. sodium, potassium etc), alkaline earth metal (e.g. calcium, magnesium etc), aluminum, 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. are Examples of the salt with inorganic acid include a salt with hydrochloric 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, methanesulfonic acid, benzosulfimide acid, malic acid, p-toluensulfonate acid, etc. Examples of salts with basic amino acid include a salt with arginine, lysine, ornithine, etc. Examples of salts with acidic amino acids include the salt with aspartamus acid, glutamic acid, etc. the Term "non-toxic" in this context should be considered taking into account the forecast for the infected patient is not treated.

Ways of carrying out the invention

The present invention relates to compounds of formula (1), which can act as agents for modulation of the activity of the chemokine receptor. Such chemokine receptors include, but are not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 and CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5, preferably CXR4 and/or CCR5.

Compounds affect the binding of the natural ligand or chemokine to the receptor of target cells, such as CXR4 and/or CCR5.

Thus, the compounds have an effect on chemokine receptors such as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 and CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5, where such chemokine receptors are important mediators of many inflammatory processes in humans and immunoregulatory disease and cancer, and modulate the activity of these chemokine receptors in such a way as to be useful for the treatment or prevention of such diseases.

In particular, the compounds of formula (1) have protective effects on target cells against HIV infection, the method comprising specific binding to the chemokine receptor.

It is implied that the term "modulate," as it is used in the present description, includes an antagonist, agonist, partial antagonist and/or a partial agonist, inhibitors and activators. In a preferred embodiment of the present invention the compounds of formula (1) demonstrate a protective effect against HIV infection by inhibiting the binding of HIV chemokine receptor target cells, such as CXR4 and/or CCR5. The invention includes a method that includes contacting the target cell with an amount of compound effective to inhibit binding to the chemokine receptor.

The term "therapeutically effective amount" means the number of connections, which is achieved by biological or medical response in a cell, tissue, organ, system, animal or human being, which is required for the researcher, veterinarian, physician, or other clinical doctor.

The term "introduction" and/or "use as directed" presents the connection should be understood as meaning the provision of connection according to the invention, including the prodrug compounds according to the invention, the individual in need of treatment.

Compounds according to the invention that inhibit chemokine receptors, can be used to treat both prevention and therapy of diseases associated with hematopoiesis (CR what otvorenie), including, but not limited to, controlling the side effects of chemotherapy, increasing the success of bone marrow transplantation, enhancing wound healing and the treatment of burns, as well as for combating bacterial infections in leukemia.

Compounds according to the invention, which inhibit the activity and function of the chemokine receptor, 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, hypersensitivity pneumonia, eosinophilic pneumonia, allergic delayed-type interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, multiple sclerosis, Sjogren syndrome (xeroderma), polymyositis or dermatomyositis); systemic anaphylaxis or allergic reactions, allergies to medicines, allergies to insect bites, autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, asthenic bulbar palsy, juvenile diabetes, acute glomerulonephritis, autoimmune Trodat, graft rejection, including allograft rejection or disease is the development of graft-versus-host; inflammatory bowel disease such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including mediated by T-cells in psoriasis) and inflammatory skin diseases such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, nettle fever, vasculitis (e.g., nekrotizirovannye, skin and allergic vasculitis); eosinophilic, miotic, eosinophilic fasciitis; cancers.

Compounds according to the invention, which can activate or maintain the function of the chemokine receptor, can be used for the treatment of diseases that are associated with immune suppression, such as individuals undergoing chemotherapy, radiation therapy, to enhance the healing of wounds and burns treatment, therapy for autoimmune disease or other drug therapy (corticosteroid therapy) or combination of conventional drugs used in the treatment of autoimmune diseases and graft rejection/transplantation, which causes immunosuppression; c immunosuppression due to congenital deficiency of function of the receptor or in other cases; in infectious diseases, such as diseases caused by parasites, including, but not limited to, infection by helminths, so the mi as nematodes (round worms); trichocephalosis, enterobiasis, ascariasis, hookworm, Strongyloides, trichinosis, hilariuos; trematodes, visceral worms, visceral larva (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larvae (Ancylostona brazilliense, Acylostoma caninum); causing malaria protozoa Plasmodium vivax, human cytomegalovirus, herpes virus herpersvirus saimiri and herpesvirus that causes Kaposi's sarcoma, also known as human herpes virus 8, and skin virus Moluscum contagiosum.

One or more compounds of formula (1) can be used in combination with any other pharmaceutical composition, where such combination therapy modulates the activity of a chemokine receptor and thus prevents and treats diseases associated with hematopoiesis, inflammation, autoimmune diseases, inflammatory skin diseases, cancer, inflammatory bowel disease and disorders of immune regulation.

It is also assumed that the present invention can be used in combination with one or more agents useful for the prevention or treatment of HIV. Examples of such agents include:

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

(2) a non-nucleotide inhibitor revertase (reverse transcriptase) (including the agent with antioxidant activity, such as Immunocal, oltipraz etc), such as nevirapine, delavirdine, efavirenz, loviride, Immunocal, oltipraz etc.; and

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

The amount of combinations of compounds of formula (1) with HIV agents is not limited to paragraphs (1), (2) and (3), but includes in principle any combination with any pharmaceutical composition useful for the treatment of HIV. In addition, combinations of compounds of the present invention and other HIV agents can be entered separately or together. Additionally, the introduction of one element can be conducted before, together or after administration of other agent(s).

The compounds of formula (1) can be administered orally, parenterally (for example intramuscularly, intraperitoneally, intravenously, by intracisternal injection or infusion, subcutaneous injection, or implant), inhalation spray, nasal, vaginal, rectal, sublingual, or by using local routes of administration, and can be used in obtaining drugs, separately or together, in suitable standard preparative dosage forms containing the usual detoxi the data pharmaceutically acceptable carriers, adjuvant and distribution tools that are appropriate for each route of administration.

All the compounds of formula (1) are active and are used to treat animals, including, but not limited to, mice, rats, horses, cattle, sheep, dogs, cats and monkeys. Compounds according to the invention are also effective for use in humans.

The compounds of formula (1) may form a hydrate or a solvate. Those compounds of formula (1), which can exist in the form of regioisomers, configurational isomers, conformers or diastereoisomeric forms, can occur in the form of mixtures of such forms. If desired, the mixture can be processed in such a way as to isolate individual isomers using well-known methods of separation and purification. For example, when the compound of formula (1) represents the racemate, it can be divided into (S)-compound and (R)-connection by optical separation. Individual optical isomers and their mixtures are also included in the scope of the present invention.

This invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and an effective amount of the compounds of formula (1). The compound of formula (1) can be entered by itself or they can be administered orally or non-orally in the form of a mixture with a pharmaceutically pickup is acceptable carrier (e.g., solid preparative dosage forms such as tablets, capsules, granules, powders, etc.; preparative liquid dosage forms, such as syrups, injections, etc). Examples of non-oral formulation of dosage forms include injections, drops, suppositories, pessaries.

In the treatment or prevention of painful conditions that require modulation of the chemokine receptor, an appropriate dosage level will generally be about 0.01 to 500 mg per kg of body weight of the patient per day, which can be entered as a single dose or multiple doses. Preferably, the dose level will be from about 0.1 to about 250 mg/kg per day. It should be understood that the specific dose level and frequency of dosage for each individual patient can vary and will depend on many factors, including the activity of the specific compound, the metabolic stability and length of action of the compound, the age, body weight, General health, sex, diet, mode and time of administration, rate of excretion, combination of drugs, the severity of the specific disease and the patient undergoing treatment.

The present invention additionally relates to new compounds that bind chemokine receptors and prevent their link is iwaniw with the natural ligand. Compounds of the present invention can be used as agents exhibiting a protective effect for target cells from HIV infection. Compounds of the present invention can also be used as antagonists or agonists of chemokine receptors, and other biological activities related to the ability of such compounds to inhibit the binding of chemokines to their receptors.

Additional definition of deputies

In the compounds of formula (1) R can represent a linear or branched alkyl or may be cyclic, and optionally may be substituted by 1-2 substituents selected from halogen, hydroxy and alkoxy. Preferably each R is H or lower linear alkyl (1-4C), preferably methyl.

Ar represents a residue of an aromatic or heteroaromatic fragment that contains a single or condensed ring system and contains 5-6 ring members in a monocyclic system and 9-12 members in the condensed ring system. The residue is optionally may be substituted. Examples of optionally substituted aromatic and heteroaromatic groups include benzene, naphthalene, dihydronaphthalene, tetrahydronaphthalene, pyridine, quinoline, isoquinoline, imidazole, benzimidazole, azobenzenes, benzotriazole, furan, benzofuran,thiazole, benzothiazole, oxazole, benzoxazole, pyrrole, indole, imidazole, tetrahydroquinolin, tetrahydroisoquinoline, pyrazole, thiophene, isoxazol, isothiazol, triazole, tetrazole, oxadiazole, thiadiazole, imidazole and benzopyran. The present invention also includes heteroaromatic ring containing nitrogen and sulphur oxides. Particularly preferred forms of Ar is phenylene, peridinin or peridinin.

When the compounds of formula (1) contain elements that are "optionally substituted"such substituents preferably represent halogen, nitro, cyano, carboxylic acid, optionally substituted alkyl, alkeline or cycloalkyl group, optionally substituted hydroxyl group, optionally substituted Tilney group, optionally substituted by an amino group, an optionally substituted acyl group, optionally substituted carboxylate, urethane, carboxamido or sulfonamidnuyu group or optionally substituted aromatic or heterocyclic group.

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

Examples of optionally substituted alkyl include1-10alkyl, including methyl, ethyl, propyl, etc.; examples of the optionally substituted alkenyl groups include2-10alkenyl, takoyaki 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 these cases With1-6alkyl, alkenyl and cycloalkyl are preferred. Optional Deputy may also be an optionally substituted aralkyl (for example, phenyl With1-4alkyl) or heteroalkyl, for example, phenylmethyl (benzyl), phenylethyl, pyridinylmethyl, pyridinylmethyl etc. Heterocyclic group may be a 5 - or 6-membered ring containing 1-4 heteroatom.

Examples of the optionally substituted hydroxyl and Tilney groups include those in which the Deputy is an optionally substituted alkyl (for example, C1-10alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl etc., preferably (C1-6) alkyl; optionally substituted cycloalkyl (for example, C3-7cycloalkyl etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.); optionally substituted aralkyl (for example, phenyl With1-4alkyl, for example benzyl, phenethyl, and so on). When there are two adjacent hydroxyl or tylnej Deputy, the heteroatoms may be linked alkalinous group, as, n is the sample, O(CH2)nO, and S(CH2)nS (where n=1-5). Examples include methylenedioxy, Ethylenedioxy etc. are Also covered by the simple oxides thioester group, such as sulfoxidov and sulfones.

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

Substituents at optional substituted amino group can be connected to each other to form a cyclic amino group (for example, 5-6-membered cyclic amino, etc. such as tetrahydropyrrole, piperazine, piperidine, pyrrolidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.). These cyclic amino group may have a Deputy, and examples of the substituents include halogen (e.g. fluorine, chlorine, bromine, iodine etc), nitro, cyano, hydroxyl 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), 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) such group optionally substituted alkyl group, including C1-10alkyl (e.g. methyl, ethyl, propyl, etc.); optionally substituted alenalena group, such as allyl, crotyl, 2-pentenyl, 3-hexenyl etc., or optionally substituted cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. In such cases1-6alkyl, alkenyl and cycloalkyl are preferred. Amine group may also be optionally substituted aromatic or heterocyclic group, aralkyl (for example, panels1-4by alkyl) or heteroalkyl, for example, phenyl, pyridine, vinylmation (benzyl), Venetian, pyridinylmethyl, pyridinylamino etc. Heterocyclic group may be a 5 - or 6-membered ring containing 1-4 heteroatoms. Optional substituents in "optionally substituted amino group" are the same as defined above for the "optionally substituted cyclic amino group".

The amino group may be substituted by an optionally substituted C-4 alkanoyl, such as acetyl, propionyl, Boutillon, isobutyryl etc. or1-4alkylsulfonyl (for example, methanesulfonyl, acanalonia etc), or carbonyl - or sulfanilamidnam aromatic or heterocyclic ring, such as benzosulfimide, benzoyl, pyridylsulfonyl, pyridylcarbonyl etc. Heterocycles are as defined above.

Examples of the optionally substituted acyl groups include a carbonyl group, or sulfonyloxy, or sulfonyloxy group associated with hydrogen or optionally substituted alkyl (for example, C1-10the alkyl, 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 by cycloalkyl (for example, C3-7cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.); optionally substituted by alkenyl (for example, C2-10alkenyl, such as allyl, crotyl, 2-pentenyl etc., preferably lower (2-6)alkenyl etc.); optionally substituted by cycloalkenyl (for example, C3-7cycloalkenyl, such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentylmethyl, 2-cyclohexenylmethyl etc), optional replacement of the military 5-6-membered monocyclic aromatic group (for example, the phenyl, pyridium etc).

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, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (1-6)alkyl, etc.); optionally substituted cycloalkyl (for example, C3-7cycloalkyl, 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 (2-6)alkenyl etc.); optionally substituted cycloalkenyl (for example, C3-7cycloalkenyl, such as 2-cyclohexenylmethyl etc), optionally substituted aryl (e.g. phenyl, naphthyl, etc.) and (C1-4aryl, such as benzyl, phenethyl etc., are Also covered by such groups as methoxymethyl, methoxyethyl etc.

Examples of optionally substituted carboxamide and sulfonamidnuyu groups are identical to the terms definitions amine as defined above "optionally substituted amino group".

Examples of optionally substituted aromatic and heterocyclic groups are phenyl, naphthyl or 5 - or 6-membered, heterocy the symbolic ring, containing 1-4 heteroatoms. Optional substituents is essentially identical to the above.

Substituents which do not create obstacles, R1, R2and R3similar to those listed as "optional substituents". Preferably R1choose from the above optional substituents, preferably from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted thiol, and substituted or unsubstituted acyl. Preferably k is 0-2, preferably 0-1 and more preferably 0.

The substituents R2and R3preferably selected from the preferred embodiments, R1just listed above, or, more preferably, they can be merged to form a saturated or unsaturated ring system, preferably a benzene ring system.

In the above formula (1) examples of the optionally substituted ring system containing ring And are dihydroquinoline, tetrahydroquinoline, pornobilder, dihydropyrimidin, capitanerie, dihydrocapsaicin, dihydronaphthalene, tetrahydronaphthalene. The present invention also encompasses heterocycles containing sulfur oxides. In specified you the e ring system, containing ring And optional nitrogen atom may be substituted by hydrogen, substituted alkyl, alkenylphenol, cycloalkyl or aryl group, or may represent a nitrogen atom of the carboxamide, carbamate or sulfonamida. For l, preferably l=1, it is preferable that the ring And was saturated. The most preferred combination is tetrahydroquinolin.

In the above formula (1) X can represent CH (pyrrole), (oxisol), S (thiazole), NH or NR (imidazole), where R represents a C1-6alkyl group or acyl, sulfonyloxy group. In the formula (1) or two adjacent R1and/or R2and R3can be combined with education optionally substituted condensed 5-7 membered ring. Examples of the condensed ring systems include, but are not limited to, indole, tetrahydroindole, benzimidazole, tetrahydroimidazo, azobenzenes, benzoxazol, tetrahydrobenzoic, benzothiazole, tetrahedralisation. Preferred ring system formed of R2and R3include those which lead to the benzothiazole and benzimidazole.

In the compounds of formula (1) preferably one of (CR2)nbinding fragments between ring system containing ring a and ring E, was one in which n=0, then there is a connection made which allows only a covalent bond. Also preferred variant embodiment (CR2)nin this context, are ethylene or methylene, preferably methylene. In the most preferred embodiments, the implementation of the coupling between nitrogen specified in the formula (1), and ring And represented the relationship and link between the specified nitrogen and the ring E represents CH2. As shown, the ring E may be connected with a connecting slice through any position, but preferably via position 2, 4 or 5, most preferably via position 2.

In the compounds of formula (1), the preferred values of j are 0-2, preferably 1-2. Embodiments of Y can vary widely, provided that Y does not contain nitrogen. Thus, Y may be halogen, HE, SH, SO, SO2and the like, or Deputy of 1-20 carbon atoms, optionally containing as a substitution of one or more of these carbon atoms heteroatom such as O or S. Preferred options for implementation, in which N is not present in Y include halogen, optionally substituted alkyl, optionally substituted hydroxyl, optionally substituted thiol, and optionally substituted carboxyl and saturated or unsaturated ring. Such substituents described above. When N is included in Y, Y is chosen from the above fragment of the century Such substituents Z represents an aromatic or heteroaromatic fragment containing 5-12 ring members. Thus, Y may include a single or condensed ring. Examples of preferred types of Z is identical to that specified in relation to the aromatic residue Ar specified above, but are monovalent.

As shown, in some embodiments, the implementation of the R, defined as H or alkyl (1-6C)replaced by R4or R5that have a more broad definition and can include embodiments of R, and also to represent optionally substituted of alkenyl, acyl and the like, as described above. Preferred types of R4and R5include typical R and optionally substituted of alkenyl. Also preferred are embodiments of which two R5connected with the formation of a cyclic amine, including those that contain one or more additional heteroatoms, such as N, O and/or S.

The preferred species of Y, when Y contains N, are those in which R in all cases represents H or methyl, preferably H, and those in which two R5United. Especially preferred are those which have the formula:

and those in which Y includes guanidino, or NHNHR, or amidino;

especially where (CR2)m is CH2CH2CH2or CH2CH2CH2or where m is equal to 0, and those in which R4or R5represents H or lower alkyl, alkenyl or hydrogen, or those in which both R5are the same.

Especially preferred is-CH2NH2CH2CH2NH2, -CH2NMe2, -CH2CH2NMe2, -CONH2, -CONMe2and the like.

Preferred Z are optionally substituted residues of benzene, oxazole, imidazole, thiazole, benzimidazole, benzthiazole, benzoxazole, indole, thiophene, tetrazine, pyrimidine, pyridine and the like.

The new compounds of formula (1) according to the present invention can be incorporated into pharmaceutical compositions that can be administered topically; subcutaneous injection, including intravenous; oral and other standard routes of pharmaceutical administration subjects-mammals, as determined in accordance with routine clinical practice.

After the invention has been described in General terms, the same will be more readily available with reference to the following examples, which are presented as illustrations and are not intended to limit the invention, if not precisely determined.

Experimental part

Intermediate compound 8-hydroxy-,6,7,8-tetrahydroquinolin and 8-amino-5,6,7,8-tetrahydroquinolin obtained in accordance with methods, described Bridger et el., in the application for U.S. patent USSN 09/535314 included in this description by reference. The intermediate compound N'-(1H-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-1,4-resolvenames obtained as described Bridger et el., in applications for U.S. patent USSN 60/232891 and USSN 60/234510 included in this description by reference. Intermediate compound 1-N-tert-butoxycarbonyl-2-chloromethylbenzene obtained as described'an H.; Wang, T.; Mohan, V.; Griffey, R.H.; Cook, P.D. Tetrahedron, 1998, 54, 3999-4012.

General methods

The General procedure of N-alkylation (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine-mesylates or alkylchloride

To a solution of (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (or amine) (1-1,4 equivalents), N,N-diisopropylethylamine (or2CO3) (1.5-2 equivalents) and KI (0.05 to 0.16 equivalent) in acetonitrile (concentration ˜0.1 to 0.2 M) was added mesilate or alkylchloride (such as 1-N-tert-butoxycarbonyl-2-chloromethylbenzene) (1-1,4 equivalents) and the mixture was stirred at 50-70°within 3-25 hours, monitoring was carried out by analytical thin-layer chromatography. The reaction mixture was cooled, diluted with CH2Cl2(10 ml/mmol amine) and poured either in a saturated aqueous solution of NaHCO3or in a saturated salt solution (10 ml/mmol of alcohol). Phase is abdelali and the aqueous phase was extracted with CH 2Cl2(3 × 10 ml/mmol amine). The combined organic phases were dried (Na2SO4or MgSO4) and concentrated under reduced pressure. The crude substance was purified by chromatography, obtaining the target N-alkilirovanny product.

General procedure a: Direct reductive amination using NaBH3CN

To a stirred solution of amine (1 equivalent) in anhydrous methanol (concentration ˜0.1 M) at room temperature was added in one portion carbonyl compound (1˜2 equivalent). After the dissolution of carbonyl compounds (˜5 minutes) was added in one portion NaBH3CN (˜2-4 equivalents) 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 × 10 ml/mmol amine). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The crude substance was purified by chromatography.

General procedure b: Direct reductive amination using NaBH(SLA)3or NaBH4

To a stirred solution of amine (1 equivalent) in CH2Cl2(concentration &x002DC; 0.2 M) at room temperature was added the carbonyl compound (1-2 equivalents), glacial acetic acid (0-2 equivalent) and NaBH(SLA)3(˜1.5-3 equivalents) and the resulting solution was stirred at room temperature. The reaction mixture was poured either into saturated aqueous NaHCO3or 1.0 M aqueous NaOH (10 ml/mmol amine). The phases were separated and the aqueous phase was extracted with CH2Cl2(3 × 10 ml/mmol amine). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The crude substance was purified by chromatography.

Similarly, to stir a solution of amine (1 equivalent) in anhydrous Meon (concentration ˜0.1 M) at room temperature was added the carbonyl compound (1 equivalent). The resulting solution was stirred at room temperature or boiled under reflux for 4-24 hours. Added NaBH4(1-2 equivalents) and the resulting mixture was stirred at room temperature for ˜20 minutes. The reaction mixture was concentrated, dissolved in CH2Cl2, washed successively with a saturated aqueous solution of NaHCO3and saturated aqueous NaCl. The aqueous layers was extracted with CH2Cl2(2x), the combined organic extracts were dried (MgSO4) and concentrated.

General procedure C: Vzaimodeistviyu with methanesulfonamido

To a stirred solution of alcohol (1 equivalent) and Et3N (1.5-2 equivalents) in CH2Cl2(or THF) (concentration ˜0,1M) at room temperature (or 0° (C) was added methanesulfonamide (˜1.5 equivalents) and the reaction mixture was stirred at room temperature for 0.5-1 hour. The reaction mixture was poured either in a saturated aqueous solution of NaHCO3or in a saturated solution of NH4Cl (10 ml/mmol of alcohol). The phases were separated and the aqueous phase was extracted with CH2Cl2(3 × 10 ml/mmol amine). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The crude substance was purified by chromatography or used without additional purification stage N-alkylation.

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

To a solution of free base in glacial acetic acid (2 ml) was added a saturated solution of HBr(gas) in acetic acid (2 ml). Then add a large amount of diethyl ether (25 ml) to precipitate a solid substance, which gave the opportunity to settle on the bottom of the flask, and the supernatant solution decantation. The solid was washed by decantation with ether (3 × 25 ml) and the remaining traces of solvent were removed in vacuum. For further purification, the solid R who was storyli in methanol and again besieged by a large volume of ether. Washing the solids with ether by decantation, followed by drying the solid in vacuo (0,1 Iopp) gave the target compound.

The intermediate connection:

Getting 4-hydroxymethylbenzene:

Terephthaldicarboxaldehy (30,02 g, 224 mmol), methanol (200 ml), palladium on charcoal (10%, to 3.02 g) and 2-(aminomethyl)pyridine (2.3 ml, 22 mol, 0.01 mol equiv.) were combined in a vessel for hydrogenation and the reaction mixture was shaken in the device Parra for hydrogenation for 2.5 hours under hydrogen pressure of 40 lb/inch2(276 kPa). The mixture was filtered through celite, the residue washed with methanol and the solvent from the eluent removed in vacuum. Purification of the crude product column chromatography on silica gel (EtOAc/hexane, 1:1) gave specified in the header connection (23,8 g, 78%) as a white solid.1H NMR (CDCl3) δ 4,80 (s, 2H), 7,53 (d, 2H, J=9 Hz), 7,87 (d, 2H, J=9 Hz), 10,00 (s, 1H).

Obtain 6,7-dihydro-5H-quinoline-8-she

To a stirred solution of 8-hydroxy-5,6,7,8-tetrahydroquinolin (13,96 g, 93,6 mmol) in anhydrous CH2Cl2(400 ml) was added activated manganese dioxide (85% purity, 82,22 g, 804 mmol). The obtained heterogeneous mixture was stirred 18 hours at this point, the black suspension was filtered through a layer of celite and washed CH2Cl2(3 x 50 ml). Unite the n leaching liquid was concentrated, getting 11,27 g (82%) indicated in the title compounds as a pale yellow solid, which was used in the subsequent reactions without further purification.1H NMR (CDCl3) δ 2,17-of 2.25 (m, 2H), 2,82 (t, 2H, J=7 Hz), 3.04 from (t, 2H, J=6 Hz), 7,37 (DD, 1H, J=9, 6 Hz), 7,66 (DD, 1H, J=9, 1 Hz), 8,71 (DD, 1H, J=6, 1 Hz);13C NMR (CDCl3) δ 22,2, 28,6, 39,2, 126,6, 137,3, 140,5, 147,6, 148,6, 196,5. ES-MS m/z 148 (M+H).

Obtain (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine

Using General method, N-alkylation, to stir a solution of 8-amino-5,6,7,8-tetrahydroquinoline (7,34 g of 49.6 mmol) in anhydrous CH3CN (250 ml) was added 1-N-tert-butoxycarbonyl-2-chloromethylbenzene (13,22 g of 49.6 mmol), N,N-diisopropylethylamine (15,5 ml of 89.2 mmol) and potassium iodide (0,41 g, 8.2 mmol) and the mixture was stirred at 60°C for 3.5 hours. Purification of column chromatography on silica gel (CH2Cl2/MeOH, 99:1, then 97:3 96:4) gave the intermediate amine (6,38 g, 34%) as an orange sticky oil.1H NMR (CDCl3) δ to 1.76 (s, 9H), 1,81 is 2.10 (m, 2H), 2,25-is 2.37 (m, 1H), 2,72-2,89 (m, 2H), of 3.77-a-3.84 (m, 1H), 4,39 (d, 1H, J=15,0 Hz), 4,56 (d, 1H, J=15,0 Hz), 7,00-7,06 (m, 1H), 7,27-7,37 (m, 1H), of 7.64-7,74 (m, 1H), of 7.90-of 7.96 (d, 2H, J=8.1 Hz), a 8.34 (d, 1H, J=3.0 Hz);13C NMR (CDCl3) δ 20,13, 28,48, 29,00, 29,20, 47,15, 56,89, 86,20, 115,32, 120,28, 122,06, 124,43, 124,85, 132,77, 133,74, 137,01, 142,44, 147,10, 149,22, 154,90, 157,72; ES-MS m/z279 (M+H-boc).

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

To a stirred solution of the dihydrochloride hydrate (2-aminomethyl)benzimidazole (5,96 g, 27,1 mmol) in anhydrous MeOH (225 ml) were added 6,7-dihydro-5H-quinoline-8-he (3,99 g, 27,1 mmol) and the mixture was stirred at room temperature for 69 hours. To the resulting solution was added sodium borohydride (of 2.06 g, a 54.2 mmol) in two portions and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated in vacuo and diluted with CH2Cl2(150 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (200 ml), the aqueous layer was extracted with CH2Cl2(2 × 50 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuum. Purification of column chromatography on silica gel (CH2Cl2/MeOH, 99:1, then 98:2 and 96:4) gave the intermediate amine (3,59 g, 50%) as a yellow foam.1H NMR (CDCl3) δ 1,66-1,90 (m, 3H), 1.91 a is 2.00 (m, 1H), 2,00-2,17 (m, 1H), 2,33-2,69 (user. m, 1H), 3,88-of 3.96 (m, 1H), 4,37 (d, 1H, J=3.0 Hz), 7.18 in-7,26 (m, 4H), of 7.48 (d, 1H, J=6.0 Hz), 7,58-7,78 (user. m, 1H), 8,55-8,58 (m, 1H);13C NMR (CDCl3) δ 19,66, 29,12, 30,24, 46,62, 57,28, 122,21, 122,83, 133,55, 138,07, 146,98, 156,17, 157,73.

Example: 1

AMD9679: Obtaining N'-(1H-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-1,3-benzilpenetsillina.

To stir RA is Toru 8-amino-5,6,7,8-tetrahydroquinoline (to 6.43 g, 43 mmol) in CH2Cl2(450 ml) at room temperature was added 3-cyanobenzaldehyde (5,69 g, 43 mmol) and triacetoxyborohydride sodium (17.0 g, 80 mmol) and the mixture was stirred 16 hours. The reaction is extinguished 1 N. NaOH (200 ml) and the phases were separated. The organic phase was dried (Na2SO4) and concentrated under reduced pressure, obtaining a yellow oil (11.7 g), which was purified flash chromatography on silica gel (97:3 CH2Cl2/CH3IT), obtaining N-(5,6,7,8-tetrahydro-8-chinoline)-3-cyanoaniline (9,10 g, 81%) as a pale yellow solid.

Using General method, N-alkylation, the solution of the above substances (4,17 g, 15.8 mmol), potassium iodide (130 mg, 0.80 mmol) and N,N-diisopropylethylamine (5.2 ml, 30 mmol) in CH3CN (160 ml) was subjected to interaction with N-(tert-butoxycarbonyl)-2-chloromethylthiazole (obtained as described'an, H.; Wang, T.; Mohan, V.; Grifley, R.H.; Cook, P.D. Tetrahedron 1998, 54, 3999-4012) (4,22 g, 15.8 mmol). Purification of the crude substance flash chromatography on silica gel (1:1 EtOAc/hexane) gave alkilirovanny product (6,86 g, 88%) as a yellow foam.

To the solution obtained above substances (6,86 g, a 13.9 mmol) in saturated NH3methanol (100 ml) in a vessel Parra was added Raney Nickel (about 1 g) and the mixture was first made when hydrogen pressure of 50 lb/in2(345 kPa) in a Parr apparatus for hydrogenation for 17 hours. The resulting mixture filtration is ovali through Celite 521 and the solvent from the eluent removed in vacuum. Purification of the crude substance flash chromatography on silica gel (5% CH2Cl2/CH3OH/NH4OH, 19:1:0, then 18:1:1) gave AMD9679 (4,36 g, 79%) as a yellow foamy solid.1H NMR (CDCl3) δ 1,58-1,75 9M, 1H), 1,96-of 2.09 (m, 2H), 2,24-of 2.30 (m, 1H), 2,70-to 2.94 (m, 2H), 3,74 (s, 2H), of 3.78 (s, 2H), 3,94-4,20 (m, 3H), 7,07 (d, 1H, J=7.5 Hz), 7,15-7,21 (m, 4H), 7,30 (d, 1H, J=7.5 Hz), was 7.36 (s, 1H), the 7.43 (d, 1H, J=7.5 Hz), 7,47 (users, 2H), 8,67 (d, 1H, J=4, 2 Hz).13C NMR (CDCl3) δ 21,77, 23,70, 29,65, 46,47, 49,12, 54,51, 60,78, 121,93(2), 122,65, 126,45, 127,61, 127,98, 128,83, 135,23, 137,70, 140,08, 142,72, 147,27, 156,35, 157,72. ES-MS m/z 398 (M+H). Elemental analysis. Calculated for C25H27N5·1.0 h2About·0,SN2Cl2: C, 69,65; H, PC 6.82; N, 16,10, Found: C, 69,57; H, 6,91; N, 16,30.

Example: 2

AMD9720: Receive (1H-benzimidazole-2-ylmethyl)-(2-aminomethylbenzoic)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Obtain [1-(tert-butoxycarbonyl)-(1H-benzimidazole-2-ylmethyl)]-(2-cyanobenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine:

According to the General method b to a solution of [1-(tert-butoxycarbonyl)-(1H-benzimidazole-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (197 mg, 0,523 mmol) and 2-cyanobenzaldehyde (91,2 mg, 0,695 mmol) in CH2Cl2(5 ml) was added NaBH(SLA)3(240 mg, 1.13 mmol) and the mixture was stirred over night. Purification of the resulting oil flash chromatography (15 g dio is sid silicon, 50:1:1 CH2Cl2/CH3OH/NH4OH) gave the target intermediate compound (167 mg, 65%).1H NMR (CDCl3) δ 1,72 (s, 9H), 1,91-of 2.15 (m, 2H), 2,31-to 2.42 (m, 1H), 2,62-of 2.86 (m, 2H), 4,12 (d, 1H, J=15.6 Hz), the 4.29 (d, 1H, J=15,8 Hz), to 4.38 (DD, 1H, J=9,6, 6,1 Hz), with 4.64 (s, 2H), 6,93 (t, 1H, J=7,6 Hz), 7,00 (DD, 1H, J=7,5, 4,7 Hz), 7,14-to 7.32 (m, 5H), 7,58-of 7.69 (m, 3H), 8,44 (d, 1H, J=4,6 Hz).

To the solution obtained above substance (101 mg, 0,204 mmol) in saturated NH3CH3OH (4 ml) in a vessel Parra was added Raney Nickel (200 mg) and the mixture was first made when hydrogen pressure of 50 lb/in2(345 kPa) in a Parr apparatus for hydrogenation for 16 hours. The resulting mixture was filtered through celite and the solvent from the eluent removed in vacuum. Purification of the crude substance flash chromatography (12 g silica, 50:1:1 CH2Cl2/CH3OH/NH4OH) gave unprotected free base (30 mg, 37 %).

According to the General procedure D conversion of the above amine (30 mg) in hydrobromide salt gave AMD9720 (39 mg, 77%).1H NMR (D2O) δ 1,80-of 1.97 (m, 1H), 2,17-is 2.37 (m, 2H), 2,42-of 2.54 (m, 1H), 2,99-is 3.08 (m, 2H), 3,91 (d, 1H, J=13,0 Hz), 4,16 (d, 2H, J=13,7 Hz), 4,32-to 4.41 (m, 2H), 4,54 (d, 1H, J=16.4 Hz), 6.89 in-7,00 (m, 2H), 7,15 (t, 1H, J=7,2 Hz), 7,41 (d, 1H, J=7.5 Hz), of 7.48-to 7.61 (m, 4H), 7,88 (DD, 1H, J=7,7, 5,9 Hz), at 8.36 (d, 1H, J=8.0 Hz), 8,71 (d, 1H, J=5.7 Hz).13C NMR (D2O) δ 20,46, 20,90, 27,92, 40,14, 48,91, 53,45, 62,31, 113,93 (2 carbon), 126,12, 126,79 (2 carbon), 129,35, 129,84, 129,98, 130,67, 131,52, 131,94, 135,10, 140,10, 141,02, 148,08 (2 carbon), 150,57, 150,88. ES-MS m/z 398 (M+H). Ele is entry analysis. Calculated for C25H27N5·3,NVG·1,9H2O: C, 44,52; H, Of 5.05; N, 10,38; Br, 35,54. Found: C, 44,42; H, Equal To 4.97; N, 10,15; Br, 35,86.

Example: 3

AMD11090: Receive (2-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(S)-5,6,7,8-tetrahydroquinolin-8-yl-amine (cleaners containing hydrochloride salt).

Getting 2-(phthalimidomethyl)benzaldehyde

To a stirred cooled (0° (C) to a solution of 2-cyanobenzaldehyde (10.4 g, 79,0 mmol) in anhydrous THF (320 ml) was added in portions'lah (14.3 g, 377 mmol). The suspension was stirred in an atmosphere of N2at room temperature for 15 hours. The reaction was slowly extinguishing distilled water (15 ml), then 15% (mass/V) NaOH (15 ml), then with distilled water (45 ml). The mixture was stirred for 20 minutes, diluted with diethyl ether (200 ml) and a white fluffy precipitate was removed by filtration. The filtrate was dried (MgSO4) and concentrated in vacuum. The resulting aminoplast (12,6 g) was used without further purification in the next reaction.

The solution obtained above alcohol (presumably 79 mmol) and phthalic anhydride (12.3 g, 83 mmol) in 20% MeOH/CHCl3(200 ml) was stirred while boiling under reflux for 19 hours. The mixture was cooled to room temperature and was purified flash chromatography (8 cm inner diameter, 300 g of silica gel, was suirable 1% MeOH/CH2Cl2) with the second by recrystallization from hot dichloromethane, receiving target alcohol as a pale pink solid (7,11 g, 34% in two stages).

To a stirred suspension TPAP (465 mg, 1.3 mmol), NMO (4.7 g, 40 mmol) and 3Å molecular sieves (14 g) in CH2Cl2(220 ml) was added dropwise a solution of the above alcohol (7,11 g, 27 mmol) in CH2Cl2(50 ml) for 30 minutes. The black suspension was stirred in an atmosphere of N2within 40 minutes after the additions were concentrated in vacuo, and purified flash chromatography (8 cm inner diameter, 300 g of silica gel, elution EtOAc)to give pure indicated in the title compound as a white solid (5.75 g, 82%).1H NMR (CDCl3) δ 5,38 (s, 2H), 7.24 to 7,28 (m, 1H), 7,44-rate of 7.54 (m, 2H), 7,74 for 7.78 (m, 2H), a 7.85-a 7.92 (m, 3H), 10,35 (s, 1H).

Receive (2-aminomethylbenzoic)-(1H-benzimidazole-2-ylmethyl)-(S)-5,6,7,8-tetrahydroquinolin-8-yl-amine (cleaners containing hydrochloride salt) (AMD11090)

Using General procedure b, the result of the above 2-(phthalimidomethyl)benzaldehyde (5,44 g of 20.5 mmol) was subjected to interaction with S-(5,6,7,8-tetrahydroquinolin-8-yl)amine (3,34 g, and 22.6 mmol) and NaBH(OAc)3(21.2 g, 100 mmol) in dichloromethane (2.0 l). Flash chromatography (8 cm inner diameter, 250 g of silica gel, elution with 5% MeOH/CH2Cl2) gave the pure amine as a white foam (6,83 g, 84%).

To the solution obtained above amine (6,83 g, 17 mmol) in acetonitrile (170 ml) was added diisopropylethylamine (4,5 ml, 26 mmol),1-Boc-2-chloromethylbenzene (5.0 g, 19 mmol) and potassium iodide (145 mg, 0.86 mmol). The mixture was stirred in an atmosphere of N2at 60°C for 15 hours, cooled to room temperature and concentrated in vacuum. The residue was distributed between dichloromethane (200 ml) and saturated salt solution (100 ml). The separated organic layer was dried (MgSO4), concentrated and purified flash chromatography (8 cm inner diameter, 300 g of silica gel, was suirable CH2Cl2to remove unreacted chloride, then 2% Meon/CH2Cl2removal of the target product), receiving net target amine (7.6 g, 70%).

The solution obtained above amine (4.44 g, 7.1 mmol) in ethanol (35 ml) and dichloromethane (2 ml solubility) was treated with hydrazine monohydrate (2.2 g, 44 mmol) and was stirred for 16 hours. Then the mixture was concentrated in vacuo, and purified flash chromatography (5 cm inner diameter, 80 g of silica gel, was suirable 3% Meon/CH2Cl2) to obtain the unprotected amine as a white foamy solid (2,05 g, 73%).

Gaseous HCl was barbotirovany through a solution of the above amine (2,05 g, 5.2 mmol) in glacial acetic acid (20 ml) over 10 minutes under stirring. The solid was allowed to mix at room temperature for 5 minutes, then it slowly dropwise added to diethyl ether (200 ml) at intense the nom stirring. The resulting suspension was filtered with suction in a vacuum through a glass funnel with a porous filter, the filter cake washed with diethyl ether (5 x 50 ml) and dried in a vacuum oven at 40°C for 60 hours, getting AMD 11090 in the form of a white solid (2,71 g, 96%).1H NMR (D2O) δ 1,79-of 1.97 (m, 1H), 2,17 to 2.35 (m, 2H), 2,44-2,49 (m, 1H), 3.00 and was 3.05 (m, 2H), 3,89 (d, 1H, J=13.5 Hz), 4,15 (d, 2H, J=14.1 Hz), 4,30-and 4.40 (m, 2H), to 4.52 (d, 1H, J=16.4 Hz), 4,73-4,78 (m, 1H), 6.87 in-6,98 (m, 2H), 7,12 (TD, 1H, J=1,2, 7.5 Hz), 7,38 (d, 1H, J=7,5 Hz), 7,47-7,52 (m, 2H), 7,54-of 7.60 (m, 2H), a 7.85-of 7.90 (m, 1H), at 8.36 (d, 1H, J=8.1 Hz), 8,71 (d, 1H, J=5,1 Hz);13C NMR (D2O) δ 20,44, 20,86, 27,91, 40,16, 48,88, 53,52, 62,31, 113,91 (2 carbon), 126,15, 126,80 (2 carbon), 129,33, 129,78, 129,89, 130,58, 131,54, 131,96, 135,01, 140,03, 141,08, 148,19, 150,45, 150,82. ES-MS m/z 398 (M+H). Elemental analysis. Calculated for C25H27H5·3Cl·2H2About·0,1 CH3COOH: C, 55,14; H, 6,32; N, 12,76; Cl, 19,38. Found: C, 55,47; H, 6,50; N, 12,38; Cl, (Jn 19 : 26.

Enantiomeric purity AMD11090 was estimated as 100% method chiral HPLC using the following conditions: Instrument: Hewlett Packard 1100 HPLC (VWD4). Column: ChiralCel OD, and 0.46 cm x 25 cm, Mobile phase: A: 95:5 hexane/methanol with 0.1% DEA, B: hexane; isocratic elution: 80% A, 20% b Total time: 45 min. Volume flow: 0.5 ml/min Temperature: 40°C. the UV Detector at 270 nm. Volume of sample: 10 μl.

The retention time of S-enantiomer = 28,7 minutes

The retention time of the R-enantiomer = 32,6 minutes

Example: 4

AMD11083: Receive (3-aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)methanol.

Obtaining methyl ester 4-methyl bromide-3-cyanobenzoic acid

1,2-Dibromethane (0,016 ml to 0.19 mmol) was added to a suspension of zinc dust (288 mg, to 4.41 mmol) in THF (1 ml) and the mixture was heated to 70°C for 10 minutes. The mixture was left to cool to room temperature, was added TMSCl (trimethylchlorosilane) (0,016 ml, 0.13 mmol) and stirring continued at room temperature for 30 minutes. The mixture was cooled to 0°C, a solution of methyl 4-(methyl bromide)benzoate (842 mg, 3,68 mmol) in THF (4 ml) was added over 2 hours and stirring was continued at 0°C for 2 hours. The mixture was cooled to -78°C, the solution was added tailland (571 mg, 3,15 mmol) in THF (4 ml) and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo and the residue was distributed between CH2Cl2(20 ml) and saturated NaHCO3(aq.) (20 ml). The aqueous phase was extracted with CH2Cl2(3 × 10 ml), the combined organic extracts were dried (MgSO4) and concentrated in vacuum. Purification of the crude substances column chromatography on silica gel (10% EtOAc/hexane) gave colorless crystals (379 mg). This substance was determined according to the1NMR as a mixture of methyl ester of 3-cyano-4-methylbenzoic acid and unidentified by-product and used in the next stage without additional purification.

The mixture obtained above nitrile (379 mg), NBS (400 mg, 2.25 mmol) and AIBN (53 mg, 0.32 mmol) in CCl4(11 ml) was boiled under reflux for 4 days, then left to cool to room temperature. The mixture was filtered and the filtrate was concentrated in vacuum. Purification of the crude substances column chromatography on silica gel (5% EtOAc/hexane) gave colorless crystals (100 mg, 12%).1H NMR (CDCl3) δ of 3.96 (s, 3H), of 4.66 (s, 2H), 7,65 (d, 1H, J=8.1 Hz), 8,23 (DD, 1H, J=8,1, 1.5 Hz), with 8.33 (d, 1H, J=1.5 Hz).

A mixture of tert-butyl ester 2-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzoimidazol-1-carboxylic acid (175 mg, 0,462 mmol), methyl ester 4-methyl bromide-3-cyanobenzoic acid (98 mg, 0,39 mmol), potassium iodide (4 mg, 0.02 mmol) and N,N-diisopropylethylamine (0.10 ml, or 0.57 mmol) in acetonitrile (4.0 ml) was heated at 60°C for 16 hours. Was added a saturated NaHCO3(aq.) (15 ml) and the mixture was extracted with CH2Cl2(3×10 ml). The organic extracts were dried (MgSO4) and concentrated in vacuum. Purification of the crude substances on silica gel (500:5:1 CH2Cl2/Meon/NH4HE gave a yellow oil (213 mg, 100%).1H NMR (CDCl3) δ at 1.73 (m, 10H), a 2.01 (m, 2H), 2,3 (m, 1H), was 2.76 (m, 2H), 3,86 (s, 3H), 4,17 (d, 1H, J=17 Hz), the 4.29 (d, 1H, J=17 Hz), 4,37 (m, 1H), 4,58 (d, 1H, J=14 Hz), 4,69 (d, 1H, J=14 Hz), 7,01 (DD, 1H, J=7,5, and 4.5 Hz), 7,18 (m, 2H), 7,31 (d, 1H, J=7.5 Hz), 7,58 (m, 2H), 7,76 (d, 2H, J=1.2 Hz), 7,87 (s, 1H), 8,44 (m, 1H).

Rest the R tert-butyl ester 2-{[(2-cyano-4-methoxycarbonylbenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazol-1-carboxylic acid (213 mg, 0,386 mmol) in saturated NH3(g)/MeOH (10 ml) was shaken at room temperature with a suspension of Raney Nickel (1.5 g) in an atmosphere of hydrogen (45 lb/in2) for 17 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuum, obtaining a green foam (195 mg).

To the solution obtained above crude amine (195 mg) in THF (4 ml) was added di-tert-BUTYLCARBAMATE (220 mg, 1.01 mmol) and the solution was stirred at room temperature for 3 days. The solution was concentrated in vacuo and the residue was filtered through silica gel (600:5:1 CH2Cl2/MeOH/NH4OH), receiving a yellow foam (130 mg).

To the solution obtained above crude complex ester (130 mg) in THF (2 ml) was added LiAlH4(1.0 M/THF, of 0.20 ml, 0.20 mmol) at 0°C and the mixture was stirred at 0°C for 15 minutes. Was added methanol (1 ml), then 10% HCl (aq.) (1 ml). The mixture was podslushivaet using a saturated solution of NaHCO3(aq.) (30 ml) and then was extracted with CH2Cl2(4 x 12 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuum, obtaining a yellow foam (116 mg).

The solution obtained above crude alcohol (116 mg) in a mixture of 3:1 TFWC/CH2Cl2(4 ml) was stirred at room temperature for 50 minutes, then concentrated in vacuo. The residue was distributed between CH2Cl2(10 ml) and 1 is. NaOH (aq.) (15 ml) and the aqueous phase was extracted with CH2Cl2(2 × 10 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuum. Purification of the crude substances column chromatography on silica gel (200:5:1-50:5:1 CH2Cl2/Meon/NH4OH) gave AMD11083 as a yellow foam (25 mg, 12%).1H NMR (CDCl3) δ and 1.54 (m, 1H), 1.93 and (m, 2H), 2,19 (m, 1H), 2.57 m) is 2.80 (m, 2H), 3,52-3,88 (m, 7H), of 4.54 (s, 2H), 6,93 (m, 1H),? 7.04 baby mortality (d, 1H, J=7.5 Hz), to 7.15 (m, 4H), 7,25 (m, 1H), 7,54 (m, 2H), 8,39 (d, 1H, J=3,6 Hz);13C NMR (CDCl3) δ 21,77, 21,94, 29,47, 43,14, 49,34, 53,99, 59,72, 64,62, 115,42, 122,27, 122,36, 126,33, 129,10, 131,52, 135,04, 135,66, 137,51, 141,25, 142,14, 147,24, 154,27, 156,94. ES-MS m/z 428 (M+H). Elemental analysis. Calculated for C26H29N5O·0,2H2O·1,2CH2Cl2: C, 61,29; H, 6,01; N, 13,14. Found: C, 61,36; H, Of 6.02; N, 12,84.

Example: 5

AMD11120: Receive (2-aminomethyl-3-methoxybenzyl)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

To a solution of ethyl 2-methoxy-6-methylbenzoate (1,23 g, 6,33 mmol) in anhydrous diethyl ether (58 ml) was added LiAlH4(0,467 g, 12,31 mmol) and the resulting mixture was boiled under reflux for 2 hours, and then cooled to room temperature. The mixture was treated sequentially with water (0.45 ml), 15%aqueous NaOH (0.45 ml) and water (1.35 ml). The mixture was filtered through celite and the precipitate was washed with ether (200 m is). The filtrate was concentrated under reduced pressure and obtained 0.96 g (99%) 2-methoxy-6-methylbenzylamino alcohol as a yellow solid.1H NMR (CDCl3) δ and 2.27 (t, 1H, J=6.3 Hz), 2,39 (s, 3H), 3,86 (s, 3H), and 4.75 (d, 2H, J=6.3 Hz), 6,76 (d, 1H, J=8,4 Hz), for 6.81 (d, 1H, J=7.8 Hz), 7,17 (DD, 1H, J=7,8, 8,4 Hz).

To a solution of 2-methoxy-6-methylbenzylamino alcohol (0.96 g, 6,32 mmol) in CH2Cl2(35 ml) was added triethylamine (2.00 ml, 14,35 mmol), then methanesulfonanilide (0,90 ml, 11,63 mmol) and the resulting solution was heated at 40°C for 45 minutes, then cooled to room temperature. The mixture was diluted with CH2Cl2(35 ml), washed with saturated salt solution (3×15 ml), dried (Na2SO4) and concentrated, obtaining a pale yellow solid. Solid (1.12 g) was dissolved in DMF (35 ml)was treated with phthalimide potassium (2,62 g, 14,15 mmol) and was heated at 80°C during the night. The mixture was cooled to room temperature and diluted with EtOAc (70 ml), saturated salt solution (35 ml) and water (20 ml). The phases were separated and the organic phase was washed with 1.0 N. NaOH (6 × 10 ml) and saturated salt solution (2 × 20 ml). The organic phase was dried (MgSO4) and concentrated, obtaining a pale yellow solid. The solid is washed with hexane (3x10 ml) and obtained 1.18 g (66%) of (2-methoxy-6-methylbenzyl)phthalimide in the form of a white solid.1H NMR (CDCl ) δ of 2.53 (s, 3H), of 3.75 (s, 3H), 4,89 (s, 2H), 6,70 (d, 1H, J=8,4 Hz), to 6.80 (d, 1H, J=7.5 Hz), to 7.15 (DD, 1H, J=7,5, and 8.4 Hz), 7,66-to 7.68 (m, 2H), 7,76-7,80 (m, 2H);13C NMR (CDCl3) δ 20,27, 34,95, 55,90, 108,61, 122,38, 123,17, 123,41, 128,97, 132,60, 134,07, 139,55, 158,70, 168,36.

To a solution of (2-methoxy-6-methylbenzyl)phthalimide (0,286 g of 1.02 mmol) in CCl4(25 ml) was added recrystallized N-bromosuccinimide (0,177 g 0,99 mmol)followed by benzoyl peroxide (28 mg, 0.11 mmol). The resulting mixture was boiled under reflux for 90 minutes, then cooled to room temperature. The mixture was diluted with diethyl ether (25 ml), filtered through paper filter and the filtrate was concentrated. Purification of the crude substances column chromatography (3:1 hexane/EtOAc) gave 0.31 g (86 %) of (6-(methyl bromide)-2-methoxybenzyl)phthalimide in the form of a white solid.1H NMR (CDCl3) δ of 3.78 (s, 3H), of 4.90 (s, 2H), 5,00 (s, 2H), 6,83 (d, 1H, J=8,4 Hz), 6,98 (d, 1H, J=7,2 Hz), 7,25 (DD, 1H, J=7,2, 8,4 Hz), to 7.67-of 7.69 (m, 2H), 7,78-7,81 (m, 2H). ES-MS m/z 382 (M+Na), 384 (M+Na).

To a solution of (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,202 g of 0.53 mmol) in CH3CN (5 ml) was added N,N-diisopropylethylamine (of 0.20 ml, 1.15 mmol), then the suspension of (6-(methyl bromide)-2-methoxybenzyl)phthalimide (0,30 g, 0.83 mmol) in CH3CN (5 ml). The resulting mixture was heated at 60°C for 18 hours, then cooled to room temperature. The mixture was concentrated and the residue was distributed settled between CH 2Cl2(40 ml) and saturated salt solution (10 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2(3 × 10 ml). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude substances column chromatography on silica gel (50:1 CH2Cl2/CH3OH) gave 0,212 g (60%) of a white solid.

The above solid (0.21 g) was dissolved in ethanol (6 ml)was treated with hydrazine monohydrate (0.31 in ml, 6.4 mmol) and stirred at room temperature overnight. The mixture was concentrated and to the residue was added CH2Cl2(50 ml). The resulting suspension was filtered through celite and the precipitate washed CH2Cl2(50 ml). The filtrate was concentrated under reduced pressure and the residue was distributed between CH2Cl2(40 ml) and 1.0 N. NaOH (10 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2(3 x 10 ml). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude substances by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2/CH3HE/NH4HE gave 30 mg (22%) of free base specified in the title compound as a white solid.

Using General method D, the transformation obtained above solid (30 mg, 0,071 mmol) in hydro is raidou salt with subsequent presidenial intermediate solid from methanol/ether gave AMD11120 (34 mg, 67%) as a white solid.1H NMR (D2O) δ 1,91 of 1.99 (m, 1H), 2,20-of 2.38 (m, 2H), 2,46-of 2.50 (m, 1H), 3,05-3,13 (m, 2H), 3,38 (s, 3H), 3,90 (d, 1H, J=12.9 Hz), 4,11 (d, 1H, J=12.9 Hz), 4,16 (d, 1H, J=12.9 Hz), the 4.29 (d, 1H, J=12.9 Hz), 4,34 (d, 1H, J=16.5 Hz), of 4.54 (d, 1H, J=16.5 Hz), 4,74-rate 4.79 (m, 1H, overlap with HOD), of 6.50 (d, 1H, J=8,4 Hz), 7,01 (d, 1H, J=7.8 Hz), 7,21 (DD, 1H, J=7,8, and 8.4 Hz), 7,52-to 7.61 (m, 4H), 7,94 (DD, 1H, J=6,0, 7,8 Hz), 8,42 (d, 1H, J=7.8 Hz), 8,77 (d, 1H, J=6.0 Hz);13C NMR (D2O) δ 20,44, 20,98, 27,93, 35,25, 48,97, 53,77, 55,72, 62,69, 111,43, 113,85, 119,53, 124,35, 126,25, 126,89, 130,42, 131,20, 136,39, 139,95, 141,28, 148,39, 150,35, 151,05, 157,88. ES-MS m/z 428 (M+H). Elemental analysis. Calculated for C26H22N5About·3,NVG·2,8H2About: With, 43,33; H, 5,26; N, 9,72; Br, Of 33.26. Found: C, 43,47; H, 5,14; N, Being 9.61 ; Br, 33,00.

Example: 6

AMD9903: Receive (2-aminomethyl-oxazole-4-ylmethyl)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt)

Obtain tert-butyl ester (4-hydroxymethyl-oxazol-2-ylmethyl)carbamino acid:

Using the methodology developed by P. Wipf and others (A.J. Phillips, Y. Uto, P. Wipf, M. J. Reno and D.R. Williams, Org. Lett. 2000, 2(8), 1165-1168), cooled to -20°C a solution of N-(tert-butoxycarbonyl)-Gly-Ser-OMe (170 mg, of 0.615 mmol) in dichloromethane (5 ml) was treated with TRIFLUORIDE bis(2-methoxyethyl)aminocore (0,125 ml, 0,677 mmol). The resulting solution was then stirred at -20°C for 30 minutes and was added bromotrichloromethane (0,212 ml, 2.21 mmol), then DB is (0,330 ml, 2.21 mmol). The reaction mixture was left to warm to 0°C and stirred at this temperature for 5 hours, then was added aqueous ammonium chloride (5 ml). After separation of the aqueous and organic layers, the aqueous layer was twice extracted with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate and concentrated. Purification by chromatography on silica gel (2% methanol in dichloromethane) gave the methyl ester of 2-(tert-butoxycarbonylamino-methyl)-oxazol-4-carboxylic acid in the form of oil (123 mg, 78%).1H NMR (CDCl3) δ 1,25 (s, 9H), 3,88 (s, 3H), 4,51 (d, 2H, J=5.8 Hz), 5,22 (user. s, 1H), 8,19 (s, 1H).

Ester (178 mg, 0,695 mmol) cooled to 0°C dichloromethane (8 ml) was treated with DIBAL-H (1M in dichloromethane, 2,08 ml of 2.08 mmol). The mixture was then stirred at 0°C for 2 hours before treatment aqueous 5%solution of sodium tartrate, potassium (8 ml). The mixture was vigorously stirred for 30 minutes (up until the aqueous and organic layers do not become transparent) and then the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate and concentrated. Purification by chromatography on silica gel (5% methanol in dichloromethane) gave tert-butyl ester (4-hydroxymethyl-oxazol-2-ylmethyl)carbamino acid in the form of oil (45 is g, 28%).1H NMR (CDCl3) δ of 1.40 (s, 9H), 4,43 (d, 2H, J=5.6 Hz), 4,56 (s, 2H), lower than the 5.37 (s, 1H), 7,54 (s, 1H).

To a stirred solution of tert-butyl methyl ether (4-hydroxymethyl-oxazol-2-ylmethyl)carbamino acid (45 mg, 0,197 mmol) in dichloromethane (5 ml) was added triethylamine (by 0.055 ml, 0.4 mmol), then methanesulfonanilide (0,023 ml, 0.3 mmol). The resulting solution was stirred at room temperature for 20 minutes before treatment aqueous saturated solution of ammonium chloride (5 ml). The aqueous layer was extracted twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate and concentrated, obtaining the target mesilate, which is used directly and immediately in the next reaction without further purification.1H NMR (CDCl3) δ 1,45 (s, 9H), of 3.07 (s, 3H), 4,43 (d, 2H, J=5.6 Hz), further 5.15 (s, 2H), 7,73 (s, 1H).

Using General method N-alkylation of 2-(tert-butoxycarbonylamino-methyl)-oxazol-4-yl methyl ether methansulfonate acid (0,197 mmol) was stirred at 60°C in acetonitrile (5 ml) for 4 hours with diisopropylethylamine (0.05 ml, 0,295 mmol) and (1H-N-tert-butoxycarbonylamino-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) - amine (95 mg, 0.25 mmol). The reaction mixture was then cooled and concentrated. The residue was placed in dichloromethane and extracted with aqueous ammonium chloride, dried, concentrated and the eyes of the Ali chromatography on silica gel (20:1 dichloromethane:methanol), getting tert-butyl ester 2-{[[2-tert-butoxycarbonylamino-methyl)-oxazol-4-ylmethyl]-(5,6,7,8-tetrahydro-quinoline-8-yl)amino]-methyl}benzimidazole-1-icarbonell acid (23 mg, 19%).1H NMR (CDCl3) δ of 1.46 (s, 9H), and 1.63 (s, 9H), 1.91 a (m, 1H), 2,02 (m, 1H), 2,24 (DK, 1H, J=6,8, and 2.1 Hz), of 2.51 (m, 1H), 2,61-2,78 (m, 2H), 4,27 (m, 1H), 4,43 (d, 2H, J=5.8 Hz), of 4.49 (s, 2H), 4,73 (d, 1H, J=16.1 Hz), 5,09 (d, 1H, J=16.1 Hz), 5,15 (m, 1H), to 6.88 (DD, 1H, J=7,1, 5,4 Hz), 7,13 (d, 1H, J=7,1 Hz), 7,24 (m, 2H), to 7.61 (s, 1H), to 7.61 (m, 1H), 7,74 (m, 1H), 8,23 (d, 1H, J=5.4 Hz).

Tert-butyl ester 2-{[[2-tert-butoxycarbonylamino-methyl)-oxazol-4-ylmethyl]-(5,6,7,8-tetrahydro-quinoline-8-yl)amino]-methyl}benzimidazole-1-icarbonell acid (23 mg, 0,039 mmol) were placed in acetic acid (1 ml)to which was added a saturated solution of HBr in acetic acid (1 ml). The mixture was then stirred, besieged and isolated according to method D, receiving AMD9903 in the form of a white crystalline solid (14 mg).1H NMR (D2O) δ of 1.84 (m, 1H), 2.05 is (m, 2H), of 2.21 (m, 1H), 3,00 (m, 2H), and 3.72 (d, 1H, J=14.1 Hz), 3,92 (d, 1H, J=14.1 Hz), 3,99 (d, 2H, J=6.0 Hz), 4,39 (d, 1H, J=16.5 Hz), 4,58 (d, 1H, J=16.5 Hz), 4.72 in (m, 1H), to 7.59 (m, 2H), to 7.75 (m, 2H), to 7.84 (s, 1H), 7,86 (m, 1H), with 8.33 (d, 1H, J=8,1, 15 Hz), 8,67 (d, 1H, J=5.8 Hz).13C NMR (D2O) δ 20,35, 20,57, 27,62, 35,70, 46,40, 48,16, 60,94, 114,15 (2C), 125,95, 127,06 (2C), 139,57, 140,46, 148,03, 151,23, 154,96. ES-MS m/z 389 (M+H). Elemental analysis. Calculated for (C22H24N6O·4HBr·2,6H2O): C, 34,82; H, To 4.41; N, 11,07; Br, 42,11. Found: C, 35,10; H, Of 4.44; N, Of 10.73; Br, 41,80.

Example: 7

AMD9986: Receive (1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[(1-benzyl-2-aminoethyl)imidazol-5-ylmethyl]amine.

Obtaining 2,5-bis-(hydroxymethyl)-N-benzimidazole

Using the methodology developed by S. Zimmerman et al. (S.C. Zimmerman, K.D. Cramer and A. A. Galan J. Org. Chem. 1989, 54, 1256-1264), N-benzylimidazole (15 g, 95 mmol) was treated with formaldehyde (60 ml 37%aqueous solution), to which was added glacial acetic acid (8 ml) and sodium acetate (10.5 g). The mixture was mixed to homogeneity, and then transferred in costosternal glass ampoule, which was sealed and placed at 140°C on an oil bath for 12 hours. The vial was then cooled, the contents were concentrated, was podslushivaet 10 N. NaOH and was extracted twice with a mixture of 10:1 isopropanol:chloroform. The combined organic fractions were then dried over anhydrous sodium sulfate and concentrated. Purification by chromatography on silica gel (7% methanol in dichloromethane) gave 2,5-bis(hydroxymethyl)-N-benzylimidazole in the form of a white crystalline solid (4.9 g, 24%).1H NMR (CDCl3) δ to 4.41 (s, 2H), 4,48 (s, 2H), are 5.36 (s, 2H), 6,77 (s, 1H), 7,00 (m, 2H), 7,28 (m, 3H).

To a solution of 2,5-bis-(hydroxymethyl)-N-benzylimidazole (436 mg, 2.0 mmol) in dichloromethane (10 ml) was added triethylamine (0.35 ml, 2.0 mmol) and acetic anhydride (to 0.19 ml, 2.0 mmol). The mixture was then stirred overnight (casos) at room temperature. The reaction mixture was then washed with an aqueous solution of ammonium chloride and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate and concentrated. Purification by chromatography on silica gel (5% methanol in dichloromethane) gave monoacetate, 2-acetoxymethyl-5-hydroxymethyl-N-benzylimidazole, in the form of a white powder (300 mg, 58%).1H NMR (CDCl3) δ to 1.83 (s, 3H), of 4.49 (s, 2H), is 5.06 (s, 2H), 5,33 (s, 2H), 6,97 (m, 2H), 7,28 (m, 3H).

To a stirred solution of 2-acetoxymethyl-5-hydroxymethyl-N-benzylimidazole (130 mg, 0.5 mmol) in dichloromethane (5 ml) was added triethylamine (0.104 g ml, 0.75 mmol) followed by the addition of methanesulfonanilide (0,046 ml, 0.6 mmol). The resulting solution was stirred at room temperature for 20 minutes before treatment aqueous saturated solution of ammonium chloride (5 ml). The aqueous layer was extracted twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate and concentrated, obtaining the target mesilate, which immediately directly used in the next reaction without further purification.1H NMR (CDCl3) δ to 1.86 (s, 3H), of 4.44 (s, 2H), by 5.18 (s, 2H), from 5.29 (s, 2H), 6,97 (m, 2H), 7,33 (m, 3H).

Using General method, N-alkylation, O-methanesulfonyl-2-acetoxymethyl-5-hydroxymethyl-N-benzylimidazole (0,5 shall mol) was stirred at 60° C in acetonitrile (5 ml) for 4 hours with diisopropylethylamine (0,130 ml, 0.75 mmol) and (1H-N-tert-butoxycarbonylamino-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (226 mg, 0.6 mmol). The reaction mixture was cooled and concentrated. The residue was placed in dichloromethane and extracted with aqueous ammonium chloride, dried, concentrated and purified by chromatography on silica gel (20:1 dichloromethane:methanol)to give [N-(tert-butoxycarbonyl)benzimidazole-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-acetoxymethyl-N-benzylimidazole-5-yl)methyl]amine together with the product formed during the cleavage of the acetate group (a mixture of 138 mg).

The mixture obtained above product (138 mg) was treated with potassium carbonate (100 mg) in methanol (5 ml) and the suspension was stirred for 8 hours at room temperature. The mixture then was filtered and concentrated, the residue was purified flash chromatography on silica gel using a mixture of 20:1 dichloromethane:methanol as eluent, obtaining [1H-benzimidazole-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-hydroxymethyl-N-benzylimidazole-5-yl)methyl]amine as a pale yellow foam (100 mg, 43% for 2 stages).1H NMR (CDCl3) δ to 1.61 (m, 1H), 1,89 (m, 2H), 2,15 (m, 1H), 2,70 (m, 2H), 3,56 (d, 1H, J=15.1 Hz), 3,68 (d, 1H, J=15.1 Hz), 4.00 points (s, 2H), 4,01 (m, 1H), 4,35 (s, 2H), 5,28 (s, 2H), only 6.64 (m, 2H), to 6.88 (s, 1H), 7,07 (m, 4H), 7,17 (m, 2H), 7,34 (d, 1H, J=7.8 Hz), 7,54 (user. s, 1H), 8,45 (d, 1H, J=4,8 Hz).

To a solution of[1H-benzimidazole-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-hydroxymethyl-N-benzylimidazole-5-yl)methyl]amine (81 mg, 0,17 mmol) in dichloromethane (5 ml) was added triethylamine (0,095 ml of 0.68 mmol), after which methanesulfonanilide (0,040 ml, 0.5 mmol). The resulting solution was stirred at room temperature for 20 minutes before treatment aqueous saturated solution of ammonium chloride (5 ml). The aqueous layer was extracted twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate and concentrated, obtaining the target mesilate, which is directly used in the next reaction without further purification.

To a solution of nelfinavir (0,17 mmol) in DMF (2 ml) and dichloromethane (2 ml) was added sodium azide (33 mg, 0.51 mmol). The mixture then was heated at 50°C for 2 hours. After cooling, the solution washed with 1 N. NaOH (5 ml) and was extracted several times with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate, concentrated and purified flash chromatography on silica gel using a mixture of 20:1 dichloromethane:methanol as eluent, obtaining [1H-benzimidazole-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-isomethyl-N-benzylimidazole-5-yl)methyl]amine as a white foam (34 mg, 40% over 2 stages).1H NMR (CDCl3) δ by 1.68 (m, 1H), 1,95 (m, 2H), 2,44 (m, 1H), 2,88 (m, 2H), 2,64 (d, 1H, J=16.1 Hz), 3,79 (s, 2H), 4.09 to (m, 1H), 4,11 (d, 1H, J=13,8 Hz), 4,18 (d, 1H, J=13,8 Hz), 4,49 (d, 1H, J=12,8 Hz), 5,71 (d, 1H, J=16.1 Hz), 6,70 (m, 2H), 6.90 to (m, 1H), 6,91 (who, 1H), 7,18 (m, 2H), 7,20 (m, 1H), 7,32 (m, 3H), 7,58 (d, 1H, J=8.1 Hz), 7,81 (m, 1H), of 8.09 (d, 1H, J=4,9 Hz).

To a solution of [1H-benzimidazole-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-isomethyl-N-benzylimidazole-5-yl)methyl]amine (34 mg, 0,068 mmol) in methanol (10 ml) was added 5% palladium on calcium carbonate (Lindlar catalyst, 30 mg). Then the suspension was placed in an atmosphere of hydrogen gas at a pressure of 1 atmosphere and was stirred for 12 hours at room temperature. The mixture is then filtered and the filtrate was concentrated, obtaining [1H-benzimidazole-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-aminomethyl-N-benzylimidazole-5-yl)methyl]amine (23 mg, 71%) as a white foam.1H NMR (CDCl3) δ by 1.68 (m, 1H), 2,02 (m, 2H), 2,35 (m, 1H), 2,64 (m, 2H), 3,48 (user. s, 2H, NH2), 3,80 (m, 2H), a 3.87 (s, 2H), 4,01 (m, 1H), 4.16 the (d, 1H, J=15.3 Hz), 4,51 (d, 1H, J=15.3 Hz), 5,26 (d, 1H, J=16.1 Hz), 5,73 (d, 1H, J=16.1 Hz), of 6.71 (m, 2H), 6,94 (m, 2H), 7,16 (m, 2H), 7,22 (m, 2H), 7.24 to (s, 1H), 7,32 (m, 2H), 7,66 (m, 1H), a 7.85 (m, 1H), 8,08 (d, 1H, J=4,8 Hz).

[1H-Benzimidazole-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-aminomethyl-N-benzylimidazole-5-yl)methyl]amine (23 mg, 0,048 mmol) were placed in acetic acid (1 ml)to which was added a saturated solution of HBr in acetic acid (1 ml). The mixture was then stirred, besieged and isolated according to method D, receiving AMD9986 in the form of a white crystalline solid (19 mg).1H NMR (D2O). δ or 1.77 (m, 1H), 2,01 (m, 2H), measuring 2.20 (m, 1H), 2,78 (m, 2H), 3,53 (d, 1H, J=14,8 Hz), 4.00 points (d, 1H, J=14,8 Hz), the 4.29 (m, 2H), 4,4 (d, 1H, J=15.3 Hz), a 4.53 (d, 1H, J=15.3 Hz), 4,58 (m, 1H), and 5.30 (m, 2H), 6,76 (m, 2H), 7,19 (m, 4H), 7,51 (s, 1H), to 7.64 (m, 2H), 7,82 (m, 2H), 8,28 (d, 1H, J=7.8 Hz), 8,63 (d, 1H, J=4,9 Hz).13C NMR (D2O) δ 20,01, 20,19, 27,69, 33,06, 33,81, 45,27, 48,21, 48,74, 59,46, 114,36, 125,27, 125,72, 125,89, 126,09, 127,24, 129,02, 129,71, 130,91, 130,99, 133,72, 138,88, 140,95, 141,29, 148,26, 149,94. ES-MS m/z 478 (M+H). Elemental analysis. Calculated for (C22H24N6O·4HBr·2,5H2O·0,7HOAc): C, 41,10; H, a 4.86; N, 11,04; Br, 35,98. Found: C, 41,16; H, 4,82; N, 11,04; Br, 36,06.

Example: 8

AMD9813: Obtain 6-aminomethylpyridine-3-ylmethyl-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

Obtaining 3-hydroxymethyl-6-cyanopyridine

To a solution of ethyl-6-canonicaldata (obtained as in the publication by T. Sakamoto, S. Kaneda, S. Nishimura, and H. Yamanaka Chem. Pharm. Bull. 1985, 33, 565) (1,58 g, 8,97 mmol) in MeOH (40 ml) was added NaBH4(1,00 g of 26.4 mmol) and the reaction mixture was stirred at room temperature for 8 hours. After removal of solvent the residue was placed in 15% NaOH (5 ml) and was stirred for 20 minutes. The mixture then was extracted several times CH2Cl2and the combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (EtOAc/hexane, 1:1) gave 3-hydroxymethyl-6-cyanopyridine (414 mg, 34%).1H NMR (CDCl3) δ 5,16 (who, 2H), 7,69 (d, 1H, J=6,8 Hz), to 7.84 (d, 1H, J=6,8 Hz), 8,71 (s, 1H).

Using General method C, to a solution of 3-hydroxymethyl-6-cyanopyridine (30 mg, 0,222 mmol) in CH2Cl2(2 ml) was added methanesulfonamide (of 0.022 ml, 0,289 mmol) and triethylamine (0,046 ml of 0.333 mmol) and the mixture was stirred for 60 minutes at room temperature. Purification of the crude product by chromatography on silica gel (10:1 CH2Cl2/MeOH) gave the target mesilate in the form of a pale yellow solid (22 mg, 47%).1H NMR (CDCl3) δ 3,14 (s, 3H), 5,32 (s, 2H), of 7.75 (d, 1H, J=6,8 Hz), to $ 7.91 (d, 1H, J=6,8 Hz), the rate of 8.75 (s, 1H).

Using General method, N-alkylation, to the solution obtained above nelfinavir (22 mg, 0.104 g mmol), potassium iodide (3 mg, 0.015 mmol) and potassium carbonate (22 mg, 0,156 mmol) in CH3CN (3 ml) was added 1-tert-butoxycarbonylamino-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (60 mg, 0,156 mmol) and the mixture was heated at 70°C for 4 hours. Purification of the crude substances by chromatography on silica gel (10:1 CH2Cl2/Meon) gave 6-cyano-3-yl-(1H-N-tert-butoxycarbonylamino-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (32 mg, 63%).1H NMR (CDCl3) δ by 1.68 (s, 9H), 1.91 a-2,04 (m, 2H), 2,22 (m, 1H), 2,72-and 2.79 (m, 2H), 3,80 (d, 1H, J=16.1 Hz), 3,98 (d, 1H, J=16.1 Hz), or 4.31 (DD, 1H, J=12,1, 6.2 Hz), 4,58 (d, 1H, J=16,8 Hz), was 4.76 (d, 1H, J=16,8 Hz), 7,02 (m, 2H), 7.24 to 7,31 (m, 3H), to 7.61-7,63 (m, 3H), 8,44 (d, 1H, J=5,1 Hz), 8,53 (d, 1H, J=4,1 Hz).

To a solution of 6-cyan is pyridin-3-yl-(1H-N-tert-butoxycarbonylamino-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (32 mg, 0,065 mmol) in MeOH (2 ml) was added Raney Nickel (65 mg 65%suspension in water) and the solution was saturated with anhydrous ammonia. The mixture was first made in the vessel Parra at a pressure of 50 lb/in2(345 kPa) for 6 hours and the mixture was filtered through celite, washing the precipitate MeOH. The solvent from the eluent was removed under reduced pressure and the crude substance was purified by chromatography on silica gel (85% CH2Cl2, 12% MeOH, 3% NH4OH), receiving 6-aminomethylpyridine-3-yl-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine as a white foam (18 mg, 70%).1H NMR (CDCl3) δ of 1.62 (m, 1H), 1,94-of 2.08 (m, 2H), 2,25-2,31 (m, 1H), 2.70 height of 2.92 (m, 2H), 3,49 (s, 2H), and 3.72 (s, 2H), 3,85 (users, 2H (NH)), 4,00 (d, 2H, J=16.5 Hz), 4,08 (DD, 1H, J=12,1, 8,3 Hz), 4,13 (d, 1H, J=16.5 Hz), 7,10-7,22 (m, 4H), 7,43 (d, 1H, J=7,2 Hz), 7,53 (m, 2H), 7,69 (d, 1H, J=7.8 Hz), 8,58 (s, 1H), 8,66 (d, 1H, J=4,8 Hz).

According to the General procedure D conversion result of the above amine (18 mg, 0.045 mmol) in hydrobromide salt gave AMD9813 in the form of a white solid (28 mg).1H NMR (D2About). δ to 1.86 (m, 1H), 2,23 (m, 2H), 2,46 (m, 1H), 3.04 from (m, 2H), 3,69 (d, 1H, J=14,9 Hz), 3,76 (d, 1H, J=14,9 Hz), 3,93 (q, 2H, J=13,4 Hz), 4,46 (d, 1H, J=16,8 Hz), of 4.67 (d, 1H, J=16,8 Hz), 4,78 (m, 1H), 7,06 (d, 1H, J=7.8 Hz), 7,55 (m, 2H), 7.62mm (m, 2H), 7,69 (DD, 1H, J=8,1, 6,0 Hz), 8,35 (d, 1H, J=1.8 Hz), 8,44 (d, 1H, J=8.1 Hz), 8,77 (d, 1H, J=4.5 Hz).13C NMR (D2O) δ 20,38, 20,83, 27,84, 42,67, 49,63, 53,93, 62,71, 114,05 (2C), 122,99, 126,22, 127,03 (2C), 130,50, 132,87, 133,10, 139,87 (2C), 141,14, 148,41, 149,98, 150,49, 151,44, 154,29. ES-MS m/z 399 (M+H). Elemental analysis. In Chiclana for C 24H26N6·3,8HBr·2,2H2O: C,Amounted To 38.66; H, To 4.62; N, 11,27; Br, 40,72. Found: C, 39,98; H, To 4.68; N, 10,97; Br, 40,63.

Example: 9

AMD9739: Obtain [4-(2-amino-ethyl)benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Obtain tert-butyl ester [2-(4-formylphenyl)ethyl]carbamino acid

A mixture of methyl 4-(methyl bromide)benzoate (to 10.09 g, 44,05 mmol), sodium cyanide (6.42 per g, 131 mmol) and cetyltrimethylammonium bromide (1,59 g, 4,36 mmol) in a mixture of benzene/water (2:1, 187.5 ml) was boiled under reflux for 5 hours, then was extracted with CH2Cl2(3 x 50 ml). The organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification of the crude substances by chromatography on silica gel (35% EtOAc/hexane) gave methyl ether 4-cyanomethylene acid as a colourless solid (with 4.64 g, 60%).1H NMR (CDCl3) δ 3,82 (s, 2H), 3,93 (s, 3H), 7,42 (d, 2H, J=9 Hz), of 8.06 (d, 2H, J=9 Hz).

To the solution obtained above nitrile (1,57 g, 8,96 mmol) in CH3OH, saturated NH3(30 ml)in a vessel Parra was added Raney Nickel (5 g) and the mixture was first made when hydrogen pressure of 45 lb/in2(310 kPa) in a Parr apparatus for hydrogenation over 67 hours. The mixture of products was filtered through celite and the solvent of e is wenta was removed in vacuum, getting green liquid (1.30 grams). The solution of green liquid (1.29 g) and di-tert-BUTYLCARBAMATE (1.90 g, 8,71 mmol) in THF (24 ml) was stirred at room temperature for 2 hours, then concentrated. Purification of the crude substances on silica gel (20% EtOAc/hexane) gave the methyl ester of 4-(2-tert-butoxycarbonylamino)benzoic acid (1,37 g, 55%) as colorless crystals.1H NMR (CDCl3) δ of 1.43 (s, 9H), of 2.86 (m, 2H), 3,39 (m, 2H), 3,91 (s, 3H), 4.53-in (users, 1H), 7,26 (d, 2H, J=8.1 Hz), 7,98 (d, 2H, J=8.1 Hz).

To the solution obtained above of ester (606 mg, 2,17 mmol) in THF (4 ml) at 0°C was added diisobutylaluminium (1.0 M/THF, 13 ml, 13 mmol). The mixture was stirred at room temperature for 1 hour, then added water, followed by adding 10%aqueous HCl until acidic environment (pH 1-2). The mixture was podslushivaet 1 N. NaOH (aq.) and was extracted with CH2Cl2. The organic extracts were dried (MgSO4), filtered and concentrated. Purification of the crude substances by chromatography on silica gel (30% EtOAc/hexane) gave tert-butyl ether [2-(4-hydroxymethylene)ethyl]carbamino acid (370 mg, 68%) as colorless crystals.1H NMR (CDCl3) δ the 1.44 (s, 9H), 2,80 (m, 2H), 3,37 (m, 2H), 4.53-in (user. s, 1H), and 4.68 (d, 2H, J=5.7 Hz), 7,19 (d, 2H, J=7.8 Hz), 7,32 (d, 2H, J=7,8 Hz).

To a solution of the alcohol obtained above (200 mg, coefficient was 0.796 mmol) in CH2Cl2(8 ml) add the Yali activated MnO 2(814 mg, of 7.96 mmol) and the mixture was stirred at room temperature for 69 hours. The reaction mixture was filtered through celite and the precipitate washed CH2Cl2. The solvent was removed from the filtrate under reduced pressure, obtaining the target aldehyde in the form of colorless crystals (175 mg, 88%).1H NMR (CDCl3) δ of 1.43 (s, 9H), 2,89 (m, 2H), 3,41 (m, 2H), 4,55 (user. s, 1H), 7,37 (d, 2H, J=8.1 Hz), 7,83 (d, 2H, J=7.8 Hz), 9,99 (s, 1H).

Using General method B to a solution of [1-(tert-butoxycarbonyl)-(1H-benzimidazole-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (102 mg, 0.27 mmol) and tert-butyl methyl ether [2-(4-formylphenyl)ethyl]carbamino acid (81 mg, 0.32 mmol) in THF (3 ml) was added acetic acid (0,017 ml, 0.30 mmol) and NaBH(OAc)3(187 mg, 0,882 mmol) and the mixture was stirred for 46 hours. Purification of the crude yellow oil by chromatography on silica gel (300:5:1 CH2Cl2/MeOH/NH4OH) gave a colorless foam (153 mg).

The solution is colorless foam in a mixture of 1:1 triperoxonane acid/CH2Cl2(4 ml) was stirred at room temperature for 45 minutes, then concentrated. The residue was distributed between CH2Cl2(10 ml) and saturated aqueous NaHCO3(10 ml) and the aqueous phase was extracted with CH2Cl2(3 × 10 ml). The combined organic phases were dried (MgSO4) and concentrated. Purification of the crude substances Colo is face-to-face chromatography on silica gel (100:5:1 EtOAc/MeOH/NH 4OH) gave a colourless oil (38 mg, 35%).

Using General method D, the transformation obtained above colourless oil (38 mg, 0,092 mmol) in hydrobromide salt gave AMD9739 (50 mg, 79%) as a colourless solid.1H NMR (D2O) δ of 1.94 (m, 1H), and 2.26 (m, 2H), 2,43-2,60 (m, 5H), 3,03 (m, 2H), 3,74 (d, 1H, J=13 Hz), 3,82 (d, 1H, J=13 Hz), 4,42 (d, 1H, J=16 Hz), 4,60 (d, 1H, J=16 Hz), 4,79 (m, 1H), 6,85 (d, 2H, J=7,8 Hz), 7,14 (d, 2H, J=7.8 Hz), 7,47-to 7.59 (m, 4H), to $ 7.91 (m, 1H), of 8.37 (d, 1H, J=7.8 Hz), the rate of 8.75 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 18,88, 19,33, 26,26, 30,88, 38,90, 48,70, 55,03, 61,59, 112,33, 124,34, 124,75, 127,27, 128,98, 129,38, 133,59, 135,32, 138,18, 139,18, 146,31, 149,49, 150,55. ES-MS m/z 412 (M+H). Elemental analysis. Calculated for C26H29N5·3,0HBr·1,8H2O: C, 45,48; H, 5,23; N, 10,20; Br, 34,91. Found: C, 45,45; H, 5,13; N, 9,95; Br, 34,94.

Example: 10

AMD9756: Obtain [4-(3-aminopropyl)benzyl]-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt)

Obtaining 3-(4-chloromethylene)-propionitrile

Acetonitrile (0,30 ml, 5.7 mmol) was added to a solution of n-utility (2,4M in hexano, a 1.96 ml, 4.7 mmol) in anhydrous THF (5 ml) at -78°C and was stirred for 45 minutes, was added to the solution α,α'-dichloro-p-xylene (2,485 g of 14.2 mmol) in anhydrous THF at -78°C, receiving a yellow turbid solution. The mixture was stirred at -78°C optional for hours and extinguished saturated the electroplated in an aqueous solution of NaCl (30 ml) before heating to room temperature. The mixture was extracted with CH2Cl2(3 x 200 ml). The combined organic extracts were dried over MgSO4and focused, getting a white solid (2,45 g). The product was purified column chromatography on silica gel (10:1 EtOAc:hexane)to give the target nitrile (1,49 g, 60%) as light yellow syrup.1H NMR (300 MHz, CDCl3) δ 7,37 (d, 2H, J=8.1 Hz), 7,24 (d, 2H, J=8.1 Hz), 4,58 (s, 2H), 2,96 (t, 2H, J=7.4 Hz), 2,62 (t, 2H, J=7,4 Hz).

Using the General method of alkylation With, to stir a solution of 3-(4-chloromethylene)propionitrile (63 mg, 0.35 mmol) and (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (121 mg, 0.32 mmol) in anhydrous CH3CN (3 ml) was added KI (2.6 mg, to 0.016 mmol) and N,N-diisopropylethylamine (of 0.08 ml, 0.48 mmol) and the mixture was heated at 60°C within 24 hours. The product was purified column chromatography on silica gel (200:1:1 CH2Cl2:MeOH:NH4OH), receiving the target condensation product (128 mg, 77%) as a yellow syrup.1H NMR (300 MHz, CDCl3) δ 8,46 (d, 1H, J=3.6 Hz), 7,65-to 7.61 (m, 1H), 7,55-7,51 (m, 1H), 7,28 (d, 1H, J=9.6 Hz), 7,20-to 7.15 (m, 4H),? 7.04 baby mortality-7,00 (m, 1H), 6,77 (d, 2H, J=8.1 Hz), 4,74 (d, 1H, J=14.4 Hz), of 4.66 (d, 1H, J=14.4 Hz), 4,36-4,30 (t, 1H), a 3.87 (4 1H, J=14,7 Hz), to 3.73 (d, 1H, J=14,7 Hz), 2.77-to 2,63 (t, 4H), 2,30 was 2.25 (t, 3H), 2,02-of 1.94 (t, 2H), 1,74-1,71 (m, 10H).

A solution of tert-butyl ester 2-{[[4-(2-cyanoethyl)benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazol-1-carboxylic acid (128 mg,0.24 mmol) in MeOH (10 ml) was saturated NH 3(g). The Raney-Nickel (˜2 g, excess) were washed in MeOH (3x), transferred to a hydrogenation flask containing the nitrile and the mixture was first made at a pressure of 45 lb/in2(310 kPa) for 16 hours. The mixture of products was diluted in MeOH (100 ml) and filtered through celite and the solvent from the eluent removed in vacuum. The product was purified column chromatography on silica gel (100:1:1 CH2Cl2:MeOH:NH4OH), receiving the target amine (51 mg, 50%) as a white foam.1H NMR (300 MHz, CDCl3) δ to 8.70 (d, 1H, J=3.6 Hz), to 7.59 (user. s, 2H), 7,42 (d, 1H, J=8.1 Hz), 7,30 (d, 2H, J=8.1 Hz), 7,20-to 7.15 (m, 3H),? 7.04 baby mortality (d, 2H, J=7.8 Hz), 4,17 (d, 1H, J=16,8 Hz), 4,12-4,06 (m, 1H), 3,97 (d, 1H, J=16,8 Hz), 3,71 (s, 2H), 2,86-to 2.74 (m, 2H), 2,66 (t, 2H, J=6.9 Hz), of 2.56 (t, 2H, J=7.8 Hz), 2,33-of 2.24 (m, 1H), 2,09-to 1.98 (m, 2H), 1,73-of 1.64 (m,3H).

According to the General procedure D conversion result of the above foam (51 mg) in hydrobromide salt gave AMD9756.1H NMR (300 MHz, D2O) δ is 8.75 (d, 1H, J=5.7 Hz), 8,40 (d, 1H, J=7.8 Hz), to 7.93 (DD, 1H, J=7,8, 5.7 Hz), 7,60-7,56 (m, 2H), 7,53-7,47(m, 2H), 7,11 (d, 2H, J=7.8 Hz), 6,83 (d, 2H, J=8.1 Hz), 4,78-to 4.73 (m, 1H), to 4.62 (d, 1H, J=16.5 Hz), of 4.44 (d, 1H, J=16.5 Hz), 3,82 (d, 1H, J=12.3 Hz in), 3.75 (d, 1H, J=12.3 Hz), 3,06-3,03 (m, 2H), was 2.76 (t, 2H, J=7.8 Hz), 2,46 is 2.43 (m, 1H), 2,34-2,17 (m, 4H), 2,97 is 1.91 (m, 1H), 1,46 is 1.35 (m, 2H);13C NMR (75.5 MHz, D2O) δ 153,8, 152,7, 150,0, 143,1, 142,7, 141,4, 135,8, 132,3, 132,2, 130,3, 128,4, 127,9, 115,7, 65,0, 58,4, 52,1, 41,2, 33,3, 30,4, 29,7, 22,7, 22,3. ES-MS m/z 426,3 (M+H). Elemental analysis. Calculated for (C27H31N5)·2,9(HBr)·1,9(H2O): C, 46,70; H, Vs. 5.47; N, 10,08; Br, 33,37. Found: C, 46,69; H 5,14; N, There Is A 10.03; Br, 33,43.

Example: 11

AMD9768: Obtaining N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)hydroxylamine.

A solution of 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde (350 mg, 0,883 mmol) and hydroxylamine hydrochloride (100 mg, 1.44 mmol) in MeOH (3 ml) was stirred at room temperature for 45 minutes, then concentrated in vacuo. The residue was distributed between saturated solution of NaHCO3(aq.) (15 ml) and CH2Cl2(20 ml) and the aqueous phase was extracted with CH2Cl2(10 ml). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuum, obtaining a yellow solid (363 mg).

To the solution obtained above the crude oxime (90 mg, 0.22 mmol) in a mixture of 6:1 MeOH/THF (2.2 ml) was added NaBH4(19 mg, 0.50 mmol) and the solution was brought to pH 4 using a solution of saturated HCl/1,4-dioxane. The mixture was stirred at room temperature for 15 minutes, then further added NaBH4(19 mg, 0.50 mmol) and the solution was brought to pH 4. The mixture was stirred for 15 minutes, then podslushivaet using 1 N. NaOH (aq.) and was extracted with CH2Cl2(3 × 15 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuum. Purification of the crude substances is TBA column chromatography on silica gel (100:5:1 CH 2Cl2/MeOH/NH4OH) gave AMD9768 (67 mg, 68%) as a colourless foam.1H NMR (CDCl3) δ of 1.66 (m, 1H), 1,99 (m, 2H), 2,24 (m, 1H), 2,67-2,90 (m, 2H), 3,71 (s, 2H), 3,94 (d, 1H, J=17 Hz), of 3.94 (s, 2H), 4,07 (m, 1H), 4,14 (d, 1H, J=17 Hz), 7,17 (m, 5H), 7,38 (m, 3H), 7,55 (m, 2H), 8,66 (d, 1H, J=3,9 Hz);13C NMR (CDCl3) δ 21,34, 23,30, 29,18, 48,50, 53,81, 57,91, 60,37, 121,87, 122,36, 128,80, 129,06, 134,94, 136,13, 137,55, 138,46, 146,72, 155,89, 157,15. ES-MS m/z 414 (M+H). Elemental analysis. Calculated for C25H27N5O·0,3H2O·0,36CH2Cl2: C, 67,76; H, 6.35MM; N, 15,58. Found: C, 67,85; H, To 6.39; N, 15,51.

Example: 12

AMD11088: Receive (5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)methanol.

Obtain methyl ester of 2-methyl-5-nitrobenzoic acid

A solution of 2-methyl-5-nitrobenzoic acid (1.51 g, a 8.34 mmol) and H2SO4(catalytic amount) in MeOH (20 ml) was boiled under reflux for 17 hours, then concentrated in vacuo. The residue was dissolved in CH2Cl2(40 ml), washed with saturated solution of NaHCO3(aq.) (30 ml), then dried (MgSO4) and concentrated in vacuum, obtaining yellow crystals (1,62 g, 99%).1H NMR (CDCl3) δ of 2.72 (s, 3H), of 3.96 (s, 3H), 7,44 (d, 1H, J=8.7 Hz), 8,24 (DD, 1H, J=8,7, 2.7 Hz), 8,78 (d, 1H, J=2.7 Hz).

Obtain methyl ester of 5-amino-2-methylbenzoic acid

A solution of methyl ester of 2-methyl-5-nitrobenzoic acid (a 1.96 g, 10.0 mmol) in a mixture of 4:1 MeOH/EtOAc (25 ml) was shaken at room temperature with a suspension of 10% Pd/C (200 mg, 0,19 mmol) in hydrogen atmosphere 35 lb/in2(241 kPa) for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuum, obtaining an orange oil (1.64 g, 99%).1H NMR (CDCl3) δ 2,47 (s, 3H), 3,62 (user. s, 2H), a 3.87 (s, 3H), 6.75 in (DD, 1H, J=8,1, 2.7 Hz), 7,02 (d, 1H, J=8.1 Hz), 7,25 (d, 1H, J=2.7 Hz).

Obtain methyl ester of 5-cyano-2-methylbenzoic acid

To a stirred suspension of methyl ester of 5-amino-2-methylbenzoic acid and 1.00 g, 6.05 mmol) in H2O (1.5 ml) was slowly added conc. HCl (1.5 ml) at room temperature. Added additional H2O (7 ml) and the mixture was stirred at 0°C as add (dropwise) a solution of NaNO2(459 mg, of 6.65 mmol) in H2O (1 ml). After complete dissolution of the amine slowly at 0° (C) was added To a2CO3(solid) to neutralize the solution.

The copper cyanide(I) (651 mg, 7,27 mmol) was dissolved in a solution of NaCN (712 mg, 14.5 mmol) in H2O (2.2 ml) and the solution was heated to 60°C. To intensively mix the cyanide solution at 60°C was added dropwise a cold solution neutralized diazonium salts. The mixture was heated to 110°C for 30 minutes, then left the OHL the legal to room temperature. The mixture was diluted with saturated solution of NaHCO3(aq.) (10 ml) and was extracted with CH2Cl2(4x12 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuum. The crude product was filtered through silica gel (10% EtOAc/hexane)to give yellow crystals (896 mg, 85%).1H NMR (CDCl3) δ of 2.68 (s, 3H), 3,93 (s, 3H), 7,37 (d, 1H, J=8.1 Hz), 7,66 (DD, 1H, J=7,8, 1.8 Hz), by 8.22 (d, 1H, J=1.8 Hz).

Obtaining methyl ester 2-methyl bromide-5-cyanobenzoic acid

A mixture of methyl ester of 5-cyano-2-methylbenzoic acid (894 mg, 5,10 mmol), NBS (1,00 g, 5,62 mmol) and AIBN (125 mg, 0,761 mmol) in CCl4(20 ml) was boiled under reflux for 3 days, then left to cool to room temperature. The mixture was filtered and the filtrate was concentrated in vacuum. Purification of the crude substances column chromatography on silica gel (5% EtOAc/hexane) gave yellow crystals (800 mg, 62%).1H NMR (CDCl3) δ 3,99 (s, 3H), 4,96 (s, 2H), to 7.61 (d, 1H, J=8.1 Hz), to 7.77 (DD, 1H, J=8,1, 1.8 Hz), of 8.27 (d, 1H, J=1.8 Hz).

A mixture of tert-butyl ester 2-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzoimidazol-1-carboxylic acid (253 mg, 0,668 mmol), methyl ester 2-methyl bromide-5-cyanobenzoic acid (170 mg, 0,669 mmol), potassium iodide (6 mg, 0.04 mmol) and N,N-diisopropylethylamine (0.17 ml, 0.98 mmol) in acetonitrile (6,7 ml) was heated at 60°C for the of 18 hours. Was added a saturated solution of NaHCO3(aq.) (15 ml) and the mixture was extracted with CH2Cl2(3 × 15 ml). The organic extracts were dried (MgSO4) and concentrated in vacuum. Purification of the crude substances on silica gel (500:5:1 CH2Cl2/MeOH/NH4OH) gave a yellow foam (360 mg, 98%).1H NMR (CDCl3) δ of 1.74 (m, 10H)to 1.99 (m, 2H), to 2.29 (m, 1H), 2,74 (m, 2H), 3,86 (s, 3H), 4,22 (d, 1H, J=17 Hz), 4,33 (m, 1H), 4,36 (d, 1H, J=17 Hz), 4,59 (d, 1H, J=14 Hz)and 4.65 (d, 1H, J=14 Hz), 6,98 (DD, 1H, J=8,0, 4,7 Hz), 7,25 (m, 3H), 7,33 (DD, 1H, J=8,1, 1.8 Hz), to 7.50 (m, 1H), 7,68 (m, 2H), 8,11 (d, 1H, J=8.1 Hz), to 8.41 (m, 1H).

A solution of tert-butyl ester 2-{[(4-cyano-2-methoxycarbonylbenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazol-1-carboxylic acid (356 mg, to 0.645 mmol) in saturated NH3(g)/MeOH (20 ml) was shaken at room temperature with a suspension of Raney Nickel (1.5 g) in a hydrogen atmosphere at a pressure of 45 lb/in2(310 kPa) for 20 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuum. The crude product was filtered through silica gel (100:5:1 CH2Cl2/MeOH/NH4OH), receiving a yellow oil (203 mg, 69%).1H NMR (CDCl3) δ was 1.69 (m, 1H), 2,01 (m, 2H), and 2.27 (m, 1H), 2,80 (m, 2H), 3,69 (user. s, 2H), 3,90 (m, 5H), 4,10 (d, 1H, J=17 Hz), to 4.15 (m, 1H), 4.53-in (d, 1H, J=14 Hz), 7,19 (m, 4H), 7,41 (m, 1H), 7,47 (m, 1H), 7,58 (m, 2H), 7,68 (d, 1H, J=7.8 Hz), to 8.62 (m, 1H).

To a solution of methyl ester 5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahed chinolin-8-yl)amino]methyl}benzoic acid (192 mg, 0,421 mmol) in THF (4,2 ml) was added LiAlH4(1.0 M/THF, at 0.42 ml, 0.42 mmol) at 0°C and the mixture was stirred at 0°C for 15 minutes. To the mixture was added H2O (0,016 ml), then 15% NaOH (aq.) (0,016 ml) and H2On (0,048 ml). The mixture was left to warm to room temperature, then filtered and concentrated in vacuum. Purification of the crude substances column chromatography on silica gel (100:5:1 CH2Cl2/MeOH/NH4OH) gave AMD11088 in the form of a colourless foam (29 mg, 15%).1H NMR (CDCl3) δ was 1.69 (m, 1H), 2,04 (m, 2H), a 2.36 (m, 1H), 2,80 (m, 2H), 3,69 (s, 2H), 3,78-4,07 (m, 5H), to 4.52 (d, 1H, J=12 Hz), to 4.62 (d, 1H, J=12 Hz), 6,97 (DD, 1H, J=7,5, 1.5 Hz), 7,13 (m, 4H), 7,29 (d, 1H, J=1.5 Hz), 7,44 (m, 3H), 8,46 (m, 1H);13C NMR (CDCl3) δ 21,09, 21,41, 29,05, 45,95, 49,53, 55,39, 61,07, 62,90, 121,81, 122,28, 126,35, 130,44, 131,20, 134,88, 135,67, 137,72, 140,42, 143,53, 146,80, 153,73, 156,25. ES-MS m/z 428 (M+H). Elemental analysis. Calculated for C26H29N5O·0,4H2O·0,3CH2Cl2: C, 68,64; H, 6,66; N, 15,22. Found: C, 68,67; H, To 6.67; N, 15,25.

Example: 13

AMD11071: Getting 2-aminomethyl-5-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenol (hydrobromide salt).

2-Hydroxy-4-methylbenzonitrile were obtained using the following modification of the techniques described Makoto Adachi and Tsutomu Sugasawa (Synthetic Communications, 1990, 20, 71-84). To a cooled (0° (C) the solution BCl3(1.0m in heptane, 12.0 ml of 12.0 mmol) in 1,2-dichloroethane add the Yali undiluted m-cresol (1,00 ml, of 9.56 mmol), then CH3SCN (0,83 ml, 12.1 mmol) and AlCl3(1,38 g, 10.4 mmol). The cooling bath was removed and the resulting mixture was heated at 80°C for 3 hours, then cooled to room temperature. The mixture was poured into 4 N. NaOH (35 ml) and heated at 80°C for 45 minutes, then cooled to room temperature. The phases were separated and the aqueous phase was extracted with CH2Cl2(3 x 50 ml). The aqueous phase was acidified using 6 N. HCl (30 ml) and was extracted with diethyl ether (3 x 50 ml). The combined ether extracts were dried (MgSO4) and concentrated. Purification of the crude substances column chromatography on silica gel (20:1 CH2Cl2:EtOAc) gave of 1.16 g (91%) of 2-hydroxy-4-methylbenzonitrile in the form of a white solid.1H NMR (CDCl3) δ a 2.36 (s, 3H), 6,20 (user. s, 1H), 6,79-for 6.81 (m, 2H), 7,38 (d, 1H, J=9 Hz).

To a solution of 2-hydroxy-4-methylbenzonitrile (0,563 g, to 4.23 mmol) in CH2Cl2(21 ml) was added acetic anhydride (0,60 ml, 6,36 mmol), then triethylamine (1.20 ml, 8,61 mmol) and the resulting solution was stirred at room temperature for 30 minutes. The mixture was diluted with CH2Cl2(60 ml), washed with saturated aqueous NaHCO3(20 ml) and saturated salt solution (2 × 20 ml). The organic phase was dried (Na2SO4), concentrated and got to 0.72 g (97%) of (2-cyano-5-were)acetate as a white solid.1 3) δ of 2.38 (s, 3H), 2,43 (s, 3H), was 7.08 (s, 1H), 7,13 (d, 1H, J=9 Hz), 7,54 (d, 1H, J=9 Hz).

To a solution of (2-cyano-5-were)acetate (0,72 g, 4,11 mmol) in CCl4(10 ml) was added recrystallized N-bromosuccinimide (0,767 g, or 4.31 mmol)followed by benzoyl peroxide (56 mg, 0.23 mmol). The resulting mixture was boiled under reflux for 2.5 hours, then cooled to room temperature. The mixture was diluted with diethyl ether (50 ml), filtered through paper filter and the filtrate was concentrated. Purification of the crude substances column chromatography (6:1 hexane:EtOAc) gave 0.31 g (30%) (5-methyl bromide-2-cyanophenyl)acetate as a colorless oil.1H NMR (CDCl3) δ to 2.40 (s, 3H), of 4.45 (s, 2H), 7,33 (s, 1H), 7,35 (d, 1H, J=9 Hz), the 7.65 (d, 1H, J=9 Hz).

To a solution of (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0.375 g, 0,99 mmol) in CH3CN (5 ml) was added N,N-diisopropylethylamine (0.35 ml, 2.00 mmol), then the solution of (5-methyl bromide-2-cyanophenyl)acetate (0,318 g, 1.25 mmol) in CH3CN (5 ml). The resulting mixture was heated at 60°C for 15 hours, then cooled to room temperature. The mixture was concentrated and the residue was distributed between CH2Cl2(40 ml) and saturated salt solution (10 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2(3×10 ml). The combined organic extracts were dried (Na2SO4) and conc is listed. Purification of the crude substances column chromatography on silica gel (20:1 CH2Cl2/CH3IT), then by radial chromatography on silica gel (2 mm plate, 2:1 hexane/EtOAc) gave 0.28 g (51%) of yellowish-brown foam.

The above foam (0.28 g, 0.51 mmol) was dissolved in a saturated NH3methanol (10 ml)was treated with Raney Nickel (140 mg) and placed in a standard Parr apparatus at a pressure of H250 lb/in2(345 kPa) for 17 hours. The mixture was filtered through celite and the residue washed with methanol. Eluent was concentrated under reduced pressure. Purification of the crude substances column chromatography on silica gel (20:1:1 CH2Cl2/CH3OH/NH4OH) followed by radial chromatography on silica gel (1 mm plate, 100:1:1 CH2Cl2/CH3OH/NH4OH) gave 76 mg (33%) of free base specified in the title compound as a yellow foam.

Using General method D, the transformation obtained above foam (72 mg, 0.16 mmol) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/simple ether gave AMD11071 (73 mg, 65%) as a white solid.1H NMR (D2O) δ 1,83-of 1.95 (m, 1H), 2,19-of 2.30 (m, 2H), 2.40 a at 2.45 (m, 1H), 3,02 totaling 3.04 (m, 2H), 3,55 (s, 2H), and 3.72 (d, 1H, J=12.9 Hz), of 3.77 (d, 1H, J=12.9 Hz), of 4.44 (d, 1H, J=16.2 Hz), to 4.62 (d, 1H, J=16.2 Hz), 4.72 in-4,79 (m, 1H, overlap with HOD), is 6.61 (s, 1 is), 6,72 (d, 1H, J=7.8 Hz), 6.90 to (d, 1H, J=7.8 Hz), 7,50-of 7.55 (m, 2H), 7,58 to 7.62 (m, 2H), 7,92 (DD, 1H, J=6,0, 7,8 Hz), 8,40 (d, 1H, J=7.8 Hz), a total of 8.74 (d, 1H, J=5,1 Hz);13C NMR (D2O) δ 20,44, 20,88, 27,83, 38,85, 50,22, 56,74, 63,17, 113,86, 116,57, 118,99, 122,04, 126,07, 126,69, 130,58, 131,10, 139,63, 139,66, 140,96, 148,21, 150,83, 151,77, 154,96. ES-MS m/z 414 (M+H). Elemental analysis. Calculated for C25H27N5O·3,1HBr·to 2.5·N2O: C, 42,33; H, 4,99; N, 9,87; Br, 34,92. Found: C, 42,26; H, 4,94; N, 9,87; Br, 35,06.

Example: 14

AMD11077: Receive (4-aminomethyl-3-methoxybenzyl)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

To a solution of 2-hydroxy-4-methylbenzonitrile (0,46 g, 3.46 mmol) in THF (17 ml) was added monohydrate of lithium hydroxide (0,292 g, 6.95 mmol), then dimethylsulfate (0,50 ml, 5,28 mmol). The resulting mixture was boiled under reflux for 2 hours, then cooled to room temperature. The mixture was diluted with diethyl ether (50 ml), washed with saturated aqueous NaHCO3(3 × 15 ml), dried (MgSO4) and concentrated. Purification of the crude substances column chromatography on silica gel (4:1 hexane/EtOAc) gave 0,456 g (90%) 2-methoxy-4-methylbenzonitrile in the form of a white solid.1H NMR (CDCl3) δ to 2.41 (s, 3H), 3,91 (s, 3H), 6,77 (s, 1H), for 6.81 (d, 1H, J=6 Hz), the 7.43 (d, 1H, J=6 Hz). ES-MS m/z 148 (M+H).

To a solution of 2-methoxy-4-methylbenzonitrile (0,438 g, 2,98 mmol) in CCl4(6 ml) is obavljale recrystallized N-bromosuccinimide (0,544 g, 3,05 mmol)followed by benzoyl peroxide (47 mg, 0,19 mmol). The resulting mixture was boiled under reflux for 45 minutes, then cooled to room temperature. The mixture was diluted with diethyl ether (30 ml), filtered through paper filter and the filtrate was concentrated. Purification of the crude substances column chromatography (6:1 hexane:EtAc) gave 0,46 g (68%) of 4-(methyl bromide)-2-methoxybenzonitrile in the form of a white solid.1H NMR (CDCl3) δ of 3.96 (s, 3H), of 4.45 (s, 2H), 6,99 (s, 1H), 7,03 (d, 1H, J=9 Hz), 7,53 (d, 1H, J=9 Hz).

To a solution of (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,386 g of 1.02 mmol) in CH3CN (10 ml) was added N,N-diisopropylethylamine (0.35 ml, 2.00 mmol), then 4-(methyl bromide)-2-methoxybenzonitrile (0,363 g to 1.60 mmol). The resulting mixture was heated at 60°C for 15 hours, then cooled to room temperature. The mixture was concentrated and the residue was distributed between CH2Cl2(40 ml) and saturated salt solution (10 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2(3 × 10 ml). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude substances column chromatography on silica gel (20:1 CH2Cl2/CH3HE) followed by radial chromatography on silica gel (2 mm plate, 2:1 hexane/EtAc) gave 0,30 g(56%) of a white foam.

The above foam (0.29 grams, 0.55 mmol) was dissolved in a saturated NH3methanol (15 ml)was treated with Raney Nickel (300 mg) and placed in an atmosphere at a pressure of H250 lb/in2(345 kPa) in a shaking apparatus Parra for 7 hours. The mixture was filtered through celite and the residue washed with methanol. Eluent was concentrated under reduced pressure. Purification of the crude substances column chromatography on silica gel (10:1:1 CH2Cl2/CH3OH/NH4OH) gave 0,197 g (83%) of free base specified in the title compound as a white solid.

Using General method D, the transformation obtained above solid (183 mg, 0.43 mmol) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/simple ether gave AMD11077 (268 mg, 88%) as a white solid.1H NMR (D2O) δ 1,84-of 1.97 (m, 1H), 2,20-2,31 (m, 2H), 2,43-of 2.50 (m, 1H), 3,03-of 3.06 (m, 2H), 3,55 (s, 2H), of 3.73 (s, 3H), 3,82 (d, 1H, J=12,6 Hz), 3,88 (d, 1H, J=12,6 Hz), of 4.45 (d, 1H, J=16.5 Hz), 4,63 (d, 1H, J=of 16.5 Hz), 4,72-rate 4.79 (m, 1H, overlap with HOD), to 6.75 (s, 1H), 6,83 (d, 1H, J=7.5 Hz), of 6.99 (d, 1H, J=7.5 Hz), 7,50-rate of 7.54 (m, 2H), EUR 7.57-to 7.61 (m, 2H), to 7.93 (DD, 1H, J=6,0, 7.5 Hz), 8,40 (d, 1H, J=8.1 Hz), a total of 8.74 (d, 1H, J=6,0 Hz);13C NMR (D2O) δ 20,46, 20,94, 27,86, 39,08, 50,07, 55,62, 57,24, 63,25, 112,27, 113,78, 120,28, 122,61, 126,16, 126,82, 130,47, 131,11, 139,65, 140,03, 141,06, 148,30, 150,77, 151,78, 157,51. ES-MS m/z 428 (M+H). Elemental analysis. Calculated for C26H22N5 O·3,NVG·2,4H2About: With, 43,77; H, 5,20; N, 9,82; Br, 33,60. Found: C, 43,61; H, 5,18; N, 9,45; Br, 33,88.

Example: 15

AMD9923: Receive (1H-benzoimidazol-2-ylmethyl)-(2,4-bicamerality)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt)

Getting 4-bromocrotonate

To a stirred solution of 4-methylisothiourea (obtained as described Klement, I.; Lennick, K.; Tucker, C.E.; Knochel, P. Tetrahedron Lett. 1993, 34, 4623-4626) (500 mg, to 3.52 mmol) in CCl4(4 ml) was added solid N-bromosuccinimide (1,25 g, 7.0 mmol)followed by benzoyl peroxide (8 mg, 0.04 mmol). The resulting mixture was boiled under reflux for 8 hours, then cooled to room temperature and concentrated in vacuum. The crude substance was purified flash chromatography (silica gel, 4:1 hexane/EtOAc)to give 457 mg of a mixture of 4-methylisophthalic and 4-bromocrotonate in a molar ratio of 3:1 respectively. 4-Bromocrotonate had1H NMR (CDCl3) δ 2,04 (s, 2H), 7,70-7,74 (t, 1H), 7,86-7,74 (m, 1H), of 7.96 (s, 1H).

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

According to the General method N-alkylation mixture of 3:1 4-methylisophthalic and 4-bromocrotonate obtained at the preceding is adequate stage (457 mg), and (1H-N-tert-butoxycarbonylamino-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (257 mg, of 0.68 mmol) were converted into the corresponding alkylation product using the following quantities of reagents and solvents: diisopropylethylamine (237 μl, of 1.36 mmol), CH3CN (5 ml). The reaction time in this case was 3 days at the reaction temperature of 40°C. the crude substance was purified flash chromatography (silica gel, 20:1:1 CH2Cl2/MeOH/NH4OH)to give 326 mg (93%) of tert-butyl ester 2-{[(2,4-dicyanovinyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazol-1-carboxylic acid.1H NMR (CDCl3) δ at 1.73 (s, 9H), 1,75-of 2.20 (m, 3H), 2,38-of 2.50 (m, 1H), 2,65-2,90 (m, 2H), 4,18 (d, 2H, J=6 Hz), 4,30-and 4.40 (m, 1H), 4.53-in (d, 1H, J=15 Hz), 4,70 (d, 1H, J=15 Hz), 7,02? 7.04 baby mortality (m, 1H), 723-7,26 (m, 2H,), 7,30-to 7.32 (m, 2H), 7,38 (s, 1H), 7,52-of 7.70 (m, 2H), a 7.85 (d, 1H, J=9 Hz), 8,45-of 8.50 (m, 1H).

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

In a hydrogenation flask was loaded in 50%suspension of Raney Nickel in water (300 mg), which was then washed with methanol (3 × 10 ml). Then the solution was added tert-butyl ester 2-{[(2,4-dicyanovinyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazol-1-carboxylic acid (326 mg, to 0.63 mmol) in MeOH (10 ml) and gaseous N 3was barbotirovany through the solution for 5 minutes. The obtained heterogeneous mixture was first made at 50 lb/in2(345 kPa) in shaking the Parr apparatus for 18 hours, at this point, the crude mixture was filtered through celite, washed with MeOH (3 × 20 ml) and concentrated in vacuum. Flash chromatography (silica gel, 20:2:1 CH2Cl2/MeOH/NH4OH, then 10:1 MeOH/N4HOH) received substance gave 124 mg (46%) of free base AMD9923 in the form of a white solid substance; however, the combustion analysis revealed that this material was contaminated with silica gel, and this contamination could not be removed by repeated filtration and chromatography (celite, Florisil, silica, basic alumina). Thus, this compound (60 mg, 0.14 mmol) were placed in a mixture of THF (5 ml), MeOH (1 ml) and water (3 drops)was then added di-tert-BUTYLCARBAMATE (92 mg, 0.42 mmol). The resulting solution was stirred 2 hours at this point was added saturated aqueous sodium bicarbonate solution (5 ml) and the resulting mixture was extracted with CH2Cl2(3 × 10 ml)then the combined organic extracts were dried (MgSO4) and concentrated in vacuum. Purification of the thus obtained crude substance radial chromatography (silica gel, 1 mm plate, 50:1:1 CH2Cl2/MeOH/NH4OH) gave 71 mg (69%) of tert-butyl ester 2-{[[2,4-bis-(Trets the-butoxycarbonylamino)benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazole-1-carboxylic acid as a colourless oil. 1H NMR (CDCl3) δ the 1.44 (s, 18H), 1,53-and 1.54 (m, 1H), 1.69 in (s, 9H), 1,99-2,04 (m, 1H), 2,17-to 2.29 (m, 2H), 2,49-of 2.54 (m, 1H), 2,72-and 2.83 (m, 1H), 3,84-of 3.94 (m, 2H), 4,19 (d, 2H, J=5 Hz), 4,28-of 4.54 (m, 6H), 4,68 (user. s, 1H), 6,63 (DD, 1H, J=8, 5 Hz), 6,70 (DD, 1H, J=18, 8 Hz), 7,17-7,24 (m, 3H), of 7.36 (s, 1H), 7,52-of 7.55 (m, 1H), to 7.67-of 7.70 (m, 1H), 8,24 (d, 1H, J=4 Hz), 8,80 (user. s, 1H).

According to the General procedure D for the attendant removal of the BOC-protective group and education HBr salt, processed oils from the previous stage (71 mg, 0.10 mmol) saturated HBr acetic acid (1 ml) gave 48 mg (60%) HBr salt AMD9923 in the form of a white solid.1H NMR (CD3OD) δ 1,48-to 1.59 (m, 1H), 2,07 with 2.14 (m, 2H), 2,29-of 2.30 (m, 1H), 2.63 in (user. d, 1H, J=17 Hz), 2,78-2,89 (m, 1H), 3,76 (d, 1H, J=14 Hz), 3,74-4,08 (m, 7H), 4.16 the (d, 1H, J=13 Hz), of 6.99 (DD, 1H, J=8, 5 Hz), 7,16-7,20 (m, 2H), 7,34-7,39 (m, 3H), 7,54-EUR 7.57 (m, 2H), 7,65 (s, 1H), 8,31 (d, 1H, J=5 Hz);13C NMR (CD3OD) δ 21,3, 22,6, 22,8, 41,8, 43,6, 48,6, 55,7, 60,9, 115,9, 123,4, 123,8, 130,9, 133,2, 134,2, 135,0, 135,8, 136,4, 138,9, 140,2, 147,5, 152,8, 156,6. ES-MS m/z 427 (M+H). Elemental analysis. Calculated for C26H30N6·NVG·1,5H2About·0,7C2H4About2: C, 40,17; H, The 4.90; N, 10,26; Br, 39,01. Found: C, 40,13; H, 5,15; N, 10,20; Br, 39,08.

Example: 16

AMD11038: obtain the methyl ester of 5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid (hydrobromide salt).

A solution of tert-butyl ester 2-{[(4-cyano-2-methoxycarbonylbenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine is]methyl}benzimidazol-1-carboxylic acid (710 mg, 1,29 mmol) in saturated NH3(g)/MeOH (25 ml) was shaken at room temperature with a suspension of Raney Nickel (1.2 g) under hydrogen pressure of 50 lb/in2(345 kPa) for 17 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuum. The crude product was filtered through silica gel (20:1:1 CH2Cl2/Meon/NH4IT), getting a white foam (416 mg, 71%).

Using General method D, the conversion obtained above a white foam (46 mg, 0.10 mmol) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/simple ether gave AMD11138 (51 mg, 69%) as a colourless solid.1H NMR (D2O) δ 1,85 of 1.99 (m, 1H), 2,17-is 2.37 (t, 2H), 2.40 a-2,49 (m, 1H), 3.04 from (t, 2H), 3,63 (d, 1H, J=13.5 Hz in), 3.75 (d, 1H, J=13,8 Hz), of 3.94 (s, 3H), 4,10 (d, 1H, J=12,6 Hz), 4,35 (d, 1H, J=12,6 Hz), of 4.44 (d, 1H, J=16.2 Hz), 4,55 (d, 1H, J=16.2 Hz), 7,26 (DD, 1H, J=8,1, 1.8 Hz), 7,42 (d, 1H, J=8.1 Hz), 7,50-to 7.61 (m, 5H), 7,92 (DD, 1H, J=7,8, 6,0 Hz), 8,40 (d, 1H, J=7.8 Hz), 8,77 (d, 1H, J=5,1 Hz);13C NMR (D2O) δ 20,52, 20,95, 27,80, 42,02, 49,21, 53,44, 54,23, 63,26, 113,88, 126,10, 126,89, 130,46, 130,70, 131,45, 132,75, 133,22, 133,67, 138,50, 139,66, 140,83, 148,14, 150,33, 151,34, 168,79. ES-MS m/z 456 (M+H). Elemental analysis. Calculated for C27H29N5O2·3,0HBr·2,2H2O: C, 43,95; H, Equal To 4.97; N, 9,49; Br, 32,48. Found: C, 43,86; H, Equal To 4.97; N, 9,35; Br, 32,77.

Example: 17

AMD11163: Getting hydrobromide salt 3-aminomethyl-4-{[(1H-b is Intimidator-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid.

To a stirred solution of LiOH (41 mg, 1.7 mmol) in deionized water (2 ml) solution was added AMD11140 (77 mg, 0,17 mmol) in THF (2 ml). The mixture was heated to 50°C, was stirred for 15 hours and then concentrated to remove THF. Was slowly added 1 N. HCl (1.7 ml) and the aqueous solution was extracted with CHCl3(3 × 10 ml). The combined organic extracts were dried over MgSO4and concentrated in vacuum. Pale yellow solid (75 mg) was purified column flash chromatography (1.5 cm inner diameter, 7 g of silica gel, was suirable 10% NH4OH/10% MeOH/CHCl3), receiving the target amino acid in the form of a white solid (32 mg).

A saturated solution of HBr in acetic acid (0.5 ml) was added dropwise to the mixed solution obtained above amino acid (30 mg, 0,068 mmol) in acetic acid (0.5 ml) and stirring was continued for 1 hour. Quickly added diethyl ether (25 ml) and the resulting white precipitate was left to settle. Ether decantation, the white solid was washed several times with diethyl ether (5 × 25 ml) and the residual ether was removed in vacuum. The residue was dried in a vacuum oven at 50°C for 85 hours, getting AMD11163 in the form of a white solid (35 mg, 28% over 2 stages).1H NMR (D2O) δ 1,81 is 2.01 (m, 1H), measuring 2.20 to 2.35 (m, 2H), 2,43-of 2.54 (m, 1H), 3.00 and-is 3.08 (m, 2H), 3.96 points (d, 1H, J=15 Hz), 4,19-4,56 (m, 5H), 4,76 to 4.92 (m, 1H, overlap with HOD) 7,42-of 7.55 (m, 6H), the 7.62 (d, 1H, J=8.0 Hz), to $ 7.91 (t, 1H, J=6,8 Hz), scored 8.38 (d, 1H, J=8.0 Hz), the rate of 8.75 (d, 1H, 5.7 Hz);13C NMR (D2O) δ 20,44, 21,15, 27,94, 40,03, 49,09, 53,60, 63,12, 113,83 (2 carbon), 126,23, 127,06 (2 carbon), 130,39, 130,53, 130,93, 131,85, 132,33, 140,23, 140,38, 141,18, 148,22, 150,33, 150,58, 169,92. ES-MS m/z 442 (M+H). Elemental analysis. Calculated for C26H27N5O2·3,0HBr·2,5H2A: C, 42,82; H, 4,84; N, 9,60; Br, 32,87. Found: C, 42,74; H, 4,55; N, 9,51; Br, 32,53.

Example: 18

AMD11177: Getting hydrobromide salt 3-aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-hydroxybenzamide.

To a stirred solution of metallic sodium (42 mg, 1.8 mmol) in anhydrous methanol (6 ml) was slowly added to the solution AMD11140 (159 mg, 0.36 mmol) and hydroxylamine hydrochloride (75 mg, 1.1 mmol) in anhydrous methanol (6 ml). The mixture was boiled under reflux with stirring in nitrogen atmosphere. After 16 hours, concentrated and the obtained residue was distributed between CHCl3(15 ml) and deionized H2O (10 ml). The aqueous layer was extracted with CHCl3(10 ml) and the combined organic extracts were dried over MgSO4and concentrated in vacuum. Pale yellow solid (185 mg) was purified column flash chromatography (3 cm inner diameter, 15 g of silica gel, was suirable 10% NH4OH/10% MeOH/CHCl3), then the radial chromatography (1 mm plate, AluI is ovali 50:1:1 CH 2Cl2/MeOH/NH4OH), receiving the target hydroxyamide in the form of a white solid (63 mg).

A saturated solution of HBr in acetic acid (3 ml) was added dropwise to the mixed solution obtained above hydroxyamide (63 mg, 0.11 mmol) in acetic acid (3 ml) and stirring was continued for 10 minutes, quickly added diethyl ether (50 ml) and the resulting white precipitate was left to settle. Ether decantation, the white solid was washed several times with diethyl ether (5 × 50 ml) and simple residual ether was removed in vacuum. The residue was dried in a vacuum oven at 50°C for 42 hours, getting AMD11177 in the form of a white solid (80 mg, 28% over 2 stages).1H NMR (D2O) δ 1,74 is 1.86 (m, 1H), 2,11-of 2.30 (m, 2H), 2,35 is 2.44 (m, 1H), 2,85-of 2.93 (m, 2H), 3.96 points (d, 1H, J=15 Hz), 4,12-4,39 (m, 5H), 4,57-to 4.62 (m, 1H), 7,31 (s, 1H), 7,38-the 7.43 (m, 3H), of 7.48-7,52 (m, 3H), to 7.59-of 7.64 (m, 1H), 8,03 (d, 1H, J=8.0 Hz), 8,56 (d, 1H, 5.7 Hz);13C NMR (D2O) δ 20,73, 21,28, 28,23, 40,14, 48,90, 54,08, 62,97, 114,15 (2 carbon), 124,98, 125,90 (2 carbon), 127,60, 128,81, 132,42, 132,82, 139,26, 140,89, 142,38, 144,62. ES-MS m/z 457 (M+H). Elemental analysis. Calculated for C26H28N6O2·3,2HBr·3,0H2About·0,17NH4Br. C, 39,72; H, A 4.86; N, 10,99; Br, 34,25. Found: C, To 39.34; H, 4,78; N, 11,36; Br, 34,51.

Example: 19

AMD11180: Getting hydrobromide salt 3-aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)the Mino]methyl}benzamide.

Obtain 3-cyano-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzamide

To a stirred solution of LiOH (120 mg, 5.0 mmol) in deionized water (5 ml) solution was added tert-butyl ester 2-{[(2-cyano-4-methoxycarbonylbenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazole-1-carboxylic acid (273 mg, 0.49 mmol) in THF (5 ml). The mixture was heated at 50°C and was stirred for 17 hours. The solution was cooled to room temperature, concentrated to remove THF and neutralized 1 N. HCl. The aqueous solution was extracted with CHCl3(3 × 25 ml) and the combined organic extracts were dried over MgSO4and concentrated in vacuum, obtaining the target acid as a yellow solid (224 mg).

Stir the solution obtained above acid (220 mg, 0.41 mmol) in CH2Cl2(1.6 ml) was treated with oxalylamino (of 0.41 ml, 0.82 mmol) and boiled under reflux for 1 hour. The red solution was cooled to room temperature, then gaseous ammonia was barbotirovany through stir the solution for 10 minutes. The crude mixture was poured into a saturated solution of NaHCO3the solution was extracted with CHCl3(5 × 10 ml), the combined organic extracts were dried over MgSO4and concentrated in vacuum. Orange foam (200 mg) was purified flash column chromatography the raffia (2 cm inner diameter, 10 g of silicon dioxide were suirable 5% NH4OH/5% MeOH/CH2Cl2), getting mentioned in the title compound as an orange foam (106 mg, 50% over 2 stages).1H NMR (CDCl3) δ 1,70-of 1.93 (m of user., 1H), 1,99-2,11 (m, 2H), 2,34-of 2.38 (m, 1H), 2,74-is 2.88 (m, 2H), 3,88-to 3.99 (m, 2H), 4,13-to 4.28 (m, 3H), 5,70 (user., 1H), 6,05 (user., 1H), 7,17-7,22 (m, 3H), 7,46 (d, 1H, J=7.5 Hz), 7,50-to 7.68 (m of user., 2H), 7,79-to 7.95 (m, 3H), 8,64 (d, 1H, J=3.0 Hz).

Getting hydrobromide salt 3-aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzamide (AMD11180)

A solution of 3-cyano-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzamide (105 mg, 0.24 mmol) in MeOH (10 ml) was treated with Raney Nickel (50 mg, cat.) and was placed in an atmosphere of H250 lb/in2(345 kPa) in a shaking device for 3.5 hours. The suspension was filtered through diatomaceous earth, concentrated in vacuo, and purified flash column-chromatography (3 cm inner diameter, 20 g of silica, elution 5% NH4OH/5% MeOH/CH2Cl2), receiving the target amide (35 mg).

A saturated solution of HBr in acetic acid (2 ml) was added dropwise to the mixed solution obtained above amide (35 mg, 0.079 in mmol) in acetic acid (2 ml) and stirring was continued for 10 minutes. Quickly added diethyl ether (50 ml) and the resulting white precipitate was left to settle. Ether decantation, the solid white vases which was washed several times with diethyl ether (5 × 50 ml) and the remains of the ether was removed in vacuum. The residue was dried in a vacuum oven at 50°C for 17 hours, getting AMD11180 in the form of a white solid (49 mg, 25% over 2 stages).1H NMR (D2O) δ 1,84 is 2.00 (m, 1H), 2,19 to 2.35 (m, 2H), 2,46-of 2.54 (m, 1H), 3.00 and-is 3.08 (m, 2H), 3,97 (d, 1H, J=15 Hz), 4,21-4,58 (m, 5H), 4.75 V to 4.92 (m, 1H, overlap with HOD), 7,40 (s, 1H), 7,44-of 7.55 (m, 6H), to 7.93 (t, 1H, J=6,8 Hz), 8,40 (d, 1H, J=8.0 Hz), 8,77 (d, 1H, 5.5 Hz);13C NMR (D2O) δ 20,43, 21,17, 27,94, 40,12, 49,11, 53,67, 63,17, 113,83 (2 carbon), 126,33, 127,19 (2 carbon), 128,29, 129,24, 130,38, 132,10, 132,51, 132,66, 139,96, 140,12, 141,33, 148,49, 150,15, 150,57, 170,44. ES-MS m/z 441 (M+H). Elemental analysis. Calculated for C26H28N6O·3,3HBr·2,4H2O·0,7NH4Br: C, 38,11; H, 4,79; N, Of 11.45; Br, 39,01. Found: C, 37,73; H, With 4.64; N, To 11.56; Br, 39,27.

Example: 20

AMD11190: Hydrazide 3-aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid (hydrobromide salt).

Obtain tert-butyl ether (2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-5-hydrazinecarboxamide)carbamino acid

To a solution of methyl ester 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-3-(tert-butoxycarbonylamino)benzoic acid (100 mg, 0.18 mmol) in ethanol (2 ml) was added hydrazinehydrate (0.5 ml, 10,31 mmol). The reaction mixture was heated at 80°C during the night. Then her ohlord the Lee, extinguished saturated sodium bicarbonate (2 ml) and washed with CH2Cl2(4 × 5 ml). The combined organic layers were dried (MgSO4), filtered, concentrated and dried in vacuum, obtaining a yellow oil. Purification by radial chromatography on silica gel (1 mm plate, using CH3OH/NH4OH/CH2Cl2; 1:1:98, then 2:1:97) gave the product as a crude white solid (60 mg)which was used without further purification.1H NMR (CDCl3) δ of 1.55 (s, 9H), 1.61 of-1,71 (m, 1H), 189-1,96 (m, 1H), 2,27 (user. s, 3H), 2,35 (user. t, 1H), 2,69-2,90 (t, 2H), 3,80 (q, 2H, J=15 Hz), 3,92-Android 4.04 (m, 4H), to 4.41 (user. m, 1H), 7,11-to 7.18 (m, 3H), 7,18 (s, 1H), 7,28-7,42 (m, 3H), 7,60-to 7.61 (m, 1H), 7,72 (s, 1H), 7,72 (user. t, 1H), 8,66 (d, 1H, J=3,7 Hz). ES-MS m/z 557 [M+H]+.

Getting hydrazide 3-aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid (hydrobromide salt)

To a solution of the above solid (30 mg, 0,054 mmol) in acetic acid (1 ml) was added a solution of Hydrobromic acid in acetic acid (0.5 ml) and the reaction mixture was stirred for 30 minutes. Then added diethyl ether until then, were not deposited until AMD11190 in the form of a white solid (35 mg, 77%).1H NMR (D2O) δ 1,90-2,00 (t, 1H), 2,23-of 2.34 (m, 2H), 2,48-2,52 (m, 1H), 3.04 from (users, 2H), 3,98 (d, 1H, J=13,8 Hz)to 4.23 (d, 1H, J=7.5 Hz), the 4.29 (t, 1H, J=8.7 Hz), to 4.38 (s, 1H), 4,45 (s, 1H), 4,51 (d, 1H, J6,0 Hz), of 4.57 (s, 1H), 7,43-rate of 7.54 (m, 7H), 7,92 (t, 1H, J=7.5 Hz), 8,40 (d, 1H, J=7.8 Hz), the rate of 8.75 (d, 1H, J=5,1 Hz).13C NMR (D2O) δ 20,40, 21,09, 27,91, 39,99, 48,94, 53,55, 62,94, 113,90, 126,31, 127,04, 128,04, 129,15, 130,45, 132,47, 140,11, 140,65, 141,31, 148,47, 150,13, 150,53. ES-MS m/z 456 [M+H]+. Elemental analysis. Calculated for C26H29N7About·4,NVG·3,6N2About: With 37,00; H, 4,80; N, Are 11.62; Br, 37,87. Found: C, 37,18; H, With 4.64; N, 11,31; Br, 37,91.

Example: 21

AMD11175: Receive (2-aminomethyl-5-terbisil)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Getting 4-fluoro-2-methylbenzonitrile

A solution of CuCN (4,45 g, 50.0 mmol) and NaCN (3,91 g, 80,0 mmol) in H2O (15 ml) was heated to 60°C. Suspension of 4-fluoro-2-methylaniline (5,16 g, 412 mmol) in H2O (20 ml) was acidified with concentrated HCl (10 ml). Additionally added H2O (50 ml) until then, until the suspension was mixed freely, and the mixture was cooled to a temperature below 0°C using a bath of ice/salt water. A solution of NaNO2(3,19 g, 46.2 mmol) in H2O (8 ml) was added dropwise together with crushed ice, to ensure the constant presence of ice in the solution of diazonium salts. The mixture was stirred at 0°C for 15 minutes, then for neutralization solution was added in portions powdered To2CO3(6,62 g of 47.9 mmol). Received a bright orange solution was then added portion and to the cyanide solution at 60° C for about 40 minutes. Received the green suspension was heated at 110°C for 45 minutes and, after cooling to room temperature, was added a saturated aqueous solution of NaHCO3(80 ml). Extraction produced thick black solution of CH2Cl2(150 ml x 3) did not give the desired substance.

Orange solid, which was confirmed fotogramas in the reflux condenser during boiling under reflux, washed CH2Cl2(100 ml) and washed with H2O (50 ml). The aqueous solution was extracted with CH2Cl2(25 ml x 2) and the combined organic solution was dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the nitrile as a yellow solid (3.00 g, of 22.2 mmol, 54%).1H NMR (CDCl3) δ to 2.55 (s, 3H), 6,94? 7.04 baby mortality (m, 2H), 7,60 (DD, 1H, J=8,6, 5,6 Hz). IR (thin film, KBr) ν 2223 cm-1.

Getting 2-methyl bromide-4-perbenzoate

To a solution of o-tolunitrile (1,62 g, 12,0 mmol) in benzene (80 ml) was added NBS (1,33 g, 7,47 mmol) and AIBN (153 mg, of 0.93 mmol). The solution was boiled under reflux in nitrogen atmosphere for 3 hours and added the second portion of each of NBS (1,25 g, 7,02 mmol) and AIBN (150 mg, of 0.91 mmol). The reaction mixture is boiled under reflux additionally for 2 hours and, after cooling, the solution was washed H2O (80 ml x 2) and saturated RA is tworoom salt (80 ml). The organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. Purification column flash chromatography on silica (EtOAc/hexane 1:9) gave the bromide as an orange solid (721 mg, 3,37 mmol, 28%).1H NMR (CDCl3) δ 4,60 (s, 2H), 7,13 (TD, 1H, J=8,2, 2,5 Hz), 7,28 (DD, 1H, J=8,9, and 2.6 Hz), 7,69 (DD, 1H, J=8,6, a 5.3 Hz).

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

The solution benzylbromide (263 mg, of 1.23 mmol), (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (381 mg, 1.01 mmol), DIPEA (of 0.26 ml, 1.5 mmol) and KI (10 mg, 0.06 mmol) in CH3CN (7 ml) was stirred at 60°C in nitrogen atmosphere for 17 hours. After cooling to room temperature was added saturated aqueous NaHCO3(10 ml) and the mixture was extracted with CH2Cl2(25 ml x 3). The combined organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. Purification column flash chromatography on silica (EtOAc/hexane 1:1) gave the tertiary amine as a pale yellow foam (411 mg, 0.80 mmol, 80%).1H NMR (CDCl3) δ a 1.75 (s, 9H), 1.85 to 2,11 (m, 3H), 2,31-to 2.41 (m, 1H), 2,64 of 2.92 (m, 2H), a 4.03 (d, 1H, J=16.2 Hz), 4,18 (d, 1H, J=16.2 Hz), 4,34 (DD, 1H, J=10,2, 5.7 Hz), to 4.62 (d, 1H, J=14.1 Hz), 4,74 (d, 1H, J=14.1 Hz), 6,55 (TD, 1H, J=8,1, 2.7 Hz), 7,00 (DD, 1H, J=7,7, a 4.7 Hz), 7,14 (DD, 1H, J8,4, a 5.4 Hz), 7,20 (DD, 2H, J=6,2, 3.2 Hz), 7.23 percent-7,31 (m, 1H), 7,56-7,66 (m, 3H), 8,44 (DD, 1H, J=4,5, 1.2 Hz).

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

To LiOH·H2O (51 mg, 1.2 mmol) and 10% Pd/C (39 mg, 0.04 mmol) in 50 ml round-bottom flask, purged with nitrogen, was added H2O (2 ml). Was added a solution of nitrile (201 mg, 0,39 mmol) in dioxane (6 ml), then Ni Raney (of 0.07 ml, 0.6 mmol) in the form of a 50% suspension in H2O (as described Klenke, B.; Gilbert, LH. J.Org. Chem. 2001, 66, 2480-2483). The flask was purged H2and was heated at 45°C for 15 hours. After cooling to room temperature, and blowing with nitrogen and the mixture was filtered through celite, washing EtOAc. The filtrate was concentrated under reduced pressure, the residue was placed in a saturated aqueous NaHCO3(15 ml) and was extracted with CH2Cl2(25 ml x 3). The organic solution was dried (MgSO4), filtered and evaporated under reduced pressure, obtaining the free benzimidazole in the form of a pale yellow solid (153 mg, and 0.37 mmol, 95%).1H NMR (CDCl3) δ 1,63-of 1.78 (m, 1H), 1.93 and-a 2.13 (m, 3H), 2,30-to 2.42 (m, 1H), 2,69-2,90 (m, 2H), 3,88 (d, 1H, J=14,9 Hz), 3,93 (d, 1H, J=14,9 Hz), 4.09 to-4,13 (m, 1H), 4,21 (d, 1H, J=16.1 Hz), 4,28 (d, 1H, J=16.1 Hz), 6,95 (TD, 1H, J=8,3, and 2.6 Hz), 7.18 in-7,22 (m, 3H), 7,45-EUR 7.57 (m, 3H), 7,63-to 7.67 (m, 2H), 8,67 (DD, 1H, J=4,8, 1.5 Hz).

Getting AMD11175

Nitrile (153 mg, and 0.37 mmol) in a solution of MeOH saturated NH3(10 ml), was first made over Raney Nickel at a pressure of 50 fnkum (345 kPa) for 4 hours the Mixture was filtered through celite, washed with MeOH and the filtrate was concentrated under reduced pressure. Purification column flash chromatography on silica (CH2Cl2/MeOH/NH4OH 19:1:0.1, then 9:1:0,05) gave the primary amine as a white solid (44 mg, 0.11 mmol, 29%), along with the selected nitrile (24 mg, 0.06 mmol, 16%).

To the amine (42 mg, 0.10 mmol) in glacial HOAc (1 ml) was added a saturated solution of HBr in HOAc (0.5 ml) and the solution was stirred at room temperature for 30 minutes. Added Et2O (5 ml), the precipitate was allowed to settle and the solvent decantation. The precipitate was rinsed Et2O (1 ml x 5) and dried at 90°C under reduced pressure, getting AMD11175 in the form of a beige solid (66 mg, 0,095 mmol, 95%).1H NMR (D2O) δ 1,82-of 1.97 (m, 1H), 2,17-of 2.36 (m, 2H), 2,41 of $ 2.53 (m, 1H), 2,98-is 3.08 (m, 2H), 3,91 (d, 1H, J=13,8 Hz), 4,16 (d, 2H, J=13,8 Hz), 4,32-to 4.38 (2 x d, 2H, J=16.2 and a 13.8 Hz), of 4.54 (d, 1H, J=16.2 Hz), of 6.68 (TD, 1H, J=8,6, 2.7 Hz),? 7.04 baby mortality (DD, 1H, J=8,4, 6,0 Hz), 7,19 (DD, 1H, J=a 9.9, 2.4 Hz), 7,51-of 7.55 (m, 2H), 7,60-7,63 (m, 2H), 7,89 (t, 1H, J=6,8 Hz), of 8.37 (d, 1H, J=7.8 Hz), 8,72 (d, 1H, J=5.4 Hz).13C NMR (D2O) δ 20,4, 20,9, 27,9, 39,5, 48,7, 53,3, 62,2, 113,9, 116,1 (d, J=21,7 Hz), 118,1 (d, J=22,0 Hz), 126,2, 127,0, 127,6, 130,7, 132,5 (d, J=8.7 Hz), 138,1, 140,2, 141,1, 148,2, 150,5 (d, J=20,9 Hz).19F NMR (D2O) δ -35,9. ES-MS m/z 416 (M+H). Elemental analysis. Calculated for C25H26FN5·3,0HBr·2,3H2O: C, 42,92; H, 4,84; N, 10,01; Br, 34,26. Found: C, 43,00; H, Is 4.85; N, 9,71; Br, 34,37.

Example: 22

AMD11140: obtain the methyl ester of 3-aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid.

Obtaining methyl ester 4-methyl bromide-3-cyanobenzoic acid

A suspension of zinc dust (792 mg, 12,12 mmol) and 1,2-dibromoethane (44 μl, 0.51 mmol) in THF (3 ml) was stirred at 70°C for 10 minutes. The mixture was cooled to room temperature and added chlorotrimethylsilane (45 μl, 0.36 mmol). The mixture was cooled to 0°C and was added at 0°C for 2 hours a solution of methyl 4-(methyl bromide)benzoate (2,314 g, 10,10 mmol) in THF (11 ml) and then stirred additionally for 2 hours at 0°C. the Reaction mixture was cooled to -78°C and the solution was added tailland (1,556 g, 8,59 mmol) in THF (11 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, diluted with CH2Cl2(100 ml) and saturated aqueous NaHCO3(15 ml) and filtered. The phases were separated and the aqueous layer was extracted with CH2Cl2(3 × 50 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification of column chromatography on silica gel (hexane/EtOAc 10:1) gave the target nitrile (973 mg) in a mixture in the ratio of 16:1 (target product/by-product).

The solution obtained above is of itria (973 mg), N-bromosuccinimide (1,087 g, 6,11 mmol) and AIBN (137 mg, 0.83 mmol) in CCl4(18.5 ml) was boiled under reflux for 4 days. The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. Clean yellow syrup column chromatography on silica gel (hexane/EtOAc 20:1, and 40:3) gave the target bromide (800 mg, 37% over 2 stages) as a white solid.1H NMR (CDCl3) δ of 3.96 (s, 3H), of 4.66 (s, 2H), 7,65 (d, 1H, J=8.1 Hz), 8,23 (DD, 1H, J=8,1, 1.8 Hz), with 8.33 (d, 1H, J=1.5 Hz).

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

A solution of methyl ester 4-methyl bromide-3-cyanobenzoic acid (800 mg, 3,15 mmol), tert-butyl ester 2-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzimidazole-1-carboxylic acid (1,253 g and 3.15 mmol), KI (26 mg, 0.16 mmol) and DIPEA (of 0.82 ml, 4,72 mmol) in CH3CN (31.5 ml) was heated at 60°C during the night. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained brown syrup was diluted in CH2Cl2(100 ml) and washed with saturated aqueous NaCl (30 ml). The aqueous phase was extracted with CH2Cl2(2 × 50 ml) and the combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Cleaning the brown foam column chromatography on silica gel (CH 2Cl2/MeOH 20:1) gave the target methyl ester (1,74 g, 100%) as a beige foam.1H NMR (CDCl3) δ 1,69-of 1.78 (m, 10H), 1,95-of 2.09 (m, 2H), 2,36-to 2.41 (m, 1H), 2,63-to 2.85 (m, 2H), 3,86 (s, 3H), 4,17 (d, 1H, J=16.2 Hz), 4,20 (d, 1H, J=15,9 Hz), 4,35-and 4.40 (m, 1H), 4,58 (d, 1H, J=14.4 Hz), 4,69 (d, 1H, J=14.4 Hz), 7,01 (DD, 1H, J=7,8, and 4.8 Hz), 7,13-of 7.23 (m, 2H), 7,31 (d, 1H, J=7.5 Hz), 7,55-to 7.61 (m, 2H), 7,76 (d, 2H, J=1.2 Hz), 7,87 (s, 1H), 8,44 (d, 1H, J=4.5 Hz).

Tert-butyl ester 2-{[(2-cyano-4-methoxycarbonylbenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazole-1-carboxylic acid (1.23 g, of 2.23 mmol) was dissolved in a saturated NH3MeOH (˜15 ml)was treated with Raney Nickel (excess) and placed in the atmosphere of H2under pressure of 45 lb/in2(310 kPa) in a Parr apparatus for 16 hours. The mixture was diluted with MeOH and filtered through celite. The filter cake washed with MeOH and the combined filtrate was concentrated under reduced pressure. The resulting syrup was filtered through a layer of silica gel (CH2Cl2/Meon/NH4OH 100:2:1), obtaining the target amine (720 mg)which was used without further purification in the next reaction.

To the solution obtained above amine (64 mg) in CH2Cl2(1 ml) was added TFA (1 ml) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting syrup was dissolved in H2O and podslushivaet 1 N. NaOH (pH 8). Added CHCl3(75 ml), F. the gases were separated and the aqueous layer was extracted with CHCl 3(2 × 75 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Clean yellow foam radial chromatography on silica gel (CH2Cl2/Meon/NH4OH 100:1:1, and 200:3:1) gave AMD11140 (39 mg, 43% over 2 stages) as a white foam.1H NMR (CDCl3) δ 1,55-of 1.73 (m, 1H), 1,92-2,07 (m, 2H), 2,23 to 2.35 (m, 1H), 2,63-2,89 (m, 2H), 3,74-was 4.02 (m, 10H), 7,06 (DD, 1H, J=7,5, 4,8 Hz), 7,16-7,19 (m, 2H), 7,35 (d, 1H, J=7.5 Hz), 7,47 (d, 1H, J=7.8 Hz), EUR 7.57 (user. s, 2H), 7,79-of 7.82 (m, 1H), 7,93 (user. s, 1H), 8,49 (d, 1H, J=3,9 Hz);13C NMR (CDCl3) δ 21,75, 22,72, 29,47, 43,47, 49,67, 52,47, 53,72, 60,08, 122,16, 122,49, 128,59, 130,22, 131,01, 131,25, 135,03, 137,53, 142,15, 142,66, 147,34, 154,59, 156,99, 167,19. ES-MS m/z 456,4 (M+H). Elemental analysis. Calculated for C27H29N5O2·1,0H2O: C, 68,48; H, 6,60; N, 14,79. Found: C, 68,54; H, Of 6.52; N, 14,51.

Example: 23

AMD11158: Receive (2-aminomethyl-4-ethoxymethylene)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

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

tert-Butyl ester 2-{[(2-aminomethyl-4-methoxycarbonylbenzyl)amino]methyl}benzimidazole-1-carboxylic acid (1.23 g, of 2.23 mmol) was dissolved in a saturated NH3MeOH (˜15 ml)was treated with Raney Nickel (excess) and was placed when Yes is tion H 245 lb/in2(310 kPa) vibration in a Parr apparatus for 16 hours. The mixture was diluted with MeOH and filtered through celite. The filter cake washed with MeOH and the combined filtrate was concentrated under reduced pressure. The resulting syrup was filtered through a layer of silica gel (CH2Cl2/MeOH/NH4OH 100:2:1), obtaining the target amine (720 mg)which was used without further purification in the next reaction.

To the solution obtained above amine (500 mg) in THF (7.2 ml), cooled to 0°C, was added dropwise LiAlH4(1,0M in THF, 1.80m, of 1.80 mmol). The mixture was stirred at room temperature for 15 minutes. Added MeOH (2 ml) and the mixture was concentrated. This operation is repeated two more times. Light yellow foam (410 mg) was used in the next reaction without further purification.

To the solution obtained above alcohol (330 mg) in THF (2 ml) was added a solution of BOC2(205 mg, of 0.94 mmol) in THF (4 ml) and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. Clean yellow foam column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 100:2:1) gave the target amine (230 mg, 30% for 3 stages) as a pale yellow foam.1H NMR (CDCl3) δ the 1.44 (s, 9H), 1,65-1,70 (m, 10H), 1,96-of 2.08 (m, 1H), 2,16-of 2.27 (m, 2H), 2,46-to 2.57 (m, 1H), 2.71 to to 2.85 (m, 1H), 3,86-of 3.97 (m, 2H), or 4.31 (d, 1H, J=15,0 Hz), to 4.38-4,48 (m, 2H, 4,54-4,59 (m, 4H), 6,63 (DD, 1H, J=7,2, 4.5 Hz), 6,98 (d, 1H, J=7.8 Hz), 7,13-7,24 (m, 4H), 7,45 (s, 1H), 7,53-7,56 (m, 1H), 7.68 per-7,71 (m, 1H), 8,24 (d, 1H, J=3,9 Hz), 8,82-8,87 (m, 1H).

A solution of tert-butyl ester 2-{[[2-(tert-butoxycarbonylamino)-4-hydroxymethylbenzene]-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazole-1-carboxylic acid (230 mg, and 0.37 mmol) and NaH (60% dispersion in mineral oil, and 13.3 mg of 0.56 mmol) in DMF (2.0 ml) was stirred at room temperature for 30 minutes. Added modesty methyl (0,12 ml of 1.85 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, diluted with EtOAc and washed sequentially with saturated aqueous NaHCO3(2 × 5 ml) and saturated aqueous NaCl (10 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure. Clean yellow foam column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 200:1:1, and 200:2:1) gave the desired product (97 mg), which was used in the next reaction without further purification.

To the solution obtained above amine (96 mg) in CH2Cl2(1 ml) was added TFOC (1 ml) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the syrup was dissolved in H2O and podslushivaet 1 N. NaOH (pH 8). Added CHCl3(75 ml), the phases were separated and the aqueous layer was extraheavy and CHCl 3(2 × 75 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Clean yellow foam radial chromatography on silica gel (CH2Cl2/Meon/NH4IT is 100:1:1, and 200:3:1) gave AMD11158 (20.2 mg, 13% over 2 stages) as a white solid.1H NMR (CD3OD) δ 1,52-of 1.66 (m, 1H), 2,04 was 2.25 (m, 3H), 2,61-a 2.71 (m, 1H), 2,82-of 2.93 (m, 1H), 3,60-the 3.65 (m, 1H), 3.72 points of 3.75 (m, 4H), 3,81 (d, 1H, J=12.9 Hz), 3,91-3,98 (m, 3H), 4,13 (d, 1H, J=13,2 Hz), a 4.53 (s, 2H), 7,02 (DD, 1H, J=7,5, and 4.5 Hz), 7,14-7,27 (m, 4H), 7,33-7,40 (m, 3H), 7,54-7,56 (m, 1H), 8,32-at 8.36 (m, 1H);13C NMR (CD3OD) δ 23,27, 23,34, 30,59, 31,18, 44,23, 48,33, 55,77, 60,96, 65,21, 111,37, 119,67, 123,44, 123,69, 124,30, 127,17, 130,03, 132,72, 136,74, 136,87, 138,48, 142,81, 143,24, 148,08, 153,81, 158,22. ES-MS m/z 442,4 (M+H). Elemental analysis. Calculated for C27H31N5O·1,2CH4O·0,2CH2Cl2: C, 68,63; H, 7,34; N, 14,09. Found: C, 69,03; H, To 7.09; N, 13,79.

Example: 24

AMD9852: Obtaining N-(2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)guanidine.

To a solution of (1H-benzimidazole-2-ylmethyl)-(2-aminomethylbenzoic)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (see AMD9720) (50 mg, 0.125 mmol) in THF (5 ml) was added N,N'-di-tert-butoxycarbonylamino-1-carboxamide (60 mg, 0,187 mmol) and potassium carbonate (35 mg, 0.25 mmol) and the mixture was stirred over night. The reaction mixture was diluted with aqueous NH4Cl (5 ml) and was extracted with er what ilaclama (3 x 10 ml). The combined organic fractions were dried (Na2SO4), concentrated and purified by chromatography on silica gel (5% MeOH/CH2Cl2), obtaining the target product as a faint foam (51 mg, 64%).1H NMR (CDCl3) δ to 1.47 (s, 9H), to 1.48 (s, 9H), is 1.81 (m, 1H), 2,00 (m, 2H), and 2.26 (m, 2H), 2.71 to is 2.88 (m, 2H), 3,89-of 4.05 (m, 5H), to 4.73 (DD, 1H, J=15,5, 5,1 Hz), 4,96 (DD, 1H, J=15,5, 5.7 Hz), 7,12 (m, 7H), was 7.36-7,44 (m, 3H), 7,55 (user. s, 1H (NH)), 8,55 (m, 1H (NH)), 8,66 (d, 1H, J=5,1 Hz).

Using General method D, the transformation obtained above foam (51 mg, 0.08 mmol) in hydrobromide salt gave AMD9852 in the form of a white solid (108 mg).1H NMR (D20). δ of 1.88 (m, 1H), of 2.21 (m, 2H), 2,43 (m, 1H), 3,01 (m, 2H), 3,81 (d, 1H, J=13.5 Hz), 4,01 (d, 1H, J=13.5 Hz), 4,34 (d, 1H, J=16.2 Hz), to 4.38 (d, 1H, J=14.4 Hz), of 4.44 (d, 1H, J=14.4 Hz), 4,55 (d, 1H, J=of 16.2 Hz), 4,78 (m, 1H), 6,99 (m, 2H), 7,10 (dt, 1H, J=7,2, 1.2 Hz), 7,40 (d, 1H, J=6.9 Hz), 7,55 (m, 2H), 7.62mm (m, 2H), 7,87 (DD, 1H, J=7,8, 5.7 Hz), 8,35 (d, 1H, J=7.8 Hz), 8,68 (d, 1H, J=5,1 Hz).13C NMR (D2O) δ 18,03, 18,26, 25,51, 40,78, 46,69, 50,49, 59,14, 111,69 (2C), 123,74, 124,50 (2C), 126,48, 126,65, 126,74, 128,35, 128,98, 132,04, 137,48, 138,22, 145,85, 150,02. ES-MS m/z 440 (M+H). Elemental analysis. Calculated for C26H29N7·3,0HBr·3,0H2O: C, 42,41; H, 5,07; N, 13,32; Br, Worth 32.55. Found: C, 42,67; H, 5,07; N, 13,24; Br, 32,77.

Example: 25

AMD9596: Obtaining N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)guanidine (hydrobromide salt).

To a solution of N'-(1H-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahed is about-8-chinoline)-1,4-benzilpenetsillina (397 mg, 1.0 mmol) in THF (10 ml) was added N,N'-di-tert-butoxycarbonylamino-1-carboxamidine (370 mg, 1.2 mmol) and potassium carbonate (207 mg, 1.5 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with aqueous NH4Cl (15 ml) and the mixture was extracted with ethyl acetate (3 × 10 ml). The combined organic fractions were dried (Na2SO4), filtered, concentrated and purified by chromatography on silica gel (19:1 CH2Cl2/MeOH)to give N',N"-di-tert-butoxycarbonyl-N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)guanidine in the form of dim foam (426 mg, 67%).1H NMR (CDCl3) δ 1,25 (s, 9H), of 1.44 (s, 9H), of 1.65 (m, 1H), 1,99 (m, 2H), 2,04 (m, 1H), 2,72-and 2.79 (m, 2H), of 3.73 (s, 2H), 3,94 (d, 1H, J=16.1 Hz), 4,07 (m, 1H), 4,11 (d, 1H, J=16.1 Hz), 4,51 (d, 2H, J=6.2 Hz), 7,14 (m, 4H), 7,39 (m, 3H), 7,55 (m, 1H), 7,63 (m, 1H), of 8.47 (m, 1H (NH)), 8,66 (d, 1H, J=4,8 Hz).

Using General method D, the transformation obtained above substances (106 mg, 0.1 mmol) in hydrobromide salt with simultaneous removal of the Boc group gave AMD 9596 (108 mg) as a white crystalline solid.1H NMR (D2O) δ of 1.88 (m, 1H), of 2.21 (m, 2H), 2,43 (m, 1H), 3,01 (m, 2H), 3,78 (d, 1H, J=12,6 Hz), 3,83 (d, 1H, J=12,6 Hz)to 3.89 (s, 2H), 4,45 (d, 1H, J=16.5 Hz), 4,60 (d, 1H, J=16.5 Hz), 4,79 (m, 1H), 6.89 in (d, 2H, J=7.8 Hz), to 7.15 (d, 2H, J=7.8 Hz), to 7.50 (m, 2H), EUR 7.57 (m, 2H), to $ 7.91 (DD, 1H, J=8,1, 6,0 Hz), 8,39 (d, 1H, J=8.1 Hz), 8,73 (d, 1H, J=6.0 Hz).13C NMR (D2O) δ 20,46, 20,87, 27,83, 43,90, 50,31, 56,69, 63,17, 113,76 (C), 126,04, 126,62 (2C), 127,03 (2C), 130,52 (2C), 135,98, 136,24, 139,58, 140,92, 148,20, 150,93, 151,86. ES-MS m/z 440 (M+H). Elemental analysis. Calculated for C26H29N7·3,2 HBr·2,2 H2O: C, 42,31; H; 5,00; N, 13,28; Br 33,64. Found: C, 42,48; H, Of 5.05; N, 13,15; Br, 32,64.

Example: 26

AMD9735: Obtaining N'-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-N,N-dimethylguanidine (hydrobromide salt).

Obtain hydrochloride of N,N-dimethyl-1H-pyrazole-1-carboxamidine

To a solution of pyrazole (1.01 g, of 14.8 mmol) and dimethylaniline (1.20 ml of 14.8 mmol) in 1,4-dioxane (15 ml) was added HCl (4,0 N. in 1,4-dioxane, and 3.8 ml of 15.2 mmol) and the resulting mixture was boiled under reflux for 3 hours. The reaction mixture was cooled to room temperature and diluted with anhydrous ether (15 ml) to precipitate a yellow solid. The obtained precipitate was allowed to settle to the bottom of the flask (during the night) and the supernatant solution decantation. The solid was dried in vacuum and has been specified in the header connection (2,01 g, 78%). ES-MS m/z 139 (M+H).

To a solution of N'-(1H-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-1,4-benzilpenetsillina (0,221 g of 0.56 mmol) in DMF (1 ml) was added the hydrochloride of N,N-dimethyl-1H-pyrazole-1-carboxamidine (0,250 g, 1.18 mmol) and N,N-diisopropylethylamine (0,70 ml, 4.02 mmol) and the resulting mixture was stirred at room temperature is in d for 19 hours. The reaction mixture was diluted with water (5 ml) and CH2Cl2(25 ml) and the pH of the aqueous phase was brought to ˜4 using dilute aqueous HCl (1 ad, 3 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2(3×10 ml). The aqueous phase was concentrated under reduced pressure and the obtained colorless oil was dissolved in 10 N. NaOH (4 ml). Basic aqueous solution was extracted with CH2Cl2(4 × 10 ml) and the combined organic extracts were dried (Na2SO4) and concentrated. The crude substance was purified by radial chromatography on silica gel (1 mm plate, 1:1:1 CH3CN/CH3OH/NH4OH) and got a white solid (147 mg).

Using General method D, the transformation of the free base (124 mg) in hydrobromide salt, with subsequent presidenial intermediate solid from methanol/ether, gave AMD9735 (121 mg) as a white solid.1H NMR (D2O) δ 1,84-to 1.98 (m, 1H), 2,20-of 2.34 (m, 2H), 2.40 a-2,47 (m, 1H), 2,99-of 3.06 (m, 8H), of 3.77 (d, 1H, J=12,6 Hz), 3,84 (d, 1H, J=12,6 Hz), of 3.96 (s, 2H), 4,47 (d, 1H, J=16.5 Hz)and 4.65 (d, 1H, J=16.5 Hz), 4.72 in-4,79 (m, 1H, overlap with HOD), 6,93 (d, 2H, J=7.8 Hz), 7,18 (d, 2H, J=7.8 Hz), 7,50-7,53 (m, 2H), 7,58-7,63 (m, 2H), to 7.93 (DD, 1H, J=6,6, 7,2 Hz), 8,39 (d, 1H, J=7.8 Hz), 8,77 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,29, 20,70, 27,67, 37,99, 44,43, 50,09, 56,39, 62,91, 113,65, 125,86, 126,39, 126,86, 130,33, 130,36, 135,80, 136,43, 139,47, 140,75, 148,01, 150,75, 151,75, 155,99; ES-MS m/z468 (M+H). Elemental analysis. Calc is but for C 28H33N7·3,2HBr·2,6H2O·1,4NH4Br: C, 36,94; H, 5,20; N, 12,92; Br, 40,37. Found: C, 36,94; H, Is 5.06; N, 12,88; Br, 40,45.

Example: 27

AMD9777: Obtain [4-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)aminomethylbenzoic]-N,N-dimethylformamidine (hydrobromide salt).

A solution of 2-pyridinesulfonamide (41 mg, 0.23 mmol) in DMF (0.75 ml) was stirred for 10 minutes, after which the solution was added N'-(1H-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-1,4-benzilpenetsillina (62 mg, 0.16 mmol) in DMF (0.8 ml) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and diluted with CH2Cl2(5 ml) and saturated aqueous K2CO3(5 ml). The layers were separated and the organic phase was dried (MgSO4), filtered, concentrated and purified column chromatography on silica gel (5% MeOH/CH2Cl2), receiving the target N,N-dimethylformamide (23 mg, 32%).1H NMR (CDCl3) δ to 1.67 (m, 1H), 2,03 (m, 2H), 2,24 (m, 1H), 2,70 (m, 1H), 2,84 (m, 1H), 2,84 (s, 6H), 3,71 (s, 2H), 3.96 points (d, 1H, J=15,0 Hz), 4,07 (m, 1H), 4,15 (d, 1H, J=18,0 Hz), 4,36 (s, 2H), 7,16 (m, 5H), 7,31 (s, 1H), 7,35 (d, 2H, J=7.8 Hz), 7,42 (d, 1 H, J=7.8 Hz), 7,51 (user., 1H), to 7.64 (user., 1H), 8,68 (d, 1H, J=3.5 Hz).

Using General method D, the transformation obtained above substances (23 mg) in hydrobromide salt gave AMD9777 (38 mg) in the form Belogorodka substances. 1H NMR (D2O) δ 1,91 (user. m, 1H), and 2.26 (m, 2H), 2,45 (user. m, 1H), 2,97 (s, 3H), 3,03 (user. m, 2H), 3,24 (s, 3H), of 3.78 (d, 1H, J=12.9 Hz), 3,85 (d, 1H, J=12.9 Hz), Android 4.04 (s, 2H), 4,45 (d, 1H, J=16.5 Hz), 4,63 (d, 1H, J=16.5 Hz), 4,80 (m, 1H), 6.90 to (d, 2H, J=8.1 Hz), 7,18 (d, 2H, J=7.8 Hz), 7,52 (DD, 2H, J=3,0, 6.3 Hz), to 7.59 (DD, 2H, J=3,0, 6.3 Hz), to 7.64 (s, 1H (NCHN)), 7,94 (t, 1H, J=6.9 Hz), to 8.41 (d, 1H, J=7.8 Hz), 8,76 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,47, 20,92, 27,85, 36,27, 43,38, 49,66, 50,21, 56,67, 63,21, 113,87 (2C), 126,09, 126,50 (2C), 127,63 (2C), 130,61 (2C), 136,44 (2C), 139,65, 141,01, 148,27 (2C), 150,90, 151,94, 156,35 (2C). ES-MS m/z 453 (M+H). Elemental analysis Calculated for C28H32N6·3,3HBr·2,3H2O: C, 44,29; H, And 5.30; N, 11,07; Br, 34,46. Found: C, 44,36; H, 5,14; N, A 10.74; Br, 34,44.

Example: 28

AMD9783: Obtaining N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)benzamidine (hydrobromide salt).

Getting hydrobromide S-benzylcyanide

To a solution of thiobenzamide (0,307 g, 2,24 mmol) in CH2Cl2(11 ml) was added benzylbromide (of 0.26 ml, 2,19 mmol) and the resulting solution was boiled under reflux for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The obtained yellow solid was dried in vacuum, obtaining the hydrobromide S-benzylcyanide (0,573 g, 85%).1H NMR (DMSO-d6) δ was 4.76 (s, 2H), 7,34-7,44 (m, 3H), 7,51-rate of 7.54 (m, 2H), to 7.61-7,66 (m, 2H), 7,78-7,83 (m, 1H), 7,88-to $ 7.91 (m, 2H), 11,92 (user. s, 1H).

To a solution of N'-(N-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-1,4-benzilpenetsillina (0,130 g, 0.33 mmol) in ethanol (2 ml) was added hydrogen bromide S-benzylcyanide (0,100 g, 0.33 mmol) and the resulting mixture was stirred at room temperature for 45 minutes. The mixture was treated with acetic acid, a saturated HBr (3 ml). Added ether (50 ml) to precipitate a white solid, which was allowed to settle to the bottom of the flask, and the supernatant solution decantation. The solid was washed with ether (3 × 50 ml) and the remaining traces of ether were removed under reduced pressure. The solid is distributed between NaOH solution (10 N., 5 ml) and CH2Cl2(20 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2(4 × 10 ml). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude substances by radial chromatography on silica gel (1 mm plate, 20:1:1 CH2Cl2/CH3OH/NH4OH) gave 50 mg (32%) of free base specified in the title compound as a white solid.

Using General method D, the transformation of the free base (50 mg) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether gave AMD9783 (56 mg) as a white solid.1H NMR (D2O) δ 1,83-of 1.97 (m, 1H), measuring 2.20 to 2.35 (m, 2H), 2,42-2,48 (m, 1H), 3.04 from (user. s, 2H), 3,79 (d, 1H, J=12.3 Hz), a 3.87 (d, 1H, J=12.3 Hz), is 4.21 (s, 2H), 4,47 (d, 1H, J=16.5 Hz) with 4.65 (d, 1H, J=16.5 Hz), 4,74-rate 4.79 (m, 1H, overlap with HOD), 7,02 (d, 2H, J=7.8 Hz), 7,22 (d, 2H, J=7.8 Hz), 7,29 (DD, 2H, J=of 3.0, 6.0 Hz), 7,54 (DD, 2H, J=of 3.0, 6.0 Hz), 7,62-to 7.64 (m, 4H), 7,74 for 7.78 (m, 1H), to $ 7.91 (DD, 1H, J=6,3, 7,2 Hz), 8,39 (d, 1H, J=8.1 Hz), 8,76 (d, 1H, J=5.7 Hz);13C NMR(D2O) δ 20,47, 20,93, 27,86, 45,43, 50,31, 56,67, 63,26, 113,73, 126,07, 126,55, 127,64, 128,09, 128,89, 129,83, 130,50, 130,67, 134,41, 136,54, 139,65, 140,99, 148,23, 150,92, 151,93, 164,65; ES-MS m/z 501 (M+H). Elemental analysis. Calculated for C32H32N6·3,0HBr·2,4H2O: C, 48,86; H, 5,10; N Is 10.68; Br, 30,47. Found: C, 48, 97mm; H, 4,89; N, To 10.62; Br, 30,30.

Example: 29

AMD9784: Obtaining N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)acetamidine (hydrobromide salt).

Getting hydrobromide S-benzylcyanide

To a solution of thioacetamide (0,478 g, 6,36 mmol) in CHCl3(16 ml) was added benzylbromide (0,76 ml, to 6.39 mmol) and the resulting solution was boiled under reflux for 2 hours. The mixture was cooled to room temperature. Added ether (50 ml) and the mixture was cooled in a bath of ice water to precipitate a white solid. The supernatant solution decantation and the solid was washed with ether (2 × 50 ml). The solid was dried in vacuum, obtaining 1.44 g (92%) of the hydrobromide S-benzylcyanide in the form of a white solid.1H NMR (DMSO-d6) δ 2,63 (s, 3H), br4.61 (s, 2H), 7,34-7,46 (m, 5H), 11,89 (users, 1H).

To a solution of N'-(1H-benzo is midazol-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-1,4-benzilpenetsillina (0,154 g, 0,39 mmol) in ethanol (2 ml) was added hydrogen bromide S-benzylcyanide (0,099 g, 0.40 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was treated with acetic acid, a saturated HBr (3 ml). The mixture was concentrated under reduced pressure and the residue was distributed between NaOH solution (10 N., 5 ml) and CH2Cl2(10 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2(3 × 10 ml). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude substances by radial chromatography on silica gel (1 mm plate, 1:1:1 CH3CN/CH3OH/NH4OH) gave 97 mg (57%) of free base specified in the title compound as a white solid.

Using General method D, the transformation of the free base (97 mg) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether gave AMD9784 (113 mg) as a white solid.1H NMR. (D2O) δ 1,83-to 1.98 (m, 1H), 2,17 is 2.33 (m, 5H), 2,41-2,47 (m, 1H), 3,03 was 3.05 (m, 2H), 3,78 (d, 1H, J=12.3 Hz), 3,85 (d, 1H, J=12.3 Hz), of 3.96 (s, 2H), 4,46 (d, 1H, J=16.5 Hz), with 4.64 (d, 1H, J=16.5 Hz), 4,74-4,79 (m, 1H, overlap with HOD), 6,91 (d, 2H, J=7.8 Hz), 7,18 (d, 2H, J=7.8 Hz), 7,49-of 7.60 (m, 4H), 7,92 (DD, 1H, J=6,0, 7,8 Hz), 8,39 (d, 1H, J=7.5 Hz), the rate of 8.75 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 18,91, 20,47, 20,91, 27,86, 44,99, 50,26, 56,65, 63,18, 113,84, 126,08, 126,63, 127,58, 130,52, 130,60, 134,29, 136,43, 39,64, 140,99, 148,25, 150,91, 151,90, 164,99; ES-MS m/z 439 (M+H). Elemental analysis. Calculated for C27H30N6·3,1HBr·2,2H20: C, 44,48; H, 5,18; N, 11,53; Br, 33,98. Found: C, 44,49; H, 5,19; N, 11,25; Br, 34,13.

Example: 30

AMD9689: Obtaining N-isobutyl-N'-(1H-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-1,4-benzilpenetsillina (hydrobromide salt).

Isobutyraldehyde (0.1 ml, 1.1 mmol) are condensed with N'-(1H-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-1,4-benzodiacepinas (152 mg, 0,382 mmol) in anhydrous CH3OH (5 ml) for 17 hours and the resulting Imin restored NaBH4(81 mg, 2.14 mmol) for 1 hour (see General methods A and B). Purification of the crude product by radial chromatography (2 mm TLC plate, 50:1:1 CH2C12/CH3HE/NH4HE gave the free amine (43 mg, 25 %).

According to the General procedure D conversion result of the above substances (43 mg) in hydrobromide salt gave AMD9689 (52 mg, 75%) as a white solid.1H NMR (D2O) δ to 0.88 (d, 6H, J=6,1 Hz), 1,82 is 1.96 (m, 2H), 2,17-of 2.34 (m, 2H), 2.40 a-2,50 (m, 1H), 2.63 in (d, 2H, J=7,6 Hz), 3,01-is 3.08 (m, 2H), the 3.65 (s, 2H), 3,81 (d, 1H, J=a 12.7 Hz), 3,88 (d, 1H, J=a 12.7 Hz), 4,46 (d, 1H, J=16.6 Hz), with 4.64 (d, 1H, J=16.1 Hz), 7,02 (d, 2H, J=7.9 Hz), 7.23 percent (d, 2H, J=8.0 Hz), 7,51 (DD, 2H, J=6,2, 3.1 Hz), to 7.59 (DD, 2H, J=6,0, 3.6 Hz), 7,94 (DD, 1H, J=8,1, 6,0 Hz), to 8.41 (d, 1H, J=7.9 Hz), 8,76 (d, 1H, J=5.7 Hz).13C (D2O) δ 19,67 (2 carbon), 20,64, 21,12, 25,95, 28,04, 50,35, 50,67, 54,46, 56,86, 63,38, 14,11 (2 carbon), 126,30, 126,90 (2 carbon), 130,35 (2 carbon), 130,75, 130,93 (2 carbon), 138,13, 139,87, 141,21, 148,46 (2 carbon), 151,03, 151,95. ES-MS m/z 454 (M+H). Elemental analysis. Calculated for C29H35N5·3,NVG·1,9H20: C, 47,68; H, 5,77; N, 9,59; Br, 32,81. Found: C, 47,53; H, Of 5.68; N, 9,46; Br, 32,94.

Example: 31

AMD9776: Receive (1H-benzimidazole-2-ylmethyl)-(4-piperidine-2-ylbenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Getting 4-[(1-butoxycarbonyl)piperidine-2-yl]benzaldehyde

To a solution of 4-pyridine-2-albenzaalbenza (1,036 g, the 5.65 mmol) in EtOH (95%, and 3.1 ml) and conc. HCl (0,48 ml) in a Parr flask for hydrogenation was added PtO2(57 mg, 0,251 mmol) and the mixture was first made at a pressure of H250 lb/in2(345 kPa) for 40 hours. The mixture was filtered through celite, the filter cake washed with MeOH and the solvent was removed from the eluent under reduced pressure. The obtained yellow solid was dissolved in 1 N. NaOH (30 ml) and was extracted with ether (4 x 50 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure, obtaining the crude 1-(hydroxymethyl)-4-(piperidine-2-yl)benzene (0,98 g) as a white solid. To a solution of the solid in THF (25 ml), triethylamine (10 drops) and water (10 drops) was added di-tert-BUTYLCARBAMATE (1.51 g, 6,92 mmol who) and the reaction mixture was stirred at room temperature for 20 hours. The mixture was concentrated under reduced pressure and the residue was placed in CH2Cl2(100 ml) and washed with saturated solution of salt (3 × 75 ml). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure, obtaining the crude 1-(hydroxymethyl)-4-[(1-butoxycarbonyl)piperidine-2-yl]benzene (1,87 g) in the form of oil.

To the solution obtained above oil (1,87 g) in CH2Cl2(100 ml) was added to MnO2(85 %, 5,90 g, 57,7 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite and the solvent from the eluent was removed under reduced pressure. Purification of the crude product (1.50 g) flash chromatography (38 g of silica, 99:1 CH2Cl2: CH3OH) gave specified in the header connection (0,98 g, 60%).1H NMR (CDCl3) δ 1,25 was 1.69 (m, 13H), 1,95 (TT, 1H, J=13,4, 4.6 Hz), 2,31 (d, 1H, J=12.9 Hz), 2,77 (TD, 1H, J=12,4, a 4.3 Hz), 4.09 to (d, 1H, J=13,7 Hz), 5,44 (s, 1H), 7,39 (d, 2H, J=7,7 Hz), 7,87 (d, 2H, J=8,2 Hz), 10,00 (with, 1H).

According to the General method B to a solution of 4-[(1-butoxycarbonyl)piperidine-2-yl]benzaldehyde (189 mg, 0,651 mmol) and [1-(tert-butoxycarbonyl)-(1H-benzimidazole-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (138 mg, 0,366 mmol) in CH2Cl2(8 ml) was added NaBH(OAc)3(219 mg, of 1.03 mmol) and the reaction mixture was stirred over night. Purification of the crude oil column chromatography (12 g d is silicon oxide, 40:1:1 CH2Cl2:CH3OH:NH4OH) followed by radial chromatography (1 mm TLC plate, 100:1:1 CH2Cl2: CH3OH: NH4OH) gave the target free base (59 mg, 29%).

According to the General procedure D conversion result of the above oil (59 mg) in hydrobromide salt gave AMD9776 (59 mg, 75%).1H NMR (D2O) δ 1,07-1,22 (m, 1H), 1,24-of 1.40 (m, 1H), 1,43 by 1.68 (m, 2H), 1,81-to 1.98 (m, 3H), 2,18-of 2.36 (m, 2H), 2.40 a is 2.51 (m, 1H), 2.95 and-3,10 (m, 3H), at 3.35 (d, 1H, J=13.3 Hz), 3.75 to to 3.92 (m, 3H), 4,48 (DD, 1H, J=16,7, to 8.7 Hz), of 4.66 (DD, 1H, J=16,7, 5.7 Hz), 7,01 (d, 2H, J=7.5 Hz), 7,26 (DD, 2H, J=7,8, and 4.9 Hz), of 7.48-rate of 7.54 (m, 2H), 7,55-to 7.61 (m, 2H), to $ 7.91-of 7.97 (m, 1H), to 8.41 (d, 1H, J=8,3 Hz), 8,75-8,80 (m, 1H).13C NMR (D2O) δ 20,48, 20,97, 21,84, 22,29, 27,88, 29,86, 45,87, 50,32, 50,49, 56,61, 60,24, 63,27, 63,37, 113,94 (2 carbon), to 126.14, 126,71 (2 carbon), 127,06 (2 carbon), 130,46, 131,03 (2 carbon), 136,85, 137,49, 139,71, 141,02, 148,30 (2 carbon), 150,83, 151,88. ES-MS m/z 452 (M+H). Elemental analysis. Calculated for C29H33N5·3,NVG·2,0H2O: C, 47,69; H, 5,52; N, 9,59; Br, 32,82. Found: C, 47,54; H, 5,42; N, 9,48; Br, 33,09.

Example: 32

AMD9713: Receive (1H-benzimidazole-2-ylmethyl)-(4-piperidine-1-iletileri)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Using General method A, to stir a solution of 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde (AMD9882) (144 mg, 0.36 mmol) in anhydrous MeOH (5 ml) was added piperidine (0,040 ml, 0.40 mmol) and tianbo the sodium hydride (44 mg, 0.70 mmol) and the mixture was stirred for 5 hours. Purification of the crude product by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH 50:1:1) gave the target adduct (50 mg, 30%) as a white foam.

Using General method D, the conversion obtained above foam (25 mg, 0,053 mmol) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether gave AMD9713 (40 mg, 98%) as a yellow solid.1H NMR (D2O) δ 1,32-of 1.57 (m, 3H), 1.70 to of 1.93 (m, 4H), 2,22-2,31 (m, 2H), 2,44-2,48 (m, 1H), 2,65 (user. t, 2H, J=11,4 Hz), 3,01-3,03 (user. m, 4H), of 3.75 (s, 2H), 3,81 (d, 1H, J=12,6 Hz)to 3.89 (d, 1H, J=12,6 Hz), 4,48 (d, 1H, J=16.5 Hz), of 4.67 (d, 1H, J=16.5 Hz), 4,77-rate 4.79 (m, 1H, overlap with HOD),? 7.04 baby mortality (d, 2H, J=7.8 Hz), 7,25 (d, 2H, J=7.8 Hz), 7,51 (DD, 2H, J=6,3, 3 Hz), to 7.59 (DD, 2H, J=6,3, 3 Hz), 7,94 (DD, 1H, J=7,5, and 6.3 Hz), to 8.41 (d, 1H, J=8.1 Hz), 8,78 (d, 1H, J=5.4 Hz);13C NMR (D2O) δ 20,30, 20,82, 21,25, 22,91, 27,71, 50,19, 52,80, 56,58, 59,44, 63,22, 113,70, 125,98, 126,62, 128,69, 130,29, 130,58, 131,14, 138,14, 139,55, 140,92, 148,17, 150,66, 151,68. ES-MS m/z 466 (M+H). Elemental analysis. Calculated for C30H35N5·3,NVG·1,5H2About: With, 47,94; H, Of 5.53; N, To 9.32; Br, 34,02. Found: C, 47,72; H, 5,54; N, Which 9.22; Br, 34,32.

Example: 33

AMD9722: Receive (1H-benzimidazole-2-ylmethyl)-(4-methylaminomethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Using General method B to a solution of 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde (AMD9882) (120 mg, 0.30 mmol) in MeOH (2 ml) was added methylamine (2.0m solution in methanol, 1 ml, 2.00 mmol) and the resulting solution was stirred at room temperature for 5 hours. To the solution was added solid NaBH4(18 mg, 0.48 mmol) and the mixture was stirred at room temperature for additional 30 minutes. Purification of the crude substances by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2/CH3OH/NH4OH) gave the free base specified in the title compound (74 mg, 59%) as a white solid.

Using General method D, the transformation of the free base (74 mg) in hydrobromide salt, with subsequent presidenial intermediate solid from methanol/ether, gave AMD9722 (111 mg) as a white solid.1H NMR (D2O) δ 1,84-of 1.97 (m, 1H), 2.21 are 2,47 (m, 6H), 3.04 from (user. s, 2H), 3,66 (s, 2H), 3,81 (d, 1H, J=12,6 Hz), 3,88 (d, 1H, J=12,6 Hz), 4,46 (d, 1H, J=16.5 Hz), with 4.64 (d, 1H, J=16.5 Hz), 4,77-rate 4.79 (m, 1H, overlap with HOD), 7,01 (d, 2H, J=8.1 Hz), 7,24 (d, 2H, J=8.1 Hz), 7,49-7,53 (m, 2H), 7,56-of 7.60 (m, 2H), to 7.93 (DD, 1H, J=6,0, 7.5 Hz), 8,40 (d, 1H, J=8.1 Hz), 8,76 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 18,71, 19,20, 26,11, 30,37, 48,50, 49,69, 54,93, 61,49, 112,19, 124,37, 124,95, 128,27, 128,77, 128,84, 129,07, 136,21, 137,94, 139,28, 146,54, 149,08, 150,08; ES-MS m/z 412 (M+H). Elemental analysis. Calculated for C26H29N5·3,0HBr·2,0H2O: C, 45,24; H, 5,26; N, 10,15; Br, 34,73. Found: C, 45,13; H, 5,20; N, 10,02; Br, 34,81.

Example: 34

AMD9724: Receive (1H-benzimidazole-2-ylmethyl)-(4-piperazine-1-iletileri)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Getting 2,2,2-Cryptor-1-piperazine-1-ratanana (Xu, D.; Repic, O.; Blacklock, J. Tetrahedron Lett. 1995, 41, 7357-7360):

To a solution of piperazine (1,444 g, a 16.8 mmol) in MeOH (10 ml) was added ethyl ether triperoxonane acid (2.0 ml, is 16.8 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and was purified column chromatography on silica gel (CH2Cl2/MeOH 9:1), obtaining the target monogamistic adduct of piperazine (1.77 g, 58%) as a pale yellow oil.1H NMR (CDCl3) δ 1,70 (users, 1H), 2,90-to 2.94 (m, 4H), 3,56-3,59 (m, 2H), 3,64-to 3.67 (m, 2H).

Using General method A, to stir a solution of 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde (AMD9882) (262 mg, 0.66 mmol) in anhydrous MeOH (10 ml) was added 2,2,2-Cryptor-1-piperazine-1-ylatason (172 mg, 0.95 mmol) and cyanoborohydride sodium (54 mg, 0.86 mmol) and the mixture was stirred over night. Purification of the crude product column chromatography on silica gel (CH2Cl2/Meon/NH4OH 100:1:1) followed by radial chromatography on silica gel (2 mm plate, CH2Cl2/Meon/NH4OH 50:1:1) gave the target adduct (68 mg, 18%) as a white foam.

To the solution obtained above TFUC-protected the CSOs adduct (68 mg, 0.12 mmol) in MeOH (3 ml) was added powdered To2CO3(55 mg, 0.40 mmol) and the mixture was stirred while boiling under reflux for 1.5 hours and at room temperature over night. The reaction mixture was diluted with CH2Cl2(30 ml) and water (20 ml), the phases were separated and the aqueous layer was extracted with CH2Cl2(2 × 15 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuum. Purification of the crude product by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH 100:1:1 then 50:1:1) gave the target adduct (54 mg, 97%) as a clear oil.

Using General method D, the transformation obtained above foam (23 mg, 0,049 mmol) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether gave AMD9724 (35 mg, 85%) as a white solid.1H NMR (D2O) δ 1,89-of 1.93 (m, 1H), 2.21 are of 2.33 (m, 2H), 2,42-2,48 (m, 1H), 3,03 was 3.05 (m, 2H), 3,24 of 3.28 (m, 4H), 3,42-3,44 (m, 4H), 3,82 (d, 1H, J=12.9 Hz), a 3.87 (s, 2H), 3,90 (d, 1H, J=12,6 Hz), 4,46 (d, 1H, J=16.5 in Hz)and 4.65 (d, 1H, J=16.5 Hz), 4,77-rate 4.79 (m, 1H, overlap with HOD), 7,07 (d, 2H, J=7.8 Hz), 7,27 (d, 2H, J=7.8 Hz), 7,51 (DD, 2H, J=6, 3 Hz), to 7.59 (DD, 2H, J=6, 3 Hz), 7,94 (DD, 1H, J=7,2, and 6.6 Hz), to 8.41 (d, 1H, J=8.1 Hz), 8,78 (d, 1H, J=6.2 Hz);13C NMR (D2O) δ 20,45, 20,97, 27,87, 41,14, 48,19, 50,17, 56,75, 59,92, 63,27, 113,97, 126,15, 126,68, 128,00, 130,53, 130,94, 131,34, 138,82, 139,74, 141,09, 148,33, 150,78, 151,81. ES-MS m/z 467(M+H). Elemental analysis. Calculated for C29H34N6·NVG·2,5H2A: C, 41,70; H, 5,19; N, 10,06; Br, 38,26. Found: C, 41,72; H, 5,16; N, 9,82; Br, 38,41.

Example: 35

AMD9733: Obtain [4-(4-arylpiperazine-1-ylmethyl)benzyl]-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Obtain 1-allyl-1-piperazine

To a stirred solution of 2,2,2-Cryptor-1-piperazine-1-ratanana (515 mg, and 2.83 mmol) in anhydrous CH3CN (6 ml) was added allylbromide (0,32 ml, 3.7 mmol) and powdered potassium carbonate (0,78 g, the 5.65 mmol) and the mixture was stirred over night. The reaction mixture was concentrated under reduced pressure, diluted with CH2Cl2(30 ml) and water (30 ml) and the aqueous layer was extracted with CH2Cl2(2 x 20 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuum, obtaining the crude diseasesandy piperazine (0,554 g)which was used without further purification in the next reaction.

To the solution obtained above TFUC-protected piperazine (0,554 g) in MeOH (10 ml) was added powdered To2CO3(0,689 g, 5.0 mmol) and the mixture was stirred while boiling under reflux for 1.5 hours and at room temperature over night. The reaction mixture was diluted with CH2Cl2(30 ml) and water (20 ml, the phases were separated and the aqueous layer was extracted with CH2Cl2(2 x 15 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuum, obtaining specified in the header connection (0,132 g, 42%) as a pale yellow oil.1H NMR (CDCl3) δ 1,96 (user. s, 1H), 2,39-2,44 (user. m, 4H), 2,89 of 2.92 (m, 4H), 2,98 (d, 2H, J=6 Hz), 5,13-to 5.21 (m, 2H), 5,79-to 5.93 (m, 1H).

Using General method B, to stir a solution of 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde (AMD9882) (262 mg, 0.66 mmol) and 1-arylpiperazine (132 mg, 1.05 mmol) in CH2Cl2(6 ml) was added NaBH(OAc)3(184 mg, 0.87 mmol) and the resulting mixture was stirred at room temperature for 2 hours. Purification of the crude substances column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 95:4:1) gave the target adduct (267 mg) as a clear oil.

Using General method D, the transformation obtained above oil (233 mg) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether gave AMD9733 (335 mg, 56% over 2 stages) as a yellow solid.1H NMR (D2O) δ 1,89-of 1.94 (m, 1H), 2.21 are of 2.33 (m, 2H), 2,42 is 2.46 (m, 1H), 3,03 was 3.05 (m, 2H), 3,30-to 3.34 (m, 4H), 3,44-3,51 (m, 4H), 3,80-3,90 (m, 6H), 4,47 (d, 1H, J=16.5 Hz)and 4.65 (d, 1H, J=16.5 Hz), 4,77-rate 4.79 (m, 1H, overlap with HOD), 5,62 (d, 1H, J=17,1 Hz), 5,64 (d, 1H, J=9.6 Hz), 5,81-5,91(m, 1H), 7,07 (d, 2H, J=7.8 Hz), 7,28 (d, 2H, J=7.8 Hz), to 7.50 (DD, 2H, J=6, 3 Hz), to 7.59 (DD, 2H, J=6, 3 Hz), 7,95 (DD, 1H, J=7,8, 6 Hz), 8,42 (d, 1H, J=7.8 Hz), 8,78 (d, 1H, J=5.5 Hz);13C NMR (D2O) δ 20,72, 21,26, 28,15, 48,52, 48,64, 50,48, 56,99, 59,47, 59,73, 63,48, 114,29, 125,18, 126,44, 126,97, 127,79, 128,76, 130,70, 131,28, 131,71, 139,20, 140,03, 141,33, 148,62, 150,97, 152,01. ES-MS m/z 507 (M+H). Elemental analysis. Calculated for C32H38N6·3,NVG·2,7N2About·0,4C4H10About: With, 44,81; H, 5,74; N, Was 9.33; Br, 34,60. Found: C, 44,62; H, 5,49; N, 9,26; Br, 34,84.

Example: 36

AMD9734: Receive (1H-benzimidazole-2-ylmethyl)-(4-dimethylaminomethylene)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Using General method B, the interaction of 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde (AMD9882) (157 mg, 0.40 mmol) and dimethylamine (2.0m in THF, 0.4 ml, 0.80 mmol) with NaBH(OAc)3(0,179 g, 0.84 mmol) in CH2Cl2(4 ml) overnight, followed by purification of the crude substances by radial chromatography on silica gel (2 mm plate, 50:1:1 CH2Cl2/CH3OH/NH4HE gave the free base specified in the title compound (72 mg, 43%) as a colourless oil.

Using General method D, the transformation of the free base (72 mg) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether gave AMD9734 (77 mg) in the form of blog is solid. 1H NMR (D2O) δ 1,86-to 1.98 (m, 1H), 2,20-2,48 (m, 9H), 3,05 (user. s, 2H), 3,80 (s, 2H), 3,81 (d, 1H, J=12,6 Hz), 3,90 (d, 1H, J=2.6 Hz), 4,50 (d, 1H, J=16.5 Hz), and 4.68 (d, 1H, J=16.5 Hz), 4,78 of 4.83 (t, 1H, overlap with HOD), 7,06 (d, 2H, J=7.8 Hz), 7,28 (d, 2H, J=7.8 Hz), of 7.48-7,52 (t, 2H), EUR 7.57-to 7.61 (m, 2H), 7,95 (DD, 1H, J=6,0, 7.5 Hz), 8,42 (d, 1H, J=7.8 Hz), 8,79 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,47, 21,03, 27,90, 42,16, 50,41, 56,77, 60,12, 63,45, 113,98, 126,18, 126,85, 129,16, 130,43, 130,91, 131,12, 138,45, 139,74, 141,11, 148,37, 150,77, 151,99; ES-MS m/z 426 (M+H). Elemental analysis. Calculated for C27H31N5·3,2HBr·2,2H2O: C, 44,78; H, Lower Than The 5.37; N, 9,67; Br, 35,31. Found: C, 44,76; H, 5,27; N, 9,52; Br, 35,29.

Example: 37

AMD 9775: Receive (1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[4-(1,2,4-triazole-4-illuminometer)benzyl]amine (hydrobromide salt).

Using General method B, the interaction of 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde (AMD9882) (206 mg, 0.52 mmol) and 4-amino-1,2,4-triazole (70 mg, 0.82 mmol) with NaBH(OAc)3(0,223 g, 1.05 mmol) in CH2Cl2(4 ml) and acetic acid (0,12 ml) overnight, followed by purification of the crude substances by radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2/CH3OH/NH4OH) gave 87 mg (36%) of free base specified in the title compounds as colorless oils.

Using General method D, the transformation of the free base (87 mg) in g is tribromide salt with subsequent presidenial intermediate solid from methanol/ether gave AMD9775 (83 mg) as a white solid, 1H NMR (D2O) δ 1,85 of 1.99 (m, 1H), 2,20-of 2.34 (m, 2H), a 2.45-2.49 USD (m, 1H), 3,06 (s, 2H), 3,82 (d, 1H, J=12,6 Hz), 3,91 (d, 1H, J=12,6 Hz), 4,46 (d, 1H, J=16.5 Hz)and 4.65 (d, 1H, J=16.5 Hz), 4,79 of 4.83 (t, 1H, overlap with HOD), 7,27-to 7.32 (t, 2H), was 7.36-7,44 (t, 4H), 7,50-7,56 (t, 2H), 7,95 (DD, 1H, J=6,3, 7.5 Hz), to 8.41-8,43 (m, 2H), 8,79 (d, 1H, J=5.4 Hz), 9,07 (user. s, 2H);13C NMR (D2O) δ 20,44, 21,04, 27,86, 50,24, 56,96, 63,44, 113,90, 113,97, 126,21, 126,53, 126,82, 129,02, 129,99, 130,44, 130,69, 130,84, 135,15, 139,77, 141,11, 141,88, 144,07, 148,36, 150,67, 151,27, 151,54, 160,78, 195,56; ES-MS m/z 463 (M+H). Elemental analysis. Calculated for C27H26N8·3,0HBr·1,8H2O: C, 43,96; H, Of 4.45; N, 15,19; Br, 32,49. Found: C, 43,99; H, And 4.40; N, 14,83; Br, 32,61.

Example: 38

AMD9671: Obtaining N'-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)ethane-1,2-diamine (hydrobromide salt).

Using General method B, to mix a solution of N'-(1H-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-1,4-benzilpenetsillina (250 mg, 0,629 mmol) and tert-butyl methyl ether (2-oxoethyl)carbamino acid (100 mg, 0,628 mmol) in THF (6.3 ml) was added NaBH(SLA)3(173 mg, 0,816 mmol) and the mixture was stirred at room temperature for 22 hours. Purification of the crude substances column chromatography on silica gel (200:5:1 CH2Cl2/MeOH/NH4OH) gave a colourless oil (47 mg).

Using General method D, the transformation of the oil obtained above (47 mg, 0.11 mmol) in hydrobromide the ol subsequent presidenial intermediate solid from methanol/ether gave AMD9671 (72 mg, 14%) as a colourless solid.1H NMR (D2O) δ of 1.88 (m, 1H), 2,24 (m, 2H), 2,42 (m, 1H), 3,01 (m, 2H), 3,25 (m, 4H), to 3.73 (m, 2H), 3,82 (DD, 2H, J=19,12 Hz), and 4.40 (d, 1H, J=16 Hz), 4,59 (d, 1H, J=16 Hz), and 4.75 (m, 1H), 7,03 (d, 2H, J=7,8 Hz), of 7.23 (d, 2H, J=7.8 Hz), of 7.48 (m, 2H), 7,55 (m, 2H), 7,88 (DD, 1H, J=7,8, 6,0 Hz), 8,35 (d, 1H, J=7.8 Hz), 8,73 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,46, 20,91, 27,85, 35,73, 43,93, 50,12, 50,82, 56,63, 63,00, 114,01, 126,02, 126,50, 130,05, 130,86, 138,33, 139,77, 140,88, 148,06, 150,92, 151,74. ES-MS m/z 441 (M+H). Elemental analysis. Calculated for C27H32N6·3,9HBr·2,5H2O: C, 40,48; H, 5,15; N, 10,49; Br, 38,90. Found: C, 40,35; H, 4,96; N, Of 10.25; Br, 39,04.

Example: 39

AMD9701: Receive (1H-benzimidazole-2-ylmethyl)-(4-butylaminoethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

A solution of N'-(1H-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-1,4-benzilpenetsillina (165 mg, 0,415 mmol) and Butyraldehyde (50 mg, 0.69 mmol) in MeOH (4 ml) was boiled under reflux for 30 minutes. The solution was left to cool to room temperature, was added 10% Pd/C (20 mg, 0.019 mmol) and the mixture was stirred in hydrogen atmosphere (1 ATM) at room temperature for 20 hours. The mixture was filtered through celite and the solvent from the filtrate was removed under reduced pressure. Purification of the crude substances column chromatography on silica gel (200:5:1 CH2Cl2/MeOH/NH4OH) gave AMD9701 (16 mg, 8%) as a colourless foam. H NMR (CDCl3) δ 0.87 (m, 3H), 1,24-1,49 (m, 4H), by 1.68 (m, 1H), 2,02 (m, 2H), and 2.26 (m, 1H), has 2.56 (m, 2H), and 2.79 (m, 2H), 3,68 (s, 2H), of 3.73 (s, 2H), 3,97 (d, 1H, J=17 Hz), 4,08 (m, 1H), 4,17 (d, 1H, J=17 Hz), to 7.18 (m, 5H), 7,35 (m, 2H), 7,42 (m, 1H), 7,58 (m, 2H), 8,69 (d, 1H, J=3,9 Hz);13C NMR (CDCl3) δ 14,39, 20,84, 21,79, 23,77, 29,63, 32,57, 48,88, 49,53, 54,11, 60,58, 111,30, 119,11, 121,68, 122,04, 122,60, 128,47, 128,99, 135,09, 137,55, 138,30, 139,82, 147,33, 156,73, 157,89. ES-MS m/z 454 (M+H). Elemental analysis. Calculated for C29H35N5·1,3H2O: C, 73,02; H, 7,94; N, 14,68. Found: C, 73,06; H, Of 7.70; N, 14,32.

Example: 40

AMD9725: Receive (1H-benzimidazole-2-ylmethyl)-(4-diallylmethylamine)-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

To a solution of N'-(1H-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-1,4-benzilpenetsillina (156 mg, 0,39 mmol) in CH2Cl2(4 ml) was added N,N-diisopropylethylamine (65 μl, of 0.37 mmol). Was added dropwise allylbromide (35 μl, 0.40 mmol) and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with CH2Cl2(50 ml) and washed successively H2O (2 × 5 ml), saturated aqueous NaHCO3(5 ml) and saturated aqueous NaCl (5 ml). The aqueous layer was extracted with CH2Cl2(20 ml) and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure, obtaining a light yellow foam (100 mg). Purification of column chromatography in which silicagel (200:1:1, then 100:1:1 CH2Cl2:MeOH:NH4OH) followed by radial chromatography on silica gel (1000:1:1 EtOAc:MeOH:NH4OH) gave AMD9725 (24.5 mg, 14%) as a pale yellow foam.1H NMR (CDCl3) δ of 1.62 and 1.75 (m, 1H), 1,97-of 2.08 (t, 2H), 2,22-of 2.30 (m, 1H), 2,66-2,77 (m, 1H), 2.77-to of 2.92 (m, 1H), 3,01 (d, 4H, J=6.3 Hz), of 3.48 (s, 2H), 3,74 (s, 2H), 3,99 (d, 1H, J=16,8 Hz), 4,07-4,12 (m, 1H), 4,18 (d, 1H, J=16,8 Hz), 5,09-5,17 (m, 4H), of 5.83 (DDT, 2H, J=16,8, to 10.2, 6.3 Hz), 7,15-7,20 (m, 5H), 7,34 (d, 2H, J=7.8 Hz), 7,41 (d, 1H, J=7.8 Hz), of 7.48-7,56 (m, 1H), 7,60-of 7.69 (m, 1H), 8,69 (d, 1H, J=4, 2 Hz);13C NMR (CDCl3) δ 19,69, 21,65, 27,53, 46,90, 52,08, 54,63, 55,44, 58,47, 109,24, 115,61, 117,04, 119,79, 120,49, 126,67, 127,13, 132,99, 134,17, 135,45, 136,13, 136,56, 145,22, 154,64, 155,80. ES-MS m/z 478,4 (M+H). Elemental analysis. Calculated for C31H35N5·0,5H2O: C, 76,51; H, 7,46; N, 14,39. Found: C, 76,67; H, Was 7.45; N, 14,18.

Example: 41

AMD9726: Receive (4-allylaminogeldanamycin)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

To a solution of N'-(1H-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-1,4-benzilpenetsillina (200 mg, 0,39 mmol) in CH2Cl2(˜0.4 ml) was added N,N-diisopropylethylamine (90 μl, 0.52 mmol). Allylbromide (35 μl, 0.40 mmol) was dissolved in CH2Cl2(˜9.6 ml) was added to a mixture of amines with a rate of 5.5 ml/hour. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with CH2Cl2(50 ml) and washed following the preliminary H 2O (5 ml), saturated aqueous NaHCO3(5 ml) and saturated aqueous NaCl (5 ml). The aqueous layer was extracted with CH2Cl2(20 ml) and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification of column chromatography on silica gel (200:1:1, then 100:1:1 EtOAc:MeOH:NH4OH) followed by radial chromatography on silica gel (250:1:1 EtOAc:MeOH:NH4OH) gave AMD9725 (36 mg, 21%) as a pale yellow foam.1H NMR (CDCl3) δ 1.56 to about 1.75 (t, 1H), 1,97-of 2.08 (m, 2H), 2,24-2,31 (t, 1H), 2,65-2,77 (t, 1H), 2.77-to 2.91 in (t, 1H), 3,21 (d, 2H, J=5.7 Hz), of 3.69 (s, 2H), of 3.73 (s, 2H), 3,97 (d, 1H, J=16,8 Hz), 4.04 the-4,16 (m, 1H), 4,17 (d, 1H, J=16,8 Hz), 5,07 (d, 1H, J=9.9 Hz), 5,15 (DD, 1H, J=17,1, 1.2 Hz), 5,88 (DDT, 1H, J=17,1, 10,5, 6,0 Hz), 7,10-7,19 (m, 5H), 7,35 (d, 2H, J=7.8 Hz), 7,42 (d, 1H, J=7.5 Hz), 7,45-EUR 7.57 (m, 1H), 7,58-to 7.68 (m, 1H), 8,69 (d, 1H, J=4, 2 Hz);13C NMR (CDCl3) δ 20,83, 22,89, 28,67, 47,95, 51,11, 52,33, 53,17, 59,68, 110,37, 115,39, 118,11, 120,91, 121,66, 127,59, 128,07, 134,13, 136,17, 136,60, 137,48, 138,56, 146,38, 155,80, 156,94. ES-MS m/z 438,3 (M+H). Elemental analysis. Calculated for C28H31N5·0,8H2O: C, 74,40; H, 7,27; N, 15,49. Found: C, 74,36; H, 7,25; N,15,31.

Example: 42

AMD9754: Receive (1H-benzimidazole-2-ylmethyl)-(4-pyrrolidin-1-iletileri)-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

Using General method B, to stir a solution of 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde (150 mg, and 0.37 mmol), PIR is alidina (30 μl, 0.36 mmol) and AcOH (20 μl, of 0.37 mmol) in THF (4 ml) was added NaBH(SLA)3(235 mg, 1.11 mmol) and the mixture was stirred at room temperature for 1.5 hours. Purification of the crude white foam (205 mg) column chromatography on silica gel (100:1:1 CH2Cl2:MeOH:NH4OH) gave the desired product (160 mg, 96%) as a white foam.

Using General method D, the conversion obtained above foam in hydrobromide salt gave AMD9754 in the form of a white solid.1H NMR (CD3OD) δ 1,82-to 1.98 (m, 3H), 1,98-of 2.15 (m, 2H), 2,18-of 2.36 (m, 2H), 2,42 of $ 2.53 (m, 1H), 2,85-of 2.97 (m, 2H), 3,03-3,14 (m, 4H), 3,85 (d, 1H, J=12.9 Hz), of 3.94 (d, 1H, J=12.9 Hz), 4,07 (s, 2H), 4,45 (d, 1H, J=16.5 in Hz), of 4.66 (d, 1H, J=16.2 Hz), 4,74-rate 4.79 (m, 1H), 7,27 (d, 2H, J=7.8 Hz), 7,55 (DD, 2H, J=6,3, and 3.3 Hz), 7,63 (d, 2H, J=7.8 Hz), to 7.77 (DD, 2H, J=6,3, and 3.3 Hz), of 7.97 (DD, 1H, J=7,8, 6,0 Hz), 8,42 (d, 1H, J=8,1 Hz), 9,01 (d, 1H, J=5.4 Hz);13C NMR (D2O) δ 20,47, 21,05, 22,81, 27,90, 50,46, 53,75, 56,76, 57,26, 63,49, 113,98, 126,18, 126,74, 130,31, 130,42, 130,62, 130,94, 138,04, 139,76, 141,10, 148,36, 150,77, 152,06. ES-MS m/z 452,3 (M+H). Elemental analysis. Calculated for C29H33N5·3,NVG·2,1H2About: With, 47,57; N, Of 5.53;N, To 9.57; Br, 32,74. Found: C, 47,69; H, Of 5.53; N, 9,48; Br, 32,48.

Example: 43

AMD9723: Receive (1H-benzimidazole-2-ylmethyl)-(4-(morpholine-4-iletileri)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Using General method A, to stir a solution of 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]m is Teal}benzaldehyde (0,285 g, to 0.72 mmol) in anhydrous MeOH (5 ml) was added morpholine (0,068 ml, 0.78 mmol) and cyanoborohydride sodium (0,107 g, 1.7 mmol) and the mixture was stirred at room temperature for 24 hours. Purification of the crude product by radial chromatography on a 2 mm plate for TLC (CH2Cl2/MeOH/NH4OH, 100:1:1) gave the desired product (23 mg, 7%) as a colourless oil.

Using General method D, the transformation obtained above oil (23 mg, 0,049 mmol) in hydrobromide salt gave AMD9723 in the form of a white solid (36 mg).1H NMR (D2O) δ 1,79-2,03 (user. m, 1H), 2,14-2,38 (user. m, 2H), 2,38-2,54 (user. m, 1H), 2,83 is 3.15 (m, 6H), 3,51-3,71 (m, 2H), 3,76-4,10 (m, 6H), 4,48 (d, 1H, J=16.5 Hz), of 4.66 (d, 1H, J=16,8 Hz), 7,07 (d, 2H, J=7.8 Hz), 7,27 (d, 2H, J=7.5 Hz), 7,12-to 7.68 (m, 4H), 7,94 (t, 1H, J=6.3 Hz), to 8.41 (d, 1H, J=7.8 Hz), 8,78 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,45, 20,99, 27,87, 50,33, 51,31 (2 carbon), 56,75, 59,89, 63,39, 63,98 (2 carbon), 113,92 (2 carbon), 126,13, 126,66 (2 carbon), 127,83, 130,56, 130,84 (2 carbon), 131,47 (2 carbon), 138,67, 139,75, 141,07, 148,27, 150,81, 151,94; ES-MS m/z468 (M+H). Elemental analysis. Calculated for C29H33N5About·3,NVG·2,0N2A: C, 46,67; H, Of 5.40; N, 9,38; Br, 32,12. Found: C, 46,71; H, Of 5.34; N, Which 9.22; Br, 32,17.

Example: 44

AMD9698: Receive (1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(4-thiomorpholine-4-iletileri)Amin

According to General method A, 4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-yl)amino]methyl}benzaldehyde (200 mg, 0.50 mmol) and thiomorpholine (51 μl, 0.50 mmol) was converted to the corresponding product reductive amination using the following quantities of reagents and solvents: cyanoborohydride sodium (63 mg, 1.0 mmol), MeOH (3 ml). The reaction time in this case was 5 hours. Purification of the thus obtained crude substance radial chromatography (silica gel, 1 mm plate, 50:2:1 CH2Cl2:MeOH:NH4OH) gave 63 mg (26%) AMD9698 in the form of a white foam.1H NMR (CDCl3) δ 1,67-1,72 (m, 1H), 2,02-of 2.09 (m, 2H), 2,25-of 2.27 (m, 1H), 2,62 (s, 8H), 2,68-by 2.73 (m, 1H), 2,80-to 2.85 (m, 1H), 3,40 (s, 2H), 3,74 (s, 2H), 3,98 (d, 1H, J=16 Hz), 4,10 (DD, 1H, J=9.6 Hz), 4,19 (d, 1H, J=16 Hz), 7,14-7,20 (m, 5H), 7,35 (d, 2H, J=8 Hz), 7,42 (DD, 1H, J=8, 1 Hz), 7,53-7,63 (m, 2H), 8,70 (DD, 1H, J=5, 1 Hz);13C NMR (CDCl3) δ 21,3, 23,4, 27,9, 29,1, 48,5, 53,6, 54,8, 60,2, 63,3, 110,8, 118,6, 121,3, 122,2, 128,3, 128,9, 134,6, 136,9, 137,1, 138,1, 146,9, 156,3, 157,4. ES-MS m/z 484 (M+H). Elemental analysis. Calculated for C29H33N5S·0,1 CH2Cl2·0,3H2ABOUT: WITH, 70,25; H, 6,85; N, 14,08; S, 6,44. Found: C, 70,42; H, 6.90 To; N 13,70; S, 6,29.

Example: 45

AMD11173: Receive (1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(2-cyclopropanecarbonyl)amine (HBr salt).

Using General procedure b {direct reductive amination using NaBH(OAc)3}, the interaction of phthalic dicarboxaldehyde (0,960 g, 7,16 mmol) and (1H-benzimidazole-2-elmet the l)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,991 g, 3.58 mmol) with NaBH(OAc)3(3,24 g of 15.3 mmol) in CH2Cl2(20 ml) for 65 hours, followed by stirring in THF (10 ml) and 4n. HCl (20 ml) gave the crude product. Purification of the crude substances column chromatography on silica gel (37 g of silicon dioxide, 30:1 CH2Cl2:CH3OH) gave 1,21 g (45%) of a mixture of products of benzyl aldehyde and benzyl alcohol.

This mixture of aldehyde and alcohol (1,21 g, 3.04 from mmol) was dissolved in CH2Cl2(20 ml), was treated with MnO2(1,990 g of 19.5 mmol) and was stirred for 48 hours. The suspension was filtered through celite and concentrated, obtaining the crude product. Purification of column chromatography on silica gel (51 g of silica, 60:1 CH2Cl2:CH3HE gave 942 mg (66% in three stages) intermediate o-benzyl aldehyde as a yellow foam.

The above aldehyde (0,119 g, 0,300 mmol) was stirred with cyclopropylamine (32 μl, 0,461 mmol) in CH3OH (2.5 ml) for 1 h, then was treated with NaBH4(18 mg, 0.475 mmol). After 1 hour the mixture was concentrated. The residue was diluted with CH2Cl2(20 ml) and washed with saturated solution of salt (3 × 10 ml). The combined aqueous phase was extracted with CH2Cl2(1 × 15 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated, obtaining the crude product. Cleaning idealnoi chromatography on silica gel (1 mm plate, 100:1:1 CH2Cl2:CH3OH:NH4OH) gave of 0.066 g (50%) of a white foam.

Using General method D, the transformation obtained above foam (66 mg, 0,151 mmol) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether gave AMD11173 (100 mg, 92%) as a white solid.1H NMR (D2O) δ 0,63-of 0.79 (m, 4H), 1,83-to 1.98 (m, 1H), 2,18-of 2.30 (m, 1H), 2,31-to 2.41 (m, 1H), 2,43-of 2.58 (m, 2H), 2,98-3,13 (m, 2H), 3,92 (d, 1H, J=13.1 Hz), 4,14 (d, 1H, J=13,2 Hz), 4,24 (d, 1H, J=13,6 Hz)to 4.41 (d, 1H, J=16.6 Hz), 4,48 (d, 1H, J=13.1 Hz), 4,59 (d, 1H, J=16.4 Hz), 6,92 (t, 1H, J=7.5 Hz), 7,00 (d, 1H, J=7.4 Hz), 7,19 (t, 1H, J=7,0 Hz), 7,41 (d, 1H, J=7.4 Hz), 7,51-7,56 (m, 2H), 7,58-7,63 (m, 2H), to $ 7.91 (DD, 1H, J=7,7, 6,1 Hz), 8,40 (d, 1H, J=7.9 Hz), a total of 8.74 (d, 1H, J=5,22);13C NMR (D2O) δ 3,53, 20,43, 20,93, 27,92, 30,04, 48,44, 49,35, 53,22, 62,29, 113,95, 126,24, 126,91, 129,42, 129,54, 130,32, 130,60, 131,16, 132,17, 135,58, 139,96, 141,16, 148,33, 150,52, 150,89. ES-MS m/z 438 (M+H). Elemental analysis. Calculated for C28H31N5·3,0HBr·2,2H2O: C, 46,71; H, 5,38; N, 9,73; Br, 33,30. Found: C, 46,72; H, Are 5.36; N, 9,59; Br, 33,21.

Example: 46

AMD 11173: Receive (1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(2-allylaminogeldanamycin)amine (HBr salt).

Using General method B (direct reductive amination using NaBH(SLA)3), the interaction of phthalic dicarboxaldehyde (0,960 g, 7,16 mmol) and (1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,991 g, 3.58 mmol) NaBH(OAc) 3(3,24 g of 15.3 mmol) in CH2Cl2(20 ml) for 65 hours, followed by stirring in THF (10 ml) and 4n. HCl (20 ml) gave the crude product. Purification of the crude substances column chromatography on silica gel (37 g of silicon dioxide, 30:1 CH2Cl2:CH3HE gave 1,21 g (45%) of a mixture of products of benzyl aldehyde and benzyl alcohol. A mixture of aldehyde and alcohol (1,21 g, 3.04 from mmol) was dissolved in CH2Cl2(20 ml), was treated with MnO2(1,990 g of 19.5 mmol) and was stirred for 48 hours. The suspension was filtered through celite and concentrated, obtaining the crude product. Purification of column chromatography on silica gel (51 g of silica, 60:1 CH2Cl2:CH3HE gave 942 mg (66% in three stages) intermediate o-benzyl aldehyde as a yellow foam.

The above aldehyde (0,150 g, 0,378 mmol) was stirred with allylamine (42 μl, 0,968 mmol) in CH3OH (2.5 ml) for 18 hours, then was treated with NaBH4(24 mg, 0,634 mmol). The mixture was concentrated after 90 minutes. The residue was diluted with CH2Cl2(30 ml) and washed with saturated solution of salt (3 × 15 ml). The combined aqueous phase was extracted with CH2Cl2(1 × 15 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated, obtaining the crude product. Purification by radial chromatography on when likehere (2 mm plate, 100:1:1 CH2Cl2:CH3OH:NH4HE gave 53 mg (32%) of a white foam.

Using General method D, the transformation obtained above foam (53 mg, 0,121 mmol) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether gave D1174 (77 mg, 88%) as a white solid.1H NMR (D2O) δ 1,83 of 1.99 (m, 1H), 2,19-to 2.40 (m, 2H), 2,45 is 2.55 (m, 1H), 2,99-of 3.12 (m, 2H), 3,61 (d, 2H, J=6.5 Hz), 3,92 (d, 1H, J=13.5 Hz), 4,12-4,20 (m, 2H), 4,36-4,43 (m, 2H), 4,58 (d, 1H, J=16,3 Hz), 5,44 (s, 1H), of 5.89 (d, 1H, J=5,2 Hz), 5,77-5,91 (m, 1H), 6,93 (t, 1H, J=7.5 Hz), 7,02 (d, 1H, J=7.9 Hz), 7,18 (t, 1H, J=7,7 Hz), the 7.43 (d, 1H, J=7.9 Hz), 7,51-7,56 (m, 2H), 7,58-to 7.64 (m, 2H), 7,92 (t, 1H, J=6,8 Hz), to 8.41 (d, 1H, J=8,4 Hz), the rate of 8.75 (d, 1H, J=5.8 Hz);13C NMR (D2O) δ 20,43, 20,96, 27,90, 47,07, 49,16, 49,69, 53,30, 62,33, 113,95, 124,80, 126,25, 126,93, 127,51, 129,38, 129,67, 130,31, 130,53, 130,96, 132,10, 135,49, 139,88, 141,18, 148,44, 150,41, 150,73. ES-MS m/z 438 (M+H). Elemental analysis. Calculated for C28H31N5·3,0HBr·2,2H2O: C, 46,71; H, 5,38; N, 9,73; Br, 33,30. Found: C, 46,79; H, 5,27; N, 9,62; Br, 33,17.

Example: 47

AMD11133: Receive (1H-benzimidazole-2-ylmethyl)-[2-(R)-(2-aminopropionitrile)benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

To a solution of N-tert-butoxycarbonyl-l-alanine (37 mg, of € 0.195 mmol) in dichloromethane (5 ml) was added, in the following sequence: diisopropylethylamine (0,08 ml, 0,468 mmol), 1-hydroxybenzotriazole ((HOBT) 32 mg, 0,234 mmol), (1H-benzimidazole-2-metil)-(2-aminomethylbenzoic)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (62 mg, 0,156 mmol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ((EDAC) 45 mg, 0,234 mmol). The resulting solution was then stirred overnight at room temperature in a nitrogen atmosphere. The solution then was extracted with aqueous ammonium chloride, dried, concentrated and purified flash chromatography on silica gel using a solution of 20:1 dichloromethane:methanol as eluent, obtaining (1H-benzimidazole-2-ylmethyl)-{2-(R)-[2-(N-tert-butoxycarbonyl)aminopropionitrile]benzyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amine as a mixture of two diastereoisomers with yield 61 mg (69%).1H NMR (CDCl3) δ 1,14 and 1.56 (d, total 3H, J=6.9 Hz), 1,370 and 1,483 (s, total 9H), of 1.88 (m, 1H), 1.93 and (m, 1H), 2,03 (m, 1H), a 2.36 (m, 1H), 2,75-of 2.86 (m, 2H), 3,74 (m, 3H), 3,91 (m, 2H), 4,05 and to 4.41 (m, total 1H), of 4.66 (m, 1H), 5,34 (m, 1H), 7,13 (m, 5H), 729-7,44 (m, 4H), 7,68 (user. s, 1H (NH)), and scored 8.38 8,56 (m, total 1H), 8,59 and 8.76 (d, total 1H, J=4,9 Hz).

(1H-Benzimidazole-2-ylmethyl)-{2-(R)-[2-(N-tert-butoxycarbonyl)aminopropionitrile]benzyl}-(5,6,7,8-tetrahydroquinolin-8-yl)amine (61 mg 0,107 mmol) were placed in acetic acid (1 ml)to which was added a saturated solution of HBr in acetic acid (1 ml). The mixture was then stirred, besieged and isolated according to method D, receiving AMD11133 in the form of a white crystalline solid with a yield of 64 mg1H NMR (D2O) δ 1,43 and of 1.46 (d, total 3H, J=6.9 Hz), a 1.88 (m, 1H), 2,28 (m, 2H), 2,46 (m, 1H), 3,00 (m, 2H), 3,81 (d, 1H, J=12,8 Hz), a 4.03 (m, 2H), 4,21 (d, 1H, J=128 Hz), 4,43-of 4.77 (m, 4H), of 6.68 (m, 2H), 6,91 (m, 1H), 7,25 (t, 1H, J=6,1 Hz), 7,51 (m, 4H), 7,88 (m, 1H), 8,28 (m, 1H), 8,68 (d, 1H, J=4,8 Hz);13C NMR (D2O) 17,01, 20,43 and 20,67 (1C only), 27,89, 40,78, 48,93 and 49,22 (1C only), 49,43, 53,87 and 54,46 (1C only), 62,01 and 62,15 (1C only), 113,92 and 113,97 (2C), 126,08, 126,74 (2C), 128,03, 129,13, 131,45, 131,55, 133,92, 136,00, 139,91, 140,78, 148,19 and 148,27 (1C only), 150,25 and 150,43 (1C only), 170,69 and 170,91 (1C only). ES-MS m/z 469 (M+H). Elemental analysis. Calculated for (C28H32N6About·3,1HBr·1,1H2O·1,0HOAc): C, for 45.04; H, to 5.21; N, 10,53; Br 31,04. Found: C, For 45.04; H, 5,19; N, 10,53; Br, 31,04.

Example: 48

AMD9872: Receive (1H-benzimidazole-2-ylmethyl)-[2-(1H-benzimidazole-2-ylmethyl)aminobenzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

Receiving (5,6,7,8-tetrahydroquinolin-8-yl)-(2-aminobenzyl)Amin

Using General method B to a solution of 2-aminobenzoylamino (0.36 g, 2.9 mmol) and 6,7-dihydro-5H-quinoline-8-it (0,43 g, 2.9 mmol) in CH2Cl2(15 ml) was added NaBH(SLA)3(0,92 g, 4.4 mmol) and the mixture was stirred at room temperature for 64 hours. Purification of the crude substances column chromatography on silica gel (2% MeOH/CH2Cl2) gave (5,6,7,8-tetrahydroquinolin-8-yl)-(2-aminobenzyl)amine (0.39 g, 52%) as a yellow oil.1H NMR (CDCl3) δ of 1.80 (m, 1H), was 1.94 (m, 2H), 2,17 (m, 1H), and 2.79 (m, 2H), 3,84 (m, 1H), a 3.87 (d, 1H, J=11.7 Hz), was 4.02 (d, 1H, J=12.0 Hz), only 6.64 (d, 1H, J=7.8 Hz), to 6.67 (t, 1H, J=7.8 Hz), to 7.09 (m, 3H), 7,38 (d, 1H, J=3.0 Hz), scored 8.38 (d, 1H, J=3,9 Hz).

Use the General methodology of N-alkylation, a solution of (5,6,7,8-tetrahydroquinolin-8-yl)-(2-aminobenzyl)amine (0.16 g, 0.6 mmol), N,N-diisopropylethylamine (of 0.32 ml, 1.8 mmol) and potassium iodide (10 mg, 40 mmol) in CH3CN (6 ml) was subjected to interaction with 1-(N-tert-butoxycarbonyl)-2-chloromethylthiazole (0.32 g, 1.2 mmol) at 70°C for 16 hours, after receiving the purification column chromatography on silica gel (CH2Cl2/MeOH, 250:1) N-alkilirovanny product (0.16 g, 37%) as a pale yellow solid.1H NMR (CDCl3) δ and 1.56 (s, 9H), 1.70 to (s, 10H), of 1.95 (m, 2H), 2,48 (m, 1H), 2,65 (m, 2H), 4,23 (d, 1H, J=3.0 Hz), 4,27 (d, 1H, J=8.1 Hz), the 4.29 (m, 1H), 4,48 (d, 1H, J=3.0 Hz), a 4.53 (d, 1H, J=8,4 Hz), is 4.93 (m, 2H,), 6,55 (m, 2H), 6,98 (m, 2H), 7,10 (d, 1H, J=7.8 Hz), 7,20-to 7.32 (m, 4H), 7,55 (m, 1H), 7,68 (m, 1H), 7,82 (m, 2H), of 7.90 (m, 1H), 8,44 (d, 1H, J=3.2 Hz).

The solution obtained above substances (0.17 g, 0.24 mmol) in a mixture of CH2Cl2/TFOC (1:1, 2 ml) was stirred for 0.5 hour and the solution was concentrated under reduced pressure. The reaction mixture was distributed between 15% aqueous NaOH (5 ml) and CH2Cl2(5 ml), the phases were separated and the organic extract was dried (MgSO4), filtered, concentrated and purified by radial chromatography on silica gel (Meon/NH4OH/CH2Cl2; 1:1:98), receiving AMD9872 (48 mg, 40%) as a pale yellow solid.1H NMR (CDCl3) δ 1,71 (user., 1H), 2,09 (m, 2H), 2,29 (user., 1H), 2,73 (m, 1H), 2,85 (m, 1H), 3,81 (d, 1H, J=12.9 Hz), 3,90 (d, 1H, J=12,6 Hz)4,06 (d, 2H, J=6.9 Hz), 4.09 to (m, 1H), 4,7 (s, 2H), 6,50 (d, 1H, J=8.1 Hz), 6,62 (t, 1H, J=7,4 Hz)6,94 (user., 1H),? 7.04 baby mortality (t, 1H, J=7.8 Hz), 7,05-7,25 (user. m, 6H), the 7.43 (d, 1H, J=7.8 Hz), 7,66 (user., 3H), to 8.41 (d, 1H, J=3,9 Hz);13C NMR (CDCl3) δ 21,45, 21,80, 29,23, 42,32, 48,18, 54,10, 59,88, 110,27 (2C), 117,06 (2C), 121,71, 122,25 (5C), 122,48 (2C), 129,23 (2C), 130,91 (2C), 135,18, 137,70 (2C), 146,91 (2C), 147,16, 154,00, 154,19, 157,03. ES-MS m/z 514 (M+H). Elemental analysis. Calculated for C32H31N7·1,SN2Cl2·0,3C6H14: C, 66,57; H, 5,98; N, 15,60. Found: C, 66,61; H, 5,78; N, 15,51.

Example: 49

AMD9883: Receive (2-aminobenzyl)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

Using General method, N-alkylation, the solution of (5,6,7,8-tetrahydroquinolin-8-yl)-(2-aminobenzyl)amine (0.20 g, 0.8 mmol), N,N-diisopropylethylamine (of 0.14 ml, 0.8 mmol) and potassium iodide (5 mg, 30 mmol) in CH3CN (8 ml) was subjected to interaction with 1-(N-tert-butoxycarbonyl)-2-chloromethylthiazole (0,145 g, 0.55 mmol) at 70°C for 16 hours, getting after purification by radial chromatography on silica gel (MeOH/NH4OH/CH2Cl2; 1:1:98) mono N-alkilirovanny product (65 mg, 25%) as a pale yellow solid.1H NMR (CDCl3) δ to 1.61 (s, 10H), was 1.94 (m, 2H), 2,03 (user., 1H), to 2.67 (m, 2H), 3,98 (d, 1H, J=12.3 Hz), 4,22 (m, 1H), 4,30 (d, 2H, J=9.9 Hz), 4,37 (d, 1H, J=11,1 Hz), 5,44 (user., 2H), 6,53 (m, 2H), 6.90 to (m, 1H), 6,97 (t, 1H, J=6,7 Hz), 7,06 (d, 1H, J=7.5 Hz), 7,17 (d, 1H, J=7.5 Hz), 7,25 (d, 2H, J=7,2 Hz), to 7.61 (m, 1H), 7,81 (m, 1H, J=3.6 Hz), 8,40 (d, 1H, J=45 Hz).

The solution obtained above substances (65 mg, 0.13 mmol) in a mixture of CH2Cl2/TFOC (1:1, 1 ml) was stirred for 0.5 hour and the solution was concentrated under reduced pressure. The reaction mixture was distributed between 15% aqueous NaOH (3 ml) and CH2Cl2(5 ml), the phases were separated and the organic extract was dried (MgSO4), filtered, concentrated and purified by radial chromatography on silica gel (Meon/NH4OH/CH2Cl2; 1:1:150), receiving AMD9883 (33 mg, 64%) as a pale yellow solid.1H NMR (CDCl3) δ 1,71 (user., 1H), 2.05 is (m, 2H), 2,32 (user., 1H), 2,70 (m, 1H), 2,85 (m, 1H), 3,65 (d, 1H, J=12,6 Hz), 3,80 (d, 1H, J=12,6 Hz), of 4.05 (m, 1H), 4,08 (d, 2H, J=4,8 Hz), 6,63 (t, 1H, J=8.7 Hz), only 6.64 (t, 1H, J=6.6 Hz), 7,03 (t, 2H, J=7,2 Hz), 7,17 (m, 3H), 7,42 (d, 1H, J=7,2 Hz), 7,54 (user., 2H), 8,53 (d, 1H, J=4, 2 Hz).13C NMR (CDCl3) δ 21,64, 21,91, 29,55, 48,22, 53,20, 60,93, 111,08, 116,59, 118,09, 119,14, 122,05 (4C), 122,52, 122,83, 129,19, 131,83, 135,22, 137,98, 147,09, 147,17, 156,04, 157,47. ES-MS m/z 384 (M+H). Elemental analysis. Calculated for C24H25N5·0,6CH2Cl2: C 67,49; H, 6,04; N, 15,97. Found: C, 67,60; H, 6,21; N, 15,57.

Example:50

AMD9736: Receive (1H-benzimidazole-2-ylmethyl)-(2-cyanobenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

The intermediate [1-(tert-butoxycarbonyl)-(1H-benzimidazole-2-ylmethyl)]-(2-cyanobenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (see, AMD9720) (72 mg, 0,145 mmol) was heated with reverse holo is rinicom in 6N. HCl (5 ml) for 16 hours. The solvent was removed under reduced pressure and the resulting salt was dissolved in distilled water (0.8 ml) and ethanol (95%, 0.8 ml) and was treated with NaOH (0,148 g of 3.69 mmol). The mixture was heated at 90°C within 2 hours and was stirred at room temperature for 64 hours. A two-phase system was diluted with water (4 ml) and was extracted with ether (3 × 10 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure, obtaining a white powder. Purification of solids by radial chromatography (1 mm plate for TLC, 60:1:1 CH2Cl2/CH3OH/NH4OH) gave the target free base (48 mg, 84 %).

According to the General procedure D conversion result of the above substances (48 mg) in hydrobromide salt gave AMD9736 (45 mg, 64%).1H NMR (D2O) δ 1,85 for 2.01 (m, 1H), 2,17-2,52 (m, 3H), 2,98-3,14 (m, 2H), 3,95 (d, 1H, J=13,2 Hz), 4,15 (d, 1H, J=13,2 Hz), 4,46 (d, 1H, J=16,3 Hz), 4,63 (d, 1H, J=16.6 Hz), of 6.96 (t, 1H, J=7,7 Hz), 7,27 (t, 1H, J=7,7 Hz), 7,35 (t, 1H, J=8.1 Hz), 7,49-of 7.60 (m, 4H), 7,92 (DD, 1H, J=7,9, and 5.5 Hz), 8,40 (d, 1H, J=7.8 Hz), 8,71 (d, 1H, J=5.8 Hz);13C NMR (D2O) δ 18,14, 18,68, 25,56, 47,43, 53,07, 60,81, 109,76, 111,60 (2 carbon), 116,68, 123,81, 124,55 (2 carbon), 126,70, 128,29, 129,19, 131,29, 131,46, 137,66, 137,84, 138,58, 145,88, 147,73, 148,64. IR (CsI) ν 2224 (CN). ES-MS m/z 394 (M+H). Elemental analysis. Calculated for C25H23N5·2,0HBr·1,3H2O: C, 51,88; H, To 4.81; N, 12,10; Br, 27,61. Found: C, 51,86; H, a 4.86; N, 11,78; r, 27,78.

Example: 51

AMD11091: obtaining the ethyl ester of 2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-6-methoxybenzoic acid (hydrobromide salt).

To a solution of ethyl 6-methyl salicylate (1.27 g, 6,97 mmol) in THF (35 ml) was added monohydrate of lithium hydroxide (0,594 g of 14.2 mmol) followed by the addition of dimethylsulfate (1,00 ml, 10.6 mmol). The resulting mixture was boiled under reflux for 1 hour, then cooled to room temperature. The mixture was diluted with diethyl ether (70 ml), washed with saturated aqueous NaHCO3(4 × 10 ml), dried (MgSO4) and concentrated. Purification of the crude substances column chromatography on silica gel (9:1 hexane-EtOAc) gave 1.23 g (91%) of ethyl 2-methoxy-6-methylbenzoate in the form of a white solid.1H NMR (CDCl3) δ to 1.38 (t, 3H, J=7.2 Hz), is 2.30 (s, 3H), 3,82 (s, 3H), and 4.40 (q, 2H, J=7,2 Hz), 6,76 (d, 1H, J=8,4 Hz), 6,79 (d, 1H, J=7.8 Hz), 7.23 percent (DD, 1H, J=7,8, 8,4 Hz).

To a solution of ethyl 2-methoxy-6-methylbenzoate (0,813 g, 4,19 mmol) in CCl4(8 ml) was added recrystallized N-bromosuccinimide (0,751 g, 4,22 mmol) followed by the addition of benzoyl peroxide (52 mg, 0.22 mmol). The resulting mixture was boiled under reflux for 90 minutes, then cooled to room temperature. The mixture was diluted with diethyl ether (50 ml), filtered through a boom is iny filter and the filtrate was concentrated. Purification of the crude substances column chromatography (8:1 hexane-EtOAc) gave 0.68 g (60%) of ethyl 6-(methyl bromide)-2-methoxybenzoate in the form of a colorless oil.1H NMR (CDCl3) δ of 1.42 (t, 3H, J=7.2 Hz), of 3.84 (s, 3H), of 4.45 (q, 2H, J=7,2 Hz), 4,50 (s, 2H), 6.89 in (d, 1H, J=8,4 Hz), 7,01 (d, 1H, J=7,2 Hz), 7,34 (DD, 1H, J=7,2, 8,4 Hz).

To a solution of (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,409 g at 1.08 mmol) in CH3CN (5 ml) was added N,N-diisopropylethylamine (0,38 ml of 2.18 mmol), then a solution of ethyl 6-(methyl bromide)-2-methoxybenzoate (0,454 g of 1.66 mmol) in CH3CN (6 ml). The resulting mixture was heated at 60°C for 22 hours, then cooled to room temperature. The mixture was concentrated and the residue was distributed between CH2Cl2(50 ml) and saturated salt solution (10 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2(3×10 ml). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude substances column chromatography on silica gel (25:1 CH2Cl2-CH3IT) with subsequent chromatographic purification column chromatography on silica gel (2:1 hexane-EtOAc) and radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2-CH3HE-NH4HE gave 0,38 g (62%) of a white solid.

Using General method D, not Amenia obtained above solid (55 mg, 0.10 mmol) in hydrobromide salt with simultaneous removal of the BOC-protective group, followed by presidenial intermediate solid from methanol/ether gave AMD11091 (35 mg, 51%) as a Golden solid.1H NMR (D2O) δ of 1.23 (t, 3H, J=7.2 Hz), 1,82-1,90 (m, 1H), 2,17-of 2.28 (m, 2H), 2,34-to 2.40 (m, 1H), 3.00 and (OSiR. s, 2H), 3.45 points (s, 3H), of 3.69 (d, 1H, J=12,6 Hz), 3,82 (d, 1H, J=12,6 Hz), 4,25-4,37 (m, 2H), and 4.40 (d, 1H, J=15,9 Hz)to 4.52 (d, 1H, J=15,9 Hz), and 4.68 (DD, 1H, J=6,0, and 9.3 Hz), is 6.54 (d, 1H, J=8,4 Hz), of 6.99 (d, 1H, J=7.5 Hz), to 7.15 (DD, 1H, J=7,5, and 8.4 Hz), 7,50-7,53 (m, 2H), to 7.59 to 7.62 (m, 2H), of 7.90 (DD, 1H, J=6,3, 7.5 Hz), at 8.36 (d, 1H, J=7.8 Hz), 8,77 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 13,77, 20,42, 20,79, 27,77, 49,29, 53,67, 56,45, 62,55, 63,59, 112,11, 113,95, 123,03, 123,84, 126,07, 126,74, 130,62, 131,76, 134,36, 139,77, 140,89, 148,12, 150,49, 150,81, 156,10, 169,70. ES-MS m/z 471 (M+H). Elemental analysis. Calculated for C28H30N4O3·2,NVG·1,7N2About: With, 49,52; H, 5,28; N, 8,25; Br, 25,88. Found: C, 49,89; H, 5,33; N, 8,19; Br, 25,53.

Example: 52

AMD9837: Receive (6-aminopyridine-3-ylmethyl)-(benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Getting 6-(N-tert-butoxycarbonylamino)-3-hydroxymethylpropane.

A solution of 6-aminonicotinic acid (2.0 g, 14.4 mmol) in anhydrous EtOH (70 ml) and concentrated sulfuric acid (14 ml) was boiled under reflux for 16 hours. The solution was concentrated under reduced pressure, neutralized nassen the m aqueous Na 2CO3(50 ml) and was extracted with CH2Cl2(3 × 50 ml). The combined organic phases were dried (MgSO4), filtered and concentrated, obtaining the ethyl ester of 6-aminonicotinic acid (2,18 g, 92%) as a white powder.1H NMR (CDCl3) δ to 1.37 (t, 3H, J=6.0 Hz), 4,34 (q, 2H, J=7.0 Hz), 4,89 (user. C, 2H (NH2), 6,46 (d, 1H, J=7.5 Hz), 8,02 (d, 1H, J=7.5 Hz), 8,73 (s, 1H).

To a solution of ethyl ester of 6-aminonicotinic acid (1.18 g, 7.1 mmol) in anhydrous THF (24 ml) solution was added sociallyengaged (0,41 g, 10.6 mmol) in THF (12 ml) at 0°C for 10 minutes and the mixture was stirred for 1.5 hours. To the reaction mixture were added successively 0.5 ml of H2O, 0.5 ml of 15%aqueous NaOH and 1.5 ml of H2O, and the resulting suspension was filtered. The filtrate was dried (MgSO4), filtered, concentrated and purified column chromatography (10% MeOH/CH2Cl2)to give 6-amino-3-hydroxymethyluracil (0,61 g, 69%) as colorless crystals.1H NMR (MeOD) δ and 3.31 (s, 1H (OH)), 4,43 (s, 2H), return of 6.58 (d, 1H, J=8,4 Hz), of 7.48 (d, 1H, J=8.7 Hz), the 7.85 (s, 1H).

To a solution of 6-amino-3-hydroxymethylbilane (0,30 g, 2.4 mmol) in anhydrous tert-butanol (12.4 g, 16 ml) was added di-tert-BUTYLCARBAMATE (of 0.58 g, 2.7 mmol) and the mixture was stirred 16 hours at 40°C. the Reaction mixture was concentrated under reduced pressure and the crude residue was purified column chromatography on silicagel the (7,5% MeOH/CH 2Cl2), getting listed in the title alcohol (0,42 g, 77%) as a white solid.1H NMR (CDCl3) δ and 1.54 (s, 9H), 1,74 (t, 1H (OH), J=6.0 Hz)and 4.65 (d, 2H, J=6.0 Hz), to 7.68 (d, 1H, J=9.0 Hz), 7,83 (user. s, 1H (NH)), 7,95 (d, 1H, J=9.0 Hz), 8,24 (s, 1H).

Using General method C, to a solution of 6-(N-tert-butoxycarbonylamino)-3-hydroxymethylbilane (0,42 g, 1.9 mmol) and triethylamine (and 0.40 ml, 2.8 mmol) in CH2Cl2(19 ml) was added methanesulfonamide (0,20 ml, 2.4 mmol) and the mixture was stirred at room temperature for 1 hour. Purification of the crude product column chromatography on silica gel (4% Meon/CH2Cl2) gave the target mesilate (0,23 g, 42%).1H NMR (CDCl3) δ and 1.54 (s, 9H), 3,37 (s, 3H), and 4.40 (s, 2H), 7,68 (d, 1H, J=9.0 Hz), 7,95 (d, 1H, J=9.0 Hz), 8,11 (users, 1H), of 8.25 (s, 1H).

Using General method, N-alkylation, the solution obtained above nelfinavir (0,22 g, 0.8 mmol), N,N-diisopropylethylamine (0,20 ml, 1.2 mmol) and potassium chloride (10 mg, 0.04 mmol) in CH3CN (8 ml) was subjected to interaction with (1-tert-butoxycarbonylamino-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,30 g, 0.8 mmol) at 70°C for 16 hours. Purification of the crude substances by radial chromatography on silica gel (MeOH/NH4OH/CH2Cl2; 1:1:98) gave N-alkilirovanny product (180 mg, 40%) as a flaky white solid.1H NMR (CDCl3) δ for 1.49 (s, 9H), 1.70 to (ush the D.C, 10H)to 1.96 (m, 2H), 2.13 in (m, 1H), 2,70 (m, 2H), 3,76 (d, 1H, J=15,0 Hz), a 4.03 (d, 1H, J=15,0 Hz), 4,25 (m, 1H), 4,58 (s, 2H), 7,00 (m, 1H), 7,20 (m, 2H), 7,30 (s, 1H), 7,66 (m, 4H), of 8.04 (s, 2H), 8,43 (DD, 1H, J=3.0 Hz).

Using General method D, the transformation obtained above solid (30 mg) in hydrobromide salt with simultaneous removal of the Boc group gave AMD9837 (0,034 g) as a white solid.1H NMR (D2O) 1,90 (osirm, 1H), measuring 2.20 (m, 2H), 2.40 a (osirm, 1H), 3,02 (osirm, 2H), 3,70 (d, 1H, J=13.5 Hz), 3,83 (d, 1H, J=13.5 Hz), 4,37 (d, 1H, J=15,9 Hz), 4,58 (d, 1H, J=16.2 Hz), and 4.75 (m, 1H), 6,62 (d, 1H, J=9.3 Hz), 7,53 (d, 1H, J=1.5 Hz), EUR 7.57 (DD, 2H, J=of 3.0, 6.0 Hz), to 7.68 (d, 1H, J=2.1 Hz), of 7.70 (m, 2H), 7,92 (DD, 1H, J=6,0, 7,8 Hz), 8,40 (d, 1H, J=7,2 Hz), the rate of 8.75 (d, 1H, J=4,8 Hz);13C NMR (D2O) δ 20,38, 20,92, 27,86, 49,32, 53,02, 62,53, 114,11 (4C), 121,78, 126,19, 127,24 (2C), 130,91, 134,41, 140,07 (2C), 141,11, 145,36, 148,33, 150,36, 151,72. ES-MS m/z 385 (M+H). Elemental analysis. Calculated for C23H24N6·2,9HBr·2,1H2O: C, 42,21; H, 4,78; N, 12,84; Br, 35,10. Found: C, 42,29; H, 4,71 ;N, 12,58; Br, 35,09.

Example: 53

AMD9840: Receive (2-aminopyridine-3-ylmethyl)-(benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydro-8-quinoline)amine (hydrobromide salt).

Getting 2-aminonicotinamide aldehyde

A solution of 2-aminonicotinic acid (2.0 g, 14.4 mmol) in anhydrous EtOH (70 ml) and concentrated sulfuric acid (14 ml) was boiled under reflux for 16 hours. The solution was concentrated under reduced pressure, neutralized by saturated in denim solution of NaHCO 3(50 ml) and was extracted with CH2Cl2(3 × 50 ml). The combined organic phases were dried (MgSO4), filtered and concentrated, obtaining the ethyl ester of 2-aminonicotinic acid as a yellow solid (1,74 g, 74%).1H NMR (CDCl3) δ of 1.40 (t, 3H, J=6.0 Hz), 4,34 (q, 2H, J=7.0 Hz), 6,41 (users, 2H (NH2)), 6,63 (m, 1H), 8,14 (d, 1H, J=7.8 Hz), by 8.22 (s, 1H).

To a solution of ethyl ester of 2-aminonicotinic acid (1,74 g, 10.5 mmol) in anhydrous THF (35 ml) solution was added sociallyengaged (0,60 g, 15.7 mmol) in THF (17 ml) at 0°C for 15 minutes and the mixture was stirred for 1.5 hours. To the reaction mixture were added successively 0.6 ml H2O, 0.6 ml 15%aqueous NaOH and 1.8 ml of H2O and filtered the resulting suspension. The filtrate was dried (MgSO4), filtered, concentrated and purified column chromatography (10% Meon/CH2Cl2)to give 2-amino-3-hydroxymethyluracil (1,03 g, 79%) as a yellow crystalline solid.1H NMR (CDCl3) δ 3,14 (users, 1H (OH)), 4,60 (s, 2H), 5,00 (users, 1H (NH)), 6,59 (t, 1H, J=6.0 Hz), 7,28 (d, 1H, J=7.5 Hz), 7,94 (d, 1H, J=7.5 Hz).

The above alcohol (0.10 g, 0.8 mmol) was dissolved in CH2Cl2(8 ml), treated with activated MnO2(0,70 g, 8 mmol) and was stirred at room temperature for 1.5 hours. The mixture was filtered through celite and the filter cake was washed CH2l 2. The solvent was removed from the filtrate under reduced pressure and obtained 2-aminonicotinic aldehyde (0.10 g, 99%) as a pale yellow crystalline solid.1H NMR (CDCl3) δ to 6.75 (t, 1H, J=6.0 Hz), 7,81 (d, 1H, J=7.5 Hz), of 8.27 (d, 1H, J=4.5 Hz), 9,86 (s, 1H, (CHO)).

Using General method B to a solution of 2-aminonicotinamide aldehyde (47 mg, 0.4 mmol) and (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (132 mg, 0.35 mmol) in CH2Cl2(4 ml) was added triacetoxyborohydride sodium (126 mg, 0.59 mmol) and the mixture was stirred at room temperature for 16 hours. Purification of the crude product column chromatography on silica gel (2% MeOH/CH2Cl2) gave the target N-acylated product (68 mg, 40%) as a white solid.1H NMR (CDCl3) δ was 1.58 (s, 9H), of 1.62 (m, 1H), 1.91 a (m, 2H), 2,17 (m, 1H), 2,64 (m, 2H), 3,93 (d, 1H, J=12.0 Hz), to 4.15 (m, 1H), 4.26 deaths (d, 2H, J=3.0 Hz), to 4.38 (d, 1H, J=12.0 Hz), 6,40 (t, 1H, J=4.5 Hz), 6,47 (user. s, 2H), 6,97 (m, 1H), 7,27 (m, 4H), to 7.61 (m, 1H), to 7.84 (m, 2H), 8,40 (d, 1H, J=3.0 Hz).

Using General method D, the transformation obtained above substances (25 mg) in hydrobromide salt with simultaneous removal of the Boc group gave AMD9840 (0.025 g) as a white solid.1H NMR (D2O) δ 1,87 (user. m, 1H), 2,18 (m, 2H), 2,46 (user. m, 1H), 2,98 (user. m, 2H), 3,95 (d, 1H, J=14.1 Hz), 4,07 (d, 1H, J=14.1 Hz), 4,33 (d, 1H, J=16.2 Hz), 4,49 (d, 1H, J=15,9 Hz), 4,74 (m, 1H), only 6.64 (t, 1H, J=6,9 G is), 725 (DD, 1H, J=1,5, and 6.3 Hz), 7,55 (m, 2H), 7,66 (m, 2H), 7,83 (t, 1H, J=6.9 Hz), to 7.93 (DD, 1H, J=1,5, with 7.4 Hz), of 8.28 (d, 1H, J=7,2 Hz), to 8.70 (d, 1H, J=5,1 Hz);13C NMR (D2O) δ 20,45, 20,68, 27,95, 48,36, 52,51, 62,20, 113,24, 114,03 (2C), 120,49, 120,73, 126,09, 127,17 (2C), 130,89, 135,44, 140,70, 140,81, 146,12 (2C), 147,61, 150,32, 150,71. ES-MS m/z 385 (M+H). Elemental analysis. Calculated for C23H24N6·3,NVG·2,2H2About: With, 41,49; H, 4,74; N, Br12.62; Br, 35,95. Found: C, 41,56; H, Br4.61; N, 12,38; Br, 35,94.

Example: 54

AMD9681: Obtaining N-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)guanidine (hydrobromide salt).

To a solution of 4-aminobenzamide alcohol (to 0.127 g of 1.03 mmol) in anhydrous THF (1 ml) was added N,N'-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (Tetrahedron Lett. 1993, 34, 3389) and the resulting mixture was stirred at room temperature for 26 hours. The mixture was diluted with hexane (1 ml) and filtered through a short column with silica gel (100% hexane, then a mixture of 1:1 hexane/ethyl acetate). The appropriate fractions were concentrated, obtaining N,N'-bis-(tert-butoxycarbonyl)-N-(4-hydroxymethylene)guanidine (0,309 g, 85%) as a white solid.

The above alcohol (0,282 g, 0,771 mmol) was dissolved in CH2Cl2(7 ml), treated with activated MnO2(0,696 g, 8,01 mmol) and stirred at room temperature overnight. The mixture was filtered through celite and the precipitate on the filter p is washed CH 2Cl2. The solvent was removed from the filtrate under reduced pressure and obtained N,N'-bis-(tert-butoxycarbonyl)-N'-(4-formylphenyl)guanidine (is 0.260 g, 93%) as a white solid.1H NMR (CDCl3) δ of 1.53 (s, 9H), of 1.55 (s, 9H), a 7.85 (s, 4H), to 9.93 (s, 1H), 10,34 (users, 1H).

Using General method B, the interaction of N,N'-bis-(tert-butoxycarbonyl)-N'-(4-formylphenyl)guanidine (0.167 g, 0.49 mmol) and (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,151 g, 0.42 mmol) with NaBH(OAc)3(0,184 g, 0.87 mmol) in CH2Cl2(4 ml) for 4.5 hours followed by purification of the crude substances by radial chromatography on silica gel (2 mm plate, 20:1:1 CH2Cl2/CH3OH/NH4OH) gave the target tertiary amine (0,101 g, 33%) as a white solid.

Using General method D, the transformation of white solid (101 mg) in hydrobromide salt with simultaneous removal of the BOC-protective group, followed by presidenial intermediate solid from methanol/ether gave AMD9681 (66 mg) as a white solid.1H NMR (D2O) δ 1,81-of 1.92 (m, 1H), 2,19-of 2.30 (m, 2H), 2,41 is 2.46 (m, 1H), 3,01 (users, 2H), 3,78 (d, 1H, J=12.9 Hz), 3,84 (d, 1H, J=12.9 Hz), 4,43 (d, 1H, J=16.5 Hz), to 4.62 (d, 1H, J=16.5 Hz), 4,72-rate 4.79 (m, 1H, overlap with HOD), at 6.84 (d, 2H, J=8.1 Hz), 7,21 (d, 2H, J=8.1 Hz), 7,49-7,53 (m, 2H), 7,56-of 7.60 (m, 2H), to $ 7.91 (DD, 1H, J=6,0, 7,8 Hz), scored 8.38 (d, 1H, J=7.8 Hz), 8,73 (d, 1H, J=5.7 Hz); C NMR (D2O) δ 20,43, 20,86, 27,83, 50,03, 56,40, 62,98, 113,84, 124,65, 126,08, 126,76, 130,47, 131,50, 134,21, 135,70, 139,65, 141,00, 148,26, 148,28, 150,83, 151,77; ES-MS m/z 426 (M+H). Elemental analysis. Calculated for C25H27N·3,0HBr·3,4H2O: C, 41,16; H, To 5.08; N, 13,44; Br, 32,86. Found: C, 41,12; H, A 4.86; N, 13,32; Br, 32,81.

Example: 55

AMD9730: Receive (4-aminobenzyl)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Obtain tert-butyl ester (4-formylphenyl)carbamino acid

A solution of 4-aminobenzamide alcohol (607 mg, is 4.93 mmol) and di-tert-BUTYLCARBAMATE (1.3 g, 6.0 mmol) in THF (16 ml) was stirred at room temperature for 24 hours, then concentrated. Purification of the crude substances on silica gel (30% EtOAc/hexane) gave a colorless oil (906 mg, 82%).1H NMR (CDCl3) δ of 1.52 (s, 9H), 4,63 (d, 2H, J=5.7 Hz), 6.48 in (users, 1H), 7,32 (m, 4H).

To a solution of the alcohol obtained above (200 mg, 0,896 mmol) in CH2Cl2(9 ml) was added activated MnO2(916 mg, 8,96 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite and the filter cake was washed CH2Cl2. The solvent was removed from the filtrate under reduced pressure, obtaining mentioned in the title compound as colorless crystals (170 mg, 86%).1H the Mr (CDCl 3) δ and 1.54 (s, 9H), 6.73 x (users, 1H), 7,54 (d, 2H, J=9 Hz), 7,83 (d, 2H, J=9 Hz), for 9.90 (s, 1H).

Using General method B to a solution of [1-(tert-butoxycarbonyl)-(1H-benzimidazole-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (83 mg, 0.22 mmol) and tert-butyl methyl ether (4-formylphenyl)carbamino acid (66 mg, 0.30 mmol) in THF (3 ml) was added acetic acid (0,017 ml, 0.30 mmol) and NaBH(OAc)3(190 mg, 0,896 mmol) and the mixture was stirred at room temperature for 4 hours. Purification of the crude yellow oil by chromatography on silica gel (300:5:1 CH2Cl2/MeOH/NH4OH) gave a colorless foam (128 mg).

The solution obtained above foam in a mixture of 1:1 triperoxonane acid/CH2Cl2(4 ml) was stirred at room temperature for 45 minutes then concentrated. The residue was distributed between CH2Cl2(10 ml) and saturated aqueous NaHCO3(10 ml) and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. Purification of the crude substances by chromatography on silica gel (600:5:1 EtOAc/Meon/NH4OH) gave a colorless foam (49 mg, 53%).

Using General method D, the transformation obtained above colorless foam (49 mg, 0.13 mmol) in hydrobromide salt gave AMD9730 (56 mg, 67%) as a yellow solid.1H NMR (D2O) δ of 1.88(m, 1H), and 2.26 (m, 2H), 2,44 (m, 1H), to 3.02 (m, 2H), 3,83 (d, 1H, J=13 Hz), with 3.89 (d, 1H, J=13 Hz), 4,46 (d, 1H, J=16 Hz), with 4.64 (d, 1H, J=16 Hz), 4,79 (m, 1H), 6,95 (d, 2H, J=8.1 Hz), 7,29 (d, 2H, J=8.4 and Hz), 7,51-7,63 (m, 4H), to $ 7.91 (m, 1H), scored 8.38 (d, 1H, J=7.8 Hz), a total of 8.74 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,45, 20,86, 27,85, 50,06, 56,31, 62,82, 113,94, 122,85, 126,12, 126,85, 130,03, 130,50, 131,58, 137,51, 139,70, 140,98, 148,28, 150,75, 151,51. ES-MS m/z 384 (M+H). Elemental analysis. Calculated for C24H25N5·3,0HBr·1,6H20: C, 44,01; H, 4,80; N, 10,69; Br, 36,59. Found: C, 43,84; H, A 4.86; N, The 10.40; Br, Eur36, 85.

Example: 56

AMD9774: Obtaining N'-({[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)-N,N-dimethylformamidine.

Receiving O-methanesulfonyl-4-(tert-butoxycarbonyl)aminobenzamide alcohol

Using General method C, to a solution of 4-(tert-butoxycarbonyl)aminobenzamide alcohol (446 mg, 2 mmol) in CH2Cl2(10 ml) was added methanesulfonamide (0,23 ml, 3 mmol) and triethylamine (of 0.56 ml, 4 mmol). The solution was stirred for 60 minutes at room temperature. Purification of the crude product by chromatography on silica gel (2% MeOH/CH2Cl2) gave specified in the title compound (320 mg, 56%) as oil.1H NMR (CDCl3) δ 3,14 (s, 3H), 4,39 (s, 2H), 6,53 (users, 1H (NH)), 7,31 (m, 4H).

Using General method, N-alkylation, to the solution obtained above nelfinavir (213 mg, 0.75 mmol) and N,N-diisopropylethylamine (0,178 ml, 1.0 mmol) in CH3 CN (10 ml) was added 1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (210 mg, 0.55 mmol) and the mixture was stirred at 60°C for 4 hours. Purification of the crude product by chromatography on silica gel (20:1 CH2Cl2/MeOH) to give (1H-N-tert-butoxycarbonylamino-2-ylmethyl)-[4-(tert-butoxycarbonylamino)benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (126 mg, 39%).1H NMR (CDCl3) δ of 1.41 (s, 9H), by 1.68 (s, 9H), 2,03 (m, 3H), of 2.20 (m, 1H), 2,75 (m, 2H), 3,83 (m, 1H), 3,99 (m, 1H), 4,30 (DD, 1H, J=8,4, 6.5 Hz), br4.61 (m, 2H), 6,26 (users, 1H (NH)),? 7.04 baby mortality (m, 2H), 7,26 (m, 5H), 7,31 (m, 2H), 7,63 (m, 2H), 8,44 (m, 1H).

To a solution of (1H-N-tert-butoxycarbonylamino-2-ylmethyl)-[4-(tert-butoxycarbonylamino)benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (62 mg, 0,106 mmol) in CH2Cl2(2 ml) was added triperoxonane acid (1 ml). The mixture was stirred at room temperature for 2 hours, then concentrated. The residue was placed in CH2Cl2off , washed with 15%NaOH (3 ml) and was extracted several times CH2Cl2,The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated. Untreated (1H-benzimidazole-2-ylmethyl)-[4-aminobenzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amine was then added to a solution of 2-pyridinesulfonamide (27 mg, 0.15 mmol) in DMF (1 ml). The resulting solution was stirred at room temperature during the course the e 30 minutes. The mixture was then concentrated, was placed in CH2Cl2and washed with aqueous potassium carbonate. The organic fraction was then dried over anhydrous sodium sulfate, filtered, concentrated and purified by chromatography on silica gel (10:1:0.1 to CH2Cl2:MeOH:NH4OH)to give N'-({[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)-N,N-dimethylformamide (21 mg, 47%).1H NMR (CDCl3) δ was 1.69 (m, 1H), 2,01 (m, 3H), of 2.25 (m, 1H), 2,73 (m, 2H), 2,93 (s, 3H), of 3.60 (s, 3H), 3,62 (d, 1H, J=13,2 Hz), 3,68 (d, 1H, J=13,2 Hz), 3,98 (d, 1H, J=16.2 Hz), 4,01 (m, 1H), 4,12 (d, 1H, J=16.2 Hz), to 6.80 (d, 2H, J=8.1 Hz), 7,16 (m, 4H), 7,26 (d, 1H, J=8.1 Hz), 7,38 (m, 2H), 7,40 (user. s, 1H), 8,55 (d, 1H, J=4,8 Hz).

Using General method D, the conversion of N'-({[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)-N,N-dimethylformamidine (21 mg, 0,047 mmol) in hydrobromide salt gave AMD9774 (14 mg) as a white solid.1H NMR (D2O) δ at 1.91 (m, 1H), to 2.29 (m, 2H), 2,43 (m, 1H), 3,05 (m, 2H), 3,13 (s, 3H), 3,37 (s, 3H), 3,79 (d, 1H, J=12.3 Hz), 3,86 (d, 1H, J=12.3 Hz), of 4.44 (d, 1H, J=16.5 Hz), 4,63 (d, 1H, J=16.5 Hz), 4,82 (m, 1H), PC 6.82 (d, 2H, J=8.1 Hz), 7,22 (d, 2H, J=8.1 Hz), 7,50-7,63 (m, 4H), 7,95 (DD, 1H, J=7,8, 5.7 Hz), to 8.41 (d, 1H, J=7.8 Hz), 8,78 (d, 1H, J=5.7 Hz).13C NMR (D2O) δ 20,45, 21,01, 27,86, 37,17, 44,08, 50,20, 54,46, 63,43, 114,05, 119,10, 126,14, 126,49, 130,54, 131,70, 134,46, 136,98, 139,73, 142,33, 148,32, 152,16, 152,94. ES-MS m/z 439 (M+H). Elemental analysis. Calculated for (C27H30N6·3,2HBr·0,6H2O·0,6HOAc): C, 45,51; H, to 4.98; N, 11,29; Br 3435. Found: C, 45,28; H, 5,13; N, 11,14; Br, 34,32.

Example: 57

AMD9685: Getting oxime 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde.

To a stirred solution of N'-(1H-benzimidazole-2-ylmethyl)-N'-(5,6,7,8-tetrahydro-8-chinoline)-l,4-benzilpenetsillina (200 mg, 0.50 mmol) in MeOH (5 ml) was added solid dihydrate sodium tungstate (332 mg, 1.0 mmol) followed by addition of 35 wt.% aqueous hydrogen peroxide solution (2.9 ml, 30 mmol). The resulting suspension was stirred for 3 hours, then was added a saturated aqueous sodium bicarbonate (5 ml). The phases were separated and the aqueous layer was extracted with CH2Cl2(3×10 ml)then the combined organic extracts were washed once with saturated salt solution (10 ml), dried (MgSO4) and concentrated in vacuum. Purification of the crude substance flash chromatography (silica gel, 75:1:1 CH2Cl2/MeOH/NH4OH) gave specified in the title compound (130 mg, 63%) as a white solid.1H NMR (CDCl3) δ 1,63-of 1.66 (m, 1H), 1,97-2,07 (m, 2H), 2,25-of 2.27 (m, 1H), 2,66-of 2.72 (m, 1H), 2,80-to 2.85 (m, 1H), 3,65 (d, 1H, J=14 Hz), 3,71 (d, 1H, J=14 Hz), to 5.03 (d, 1H, J=16 Hz), 4,14 (DD, 1H, J=9, 7 Hz), is 4.21 (d, 1H, J=16 Hz), 7,11-7,19 (m, 3H), 7,41-of 7.48 (m, 6H), 7,65 (user. 4 1H, J=5 Hz), 8,18 (s, 1H), 8,67 (DD, 1H, J=5,1 Hz);13C NMR (CDCl3) δ 22,2, 23,9, 30,2, 49,5, 55,0, 61,2, 112,1, 119,4, 122,7, 123,3, 127,8, 130,1, 133,0, 136,2, 138,7, 141,4, 147,8, 150,0, 156,2, 157,7. ES-MS m/z 412 (M+H). elementry analysis. Calculated for C25H25N5O·0,4H2O·0,SN2Cl2: C, 68,41; H, OF 5.99; N, 15,77. Found: C, 68,57; H, 5,86; N,15,48.

Example 58

AMD9773: Obtain [4-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)aminomethyl]benzamidine (hydrobromide salt).

Using General method B to a solution of 4-cyanobenzaldehyde (0.15 g, 1.1 mmol) and (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,38 g, 1.0 mmol) in CH2Cl2(10 ml) was added NaBH(OAc)3(0.36 g, 1.7 mmol) and the mixture was stirred at room temperature for 6 hours. Purification of the crude substances column chromatography on silica gel (2% MeOH/CH2Cl2) gave N-alkilirovanny product (0.26 g, 72%) as a white solid.1H NMR (CDCl3) δ 1,74 (s, 10H), of 1.95 (m, 1H), 2,02 (m, 1H), 2,30 (m, 1H), 2,75 (m, 2H), 3,80 (d, 1H, J=15,0 Hz), of 3.97 (d, 1H, J=15,0 Hz), or 4.31 (m, 1H)and 4.65 (d, 1H, J=12.0 Hz), and 4.75 (d, 1H, J=12.0 Hz),? 7.04 baby mortality (m, 1H), 7,16 (d, 1H, J=7,2 Hz), 7,22-7,30 (m, 5H), 7,51 (m, 1H), to 7.61 (m, 1H), 8,45 (d, 1H, J=3.5 Hz).

In the solution obtained above substances (0.26 g, of 0.53 mmol) in anhydrous EtOH (3.5 ml) at 0°C barbotirovany gaseous HCl for 30 minutes and the mixture was stirred at room temperature for additional 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was washed with diethyl ether (3 × 20 ml)and dried in vacuum, receiving targeted HCl salt amoxiillin, which is directly used in the next reaction.1H NMR (D2O) δ and 1.54 (t, 3H, J=6.9 Hz), at 1.91 (m, 1H), 2,23 (m, 2H), 2,47 (m, 1H), 3.04 from (m, 2H), 3,88 (d, 1H, J=12.9 Hz), 3.96 points (d, 1H, J=13,2 Hz), of 4.44 (d, 1H, J=15.6 Hz), to 4.46 (q, 2H, J=6.9 Hz), 4,63 (d, 1H, J=16.5 Hz), 4,78 (m, 1H), 7,35 (d, 2H, J=8,4 Hz), 7,47-7,58 (m, 5H), 7,95 (t, 1H, J=6.2 Hz), to 8.41 (d, 1H, J=6.2 Hz), 8,82 (d, 1H, J=3.5 Hz).

To a solution of cleaners containing hydrochloride salt (N-tert-butoxycarbonylamino-2-ylmethyl)-(4-ethoxyaniline)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (obtained above) in anhydrous EtOH (3 ml) was added ammonium carbonate (0.24 g, 2.5 mmol) and the solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by chromatography through a layer of silica gel (Meon/NH4OH/CH2Cl2, 15:10:75), receiving targeted benzamide (0.10 g, 48% yield over 2 stages) in the form of a white powder.1H NMR (CDCl3) δ by 1.68 (m, 1H), 2,03 (m, 2H), and 2.27 (m, 1H), 2,78 (m, 2H), of 3.78 (s, 2H), 3,92 (d, 1H, J=15,0 Hz), 4.09 to (m, 1H), 4,20 (d, 1H, J=15,0 Hz), 5,68 (user., 1H), 6,12 (user., 1H), 7,18 (m, 3H), 7,46 (m, 3H), EUR 7.57 (m, 2H), 7,65 (d, 2H, J=7,2 Hz), 8,71 (d, 1H, J=3.5 Hz).

Using General method D, the transformation obtained above substance (100 mg) in hydrobromide salt gave AMD9773 (70 mg) as a white solid.1H NMR (D2O) δ 1,88 (user. m, 1H, in), 2.25 (m, 2H), 2,45 (user. m, 1H), 3,03 (user. m, 2H), 3,88 (d, 1H, J=12.9 Hz), 3,95 (d, 1H, J=12.9 Hz), of 4.45 (d, 1H, J=16.2 Hz), 4,63 (d, 1H, J=16.2 G is), rate 4.79 (m, 1H), was 7.36 (s, 4H), 7,47 (DD, 2H, J=3,0, 6.3 Hz), 7,58 (DD, 2H, J=3,0, 6.3 Hz), to 7.93 (t, 1H, J=6.9 Hz), 8,40 (d, 1H, J=8.1 Hz), 8,77 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,43, 21,00, 27,87, 50,12, 56,72, 63,21, 113,97 (2C), 126,17, 126,67, 126,87 (2C), 127,56 (2C), 130,61, 130,85 (2C), 139,85, 141,09, 143,36 (2C), 148,27, 150,71, 151,44, 165,18. ES-MS m/z 411 (M+H). Elemental analysis. Calculated for C25H26N6·2,9HBr·2,0H2O: C, 43,89; H, Is 4.85; N, To 12.28; Br, 34,34. Found: C, 43,97; H, The 4.90; N, 12,02; Br, 34,35.

Example: 59

AMD9717: Obtain 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl alcohol.

To a stirred solution of 8-amino-5,6,7,8-tetrahydroquinoline (5,56 g, 37.5 mmol) in anhydrous MeOH (150 ml) was added 4-hydroxymethylbenzene (7,22 g of 52.5 mmol) in an argon atmosphere and the mixture was stirred over night at room temperature. To the resulting solution was added sodium borohydride (2.85 g, 75 mmol) in three portions over 45 minutes and the reaction mixture was stirred for 24 hours, obtaining a pale yellow oil, which was used in the next stage without any further purification (see, General method B).

To the mixed solution obtained above oil (of 7.64 g) in anhydrous CH3CN (100 ml) was added N,N-diisopropylethylamine (10 ml, 57 mmol), potassium iodide (0.24 g, 1.4 mmol) and 1-N-tert-butoxycarbonyl-2-chloromethylbenzene (7.98 g, and 29.9 mmol) in solution in CH3CN (50 ml). With the ect was stirred in argon atmosphere at 60° C during the night. The reaction mixture was concentrated in vacuum, diluted with CH2Cl2(100 ml) and washed with saturated aqueous ammonium chloride (150 ml). The aqueous layer was extracted with CH2Cl2(2 × 50 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuum.

The solution obtained above crude substance in a mixture of CH2Cl2/triperoxonane acid (2:1, 30 ml) was stirred for 3 hours at room temperature. The reaction mixture was diluted with CH2Cl2(30 ml) and concentrated in vacuum. The residue was diluted with CH2Cl2(50 ml) and washed with 1N. NaOH (50 ml). The aqueous layer was extracted with CH2Cl2(2 × 30 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuum, obtaining a brown foam. A small portion (111 mg) of the crude substance was purified by radial chromatography (1 mm plate of silica gel for TLC (CH2Cl2/MeOH/NH4OH, 100:1:1), obtaining the free base AMD9717, (31,4 mg, 28%) as a white foam.1H NMR (CDCl3) δ 1,68-1,77 (user. m, 1H), 1,97-of 2.08 (m, 2H), 2,24-of 2.28 (m, 1H), 2,70-only 2.91 (m, 2H, in), 3.75 (s, 2H), 3,95 (d, 1H, J=16,8 Hz), 4.09 to (m, 1H), 4,17 (d, 1H, J=16,8 Hz), 4,59 (s, 2H), 7,14-7,24 (m, 6H), 7,38 was 7.45 (m, 3H), 7,49-7,51 (m, 1H), to 7.61-the 7.65 (m, 1H), to 8.70 (d, 1H, J=4,8 Hz);13C NMR (CDCl3) δ 20,24, 21,78, 28,17, 47,73, 52,85, 59,21, 63,41, 120,42, 121,11, 125,75, 127,78, 133,84, 136,27, 137,16 139,22, 145,76, 154,60, 156,10; ES-MS m/z 399 (M+H). Elemental analysis. Calculated for C25H26N4O·0,3CH2Cl2·0,25H2O: C, 70,92; H, 6,37; N, 13,08. Found: C, 71,25; H, 6,53; N, 12,68.

Example: 60

AMD9882: Obtain 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde.

To the mixed solution obtained above alcohol, 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl alcohol (AMD9717), (9,29 g) in anhydrous CH2Cl2(200 ml) was added to MnO2(20,3 g, 233 mmol) and the mixture was stirred for 4 hours at room temperature. Then added an additional portion of MnO2(8.5 g, 97.8 mmol) and the mixture was stirred over night at room temperature. The reaction mixture was filtered through a layer of celite, the filter cake washed with CHCl3and the obtained filtrate was concentrated in vacuum. Purification of the crude product column chromatography on silica gel (CH2Cl2/MeOH, 97:3 then 96:4) gave the aldehyde (5,08 g, 34%, 5 stages) as a pale yellow solid.1H NMR (CDCl3) δ 1,56-1,74 (user. m, 2H), 1,92-of 2.09 (m, 2H), 2,28 of-2.32 (m, 1H), 2,70-to 2.94 (m, 2H), 3,84 (s, 2H), 3,94 (d, 1H, J=16.5 Hz), 4,08-to 4.14 (m, 1H), 4,23 (d, 1H, J=16.5 Hz), 7.18 in-7,26 (m, 4H), 7,45 (d, 1H, J=7.8 Hz), 7,56 (m, 4H), 7,76 (d, 2H, J=8.1 Hz), 8,72 (d, 1H, J=4, 2 Hz), 9,92 (s, 1H);13C NMR (CDCl3) δ 21,29, 23,73, 29,11, 48,90, 53,90, 60,56, 121,5 (2 carbon), 122,53 (2 carbon), 129,04 (2 carbon), 129,86 (2 carbon), 134,89, 135,58, 137,57 (2 carbon), 146,69, 146,85, 155,58, 156,99, 191,85. ES-MS m/z 397 (M+H). Elemental analysis. Calculated for C25H34N4O·0,15CH2Cl2: C, 73,82; H, 5,98; N, 13,69. Found: C, 73,69; H, 6,16; N, 13,78.

Example: 61

AMD9711: obtain the methyl ester of 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid.

According to the General method B to a solution of (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (680 mg, 1.8 mmol) and methyl 4-formylbenzoate (295 mg, 1.8 mmol) in CH2Cl2(10 ml) was added NaBH(OAc)3(763 mg, 3.6 mmol) and the mixture was stirred for 18 hours. The crude substance was placed in undiluted TFOC (2 ml) and stirred 3 hours. Was carefully added to saturated aqueous sodium bicarbonate solution (10 ml), the mixture was extracted with CH2Cl2(3 × 20 ml), the combined organic extracts were dried (MgSO4) and concentrated in vacuum. Purification of the crude substance flash chromatography (silica gel, 50:2:1 CH2Cl2/MeOH/NH4OH) gave specified in the title compound (565 mg, 74%) as a white solid.1H NMR (CDCl3) δ 1,64 is 1.75 (m, 1H), 2,01-of 2.08 (m, 2H), 2.26 and-of 2.28 (m, 1H), 2,74 was 2.76 (m, 1H), 2,81-of 2.86 (m, 1H), 3,81 (s, 2H), 3,86 (s, 3H), of 3.94 (d, 1H, J=17 Hz), 4.09 to (DD, 1H, J=9, 7 Hz), 4.2V (d, 1H, J=17 Hz), 7.18 in-7,22 (m, 3H), 7,44 (userd, 1H, J=8 Hz), 7,49 (d, 2H, J=8 Hz), 7,50-7,53 (m, 1H), of 7.64-7,66 (m, 1H), to $ 7.91 (d, 2H, J=8 Hz), to 8.70 (DD, 1H, J=5,1 Hz);13C NMR (CDCl3) δ 21,2, 23,6, 29,0, 48,7, 51,9, 53,7, 111,0, 118,6, 121,5, 122,3, 129,3, 128,9, 129,5, 134,7, 137,2, 144,8, 146,8, 155,7, 157,1, 166,8. ES-MS m/z 427 (M+H). Elemental analysis. Calculated for C26H26N4O2·0,6H2O·0,3CH2Cl2: C, 68,26; H, EQUAL TO 6.05; N, 12,11. Found: C, 68,57; H, 6,12; N, 11,75.

Example: 62

AMD9738: Receiving (R,S)-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-hydroxybenzamide.

To a stirred solution of methyl ester 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid (AMD9711) (120 mg, 0.23 mmol) in anhydrous MeOH (3 ml) was added hydroxylamine hydrochloride (32 mg, 0.46 mmol) followed by the addition of potassium hydroxide (39 mg, 0.69 mmol). The resulting solution was stirred for 18 hours and at this point was added water (5 ml) and CH2Cl2(5 ml). The phases were separated and the aqueous layer was brought to pH 7 by adding saturated aqueous solution of ammonium hydroxide, then was extracted with CH2Cl2(3 × 10 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuum. Purification of the crude substances by radial chromatography (1 mm plate, 10:1:1 CH2Cl2/MeOH/NH4OH) gave specified the title compound (52 mg, 43%) as a white solid.1H NMR (CDCl3) δ 1,58-to 1.61 (m, 1H), 1,87 is 1.91 (t, 2H), 2,12 with 2.14 (m, 1H), 2,61-of 2.66 (m, 1H), 2,73-2,77 (m, 1H), 3,55 (users, 2H), 3,79 (userd, 1H, J=16 Hz), 3,98-4,00 (m, 1H), 4.09 to (userd, 1H, J=16 Hz), 7,08-7,11 (m, 3H), 7.23 percent-7,26 (m, 2H), 7,38 (user. d, 1H, J=8 Hz), of 7.48-7,51 (m, 4H), at 8.60 (userd, 1H, J=4 Hz);13C NMR (CDCl3) δ 21,2, 23,1, 29,1, 48,6, 53,9, 60,5, 121,9, 122,4, 127,0, 128,8, 130,7, 135,1, 137,7, 142,9, 146,7, 155,2, 156,7, 166,3. ES-MS m/z 428 (M+H). Elemental analysis. Calculated for C25H25N5O·0,8CH2Cl2: C, 64,63; H, 5,59; N, 14,61. Found: C, 64,94; H, 5,69; N, 14,23.

Example: 63

AMD9743: Getting hydrazide 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid.

To a stirred solution of methyl ester 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid (AMD9711) (140 mg, 0.33 mmol) in anhydrous ethanol (3 ml) was added hydrazine monohydrate (0.5 ml, of 10.3 mmol) and the resulting mixture was heated at 80°C within 24 hours. Was added a saturated aqueous solution of ammonium bicarbonate (5 ml), the phases were separated and the aqueous layer was extracted with CH2Cl2(3 × 10 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuum. Purification of the crude substances by radial chromatography (1 mm plate, 75:1:1 CH2Cl2-MeOH-NH4OH) gave specified in the header link is (89 mg, 61%) as a white solid.1H NMR (CDCl3) δ 1,64 by 1.68 (m, 1H), 1,94-2,04 (m, 2H), 2,20-of 2.24 (m, 1H), 2,66-of 2.72 (m, 1H), 2,78-and 2.83 (m, 1H), of 3.73 (s, 2H), 3,93 (d, 1H, J=16 Hz), 4,00-4,12 (m, 3H), 4,15 (d, 1H, J=16 Hz), 7,14-to 7.18 (m, 3H), 7,40 (d, 2H, J=8 Hz), 7,50 (userd, 1H, J=7 Hz), 7,58 (d, 2H, J=8 Hz), 7.62mm (userd, 1H, J=7 Hz), of 8.06 (s, 1H), 8,66 (DD, 1H, J=5,1 Hz);13C NMR (CDCl3) δ 21,2, 23,6, 29,0, 48,7, 53,7, 60,4, 111,4, 118,4, 121,5, 122,3, 126,9, 128,6, 131,5, 134,7, 137,3, 143,5, 146,8, 155,8, 157,1, 168,4. ES-MS m/z 427 (M+H). Elemental analysis. Calculated for C25H26N6O·0,5CH2Cl2: C, 65,31; H, 5,80; N, 17,92. Found: C, 65.22 Per; H, 5,77; N, 17,97.

Example: 64

AMD9769: Obtain 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid (hydrobromide salt).

To a solution of methyl ester 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid (AMD9711) (90 mg, 0.21 mmol) in MeOH (2.5 ml) was added aqueous NaOH (3.5 m of 0.30 ml, 1.05 mmol). The reaction mixture was heated at 40°C for 16 hours, after which the solution was concentrated, washed with saturated aqueous NaHCO3(10 ml) and was extracted with CH2Cl2(2 × 50 ml). The aqueous layer was acidified to pH 4 with 10% aqueous HCl, saturated NaCl (solid) and the product was extracted with CH2Cl2(3 x 75 ml). The combined organic extracts were dried over MgSO4and concentrated, obtaining a light yellow foam.1H NMR (300 MHz, CDCl3/sub> ) δ 8,71 (d, 1H, J=5.8 Hz), to 7.84 (d, 2H, J=8.1 Hz), 7.62mm (users, 2H), 7,52 (d, 1H, J=8.1 Hz), 7,35 (d, 2H, J=8.1 Hz), 7.23 percent-7,17 (m, 3H), 4,29-is 4.21 (m, 2H), 3,95 (d, 1H, J=16.2 Hz), 3,74 (s, 2H), 2.95 and-2,86 (m, 1H), 2,79-to 2.74 (m, 1H), 2,37 was 2.25 (m, 1H), 2,18-2,11 (m, 2H), 1,83-of 1.74 (m, 1H).

According to the General procedure D conversion result of the above foam in hydrobromide salt gave AMD9769.1H NMR (300 MHz, D2O) δ 8,77 (d, 1H, J=6.0 Hz), to 8.41 (d, 1H, J=7.8 Hz), 7,94 (DD, 1H, J=7,5, 5.7 Hz), 7,53-7,42 (m, 6H), 7,22-7,19 (m, 2H), 4,78-to 4.73 (m, 1H), to 4.62 (d, 1H, J=16.2 Hz), 4,43 (d, 1H, J=16.2 Hz), a 3.87 (d, 1H, J=12.9 Hz), of 3.78 (d, 1H, J=12.9 Hz), 3,05-3,03 (m, 2H), 2,47 is 2.43 (m, 1H), 2,32-of 2.21 (m, 2H), 1.93 and-of 1.87 (m, 1H);13C NMR (75.5 MHz, D2O) δ 172,1, 153,5, 152,9, 150,4, 144,2, 143,2, 141,8, 132,6, 132,3, 131,7, 131,2, 128,9, 128,3, 115,9, 65,6, 58,9, 52,4, 30,0, 23,1, 22,5. ES-MS m/z 413,2 (M+H). Elemental analysis. Calculated for C25H24N4O2·2HBr·1,3H2O: C, 50,24; H, 4,82; N, 9,37; Br, 26,74. Found: C, 50,58; H, 4,96; N, 9,00; Br, 26,35.

Example: 65

AMD9770: Obtain 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzamide.

Getting 4-formylbenzoate

Neat thionyl chloride (1,94 ml, 27 mmol) was added dropwise to a stirred suspension of 4-formylbenzoate acid (2.0 g, 13 mmol) in anhydrous CH2Cl2(50 ml). The resulting suspension was stirred 18 hours at this point, the solvent and excess thionyl chloride were removed in vacuo. The remaining solid was re-dissolved in baie the aqueous THF (50 ml) and was barbotirovany through a solution of gaseous ammonia for 15 minutes, which led to the formation of a white precipitate. The mixture was poured into saturated aqueous sodium bicarbonate solution (30 ml) was added chloroform (100 ml). The phases were separated and the aqueous layer was extracted with CHCl3(3 × 30 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuum. Purification of the crude substance flash chromatography on silica gel (20:1:1 CH2Cl2-Meon-NH4OH) gave specified in the title compound (85 mg, 4%) as a white solid.1H NMR (CDCl3) δ 5,96 (users, 1H), to 6.19 (user, 1H), 7,97 (s, 4H), to 10.09 (s, 1H).

According to the General method B to a solution of (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (216 mg, or 0.57 mmol) and 4-formylbenzoate (85 mg, or 0.57 mmol) in CH2Cl2(5 ml) was added triacetoxyborohydride sodium (242 mg, to 1.14 mmol) and the reaction mixture was stirred for 18 hours. The crude substance was placed in undiluted TFOC (2 ml) and stirred 3 hours. Was carefully added to saturated aqueous sodium bicarbonate solution (10 ml) and the resulting mixture was extracted with CH2Cl2(3 × 20 ml)then the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuum. Purification of the crude substances by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH-NH 4OH) gave specified in the title compound (66 mg, 28%) as a white solid.1H NMR (CDCl3) δ 1,67-of 1.73 (m, 1H), 2.00 in of 2.08 (m, 2H), 2.26 and-of 2.30 (m, 1H), 2,71 was 2.76 (m, 1H), 2,82-2,87 (m, 1H), 3,80 (s, 2H), 3,92 (d, 1H, J=16 Hz), 4.09 to (DD, 1H, J=9.7 Hz), 4,20 (d, 1H, J=16 Hz), 5.56mm (users, 1H), 6,01 (users, 1H), 7,17-7,22 (m, 3H), 7,43-7,53 (m, 4H), 7,65-to 7.67 (m, 3H), to 8.70 (DD, 1H, J=5,1 Hz);13C NMR (CDCl3) δ 21,3, 23,7, 29,1, 48,7, 53,7, 60,5, 121,7, 122,4, 127,4, 128,7, 132,3, 134,8, 137,4, 143,8, 146,9, 155,8, 157,1, 169,1. ES-MS m/z 412 (M+H). Elemental analysis. Calculated for C25H25N5About·1,45H2O·0,6CH2Cl2: C, 63,84; H, 6,34; N, 13,76. Found: C, 64,03; H, 5,95; N, 13,37.

Example: 66

AMD11130: Receive (6-aminopyridine-2-ylmethyl)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Using General method, N-alkylation, to stir a solution of N-[6-(methyl bromide)-2-pyridyl]palamida (obtained as described Harata, M.; Hasegawa, K.; Jitsukawa, K.; Masuda, H.; Einaga, H. Bull. Chem. Soc. Jpn 1998, 71,1031-1038) (0,129 g, 0.45 mmol) in anhydrous CH3CN (10 ml) was added 1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,176 g, 0.47 mmol), N,N-diisopropylethylamine (of 0.20 ml, 1.15 mmol) and potassium iodide (12 mg, 0,048 mmol). The mixture was stirred in argon atmosphere at 60°C for 3.75 hours. Purification of the crude substances column chromatography on silica gel (CH2Cl2/Meon, 98:2 then 6:4) gave alkilirovanny product (0,148 g, 54%) as a brown oil.

Using General method D, the transformation obtained above amine (43 mg, 0,074 mmol) in hydrobromide salt with simultaneous removal of the BOC group gave AMD 11130 (41 mg, 84%) as a yellow solid.1H NMR (D2O) δ 1,86-of 1.92 (m, 1H), 2,15-of 2.26 (m, 2H), 2.40 a at 2.45 (m, 1H), 3.00 and-a 3.01 (m, 2H), 3,99 (d, 1H, J=14 Hz, 4,15 (d, 1H, J=14,7 Hz), 4,36 (d, 1H, J=15,9 Hz)to 4.52 (d, 1H, J=15,9 Hz), 4,76-rate 4.79 (m, 1H, overlaps with HOD), of 6.45 (d, 1H, J=9 Hz), 6,70 (d, 1H, J=6.9 Hz), the 7.43 (DD, 1H, J=9, 7.5 Hz), EUR 7.57 (DD, 2H, J=6,3, 3 Hz), to 7.67 (DD, 2H, J=6,3, 3 Hz), 7,89 (DD, 1H, J=7,8, 6 Hz), of 8.37 (d, 1H, J=7.5 Hz), a total of 8.74 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,30, 20,86, 27,81, 48,12, 54,65, 62,49, 113,24, 113,78, 114,19, 126,26, 127,22, 127,36, 130,88, 140,30, 141,10, 143,85, 148,38, 149,38, 149,63; ES-MS m/z 385 (M+H). Elemental analysis. Calculated for C25H24N6·3,0HBr·1,8H2O: C, 41,88; H, To 4.68; N, 12,74; Br, 36,34. Found: C, 41,85; H, Br4.61; N, 12,45; Br, 36,44.

Example: 67

AMD11157: Receive (2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)methanol (as free base).

Using General procedure b {direct reductive amination using NaBH(OAc)3}, the interaction of phthalic dicarboxaldehyde (0,139 g, 1.04 mmol) and (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,183 g, 0.48 mmol) with NaBH(OAc)3(0,504 g of 2.38 mmol) in CH2Cl2(5 ml) for 20 hours with subsequent cleaning and the th of the crude substances by radial chromatography on silica gel (2 mm plate, 100:1 CH2Cl2-CH3OH) gave to 0.108 g (45%) of a white foam. The foam was dissolved in CH2Cl2(2 ml) and treated triperoxonane acid (1 ml). The resulting solution was stirred at room temperature for 90 minutes, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2(10 ml) and NaOH (1.0m, ˜10 ml) so that the aqueous phase was basic (pH 14). The phases were separated and the aqueous phase was extracted with CH2Cl2(3 × 10 ml). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude substances by radial chromatography on silica gel (1 mm plate, 100:1:1 CH2Cl2-CH3OH-NH4OH) gave 0,079 g (91%) AMD 11157 in the form of a white solid.

1H NMR (CDCl3) δ 1,61 to 1.76 (m, 2H), 1,89-2,02 (m, 1H), 2,07 and 2.13 (m, 1H), 2,33-to 2.40 (m, 1H), 2,69-2,90 (m, 2H), 3,81 (d, 1H, J=15,0 Hz), 3,82 (d, 1H, J=12,6 Hz), 3,95 (d, 1H, J=15,0 Hz), 3,98 (t, 1H, J=8,1 Hz)4,06 (d, 1H, J=12,6 Hz), 4,50 (d, 1H, J=11.7 Hz), 4,63 (d, 1H, J=11.7 Hz), 7,06-7,21 (m, 6H), 7,38-7,46 (m, 3H), 7.62mm (user. s, 1H), 8,09 (user. s,1H), 8,44 (user. d, 1H, J=4, 2 Hz);13C NMR (CDCl3) δ 20,90, 21,40, 29,04, 49,28, 55,26, 60,09, 62,90, 111,04, 118,81, 121,48, 122,23, 127,93, 128,50, 130,95, 131,83, 134,83, 137,27, 137,63, 140,38, 146,78, 153,60, 156,28. ES-MS m/z 399 (M+H). Elemental analysis. Calculated for C25H26N4O·1,0H2O: C, 72,09; H, IS 6.78; N, 13,45. Found: C, 72,15; H, To 6.43; N, To 13.29.

Example: 68

AMD11156: Recip is of O-(2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)hydroxylamine (hydrobromide salt).

Obtaining 2-(2-Bromoethylamine)isoindole-1,3-dione

To a stirred solution of N-hydroxyphthalimide (0,60 g, 3,68 mmol) and Et3N (of 0.60 ml, 4.30 mmol) in DMF (6 ml) was added α,α'-dibromo-o-xylene (3,30 g of 0.0125 mol) and the mixture was stirred at room temperature for 4 hours. The obtained brown precipitate was filtered and washed with CH2Cl2. The filtrate was diluted with EtOAc (40 ml) and water (30 ml) and the organic phase is washed with saturated salt solution (1 × 30 ml), dried (Na2SO4) and concentrated under reduced pressure. The obtained yellow oil was purified column chromatography on silica gel (4:1 hexane/EtOAc)to give specified in the title compound (581 mg, 46%) as a white solid.1H NMR (CDCl3) δ 4,99 (s, 2H), lower than the 5.37 (s, 2H), 7,27-7,40 (m, 2H), 7,41 was 7.45 (m, 2H), 7,73-7,76 (m, 2H), 7,81-to 7.84 (m, 2H).

Using the General method of alkylation, to mix a solution of 2-(2-bromoethylamine)isoindole-1,3-dione (0,308 g, 0.89 mmol) in anhydrous CH3CN (10 ml) was added 1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,274 g, 0,725 mmol), N,N-diisopropylethylamine (of 0.21 ml of 1.21 mmol) and potassium iodide (12 mg, 0,048 mmol). The mixture was stirred in argon atmosphere at 60°C for 2.75 hours. Purification of the crude substances column chromatography on silica gel CH 2Cl2/MeOH, 98:2 then 96:4) gave alkilirovanny product (0.32 g, 69%) as a white foam.

To the solution obtained above foam (219 mg, 0.34 mmol) in EtOH (96%, 5 ml) was added hydrazine monohydrate (0.10 ml, 2 mmol) and the solution was stirred at room temperature for 3 days. The mixture was filtered (to remove the obtained solid substance) and washed with CH2Cl2. The filtrate was concentrated under reduced pressure and was purified by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:1:1), obtaining the target amine with the corresponding protective groups (44 mg, 31%) as a white foam.

Using General method D, the transformation of the amine obtained above (39 mg, 0,094 mmol)in hydrobromide salt gave AMD11156 (59 mg, 90%) as a white solid.1H NMR (D2O) δ 1,88-of 1.93 (m, 1H), 2,19 of-2.32 (t, 2H), a 2.45-2.49 USD (m, 1H), 3,03 totaling 3.04 (t, 2H), 3,85 (d, 1H, J=13.5 Hz), 4,17 (d, 1H, J=13.5 Hz), 4,36 (d, 1H, J=16.2 Hz), 4,55 (d, 1H, J=16.2 Hz), 4,76-rate 4.79 (m, 1H, overlap with HOD), 5,10 (d, 1H, J=10,8 Hz), 5,24 (d, 1H, J=10,8 Hz)6,91 (t, 1H, J=7.5 Hz), 7,07 (d, 1H, J=6.9 Hz), 7,14 (t, 1H, J=7.5 Hz), 7,42 (d, 1H, J=7.5 Hz), 7,51 (DD, 2H, J=6,3, 3 Hz), 7,58 (DD, 2H, J=6,3, 3 Hz), of 7.90 (DD, 1H, J=7,8, 6 Hz), scored 8.38 (d, 1H, J=7.5 Hz), 8,73 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,42, 20,80, 27,88, 48,98, 52,84, 62,08, 74,83, 113,93, 126,16, 126,81, 128,85, 130,56, 131,21, 131,52, 131,87, 136,51, 139,88, 141,13, 148,36, 150,49, 150,80; ES-MS m/z 414 (M+H). Elemental analysis. Calculated for C25H27N5O·3,NVG·2,2H2ABOUT: WITH, 43,15; H, TO 4.98; N, 1,06; Br, 34,45. Found: C, 43,37; H, Of 5.05; N, 9,87; Br, 34,33.

Example: 69

AMD11191: Receive (4-aminopyridine-3-ylmethyl)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Using General method B, to mix a solution of (1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (252 mg, of 0.91 mmol) and tert-butyl methyl ether (3-formylpyridine-4-yl)carbamino acid (obtained as described Venuti, M.C.; Stephenson, R.A. et al. J. Med. Chem. 1988, 31, 2136-2145) (206 mg, of 0.93 mmol) in CH2Cl2(9 ml) was added NaBH(OAc)3(243 mg, 1.15 mmol) and the resulting mixture was stirred at room temperature for 16 hours. A solution of the crude yellow foam (0,30 g) in 5N HCl/THF (1:1.6 ml) was stirred for 3 days. The mixture was diluted with water (10 ml) and CH2Cl2(25 ml) and podlachian (pH>10) 10h. NaOH (10 ml). The layers were separated and the aqueous phase was washed CH2Cl2(3 × 10 ml). The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure and was purified by radial chromatography on silica gel (2 mm plate, CH2Cl2/MeOH/NH4OH, 100:1:1 then 50:1:1, then 20:1:1)to give the free amine (100 mg, 29% over 2 stages) as a clear oil.

Using General method D, the transformation obtained above amine (73 mg, 0,19 mmol) in hydrobromide salt gave AMD11191 (120 m is, 90%) as a white solid.1H NMR (D2O)δ 1,87 is 1.91 (m, 1H), 2,15-of 2.26 (m, 2H), 2,45-of 2.50 (m, 1H), 3,00-3,02 (m, 2H), was 4.02 (d, 1H, J=14.1 Hz), 4,13 (d, 1H, J=14.1 Hz), 4,34 (d, 1H, J=16.2 Hz), of 4.45 (d, 1H, J=16.2 Hz), 4,76-rate 4.79 (m, 1H, overlap with HOD), 6,40 (d, 1H, J=6.9 Hz), 7,38 (d, 1H, J=6.9 Hz), 7,56 (DD, 2H, J=6,3, 3 Hz), 7,66 (DD, 2H, J=6,3, 3 Hz), 7,89 (DD, 1H, J=7,8, 6 Hz), 8,08 (s, 1H), 8,35 (d, 1H, J=7.8 Hz), a total of 8.74 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,41 (2 carbon), 27,92, 48,03, 51,51, 61,78, 109,58, 114,04, 115,89, 126,30, 127,34, 130,58, 138,61, 140,26, 140,69, 141,07, 148,25, 149,82, 150,33, 158,82; ES-MS m/z 385 (M+H). Elemental analysis. Calculated for C23H24N6·3,NVG·1,8H2O·0,5S4H10About: With, 42,60; H, 5,11; N, 11,92; Br, To 35.15. Found: C, 42,91; H, Free 5.01; N, 11,88; Br, 34,76.

Example: 70

AMD11065: obtain the methyl ester of 2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-5-cyanobenzoic acid.

Obtain methyl ester of 2-methyl-5-nitrobenzoic acid

A solution of 2-methyl-5-nitrobenzoic acid (1,91 g, 10.6 mmol) and H2SO4(catalytic amount) in MeOH (25 ml) was boiled under reflux for 16 hours, then concentrated in vacuo. The residue was dissolved in CH2Cl2(50 ml), washed with saturated NaHCO3(aq.) (2 x 40 ml), then dried (MgSO4), filtered and concentrated in vacuum, obtaining yellow crystals (1.50 g, 73%).1H NMR (CDl 3) δ of 2.72 (s, 3H), of 3.96 (s, 3H), 7,44 (d, 1H, J=9.0 Hz), 8,24 (DD, 1H, J=9,0, 3.0 Hz), 8,78 (d, 1H, J=3.0 Hz).

Obtain methyl ester of 5-amino-2-methylbenzoic acid

A solution of methyl ester of 2-methyl-5-nitrobenzoic acid (1.50 g, 7.8 mmol) in a mixture of 4:1 MeOH/EtOAc (20 ml) was shaken at room temperature with a suspension of 10% Pd/C (175 mg, 0,17 mmol) in an atmosphere of hydrogen at 35 lb/in2(241 kPa) for 17 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuum, obtaining a pale yellow oil (1.29 g, 99%).1H NMR (CDCl3) δ the 2.46 (s, 3H), 3,63 (user. s, 2H), a 3.87 (s, 3H), 6,74 (DD, 1H, J=9,0, 3.0 Hz), 7,02 (d, 1H, J=6.0 Hz), 7,25 (d, 1H, J=3.0 Hz).

Obtain methyl ester of 5-cyano-2-methylbenzoic acid

To a stirred suspension of methyl ester of 5-amino-2-methylbenzoic acid (1.29 g, 7,80 mmol) in H2O (2.0 ml) was slowly added conc. HCl (2.0 ml) at room temperature. Added another H2O (15 ml) and the mixture was stirred at 0°C as add (dropwise) a solution of NaNO2(592 mg, 8,58 mmol) in H2O (2.2 ml). After complete dissolution of the amine was slowly added at 0°C2CO3(solid) to neutralize the solution.

The copper cyanide(I) (838 mg, 9,36 mmol) was dissolved in a solution of NaCN (918 mg, to 18.7 mmol) in H2O (2,9 ml) and the solution was heated to 60°C. To intensive the mixed solution of cyanide in 60° C was added dropwise a cold solution neutralized diazonium salts. The mixture was heated at 110°C for 1 hour, then left to cool to room temperature. The mixture was diluted with saturated solution of NaHCO3(aq.) (15 ml) and was extracted with CH2Cl2(3 × 20 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuum. The crude product was filtered through silica gel (20% EtOAc/hexane)to give yellow crystals (990 mg, 72%).1H NMR (CDCl3) δ of 2.68 (s, 3H), 3,93 (s, 3H), 7,38 (d, 1H, J=9.0 Hz), 7,66 (DD, 1H, J=9,0, 3.0 Hz), by 8.22 (d, 1H, J=1.5 Hz).

Obtaining methyl ester 2-methyl bromide-5-cyanobenzoic acid

A mixture of methyl ester of 5-cyano-2-methylbenzoic acid (913 mg, to 5.21 mmol), NBS (1,02 g, 5,73 mmol) and AIBN (128 mg, 0,780 mmol) in CCl4(20 ml) was boiled under reflux for 24 hours, then left to cool to room temperature. The mixture was filtered and the filtrate was concentrated in vacuum. Purification of the crude substances column chromatography on silica gel (10% EtOAc/hexane) gave yellow crystals (720 mg, 55%).1H NMR (CDCl3) δ 3,99 (s, 3H), 4,96 (s, 2H), a 7.62 (d, 1H, J=9.0 Hz), to 7.77 (DD, 1H, J=9,0, 3.0 Hz), of 8.27 (d, 1H, J=3.0 Hz).

A mixture of tert-butyl ester 2-[(5,6,7,8-tetrahydroquinolin-8 ylamino)methyl]benzoimidazol-1-carboxylic acid (762 mg, 2,01 IMO the b) methyl ester 2-methyl bromide-5-cyanobenzoic acid (511 mg, a 2.01 mmol), potassium iodide (19 mg, 0.10 mmol) and N,N-diisopropylethylamine (of 0.53 ml, to 3.02 mmol) in acetonitrile (16 ml) was heated at 60°C for 16 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with CH2Cl2(25 ml) and saturated NaHCO3(aq.) (30 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2(2 × 20 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuum. Purification of the crude substances on silica gel (500:10:1 CH2Cl2/Meon/NH4HE gave a white foam (935 mg, 84%).

The result of the above purified substance (50 mg, 0.11 mmol) was dissolved in anhydrous CH2Cl2(1.5 ml) and added dropwise triperoxonane acid (2.0 ml). The resulting mixture was stirred for 2.5 hours at room temperature. The reaction mixture was diluted with CH2Cl2(15 ml) and then concentrated in vacuo to remove excess triperoxonane acid. The concentrate was diluted with CH2Cl2(20 ml) and 1N. NaOH (20 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2(2 × 15 ml) and then the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuum, obtaining AMD11165 in the form of a yellow foam.1H NMR (CDCl3) δ 1,62-to 1.79 (m, 1H), 1,92 is 2.10 (m, 2H),2.26 and-of 2.34 (m, 1H), 2,69-of 2.93 (m, 2H), with 3.89 (s, 3H), 3,89 (d, 1H, J=16.5 Hz), 3,95 (d, 1H, J=6.2 Hz), 4,13 (m, 1H), 4.16 the (d, 1H, J=16.5 Hz), of 4.57 (d, 1H, J=15,9 Hz), 7,12-of 7.23 (m, 3H), 7,43 (d, 1H, J=7.8 Hz), of 7.48 (osirm, 1H), 7,58 (DD, 2H, J=7,8, 1.5 Hz), 7,94 (d, 1H, J=1.8 Hz), 8,00 (d, 1H, J=8.1 Hz), to 8.62 (d, 1H, J=5,1 Hz).13C NMR (CDCl3) δ 21,72, 24,40, 29,46, 50,21, 53,01, 53,07, 111,08, 118,26, 122,28, 122,88, 130,88, 131,50, 134,05, 135,12, 135,20, 137,97, 147,17, 147,26, 155,56, 157,27, 166,75. ES-MS m/z 452 (M+H). Elemental analysis. Calculated for C27H25N5O2·0,05CH2Cl2·0,8H2O: C, 69,10; H, 5,72; N, 14,89. Found: C, 69,44; H, By 5.87; N, 14,61.

Example: 71

AMD11179: Obtain 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-3-cyanobenzene.

To 0.5 ml of Raney Nickel in water solution was added tert-butyl ester 2-{[(2-cyano-4-methoxycarbonylbenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzimidazole-1-carboxylic acid (0.55 g, 1 mmol) in methanol (25 ml). The solution is then saturated with gaseous ammonia for 10 minutes. The reaction vessel then was intensively shaken in an atmosphere of hydrogen at 40 psig (276 kPa) for 16 hours. The mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure. The crude residue was purified column chromatography (88:12 CH2Cl2:MeOH)to give amide (0.20 g, 36%).1H NMR (CDCl3) δ at 1.73 (m, 1H), 2,01 (m, 2H), 2,35 (m, 1H), 2,85 (m, 2H), 3,88 (t, 2H, J=15,9 Hz)to 4.16 (m, 1H), 4,21 (d, 1H, J=9.6 Hz), 4.26 deaths (d,1H, J=7.8 Hz), 5,71 (user., 1H, NH), 6,12 (user., 1H, NH), 7,19 (m, 3H), 7,46 (d, 1H, J=7.8 Hz), 7,55 (user., 2H), 7,80 (d, 1H, J=8.1 Hz), 7,87 (d, 1H, J=8.1 Hz), of 7.96 (s, 1H), 8,64 (DD, 1H, J=4.5 Hz);13C NMR (CDCl3) δ 21,71, 24,65, 29,44, 49,92, 53,09, 61,84, 112,81, 117,49, 122,30 (4C), 122,97, 130,44 (2C), 131,98, 132,32, 133,56, 135,37, 138,05 (2C), 147,13, 147,29, 155,27, 156,87, 167,82. ES-MS m/z 437 (M+H). Elemental analysis. Calculated for C26H24N6About·0,SN2Cl2: C 65,54; H, TO 5.21; N, 17,24. Found: C, 65,93; H, The 5.51; N,17,44.

Example: 72

AMD9643: Obtain [3-(1H-benzimidazole-2-yl)benzyl]-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Obtaining 3-(benzimidazole-2-yl)benzyl alcohol

The solution nanometrology ether isotretinoi acid and 1.00 g, 5.6 mmol) in thionyl chloride (12 ml) was stirred at 80°C for 3.5 hours. The solvent was removed under reduced pressure, obtaining the acid chloride nanometrology ether isotretinoi acid (1.06 g, 97%).1H NMR (CDCl3) δ 3,98 (s, 3H), 7,63 (t, 1H, J=7.8 Hz), 8,30 (d, 1H, J=7.8 Hz), 8,35 (d, 1H, J=7.8 Hz), 8,78 (s, 1H).

A solution of 2-nitroaniline (of 0.62 g, 4.5 mmol) and acid chloride nanometrology ether isotretinoi acid (1.06 g, 5.3 mmol) in THF (5.6 ml) and pyridine (1.1 ml) was stirred for 2 hours at room temperature. To the mixture was added saturated NaHCO3(20 ml) and was extracted with ethyl acetate (3 × 20 ml). The combined organic extracts who left the house taking (MgSO 4), filtered, concentrated and purified column chromatography on silica gel (5% MeOH/CH2Cl2)to give the methyl ether (2-nitrophenyl)isotretinoi acid (0,70 g, 52%) as a yellow solid.1H NMR (CDCl3) δ 3,99 (s, 3H), 7,27 (t, 1H, J=7.8 Hz), the 7.65 (t, 1H, J=7.8 Hz), of 7.75 (t, 1H, J=7.8 Hz), 8,17 (d, 1H, J=7.8 Hz), 8,30 (t, 2H, J=7.8 Hz), 8,67 (s, 1H), 8,99 (d, 2H, J=7,8 Hz).

To a solution of methyl ester (2-nitrophenyl)isotretinoi acid (0,70 g, 2.3 mmol) in glacial acetic acid (8 ml) was added iron powder (sieve composition <5 μm, 0.35 g, 6.3 mmol) and the mixture was stirred while boiling under reflux for 1.5 hours. The mixture was cooled, stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was distributed between saturated sodium bicarbonate solution (20 ml) and ethyl acetate (20 ml), the phases were separated and the organic layer was washed with saturated NaHCO3(20 ml). The organic extract was dried (MgSO4), filtered and concentrated, obtaining cyklinowanie ester methyl 3-(benzimidazole-2-yl)benzoate (0,59 g, 100%).1H NMR (CDCl3) δ 3,93 (s, 3H), 7,30 (m, 2H), EUR 7.57 (t, 2H, J=7.8 Hz), 7,88 (user., 1H), 8,12 (d, 1H, J=7.8 Hz), 8,35 (d, 1H, J=7.8 Hz), 8,64 (s, 1H), 10,10 (user., 1H (NH)).

To a solution of 3-(benzimidazole-2-yl)properties of ester (0.20 g, 0.8 mmol) in THF (8 ml) at -78°C was added a solution of DIBAL-H (4,0 ml of 1.0 M in THF, 4.0 mmol). The reaction mixture was left to warm to room temperature, stirred for 0.5 hours and extinguished a saturated solution of tartrate of potassium-sodium (15 ml). A two-phase system was intensively stirred for 1 hour, the phases were separated and the organic layer was dried (MgSO4), filtered and concentrated, obtaining 3-(benzimidazole-2-yl)benzyl alcohol (0.12 g, 67%).1H NMR (CD4OD3) δ to 4.73 (s, 2H), 7,26 (m, 2H), 7,52 (m, 2H), EUR 7.57 (m, 2H), 7,99 (m, 1H), 8,10 (s, 1H).

Using General method C, to a solution of 3-(benzimidazole-2-yl)benzyl alcohol (0.12 g, 0.5 mmol) and triethylamine (of 0.11 ml, 0.8 mmol) in THF (5 ml) was added methanesulfonamide (55 μl, 0.7 mmol) and the mixture was stirred at room temperature for 1 hour. Received mesilate (0.15 g, 91%) was used without further purification in the next reaction.1H NMR (CDCl3) δ 3,14 (s, 3H), 5,38 (s, 2H), 7,27 (m, 2H), 7.62mm (m, 4H), to 8.12 (m, 1H), 8,19 (s, 1H).

Using the General method of alkylation, the solution obtained above nelfinavir (0.15 g, 0.5 mmol), N,N-diisopropylethylamine (of 0.12 ml, 0.7 mmol) and potassium iodide (6 mg, 30 mmol) in CH3CN (5 ml) was subjected to interaction with (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) - amine (0.18 g, 0.5 mmol) at 60°C for 3 hours. Purification of the crude substances column chromatography on silica gel (2% MeOH/CH2Cl2) gave the spruce N-alkilirovanny product (0.17 g, 60%) as a flaky white solid.1H NMR (CDCl3) δ 1,68 (s, 10H), was 2.05 (m, 2H), 2,30 (m, 1H), 2,80 (m, 2H), 3,69 (d, 1H, J=12.0 Hz), a 3.87 (d, 1H, J=15,0 Hz), 4,30 (d, 1H, J=15,0 Hz), of 4.45 (m, 1H), br4.61 (4 1H, J=15,0 Hz), was 7.08 (m, 1H), 7,15-7,30 (m, 7H), 7,35 (4 1H, J=7.8 Hz), to 7.67 (d, 2H, J=7.8 Hz), of 7.70 (m, 3H), 8,09 (4 1H, J=7.8 Hz), 8,49 (d, 1H, J=3.5 Hz), 9,06 (s, 1H).

Using General method D, the transformation obtained above substance (50 mg) in hydrobromide salt gave AMD9575 (0,062 g) as a beige solid.1H NMR (D2O) δ 1,91 (osirm, 1H, in), 2.25 (m, 2H), 2,45 (user. m, 1H), 3.04 from (user. m, 2H), 3,79 (d, 1H, J=12.9 Hz), of 3.94 (d, 1H, J=13,2 Hz), 4,42 (d, 1H, J=16.2 Hz), to 4.62 (d, 1H, J=16.2 Hz), 4,78 (m, 1H), 7,14 (d, 2H, J=5.4 Hz), 7,14 (m, 2H), 7,41 (m, 2H), of 7.48 (d, 2H, J=6.9 Hz), to 7.59 (DD, 2H, J=3,0, 6.3 Hz), 7,73 (DD, 2H, J=of 3.0, 6.0 Hz), 7,95 (t, 1H, J=6.9 Hz), to 8.41 (d, 1H, J=8.1 Hz), 8,79 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,43, 21,15, 27,88, 50,15, 56,67, 63,59, 113,41 (2C), 114,16 (2C), 122,13, 126,26, 126,54 (2C), 126,69, 127,03 (2C), 127,46, 130,33, 130,83, 131,71, 135,08, 138,72, 139,91 (2C), 141,14, 147,47, 148,41 (2C), 150,54, 151,56. ES-MS m/z 485 (M+H). Elemental analysis. Calculated for C31H28N6·3,0HBr·2,9H2O: C, 48,35; H, 5,09; N, 10,37; Br, 29,60. Found: C, 48,35; H, 4,96; N, 10,31; Br, 29,59.

Example: 73

AMD9902: Receive (1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(imidazol-2-yl)methylamine (hydrobromide salt).

Using standard conditions of reductive amination (A, 1H-(benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (207 mg, 0.75, and IMO is b) was mixed with imidazole-2-carboxaldehyde (96 mg, 1.0 mmol) and cyanoborohydride sodium (95 mg, 1.5 mmol) in methanol (5 ml) for 48 hours. The solution is then concentrated. The residue was placed in dichloromethane and washed with 1N. sodium hydroxide (3 ml), then dried over anhydrous sodium sulfate, concentrated and purified by chromatography on silica gel (20:1 dichloromethane:methanol)to give (1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(imidazol-2-yl)methylamine (69 mg, 56%).1H NMR (CDCl3) δ of 1.64 (m, 1H), to 1.86 (m, 1H), 2,00 (m, 1H), 2,68 (m, 1H), 2,86 (m, 1H), 3,64 (d, 1H, J=14.6 Hz), with 3.79 (d, 1H, J=15,4 Hz), 3,90 (m, 1H), 3,91 (d, 1H, J=15,4 Hz), of 3.94 (d, 1H, J=14.6 Hz), 6,97 (s, 1H), 7,18 (m, 3H), at 7.55 (d, 1H, J=9.0 Hz), 7,60 (m, 2H), of 8.47 (d, 1H, J=4,9 Hz).

(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(imidazol-2-yl)methylamine (56 mg, 0,156 mmol) were placed in acetic acid (1 ml)to which was added a saturated solution of HBr in acetic acid (1 ml). The mixture was then stirred, besieged and isolated according to method D, receiving AMD9902 in the form of a white crystalline solid (39 mg).1H NMR (D2O) δ of 1.88 (m, 1H), 2,09 (m, 1H), 2,39 (m, 1H), to 3.02 (m, 2H), or 4.31 (d, 1H, J=15.6 Hz), 4,42 (d, 1H, J=12,6 Hz), 4,48 (d, 1H, J=12,6 Hz), a 4.53 (d, 1H, J=15.6 Hz), 4,63 (m, 1H), 7,19 (s, 1H), 7,58 (m, 2H), 7,73 (m, 2H), 7,87 (DD, 1H, J=7,8, and 4.9 Hz), 8,67 (d, 1H, J=4,9 Hz);13C NMR (D2O) δ 19,83, 20,26, 20,94, 27,30, 27,71, 47,37, 48,09, 61,93, 114,33, 120,20, 126,27, 126,64, 127,36, 131,08, 140,35, 140,98, 142,76, 148,42, 149,03, 151,26, 154,87. ES-MS m/z 359 (M+H). Elemental analysis. Calculated for C21H22N6୲,7HBr· 1,9H2O·0,3HOAc): C, 40,86; H, to 4.87; N, 12,88; Br 36,73. Found: C, 41,11; H, To 4.73; N, 12,87; Br, 36,39.

Example: 74

AMD9592: Obtain 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-2,6-dichloropyridine (hydrobromide salt).

Obtaining 2,6-dichloropyridine-4-Eletropaulo ether methanesulfonate acid

To a stirred solution of 2,6-dichlorophenylamino acid (280 mg, 1.5 mmol) in THF (7.5 ml) was added dropwise a solution of BH3-THF (1M in THF, 5.8 ml, 5.8 mmol) and the mixture was stirred while boiling under reflux for 65 hours. The reaction mixture was cooled and extinguished MeOH (10 ml) and concentrated under reduced pressure. To the obtained residue was added MeOH (10 ml) and the solution was re-concentrated. This procedure was repeated five times and the resulting white solid (230 mg, 89%) was used without further purification in the next stage.

Using General method C, to stir cooled with ice to a solution obtained above substances (230 mg, 1.3 mmol) and triethylamine (and 0.50 ml, 3.9 mmol) in CH2Cl2(13 ml) was added methanesulfonamide (0.10 ml, 0.3 mmol) and the mixture was stirred for 30 minutes at 0°C. Target untreated mesilate (340 mg) was obtained as a pale yellow solid and used without further purification in the next stage.

Using General met the dick N-alkylation, the solution obtained above substances (330 mg, 1.3 mmol) and N,N-diisopropylethylamine (0.45 ml, 2.6 mmol) in CH3CN (13 ml) was subjected to interaction with (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) - amine (470 mg, 1.2 mmol) overnight. Purification of the crude substance flash chromatography on silica gel (3:1 EtOAc/hexane) gave the target amine (400 mg, 58%) as a pale yellow solid.

Using General method D, the transformation obtained above substances (264 mg, 0.49 mmol) in hydrobromide salt with simultaneous removal of the N-tert-butoxycarbonyl protective group gave AMD9592 (280 mg, 92%) as a white powder.1H NMR (D2O) δ 1,80-of 1.97 (m, 1H), 2,12-of 2.21 (m, 2H), 2,33 at 2.45 (m, 1H), 2,97-a 3.01 (m, 2H), 3,83 (q, 2H, J=15 Hz), of 3.78 (DD, 2H, J=66, 15 Hz), to 4.73 (m, 1H), 7,18 (s, 2H), 7,47-7,51 (m, 2H), to 7.59 to 7.62 (m, 2H), 7,86 (t, 1H, J=6 Hz), 8,32 (d, 1H, J=7.5 Hz), 8,72 (d, 1H, J=6 Hz);13C NMR (CDCl3) δ 25,12, 25,90, 32,66, 54,46, 60,32, 67,92, 118,95(2), 128,83(2), 131,11, 132,05(2), 135,43, 144,95, 146,02, 153,17, 154,63, 154,87, 155,07, 157,53. ES-MS m/z 439 (M+H). Elemental analysis. Calculated for C23H21N5Cl2·1.0 h2About·2,NVG: C, 44,69; H, 4,08; N, 11,33; Br, 25,85; Cl, 11,47. Found: C, 44,56; H, 4,22; N, 11,41; Br, 25,83; Cl, 11,46.

Example: 75

AMD9782: Receive (1H-benzimidazole-2-ylmethyl)benzooxazol-5-ylmethyl-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

Getting 5-bromomethylisoxazole

A mixture of 5-methylbenzotriazole (200 mg, 1.50 mmol), N-bromosuccinimide (321 mg, of 1.80 mmol) and 2,2'-azobisisobutyronitrile (37 mg, 0.23 mmol) in CCl4(3 ml) was boiled under reflux for 22 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purification of the crude substances on silica gel (5% EtOAc/hexane) gave specified in the title compound as colorless crystals (126 mg, 39%).1H NMR (CDCl3) δ with 4.64 (s, 2H), 7,46 (DD, 1H, J=8,6) and 1.7 Hz), EUR 7.57 (d, 1H, J=8,4 Hz), 7,83 (d, 1H, J=1.2 Hz), 8, 12 (s, 1H).

Using the General method N-alkylation, a solution of 5-bromomethylisoxazole (94 mg, 0.44 mmol), potassium iodide (3 mg, 0.02 mmol) and N,N-diisopropylethylamine (0.10 ml, or 0.57 mmol) in CH3CN (4 ml) was subjected to interaction with (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) - amine (152 mg, 0,402 mmol) at 60°C for 22 hours. Purification of the crude substance flash chromatography on silica gel (400:5:1 EtOAc/MeOH/NH4OH) gave a yellow foam (124 mg, 60%).

The solution yellow foam (40 mg, 0,078 mmol) in a mixture of 3:1 triperoxonane acid/CH2Cl2(4 ml) was stirred at room temperature for 1 hour, then concentrated. The residue was distributed between CH2Cl2and saturated NaHCO3(aq.) and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (MgSO4 ), filtered and concentrated, obtaining mentioned in the title compound as a yellow foam (32 mg, 89%).1H NMR (CDCl3) δ by 1.68 (m, 1H), 2,04 (m, 2H), 2,28 (m, 1H), 2,71 (m, 1H), 2,86 (m, 1H), 3,86 (s, 2H), 3,98 (d, 1H, J=17 Hz), 4.09 to (m, 1H), 4,22 (d, 1H, J=17 Hz), 7,19 (m, 3H), 7,44 (m, 3H), 7,58 (m, 2H), 7,87 (s, 1H), 8,02 (s, 1H), 8,73 (d, 1H, J=4, 2 Hz);13C NMR (CDCl3) δ 21,77, 23,76, 29,58, 48,77, 54,24, 60,59, 110,95, 120,86, 122,08, 122,75, 126,73, 135,19, 136,57, 137,77, 140,56, 147,38, 149,70, 153,13, 156,32, 157,63. ES-MS m/z 410 (M+H). Elemental analysis. Calculated for C25H23N5About·0,23H2O·0,53CH2Cl2: C, 66,86; H, OF 5.39; N, 15,27. Found: C, 66,99; H, To 5.55; N, The 14.90.

Example: 76

AMD9786: Getting pyridine-2-ylmethyl-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

Using General method, N-alkylation, hydrochloride 2-pommerellen (104 mg, 0,413 mmol) was stirred with N,N-diisopropylethylamine (0,092 ml, 0,516 mmol) in CH3CN (5 ml) for 10 minutes. Then was added potassium carbonate (71 mg, 0,516 mmol) and (1-tert-butoxycarbonylamino-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (130 mg, 0,344 mmol) and the mixture was heated at 60°C for 2 hours. The dark solution was cooled, concentrated, the obtained residue was placed in CH2Cl2and washed with an aqueous solution of ammonium carbonate. Purification of the residue by chromatography on silica gel (10% MeOH/CH2Cl2) gave the product pyridine-2-ileti is-(1H-N-tert-butoxycarbonylamino-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (32 mg, 20%) as a white foam.1H NMR (CDCl3) δ of 1.62 (s, N), 1,88-of 2.20 (m, 4H), 2,69-2,78 (m, 2H), 3,95 (d, 1H, J=16.1 Hz), 4,13 (d, 1H, J=16.1 Hz), 4,36 (t, 1H, J=6,8 Hz), 4,63 (d, 1H, J=12,8 Hz), of 4.77 (d, 1H, J=12,8 Hz)6,86 (m, 1H), of 6.96 (m, 1H), 7,22-7,29 (m, 3H), 7,38 (t, 1H, J=7.8 Hz), a 7.62 (m, 2H), 7,74 (m, 1H), 8.30 to (d, 1H, J=6.0 Hz), 8,43 (d, 1H, J=5,2 Hz).

Using General method D, the transformation obtained above foam (32 mg, 0,068 mmol) in hydrobromide salt gave AMD9786 (28 mg) as a white solid.1H NMR (D2O) δ is 1.81 (m, 1H), 2,19 (m, 2H), 2,45 (m, 1H), 3,00 (m, 2H), 4,23 (d, 1H, J=9.0 Hz), to 4.38 (s, 1H), 4,43 (s, 1H), 4,59 (d, 1H, J=9.0 Hz), of 4.77 (m, 1H), 7,46 (DD, 1H, J=5,3, 6,8 Hz), 7,53 (m, 2H), 7,63 (m, 2H), 7,72 (d, 1H, J=8.1 Hz), 7,86 (DD, 1H, J=7,8, 5.7 Hz), of 8.04 (dt, 1H, J=7,8, 1.5 Hz), a 8.34 (d, 1H, J=7.8 Hz), 8,49 (d, 1H, J=5,1 Hz), to 8.70 (d, 1H, J=6.0 Hz);13C NMR (D2O) δ 20,32, 21,06, 27,74, 48,17, 55,59, 62,28, 114,23 (2C), 126,86, 126,16, 126,87, 127,16 (2C), 131,05, 140,23, 140,95, 144,03, 144,78, 148,10, 149,33, 149,68, 152,40. ES-MS m/z 440 (M+H). Elemental analysis. Calculated for C23H23N5·2,9HBr·1,7H2O: C, 43,52; H And 4.65; N, 11,03; Br 36,51. Found: C, 43,50; H, To 4.68; N, 10,96; Br, 36,58.

Example: 77

AMD9787: Receive (1H-benzimidazole-2-ylmethyl)benzoxazol-6-ylmethyl-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

Getting 6-bromomethylisoxazole

A mixture of 6-methylbenzothiazole (422 mg, 3,17 mmol), N-bromosuccinimide (677 mg, of 3.80 mmol) and 2,2'-azobisisobutyronitrile (78 mg, 0.48 mmol) in CCl4(6.3 ml) was boiled with a reflux is m for 22 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purification of the crude substances on silica gel (4% EtOAc/hexane) gave specified in the title compound as colorless crystals (257 mg, 38%).1H NMR (CDCl3) δ with 4.64 (s, 2H), 7,42 (DD, 1H, J=8,1, 1.5 Hz), to 7.64 (d, 1H, J=1.2 Hz), 7,76 (d, 1H, J=8,4 Hz)to 8.12 (s, 1H).

Using General method, N-alkylation, a solution of 6-bromomethylisoxazole (113 mg, of 0.533 mmol), potassium iodide (4 mg, 0.02 mmol) and N,N-diisopropylethylamine (of 0.12 ml, 0.69 mmol) in CH3CN (4,4 ml) was subjected to interaction with (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) - amine (168 mg, 0,444 mmol) at 60°C for 16 hours. Purification of the crude substance flash chromatography on silica gel (600:5:1 EtOAc/Meon/NH4HE gave a yellow oil (179 mg, 79%).

A solution of the yellow oil (173 mg, 0,339 mmol) in a mixture of 3:1 triperoxonane acid/CH2Cl2(4 ml) was stirred at room temperature for 1 hour, then concentrated. The residue was distributed between CH2Cl2and a saturated solution of NaHCO3(aq.) and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and concentrated, obtaining specified in the header connection AMD9787 as a yellow foam (118 mg, 79%).1H NMR (CDCl3) δ to 1.70 (m, 1H), 2,04 (m, 2H), to 2.29 (m, 1H), 2,73 (m, 1H), 2,87 (m, 1H),3,88 (s, 2H), 3,98 (d, 1H, J=17 Hz), 4,11 (m, 1H), 4,22 (d, 1H, J=17 Hz), 7,19 (m, 3H), 7,42 (m, 2H), 7.62mm (m, 3H), 7,71 (s, 1H), 8,01 (s, 1H), 8,73 (d, 1H, J=4, 2 Hz);13C NMR (CDCl3) δ 21,23, 23,36, 29,06, 48,47, 53,88, 60,16, 110,74, 119,94, 121,52, 122,26, 125,07, 134,68, 137,25, 137,65, 139,20, 146,86, 150,08, 152,34, 155,73, 157,13. ES-MS m/z 410 (M+H). Elemental analysis. Calculated for C25H23N5O·0,6H2O·0,2EtOAc: C, 70,76; H, 5,94; N, 15,99. Found: C, To $ 70.88; H, Of 5.83; N, 16,07.

Example: 78

AMD9829: Receive (1H-benzimidazole-4-ylmethyl)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt)

Getting 4-methyl-1H-benzimidazole

To a stirred solution of 2,3-diaminotoluene (1,00 g, 8.2 mmol) in CH2Cl2(82 ml) was added triethylorthoformate (4,5 ml, 41 mmol) and triperoxonane acid (of 0.32 ml, 4.1 mmol) and the mixture was stirred at room temperature for 24 hours after which the reaction mixture was diluted with CH2Cl2(200 ml) and washed sequentially with a saturated aqueous solution of NaHCO3(40 ml) and H2O (40 ml). The aqueous layers was extracted again CH2Cl2(2 × 100 ml). The combined organic extracts were dried over MgSO4and concentrated to a tan solid (1.07 g, 97%).1H NMR (300 MHz, CDCl3) δ 8,08 (s, 1H), 7,49 (d, 1H, J=5,1 Hz), 7.23 percent-to 7.18 (m, 1H), 7,10 (d, 1H, J=7.5 Hz), of 2.64 (s, 3H).

Obtain tert-Putilov the th ether 4-bromelaids-1-carboxylic acid

To a stirred solution of 4-methyl-1H-benzimidazole (1,05 g, 7.9 mmol) in THF (10 ml) was added di-tert-BUTYLCARBAMATE (4.4 g, 20 mmol) in THF (6 ml). After 18 hours the reaction mixture was concentrated to a brown syrup. Purification of column chromatography on silica gel (20:3 - hexane:EtOAc) gave the desired product as a yellow syrup (1.66 g, 91%).1H NMR (300 MHz, CDCl3) δ to 8.41 (s, 1H), 7,81 (d, 1H, J=8.1 Hz), 7,31-7,26 (m, 1H), 7,16 (d, 1H, J=7.5 Hz), to 2.67 (s, 3H), 1.70 to (s, 9H).

To a stirred solution of tert-butyl methyl ether 4-methylbenzimidazole-1-carboxylic acid (800 mg, 3.4 mmol) in CCl4(7 ml) was added N-bromosuccinimide (730 mg, 4.1 mmol) and 2,2'-azobis(2-methylpropionitrile) (84 mg, 0.51 mmol). The resulting mixture was boiled under reflux for 18 hours, then was filtered and concentrated to a yellow-orange syrup and crystals (1.4 g). Purification of column chromatography on silica gel (200:15-hexane:EtOAc) gave the target specified in the title compound as a yellow syrup (635 mg, 60%).1H NMR (300 MHz, CDCl3) δ 8,48 (s, 1H), 7,95 (DD, 1H, J=7,8, 1.5 Hz), 7,42-7,34 (m, 2H), 4,96 (s, 2H), 1,71 (s, 9H).

Using the General method of alkylation, to stir the solution (1-tert-butoxycarbonylamino-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (153 mg, 0.40 mmol) and tert-butyl methyl ether 4-bromelaids-1-carboxylic acid (167 mg, 0.48 mmol) in CH3CN (5 is l) was added KI (3 mg, 0.02 mmol) and N,N-diisopropylethylamine (0.1 ml, 0.6 mmol) and the reaction mixture was heated at 60°C for 3 hours. The resulting foam was dissolved in a mixture of CH2Cl2(2 ml) and TFOC (2 ml). After 3 hours the solution was concentrated, re-dissolved in H2O (˜1 ml) and podslushivaet 1H. NaOH. The aqueous phase was extracted with CH2Cl2(3 × 50 ml). The combined organic extracts were dried over MgSO4and concentrated to a light brown foam. Purification of column chromatography on silica gel (200:3:2 - CH2Cl2:MeOH:NH4OH) followed by radial chromatography on silica gel (1 mm plate, 100:1:1 - CH2Cl2:MeOH:NH4OH) gave the desired product as a pale yellow foam (38 mg, 23%).1H NMR (300 MHz, CDCl3) 8,59 (d, 1H, J=3.6 Hz), 8,00 (s, 1H), 7,72 (d, 1H, J=7,0 Hz), 7,58-7,35 (m, 3H), 7,20-7,13 (m, 5H), 4,19-4,08 (m, 3H), of 3.97 (d, 1H, J=15 Hz), 3,84 (d, 1H, J=13.5 Hz), 2,90 is 2.75 (m, 2H), 2,54-of 2.50 (m, 1H), 2,15-2,11 (m, 1H), 2,04-of 1.92 (m, 1H), 1,79-65 (m, 1H).

According to the General procedure D conversion result of the above foam (38 mg) in hydrobromide salt gave AMD9829.1H NMR (300 MHz, D2O) δ to 9.15 (s, 1H), 8,78 (DD, 1H, J=5,7, 1.2 Hz), 8,39 (d, 1H, J=8.1 Hz), 7,92 (DD, 1H, J=7,8, 6,0 Hz), 7,49-7,42 (m, 3H), 7,41 and 7.36 (m, 2H), 7,28 (t, 1H, J=8.1 Hz), to 7.15 (d, 1H, J=8.1 Hz), 4,89 of 4.83 (m, 1H), 4,54 (d, 1H, J=16.5 Hz), and 4.40 (d, 1H, J=13.5 Hz), 4,34 (d, 1H, J=16.2 Hz), 4,16 (d, 1H, J=13.5 Hz), 3,06-3,03 (m, 2H), 2,56-2,52 (m, 1H), 2,31-2,22 (m, 2H), 1,97-of 1.94 (m, 1H);13C NMR (75.5 MHz, D2O) δ 150,4, 148,2, 141,0, 140,1, 140,0, 130,5, 130,0, 128,4, 126,9, 1261, 123,7, 114,1, 113,6, 66,5, 63,1, 52,8, 49,1, 27,9, 21,0, 20,5. ES-MS m/z 409,3 (M+H). Elemental analysis. Calculated for C25H24N6·2,NVG·2,2H2O: C, 43,98; H, To 4.62; N, 12,31; Br, 33,94. Found: C, 44,22; H, 4.75 V; N, 12,11; Br, 33,75.

Example: 79

AMD9780: Receive (1H-benzimidazole-2-ylmethyl)pyridine-4-ylmethyl-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

According to the General method B to a solution of (1-tert-butoxycarbonylamino-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (120 mg, 0.32 mmol) and 4-pyridinecarboxamide (30 μl, 0.32 mmol) in CH2Cl2(5 ml) was added triacetoxyborohydride sodium (136 mg, 0.64 mmol) and the reaction mixture was stirred for 18 hours. The crude substance was placed in undiluted TFOC (1 ml) and stirred 3 hours. Was added a saturated aqueous solution of sodium bicarbonate (5 ml) and the resulting mixture was extracted with CH2Cl2(3×10 ml)then the combined organic extracts were dried (MgSO4) and concentrated in vacuum. Purification of the crude substances by radial chromatography (1 mm plate, 50:1:1 CH2Cl2-MeOH-NH4OH) gave specified in the title compound (83 mg, 70%) as a white solid.1H NMR (CDCl3) δ 1,68-1,72 (m, 1H), 1,97-to 2.06 (m, 2H), 2.26 and-of 2.30 (m, 1H), 2,74-2,77 (m, 1H), 2,80-of 2.86 (m, 1H), of 3.77 (s, 2H), 3,92 (d, 1H, J=16 Hz), 4.09 to (DD, 1H, J=9, 7 Hz), 4,17 (d, 1H, J=16 Hz), 7.18 in-7,22 (m, 3H), of 7.36 (d, 2H, J=6 Hz), 7,44 (DD, 1H, =7, 1 Hz), 7,52 (userd, 1H, J=7 Hz), 7,66 (user. d, 1H, J=7 Hz), 8,46 (DD, 2H, J=5, 2 Hz), to 8.70 (DD, 1H, J=5, 1 Hz);13C NMR (CDCl3) δ 21,2, 23,8, 29,0, 49,1, 53,0, 60,5, 110,9, 118,8, 121,4, 121,9, 122,5, 123,3, 133,7, 134,7, 137,4, 144,2, 146,9, 148,7, 149,8, 155,4, 156,9. ES-MS m/z 370 (M+H). Elemental analysis. Calculated for C23H23N5·0,2N2About·0,2CH2Cl2: C, 71,44; H X 6.15; N, 17,95. Found: C, 71,63; H, 6,30; N, 17,77.

Example: 80

AMD9781: Receive (1H-benzimidazole-2-ylmethyl))-(benzo[1,3]dioxol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine

According to the General method B to a solution of 2,3-(methylenedioxy)benzaldehyde (57 mg, 0,379 mmol) and [1-(tert-butoxycarbonyl)-(1H-benzimidazole-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (140 mg, 0,371 mmol) in CH2Cl2(5 ml) was added NaBH(OAc)3(107 mg, worn : 0.505 mmol) and the reaction mixture was stirred over night. Purification of the resulting oil by radial chromatography on silica gel (2 mm TLC, 100:1:1 CH2Cl2:CH3OH:NH4OH) gave N-alkilirovanny amine (105 mg). A solution of the amine in TFOC (2 ml) was stirred for 1 hour, then concentrated under reduced pressure and the crude product was distributed between CH2Cl2(15 ml) and saturated aqueous NaHCO3(15 ml). The phases were separated and the organic layer was dried (Na2SO4), filtered, concentrated and purified by radial chromatography(1 mm TLC plate, 125:1:1 CH2Cl2:CH3OH:NH4OH), receiving AMD9781 (45% in two stages).1H NMR (CDCl3) δ 1,61 to 1.76 (m, 1H), 1.93 and-of 2.09 (m, 2H), 2.21 are 2,31 (m, 1H), 2,64-2,90 (m, 2H), to 3.67 (d, 1H, J=14,0 Hz), 3,92 (d, 1H, J=13,8 Hz), a 4.03 (d, 1H, J=16.5 Hz), 4,11 (DD, 1H, J=9,2, 6,8 Hz), is 4.21 (d, 1H, J=16,7 Hz), of 5.89 (s, 2H), only 6.64 (d, 1H, J=7,0 Hz), of 6.71 (t, 1H, J=7,7 Hz), 6,98 (d, 1H, J=8.1 Hz), 7,11-of 7.23 (m, 3H), 7,40 (d, 1H, J=7,6 Hz), 7,55-7,63 (m, 2H), 8,64 (d, 1H, J=3.6 Hz);13C NMR (CDCl3) δ 21,54, 24,21, 29,31, 29,84, 47,82, 49,15, 60,63, 100,74, 107,42 (2 carbon), 120,85, 121,70, 121,74 (2 carbon), 122,34 (2 carbon), 122,76 (2 carbon), 134,80, 137,34 (2 carbon), 145,98, 146,95 (2 carbon), 147,07, 156,34, 157,45. ES-MS m/z 413 (M+H) Elemental analysis. Calculated for C25H24N4O2·0,8H2O: C, 70,34; H, 6,04; N, 13,12. Found: C, 70,44; H, 5,98; N, 12,88.

Example: 81

AMD9789: Getting benzo[1,3]dioxol-5-ylmethyl-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

Using General method B to a solution of [1-(tert-butoxycarbonyl)-(1H-benzimidazole-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (125 mg, 0.33 mmol), piperonal (50 mg, 0.33 mmol) and AcOH (0,02 ml, 0.33 mmol) in THF (3.3 ml) was added NaBH(SLA)3(210 mg, 0,99 mmol) and the resulting suspension was stirred at room temperature for 16 hours. The crude product was dissolved in a mixture of CH2Cl2(˜2 ml) and triperoxonane acid (˜2 ml). After 1.5 hours the reaction mixture was concentrated, re-dissolved the H 2O (˜2 ml) and podslushivaet 1H. NaOH. The aqueous solution was extracted with CH2Cl2(3 x 50 ml) and the combined organic extracts were dried over MgSO4and concentrated to a yellow syrup. The product was purified column chromatography on silica gel (100:1:1 - EtOAc:Meon:NH4IT), getting mentioned in the title compound as a white foam (45 mg, 33%).1H NMR (300 MHz, CDCl3) δ 8,69 (d, 1H, J=3.3 Hz), 7,58 (user. s, 2H), 7,43 (d, 1H, J=7,2 Hz), 7,21-7,16 (m, 3H), of 6.99 (d, 1H, J=1.5 Hz), 6,79 (DD, 1H, J=8,1, 1.5 Hz), of 6.65 (d, 1H, J=7.8 Hz), 5,86-to 5.85 (m, 2H), 4,15 (d, 1H, J=16.5 Hz), 4.09 to 4,06 (m, 1H), 3,98 (d, 1H, J=16,8 Hz)to 3.64 (s, 2H), 2.91 in is 2.80 (m, 1H), 2,74-to 2.67 (m, 1H), 2,27-2,17 (m, 1H), 2.06 to of 1.64 (m, 2H), 1,75-of 1.64 (m, 1H);13C NMR (75.5 MHz, CDCl3) δ 159,2, 158,0, 149,4, 148,7, 148,5, 139,0, 136,5, 135,0, 124,0, 123,5, 123,3, 110,7, 109,5, 102,5, 61,8, 55,5, 49,9, 31,0, 25,0, 23,1. ES-MS m/z 413,3 (M+H). Elemental analysis. Calculated for C25H24N4O2·0,8H2O: C, 70,34; H, 6,04; N, 13,12, Found: C, 70,29; H, of 5.99; N, was 12.75,

Example: 82

AMD9817: Receive (1H-benzimidazole-2-ylmethyl)-(2,3-dihydrobenzofuran-7-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

According to the General method B to a solution of 2,3-dihydrobenzofuran-7-carboxaldehyde (53,6 mg, 0,362 mmol) and [1-(tert-butoxycarbonyl)-(1H-benzimidazole-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (136 mg, 0,361 mmol) CH2Cl2(5 ml) was added NaBH(OAc)3(112 mg, 0,528 mmol) and the mixture was stirred for whom the night. Purification of the crude product by radial chromatography on silica gel (1 mm TLC plate, 125:1:1 CH2Cl2: CH3OH:NH4OH) gave the target free base (48 mg, 33 %).

According to the General procedure D conversion result of the above amine (28 mg, 38 %) gave AMD9817.1H NMR (D2O) δ 1,84 is 2.01 (m, 1H), 2,08-to 2.29 (m, 2H), 2,34-of 2.54 (m, 2H), 2,70-and 2.83 (m, 1H), 2.95 and-of 3.12 (m, 2H), 3,39 (d, 1H, J=a 12.7 Hz), 3,57 (d, 1H, J=12,6 Hz), 4,37 (d, 1H, J=16.2 Hz), 4,48-to 4.73 (m, 3H) [4,60 (d, 1H, J=15,5 Hz)], 6,52-6,56 (m, 2H), 6,91 (DD, 1H, J=6,1, 2.7 Hz), to 7.50 (DD, 2H, J=6,3, 2,8 Hz), 7,58 (DD, 2H, J=6,6, 3.0 Hz), to 7.93 (DD, 1H, J=7,9, 5,9 Hz), 8,39 (d, 1H, J=7,0 Hz), 8,73 (d, 1H, J=5.0 Hz);13C NMR (D2O) δ 20,48, 20,86, 27,43, 28,73, 50,35, 51,50, 63,64, 72,17, 113,74 (2 carbon), 117,76, 121,22, 125,49, 126,17, 126,64, 127,73 (2 carbon), 129,77, 130,53, 138,83 (2 carbon), 140,34, 147,85, 150,58, 151,78, 157,51. ES-MS m/z 411 (M+H). Elemental analysis. Calculated for C26H26N4O·2,2HBr·2,1H2O: C, 49,86; H, To 5.21; N, 8,94; Br, 28,07. Found: C, 50,16; H, 5,02; N, 9,03; Br, 27,68.

Example: 83

AMD9818: Receive (1H-benzimidazole-2-ylmethyl)pyridine-3-ylmethyl-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

According to the General method B to a solution of 3-pyridinecarboxamide (29 mg, 0,271 mmol) and [1-(tert-butoxycarbonyl)-(1H-benzimidazole-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (103 mg, 0,273 mmol) in CH2Cl2(5 ml) was added NaBH(OAc)3(98 mg, 0,462 mmol) and the reaction mixture was stirred over night. Cleaning untreated the i.i.d. product by radial chromatography (1 mm TLC plate, 80:1:1 CH2Cl2:CH3OH:NH4OH) gave the target free base (64 mg, 50 %).

According to the General procedure D conversion result of the above amine (64 mg) in hydrobromide salt gave AMD9818 (69 mg, 78%).1H NMR (D2O) δ 1,80 is 1.96 (m, 1H), 2,16-2,31 (m, 2H), 2,43-of 2.54 (m, 1H), 3,01-is 3.08 (m, 2H), 4,10 (d, 1H, J=14.1 Hz), 4,24 (d, 1H, J=a 13.9 Hz), 4,43 (d, 1H, J=16.4 Hz), br4.61 (d, 1H, J=15.6 Hz), 4,72-of 4.75 (m, 1H), 7,58 (DD, 2H, J=6,5, and 3.3 Hz), 7,69 (DD, 2H, J=6,4, and 3.4 Hz), 7,81 (DD, 1H, J=8,2, 6,0 Hz), to $ 7.91 (DD, 1H, J=8,1, 6,0 Hz), at 8.36-to 8.41 (m, 2H), 8,54 (d, 1H, J=8.0 Hz), a total of 8.74-8,79 (m, 2H);13C NMR (D2O) δ 14,54, 20,29, 20,76, 27,83, 48,39, 53,46, 61,54, 66,47, 114,23 (2 carbon), 126,30, 127,29 (2 carbon), 127,42, 130,76, 137,43, 140,23, 141,21, 141,25, 141,63, 147,43, 148,44, 149,92, 150,13. ES-MS m/z 370 (M+H). Elemental analysis. Calculated for C23H23N5·3,NVG·1,8H2About: With, 42,85; N, 4,63; N, 10,86; Br, 37,19. Found: C, 43,22; N, Of 4.66; N, 10,69; Br, Eur36, 85.

Example: 84

AMD9828: Receive (1H-benzoimidazol-5-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Obtaining 1H-benzimidazole-5-carbaldehyde

LiAlH4(1.0 m in THF, 10 ml, 10 mmol) was added dropwise to a suspension of 5-benzimidazolecarbamic acid (500 mg, is 3.08 mmol) in THF (20 ml) at 0°C. the Reaction mixture was heated to room temperature and was stirred for 24 hours followed by heating at 50°C additionally within 24 hours. To allali MeOH (4 × 5 ml) was added and the solution was concentrated between each addition. The obtained brown syrup was dried in vacuum for 3 hours. The syrup was dissolved in a mixture of 100:1 - CH2Cl2:MeOH, filtered through celite and concentrated, obtaining a light brown foam (300 mg, 66%). To a stirred solution of the crude alcohol (300 mg, 2.0 mmol) in CH2Cl2(10 ml) and MeOH (0.8 ml) was added manganese oxide (IV) (85%, of 2.05 g, 20 mmol). The suspension was heated at 40°C for 18 hours, cooled to room temperature and filtered through celite. The filtrate was concentrated, obtaining a light yellow foam (260 mg). Purification of the crude substances column chromatography on silica gel (200:1:1 - EtOAc:MeOH:NH4OH) gave specified in the title compound as a white powder (139 mg, 60%).1H NMR (300 MHz, CD3OD) δ 10,0 (s, 1H), scored 8.38 (s, 1H), to 8.20 (s, 1H), 7,87 (d, 1H, J=9.0 Hz), of 7.75 (d, 1H, J=9.0 Hz).

Using a common methodology BA, to a solution of [1-(tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (215 mg, or 0.57 mmol), 1H-benzoimidazol-5-carbaldehyde (81 mg, or 0.57 mmol) and AcOH (0,03 ml, 0.55 mmol) in THF (5.5 ml) was added NaBH(OAc)3(353 mg, of 1.65 mmol) and the suspension was stirred at room temperature for 24 hours. The crude product was dissolved in a mixture of CH2Cl2(˜2 ml) and triperoxonane acid (˜2 ml). After 3 hours the reaction mixture to which has centriole, was re-dissolved in H2O (˜2 ml) and podslushivaet 1H. NaOH. The aqueous solution was extracted with CH2Cl2(3 × 50 ml), the combined organic extracts were dried over MgSO4and concentrated, obtaining a yellow foam. The product was purified column chromatography on silica gel (100:2:1 - EtOAc:MeOH:NH4OH), getting mentioned in the title compound as a pale yellow foam (52 mg, 24%).1H NMR (300 MHz, CDCl3) δ 8,68 (d, 1H, J=3.3 Hz), 7,95 (s, 1H), 7,56 (user. s, 4H), 7,41 (d, 1H, J=6.6 Hz), 7,27 (d, 1H, J=7.5 Hz), 7.18 in-7,14 (m, 3H), 4,15 (d, 1H, J=16,8 Hz), 4,10-4,06 (m, 1H), 4.00 points (d, 1H, J=16,8 Hz), 3,85 (d, 1H, J=13,2 Hz), of 3.77 (d, 1H, J=13.5 Hz), 2,90-2,73 (m, 1H), 2,73 of 2.68 (m, 1H), 2.26 and-of 2.21 (m, 1H), 2,08 is 2.00 (m, 2H), 1,79-of 1.64 (m, 1H).

According to the General procedure D conversion result of the above foam (52 mg) in hydrobromide salt gave AMD9828.1H NMR (300 MHz, D2O) δ 8,81-8,78 (m, 2H), 8,43 (d, 1H, J=6.9 Hz), 7,95 (DD, 1H, J=8,1, 6 Hz), 7,54-7,51 (m, 2H), 7,44-to 7.35 (m, 5H), 4,85-rate 4.79 (m, 1H), with 4.64 (d, 1H, J=16.2 Hz), 4,46 (d, 1H, J=16.2 Hz), 4,07 (d, 1H, J=12.9 Hz), 4.00 points (d, 1H, J=12.9 Hz), is 3.08 was 3.05 (m, 2H), of 2.51-2,48 (m, 1H), 2,35-2,22 (m, 2H), 1,98-of 1.93 (m, 1H);13C NMR (75.5 MHz, D2O) δ 151,7, 150,6, 148,4, 141,1, 139,9, 136,8, 135,8, 130,1, 129,8, 129,5, 128,9, 126,8, 126,2, 115,2, 114,7, 113,4, 63,5, 57,3, 50,0, 27,9, 21,1, 20,5. ES-MS m/z 409,3 (M+H). Elemental analysis. Calculated for C25H24N6·2,NVG·3,0H2About: With, 43,07; H, Was 4.76; N, 12,05; Br, 33,24. Found: C, 43,12; H And 4.65; N, 11,71; Br, 33,39.

Example: 85

AMD9844: Obtaining bis(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tet is hydrochinon-8-yl)amine (hydrobromide salt).

According to the General method N-alkylation to stir the solution (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (of 7.64 g, 28.5 mmol) in anhydrous CH3CN (3 ml) was added 1-N-tert-butoxycarbonyl-2-chloromethylbenzene (115 mg, 0.41 mmol), N,N-diisopropylethylamine (0,13 ml, 5 to 0.74 mmol) and potassium iodide (3 mg, 0.02 mmol) and the mixture was stirred in argon atmosphere at 60°C for 4 hours. The crude yellow oil was dissolved in anhydrous CH2Cl2(2 ml) and added dropwise triperoxonane acid (1 ml). The resulting mixture was stirred over night at room temperature. The reaction mixture was diluted with CH2Cl2(10 ml) and then concentrated in vacuo to remove excess triperoxonane acid. The concentrate was diluted with CH2Cl2(20 ml) and was extracted with 1N. NaOH (30 ml). The aqueous layer was washed with CH2Cl2(2 × 15 ml) and then the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuum. Purification by radial chromatography on a 2 mm plate of silica gel for TLC (CH2Cl2/MeOH/NH4OH, 100:1:1 then 50:1:1) gave the adduct of bibenzimidazole (134 mg, 49%, stage 2) in the form of a colorless oil.

Using General method D, the transformation of the free base (134 mg, 0.33 mmol) in hydrobromide salt gave AMD9844 in the form of a beige solid matter what (192 mg). 1H NMR (D2O) δ 1,87-2,04 (user. m, 1H), 2,15-is 2.37 (m, 2H), 2,41-2,55 (user. m, 1H), 2,99-of 3.12 (m, 2H), 4,46 (d, 2H, J=15.6 Hz)and 4.65 (d, 2H, J=15.6 Hz), to 4.92 (DD, 1H, J=10,2, 6.3 Hz), 7,34-7,44 (m, 8H), of 7.90 (DD, 1H, J=8,1, 6,0 Hz), scored 8.38 (d, 1H, J=7.8 Hz), 8,76 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,29, 21,27, 27,77, 48,75, 63,05, 113,81, 126,33, 127,28, 130,82, 140,52, 141,10, 148,45, 148,80, 148,92; ES-MS m/z 409 (M+H). Elemental analysis. Calculated for C25H24N6·3,0HBr·1,8H2O·0,3C4H10O: C, 44,58; H, 4,80; N, 11,91; Br, 33,96. Found: C, 44,52; H, To 4.68; N, 11,91; Br, 33,94.

Example: 86

AMD9875: Receive (1H-benzimidazole-2-ylmethyl)-(3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Using General method B, the interaction 4(5)-imidazolecarboxaldehyde (by 0.055 g, 5 or 0.57 mmol) and (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,164 g, 0.43 mmol) with NaBH(OAc)3(0,154 g, 0.73 mmol) in CH2Cl2(4 ml) for 24 hours followed by purification of the crude substances by radial chromatography on silica gel (2 mm plate, 20:1:1 CH2Cl2-CH3OH-NH4OH) gave 0,099 g (50%) of the target tertiary amine as a white solid.

Using General method D, the transformation of white solid (99 mg) in hydrobromide salt with simultaneous removal of the BOC-protective group, followed by presidenial intermediate solid washes the VA from methanol/ether, gave AMD9875 (97 mg) as a white solid.1H NMR (D2O) δ 1,83-of 1.97 (m, 1H), 2,15-of 2.26 (m, 2H), 2,39 is 2.46 (m, 1H), 3,03 was 3.05 (m, 2H), 4,05 (d, 1H, J=15,0 Hz), is 4.21 (d, 1H, J=15,0 Hz), of 4.44 (d, 1H, J=16.2 Hz), 4,59 (d, 1H, J=16.2 Hz), and 4.75 (DD, 1H, J=6,0, 10,2 Hz), 7,35 (s, 1H), to 7.59-the 7.65 (m, 2H), 7,73 for 7.78 (m, 2H), of 7.90 (DD, 1H, J=6,6, 7,2 Hz), scored 8.38 (d, 1H, J=8.1 Hz), 8,48 (s, 1H), 8,72 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,32, 20,66, 27,72, 46,28, 48,05, 61,54, 114,16, 118,98, 126,13, 127,27, 129,11, 130,73, 134,90, 140,07, 140,87, 148,31, 149,87, 150,31; ES-MS m/z 359 (M+H). Elemental analysis. Calculated for C21H22N6·3,0HBr·2,6H2O: C, 38,92; H, 4,70; N, 12,97; Br, 36,99. Found: C, 39,02; H, 4,59; N, 12,72; Br, 37,02.

Example: 87

AMD9575: Obtain [4-(1H-benzimidazole-2-yl)benzyl]-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Getting 4-(benzimidazole-2-yl)benzaldehyde

A solution of 2-nitroaniline (0,41 g, 3.0 mmol) and methyl 4-chlorocarbonate (0.65 g, 3.3 mmol) in THF (3,7 ml) and pyridine (0.8 ml) was stirred for 2 hours at room temperature. The reaction mixture was diluted with saturated sodium bicarbonate solution (10 ml) and EtOAc (15 ml), the phases were separated and the aqueous phase was extracted with EtOAc (2 × 10 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure, obtaining methyl ether (2-nitrophenyl)terephthalamide acid as a yellow solid (0,0 g 78%).1H NMR (CDCl3) δ of 3.97 (s, 3H), 7,25 (t, 1H, J=7.8 Hz), 7,74 (t, 1H, J=7.8 Hz), of 8.04 (d, 2H, J=7.8 Hz), to 8.20 (s, 1H (NH)), to 8.20 (d, 2H, J=7.8 Hz), 8,30 (d, 1H, J=7.8 Hz), 8,99 (d, 1H, J=7,8 Hz).

To a solution of methyl ester (2-nitrophenyl)terephthalamide acid (0,23 g, from 0.76 mmol) in glacial acetic acid (2.5 ml) was added iron powder (sieve composition <5 μm, 0.12 g, 2.1 mmol) and the mixture was stirred while boiling under reflux for 1 hour. 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 (10 ml) and ethyl acetate (10 ml), the phases were separated and the organic layer was washed with saturated NaHCO3(10 ml). The organic extract was dried (MgSO4), filtered and concentrated, obtaining cyklinowanie methyl 4-(benzimidazole-2-yl)benzoate (0,163 g, 86%).1H NMR (CDCl3) δ of 3.96 (s, 3H), 7,32 (m, 2H), 7,53 (user., 1H), 7,84 (user., 1H), 8,17 (m, 4H), 9,65 (user., 1H (NH)).

To a solution of methyl 4-(benzimidazole-2-yl)benzoate (to 0.23 g, 0.9 mmol) in THF (10 ml) at 0°C was added a solution of DIBAL-H (5.0 ml, 1.0 M in THF, 5.0 mmol). The reaction mixture was left to warm to room temperature, was stirred for 1 hour and extinguished a saturated solution of tartrate of potassium-sodium (20 ml). A two-phase system was intensively stirred for 1 hour, the phases were separated and the organic layer su is or (MgSO 4), filtered, concentrated and purified column chromatography on silica gel (7% Meon/CH2Cl2)to give 4-(benzimidazole-2-yl)benzyl alcohol (0,175 g, 87%).1H NMR (CD4OD) δ 3,30 (s, 1H (OH)), 4,69 (s, 2H), 7,26 (m, 2H), 7,53 (d, 2H, J=8,4 Hz), 7,60 (m, 2H), 8,07 (d, 2H, J=8.1 Hz).

The result of the above 4-(benzimidazole-2-yl)benzyl alcohol (0,175 g, 0.78 mmol) was dissolved in CH2Cl2(5 ml) and THF (8 ml), treated with activated MnO2(0.68 g, 7.8 mmol) and stirred at room temperature for 1.5 hours. The mixture was filtered through celite, the filter cake was washed CH2Cl2and the solvent from the eluent was removed under reduced pressure, obtaining 4-(benzimidazole-2-yl)benzaldehyde (92 mg, 42%).1H NMR (CD4OD) δ 7,28 (m, 2H), 7,60 (user., 1H (NH)), the 7.65 (d, 2H, J=7.8 Hz), of 8.09 (d, 2H, J=7.8 Hz), 8,30 (d, 2H, J=9.0 Hz), 10,08 (s, 1H (CHO)).

Using General method B to a solution of 4-(benzimidazole-2-yl)benzaldehyde (39 mg, 0,175 mmol) and (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (60 mg, 0.16 mmol) in THF (2 ml) was added acetic acid (90 μl) and triacetoxyborohydride sodium (68 mg, 0.32 mmol) and the mixture was stirred at 60°C for 3 hours. Purification of the crude product by radial chromatography on silica gel (0,7%MeOH/0.5%of NH4OH/CH2Cl2) gave the target [4-(1H-benzimidazole-2-yl)benzyl]-(N-tert-butoxycarbonylamino the ol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (30 mg, 39%) as a flaky white solid.1H NMR (CDCl3) δ 1,72 (s, 10H)of 1.97 (m, 2H), and 2.26 (m, 1H), 2,73 (m, 2H), 3,80 (d, 1H, J=15,0 Hz), 4.00 points (d, 1H, J=15,0 Hz), 4,35 (m, 1H), 4,71 (s, 2H), 7,00 (m, 1H), 7,14 (m, 2H), 7,24 (m, 3H), 7,33 (d, 2H, J=7,2 Hz), 7,47 (user., 1H), 7,53 (d, 1H, J=12 Hz), 7,63 (d, 1H, J=7.8 Hz), to 7.67 (d, 2H, J=7.8 Hz), 7,79 (user., 1H), 8,39 (d, 1H, J=3.5 Hz), 9,92 (user., 1H (NH)).

Using General method D, the transformation obtained above substance (30 mg) in hydrobromide salt to obtain AMD9575 (0,026 g) as a white solid.1H NMR (D2O) δ 1,92 (user. m, 1H, in), 2.25 (m, 2H), 2,47 (user. m, 1H), 3,06 (user. m, 2H), 3,78 (d, 1H, J=12.9 Hz), 3,92 (d, 1H, J=12,6 Hz), of 4.44 (d, 1H, J=16.5 Hz), 4,63 (d, 1H, J=15,9 Hz), 4,80 (m, 1H), 7,01 (DD, 2H, J=6,0, a 3.2 Hz), 7,37 (d, 2H, J=8.1 Hz), the 7.43 (DD, 2H, J=3.2, and 6.0 Hz), rate of 7.54 (d, 2H, J=8.1 Hz), 7,58 (DD, 2H, J=3,0, 6.3 Hz), 7,74 (DD, 2H, J=3,0, 6.3 Hz), of 7.97 (t, 1H, J=6.9 Hz), 8,44 (d, 1H, J=7.8 Hz), 8,81 (d, 1H, J=5.4 Hz);13C NMR (D2O) δ 19,74, 20,48, 27,23, 49,56, 55,99, 62,95, 113,15 (2C), 113,40 (2C), 120,78 (2C), 125,49 (2C), 125,62, 126,33 (2C), 126,41 (2C), 129,83, 130,79 (2Q, 139,23 (2C), 140,50, 141,69, 146,89, 147,76 (2C), 149,95, 150,89. ES-MS m/z 485 (M+H). Elemental analysis. Calculated for C31H28N6·3,0HBr·3,6H2O: C, 46,90; H, A 4.86; N, 10,59; Br, 30,35. Found: C, 46,93; H, 4,74; N, 10,41; Br, 30,34.

Example: 88

AMD9719: Receive (1H-benzimidazole-2-ylmethyl)-(4-pyrid-2-ylbenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

According to the General method B to a solution of (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydro the quinoline-8-yl)amine (174 mg, 0,462 mmol) and 4-pyrid-2-eventoccured (161 mg, 0,879 mmol) in CH2Cl2(5 ml) was added NaBH(SLA)3(192 mg, 0,906 mmol) and the mixture was stirred over night. Purification of the crude substances by radial chromatography (2 mm TLC plate, 100:1:1 CH2Cl2/CH3HE/NH4HE gave the free base (is 0.135 g, 66%).

According to the General procedure D conversion result of the above substances (135 mg) in hydrobromide salt gave AMD9719 (0,154 g, 69%).1H NMR (D2O) δ 1,86 is 2.00 (m, 1H), 2,19-is 2.37 (m, 2H), 2,44-of 2.54 (m, 1H), 3,03-3,11 (m, 2H), 3,90 (d, 1H, J=a 12.7 Hz), 3,98 (d, 1H, J=13,2 Hz), 4,50 (d, 1H, J=16.4 Hz), and 4.68 (d, 1H, J=16.6 Hz), 7,29 (DD, 2H, J=6,4, and 3.3 Hz), 7,40-of 7.48 (m, 4H), 7,53 (DD, 2H, J=6,2, 3.1 Hz), 7,69 (d, 1H, J=8.5 Hz), of 7.90-to 7.99 (m, 2H), 8,44 (d, 1H, J=7.9 Hz), 8,51 (t, 1H, J=8.0 Hz), to 8.62 (d, 1H, J=5.6 Hz), 8,81 (d, 1H, J=5.3 Hz);13C NMR (D2O) δ 19,95, 20,58, 27,38, 49,79, 56,32, 63,04, 113,36 (2 carbon), 125,41, 125,71, 125,78, 126,21 (2 carbon), 127,29 (2 carbon), 129,66, 129,93, 130,91 (2 carbon), 139,31, 140,63, 140,95, 146,80 (2 carbon), 147,89 (2 carbon), 150,18, 150,59, 151,15. ES-MS m/z 446 (M+H). Elemental analysis. Calculated for C29H27N5·3,1HBr·2,0H2O: C, 47,56; H, 4,69; N, 9,56; Br, 33,82. Found: C, 47,60; H, Was 4.76; N, 9,44; Br, 33,93.

Example 89

AMD9750: Receive (1H-benzimidazole-2-ylmethyl)-[4-(oxazol-2-yl)benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Getting 4-(oxazol-2-yl)benzyl alcohol (B.A. Anderson et al. J. Org. Chem. 1997, 62, 8634):

To a solution of oxazole (0,285 ml, 4 mmol) in THF (40 ml) at -78°C was added n-utility (1,83 2 ml,4M solution in hexano, 4.4 mmol) and the reaction mixture was stirred for 30 minutes at -78°C, then added zinc chloride (12 ml, 1M solution in THF, 12 mmol). The mixture is then left to rise slowly to 0°C and was stirred for 45 minutes. Solution was added methyl-4-bromobenzoate (0,860 g, 4 mmol) in THF (10 ml) followed by a solution of bis(triphenylphosphine)pallidiflora (P) (140 mg, 0.2 mmol) and n-utility (0,17 2 ml,4M solution in hexano, 0.4 mmol) in THF (4 ml). The obtained dark brown mixture was heated to boiling under reflux and was stirred for 1 hour. After cooling, the reaction mixture was diluted with ethyl acetate (30 ml), then washed with water (1 × 20 ml) and saturated salt solution (1 × 20 ml). The organic layer was dried (Na2SO4), filtered, concentrated and purified by chromatography on silica gel (98:2 CH2Cl2/MeOH)to give the target methyl-4-(oxazol-2-yl)benzoate (340 mg, 42%) as a yellow oil.1H NMR (CDCl3) δ of 3.94 (s, 3H), 7,28 (s, 1H), 7,76 (m, 1H), 8,09 (m, 4H).

To a solution of methyl-4-(oxazol-2-yl)benzoate (0,203 g, 1 mmol) in CH2Cl2(10 ml) at 0°C was added DIBAL-H (4 ml of 1,0M solution in dichloromethane, 4 mmol) for 10 minutes. The resulting solution was stirred at 0°C for 2 h, the owls, then extinguished saturated aqueous solution of tartrate of potassium-sodium (20 ml) and the biphasic mixture was rapidly stirred for 60 minutes. The phases were separated and the aqueous layer was extracted with CH2Cl2(3 x 10 ml). The combined organic fractions were dried (Na2SO4), filtered, concentrated and purified by chromatography on silica gel (10:1 CH2Cl2/Meon), getting listed in the title alcohol (0.156 g, 89%).1H NMR (CDCl3) δ 3,42 (t, 1H, J=6,0 Hz (OH)), of 4.77 (s, 2H, J=6.0 Hz), 7,24 (s, 1H), 7,47 (d, 2H, J=7.8 Hz), 7,71 (s, 1H), with 8.05 (d, 2H, J=7,8 Hz).

Using General method C, to a solution of 4-(oxazol-2-yl)benzyl alcohol (156 mg, 0.89 mmol) in CH2Cl2(10 ml) was added methanesulfonamide (is 0.102 ml of 1.34 mmol) and triethylamine (0,250 ml, to 1.79 mmol) and the mixture was stirred for 30 minutes at room temperature. End mesilate was received in the form of fine white powder and used directly in the next reaction without further purification.1H NMR (CDCl3) δ 3,00 (s, 3H), to 3.67 (s, 2H), 7,26 (s, 1H), 7,51 (d, 2H, J=8.1 Hz), 7,74 (s, 1H), 8,07 (d, 2H, J=8.1 Hz).

Using the General method of alkylation, to the solution obtained above nelfinavir (56 mg, 0.22 mmol), K2CO3(60 mg, 0.44 mmol) and KI (2 mg, 0.01 mmol) in CH3CN (10 ml) was added 1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (13 mg, 0.3 mmol) and the mixture was stirred p. and 60° C for 16 hours. Purification of the crude substances by chromatography on silica gel (10:1 CH2Cl2/MeOH) gave N-alkilirovanny product (89 mg, 93%).1H NMR (CDCl3) δ at 1.73 (s, 9H), 2,03 (m, 3H), of 2.20 (m, 1H), 2,75 (m, 2H), 3,81 (d, 1H, J=16.1 Hz), Android 4.04 (d, 1H, J=16.1 Hz), 4,34 (DD, 1H, J=9,1, 6.2 Hz), of 4.67 (s, 2H), 7,03 (m, 1H), 7,11-7,17 (m, 2H), 7,26 (m, 4H), EUR 7.57-to 7.68 (m, 5H), 8,44 (d, 1H, J=5,1 Hz).

Using General method D, the transformation obtained above amine (89 mg, at 0.020 mmol) in hydrobromide salt gave AMD9750 (14 mg) as a white solid.1H NMR (D2O) δ 2,07 (m, 1H), and 2.26 (m, 2H), 2,44 (m, 1H), 3,05 (m, 2H), 3,81 (m, 3H), 4,42 (d, 1H, J=16.2 Hz), 4,63 (d, 1H, J=16.2 Hz), 7,18 (s, 1H), 7,24 (m, 2H), 7,43 (m, 2H), 7,83 (s, 1H), 7,83 (t, 1H, J=7,8 Hz), 8,43 (d, 1H, J=8,4 Hz), 8,82 (d, 1H, J=5,2 Hz);13C NMR (D2O) δ 20,42, 21,07, 27,83, 50,22, 56,69, 63,49, 113,67 (2C), 125,02, to 126.14 (2C), 126,23 (2C), 126,69, 140,41, 130,81 (2C), 139,74, 140,35, 141,01, 148,33, 150,69, 151,41, 156,23, 161,09. ES-MS m/z 436 (M+H). Elemental analysis. Calculated for C27H25N5O·2,9HBr·2,0H2O: C, 45,92; H, 4,55; N, 9,92; Br 32,81. Found: C, 46,01; H And 4.65; N, Of 9.55; Br, 32,75.

Example: 90

AMD9755: Receive (1H-benzimidazole-2-ylmethyl)-(4-imidazol-1-ylbenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Using General method B, the interaction of 4-(imidazol-1-yl)benzaldehyde (0.075 g, 0.44 mmol) and (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,107 g, 0.29 mmol) with NaBH(OAc)3(0,171 g 0.81 mmol) in CH 2Cl2(3 ml) for 24 hours followed by purification of the crude substances column chromatography on silica gel (25:1:1 CH2Cl2-CH3OH-NH4OH) gave 0,091 g (58%) of the target tertiary amine as a white solid.

Using General method D, the transformation of white solid (91 mg) in hydrobromide salt with simultaneous removal of the BOC-protective group and subsequent presidenial intermediate solid from methanol/ether gave AMD9755 (89 mg) as a white solid.1H NMR (D2O) δ 1,86-2,02 (m, 1H), 2,22-of 2.36 (m, 2H), 2,48-2,52 (m, 1H), 3,06-is 3.08 (m, 2H), 3,90 (d, 1H, J=12,6 Hz), 3,98 (d, 1H, J=12,6 Hz), the 4.90 (d, 1H, J=16.5 Hz), 4,69 (d, 1H, J=16.5 Hz), 4,79-to 4.87 (m, 1H, overlap with HOD), 7,22 (d, 2H, J=8.7 Hz), 7,31 (DD, 1H, J=1,2, 1.5 Hz), 7,39-7,46 (m, 4H), 7,54-to 7.61 (m, 3H), 7,98 (DD, 1H, J=6,0, 7,8 Hz), to 8.45 (d, 1H, J=7.5 Hz), 8,67 (s, 1H), 8,82 (d, 1H, J=5.4 Hz);13C NMR (D2O) δ 21,03, 21,67, 28,46, 50,80, 57,18, 64,09, 114,49, 121,28, 121,87, 122,61, 126,80, 127,32, 131,06, 132,52, 134,10, 134,84, 139,32, 140,40, 141,74, 148,99, 151,26, 152,38; ES-MS m/z 435 (M+H). Elemental analysis. Calculated for C27H26N6·3,2HBr·3,4H2O: C, 42,97; H, To 4.81; N, 11,14; Br, 33,88. Found: C, 43,00; H, Br4.61; N, 10,89; Br, 33,93.

Example: 91

AMD9757: Obtain [4-(thiazol-2-yl)benzyl]-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Getting 4-(2-thiazolyl)benzaldehyde

To a solution of 2-bromothiazole (0.26 g 1.6 mmol) and 4-formylphenylboronic acid (0,48 g, 3.2 mmol) in toluene (16 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.08 mmol) and K2CO3(0.33 g, 2.4 mmol) and the solution was stirred while boiling under reflux for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and ethyl acetate (50 ml). The organic layer was separated, washed with saturated salt solution (30 ml), dried (MgSO4), filtered, concentrated and purified column chromatography on silica gel (2% MeOH/CH2Cl2)to give 4-(2-thiazolyl)benzaldehyde (45 mg, 15%).1H NMR (CDCl3) δ was 7.45 (d, 1H, J=3.0 Hz), of 7.90 (d, 1H, J=3.0 Hz), of 7.97 (d, 2H, J=7.8 Hz), 8,15 (d, 2H, J=12 Hz), 10,07 (s, 1H (SNO)).

Using General method B to a solution of 4-(2-thiazolyl)benzaldehyde (45 mg, 0.24 mmol) and (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (81 mg, 0.21 mmol) in dichloromethane (2.5 ml) was added NaBH(OAc)3(77 mg, 0.36 mmol) and the mixture was stirred at room temperature for 16 hours. Purification of the crude substances by radial chromatography on silica gel (MeOH/NH4HE/CH2Cl2, 1:1:98) gave the target amine (34 mg, 28%) as a flaky white solid.1H NMR (CDCl3) δ at 1.73 (m, 10H), of 1.97 (m, 2H), 2,25 (m, 1H), 2,75 (t, 2H), 3,84 (d, 1H, J=15,0 Hz), a 4.03 (d, 1H, J=15,0 Hz), 4,32 (m, 1H), and 4.68 (s, 2H), 7,02 (m, 1H), 7,10 (t, 1H, J=7,2 Hz), 7,18 (t, 1H, J=7,2 Hz), 7,27 (m, 4H), 7,58 (d, 2H, J=7.8 Hz), 7,0 (m, 2H), 7,78 (d, 1H, J=3.0 Hz), to 8.45 (d, 1H, J=3.5 Hz).

Using General method D, the transformation obtained above solid (34 mg) in hydrobromide salt gave AMD9757 (34 mg) as a white solid.1H NMR (D2O) δ 1,86 (user. m, 1H), 2,23 (m, 2H), 2,43 (user. m, 1H), 3,03 (user. m, 2H), 3,70 (d, 1H, J=12,6 Hz), 3,84 (d, 1H, J=12,6 Hz), 4,42 (d, 1H, J=16.5 Hz), to 4.62 (d, 1H, J=16.5 Hz), of 4.77 (m, 1H), 7,21 (d, 2H, J=12,6 Hz), 7,22 (d, 2H, J=8.7 Hz), 7,40 (d, 2H, J=8.1 Hz), was 7.45 (DD, 2H, J=of 3.0, 6.0 Hz), 7,66 (d, 1H, J=3.3 Hz), 7,83 (d, 1H, J=3.6 Hz), 7,94 (t, 1H, J=6.9 Hz), 8,40 (d, 1H, J=7.5 Hz), 8,78 (d, 1H, J=5,1 Hz);13C NMR (D2O) δ 20,43, 21,07, 27,85, 50,29, 56,73, 63,57, 113,70 (2C), 121,82, 126,19, 126,58 (4C), 130,42, 131,10 (2C), 139,75 (2C), 140,01, 140,13 (2C), 141,08, 148,36 (2C), 150,78, 151,54. ES-MS m/z 452 (M+H). Elemental analysis. Calculated for C27H25N5S·3,0HBr·2,0H2A: C, 44,21; H, To 4.41; N, Of 9.55; Br, 33,04. Found: C, 44,26; H, 4,37; N, 9,29; Br, 33,04.

Example: 92

AMD9595: Receive (1H-benzimidazole-2-ylmethyl)-[4-(benzothiazol-2-yl)benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt)

Getting 4-(benzothiazol-2-yl)benzyl alcohol

To a cooled to 0°C to a solution of methyl 4-(benzothiazol-2-yl)benzoate (obtained as described A. Brembilla, D. Roizard, and P. Lochon Synth. Commun. 1990, 20, 3379) (1.08 g, 4 mmol) in THF (20 ml) was added DIBAL-H (20 ml of 1,0M solution in THF, 20 mmol) for 10 minutes. The resulting solution was stirred at 0°C for 2 hours, then we use the water and a saturated solution of sodium tartrate, potassium and a two-phase mixture was vigorously stirred for 60 minutes. The phases were separated and the aqueous layer was extracted with ether (3 x 20 ml). The combined organic fractions were dried (Na2SO4), concentrated and purified column chromatography on silica gel (10:1 CH2Cl2/Meon), receiving specified in the header connection (0,69 g, 75%).1H NMR (CD3OD) δ 4,69 (s, 2H), 7,43 (t, 1H, J=7.8 Hz), 7,53 (m, 3H), to 7.99 (m, 1H), of 8.06 (m, 3H).

Using General method C, to a solution of 4-(benzothiazol-2-yl)benzyl alcohol (227 mg, 1.0 mmol) in CH2Cl2(10 ml) was added methanesulfonamide (0,092 ml, 1.2 mmol) and triethylamine (0,210 ml, 1.5 mmol) and the mixture was stirred at room temperature for 30 minutes. Mesilate was collected in the form of fine white powder and used without further purification in the next reaction.1H NMR (CDCl3) δ a 3.06 (s, 3H), 5,28 (s, 2H), 7,38 (t, 1H, J=6.2 Hz), 7,49 (t, 1H, J=6.2 Hz), 7,52 (d, 2H, J=7,1 Hz), of 7.90 (d, 1H, J=6.2 Hz), with 8.05 (d, 1H, J=6.2 Hz), 8,11 (d, 2H, J=7,1 Hz).

Using the General method of alkylation, the solution obtained above nelfinavir (1 mmol), N,N-diisopropylethylamine (0,093 ml, 1.2 mmol), potassium iodide (13 mg, 0.10 mmol) and (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (400 mg, 1.1 mmol) in CH3CN (10 ml) was stirred at 70°C for 3 hours. Purification of the crude substances column chromatography on silica gel (10:1 CH2Cl2/MeOH) gave alkilirovanny products is (1H-N-tert-butoxycarbonylamino-2-ylmethyl)-[4-(benzothiazol-2-yl)benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (354 mg, 71%).1H NMR (CDCl3) δ and 1.63 (s, 9H), to 2.06 (m, 3H), of 2.25 (m, 1H), 2,75 (m, 2H), 3,81 (d, 1H, J=16.1 Hz), was 4.02 (d, 1H, J=16.1 Hz), 4,34 (DD, 1H, J=8,3, 6,8 Hz)and 4.65 (d, 1H, J=13,2 Hz), 4,69 (d, 1H, J=13,2 Hz), 7,03 (m, 1H), 7,09-7,11 (m, 2H), 7,30 (m, 4H), 7,46 (t, 1H, J=8.1 Hz), a 7.62 (t, 2H, J=6,1 Hz), 7,69 (d, 1H, J=6,1 Hz), the 7.85 (d, 1H, J=6,1 Hz), 8,00 (d, 1H, J=6,1 Hz), 8,44 (d, 1H, J=4,8 Hz).

Using General method D, the transformation obtained above substances (80 mg) in hydrobromide salt with simultaneous removal of the N-tert-butoxycarbonyl protective group gave AMD9595 (14 mg) as a white crystalline solid.1H NMR (D2O) δ of 1.85 (m, 1H), 2,18 (m, 2H), 2,41 (m, 1H), is 3.08 (m, 2H), 3,48 (m, 1H), 3,54 (DD, 1H, J=14,1, 7,2 Hz), 3,71 (d, 1H, J=11.7 Hz), and 4.40 (d, 1H, J=15,9 Hz), 4,60 (d, 1H, J=15,9 Hz), 7,00 (DD, 1H, J=6,0, 3.0 Hz), 7,11 (d, 2H, J=7.8 Hz), 7,41 (m, 4H), 7,50 (d, J=7.8 Hz), 7,55 (t, 1H, J=7,2 Hz), 7,89 (d, 1H, J=8.1 Hz), of 7.97 (m, 2H), 8,43 (d, 1H, J=8.1 Hz), 8,79 (d, 1H, J=5,1 Hz);13C NMR (D2O) δ 20,46, 21,08, 26,83, 51,44, 56,69, 62,35, 113,56 (2C), 121,81, 122,57, 126,26, 126,44, 126,94, 130,27, 130,61, 139,73, 140,02, 148,43, 151,69, 151,44, 158,83. ES-MS m/z 501 (M+H). Elemental analysis. Calculated for C31H27N5S·3HBr·3H2O: C, 46,63; H, Of 4.54; N, 8,77; Br 30,02. Found: C, 46,88; H, To 4.46; N, 8,66; Br, 29,84.

Example: 93

AMD9615: Obtain [4-(benzoxazol-2-yl)benzyl]-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Getting 4-(benzoxazol-2-yl)benzyl alcohol

A solution of 2-NITROPHENOL (0.50 g, 3.6 mmol) and methyl 4-chlorocarbonates the ATA (0,79 g, 4.0 mmol) in THF (4.5 ml) and pyridine (0.9 ml) was stirred for 1 hour at room temperature. The reaction mixture was diluted with saturated sodium bicarbonate solution (10 ml) and EtOAc (15 ml), the phases were separated and the aqueous phase was extracted with EtOAc (2 × 10 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure, obtaining complex fluids (2-nitrophenyl)terephthalic acid in the form of a yellow solid (1,03 g, 96%).1H NMR (CDCl3) δ 3,98 (s, 3H), 7,40 (d, 1H, J=7.8 Hz), 7,47 (t, 1H, J=7.8 Hz), 7,74 (t, 1H, J=7,2 Hz), 8,18 (d, 1H, J=7,2 Hz), 8,19 (d, 2H, J=7.8 Hz), of 8.27 (d, 2H, J=7,8 Hz).

To a solution of diapir (2-nitrophenyl)terephthalic acid (1,02 g, 3.3 mmol) in glacial acetic acid (11 ml) was added iron powder (sieve composition <5 μm, 0.51 g, 9.0 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 (25 ml) and ethyl acetate (25 ml), the phases were separated and the organic layer was washed with saturated NaHCO3(25 ml). The organic extract was dried (MgSO4), filtered, concentrated and purified column chromatography on silica gel (2% MeOH/CH2Cl2)to give the methyl ether (2-hydroxyben the l)terephthalamide acid (0,37 g, 44%).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), 8,18 (d, 2H, J=7,8 Hz).

A solution of methyl ester (2-hydroxyphenyl)terephthalamide acid (0.35 g, 1.3 mmol) in polyphosphoric acid (˜5 ml) was boiled under reflux for 3 hours. The solution was cooled to 0°C, was added water (100 ml) and was introduced solid To2CO3to achieve a pH of 7-9. The residue was diluted with ethyl acetate (2 × 100 ml) and the organic extract was dried (MgSO4), filtered and concentrated, obtaining cyklinowanie methyl 4-(benzoxazol-2-yl)benzoate (0.15 g, 45%) as a beige powder.1H NMR (CDCl3) δ 3,98 (s, 3H), 7,40 (m, 2H), to 7.61 (m, 1H), 7,81 (m, 1H), to 8.20 (d, 2H, J=7.8 Hz), a 8.34 (d, 2H, J=7,8 Hz).

To a solution of methyl 4-(benzoxazol-2-yl)benzoate (0.20 g, 0.8 mmol) in THF (8 ml) at -78°C was added a solution of DIBAL-H (4,0 ml, 1.0 M in THF, 4.0 mmol). The reaction mixture was left to warm to room temperature, was stirred for 1 hour and extinguished a saturated solution of tartrate of potassium-sodium (15 ml). A two-phase mixture was intensively stirred for 1 hour, the phases were separated and the organic layer was dried (MgSO4), filtered and concentrated, obtaining specified in the title alcohol (0.16 g, 89%).1H NMR (CDCl3) δ of 1.80 (t, 1H (OH)), 4,82 (d, 2H, J=6.0 Hz), was 7.36 (m, 2H), 7,55 (d, 2H, J=8,4 Hz), 7,60 (m, 1H), 7,78 (m, 1H), compared to 8.26 (d, 2H, J=8,4 Hz).

Using bwuu methodology, to a solution of 4-(benzoxazol-2-yl)benzyl alcohol (0.16 g, 0.7 mmol) and triethylamine (0.15 ml, 1.1 mmol) in THF (7 ml) was added methanesulfonamide (75 μl, 1.0 mmol) and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was extinguished with saturated solution of NaHCO3(10 ml) and the aqueous phase was extracted with CH2Cl2(3 × 10 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated, obtaining mesilate (0.20 g, 93%) as a pale yellow crystalline solid.1H NMR (CDCl3) δ 3,00 (s, 3H), 5,33 (s, 2H), 7,38 (m, 2H), 7,60 (m, 3H), 7,78 (m, 1H), 8,32 (d, 2H, J=7,8 Hz).

Using the General method of alkylation, the solution obtained above nelfinavir (0.20 g, 0.66 mmol), N,N-diisopropylethylamine (0.17 ml, 1.0 mmol) and potassium iodide (6 mg, 30 μmol) in CH3CN (7 ml) was subjected to interaction with (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) - amine (0.27 g, to 0.72 mmol) at 60°C for 4 hours. Purification of the crude substances column chromatography on silica gel (4% MeOH/CH2Cl2) gave N-alkilirovanny product (0,23 g, 59%) as a flaky white solid.1H NMR (CDCl3) δ 1,74 (s, 10H), a 2.01 (m, 2H), and 2.26 (m, 1H), 2,74 (m, 2H), a 3.87 (d, 1H, J=15 Hz), 4,08 (d, 1H, J=15 Hz), 4,35 (m, 1H), 4,70 (s, 2H), 7,00-7,20 (m, 3H), 7,30-7,40 (m, 5H), 7,55-the 7.65 (m, 3H), 7,68 (m, 1H), 7,87 (d, 2H, J=7.8 Hz), 8,42 (d, 1H, J=3.5 Hz).

Use the General method D, the transformation obtained above substances (90 mg) in hydrobromide salt gave AMD9615 (0.10 g) as a pale brown solid.1H NMR (D2O) δ 1,86 (user. m, 1H), 2,08 (m, 2H), 2,34 (user. m, 1H), 3.00 and (OSiR. m, 2H), 3.04 from (d, 1H), 3,50 (d, 1H, J=12.3 Hz), 4,30 (d, 1H, J=16.2 Hz), to 4.52 (d, 1H, J=16.2 Hz), of 4.66 (m, 1H), 6,91 (user. d, 2H, J=7,2 Hz), to 6.95 (d, 2H, J=8.1 Hz), 7,30 (user. s, 2H), 7,32 (s, 2H), 7,35 (d, 2H, J=8.7 Hz), 7,49 (user. m, 2H), 7,98 (t, 1H, J=6,8 Hz), 8,44 (d, 1H, J=7.8 Hz), 8,76 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,32, 21,00, 27,87, 50,20, 55,90, 63,25, 111,25, 113,57 (2C), 119,04, 124,64, 125,47, 126,12 (2C), 126,26 (2C), 126,99 (2C), 130,29 (2C), 139,68 (2C), 139,87, 140,26, 141,00, 148,49 (2C), 149,88, 150,63, 151,29, 162,00. ES-MS m/z 486 (M+H). Elemental analysis. Calculated for C31H27N5O·2,NVG·0,N2A: C, 55,18; H, To 4.62; N, 10,38; Br, 25,28. Found: C, 55,18; H And 4.65; N, Accounted For 10.39; Br, 25,28.

Example: 94

AMD9716: Obtain [4-(1H-imidazol-2-yl)benzyl]-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

Obtaining methyl [(dimethylamide N-sulfonic acid)imidazol-2-yl]benzyl alcohol

To a solution of dimethylamine imidazol-1-sulfonic acid (1,03 g, 5.9 mmol) in THF (5,9 ml) at -78°C was added n-utility (3.2 ml, 2,42 M in THF) and the solution was stirred at -78°C for 15 minutes. To the mixture was added a solution of zinc chloride (0,80 g, 5.9 mmol) in THF (4.4 ml) at -78°C, the reaction mixture was heated to room temperature and was stirred during the 0.5 hour. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.2 mmol), a solution of methyl 4-bromobenzoate of 0.85 g, 3.9 mmol) in THF (2.6 ml) and zinc chloride (1.6 g, to 11.8 mmol) and the reaction mixture is boiled under reflux for 6 hours. The reaction mixture was extinguished with saturated solution of NH4Cl (50 ml), the layers were separated and the organic layer was washed with saturated salt solution (1 × 30 ml), dried (MgSO4), filtered, concentrated and purified column chromatography on silica gel (2% MeOH/CH2Cl2)to give methyl [(dimethylamide N-sulfonic acid)imidazol-2-yl]benzoate (0.56 g, 47%) as a brown solid.1H NMR (CDCl3) δ of 2.53 (s, 6H), of 3.95 (s, 3H), 7,14 (s, 1H), of 7.48 (s, 1H), 7,79 (d, 1H, J=7,8 Hz)to 8.12 (d, 1H, J=7,8 Hz).

To a solution of methyl [(dimethylamide N-sulfonic acid)imidazol-2-yl]benzoate (0.56 g, 1.8 mmol) in THF (18 ml) at -78°C was added a solution of DIBAL - H (9,1 ml, 1.0 M in THF). The reaction mixture was left to warm to room temperature, was stirred for 1 hour and extinguished a saturated solution of tartrate of potassium-sodium (25 ml). A two-phase system was intensively stirred for 1 hour, the phases were separated and the organic layer was dried (MgSO4), filtered and concentrated, obtaining methyl [(dimethylamide N-sulfonic acid)imidazol-2-yl]benzyl alcohol (0.39 g, 76%).1H NMR (CDCl3) δ 2,49 (s, 6H), 4.72 in (s, 2), 7,10 (s, 1H), was 7.36 (d, 2H, J=7,2 Hz), 7,45 (s, 1H), to 7.61 (d, 2H, J=7,2 Hz).

Using General method C, to a solution of the above alcohol (0.39 g, 1.4 mmol) and triethylamine (of 0.30 ml, 2.1 mmol) in THF (14 ml) was added methanesulfonamide (0.15 ml, 1.9 mmol) and the mixture was stirred at room temperature for 1 hour. Received mesilate (0.50 g) was used without further purification in the next reaction.1H NMR (CDCl3) δ of 2.54 (s, 6H), of 3.00 (s, 3H), 3,68 (s, 2H), 7,13 (s, 1H), 7,46 (s, 1H), of 7.48 (d, 2H, J=7.8 Hz), of 7.75 (d, 2H, J=7,8 Hz).

Using the General method of alkylation, the solution obtained above nelfinavir (to 0.29 g, 0.8 mmol), N,N-diisopropylethylamine (of 0.21 ml, 1.2 mmol) and potassium iodide (10 mg, 40 mmol) in CH3CN (9 ml) was subjected to interaction with (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) - amine (0.31 g, 0.8 mmol) at 60°C for 16 hours. Purification of the crude column chromatography on silica gel (6% MeOH/CH2Cl2) gave the target amine (0.25 g, 48%) as a flaky white solid.1H NMR (CDCl3) δ 1,72 (s, 10H), 1.93 and (m, 2H), 2.13 in (m, 1H), and 2.27 (s, 6H), is 2.74 (m, 2H), 3,90 (d, 1H, J=15 Hz), 4,25 (d, 1H, J=15 Hz), 4.26 deaths (m, 1H), 4,55 (d, 1H, J=15 Hz)and 4.65 (d, 1H, J=15 Hz), 7,00 (m, 2H,), 7,26 (m, 4H), 7,44 (m, 4H), 7,66 (m, 1H), to 7.75 (m, 1H), 8,44 (d, 1H, J=3.5 Hz).

The solution obtained above protected imidazolinone (0.25 g, 0.5 mmol) in 2M HCl (4 ml) was boiled under reflux for 16 hours. The mixture Rabaul is whether 15%aqueous NaOH (20 ml) and was extracted with CH 2Cl2(2 × 20 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and purified column chromatography on silica gel (5% MeOH/CH2Cl2), receiving the target amine (0.10 g, 60%) as a white solid.1H NMR (CDCl3) δ and 1.60 (m, 1H), of 1.85 (m, 2H), 2.13 in (m, 1H), 2,74 (m, 2H), 3,52 (d, 1H, J=13.5 Hz), 3,62 (d, 1H, J=13.5 Hz), 3,88 (d, 1H, J=16.5 Hz), 4.00 points (m, 1H), 4,06 (d, 1H, J=16.5 Hz), 7,02 (s, 2H), 7,15-7,25 (m, 5H), 7,38 (d, 1H, J=7.8 Hz), EUR 7.57 (m, 2H), 7,66 (d, 2H, J=8.1 Hz), 8,63 (d, 1H, J=4, 2 Hz).

Using General method D, the transformation of the solid obtained above (100 mg) in hydrobromide salt gave AMD9716 (0.125 g) as a white solid.1H NMR (D2O) δ 1,87 (user. m, 1H), and 2.26 (m, 2H), 2,47 (user. m, 1H), 3,05 (user. m, 2H), a 3.87 (d, 1H, J=12,6 Hz), of 3.94 (d, 1H, J=12.9 Hz), of 4.45 (d, 1H, J=16.2 Hz), with 4.64 (d, 1H, J=16.2 Hz), and 4.75 (m, 1H), 7,25 (DD, 2H, J=of 3.0, 6.0 Hz), 7,37 (s, 4H), 7,42 (s, 2H), 7,47 (DD, 2H, J=of 3.0, 6.0 Hz), to 7.95 (t, 1H, J=8,4 Hz), 8,42 (d, 1H, J=8.1 Hz), 8,80 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 28,72, 29,38, 36,15, 58,51, 65,13, 71,86, 122,09 (2C), 128,20 (2C), 130,21, 134,22 (2C), 134,43 (3C), 138,98, 139,62 (2C), 148,16 (2C), 149,34 (2C), 156,51 (2C), 159,04, 159,98. ES-MS m/z 435 (M+H). Elemental analysis. Calculated for C27H26N6·3,NVG·1,4H2A: C, 45,61; H, 4,74; N, 11,34; Br, 34,64. Found: C, 45,61; H, To 4.81; N, 11,37; Br, 34,65.

Example: 95

AMD 9841 Obtain (2'-aminomethylphenol-4-ylmethyl)-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt)

Using the General methods of alkylation, to a solution of (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (0,194 g, 0.51 mmol) in CH3CN (5 ml) was added N,N-diisopropylethylamine (0,30 ml, 1,72 mmol), then 4'-methyl bromide-2-cyanobiphenyl (0,303 g, 1.11 mmol) and the resulting mixture was heated at 60°C for 25 hours. Purification of the crude substances column chromatography on silica gel (10:1:1 CH2Cl2-CH3HE-NH4OH) followed by radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2-CH3HE-NH4HE gave a yellow-brown foam (79 mg).

The result of the above intermediate compound (79 mg, 0.14 mmol) was dissolved in a saturated NH3methanol (3 ml) in a Parr apparatus for hydrogenation. The Raney-Nickel (50 mg) washed with MeOH (3x), transferred to a hydrogenation flask containing the nitrile and the mixture was first made at a pressure of 50 lb/in2(345 kPa) for 24 hours. The mixture was filtered through celite and the filter cake washed with methanol. Eluent was concentrated under reduced pressure. Purification of the crude substances by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-CH3HE-NH4HE) gave 36 mg (54%) of free base specified in the title compound as a white foam.

Using General method D, the transformation of a white foam (36 mg) in hydrobromide salt, with subsequent p is residenial intermediate solid from methanol/ether, gave AMD9841 (35 mg) as a white solid.1H NMR (D2O) δ 1,87 is 2.00 (m, 1H), 2,22-2,39 (m, 2H), 2,45 is 2.51 (m, 1H), 3,06-to 3.09 (m, 2H), 3,84-of 3.96 (m, 4H), 4.53-in (d, 1H, J=16.5 Hz), 4,70 (d, 1H, J=16.5 Hz), 4,78-is 4.85 (m, 1H, overlap with HOD), of 6.26 (d, 1H, J=7,2 Hz), of 6.96 (d, 2H, J=7.8 Hz), 7,31 (d, 2H, J=7.8 Hz), 7,34-the 7.43 (m, 3H), 7,51-of 7.55 (m, 2H), 7,60-to 7.64 (m, 2H), of 7.96 (DD, 1H, J=6,0, 8.1 Hz), 8,44 (d, 1H, J=7.8 Hz), 8,79 (d, 1H, J=5.4 Hz);13C NMR (D2O) δ 20,50, 21,00, 27,90, 40,58, 50,45, 56,75, 63,43, 113,93, 126,12, 126,78, 128,91, 128,99, 129,14, 129,36, 130,05, 130,55, 130,57, 131,06, 135,97, 139,48, 139,71, 141,05, 141,20, 148,30, 150,94, 152,15; ES-MS m/z 474 (M+H). Elemental analysis. Calculated for C31H31N5·3,0HBr·2,2H2O: C, 49,25; H, 5,12; N, 9,26; Br, 31,71. Found: C, 49,31; H, to 5.21; N, 9,13; Br, 31, 62.

Example: 96

AMD9785: Receive (1H-benzimidazole-2-ylmethyl)-(2'-methoxybiphenyl-4-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt)

Obtaining 2'-methoxybiphenyl-4-carboxaldehyde

To a stirring degassed solution of 4-bromobenzaldehyde (218 mg, 1.18 mmol) and 2-methoxybenzeneboronic acid (188 mg, 1,24 mmol) in a mixture of DME/THF (5 ml, 4:1) was added 2M solution of Na2CO3(1.6 ml) and Pd(PPh3)4(63 mg, by 0.055 mmol). The reaction mixture was purged with argon and kept in an argon atmosphere by heating at 85°C during the night. The mixture was then cooled and diluted with EtOAc (25 ml) and water (25 ml). The aqueous layer was washed with EtOAc (2 × 10ml) and the combined organic extracts were dried (Na 2SO4), filtered and concentrated. Purification of the resulting oil column chromatography on silica gel (hexane/Et2O, 80:20) gave specified in the title compound (230 mg, 92%) as a clear oil.1H NMR (CDCl3) δ of 3.84 (s, 3H), 7,01-to 7.09 (m, 2H), 7,33-7,39 (m, 2H), 7,71 (d, 2H, J=6 Hz), to 7.93 (d, 2H, J=6 Hz), of 10.05 (s, 1H).

Using General method B, to mix the solution of (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (95 mg, 0.25 mmol) and 2'-methoxybiphenyl-4-carboxaldehyde (55 mg, 0.26 mmol) in CH2Cl2(5 ml) was added NaBH(OAc)3(83 mg, 0,39 mmol) and the resulting mixture was stirred at room temperature overnight. Purification of the crude substances by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2/MeOH/NH4OH) gave the target amine (75 mg, 52%) as a clear oil.

Using General method D, the transformation obtained above oil (34 mg, 0,059 mmol) in hydrobromide salt with simultaneous removal of the N-tert-butoxycarbonyl protective group and subsequent presidenial intermediate solid from methanol/ether gave AMD9785 (25 mg, 63%) as a white solid.1H NMR (D2O) δ 1,89-of 1.94 (m, 1H), 2,20-of 2.27 (m, 2H), 2,31 is 2.44 (m, 1H), 3,03 was 3.05 (m, 2H), 3,68 (s, 3H), 3,76 (d, 1H, J=12.3 Hz), 3,84 (d, 1H, J=12.3 Hz), 4,47 (d, 1H, J=16.5 Hz), 4,63 (d, 1H, J=16.5 Hz), 4,74-4,89 (m, 1H, top is raised HOD), 6,36 (d, 1H, J=7.5 Hz), of 6.96 (t, 1H, J=7.5 Hz), 7,02-7,05 (m, 3H), 7,19 (d, 2H, J=7.8 Hz), 7,33 (DD, 1H, J=8,1, 7,8 Hz), 7,44 (DD, 2H, J=6.3 Hz), 7,56 (DD, 2H, J=6.3 Hz), to 7.93 (DD, 1H, J=7,2, and 6.6 Hz), 8,40 (d, 1H, J=7.8 Hz), 8,76 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 19,71, 20,15, 27,08, 49,63, 55,13, 55,91, 62,54, 111,67, 113,02, 120,58, 125,29, 125,91, 128,68, 129,09, 129,32, 129,76, 130,34, 134,47, 137,26, 138,86, 140,17, 147,45, 150,22, 151,23, 155,17. ES-MS m/z 475 (M+H). Elemental analysis. Calculated for C31H30N4O·2,1HBr·1,3H2O: C, Is 55.74; H, 5,24; N, 8,39; Br, 25,12. Found: C, 55,67; H, 5,26; N, 8,27; Br, 25,30.

Example: 97

AMD9791: Receive (1H-benzimidazole-2-ylmethyl)-(4-oxazol-5-ylbenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt)

Getting 4-(oxazol-5-yl)benzaldehyde

To a stirred solution of 4-(oxazol-5-yl)benzyl alcohol (obtained as described Tanaka, A.; Terasawa, T.; Hagihara, H.; Sakuma, Y.; Isbibe, N.; Sawada, M.; Takasugj, H.; Tanaka, H. J. Med. Chem. 1998, 41, 2390-2410) (0,23 g of 1.31 mmol) in a mixture of CH2Cl2/MeOH (20:1, and 10.5 ml) was added activated MnO2(1.01 g, 11.6 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with CH2Cl2(10 ml) and filtered through celite, washing CHCl3. The filtrate was concentrated, obtaining the crude aldehyde in the form of a beige solid (0,164 g)which was used without further purification in the next reaction.1H NMR (CDCl3) δ 7,52 (s, 1H), 7,82 (d, 2H, J=9 Hz), 7,9 (d, 2H, J=9 Hz), to 7.99 (s, 1H), 10,02 (s, 1H).

Using General method B, to mix the solution of (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (133 mg, 0.35 mmol) and 4-(oxazol-5-yl)benzaldehyde (80 mg, 0.45 mmol) in CH2Cl2(10 ml) was added NaBH(OAc)3(107 mg, 0.50 mmol) and the resulting mixture was stirred at room temperature overnight. The crude oil was dissolved in a mixture of CH2Cl2/TFOC (1:1, 2 ml) and the mixture was stirred for 2 hours. The reaction mixture was then concentrated and diluted with CH2Cl2(30 ml) and 1N. NaOH (30 ml). The aqueous layer was washed with CH2Cl2(2 × 10 ml) and the combined organic extracts were dried (Na2SO4), filtered and concentrated. Purification of the crude foam radial chromatography on silica gel (2 mm plate, 50:1:1 CH2Cl2/MeOH/NH4OH) gave the free amine (50 mg, 33% over 2 stages) as a yellow foam.

Using General method D, the transformation obtained above foam (50 mg, 0.11 mmol) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether gave AMD9791 (70 mg, 87%) as a yellow solid.1H NMR (D2O) δ 1,86-1,90 (m, 1H), 2,16-of 2.27 (m, 2H), 2,38 is 2.43 (m, 1H), 2,99-to 3.02 (m, 2H), 3,60 (d, 1H, J=12.3 Hz), 3,76 (d, 1H, J=12.3 Hz), to 4.38 (d, 1H, J=16.5 Hz), of 4.57 (d, 1H, J=16.5 Hz), 4,72-rate 4.79 (m, 1H, overlap with HOD), 712-7,19 (m, 5H), 7.23 percent (DD, 2H, J=6.3 Hz), the 7.43 (DD, 2H, J=6.3 Hz), 7,92 (DD, 1H, J=7,8, 5.7 Hz), 8,16 (s, 1H), of 8.37 (d, 1H, J=7,2 Hz), 8,76 (d, 1H, J=5.7 Hz);13C NMR (D2O) δ 20,43, 21,01, 27,83, 50,22, 56,66, 63,41, 113,62, 120,71, 124,26, 126,12, 126,36, 126,78, 130,44, 130,76, 137,01, 139,68, 140,96, 148,27, 150,79, 151,60, 152,13. ES-MS m/z 436 (M+H). Elemental analysis. Calculated for C27H25N5O·2,8HBr·1,9H2O: C, 46,57; H, Of 4.57; N, 10,06; Br, 32,13. Found: C, 46,56; H, Br4.61; N, 9,73; Br, 32,14.

Example: 98

AMD9792: Receive (1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(4-thiophene-2-ylbenzyl)amine (hydrobromide salt)

Getting 4-thiophene-2-albenzaalbenza

To a stirring degassed solution of 4-bromobenzaldehyde (371 mg, 2.00 mmol) and thiophene-2-Bronevoy acid (287 mg, 2,24 mmol) in a mixture of DME/THF (5 ml, 4:1) was added 2M solution of Na2CO3(3.0 ml) and Pd(PPh3)4(110 mg, 0,095 mmol). The reaction mixture was purged with argon and kept in an argon atmosphere by heating at 85°C for 2 days. The mixture was then cooled and diluted with EtOAc (35 ml) and water (30 ml). The aqueous layer was washed with EtOAc (2×10 ml) and the combined organic extracts were dried (Na2SO4), filtered and concentrated. Purification of the resulting oil column chromatography on silica gel (hexane/EtOAc, 4:1) gave specified in the title compound (293 mg, 78%) as a yellow solid. H NMR (CDCl3) δ 7,14 (DD, 1H, J=5,1, 3.6 Hz), 7,40 (DD, 1H, J=5,1, 0.9 Hz), 7,46 (DD, 1H, J=3,6, and 0.9 Hz), 7,76 (d, 2H, J=8,4 Hz), 7,88 (d, 2H, J=8,4 Hz), 10,00 (s, 1H).

Using General method B, to mix a solution of (1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (144 mg, 0.52 mmol) and 4-thiophene-2-albenzaalbenza (100 mg, of 0.53 mmol) in CH2Cl2(5 ml) was added NaBH(OAc)3(160 mg, 0.75 mmol) and the resulting mixture was stirred at room temperature overnight. Purification of the crude substances by radial chromatography on silica gel (2 mm plate, 50:1:1 CH2Cl2/MeOH/NH4OH) gave the target amine (133 mg, 57%) as a yellow foam.

Using General method D, the transformation obtained above foam (115 mg, 0.26 mmol) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether gave AMD9792 (134 mg, 82%) as a yellow solid.1H NMR (D2O) δ 1,73-to 1.77 (m, 1H), 2,00-2,11 (m, 2H), 2,24-of 2.28 (m, 1H), 2,84-is 2.88 (m, 2H), 3,12 (d, 1H, J=12.3 Hz), of 3.45 (d, 1H, J=12.3 Hz), 4,20 (d, 1H, J=16.5 Hz), 4,37 (d, 1H, J=16.5 Hz), 4,46 (DD, 1H, J=10,2, 6 Hz), 6,85 (d, 2H, J=8.1 Hz), 6.90 to-6,97 (m, 4H), 7,17 (DD, 2H, J=6.3 Hz), 7,26 (d, 1H, J=5,1 Hz), 7,37 (DD, 2H, J=6.3 Hz), to 7.84 (DD, 1H, J=7,8, 5.7 Hz), of 8.25 (d, 1H, J=7.8 Hz), 8,66 (d, 1H, J=4,7 Hz);13C NMR (D2O) δ 20,39, 20,85, 27,77, 50,08, 56,18, 63,03, 113,58, 124,19, 125,34, 126,05, 126,12, 126,63, 128,72, 130,36, 130,67, 133,71, 135,22, 139,52, 140,76, 142,84, 148,28, 150,66, 151,42. ES-MS m/z 451 (M+H). Elemental analysis. Calculated for C28H26N S·2,NVG·0,N2About: With, 53,50; H, 4,78; N, 8,91; Br, 25,42. Found: C, 53,65; H, To 4.98; N, 8,66; Br, 25,32.

Example: 99

AMD9778: Receive (1H-benzimidazole-2-ylmethyl)-[4-(2-methyl-2H-tetrazol-5-yl)benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amine (hydrobromide salt).

To a stirred solution of 8-amino-5,6,7,8-tetrahydroquinoline (170 mg, 1.15 mmol) in anhydrous MeOH (10 ml) was added 4-(2-methyl-2H-tetrazol-5-yl)benzaldehyde (obtained as described Bold, G.; Fassler, A.; Capraro, H.-G.; Cozens, R.; Klimkait, T.; Lazdins, J.; Mestan, J.; Poncioni, C.; Rosel, J.; Stover, D.; Tintelnot-Blomley, M.; Acemoglu, F.; Beck, W.; Boss, E.; Eschbach, M.; Hurlimann, T.; Masso, E.; Roussel, S.; Ucci-Stoll, K.; Wyss, D.; Lang, M. J. Med. Chem. 1998, 41, 3387-3401) (220 mg, 1,17 mmol) and the mixture was stirred for 1.5 hours at room temperature. Original yellow-orange suspension turned dark orange homogeneous solution after a specified time. The mixture was concentrated in vacuo, and analyzed using1H NMR and re-dissolved in MeOH (10 ml). To the resulting solution was added NaBH4(85 mg, 2.25 mmol) and the mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo and diluted with CH2Cl2(40 ml) and saturated aqueous sodium bicarbonate (40 ml). The aqueous phase was washed CH2Cl2(2 × 10 ml) and the combined organic extracts were dried (Na2SO4), filtered and concentrated, produces the orange-brown oil (422 mg), which was used without purification in the next reaction.

According to the General method of alkylation to stir the solution obtained above secondary amine (205 mg, 0.64 mmol) in CH3CN (5 ml) was added N,N-diisopropylethylamine (0,23 ml of 1.32 mmol), KI (24 mg, 0.14 mmol) and 1-(tert-butoxycarbonyl)-2-(chloromethyl)benzimidazole (165 mg, of 0.62 mmol). The mixture was stirred at 60°C for 3 hours. Purification of the obtained brown oil column chromatography on silica gel (CH2Cl2/Meon, 98:2 then 96:4) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH, 98:2) gave the target alkilirovanny amine (44 mg, 43% over 2 stages) as a brown foam.

Using General method D, the transformation obtained above foam (44 mg, 0.08 mmol) in hydrobromide salt with simultaneous removal of the N-tert-butoxycarbonyl protective group and subsequent presidenial intermediate solid from methanol/ether gave AMD9778 (45 mg, 87%) as a pale brown solid.1H NMR (D2O) δ 1,89-of 1.94 (m, 1H), 2,19-of 2.27 (m, 2H), 2,43-2,47 (m, 1H), 3,03 was 3.05 (m, 2H), and 3.72 (d, 1H, J=12,6 Hz), 3,84 (d, 1H, J=12,6 Hz), 4,35 (s, 2H), 4,43 (d, 1H, J=16.5 Hz), br4.61 (d, 1H, J=16.5 Hz), 4,79-4,89 (m, 1H, overlap with HOD), to 7.15 (DD, 2H, J=6.3 Hz), 7,24 (d, 2H, J=8.1 Hz), 7,41 (DD, 2H, J=6.3 Hz), 7,46 (d, 2H, J=8.1 Hz), 7,95 (DD, 1H, J=7,5, and 6.3 Hz), to 8.41 (d, 1H, J=8.1 Hz), 8,79 (d, 1H, J=5,1 Hz);13C NMR (D2O) δ 20,45, 21,07, 27,6, 40,01, 50,30, 56,78, 63,54, 113,67, 125,64, 126,18, 126,32, 126,42, 130,42, 130,91, 139,31, 139,75, 141,04, 148,33, 150,77, 151,62, 163,70. ES-MS m/z 451 (M+H). Elemental analysis. Calculated for C26H26N8·2,NVG·1,5H2About: With, 48,23; H, 4,84; N, 17,31; Br, 25,92. Found: C, 48,49; H, 4,72; N, 17,05; Br, 25,63.

Example: 100

AMD9715: Receive (1H-benzimidazole-2-ylmethyl)-[4-(5-phenyloxazol-2-yl)benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amine.

Obtaining methyl-N-(2-oxo-2-phenylethyl)terephthalamide

To a solution of 2-aminoacetophenone (516 mg, 3.0 mmol) and triethylamine (from 0.84 ml, 6 mmol) in CH2Cl2(20 ml) at 0°C was added dropwise within 10 minutes, methyl 4-chlorocarbonate (594 mg, 3.0 mmol). Then the solution was left to warm to room temperature and was stirred for 90 minutes. The solution was washed with a saturated aqueous solution of NH4Cl (20 ml) and the aqueous layer was extracted with CH2Cl2(2 × 10 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuum, obtaining the target methyl N-(2-oxo-2-phenylethyl)terephthalat in the form of pale yellow crystals (835 mg, 94%).1H NMR (CDCl3) δ of 3.94 (s, 3H), equal to 4.97 (d, 2H, J=5.4 Hz), 7.35 (users, 1H), 7,50 m, 2H), 7,53 (m, 1H), 7,92 (d, 2H, J=6.6 Hz), of 8.04 (d, 2H, J=6.6 Hz), 8,11 (d, 2H, J=6,9 Hz).

Obtain methyl 4-(5-phenyloxazol-2-yl)benzoate (as described Wipf, P., Miller, C.P. J. Org. Chem. 1993, 58, 3604):

To a solution of triphenylphosphine(524 mg, 2.0 mmol) and triethylamine (of 0.56 ml, 4.0 mmol) in CH2Cl2(10 ml) was added iodine (480 mg, 1.9 mmol) and the mixture was stirred for 15 minutes. Solution was added methyl N-(2-oxo-2-phenylethyl)terephthalamide (297 mg, 1.0 mmol) in CH2Cl2(5 ml) and the resulting mixture was stirred at room temperature overnight. The organic phase is washed with 5%aqueous sodium thiosulfate solution (1 × 15 ml) and a saturated solution of NaHCO3(1 x 15 ml) and then dried (Na2SO4), filtered and concentrated in vacuum. The obtained oily residue was purified column chromatography on silica gel (1:1 hexane/EtOAc)to give the desired product, methyl 4-(5-phenyloxazol-2-yl)benzoate in the form of a yellow oil (69 mg, 24%).1H NMR (CDCl3) δ 3,86 (s, 3H), 7,20 (m, 1H), 7.23 percent (t, 1H, J=6.3 Hz), 7,41 (s, 1H), to 7.64 (m, 2H), 8,04 (m, 4H). ES-MS m/z 280 (M+H).

To a solution of methyl-4-(5-phenyloxazol-2-yl)benzoate (56 mg, 0,19 mmol) in CH2Cl2(8 ml) at -78°C was added DIBAL-H (1 ml of 1.0 M solution in CH2C12, 1.0 mmol) and the solution was stirred at -78°C for 90 minutes. To the reaction mixture were added saturated aqueous solution of sodium tartrate, potassium (5 ml) and the mixture was left to warm to room temperature. A two-phase system was intensively stirred for 60 minutes, the layers were separated and the aqueous layer was extracted with CH2Cl2(2 × 10 ml). The combined organic is their fractions were dried (Na 2SO4), filtered and concentrated in vacuum, obtaining the target alcohol, 2-(4-hydroxymethylene)-5-phenyloxazol, in the form of a pale yellow oil (46 mg, 96%).1H NMR (CDCl3) δ to 3.41 (t, 1H (OH), J=7,0 Hz), of 4.77 (d, 2H, J=7.0 Hz), 7,33 (m, 1H), 7,45 (m, 5H), 7,72 (d, 2H, J=6.4 Hz), 8,08 (d, 2H, J=8.1 Hz).

According to the General method With the solution obtained above alcohol (123 mg, 0.5 mmol) and triethylamine (0,105 ml, 0.75 mmol) in CH2Cl2(8 ml) was added methanesulfonamide (0.05 ml, of 0.65 mmol) and the mixture was stirred at room temperature for 10 minutes. The target of the crude 2-(4-(methysulfonylmethane))-5-phenyloxazol received in the form of a pale yellow oil and used directly without further purification in the next reaction.

According to the General method of alkylation to the solution obtained above nelfinavir (0.5 mmol) and (1-tert-butoxycarbonyl-1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine (264 mg, 0.7 mmol) in CH3CN (8 ml) was added N,N-diisopropylethylamine (0,145 ml, 0.8 mmol) and potassium iodide (8 mg, 0.05 mmol) and the resulting mixture was heated at 60°C during the night. The crude residue was purified column chromatography on silica gel (CH2Cl2/MeOH, 95:5)to give the target tertiary amine, (1H-1-tert-butoxycarbonylamino-2-ylmethyl)-[4-(5-phenyloxazol-2-yl)benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)amine, as pale yellow foam (209 mg, 68%).1N the Mrs (CDCl 3) δ and 1.63 (s, 9H), for 2.01 (m, 2H), and 2.26 (m, 1H), 2,69-2,82 (m, 3H), 3,83 (d, 1H, J=16.1 Hz), of 4.05 (d, 1H, J=16.1 Hz), 4,32 (m, 1H), 4,69 (s, 2H), 7,12 (m, 1H), 7,15-7,20 (m, 3H), 7,33-7,46 (m, 6H), 7,58-7,73 (m, 6H), 8,44 (d, 1H, J=4,9 Hz). ES-MS m/z 612 (M+H).

Using General method D, the transformation obtained above foam (31 mg, 0.05 mmol) in hydrobromide salt with subsequent presidenial intermediate solid from methanol/ether gave AMD9715 (28 mg) as a white solid.1H NMR (D2O) δ of 1.93 (m, 1H) 2,07 (m, 2H), 2.40 a (m, 1H), 3,05 (m, 2H), 3,37 (m, 1H), of 3.56 (m, 1H), 4,35 (d, 1H, J=16.5 Hz), 4,58 (d, 1H, J=16.5 Hz), of 4.77 (m, 1H),? 7.04 baby mortality (m, 4H), 7,30-7,37 (m, 6H), 7,49 (t, 2H, J=7,2 Hz), to 7.64 (m, 2H), 7,92 (DD, 1H, J=7,8, 5,4 Hz), 8,44 (d, 1H, J=7.8 Hz), 8,77 (d, 1H, J=5.4 Hz);13C NMR (D2O) δ 21,93, 22,13, 29,24, 50,89, 57,87, 63,37, 115,13 (2C), 124,32, 125,65 (2C), 127,33, 127,43 (2C), 127,83 (2C), 128,11, 130,40, 130,60 (2C), 132,33 (2C), 133,04, 140,22, 141,84, 144,99, 147,24, 149,33, 153,14, 154,87. ES-MS m/z 512 (M+H). Elemental analysis. Calculated for C33H29N5About·2,NVG·2H2About: With, 51,20; H, Of 4.66; N, 9,05; Br, 28,90. Found: C, 51,16; H, 4,59; N, 8,87; Br, 28,76.

Example: 101

The inhibition induced chemokine flow Ca, measured using FLIPR (Molecular Devices)

Reagents

Loading dye: Fluo-3, AM (Molecular Probes F-1241) was dissolved in anhydrous DMSO and stored frozen aliquot. To increase the solubility of the dye in the loading environment to the original solution of Fluo-3 immediately before use) was added 10% (mass/about) pluronovuyu acid (Molecular robes F-127).

The buffer flow

HBSS + 20 mM Hepes buffer + 0.2 % BSA, pH 7,4, HBSS 10 x [mass./about. Phenol red and sodium bicarbonate (Gibco 14 065-049)]; Hepes buffer 1M (Gibco 15 630-056), BSA (Sigma A3675). Buffer flow was filtered under vacuum and kept refrigerated for up to 5 days. Before use in the experiment, the buffer was heated to 37°C in a water bath.

Antagonists

The compounds were diluted in the buffer of the stream and added to 4 wells of a black microplate (4 parallel measurements of the connection). Used the following control wells: control 100% response (no inhibition), was added to the buffer flow; control 100% of inhibition: added chemokine in a 5-fold concentration required to induce Sa thread.

Getting agonistic (chemokine) tablet

Chemokines were diluted in the buffer stream to the concentration, which is 4-fold higher than the desired concentration required for stimulation of the cells (i.e. 2.5 nm for SDF-1α). Chemokines were added to untreated 96-well sero-well plate for connections (International Medical, Sterilin code 611F96). In the negative control wells (monitoring background lines) instead of the chemokine was added to the buffer stream. As a positive control to verify the load efficiency of the dye is also included 20 μm of digitonin (final concentration). Agonistic tablet encubierta and in FLIPR (37° C) for 15-30 minutes.

Protocol load cells for measuring the inhibition induced by SDF-1α Sa thread in cells SUP-T1

SUP-T1 cells were centrifuged at room temperature (RT) and re-suspended in loading medium (RPMI-1640 containing 2% FBS and 4 μm Fluo-3, AM). Cells were incubated at room temperature for 45 minutes, then washed twice with buffer flow, and then incubated in the buffer stream at room temperature for 10 minutes. Cells were centrifuged and re-suspended in the buffer stream with density 3×106cells / ml 100 ál aliquot of cell suspension (3×106cells) was added to each well black microplate (Costar 3603), which already contained 50 μl of a solution of the compounds (at concentrations that are 3-fold exceeds the desired final concentration of the compound). The microplate is then gently centrifuged at room temperature. 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

FLIPR system (camera exposure time and laser power) was regulated to obtain the initial values of fluorescence between 8000 and 10,000 units. After the ontrol 20-second background lines, agonist (chemokine) (50 μl) were added with an automatic pipette with black pipette tips. Fluorescence was measured simultaneously in all the wells of the microplate every 2 seconds (first 2 minutes) and then every 6 seconds (2 minutes). The average flow of Sa measured in each group of 4 identical holes (one test connection), was calculated using the software FLIPR.

Using the above method it was found that the compounds of the present invention inhibit induced SDF-1α Sa thread in SUP-T1 cells between 0-100% at a fixed concentration of 5 µg/ml

Example: 102

Analysis of the inhibition of replication of HIV-1 (NL4.3) in MT-4 cells.

Analysis of inhibition of replication of HIV-1 NL4.3 (or IIIB) 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). Measurement of anti-HIV activity and cytotoxicity were performed in parallel. They are based on the viability of MT-4 cells, which were infected with HIV in the presence of different concentrations of the studied compounds. After MT-4 cells allowed to proliferate for 5 days, the number of viable cells was assessed quantitatively using a colorimetric method based on the ISOE is lovanii of tetrazole (bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT)in 96-well microplate. In all such analyses of viral contribution (viral multiplicity of infection, MOI) was 0.01 or 100 times the 50% cell culture infective dose (CCID50). EC50was determined at concentrations required to protect 50% of virus-infected cells against viral cytotoxicity.

When the compounds of the present invention were tested for inhibition of HIV-1 NL4.3 or IIIBreplication in MT-4 cells, it was found that they exhibit EC500.002 to 20.0 µg/ml

The following compounds of formula 1 were also obtained in a manner analogous to the above:

(4-aminomethylpyridine-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(3-aminomethylpyridine-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

1-(3-aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)alanon

1-(5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)alanon

3-aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzosulfimide

5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzosulfimide

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

N-(5-aminomethyl--{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)hydroxylamine

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

N-(5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-O-methylhydroxylamine

(4-aminomethyl-2-ethoxymethylene)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-ethoxymethylene)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

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

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

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

(1H-benzoimidazol-2-ylmethyl)-(2,6-bis-aminomethylbenzoic)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(3-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)methanol

(2-aminomethyl-6-ethoxymethylene)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

N-(3-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)hydroxylamine

N-(3-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-O-methylhydroxylamine

[2-aminomethyl-4-(1H-imidazol-2-yl)benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-Tetra Kohinoor-8-yl)Amin

[2-aminomethyl-4-(1-methyl-1H-imidazol-2-yl)benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

[2-aminomethyl-4-(2H-pyrazole-3-yl)benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

[2-aminomethyl-4-(1-methyl-1H-pyrazole-3-yl)benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

[2-aminomethyl-4-(1H-[1,2,4]triazole-3-yl)benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

[2-aminomethyl-4-(1-methyl-1H-[1,2,4]triazole-3-yl)benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-oxazol-2-ylbenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-furan-2-ylbenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

[2-aminomethyl-4-(tetrahydrofuran-2-yl)benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-thiazol-2-ylbenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

[2-aminomethyl-4-(1H-tetrazol-5-yl)benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

[2-aminomethyl-4-(2-methyl-2H-tetrazol-5-yl)benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-pyridine-2-ylbenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-piperidine-2-ylbenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,78-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-3-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)methanol

(2-aminomethyl-5-ethoxymethylene)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-5-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}pyridine-2-yl)methanol

(4-aminomethyl-6-methoxypyridine-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(1H-benzoimidazol-2-ylmethyl)-(4,6-bis-aminomethylpyridine-3-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-allelomimetic-2-aminomethylbenzoic)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-allelomimetic-4-aminomethylbenzoic)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-cyclopropanecarbonyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-2-cyclopropanecarbonyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-5-Chlorobenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-5-bromobenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-5-nitrobenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

4-aminomethyl-3-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzonitrile/p>

(5-amino-2-aminomethylbenzoic)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-5-trifloromethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-terbisil)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-chlorbenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-bromobenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-nitrobenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

3-aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzonitrile

(4-amino-2-aminomethylbenzoic)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-trifloromethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-2-terbisil)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-2-Chlorobenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-2-bromobenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-2-nitrobenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzonitrile

(Amino-4-aminomethylbenzoic)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-2-trifloromethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(5-aminomethylation-2-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethylation-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethylphenol-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-1H-pyrrol-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-1-methyl-1H-pyrrol-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-1H-pyrazole-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-1-methyl-1H-pyrazole-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(3-aminomethyl-1H-pyrazole-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(3-aminomethyl-1-methyl-1H-pyrazole-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(5-aminomethyl-3H-imidazol-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(5-aminomethyl-1-methyl-1H-imidazol-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(5-aminomethylphenol-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(5-aminomethylpyrimidine the-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(5-aminomethylpyridine-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(5-allelomimetic-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)methanol

(3-allelomimetic-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)methanol

(4-allelomimetic-2-ethoxymethylene)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(3-allelomimetic-4-ethoxymethylene)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-5-cyclopropylmethyl)methanol

(4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-3-cyclopropylmethyl)methanol

(1H-benzoimidazol-2-ylmethyl)-(4-cyclopropylamino-2-ethoxymethylene)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(1H-benzoimidazol-2-ylmethyl)-(2-cyclopropylamino-4-ethoxymethylene)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzamide

5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-N-hydroxybenzamide

the hydrazide 5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid

5-aminomethyl-2-{[(1H-benzo idazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid

(1H-benzoimidazol-2-ylmethyl)-(2,4-bis-allylaminogeldanamycin)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-allelomimetic-2-cyclopropanecarbonyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-allelomimetic-4-cyclopropanecarbonyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(1H-benzoimidazol-2-ylmethyl)-(2,4-bis-cyclopropanecarbonyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(2-aminomethyl-4-propylbenzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-allyl-2-aminomethylbenzoic)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

3-aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl ether acetic acid

5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl ether acetic acid

4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-3-cyclopropanemethylamine ether acetic acid

2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-5-cyclopropanemethylamine ether acetic acid

3-allelomimetic-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-5-cyclopropanemethylamine ether acetic acid

5-allelomimetic-2-{[(1H-benzoimidazol-2-ILM is Teal)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-5-cyclopropanemethylamine ether acetic acid

the oxime 5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde

the oxime 3-aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde

N-(5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)ndimethylacetamide

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

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

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

(6-aminomethyl-1,3-dihydroisobenzofuran-5-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(4-aminomethyl-1,3-dihydroisobenzofuran-5-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

(7-aminomethyl-1,3-dihydroisobenzofuran-5-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)Amin

1. The compound of the formula

and its salt,

R1is N;

k = 3;

Ar represents a fragment containing 5-6-membered monocyclic or 9-12-membered condensed aromatic or heteroaromatic system containing atoms of N or O, or a combination of them;

each n is independently equal to 0 to 2;

j equals 0-3;

each Y is independently selected from the group consisting of halogen, OR;

-(CR2)mCN;

-(CR2)mNR52;

-(CR2)mNR(CR2)mNRR4;

-(CR2)mNR(CR2)mNR(CR2)mNR52;

-(CR2)mCO(CR2)mNR52;

-(CR2)mCO(CR2)mNR(CR2)mNRR4;

-(CR2)mCO(CR2)mNR(CR2)mNR(CR2)mNR52;

-(CR2)mNRCO(CR2)mNRR4;

-(CR2)mNRCO(CR2)mNR(CR2)mNR52;

-(CR2)mNRCO(CR2)mNR(CR2)mNR(CR2)mNR(CR2)mNR52;

-(CR2)mNROH;

-(CR2)mCONROH;

-(CR2)mCR=NOH;

-NR(CR2)mZ;

-guanidino;

-NHNHR;

-CH=N-Z; and

-amidino; where each R independently represents H or alkyl(1-6C), provided that R is H when present in the group -(CR2)or when attached to a nitrogen atom in the ring E;

each m independently is equal to 0-4,

each R4and each R5independently researched the mo represents H, alkyl(1-6C) or alkenyl(2-6C), each of which is optionally substituted by one or more nonaromatic(and), vegetarianism(and) substituent(s), where two R5can be combined with the formation of a cyclic amine, optionally containing one or more additional heteroatoms selected from N, O and S; and

Z represents an aromatic or heteroaromatic Deputy containing 5-12 members of the cycle and as containing heteroatoms N, O and/or S.

2. The compound according to claim 1, where (CR2)nbetween the ring a and N represents the relationship.

3. The compound according to claim 1, where (CR2)nbetween the ring E and N represents CH2.

4. The compound according to claim 1, where at least one Y is -(CH2)mNR52.

5. The compound according to claim 1, where Ar represents a residue of benzene, pyridine, benzimidazole, oxazole, benzoxazole, imidazole, benzo[1,3-dioxole] and 2,3-dihydrobenzofuran.

6. The compound according to claim 5, where Ar represents a residue of benzene, benzimidazole, imidazole, oxazole and pyridine.

7. Pharmaceutical composition for modulating the activity of a chemokine receptor comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6.

8. The use of compounds according to any one of claims 1 to 6 for the treatment of condition mediated by the chemokine receptor.

9. The application is unity according to any one of claims 1 to 6 for the treatment of human immunodeficiency virus or feline immunodeficiency virus.

10. The use of compounds of claim 8, where the chemokine receptor is CXCR4 or CCR5.

11. A compound selected from the group consisting of:

(3-aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)methanol;

(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[(1-benzyl-2-aminoethyl)imidazol-5-ylmethyl)]amine;

(5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)methanol;

methyl ester 5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid;

3-aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl} - beioley acids;

methyl ester 3-aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid;

(2-aminomethyl-4-ethoxymethylene)-(1H-benzimidazole-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amine;

N-(2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)guanidine;

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

N'-(4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)-N,N-dimethylguanidine;

[4-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetr hydrochinon-8-yl)aminomethylbenzoic]-N,N-dimethylformamidine;

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

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

ethyl ester of 2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-6-methoxybenzoic acids;

N'-({[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)-N,N-dimethylformamidine;

[4-(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)aminomethyl]benzamidine;

4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl alcohol;

4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzaldehyde;

methyl ester of 4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid;

4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzoic acid;

(2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}phenyl)methanol;

O-(2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}benzyl)hydroxylamine;

methyl ester 2-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl}-5-cyanobenzoic acid.

12. Pharmaceutical composition for modelirovanie the activity of the chemokine receptor, comprising a therapeutically effective amount of the compound according to item 11.

13. The use of compounds according to claim 11 for the treatment of condition mediated by the chemokine receptor.

14. The use of compounds according to claim 11 for the treatment of human immunodeficiency virus or feline immunodeficiency virus.

15. The use of a composition according to item 12 for the treatment of condition mediated by the chemokine receptor.

16. The use of a composition according to item 12 for the treatment of human immunodeficiency virus or feline immunodeficiency virus.

Priority items:

15.09.2000 - according to claims 1(part.), 2-16;

17.09.2001 - 1 (often.) in terms of y values.



 

Same patents:

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of bipiperidine of the formula (I): , wherein X means a direct bond, -CH2-, -CH2-CH2- or -CHR9-; R1 means optionally R10- and/or R11-substituted phenyl, optionally R10- and/or R11-substituted heteroaryl, N-oxide of optionally R10- and/or R11-substituted heteroaryl or optionally R10- and/or R11-substituted naphthyl; R2 has one of values given for R1, or it means optionally R10-substituted (C1-C6)-alkyl, optionally R10-substituted (C3-C6)-cycloalkyl, optionally R10-substituted adamantyl; R3 has one of values given for R1; each radical among R4, R5, R6 and R7 means hydrogen atom; R8 means hydrogen atom or (C1-C6)-alkyl; R9 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; R10 represents from 1 to 4 substitutes chosen independently from (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C2-C6)-alkoxyalkyl, (C1-C6)-halidealkyl, (C3-C6)-cycloalkyl, phenyl, heteroaryl, heteroaryl N-oxide, fluorine, chlorine, bromine, iodine atoms, hydroxyl, groups -OR9, -CONH2, -CONHR9, -CONR9R9, -COOH, -CF3, -CHF2, -CN, -NH2, -NHR9, -NHC(O)R9, -NR9C(O)R9; R11 represents two adjacent substitutes that form anellated 4-7-membered nonaromatic ring optionally comprising up to two heteroatoms chosen independently from nitrogen oxygen and sulfur atoms; Y means a direct bond, -C(O)-, -S(O2)-, -CH2-. Proposed compounds can be in free form as a salt. Compounds of the formula (I) and their salts possess antagonistic activity with respect to CCR5-receptors and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 6 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nicotine- or isonicotine-benzothiazole of general formulas (IA) and (IB) their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. In compounds of general formula (IA) and (IB) R1 means phenyl, piperidine-1-yl or morpholine; A means -O-; R means -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R''), -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidinyl or (C4-C6)-cycloalkyl; R'' mean(s) independently of one another hydrogen atom or lower alkyl; n= 1 or 2; A means -N(R')-; R means lower alkyl, (C4-C6)-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R'')2; R' and R'' mean independently of one another hydrogen atom or lower alkyl; n = 1 or 2; or A means -CH2-; R means -N(R'')-(CH2)m-O-lower alkyl, -N(R'')2, S-lower alkyl, or R means azethidinyl, pyrrolidinyl or piperidinyl that are substituted optionally with hydroxy-group or lower alkoxy-group; or R means morpholinyl, -N(R'')-(CH2)m-(C4-C6)-cycloalkyl, -N(R'')-(CH2)m-C(O)-O-lower alkyl, -O-(CH2)m-O-lower alkyl or alkoxy-group; R'' mean(s) independently of one another hydrogen atom or lower alkyl; m = 1, 2 or 3; or A means -S-; R means lower alkyl, or A-R mean in common piperazinyl substituted with alkyl, -C(O)-lower alkyl or oxo-group, or group A-R means piperidinyl substituted with lower alkoxy-group or hydroxy-group, or group A-R means morpholinyl substituted with lower alkyl, or group A-R means (C4-C6)-cycloalkyl, azethidine-1-yl optionally substituted with hydroxy-group or lower alkoxy-group, or group A-R means thiomorpholinyl-1,1-dioxo-group, tetrahydropyrane or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Proposed compounds can be used in treatment of diseases mediated by adenosine A2A-receptors, for example, Alzheimer disease, some depressive states, toxicomania and Parkinson's disease.

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

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

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, chemical technology, insecticides.

SUBSTANCE: invention relates to derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide represented by the general formula (I): wherein R represents (C1-C6)-alkyl group that can be substituted with one or some halogen atoms; R1 represents hydrogen atom, (C1-C6)-alkyl group that can be substituted with one or some substituted chosen from group of substitutes A, (C2-C6)-alkenyl group or acyl group; X represents group of the formula -C-R2 or nitrogen atom; each among R2 and R3 represents independently hydrogen atom, halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from group of substitutes A, (C3-C7)-cycloalkyl group, (C2-C6)-alkenyl group, (C3-C7)-cycloalkenyl group, formyl group, group of the formula: -CH=NOR4 (wherein R4 represents hydrogen atom or (C1-C6)-alkyl group, cyano-group, phenyl group that can be substituted with one or some substitutes chosen from group of substitutes B, 5- or 6-membered heterocyclic group (heterocycle comprising 1-2 heteroatoms that are similar and chosen from nitrogen atom), (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or phenoxy-group. The group of substitutes A represents group consisting of halogen atom, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group, cyano-group and phenyl group. The group of substitutes B represents group consisting of halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from above given group of substitutes A, (C1-C6)-alkoxy-group that can be substituted with one or some substitutes chosen from above given group of substitutes A, or its salt. Also, invention relates to insecticide comprising a derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide or its salt as an active component and a carrier optionally. Also, invention relates to a method for synthesis of derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide. Invention provides synthesis of derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide possessing the high insecticide activity.

EFFECT: improved method of synthesis, valuable properties of derivatives.

18 cl, 3 tbl, 91 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (1): wherein Y means -O-, -S- or -N(R2)- wherein R2 means hydrogen atom, (C1-C10)-alkyl or aralkyl; Z means 2,5-furanyl, 2,5-thiophenyl, 4,4'-stilbenyl or 1,2-ethyleneyl residue; R1 means hydrogen or halogen atom, (C1-C10)-alkyl, (C1-C10)-alkoxy-group, cyano-group, -COOM or -SO3M wherein M means hydrogen atom or alkaline or alkaline-earth metal atom. Method for synthesis involves carrying out the reaction of compound of the formula (2): with dicarboxylic acid of the formula: HOOC-Z-COOH (3) or with it ester wherein Y, Z and R1 have values given above in N-methylpyrrolidone or N,N-dimethylacetamide medium in the presence of an acid catalyst and optionally in the presence of an accessory solvent able to remove water from the reaction mixture.

EFFECT: improved method of synthesis.

11 cl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of sulfonamide of the general formula (I): wherein A means a substitute chosen from 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) optionally substituted with 1 or 2 halogen atoms, (C1-C4)-alkyl or phenyl radical, or 5- or 6-membered heteroaryl radical comprising 1 or 2 atoms of O, N or S; bicyclic heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from O, N or S and optionally substituted with 1 or 2 halogen atoms or (C1-C4)-alkyl; R1 means hydrogen atom (H), (C1-C4)-alkyl, benzyl; n means 0, 1, 2, 3 or 4; R2 means -NRR5 or the group of the formula: wherein a dotted line means optional chemical bond; R, R4 and R5 mean independently H or (C1-C4)-alkyl; or one of its physiologically acceptable salts. Compounds of the formula (1) possess antagonistic activity with respect to serotonin HT6-receptors that allows their using in pharmaceutical composition and for preparing a medicament.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, anti-microbial preparations.

SUBSTANCE: invention relates to compounds useful as anti-microbial agents. Claimed compounds are effective against to certain human and animal pathogens, including Gram-positive aerobic bacteria such as multi-resistant staphylococcus, streptococcus and enterococcus, as well as anaerobic organisms such as species Bacterioides spp. and Clostridia spp., and acid resistant organisms such as Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium spp.

EFFECT: new anti-microbial agents.

2 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel class of 5-membered heterocyclic compounds of the general formula (I): or cosmetically acceptable salts. Invention describes a compound represented by the formula (I) and its pharmaceutically or cosmetically acceptable salt wherein R1 is chosen from linear or branched (C1-C12)-alkyl, (C3-C7)-cycloalkyl, phenyl, naphthyl, C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatoms when they present are chosen independently from oxygen (O), nitrogen (N) or sulfur (S) atom and substituted optionally wherein substitutes are chosen from the first group comprising halogen atom, hydroxy0, nitro-, cyano-, amino- oxo-group and oxime, or from the second group comprising linear or branched (C1-C8)-alkyl wherein a substitute from indicated second group is optionally substituted with R10, or wherein heteroaryl is substituted with -CH2-C(O)-2-thienyl; Y is absent or chosen from the group consisting of (C1-C12)-alkyl-Z or (C2-C8)-alkyl wherein Z is chosen from sulfur, oxygen or nitrogen atom; A and B are chosen independently from nitrogen atom (N), -NH, -NR6, sulfur, oxygen atom to form heteroaromatic ring system; R2, R3 and R4 are chosen independently from the first group comprising hydrogen, halogen atom, or R3 and R4 form phenyl ring in adjacent positions; R5 is absent or chosen from the group comprising -CH2-phenyl, -CH2(CO)R7, -CH2(CO)NHR8 and -CH2(CO)NR8R9 that are substituted optionally with R10; R6, R7, R8 and R are chosen independently from the group comprising linear or branched (C1-C8)-alkyl, (C3-C7)-cycloalkyl, C5-heterocycloalkyl, benzylpiperidinyl, phenyl, naphthyl, heteroaryl, alkylheteroaryl, adamantyl, or R8 and R9 form piperidine ring, and R means 3,4-ethylenedioxyphenyl wherein substitutes in indicated group are substituted optionally with R10, and heteroaryl means C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatom when they present are chosen independently from O, N or S; R10 is chosen from halogen atom, hydroxy-, nitro-, cyano-, amino-, oxo-group, perhalogenalkyl-(C1-C6) or oxime; X means halide ion under condition that when groups/substitutes present at the same or at adjacent carbon or nitrogen atoms then can form optionally 5-, 6- or 7-membered ring optionally containing one o some double bonds and containing optionally one or some heteroatoms chosen from O, N or S. Also, invention describes a method for synthesis of these compounds, their therapeutic and cosmetic using, in particular, in regulation of age and diabetic vascular complications. Proposed compounds show effect based on the triple effect as agent destroying AGE (terminal products of enhanced glycosylation), inhibitors of AGE and scavengers of free radicals that do their suitable in different therapeutic and cosmetic using. Also, invention relates to pharmaceutical and cosmetic compositions comprising these compounds and to methods for treatment of diseases caused by accumulation of AGE and/or free radicals in body cells. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

73 cl, 4 tbl, 63 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

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

SUBSTANCE: invention describes novel derivatives of N-triazolylmethylpiperazine of the general formula (I): , wherein R1 means hydrogen atom or (lower)-alkyl; R2 means (lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, cycloalkyl with 5-6 carbon atoms in cycle, pyridinyl-(lower)-alkyl, possibly bi-substituted phenyl-(lower)-alkyl, phenyloxy-(lower)-alkyl substituted with halogen atom in phenyl ring; R3 means (lower)-alkyl, (lower)-alkyloxycarbonyl-(lower)-alkyl or (C5-C6)-cycloalkyl, or both R2 and R3 in common with nitrogen atom to which they are bound form substituted pyrrolidine ring or cyclic group of the formula (a): , wherein A means nitrogen, oxygen atom, methylene or methylidene group wherein its double bond is formed in common with adjacent carbon atom at position 3 of the group (a), and if A means nitrogen atom then this nitrogen atom has substitute R4', and in this case n means 2 or 3, and R4' means (lower)-alkyl, possibly substituted phenyl-(lower)-alkyl, possibly substituted pyridyl, pyridyl-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, pyrimidyl-(C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(lower)-alkyl or morpholinyl-(lower)-alkyl; R4 and R5 mean hydrogen atom and in all cases n means a whole number from 1 to 2; R4 means hydrogen atom, (lower)-alkyl, (lower)-alkoxy-(lower)-alkyl, (lower)-alkoxycarbonyl, (lower)-alkoxycarbonyl-(lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, phenyl, pyrrolidinyl, pyrrolidinyl-(lower)-alkyl, pyridyl or piperidinyl, cyclohexyl, cyclohexyl-(lower)-alkyl, phenyl-(lower)-alkyl, pyridyl monosubstituted with (lower)-alkyl, phenyl-(lower)-alkyl monosubstituted with (lower)-alkyl, pyrimidyl, pyridyl-(lower)-alkyl, morpholinyl-(lower)-alkyl; R5 means hydrogen atom, (lower)-alkyl or (lower)-alkoxy-(lower)-alkyl, or R4 and R5 taken in common mean spiroethylenedioxy-group bound with carbon atom of the group (a), (C3-C4)-alkylene bound with two adjacent atoms of the group (a) or phenyl anellated by two adjacent carbon atoms of the group (a), and their physiologically acceptable acid-additive salts also. Also, invention relates to methods for synthesis of these compounds, a medicinal agent based on thereof and intermediate compound in synthesis of novel compounds. Novel compounds are antagonists of neurokinin receptors and display effect in peripheral region preferably and can be used in treatment of functional and inflammatory disorders of digestive tract.

EFFECT: improved preparing method, valuable medicinal properties of derivatives.

10 cl, 4 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

Up!