RU2277092C2 - Heterocyclic compounds, their using and pharmaceutical composition for treatment of states mediated by cxcr4 and ccr5 - Google Patents

Abstract

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

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

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

EFFECT: valuable medicinal properties of compounds and composition.

15 cl, 57 ex

Description

Technical field

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

BACKGROUND OF THE INVENTION

The literature describes about 40 human chemokines that function, at least in part, by regulating many complex and overlapping biological activities that are important for lymphoid cell movement and extravasation and tissue leukocyte infiltration in response to stimulating agents (see, for example: P .Ponath, Exp. Opin. Invest. Drugs, 7: 1-18, 1998; Baggiolini, M., Nature 392: 565-568 (1998); Locati, et al., Annu. Rev. Med. 50: 425- 440 (1999)). These chemotactic cytokines, or chemokines, are a family of proteins with molecular weights of approximately 8-10 kDa. Chemokines appear to have a common structural motif, which consists of 4 conserved cysteines involved in maintaining the tertiary structure. There are two main subfamilies of chemokines: “CC” or β-chemokines and “CXC” or α-chemokines. Receptors of these chemokines are classified based on the chemokine, which is a natural receptor ligand.

Β-chemokine receptors mean "CCR", while α-chemokine receptors mean "CXCR".

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

In most cases, HIV initially binds through its envelope protein gp120 to the CD4 receptor of the target cell. Apparently, a conformational change occurs in the gp120 protein, which leads to its subsequent binding to a 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 isolates resulting from infection bind to the chemokine CXCR4 receptor.

After the initial binding of HIV to CD4 cells, the fusion of the virus and the cell occurs, which is mediated by members of the chemokine receptor family, various members that serve as joint fusion factors for macrophagotropic (M-tropic) HIV-1 isolates and tropic to T cell lines (T -tropic) HIV-1 isolates (Carroll, et al., Science, 276: 273-276 (1997); Feng, et al., Science 272: 872-877 (1996); Bleul, et al. Nature 382: 829 -833 (1996); Oberlin, et al., Nature 382: 833-835 (1996); Cocchi, et al., Science 270: 1811-1815 (1995): Dragic, et al., Nature 381: 667-673 (1996); Deng, et al., Nature 381; 661-666 (1996); Alkhatib, et al., Science 272: 1955-1958 (1996). In the course of infection, b apparently, the majority of HIV particles undergo a change from the M-tropic phenotype to the more pathogenic T-tropic viral phenotype (Blaak, et al., Proc. Natl. Acad, Sci. 97: 1269-1274 (2000); Miedema , et al., Immune. Rev., 140: 35 (1994); Simmonds, et al., J. Virol. 70: 8355-8360 (1996); Tersmette, et al., J. Virol. 62: 2026-2032 (1988); Connor, R.I., Ho, D.D. J. Virol. 68: 4400-4408 (1994); Schuitemaker, et al., J. Virol. 66: 1354-1360 (1992)). The M-tropic viral phenotype correlates with the ability of the virus to penetrate the cell after binding of the CCR5 receptor, while the T-tropic viral phenotype correlates with the penetration of the virus into the cell after binding and fusion of the membrane with the CXCR4 receptor. Based on clinical observations, it has been suggested that patients who have genetic mutations in the CCR5 receptor appear to be 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)). Despite the number of chemokine receptors that have been reported to mediate the entry of HIV into cells, the CCR5 and CXCR4 receptors appear to be the only physiologically important joint receptors for a wide range of primary clinical strains of HIV-1 (Zhang, et al., J Virol. 72: 9307-9312 (1998); Zhang, et al., J. Virol. 73: 3443-3448 (1999); Simmonds, et al., J. Virol. 72: 8453-8457 (1998)) . The fusion and penetration of T-tropic variants of viruses through the CXCR4 receptor is inhibited by the natural CXC chemokine, factor 1, produced by stromal cells, while the fusion and penetration of M-tropic variants of the virus through the CCR5 receptor is inhibited by natural CC chemokines, namely, the activation regulator normal T-cell expression and secretion (RANTES) and macrophage inflammatory proteins (MIP-1 alpha and beta).

It was suggested that in addition to the functioning of chemokines as co-factors in the penetration of HIV into cells, a possible cause of CD8 ⁺ T-cell apoptosis and AIDS-related dementia by inducing apoptosis of nerve cells is the direct interaction of the gp120 viral protein with the chemokine receptor CXCR4 (Hesselgesser, et al., Curr. Biol. 8: 595-598 (1998); Hesselgesser, et al., Curr. Biol. 7: 112-121 (1997); Hesselgesser, et al., "Chemokines and Chemokine receptors in the Brain" in Chemokines in Disease published by Humana Press (1999), Edited by 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 to their natural ligands seems to play a more evolutionary and important role than just mediated HIV infection. The binding of a natural ligand, a pre-B cell stimulating factor (PBSF / SDF-1) factor produced by stromal cells, to the CXCR4 chemokine receptor leads to an important signal transmission mechanism: mice exposed to CXCR4 or SDF-1 were found to have cerebellar, cardiac and gastrointestinal disorders and fetal death (Zou, et al., Nature, 393: 591-594 (1998); Tachibana, et al., Nature, 393: 591-594 (1998); Nagasawa, et al ., Nature 382: 635-638 (1996)). CXCR4 receptor deficient mice also showed hematopoiesis abnormalities (Nagasawa, et al., Nature 382: 635-638 (1996)); the migration of CXCR4-expressing leukocytes and hematopoietic progenitor cells to the SDF-1 factor is apparently important for maintaining the B cell line and localizing CD34 ⁺ progenitor cells in the bone marrow (Bleul, et al., Exp. Med. 187: 753-762 (1998); Viardot, et al., Ann. Hematol. 77: 195-197 (1998); Auiti, et al., J. Exp. Med. 185: 111-120 (1997); Peled , et al., Science 283: 845-848 (1999); Qing, et al., Immunity 10: 463-471 (1999); Lataillade, et al., Blood 95: 756-768 (1999); Ishii, et al., J. Immunol. 163: 3612-3620 (1999); Maekawa, et al., Internal. Medicine 39: 90-100 (2000); Fedyk, et al., J. Leukocyte Biol. 66: 667-673 (1999); Peled, et al., Blood 95: 3289-3296 (2000)).

The signal generated by the binding of factor SDF-1 to the CXCR4 receptor 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 BJRollins ; Arenburg, et al., J. Leukocyte Biol. 62: 554-562 (1997); Moore, et al., J. Invest. Med. 46: 113-120 (1998); Moore, et al., Trends cardiovasc Med. 8: 51-58 (1998); Seghal, et al., J. Surg. Oncol. 69: 99-104 (1998)); known angiogenic growth factors VEG-F and bFGF that increase CXCR4 receptor levels in endothelial cells and SDF-1 can cause in vivo revascularization (Salcedo, et al., Am. J. Pathol. 154: 1125-1135 (1999)). CXCR4 receptor leukemic cells migrate to and attach to lymph nodes and bone marrow stromal cells that 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 factor SDF-1 to the CXCR4 receptor is also related to the pathogenesis of atherosclerosis (Abi-Younes, et al., Circ. Res. 86: 131-138 (2000)), renal allograft rejection (Eitner, et al., Transplantation 66: 1551-1557 (1998)), asthma and allergic airway inflammation (Yssel, et al., Clinical and Experimantal Allergy 28: 104-109 (1998); J. Immunol. 164: 5935-5943 (2000); Gonzalo, et al., J. Immunol. 165: 499-508 (2000)), Alzheimer's disease (Xia, et al., J. Neurovirology 5: 32-41 (1999)) and arthritis (Nanki, et al., J. Immunol 164: 5010-5014 (2000)).

In an attempt to better understand the relationship between chemokines and their receptors, experiments have recently been made to inhibit the fusion, penetration and replication of HIV through the CXCR4 chemokine receptor using monoclonal antibodies or small molecules that appear to have a beneficial therapeutic effect (Schols, et al ., J. Exp. Med. 186: 1383-1388 (1997); Schols, et al., Antiviral Research 35: 147-156 (1997); Bridger, et al., J. Med. Chem. 42: 3971- 3981 (1999); Bridger, et al., "Bicyclam Derivatives as HIV Inhibitors" in Advances in Antiviral Drug Design Vol. 3: 161-229; Published by JAI press (1999); Edited by E. De Clercq). Small molecules such as bicyclams appear to specifically bind to the CXCR4 receptor, rather than the CCR5 receptor (Donzella, et al., Nature Medicine, 4: 72-77 (1998)). These experiments showed that bicyclam prevent the entry of HIV and fusion with the membrane of the target cell in vitro. Bicyclams were later shown to inhibit the fusion and replication of feline immunodeficiency virus (FIV), which is introduced into cells through the CXCR4 receptor (Egberink, et al., J. Virol. 73: 6346-6352 (1999)).

Additional experiments showed that bicycles in a dose-dependent manner inhibit the binding of ¹²⁵ I-labeled factor SDF-1 to the CXCR4 receptor and signal transduction (detected by increasing calcium inside the cell) in response to SDF-1. Thus, bicyclam also acts as an antagonist to signal transduction resulting from the binding of a factor produced by stromal cells, or SDF-1α, a natural chemokine to the CXCR4 receptor. Bicyclams also inhibit the apoptosis induced by the gp120 viral envelope protein in HIV-uninfected cells (Blanco, et al., Antimicrobial Agents and Chemother. 44: 51-56 (2000)).

US Patents Nos. 5,583,131; 5698546 and 5817807, which are incorporated herein by reference in their entirety, disclose cyclic compounds exhibiting activity against HIV-1 and HIV-2 in in vitro experiments. It was subsequently discovered and shown in interdependent applications US No. 09/111895 and US No. 60/172153 that these compounds exhibit anti-HIV activity by binding to the chemokine receptor CXCR4 expressed on the surface of certain cells of the immune system. Such competitive binding protects these target cells from HIV infection, which penetrates into the cells through the CXCR4 receptor. In addition, these compounds counteract the binding, signaling and chemotactic effects of the natural ligand for the CXCR4 receptor, factor 1α, produced by stromal cells (SDF-1). It was also disclosed that these novel compounds demonstrate a protective effect against HIV infection of target cells by binding in vitro to the CCR5 receptor.

In addition, in US patent No. 09/495298 it was disclosed that these cyclic polyamine antiviral agents described in the above patents increase the production of white blood cells and also exhibit antiviral properties. Thus, these agents are used to regulate side effects that occur during chemotherapy, to ensure a favorable outcome in bone marrow transplantation, wound healing and treatment of burns, as well as against bacterial infections in leukemia.

Later, in PCT international patent application PCT / CA00 / 00321, a series of heterocyclic compounds was disclosed that exhibit anti-HIV activity by binding to the chemokine receptors CXCR4 and CCR5 expressed on the surface of certain cells of the immune system. Thus, this competitive binding protects the target cells from HIV infection, which penetrates into the cells via CXCR4 or CCR5 receptors. In addition, these compounds counteract the binding, signaling and chemotactic effects of the natural ligand for CXCR4, chemokine, factor 1α (SDF-1) produced by stromal cells and / or the natural ligand for CCR5, chemokine RANTES.

New compounds are disclosed herein that have a protective effect against HIV infection of target cells by binding to CXCR4 or CCR5 chemokine receptors in the same manner as described above for macrocyclic compounds.

The citation of the above documents should not be construed as an admission that any of these documents represents the relevant prior art. All statements regarding the date or statement regarding the contents of these documents are based on information available to applicants and do not imply any assumption regarding the correctness of the dates or contents of these documents. In addition, all documents referred to throughout the application are incorporated into this description in their entirety by reference.

SUMMARY OF THE INVENTION

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

The compounds of the invention have the formula

and their salts and prodrug forms, where:

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

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

Ar optionally represents a substituted aromatic or heteroaromatic ring;

each of L ¹ , L ² and L ³ independently represents a bond, CO, SO ₂ or CH ₂ , where at least one of L ² and L ³ must include CO or SO ₂ ; and where L ¹ can also be alkylene (2-5C), where one or two C atoms can optionally be replaced with N and said alkylene, optionally itself can be substituted with bridged alkylene (3-4C); L ² and L ³ may also independently mean SO ₂ NH, CONH, SO ₂ NHCH ₂ or CONHCH ₂ ;

n is 0, 1 or 2;

each R ¹ and R ² independently represents an H atom or a straight or branched chain or cyclic alkyl (1-6C), which optionally may be substituted, and where R ² may be alkylene fused to Y; and

Y includes at least one aromatic or heteroaromatic ring or another heterocyclic substituted or unsubstituted ring fused directly to L ³ .

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

MODES FOR CARRYING OUT THE INVENTION

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

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

The compounds of formula 1 are used as agents that act on 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 diseases in humans, as well as immunoregulators of diseases. Thus, a compound that regulates the activity of such chemokine receptors should be suitable for the treatment or prevention of such diseases.

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

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

Compounds that suppress 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 pulmonary diseases, allergic pneumonitis, eosinophilic pneumonia, allergic delayed-type reaction, diffuse disease of the connective tissue of the lung (ILD) (for example, idiopathic pneumosclerosis, or ILD associated with rheumatoid arthritis, systemic red erythematosus, ankylosing spondylitis, systemic sclerosis, xerodermatosis, polymyositis or dermatomyositis); systemic anaphylaxis or allergic reactions, drug allergies, allergic reactions to insect bites; autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myasthenia gravis, severe pseudoparalytic, juvenile diabetes; glomerulonephritis, autoimmune thyroiditis, graft rejection, including allogeneic graft rejection or “graft versus host”; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; spondyloarthropathy; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis (e.g., necrotic, skin and allergic vasculitis); eosinophilic myositis, eosinophilic fasciitis; and malignant tumors.

Compounds that activate or support chemokine receptor function can be used to treat diseases associated with immunosuppression, for example, to chemotherapy individuals, radiation therapy, to heal wounds and treat burns, to treat autoimmune diseases or other drug therapy (for example, corticosteroid therapy) , or when using a combination of standard drugs in the treatment of autoimmune diseases and in transplantation / rejection of a transplant that causes immunosuppression th; immunosuppression due to congenital insufficiency of receptor function or other factors; and infectious diseases, such as parasitic diseases, including, but not limited to, helminth infections, such helminths as nematodes (round helminths); trichocephalosis, enterobiosis, ascariasis, hookworm, strongyloidosis, trichinosis, filariasis; diseases caused by trematodes; visceral wandering larva syndrome (eg Toxocara), eosinophilic gastroenteritis (eg Anisaki spp., Phocanema ssp.), wandering larva skin syndrome (Ancylostona braziliense, Ancylostoma caninum); malaria caused by protozoa Plasmodium vivax, human cytomegalovirus, Herpesvirus saimiri, and Kaposi’s sarcoma caused by the herpes virus, also known as human herpes virus 8, and the poxvirus Moluscum contagiosum.

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

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

(1) a nucleotide reverse transcriptase inhibitor such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fosivudine todoxil, etc .;

(2) a non-nucleotide reverse transcriptase inhibitor (including an agent having antioxidant activity, such as immunoccal, oltipraz, etc.), such as nevirapine, delavirdine, efavirenz, loviride, immunoccal, oltipraz, etc .; and

(3) protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, palinavir, lasinavir, etc.

The scope of the combinations of the compounds of formula 1 according to this invention with agents for the prevention and treatment of HIV infection is not limited to those listed in paragraphs (1), (2) or (3), but includes essentially any combination with any a pharmaceutical composition used to treat HIV infection. In addition, in such combinations, the compounds of the present invention and other agents for the prophylaxis and treatment of HIV infection can be administered separately or together. In addition, the introduction of one element can be carried out before, jointly or after the introduction of another agent (agents).

The compounds of formula 1 according to the present invention can be administered orally, parenterally (for example, intramuscularly, intraperitoneally, intravenously, by intracisternal injection or infusion, subcutaneous injection or implant), by aerosol inhalation, by nasal, vaginal, rectal, sublingual or topical routes of administration and can be prepared, separately or together, in suitable unit dosage forms containing the usual non-toxic pharmaceutically acceptable carriers, adjuvants and binders corresponding to each route of administration.

The compounds of formula 1 are all active and are used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats and monkeys. The compounds of the present invention are also effective in human use.

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

The present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of formula 1. The compound of formula 1 may be administered alone or as a mixture with a pharmaceutically acceptable carrier (for example, in the form of solid compositions such as tablets, capsules, granules, powders, etc .; liquid compositions such as syrups, injections, etc.) by the oral and non-oral route. Examples of non-oral compositions include injections, drops, suppositories, pessaries.

An appropriate dose level in the treatment or prophylaxis of conditions that require modulation of the chemokine receptor will generally be from about 0.01 to 500 mg per kg body weight of the patient per day, which can be administered in a single dose or multiple doses. Preferably, the dosage level will be from about 0.1 to 250 mg / kg per day. It is clear that the specific dosage level and dosage frequency for a particular patient may vary, and the treatment regimen will depend on a number of factors, including the activity of the specific compound used, resistance to metabolism and duration of action of such a compound, on the patient's age, his body weight, general health, gender, nutrition, method and time of administration, rate of excretion, combination of the drug, severity of the condition and therapy to which the patient is exposed.

In addition, the present invention relates to new compounds that bind to chemokine receptors and, thereby, prevent the binding of a natural ligand to them. The compounds of the present invention are used as agents exhibiting a protective effect against target cells against HIV infection. The compounds of the present invention are also used as antagonists or agonists of chemokine receptors, and also use other biological activities related to the ability of these compounds to inhibit the binding of chemokines to their receptors.

The compounds of the invention can be used as “prodrug” forms, that is, protected forms of the compounds that release the compound after administration to the patient. For example, the compound may carry protective groups that are cleaved by hydrolysis in body fluids, for example, in the bloodstream, thereby releasing the active compound, or are oxidized or reduced in body fluids to release the compound. A discussion of prodrug data can be found in Smith and William ^'s Introduction to the Principles of Drug Design, HJ Smith, Wright, Second Edition, London 1988.

Additive acid salts that are pharmaceutically acceptable, such as an inorganic base salt, an organic base salt, an inorganic acid salt, an organic acid salt, a basic or acidic amino acid salt, etc., are also contemplated by the present invention. Examples of the inorganic base salt include an alkali metal salt (e.g., sodium, potassium, etc.), alkaline earth metal (e.g., calcium, magnesium, etc.), aluminum, ammonium, etc. Examples of the organic base salt include trimethylamine salt, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N ^{'dibenzylethylenediamine,} etc. Examples of the inorganic acid salt include salts of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Examples of the organic acid salt include a salt of formic acid, oxalic acid, acetic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, malic acid, p-toluenesulfonic acid, etc. Examples of salts of the basic amino acid include a salt of arginine, lysine, ornithine, etc. Examples of salts of an acidic amino acid include a salt of aspartic acid, glutamic acid, etc. The term "non-toxic" in the present context should be considered relative to the prognosis for an infected patient without treatment.

Subsequent determination of compounds

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

In one series of preferred embodiments of the present invention, L ¹ is a chemical bond.

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

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

where m may be 0, 1 or 2.

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

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

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

Other preferred compounds include compounds of the formula

or formulas:

where l is 0-3, and R ^′ is OH, MeO, SH, SMe, CN, CO ₂ Me, F, Cl, Br, NO ₂ , CH ₃ CO, NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ CH ₃ CONH, CH ₃ SO ₂ NH, CONH ₂ , CF ₃ or Me;

each of Z ¹ , Z ² and Z ³ independently means CH, CR ^′ or N, where only two of these Z ¹ , Z ² and Z ³ can represent N;

and L ² and L ³ are as defined above.

Other preferred compounds are compounds of the formula

where l is 0-3, and R ^′ is OH, MeO, SH, SMe, CN, CO ₂ Me, F, Cl, Br, NO ₂ , CH ₃ CO, NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ CH ₃ CONH, CH ₃ SO ₂ NH, CONH ₂ , CF ₃ or Me;

k is 0-2;

each of Z ¹ , Z ² and Z ³ independently means CH, CR ^′ or N, where only two of these Z ¹ , Z ² and Z ³ can represent N;

and X, L ² and L ³ are as defined above.

In formula 1, examples of an optionally substituted ring system, X or Z, are dihydroquinoline, tetrahydroquinoline, pyranopyridine, dihydropyranopyridine, thiopyranopyridine, dihydrothiopyranopyridine, dihydronaphthyridine and tetrahydronaphthyridine. Nitrogen oxides and sulfur-containing heterocycles are also contemplated by the present invention. In the above ring system, any nitrogen atom in the ring may be substituted by hydrogen, substituted by alkyl, alkenyl, cycloalkyl or an aryl group, or may be a nitrogen atom of a carboxamide, carbamate or sulfonamide. A preferred embodiment is tetrahydroquinoline.

In Formula 1, “optional substituents” in the X or Z ring system may represent halogen, nitro, cyano, carboxylic acid, optionally substituted alkyl, alkenyl or cycloalkyl groups, optionally substituted hydroxyl group, optionally substituted thiol group, optionally substituted amino group or acyl group, optionally substituted carboxylate, carbamate, carboxamide or sulfonamide group, optionally substituted aromatic or heterocyclic group.

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

Examples of optionally substituted alkyl include C _1-10 alkyl, including methyl, ethyl, propyl, etc., examples of optionally substituted alkenyl groups include C _2-10 alkenyl, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, and t etc., and examples of optionally substituted cycloalkyl groups include C _3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In these examples, C _1-6 alkyl, alkenyl and cycloalkyl are preferred. A possible substituent may also be optionally substituted aralkyl (e.g. phenylC _1-4 alkyl) or heteroalkyl, such as phenylmethyl (benzyl), phenethyl, pyridinylmethyl, pyridinyl ethyl, etc. The heterocyclic group may be a 5- or 6-membered ring containing 1-4 heteroatoms.

Examples of optionally substituted hydroxyl and thiol groups include optionally substituted alkyl (e.g., C _1-10 alkyl) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, etc., preferably C _1-6 alkyl); optionally substituted cycloalkyl (e.g., C _3-7 cycloalkyl, etc., such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); optionally substituted aralkyl (e.g. phenyl-C _1-4 alkyl, e.g. benzyl, phenethyl, etc.). In those cases where there are two adjacent hydroxyl or thiol substituents, heteroatoms can be connected via an alkyl group, such as O (CH ₂ ) _n O and S (CH ₂ ) _n S (where n = 1-5). Examples include methylenedioxy, ethylenedioxy, etc. The invention also contemplates oxides of thioether groups such as sulfoxides and sulfones.

In addition, examples of the optionally substituted hydroxyl group include optionally substituted C _2-4 alkanoyl (e.g. acetyl, propionyl, butyryl, isobutyryl, etc.), C _1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.) and an optionally substituted aromatic and heterocyclic carbonyl group, including benzoyl, pyridinecarbonyl, etc.

The substituents on the optionally substituted amino group can bind to each other to form a cyclic amino group (e.g., a 5-6 membered cyclic amino group, etc., such as tetrahydropyrrole, piperazine, piperidine, pyrrolidine, morpholine, thiomorpholine, pyrrole, imidazole, etc. d.). Said cyclic amino group may have a substituent, and examples of substituents include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy, thiol group, amino group, carboxyl group, optionally halogenated C _{1- 4} alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C _2-4 alkanoyl (e.g. acetyl , propionyl, etc.), C _1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), the number of pre preferred substituents is 1 to 3.

An amino group may also be substituted once or twice (with the formation of a secondary or tertiary amine) by a group, such as an optionally substituted alkyl group, including C _1-10 alkyl (eg methyl, ethyl, propyl, etc.); an optionally substituted alkenyl group such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., or an optionally substituted cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In these cases, C _1-6 alkyl, alkenyl and cycloalkyl are preferred. The amino group may also be optionally substituted with an aromatic or heterocyclic group, aralkyl (e.g. phenylC _1-4 alkyl) or heteroalkyl, such as, for example, phenyl, pyridine, phenylmethyl (benzyl), phenethyl, pyridinylmethyl, pyridinyl ethyl, etc. The heterocyclic group may be a 5-6 membered ring containing 1-4 heteroatoms. Possible substituents of the “optionally substituted amino groups” are those defined above for the “optionally substituted cyclic amino group”.

The amino group may optionally be substituted with a substituted C _2-4 alkanoyl (e.g. acetyl, propionyl, butyryl, isobutyryl, etc.) or C _1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.) or carbonyl or sulfonyl, substituted aromatic or heterocyclic ring, for example, benzenesulfonyl, benzoyl, pyridinesulfonyl, pyridinecarbonyl, etc. Heterocycles are as defined above.

Examples of an optionally substituted acyl group include, as substituents on a fused ring system containing X, a carbonyl group or a sulfonyl group bonded to hydrogen; optionally substituted alkyl (e.g., C _1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and etc., preferably lower (C _1-6 ) alkyl, etc.); optionally substituted cycloalkyl (e.g., C _3-7 cycloalkyl, etc., such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); optionally substituted alkenyl (for example, C _2-10 alkenyl such as allyl, crotyl, 2-pentenyl, etc., preferably lower C _2-6 alkenyl, etc.); optionally substituted cycloalkenyl (for example, C _3-7 cycloalkenyl, etc., such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); an optionally substituted 5-6 membered monocyclic aromatic group (e.g., phenyl, pyridyl, etc.).

Examples of the optionally substituted carboxylate group (ester group) include optionally substituted alkyl (e.g., C _1-10 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C _1-6 ) alkyl, etc.); optionally substituted cycloalkyl (e.g., C _3-7 cycloalkyl, etc., such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); optionally substituted alkenyl (for example, C _2-10 alkenyl, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower C _2-6 alkenyl, etc.); optionally substituted cycloalkenyl (e.g., C _3-7 cycloalkenyl, etc., such as 2-cyclohexenylmethyl, etc.); optionally substituted aryl (e.g., phenyl, naphthyl, etc.) and C _1-4 aryl, e.g., benzyl, phenethyl, etc. Also contemplated by the invention are groups such as methoxymethyl, methoxyethyl, etc.

Examples of optionally substituted carboxamide and sulfonamide groups are identical to the above examples, which define amine as an “optionally substituted amino group”.

Examples of optionally substituted aromatic or heterocyclic groups as possible substituents are phenyl, naphthyl or a 5-6 membered heterocyclic ring containing 1-4 heteroatoms. Possible substituents are substantially identical to those listed above.

In the above examples, the number of substituents is 1-4, preferably 1-2. The substituents on the optionally substituted groups are the same as the optionally substituted groups described above. Preferred substituents are halogen (fluorine, chlorine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, carboxylate group, sulfonate group, sulfonamide group, carboxamide group, optionally halogenated C _1-4 alkyl, optionally halogenated C _1-4 alkoxy (e.g. trifluoromethoxy, etc.), C _2-4 alkanoyl (e.g. acetyl, propionyl, etc.) or aroyl, C _1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc. etc.), optionally substituted aryl or heterocyclic groups but. The number of substituents in the above groups is preferably from 1 to 3.

In the above formulas, W may be CH (pyrrole), O (oxazole), S (thiazole), NH or NR ^′ (imidazole), where R ^′ is a C _1-6 alkyl group or an acyl or sulfonyl group. Examples of fused ring systems containing X or Z include, but are not limited to, indole, tetrahydroindole, benzimidazole, tetrahydrobenzimidazole, azabenzimidazole, benzoxazole, tetrahydrobenzoxazole, benzothiazole, tetrahydrobenzothiazole. Preferred ring systems are imidazole and benzimidazole.

In the above formula 1, Y is an optionally substituted heterocyclic group, including a heteroaromatic group or aromatic group. Examples of possible substituted heterocyclic groups include 5-6 membered, saturated, partially saturated or aromatic heterocyclic rings containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Heterocycles may include pyridine, quinoline, isoquinoline, imidazole, benzimidazole, azabenzimidazol, benzotriazole, furan, benzofuran, thiazole, benzothiazole, oxazole, benzoxazole, pyrrole, indole, indoline, indazole, pyrrolidine, pyrrolidone, pyrroline, piperidine, piperazine, tetrahydroquinoline, tetrahydroisoquinoline , pyrazole, thiophene, isoxazole, isothiazole, triazole, tetrazole, oxadiazole, thiadiazole, morpholine, thiamorpholine, pyrazolidine, imidazolidine, imidazoline, tetrahydropyran, dihydropyran, benzopyran, dioxane, dithirofen, tetrahydro tetran, tetrahydro, tetrahydro, tetrahydro, tetrahydro, tetrahydro drofuran, dihydrothiophene etc. Nitric oxide and sulfur-containing heterocycles are also included in the present invention. Possible substituents for fused or non-fused aromatic or heterocyclic rings are identical to those described above.

In cases where X or Z is represented by formula A, B or C, optional substituents include additional ring systems such as cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran, tetrahydrothiophene (thiolane), tetrahydropyran, tetrahydrothiapiran (pentamethylene sulfide), phenyl, oxinepine, pyrrolidine, piperidine, etc. Nitrogen oxides and sulfur-containing heterocycles are also contemplated by the present invention. Other possible substituents are identical to those described above.

New compounds of formula 1 according to the present invention can be prepared in the form of pharmaceutical compositions that can be entered topically; transdermally, including the intravenous route of administration; orally and other standard methods of pharmaceutical administration to mammalian subjects, as determined according to normal clinical practice.

Having now a general description of the invention, its meaning is easier to understand by referring to the following examples, the purpose of which is to illustrate the invention, and the examples given do not limit the present invention, unless otherwise indicated.

EXPERIMENTAL PART

General Procedure A: Direct reductive amination with NaBH ₃ CN

To a stirred solution of an amine (1 equivalent) in anhydrous methanol (concentration ~ 0.1 M) at room temperature was added a carbonyl compound (~ 1-2 equivalents) in one portion. Once the carbonyl was dissolved (~ 5 minutes), NaBH ₃ CN (~ 2-4 equivalents) was added in one portion and the resulting solution was stirred at room temperature. The solvent was removed under reduced pressure, and CH ₂ Cl ₂ (20 ml / mmol of amine) and brine or 1.0 M aqueous NaOH (10 ml / mmol of amine) were added to the residue. The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 x 10 ml / mmol amine). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by chromatography.

General Procedure B: Direct reductive amination with NaBH (OAc) ₃

To a stirred solution of an amine (1 equivalent) in CH ₂ Cl ₂ (concentration ~ 0.2 M) at room temperature was added a carbonyl compound (~ 1-2 equivalents), glacial acetic acid (0-2 equivalents) and NaBH (OAc) ₃ (~ 1.5-3 equivalents), and the resulting solution was stirred at room temperature. The reaction mixture was poured either into a saturated aqueous solution of NaHCO ₃ or a 1.0 M aqueous solution of NaOH (10 ml / mmol of amine). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 x 10 ml / mmol of amine). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by chromatography.

General Procedure C: Deprotection of the 2-nitrobenzenesulfonyl group (nosyl)

To a stirred solution of nosyl-protected amine (1 equivalent) in anhydrous CH ₃ CN (or DMF) (concentration ~ 0.05 M) was added thiophenol (4-8 equivalents) at room temperature, followed by the addition of powdered K ₂ CO ₃ (8- 12 equivalents). The resulting bright yellow solution was stirred at room temperature (or 50 ° C) for 1-24 hours. The solvent was removed under reduced pressure, and CH ₂ Cl ₂ (10 ml / mmol of amine) and water (2 ml / mmol of amine) were added to the residue. The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 x 5 ml). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by chromatography.

Alternative work-up: the reaction mixture was filtered and concentrated to give a yellow oil, which was purified by chromatography on basic alumina (eluent CH ₂ Cl ₂ , then CH ₂ Cl ₂ —CH ₃ OH, 20: 1) to give the free base as a colorless oil.

General Procedure D: Salt Formation Using Saturated HBr (Gas) in Acetic Acid

To a solution of the free base in glacial acetic acid (or dioxane) (2 ml) was added a saturated solution of HBr (gas) in acetic acid (or dioxane) (2 ml). Then a large volume of ether (25 ml) was added to precipitate a solid, which was allowed to settle at the bottom of the flask, and the supernatant was decanted. The solid was washed with decantation with ether (3 x 25 ml) and residual traces of the solvent were removed in vacuo. For additional purification (where necessary), the solid can be dissolved in methanol and reprecipitated with a large volume of ether. Washing of the solid with ether by decantation followed by drying of the solid in vacuo (0.1 torr) resulted in the desired compound.

General Procedure E: Removing SEM Protection

To a stirred solution of the SEM-protected compound (1 equivalent) was added 6 N HCl (30 ml / mmol) and the resulting solution was stirred at 50 ° C. for the indicated time. The solution was diluted with water (50 ml / mmol), then neutralized with NaHCO ₃ and extracted with EtOAc (3 x 100 ml / mmol). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by chromatography.

General Method F: Combination Using EDCI

To a stirred solution of amine (1 equivalent), acid (1.1 equivalents), 1-hydroxybenzotriazole (1.1 equivalents), 4-methylmorpholine (1.5 equivalents) in anhydrous DMF (~ 0.3 M) at room temperature in EDCI (1.1 equivalents) was added under nitrogen atmosphere. The resulting solution was stirred at room temperature for the indicated time. Then DMF was removed in vacuo. The mixture was diluted with CH ₂ Cl ₂ (100 ml / mmol), washed with NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated.

General Procedure G: Alcohol Mesylation

To a stirred solution of alcohol (1 equivalent) and Et ₃ N (1.2 equivalents) in anhydrous CH ₂ Cl ₂ (~ 0.1 M) at 0 ° C. under an atmosphere of nitrogen was added MsCl (1.1 equivalents) dropwise. The resulting solution was stirred at the indicated temperature for the indicated time. The mixture was diluted with CH ₂ Cl ₂ (100 ml / mmol), washed with an aqueous solution of NH ₄ Cl, dried (Na ₂ SO ₄ ) and concentrated.

General Procedure H: Mesylate Substitution Reactions

To a stirred solution of amine (1.5 equivalents) and Et ₃ 3N (1.0 equivalent) in anhydrous CH ₂ Cl ₂ (~ 0.2 M) at 0 ° C in a nitrogen atmosphere was added dropwise a solution of mesylate (1.0 equivalent ) The resulting solution was stirred at room temperature for the indicated time. The mixture was diluted with CH ₂ Cl ₂ (100 ml / mmol), filtered through celite and concentrated. The crude material was purified by chromatography.

EXAMPLE 1

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

4-chloromethyl-N-pyridinyl-2-ylbenzamide

To a pre-cooled (ice bath) solution of 2-aminopyridine (304 mg, 3.22 mmol) and triethylamine (0.8 ml, 5.70 mmol) in anhydrous THF (5 ml) was added a solution of 4-chloromethylbenzoyl chloride (282 mg, 1.40 mmol) in THF (5 ml). The reaction mixture was stirred at 0 ° C. for 3 hours under N _2, and then diluted with 300 ml of ethyl acetate. The resulting organic solution was washed with saturated NH ₄ Cl, brine, dried over Na ₂ SO ₄ and evaporated. The residue was purified by flash chromatography on silica gel using 10% ethyl acetate in hexane as eluent to give the compound (170 mg, 49%) as a white solid.

¹ H NMR (CDCl ₃ ) δ 4.63 (s, 2H), 7.07 (dd, 1H, J = 5.1, 7.2 Hz), 7.50 (d, 2H, J = 8.1 ), 7.76 (ddd, 1H, J = 1.5, 7.8, 8.1 Hz), 7.92 (d, 2H, J = 8.4 Hz), 8.21 (d, 1H, J = 4.5 Hz), 8.38 (d, 1H, J = 8.4 Hz), 8.89 (br, s, 1H); ES-MS m / z 247.0 (M + H).

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

8- [N- (2-nitrobenzenesulfonyl)] amino-5,6,7,8-tetrahydroquinoline (230 mg, 0.69 mmol), 4-chloromethyl-N-pyridinyl-2-ylbenzamide (170 mg, 0.69 mmol) and K ₂ CO ₃ (285 mg, 2.06 mmol) were refluxed in CH ₃ CN (3 ml) for 24 hours under N ₂ . The reaction mixture was diluted with 200 ml of ethyl acetate and washed with saturated NaHCO ₃ solution, then brine and dried over Na ₂ SO ₄ . Evaporation of the solvent and purification of the residue by silica gel flash chromatography using 6% ethyl acetate in CH ₂ Cl ₂ as eluent gave the title compound (344 mg, 92%) as a white foam.

¹ H NMR (CDCl ₃ ) δ 1.61-1.65 (m, 1H), 1.74-1.86 (m, 2H), 2.33-2.37 (m, 1H), 2.59 -2.65 (m, 2H), 3.92 (d, 1H, J = 16.2 Hz), 4.87 (d, 1H, J = 16.5 Hz), 5.32 (dd, 1H, J = 5.8, 11.3 Hz), 7.04-7.11 (m, 2H), 7.31-7.37 (m, 3H), 7.49-7.67 (m, 3H) 7.73-7.80 (m, 3H), 8.15 (d, 1H, J = 7.8 Hz), 8.22 (d, 1H, J = 4.2Hz), 8.31 (d , 1H, J = 4.2 Hz), 8.35 (d, 1H, J = 8.4 Hz), 8.45 (w, s, 1H); ES-MS m / z 544.1 (M + H).

Using General Procedure C : Reaction 4 - {[(2-nitrobenzenesulfonyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} -N-pyridin-2-ylbenzamide (340 mg, 0.62 mmol), thiophenol (0.12 ml, 1.24 mmol) and K ₂ CO ₃ (258 mg, 1.87 mmol) in DMF (3 ml) at room temperature under N ₂ for 16 hours, followed by purification of the crude substances by radial chromatography on silica gel (2 mm plate, a mixture of CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 3: 3: 94) gave compound AMD9362 (210 mg, 93%) as a pale yellow oil .

¹ H NMR (CDCl ₃ ) δ 1.72-1.87 (m, 2H), 1.98-2.09 (m, 1H), 2.15-2.23 (m, 1H), 2.73 -2.91 (m, 2H), 3.00 (bs, 1H), 3.87 (dd, 1H, J = 5.1, 7.5 Hz), 4.02 (d, 1H, J = 13 8 Hz), 4.04 (d, 1H, J = 13.8 Hz), 7.06-7.10 (m, 2H), 7.38 (d, 1H, J = 7.5 Hz), 7.58 (d, 2H, J = 8.1 Hz), 7.76 (ddd, 1H, J = 1.8, 6.9, 8.7 Hz), 7.88 (d, 2H, J = 8.4 Hz), 8.31 (d, 1H, J = 4.2 Hz), 8.38-8.41 (m, 2H), 8.52 (br, s, 1H); ¹³ C NMR (CDCl ₃ ) δ 20.04, 29.12, 29.22, 51.87, 58.09, 114.61, 120.20, 122.31, 127.78, 128.91, 132, 87, 133.11, 137.32, 138.82, 146.04, 147.25, 148.26, 152.10, 157.63, 166.15; ES-MS m / z 359, 2 (M + H); elemental analysis: calculated for (C ₂₂ H ₂₂ N ₄ O) • 0.7 (H ₂ O): C, 71.21; H, 6.36; N, 15.10. Found C, 71.16; H, 6.02; N, 14.79.

EXAMPLE 2

AMD9370: Preparation of 4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} -N-pyridin-2-ylbenzamide.

N-BOC-chloromethylbenzimidazole (115 mg, 0.43 mmol), N-pyridin-2-yl-4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzamide ( AMD9362 ) (155 mg , 0.43 mmol) and K ₂ CO ₃ (179 mg, 1.29 mmol) in CH ₃ CN (3 ml) were refluxed for 24 hours under N ₂ . The reaction mixture was diluted with 200 ml of ethyl acetate and washed with saturated NaHCO ₃ solution, brine and dried over Na ₂ SO _4. Evaporation of the solvent and purification of the residue by silica gel flash chromatography followed by radial chromatography on silica gel (2 mm plate, CH ₃ OH- mixture NH ₃ H ₂ O-CH ₂ Cl ₂ , 3: 3: 94) afforded the compound AMD9370 (100 mg, 47%) as a white foam.

¹ H NMR (CDCl ₃ ) δ 1.68-1.75 (m, 1H), 1.97-2.08 (m, 2H), 2.26-2.32 (m, 1H), 2.71 -2.84 (m, 1H), 2.86-2.91 (m, 1H), 3.84 (s, 2H), 3.95 (d, 1H, J = 16.5 Hz), 4, 08-4.14 (m, 1H), 4.22 (d, 1H, J = 16.0 Hz), 7.03-7.07 (m, 1H), 7.16-7.22 (m, 3H), 7.45 (d, 1H, J = 6.9 Hz), 7.52-7.61 (m, 3H), 7.65 (d, 1H, J = 7.5 Hz), 7, 73 (ddd, 1H, J = 1.8, 7.2, 8.7 Hz), 7.80 (d, 2H, J = 8.1 Hz), 8.27-8.29 (m, 1H) 8.33 (d 1H, J = 8.4 Hz), 8.44 (w, s, 1H), 8.72-8.80 (m, 1H); ¹³ C NMR (CDCl ₃ ) δ 21.72, 23.30, 29.56, 49.29, 54.16, 60.83, 111.39, 114.52, 120.17, 122.29, 122, 81, 127.72, 129.28, 133.58, 135.17, 137.76, 138.77, 144.61, 147.38, 148.21, 152.00, 156.13, 157.54, 165.99; ES-MS m / z 489.2 (M + H); elemental analysis: calculated for (C ₃₀ H ₂₈ N ₆ O) • 0.6 (H ₂ O) • 0.7 (CHCl ₃ ): C, 63.25; H, 5.17; N, 14.42. Found: C, 63.56; H, 5.25; N, 14.31.

EXAMPLE 3

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

4-chloromethyl-N-pyridinyl-2-ylmethylbenzamide

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

¹ H NMR (CDCl ₃ ) δ 4.62 (s, 2H), 4.76 (d, 2H, J = 4.5 Hz), 7.21-7.26 (m, 1H), 7.32 ( d, 1H, J = 7.8 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.60 (w, s, 1H), 7.69 (ddd, 1H, J = 1 8, 7.5, 7.8 Hz), 7.86 (d, 2H, J = 8.4 Hz), 8.57 (d, 1H, J = 4.8 Hz); ES-MS m / z 261.0 (M + H).

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

8- (2-Nitrobenzenesulfonyl) amino-5,6,7,8-tetrahydroquinoline (402 mg, 1.20 mmol), 4-chloromethyl-N-pyridin-2-ylmethylbenzamide (314 mg, 1.20 mmol) and K ₂ CO ₃ (498 mg, 3.60 mmol) in CH ₃ CN (4 ml) was refluxed for 24 hours under N ₂ . The reaction mixture was diluted with 200 ml of ethyl acetate and washed with saturated NaHCO ₃ solution, brine and dried over Na ₂ SO _4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel using 50% ethyl acetate in CH ₂ Cl ₂ as eluent gave the title compound (603 mg, 90%) as a white foam.

¹ H NMR (CDCl ₃ ) δ 1.56-1.61 (m, 1H), 1.74-2.05 (m, 2H), 2.32-2.36 (m, 1H), 2.58 -2.64 (m, 2H), 3.95 (d, 1H, J = 16.2 Hz), 4.74 (d, 2H, J = 4.5 Hz), 4.85 (d, 1H, J = 15.9 Hz), 5.30 (dd, 1H, J = 11.1, 17.4 Hz), 7.05 (dd, 1H, J = 4.5, 7.5 Hz), 7, 22-7.29 (m, 2H), 7.34 (dd, 2H, J = 7.5, 7.8 Hz), 7.48-7.73 (m, 8H), 8.12-8, 15 (m, 1H), 8.20-8.24 (m, 1H), 8.45-8.59 (m, 1H); ES-MS m / z 558.2 (M + H).

Using General Procedure C : Reaction 4 - {[(2-nitrobenzenesulfonyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} -N-pyridin-2-ylmethylbenzamide (600 mg, 1.07 mmol), thiophenol (0.22 ml, 2.14 mmol) and K ₂ CO ₃ (445 mg, 3.22 mmol) in DMF (5 ml) at room temperature under N ₂ for 16 hours, followed by purification of the crude substances by radial chromatography on silica gel (2 mm plate, a mixture of CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 3: 3: 94) gave compound AMD9363 (390 mg, 93%).

¹ H NMR (CDCl ₃ ) δ 1.76-1.85 (m, 2H), 1.97-2.02 (m, 1H), 2.10-2.21 (m, 1H), 2.70 -2.89 (m, 2H), 3.82-3.86 (m, 1H), 3.94 (d, 1H, J = 13.5 Hz), 4.02 (d, 1H, J = 13 8 Hz), 4.76 (d, 2H, J = 4.8 Hz), 7.06 (dd, 1H, J = 4.8, 7.5 Hz), 7.20-7.26 (m , 1H), 7.34 (dd, 2H, J = 7.5, 15.6 Hz), 7.52 (d, 2H, J = 8.1 Hz), 7.50-7.52 (m, 1H), 7.68 (ddd, 1H, J = 1.5, 7.5, 7.8 Hz), 7.83 (d, 2H, J = 8.1 Hz), 8.39 (d, 1H , J = 3.9 Hz), 8.56 (d, 1H); ¹³ C NMR (CDCl ₃ ) δ 20.02, 29.07, 29.21, 45.14, 51.86, 57.97, 122.26, 122.51, 122.75, 127.59, 128, 65, 132.84, 133.21, 137.17, 137.28, 145.02, 147.21, 149.37, 156.78, 157.68, 167.69; ES-MS m / z 373.2 (M + H); elemental analysis: calculated for (C ₂₃ H ₂₄ N ₄ O) • 0.5 (H ₂ O) • 0.3 (CHCl ₃ ) • 0.2 (C ₄ H ₈ O ₂ ): C, 66.56; H, 6.23; N, 12.88. Found: C, 66.20; H, 6.16; N, 12.88.

EXAMPLE 4

AMD9369: Preparation of 4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} -N-pyridin-2-ylmethylbenzamide.

N-BOC-chloromethylbenzimidazole (215 mg, 0.84 mmol), N-pyridin-2-ylmethyl-4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzamide ( AMD9363 ) (300 mg , 0.84 mmol) and K ₂ CO ₃ (346 mg, 2.50 mmol) in CH ₃ CN (4 ml) were refluxed for 24 hours in a N ₂ atmosphere. The reaction mixture was diluted with 200 ml of ethyl acetate and washed with saturated NaHCO ₃ solution, brine and dried over Na ₂ SO _4. Evaporation of the solvent and purification of the residue by silica gel flash chromatography followed by radial chromatography on silica gel (1 mm plate, CH ₃ OH- mixture NH ₃ H ₂ O-CH ₂ Cl ₂ , 3: 3: 94) afforded the free base of the title compound (120 mg, 28%) as a pale yellow oil.

Using General Procedure D : The oil obtained above was converted to the corresponding hydrobromide salt to give AMD9369 .

¹ H NMR (D ₂ O) δ 1.82-1.95 (t, 1H), 2.19-2.30 (m, 2H), 2.41-2.45 (m, 1H), 3, 01-3.02 (m, 2H), 3.78 (d, 1H, J = 12.6 Hz), 3.87 (d, 1H, J = 12.6 Hz), 4.43 (d, 1H , J = 16.5 Hz), 4.62 (d, 1H, J = 16.2 Hz), 4.72 (s, 2H), 4.92-4.95 (m, 1H), 7.23 (d, 2H, J = 8.4 Hz), 7.27-7.32 (m, 2H), 7.35 (d, 2H, J = 8.4 Hz), 7.45-7.54 ( t, 2H), 7.80 (d, 1H, J = 8.1 Hz), 7.90-7.96 (t, 2H), 8.39 (d, 1H, J = 8.1 Hz), 8.52-8.59 (m, 1H), 8.67 (dd, 1H, J = 0.6, 5.7 Hz), 8.76 (d, 1H); ¹³ C NMR (D ₂ O) δ 20.43, 21.06, 27.86, 41.49, 50.28, 56.74, 63.48, 113.83, 126.15, 126.41, 127 , 31, 130.33, 130.51, 131.00, 139.78, 141.03, 141.34, 141.50, 147.59, 148.34, 150.62, 151.49, 153.11 , 169.39; ES-MS m / z 503.14 (M + H); elemental analysis: calculated for (C ₃₁ H ₃₀ N ₆ O) • 3.0 (HBr) • 2.4 (H ₂ O): C, 47.22; H, 4.83; N, 10.66; Br, 30.40. Found: C, 47.35; H, 4.98; N, 10.37; Br, 30.35.

EXAMPLE 5

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

Preparation of 4-formyl-N- (2-hydroxyphenyl) benzamide

A solution of 2-nitrophenol (1.55 g, 11.2 mmol) and methyl 4-chlorocarbonylbenzoate (2.44 g, 12.2 mmol) in THF (14 ml) and pyridine (2.8 ml) was stirred for 2 hours at room temperature. The reaction mixture was diluted with saturated sodium bicarbonate (30 ml) and EtOAc (20 ml), the phases were separated and the aqueous phase was extracted with EtOAc (2 x 15 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give terephthalic acid 4- (2-nitrophenyl) ester 1-methyl ester (3.15 g, 94%).

¹ H NMR (CDCl ₃ ) δ 3.98 (s, 3H), 7.43 (d, 1H, J = 7.8 Hz), 7.48 (t, 1H, J = 7.8 Hz,), 7.73 (t, 1H, J = 7.8 Hz), 8.20 (m, 4H), 8.27 (m, 1H).

To a solution of 1- methyl ester of 4- (2-nitrophenyl) terephthalic acid ester (3.13 g, 10.4 mmol) in glacial acetic acid (35 ml) was added iron powder (<5 μm mesh, 1.6 g, 28 , 0 mmol), and the mixture was stirred at the boil 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 partitioned between saturated sodium bicarbonate solution (75 ml) and ethyl acetate (75 ml), the phases were separated, and the organic layer was washed with saturated NaHCO ₃ solution (50 ml). The organic extract was dried (MgSO ₄ ), filtered, concentrated and purified by silica gel chromatography (2% MeOH / CH ₂ Cl ₂ ) to give (2-hydroxyphenyl) terephthalic acid methyl ester (1.31 g, 46%).

¹ H NMR (CDCl ₃ ) 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), 8.20 (m, 4H).

To a solution of (2-hydroxyphenyl) terephthalic acid methyl ester (1.31 g, 4.8 mmol) in THF (50 ml) at -78 ° C was added a solution of DIBAL-H (27 ml, 1.0 M in THF). The reaction mixture was allowed to warm to room temperature, stirred for 1 hour, and the reaction was quenched with saturated potassium sodium tartrate solution (15 ml). The biphasic mixture was stirred vigorously for 1 hour, the phases were separated and the organic layer was dried (MgSO ₄ ), filtered, concentrated and purified by silica gel column chromatography (5% MeOH / CH ₂ Cl ₂ ) to give 4-hydroxymethyl-N- (2- hydroxyphenyl) benzamide (0.58 g, 50%).

¹ H NMR (CDCl ₃ ) δ 1.83 (t, 1H (OH)), 4.82 (d, 2H, J = 6.0 Hz), 6.93 (t, 1H, J = 7.8 Hz ), 7.08 (t, 1H, J = 7.8 Hz), 7.19 (d, 2H, J = 7.8 Hz), 7.53 (d, 2H, J = 6.0 Hz), 7.92 (d, 2H, J = 7.8 Hz), 8.07 (w, 1H), 8.62 (s, 1H).

The 4-hydroxymethyl-N- (2-hydroxyphenyl) benzamide obtained above (0.56 g, 2.3 mmol) was dissolved in CH ₂ Cl ₂ (12 ml) and THF (12 ml), treated with activated MnO ₂ (2 , 0 g, 23 mmol) and stirred at room temperature overnight. The mixture was filtered through celite, the precipitate was washed with CH ₂ Cl ₂ , and the solvent was removed from the eluent under reduced pressure. Purification of the crude material by silica gel column chromatography (5% MeOH / CH ₂ Cl ₂ ) afforded 4-formyl-N- (2-hydroxyphenyl) benzamide (0.05 g, 10%).

¹ H NMR (CDCl ₃ ) δ 6.95 (t, 1H, J = 7.8 Hz), 7.05 (d, 1H, J = 7.8 Hz), 7.16 (t, 1H, J = 7.8 Hz), 7.42 (d, 1H, J = 7.8 Hz), 8.04 (m, 5H), 8.33 (br, 1H).

Using General Procedure A: To a solution of 4-formyl-N- (2-hydroxyphenyl) benzamide (50 mg, 0.2 mmol) and (N-tert-butoxycarbonylbenzimidazol-2-ylmethyl) - (5,6,7,8- tetrahydroquinolin-8-yl) amine (75 mg, 0.2 mmol) in MeOH (2 ml) was added NaBH ₃ CN (25 mg, 0.4 mmol), and the mixture was stirred at room temperature for 16 hours. Purification of the crude by radial chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 98: 1: 1) gave the alkylated product (11 mg, 10%) as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 1.69 (m, 1H), 1.97 (m, 2H), 2.17 (m, 1H), 2.80 (m, 2H), 3.70 (s, 2H), 3.92 (d, 1H, J = 16.8 Hz), 4.06 (m, 1H), 4.10 (d, 1H, J = 17.1 Hz), 6.84 (t, 1H, J = 6.0 Hz), 6.95 (d, 2H, J = 6.0 Hz), 7.20 (m, 4H), 7.44 (m, 4H), 7.63 (w, 1H), 7.73 (d, 2H, J = 7.2 Hz), 8.00 (d, 1H, J = 6.0 Hz), 8.63 (d, 1H, J = 3.5 Hz) 8.78 (s, 1H).

Using General Procedure D: The conversion of the above oil (11 mg) to the hydrobromide salt, followed by reprecipitation of the intermediate solid from a methanol / ether mixture, gave AMD9628 (15 mg) as a pale yellow solid.

¹ H NMR (D ₂ O) δ 1.87 (br, 1H), 2.25 (m, 2H), 2.44 (br, 1H), 3.05 (br, 2H), 3.78 (d , 1H, J = 12.6 Hz), 3.88 (d, 1H, J = 12.6 Hz), 4.45 (d, 1H, J = 16.2 Hz), 4.64 (d, 1H , J = 16.2 Hz), 4.75 (m, 1H), 7.02 (d, 2H, J = 7.8 Hz), 7.22 (d, 1H, J = 7.8 Hz), 7.24 (d, 2H, J = 11.4 Hz), 7.34 (d, 1H, J = 7.8 Hz), 7.41 (d, 2H, J = 7.8 Hz), 7, 45 (d, 2H, J = 9.0 Hz), 7.55 (dd, 2H, J = 3.3, 6.3 Hz), 7.96 (t, 1H, J = 8.4 Hz), 8.42 (d, 1H, J = 8.1 Hz); 8.79 (d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 20.44, 21.04, 27.86, 50.32, 56.76, 63.57, 113.82 (2C), 116.90, 121.15, 124, 08, 126.19, 126.38, 126.59, 126.81 (2C), 127.39 (2C), 128.62, 130.40 (2C), 130.47, 132.12, 139.76 141.13 (2C), 148.34 (2C), 150.16, 150.76, 151.50; ES-MS m / z 504 (M + H); elemental analysis: calculated for C ₃₁ H ₂₉ N ₅ O ₂ • 2.2HBr • 2.0H ₂ O: C, 52.05; H, 4.96; N, 9.79; Br, 24.21. Found: C, 52.07; H, 5.01; N, 9.69; Br, 24.21.

EXAMPLE 6

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

Preparation of 3-chloromethyl-N-pyridinyl-2-ylbenzamide

To a pre-cooled (ice bath) solution of 2-aminopyridine (2.0 g, 21.20 mmol) in anhydrous DMF (10 ml) was added a solution of 3-chloromethylbenzyl chloride (1.51 ml, 10.60 mmol). The reaction mixture was allowed to stir at 0 ° C for 1 hour and at 50 ° C for 0.5 hours in an atmosphere of N ₂ . The reaction mixture was concentrated in vacuo, and the resulting white solid was filtered, washing with MeOH. The filtrate was concentrated in vacuo and the resulting crude material was purified by silica gel flash chromatography (hexanes / EtOAc, 4: 1) to give the title compound (402 mg, 15%) as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 4.63 (s, 2H), 7.63 (dd, 1H, J = 5.1, 7.2 Hz), 7.49 (t, 1H, J = 7.6 Hz), 7.59 (d, 1H, J = 7.8 Hz), 7.76 (ddd, 1H, J = 1.8, 9.0, 9.0 Hz), 7.78 (d, 1H , J = 7.8 Hz), 7.96 (s, 1H), 8.22 (d, 1H, J = 4.5 Hz), 8.39 (d, 1H, J = 8.4 Hz), 8.96 (br s, 1H).

Preparation of 3 - {[(2-nitrobenzenesulfonyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} -N-pyridinyl-2-ylbenzamide

8- [N- (2-nitrobenzenesulfonyl)] amino-1,2,3,4-tetrahydroquinoline (248 mg, 0.74 mmol), 3-chloromethyl-N-pyridinyl-2-ylbenzamide (183 mg, 0.74 mmol) and K ₂ CO ₃ (308 mg, 2.23 mmol) in CH ₃ CN (2.5 ml) were heated at 80 ° C for 4 hours under N ₂ atmosphere. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and filtered through celite. Evaporation of the solvent and purification of the residue by silica gel flash chromatography (EtOAc / CH ₂ Cl ₂ , 1:19) afforded the title compound (298 mg, 74%) as a yellow foam.

¹ H NMR (CDCl ₃ ) δ 1.21-1.29 (m, 2H), 1.90-2.05 (m, 1H), 2.40-2.45 (m, 1H), 2.68 -2.75 (m, 2H), 4.06 (d, 1H, J = 15.0 Hz), 4.79 (d, 1H, J = 15.0 Hz), 5.37 (dd, 1H, J = 4.5, 12.0 Hz), 6.91-7.09 (m, 2H), 7.35-7.37 (m, 2H), 7.49-7.54 (m, 5H) 7.61-7.74 (m, 2H), 8.12 (d, 1H, J = 4.2 Hz), 8.31-8.34 (m, 3H), 8.42 (br, 1H )

Using the general method for removing the protective nosyl group C: Reaction 3 - {[((2-nitrobenzenesulfonyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} -N-pyridinyl-2-ylbenzamide (298 mg , 0.55 mmol), thiophenol (0.17 ml, 1.65 mmol) and K ₂ CO ₃ (379 mg, 2.75 mmol) in DMF (5.5 ml) at room temperature under N ₂ atmosphere for 1.5 hours followed by purification of the crude material by silica gel chromatography (CH ₃ OH / NH ₃ H ₂ O / CH ₂ Cl ₂ , 1: 1: 48) gave the desired amide (144 mg, 73%) as a white solid substances.

Using the General Method for the Preparation of Hydrobromide Salt D : The conversion of the solid product obtained above into the hydrobromide salt resulted in the compound AMD9560 in the form of a white powder.

¹ H NMR (D ₂ O) δ 2.00-2.04 (m, 2H), 2.31-2.46 (m, 2H), 2.92-3.15 (m, 2H), 4, 55 (d, 1H, J = 13.2 Hz), 4.66 (d, 1H, J = 13.2 Hz), 4.86-4.90 (m, 1H), 7.65-7.73 (m, 3H), 7.76-7.81 (m, 2H), 7.86 (d, 1H, J = 7.8Hz), 8.05 (d, 1H, J = 8.1 Hz), 8.14 (s, 1H), 8.19 (d, 1H, J = 4.8 Hz), 8.43-8.49 (m, 2H), 8.63 (d, 1H, J = 4, 8 Hz); ¹³ C NMR (D ₂ O) δ 17.21, 24.26, 27.02, 49.49, 55.03, 117.53, 121.88, 126.96, 129.82, 130.41, 130 51, 131.77, 132.95, 135.83, 137.86, 138.84, 143.71, 144.80, 145.75, 147.95, 148.09, 170.41; ES-MS m / z 359 (M + H); elemental analysis: calculated for (C ₂₂ H ₂₂ N ₄ O) • 3.0 (HBr) • 2.0 (H ₂ O): C, 41.47; H, 4.59; N, 8.79; Br, 37.62. Found: C, 41.70; H, 4.60; N, 8.60; Br, 37.33.

EXAMPLE 7

AMD9579: Preparation of N-pyridin-2-ylmethyl-3 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzene sulfamide (hydrobromide salt).

Preparation of Pyridin-2-yl-3 - ({(5,6,7,8-tetrahydroquinolin-8-yl) - [1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazol-2-ylmethyl] amino} methyl) benzamide

Using the general reductive amination technique B: Reaction of N-pyridinyl-2-yl-3 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzamide (AMD9560) (80 mg, 0.22 mmol), 1- (2-trimethylsilanylethoxymethyl) -1H-benzoimidazole-2-carbaldehyde (62 mg, 0.22 mmol), NaBH (OAc) ₃ (142 mg, 0.67 mmol) and AcOH (90 μl) for 1.5 hours at room temperature, followed by purification by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 98: 1: 1), the title compound (61 mg, 44%) was obtained as a white foam.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 0.69 (2H, dd, J = 8.4, 8.1 Hz), 1.24-1.25 (m, 1H), 2.03-2.14 (m, 2H), 2.25-2.29 (m, 1H), 2.65-2.88 (m, 2H), 3.21-3.34 ( m, 2H), 3.79 (d, 1H, J = 15.0 Hz), 3.90 (d, 1H, J = 12.0 Hz), 4.09 (dd, 1H, J = 9.0 6.0 Hz), 4.25 (s, 2H), 5.73 (d, 1H, J = 12.0 Hz), 6.16 (d, 1H, J = 12.0 Hz), 7, 03-7.10 (m, 2H), 7.16-7.20 (m, 2H), 7.30-7.34 (m, 3H), 7.45 (d, 1H, J = 7.5 Hz), 7.64-7.69 (m, 2H), 7.74-7.80 (m, 1H), 8.25 (s, 1H), 8.39-8.41 (m, 2H) 8.71 (d, 1H, J = 3.3 Hz); 8.98 (s, H).

Using the general procedure for removing the SEM-protective group E : Reaction of pyridin-2-yl-3 - ({(5,6,7,8-tetrahydroquinolin-8-yl) - [1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazole- 2-ylmethyl] amino} methyl) benzamide (61 mg, 0.10 mmol) with 6N HCl (3.5 ml) at 50 ° C for 3 hours, followed by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 98: 1: 1), the desired product (46 mg, 96%) was obtained as a white foam.

Using the General Procedure for the Preparation of HBr Salt D: The conversion of the foam obtained above into the hydrobromide salt resulted in the compound AMD9579 in the form of a white powder.

¹ H NMR (300 MHz, D ₂ O) δ 1.90-1.96 (m, 1H), 2.18-2.33 (t, 2H), 2.44-2.48 (m, 1H) 3.02-3.03 (t, 2H), 3.85 (d, 1H, J = 12.9 Hz), 3.94 (d, 1H, J = 12.9 Hz), 4.45 ( d, 1H, J = 16.5 Hz), 4.64 (d, 1H, J = 16.2 Hz), 4.67-4.78 (m, 1H), 7.26-7.40 (t , 4H), 7.43-7.50 (t, 3H), 7.61 (s, 1H), 7.66 (d, 2H, J = 8.1 Hz), 7.93 (dd, 1H, J = 7.2, 5.7 Hz), 8.40 (d, 2H, J = 7.8 Hz), 8.45 (d, 1H, J = 6.0 Hz), 8.77 (d, 1H, J = 5.4 Hz); ¹³ C NMR (75.5 MHz, D ₂ O) δ 20.45, 21.05, 27.86, 50.20, 56.72, 63.37, 113.92, 117.32, 121.93, 126.19, 126.65, 127.02, 129.50, 129.65, 130.47, 130.85, 135.53, 137.80, 139.10, 139.81, 141.07, 147, 13, 148.15, 148.35, 150.66, 151.62, 169.08; ES-MS m / z 489 (M + H); elemental analysis calculated for C ₃₀ H ₂₈ N ₆ O • 2.7 (HBr) • 3.4H ₂ O • 0.2 (C ₄ H ₁₀ O): C, 47.24; H, 5.08; N, 10.73; Br, 27.55. Found: C, 47.26; H, 4.89; N, 10.51; Br, 27.41.

EXAMPLE 8

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

Obtaining 3-chloromethyl-N-phenylbenzamide

To a stirred solution of aniline (0.4 ml, 4.30 mmol) in anhydrous CH ₂ Cl ₂ (10 ml) was added 3-chloromethylbenzoyl chloride (360 mg, 1.90 mmol). The reaction mixture was allowed to stir at room temperature overnight. The solvent was removed under reduced pressure. Purification of the residue on a strongly acidic ion-exchange resin column (elution with methanol) afforded the title compound (400 mg, 86%) as a white solid.

8- [N- (2-Nitrobenzenesulfonyl)] amino-1,2,3,4-tetrahydroquinoline (332 mg, 1.00 mmol), 3-chloromethyl-N-phenylbenzamide (245 mg, 1.00 mmol) and K ₂ CO ₃ (412 mg 2.99 mmol) was heated at 85 ° C. in CH ₃ CN (10 ml) overnight under N ₂ . The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, washed with H ₂ O, NaCl (aqueous solution) and dried (Na ₂ SO ₄ ). Evaporation of the solvent and purification of the residue by silica gel flash chromatography (EtOAc-hexanes, 3: 7; EtOAc-CH ₂ Cl ₂ , 3: 7) afforded the title compound (531 mg, 98%) as a yellow foam .

Using the general method for removing the nosyl-protective group C: Interaction 3 - {[(2-nitrobenzenesulfonyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} -N-phenylbenzamide (531 mg, 0, 98 mmol), thiophenol (0.20 ml, 1.95 mmol) and K ₂ CO ₃ (404 mg, 2.90 mmol) in DMF (5 ml) at room temperature under N ₂ for 2 hours, followed by purification the crude material by silica gel chromatography (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 1: 1: 98), the desired compound (200 mg, 57%) was obtained as a white foam.

Using General Procedure D: Conversion of the above foam (200 mg, 0.56 mmol) into the hydrobromide salt using an acetic acid / HBr solution, followed by reprecipitation of the salt from diethyl ether, afforded AMD9656 as a white solid.

¹ H NMR (CD ₃ OD) δ 1.88-1.98 (m, 1H), 2.01-2.22 (m, 2H), 2.48-2.56 (m, 1H), 2, 87-3.05 (m, 2H), 4.44 (d, 1H, J = 12.9 Hz), 4.55 (d, 1H, J = 12.9 Hz), 4.64 (dd, 1H , J = 5.7, 9.3 Hz), 7.16 (dd, 1H, J = 7.2, 7.2 Hz), 7.37 (dd, 2H, J = 8.4, 8.4 Hz), 7.45 (dd, 1H, J = 4.8, 7.8 Hz), 7.64 (dd, 1H, J = 7.8, 7.8 Hz), 7.70 (d, 2H , J = 8.1 Hz), 7.81 (dd, 2H, J = 7.3, 7.3 Hz), 8.01 (d, 1H, J = 7.8 Hz), 8.19 (s , 1H); 8.58 (d, 1H); ¹³ C NMR (CD ₃ OD) δ 20.97, 26.66, 28.77, 50.22 (overlapped CD ₃ OD) 58.15, 122.65, 126.21, 129.98, 130.26, 131.01, 131.06, 133.68, 134.71, 136.67, 137.70, 140.10, 141.45, 147.82, 150.43, 168.35; ES-MS m / z 358.2 (M + H); elemental analysis: calculated for (C ₂₃ H ₂₃ N ₃ O) • 1.7 (HBr) • 1.0 (H ₂ O): C, 53.85; H, 5.25; N, 8.19; Br, 26.48. Found: C, 53.64; H, 5.23; N, 7.92; Br, 26.77.

EXAMPLE 9

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

Using General Procedure B: Reaction of 1- (2-Trimethylsilanylethoxymethyl) -1H-benzimidazole-2-carbaldehyde (62 mg, 0.22 mmol), N-phenyl-3 - [(5,6,7,8-tetrahydroquinoline-8 -amylamino) methyl] benzamide (80 mg, 0.22 mmol) and sodium triacetoxyborohydride (46 mg, 0.29 mmol) in CH ₂ Cl ₂ (2 ml) at room temperature under N ₂ for 40 min, followed by purification the crude material by silica gel chromatography (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 1: 1: 98) afforded the title compound (127 mg, 92%) as a white foam.

Using General Procedure E: Reaction of N- [3 - ({(5,6,7,8-tetrahydroquinolin-8-yl) - [1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazol-2-ylmethyl] amino} methyl) phenyl] benzamide (127 mg, 0.20 mmol), 6N HCl solution (3 ml) at 50 ° C for 3 hours, subsequent purification of the crude material by silica gel chromatography (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 1: 1: 98) afforded the title compound (70 mg, 72%) as a white foam.

Using General Procedure D: Conversion of the above foam (70 mg, 0.14 mmol) into a hydrobromide salt using an acetic acid / HBr solution, followed by reprecipitation of the salt from diethyl ether, affords AMD9657 as a white solid.

¹ H NMR (CD ₃ OD) δ 1.87-2.01 (m, 1H), 2.24-2.37 (m, 2H), 2.47-2.51 (m, 1H), 3, 05-3.10 (m, 2H), 3.88 (d, 1H, J = 12.9 Hz), 3.94 (d, 1H, J = 12.9 Hz), 4.29 (d, 1H , J = 16.2 Hz), 4.63 (d, 1H, J = 16.2 Hz), 4.76-4.82 (m, 1H), 7.14-7.20 (m, 2H) 7.39 (ddd, 2H, J = 2.1, 5.4, 5.4 Hz), 7.45-7.54 (m, 4H), 7.65-7.69 (m, 2H) 7.77 (d, 2H, J = 8.1 Hz), 7.93 (dd, 1H, J = 6.0, 7.8 Hz), 8.04 (s, 1H), 8.38 ( d, 1H, J = 8.1 Hz), 8.95 (d, 1H, J = 5.7 Hz); ¹³ C NMR (CD ₃ OD) δ 21.97, 22.12, 29.27, 50.79, 57.90, 63.33, 115.14, 123.04, 126.22, 127.19, 127 , 93, 128.72, 130.07, 130.15, 130.63, 132.33, 134.87, 136.41, 138.10, 141.86, 142.03, 148.95, 152.29 152.96; ES-MS m / x 488.3 (M + H); elemental analysis: calculated for (C ₃₁ H ₂₉ N ₅ O) • 2.0 (HBr) • 1.7 (H ₂ O): C, 54.75; H, 5.10; N, 10.30; Br, 23.50. Found: C, 54.81; H, 5.10; N, 10.21; Br, 23.41.

EXAMPLE 10

AMD9367: Preparation of N-pyridin-2-ylmethyl-4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzenesulfamide

To a stirred solution of 4-bromomethylbenzenesulfonyl chloride (500 mg, 1.85 mmol) and Et ₃ N (269 μl, 1.85 mmol) in CH ₂ Cl ₂ (10 ml) at -78 ° C was added aminomethylpyridine (190 μl, 1, 85 mmol) in one serving. The resulting solution was stirred at -78 ° C for 20 minutes. Then a second portion of Et ₃ N (269 μl, 1.85 mmol) was added, followed by 8-amino-5,6,7,8-tetrahydroquinoline (274 mg, 1.85 mmol). The solution was stirred for 18 hours at room temperature. The mixture was diluted with CH ₂ Cl ₂ (100 ml / mmol), filtered through celite and concentrated. The crude material was purified by silica gel chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 48: 1: 1) to give AMD9367 (150 mg, 20%) as a white foam.

¹ H NMR (300 MHz, CD ₃ COCD ₃ ) δ 1.69-1.98 (m, 2H), 2.00-2.05 (m, 1H), 2.11-2.18 (m, 1H ), 2.71-2.85 (m, 3H), 3.82 (m, 1H), 3.96 (d, 2H, J = 6.0 Hz), 4.23 (br, 2H), 6 10 (br, 1H), 7.05-7.15 (m, 3H), 7.38 (d, 1H, J = 7.8 Hz), 7.49 (d, 2H, J = 9.0 Hz), 7.55-7.58 (m, 1H), 7.79 (d, 2H, J = 9.0 Hz), 8.39 (d, 1H, J = 4.8 Hz), 8, 44 (d, 1H, J = 4.5 Hz), ¹³ C NMR (75.5 MHz, CD ₃ COCD ₃ ) δ 20.05, 29.14, 29.20, 47.79, 51.70, 58 09, 122.39, 123.01, 127.68, 129.07, 132.90, 137.17, 137.40, 138.24, 146.62, 147.24, 149.38, 155.21 157.54; ES-MS m / z 409 (M + H); elemental analysis: calculated for C ₂₂ H ₂₄ N ₄ O ₂ S • 0.2H ₂ O: C, 64.12; H, 5.97; N, 13.59. Found: C, 64.10; H, 5.91; N, 13.71.

EXAMPLE 11

AMD9371: Preparation of 4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} -N-pyridin-2-ylmethylbenzenesulfamide

Preparation of N-pyridin-2-ylmethyl-4 - ({(5,6,7,8-tetrahydroquinolin-8-yl) - [1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazole-2ylmethyl] amino} methyl) benzene sulfamide.

Using General Procedure B: Reaction of N-Pyridin-2-ylmethyl-4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzenesulfamide (97 mg, 0.24 mmol), 1- (2- trimethylsilanylethoxymethyl) -1H-benzimidazole-2-carbaldehyde (72 mg, 0.26 mmol) and NaBH (OAc) ₃ (151 mg, 0.71 mmol) for 1 hour at room temperature, followed by purification by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 98: 1: 1) afforded the title compound (63 mg, 50%) as a white foam.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 0.77 (dd, 2H, J = 7.5, 7.5 Hz), 1.73-1.74 (m, 1H), 1.95-2.06 (m, 2H), 2.20-2.25 (m, 1H), 2.66-2.86 (t, 2H), 3.29-3.35 ( m, 2H), 3.78 (d, 1H, J = 14.7 Hz), 3.98 (d, 1H, J = 14.7 Hz), 4.05 (dd, 1H, J = 9.3 , 6.3 Hz), 4.13 (d, 2H, J = 6.0 Hz), 4.18 (br, 2H), 5.70 (d, 1H, J = 12.0 Hz), 5, 98 (d, 1H, J = 12.0 Hz), 7.06-7.10 (m, 2H), 7.13-7.18 (m, 3H), 7.31-7.36 (m, 2H), 7.43 (d, 2H, J = 8.1 Hz), 7.52-7.66 (t, 4H), 8.42 (d, 1H, J = 4.8 Hz), 8, 52 (d, 1H, J = 4.5 Hz).

Using General Procedure E : N-Pyridin-2-ylmethyl-4 - ({(5,6,7,8-tetrahydroquinolin-8-yl) - [1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazol-2-ylmethyl Reaction ] amino} methyl) benzenesulfamide (63 mg, 0.09 mmol) and 6N HCl (2.5 ml) at 50 ° C for 3 hours, followed by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 48: 1: 1) compound AMD9371 (38 mg, 75%) was obtained as a white powder.

¹ H NMR (300 MHz, CD ₃ OD) δ 1.68-1.71 (m, 1H), 2.01-2.09 (m, 2H), 2.29 (br, 1H), 2.73 -2.89 (m, 2H), 3.68 (br, 2H), 3.93 (br, 1H), 4.00 (br, 2H), 4.13-4.18 (m, 2H), 7.04-7.30 (t, 5H), 7.50-7.54 (t, 8H), 8.26 (br s, 1H), 8.60 (br, 1H); ¹³ C NMR (75.5 MHz, CD ₃ OD) δ 22.83, 24.68, 30.57, 51.69, 55.98, 63.36, 123.85, 124.14, 128.12, 130.93, 137.52, 138.92, 139.64, 140.66, 146.18, 148.46, 149.85, 155.92, 158.08, 158.74; ES-MS m / z 539 (M + H); elemental analysis: calculated for C ₃₀ H ₃₀ N ₆ O ₂ S: C, 66.89; H, 5.61; N, 15.60. Found: C, 66.65; H, 5.65; N, 15.60.

EXAMPLE 12

AMD9577: Preparation of N-pyridin-2-ylmethyl-3 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzene sulfamide (hydrobromide salt)

Preparation of 3 - [(pyridin-2-ylmethyl) sulfamoyl] benzoic acid

To a pre-cooled (ice bath) solution of 2- (aminomethyl) pyridine (1.05 g, 9.7 mmol) in anhydrous CH ₂ Cl ₂ (15 ml) was added 3- (chlorosulfonyl) benzoic acid (714 mg, 3, 23 mmol) in an atmosphere of N ₂ and after adding the ice bath was removed. Stirring was continued for 18 hours at room temperature, the reaction mixture was diluted with 300 ml of CH ₂ Cl ₂ and filtered through celite. Evaporation of the solvent and purification of the residue by silica gel flash chromatography using CH ₃ COOH-MeOH-CH ₂ Cl ₂ , 3: 6: 91 as eluent gave the title compound (840 mg, 89%) as a white solid substances.

Preparation of 3-hydroxymethyl-N-pyridin-2-ylmethylbenzenesulfamide

To a solution of 3 - [(pyridin-2-ylmethyl) sulfamoyl] benzoic acid (840 mg, 2.87 mmol) in THF (5 ml) was added BH _3. THF (1 M, 14.4 ml, 14.4 mmol) drop by drop. After addition, the reaction mixture was allowed to stir for 18 hours at room temperature, and 5N HCl (8 ml) was carefully added, resulting in the evolution of H ₂ . When heated at 70 ° C for 2 hours, a clear solution formed. Then water (30 ml) was added, and the resulting solution was extracted with diethyl ether (3 x 20 ml). The aqueous phase was cooled to 0 ° C, neutralized with solid NaOH and then with solid NaHCO ₃ and extracted with CHCl ₃ (6 x 20 ml). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The crude material was used for the next reaction without further purification.

Preparation of 3-Formyl-N-pyridin-2-ylmethylbenzenesulfamide

3-Hydroxymethyl-N-pyridin-2-ylmethylbenzenesulfonamide (crude product from the previous step, 2.87 mmol) and MnO ₂ (2.9 g, 28.7 mmol) in methanol (0.5 ml) and CH ₂ Cl ₂ (15 ml) were reacted at 50 ° C. under N ₂ overnight. The mixture was concentrated and purified by silica gel chromatography (50% ethyl acetate and CH ₂ Cl ₂ ) to give the title compound (600 mg, 79% in two steps) as a white foam.

Using General Procedure B: Reaction of 3-formyl-N-pyridin-2-ylmethylbenzenesulfamide (317 mg, 1.21 mmol), 5,6,7,8-tetrahydroquinolin-8-ylamine (179 mg, 1.21 mmol), acetic acid (0.2 ml) and sodium triacetoxyborohydride (513 mg, 2.4 mmol) in THF (10 ml) at room temperature in an atmosphere of N ₂ for 40 min, subsequent purification of the crude substance by chromatography on silica gel (CH ₃ OH- NH ₃ H ₂ O-CH ₂ Cl ₂ , 1: 1: 98) afforded the title compound (284 mg, 78%) as a white foam.

Using General Procedure D: Conversion of the above foam (30 mg, 0.073 mmol) into a hydrobromide salt using an acetic acid / HBr solution, followed by reprecipitation of the salt from diethyl ether, afforded AMD9677 as a white solid.

¹ H NMR (D ₂ O) δ 1.89-1.96 (m, 1H), 1.96-2.09 (m, 1H), 2.15-2.25 (m, 1H), 2, 36-2.47 (m, 1H), 2.83-3.02 (m, 2H), 4.52 (s, 2H), 4.56 (s, 2H), 4.64-4.68 ( m, 1H), 7.47-7.51 (m, 1H), 7.69 (t, 2H, J = 7.8 Hz), 7.83-7.94 (m, 4H), 8.02 (s, 1H), 8.45-8.50 (m, 2H), 8.65 (d, 1H, J = 6 Hz); ¹³ C NMR (D ₂ O) δ 17.86, 24.55, 27.11, 43.69, 48.86, 55.88, 126.33, 126.66, 128.55, 128.77, 131 , 27, 132.77, 135.88, 137.70, 139.03, 141.53, 143.94, 144.77, 147.69, 152.17; ES-MS m / z 409.2 (M + H); elemental analysis: calculated for (C ₂₂ H ₂₄ N ₄ O ₂ S) • 3.0 (HBr) • 4 (H ₂ O) • 6 (C ₄ H ₁₀ O): C, 40.06; H, 4.49; N, 8.27; Br, 35.37; S, 4.73. Found: C, 39.80; H, 4.81; Br, 35.65; S, 4.74.

EXAMPLE 13

AMD9578: Preparation of 3 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} -N-pyridin-2-ylmethylbenzenesulfamide (hydrobromide salt)

Using General Procedure B: Reaction of 1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazole-2-carbaldehyde (192 mg, 0.70 mmol), N-pyridin-2-ylmethyl-3 - [(5,6,7,8 -tetrahydroquinolin-8-ylamino) methyl] benzene sulfamide (284 mg, 0.70 mmol), acetic acid (0.2 ml) and sodium triacetoxyborohydride (442 mg, 2.08 mmol) in THF (7 ml) at room temperature in atmosphere N ₂ for 40 min, subsequent purification of the crude material by silica gel chromatography (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 1: 1: 98) afforded the title compound (177 mg, 38% ) in the form of a white foam.

Using General Procedure E : N-Pyridin-2-ylmethyl-3 - ({(5,6,7,8-tetrahydroquinolin-8-yl) - [1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazol-2-ylmethyl Interactions ] amino} methyl) benzenesulfamide (177 mg, 0.26 mmol) and 6N HCl (3 ml) at 50 ° C for 3 hours, followed by purification of the crude material by silica gel chromatography (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 2: 2: 96) gave the title compound (104 mg, 73%) as a white foam.

Using General Procedure D: Conversion of the above foam (104 mg, 0.19 mmol) into the hydrobromide salt using an acetic acid / HBr solution, followed by reprecipitation of the salt from diethyl ether, affords AMD9578.

¹ H NMR (CD ₃ OD) δ 1.91-2.01 (m, 2H), 2.22-2.37 (m, 2H), 2.49-2.53 (m, 1H), 3, 00-3.11 (m, 2H), 3.99 (d, 1H, J = 12.9 Hz), 4.07 (d, 1H, J = 13.2 Hz), 4.46 (d, 2H , J = 4.2 Hz), 4.53 (d, 1H, J = 16.5 Hz), 4.69 (d, 1H, J = 16.5 Hz), 4.77-4.81 (m , 1H), 7.34 (dd, 1H, J = 7.7, 7.7 Hz), 7.48 (d, 1H, J = 8.1 Hz), 7.52-7.56 (m, 2H), 7.72-7.76 (m, 2H), 7.85 (d, 1H, J = 7.8 Hz), 7.93-8.01 (m, 2H), 8.07 (s , 1H), 8.08 (d, 1H, J = 9.0 Hz), 8.40 (d, 1H, J = 7.8 Hz), 8.57 (ddd, 1H, J = 1.5, 7.8, 7.8 Hz), 8.76 (d, 1H, J = 6.0 Hz), 8.94 (d, 1H, J = 5.1 Hz); ¹³ C NMR (CD ₃ OD) δ 21.93, 29.27, 45.26, 50.48, 57.49, 62.41, 115.39, 127.31, 127.68, 128.05, 128 , 16, 128.24, 129.91, 130.99, 132.27, 136.64, 139.58, 140.94, 141.97, 142.15, 142.85, 148.53, 149.38 , 151.97, 152.48, 155.26; ES-MS m / z 539.3 (M + H); elemental analysis: calculated for (C ₃₀ H ₃₀ N ₆ O ₂ S) • 3.0 (HBr) • 3.1 (H ₂ O): C, 43.04; H, 4.72; N, 10.04; Br, 28.63; S, 3.83. Found: C, 43.15; H, 4.70; N, 10.03; Br, 28.56; S, 3.80.

EXAMPLE 14

AMD9622: Preparation of 3 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} -N-phenylbenzenesulfamide (hydrobromide salt)

Preparation of 3-Phenylsulfamoylbenzoic Acid

3-Chlorosulfonylbenzoic acid (300 mg, 1.36 mmol) and aniline (0.30 ml, 3.29 mmol) were stirred at room temperature in anhydrous CH ₂ Cl ₂ (10 ml) overnight under N ₂ . The reaction mixture was concentrated in vacuo. Purification of the residue on an IR-120 ion-exchange resin column (eluting with methanol) afforded the title compound (380 mg, 100%) as a white solid.

Preparation of 3-hydroxymethyl-N-phenylbenzenesulfamide

To a solution of 3-phenylsulfamoylbenzoic acid (380 mg, 1.36 mmol) in THF (10 ml) was added BH ₃ • THF (1 M, 5.4 ml, 5.4 mmol) dropwise. After addition, the reaction mixture was allowed to stir for 3 days at room temperature. Methanol was added to the reaction mixture, and the mixture was concentrated in vacuo (5 X). The resulting compound was used in the next step without further purification.

Obtaining 3-formyl-N-phenylbenzenesulfamide

Reaction of 3-hydroxymethyl-N-phenylbenzenesulfamide (crude from the previous step, 1.36 mmol), MnO ₂ (1.40 g, 13.60 mmol) in CH ₂ Cl ₂ (10 ml) at 40 ° C. under N ₂ overnight resulted in the title compound (293 mg, 82%) as a white solid.

Using General Procedure B: Reaction of tert-butyl ether 2 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzimidazole-1-carboxylic acid (172 mg, 0.46 mmol), 3-formyl- N-phenylbenzenesulfamide (119 mg, 0.46 mmol) and sodium triacetoxyborohydride (116 mg, 0.55 mmol) in THF (4 ml) at room temperature under N ₂ atmosphere overnight, followed by purification of the crude material by silica gel chromatography (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 2: 1: 97) afforded the title compound (93 mg, 33%) as a yellow foam.

Using General Procedure D: Removal of the Boc-protecting Group from 2 - {[(3-phenylsulfamoylbenzyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzimidazole-1-carboxylic acid tert-butyl ester obtained above (93 mg, 0.15 mmol) using an acetic acid / HBr solution, subsequent reprecipitation of the salt from diethyl ether gave the compound AMD9622 as a white solid.

¹ H NMR (CD ₃ OD) δ 1.76-1.85 (m, 1H), 2.15-2.25 (m, 2H), 2.35-2.39 (m, 1H), 2, 96-3.05 (m, 2H), 3.85 (s, 2H), 4.38 (d, 1H, J = 16.5 Hz), 4.60 (d, 1H, J = 16.5 Hz ), 4.59-4.61 (m, 1H), 6.90-6.93 (m, 1H), 7.00-7.10 (m, 4H), 7.22 (dd, 1H, J = 7.6, 7.6 Hz), 7.34 (d, 1H, J = 8.1 Hz), 7.51 (dd, 2H, J = 3, 6.3 Hz), 7.69-7 72 (m, 3H), 7.79-7.83 (m, 2H), 8.21 (d, 1H, J = 7.8 Hz), 8.85 (d 1H, J = 4.8 Hz ); ¹³ C NMR (CD ₃ OD) δ 20.80, 21.30, 28.11, 49.24, 55.72, 61.29, 114.20, 121.15, 124.83, 125.61, 126 , 57, 126.74, 128.23, 129.26, 129.39, 131.49, 134.64, 137.95, 138.16, 140.09, 140.26, 141.43, 146.65 151.71; ES-MS m / z 524.4 (M + H); elemental analysis: calculated for (C ₃₀ H ₂₉ N ₅ O ₂ S) • 2.0 (HBr) • 1.2 (H ₂ O): C, 50.96; H, 4.76; N, 9.90; Br, 22.60, S, 4.53. Found: C, 51.23; Y, 4.96; N, 9.80; Br, 22.42; S, 4.45.

EXAMPLE 15

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

Preparation of 3-benzylsulfamoylbenzoic acid

3-Chlorosulfonylbenzoic acid (300 mg, 1.36 mmol) and benzylamine (0.60 ml, 5.49 mmol) were stirred at room temperature in anhydrous CH ₂ Cl ₂ (10 ml) overnight under N ₂ . The reaction mixture was concentrated in vacuo. Purification of the residue on an IR-120 ion exchange resin column (eluting with methanol) afforded the title compound (395 mg, 100%) as a white solid.

Obtaining N-benzyl-3-hydroxymethylbenzenesulfamide

To a solution of 3-phenylsulfamoylbenzoic acid (380 mg, 1.36 mmol) in THF (10 ml) was added BH ₃ • THF (1 M, 5.4 ml, 5.4 mmol) dropwise. After addition, the reaction mixture was allowed to stir for 3 days at room temperature. Methanol was added to the reaction mixture, and the mixture was concentrated in vacuo (5 X). The resulting compound was used in the next step without further purification.

Obtaining 3-formyl-N-phenylbenzenesulfamide

The interaction of N-benzyl-3-hydroxymethylbenzenesulfamide (crude from the previous stage, 1.36 mmol), MnO ₂ (1.40 g, 13.60 mmol) in CH ₂ Cl ₂ (10 ml) at 40 ° C in an atmosphere of N ₂ overnight resulted in the title compound (317 mg, 85%) as a white solid.

Using General Procedure B: Reaction of 2 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzimidazole-1-carboxylic acid tert-butyl ester (141 mg, 0.37 mmol), N-benzyl- 3-formylbenzenesulfamide (104 mg, 0.37 mmol) and sodium triacetoxyborohydride (95 mg, 0.45 mmol) in THF (4 ml) at room temperature under N ₂ overnight, followed by purification of the crude material by silica gel chromatography (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 1: 1: 98) afforded the title compound (152 mg, 64%) as a yellow foam.

Using General Procedure D: Removal of the Boc Protecting Group from Tert-Butyl Ether 2 - {[(3-benzylsulfamoylbenzyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzimidazole-1-carboxylic acid (102 mg, 0.16 mmol) using an acetic acid / HBr solution, subsequent reprecipitation of the salt from diethyl ether gave the compound AMD9623 as a white solid.

¹ H NMR (CD ₃ OD) δ 1.86-1.89 (m, 1H), 2.19-2.31 (m, 2H), 2.41-2.43 (m, 1H), 3, 01-3.11 (m, 2H), 3.84 (d, 1H, J = 12.9 Hz), 3.90 (d, 1H, J = 12.9 Hz), 3.94 (s, 2H ), 4.39 (d, 1H, J = 16.2Hz), 4.59-4.67 (m, 2H), 7.10 (w, 5H), 7.27 (dd, 1H, J = 7 6, 7.6 Hz), 7.41 (d, 1H, J = 7.8 Hz), 7.51 (dd, 2H, J = 3, 6.3 Hz), 7.70-7.74 ( m, 3H), 7.88 (dd, 2H, J = 6.4, 6.4 Hz), 8.30 (d, 1H, J = 7.8 Hz), 8.88 (d, 1H); ^I3 C NMR (CD ₃ OD) δ 20.39, 20.90, 27.81, 46.73, 50.11, 56.29, 62.83, 114.02, 125.94, 126.16, 126 69, 127.55, 127.95, 128.08, 128.78, 129.90, 134.45, 137.85, 139.81, 140.96, 148.22, 151.28; ES-MS m / z 538.4 (M + H); elemental analysis: calculated for (C ₃₁ H ₃₁ N ₅ O ₂ S) • 2.0 (HBr) • 1.3 (H ₂ O): C, 51.51; H, 4.96; N, 9.69; Br, 22.11; S, 4.43. Found: C, 51.60; H, 4.91; N, 9.63; Br, 22.07; S, 4.39.

EXAMPLE 16

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

Obtaining 4-hydroxymethylbenzylamide pyridine-2-carboxylic acid

Using General Procedure F: Reaction of (4-aminomethylphenyl) methanol (200 mg, 1.46 mmol), 1-hydroxybenzotriazole (218 mg, 1.61 mmol), 4-methylmorpholine (241 μl, 2.19 mmol) and EDCI ( 309 mg, 1.61 mmol) for 2 hours at room temperature afforded the title compound (335 mg, 95%) as a yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.67 (d, 2H, J = 6.0 Hz), 4.69 (s, 2H), 7.36 (br, 4H), 7.43-7 44 (m, 1H), 7.85-7.86 (m, 1H), 8.24 (d, 1H, J = 9.0 Hz), 8.52 (br, 1H), 8.52 ( d, 1H, J = 3.0 Hz); ES-MC m / z 243 (M + H).

Preparation of 4 - {[(pyridin-2-carbonyl) amino] methyl] benzyl ester of methanesulfonic acid

Using General Procedure G: Reaction of 4-hydroxymethylbenzylamide pyridine-2-carboxylic acid (200 mg, 0.83 mmol), Et ₃ N (144 μl, 0.99 mmol) and MsCl (71 μl, 0.91 mmol) 10 minutes at 0 ° C afforded the title compound (214 mg, 81%) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.92 (s, 3H), 4.69 (d, 2H, J = 3.3 Hz), 5.23 (s, 2H), 7.41-7 47 (m, 5H), 7.85-7.87 (m, 1H), 8.24 (d, 1H, J = 7.8 Hz), 8.50 (br, 1H), 8.54 ( d, 1H, J = 3.9 Hz).

Preparation of 4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzylamide pyridin-2-carboxylic acid

Using General Procedure H: Reaction of 8-amino-5,6,7,8-tetrahydroquinoline (148 mg, 1.00 mmol) with 4 - {[(pyridin-2-carbonyl) amino] methyl} benzyl methanesulfonic acid ester (214 mg , 0.67 mmol) for 3 hours at room temperature, followed by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 48: 1: 1) to give compound AMD9397 (81 mg, 33%) in in the form of yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.72-1.83 (m, 2H), 2.00-2.06 (m, 1H), 2.16-2.20 (m, 1H), 2.75-2.83 (m, 2H), 3.82-3.84 (m, 1H), 3.88 (d, 1H, J = 13.2 Hz), 3.98 (d, 1H, J = 12.9 Hz), 4.65 (d, 2H, J = 6.0 Hz), 7.05-7.06 (m, 1H), 7.32-7.42 (m, 6H), 7.85 (ddd, 1H, J = 7.8, 7.8, 1.8 Hz), 8.23 (d, 1H, J = 7.8 Hz), 8.34 (br, 1H), 8 37 (d, 1H, J = 3.3 Hz); 8.52 (d, 1H, J = 3.9 Hz); ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 20.05, 29.00, 29.24, 43.68, 51.85, 57.85, 122.19, 122.70, 126.56, 128 , 37 (2C), 129.01 (2C), 132.83, 137.07, 137.23, 137.73, 140.41, 147.20, 148.46, 150.23, 157.82, 164 , 57. ES-MC m / z 373 (M + H); elemental analysis: calculated for C ₂₃ H ₂₄ N ₄ O • 0.3H ₂ O: C, 73.11; H, 6.56; N, 14.83. Found: C, 72.98; H, 6.58; N, 14.63.

EXAMPLE 17

AMD9401: Preparation of 4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzylamide pyridine-2-carboxylic acid.

Using General Procedure B: Reaction of 4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzylamide pyridin-2-carboxylic acid (AMD9397) (40 mg, 0.11 mmol), 1H-benzimidazole- 2-carbaldehyde (16 mg, 0.11 mmol) and NaBH (OAc) ₃ (68 mg, 0.32 mmol) for 2 hours at 60 ° C, followed by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 98: 1: 1) afforded the compound AMD9401 (28 mg, 52%) as a white foam.

¹ H NMR (300 MHz, CD ₃ OD) δ 1.60-1.63 (m, 1H), 1.95-2.06 (m, 2H), 2.20-2.22 (m, 1H) 2.66-2.83 (m, 2H); 3.51 (d, 1H; J = 13.2 Hz); 3.58 (d, 1H; J = 13.2 Hz); 3.94 ( d, 1H, J = 15.3 Hz), 4.04-4.09 (m, 3H), 4.42 (bs, 2H), 7.09-7.15 (m, 4H), 7.20 (dd, 1H, J = 7.8, 4.8 Hz), 7.20 (d, 1H, J = 8.1 Hz), 7.28 (d, 2H, J = 8.1 Hz), 7 , 41-7.47 (m, 2H), 7.48-7.52 (m, 2H), 7.91 (ddd, 1H, J = 7.5, 7.5, 1.8 Hz), 8 06 (d, 1H, J = 7.8 Hz), 8.55 (d, 1H, J = 4.5 Hz), 8.60 (d, 1H, J = 4.5 Hz); ¹³ C NMR (75.5 MHz, CD ₃ OD) δ 22.84, 24.33, 30.62, 44.13, 51.41, 56.15, 63.13, 123.55, 124.03, 128.13, 128.61, 130.80, 137.39, 138.95, 139.14, 139.51, 139.67, 148.35, 150.17, 151.40, 156.31, 158, 31, 166.94; ES-MC m / z 503 (M + H); elemental analysis: calculated for C ₃₁ H ₃₀ N ₆ O • 0.8H ₂ O • 0.3CH ₂ Cl ₂ : C, 69.30; H, 5.98; N, 15.49. Found: C, 69.63; H, 6.14; N, 15.19.

EXAMPLE 18

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

Preparation of 3,5-Dichloro-N- (4-formylbenzyl) isonicotinamide

To partially dissolved 3,5-dichloro-N- (4-hydroxymethylbenzyl) isonicotinamide (730 mg, 2.35 mmol) in a mixture of CH ₂ Cl ₂ (12 ml) and MeOH (1 ml) was added MnO ₂ (2.43 g , 23.5 mmol), and the resulting suspension was stirred at 40 ° C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The precipitate was washed with CH ₂ Cl ₂ / MeOH (100: 3), and the filtrate was concentrated under reduced pressure to obtain a white solid (630 mg). Purification by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 1: 1) afforded the desired aldehyde (480 mg, 66%) as a white solid.

¹ H NMR (CDC1 ₃ ) δ 4.78 (d, 2H, J = 6.0 Hz), 6.19 (br, 1H), 7.58 (d, 2H, J = 9.0 Hz), 7 90 (d, 2H, J = 9.0 Hz), 8.55 (s, 2H), 10.02 (s, 1H).

Using General Procedure B: A solution of the aldehyde prepared above (100 mg, 0.32 mmol) and 5,6,7,8-tetrahydroquinolin-8-ylamine (56 mg, 0.38 mmol) in MeOH (2 ml) was stirred at room temperature overnight. Then, NaBH ₄ (24 mg, 0.65 mmol) was added, and the resulting mixture was stirred at room temperature for an additional 15 minutes. Purification of the crude brown foam (160 mg) by radial chromatography on silica gel (2 mm plate, 100% EtOAc) followed by radial chromatography on silica gel (1 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 2: 1) resulted to obtain the compound AMD9927 (70 mg, 50%) as a white foam.

¹ H NMR (CDCl ₃ ) δ 1.61-1.78 (m, 2H), 1.92-2.18 (m, 2H), 2.65-2.90 (m, 3H), 3.73 -3.81 (m, 2H), 3.89 (d, 1H, J = 13.2 Hz), 4.55 (d, 2H, J = 5.7 Hz), 6.97-7.06 ( m, 2H), 7.25-7.28 (m, 2H), 7.31-7.36 (m, 3H), 8.30-8.32 (m, 1H), 8.38 (s, 2H); ¹³ C NMR (CDCl ₃ ) δ 20.05, 28.89, 29.18, 44.05, 51.66, 57.82, 122.27, 128.46, 128.97, 129.37, 132, 84, 135.83, 137.31, 140.65, 142.70, 147.14, 147.93, 157.61, 162.36; ES-MC m / z 441.2 (M + H); elemental analysis: calculated for C ₂₃ H ₂₂ N ₄ Cl ₂ O • 0.1H ₂ O: C, 62.34; H, 5.05; N, 12.64; Cl, 16.00. Found: C, 62.38; H, 5.17; N, 12.48; Cl, 15.90.

EXAMPLE 19

AMD9960: Preparation of N- (4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) -2,4-dimethylnicotinamide (hydrobromide salt )

A solution of 2,4-dimethylnicotinic acid (54 mg, 0.35 mmol) in SOCl ₂ (~ 2 ml, excess) was heated to 80 ° C for 4 hours. The reflux condenser was removed, the mixture was purged with N ₂ at 80 ° C for ~ 5 minutes, and then dried in vacuum for 10 minutes. The resulting syrup was dissolved in CH ₂ Cl ₂ (2.4 ml) and (4-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) was added to the stirred mixture. amine (187 mg, 0.47 mmol), Et ₃ N (0.33 ml, 2.35 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight at room temperature. Purification of the crude yellow foam (240 mg) by silica gel radial chromatography (2 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 2: 1) followed by radial chromatography on silica gel (1 mm plate, EtOAc / MeOH / NH ₄ OH, 400: 3: 3) gave the desired amide (61 mg, 33%) as a white foam.

Using General Procedure D: Conversion of the Foam Obtained Above to the Hydrobromide Salt gave AMD9960 as a white solid.

¹ H NMR (D ₂ O) δ 1.80-1.98 (m, 1H), 2.15-2.38 (m, 2H), 2.39-2.51 (m, 4H), 2, 56 (s, 3H), 3.02-3.05 (m, 2H), 3.77 (d, 1H, J = 12.6 Hz), 3.84 (d, 1H, J = 12.6 Hz ), 4.04 (s, 2H), 4.44 (d, 1H, J = 16.5 Hz), 4.63 (d, 1H, J = 16.5 Hz), 4.74-4.79 (m, 1H, blocked by HOD), 6.94 (d, 2H, J = 8.1 Hz), 7.17 (d, 2H, J = 8.1 Hz), 7.47-7.52 (m , 2H), 7.57-7.61 (m, 2H), 7.75 (d, 1H, J = 6.3 Hz), 7.92 (dd, 1H, J = 7.8, 5.7 Hz), 8.39 (d, 1H, J = 7.8 Hz), 8.49 (d, 1H, J = 6.3 Hz), 8.76 (dd, 1H, J = 5.7, 0 9 Hz); ¹³ C NMR (D ₂ O) δ 17.56, 19.96, 20.48, 20.92, 27.85, 43.03, 50.21, 56.67, 63.20, 113.86, 126 07, 126.66, 126.98, 127.69, 130.52, 135.29, 135.93, 137.22, 139.63, 140.81, 140.93, 148.21, 150.18 150.93, 151.87, 157.45, 166.29; ES-MC m / z 531.3 (M + H); elemental analysis: calculated for C ₃₃ H ₃₃ N ₆ O • 3.1HBr • 1.8H ₂ O • 0.4C ₄ H ₁₀ O: C, 49.32; H, 5.23; N, 9.97; Br, 29.40. Found: C, 49.31; H, 5.25; N, 9.97; Br, 29.39.

EXAMPLE 20

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

A solution of 2,4-dimethylnicotinic acid (56 mg, 0.37 mmol) in SOCl ₂ (~ 3 ml, excess) was heated to 80 ° C for 4 hours. The reflux condenser was removed, the mixture was purged with N ₂ at 80 ° C for ~ 5 minutes, and then dried in vacuum for 10 minutes. The resulting syrup was dissolved in CH ₂ Cl ₂ (2.0 ml), and (3-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) was added to the stirred mixture. ) amine (147 mg, 0.37 mmol), Et ₃ N (0.26 ml, 1.85 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight at room temperature. Purification of the crude yellow foam by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 1: 1) followed by radial chromatography on silica gel (1 mm plate, EtOAc / MeOH / NH ₄ OH, 200: 1: 1 ) yielded the desired amide (85 mg, 43%) as a light yellow foam.

Using General Procedure D: Conversion of the Foam Obtained Above to the Hydrobromide Salt yielded AMD9961 as a beige solid.

¹ H NMR (D ₂ O) δ 1.82-1.98 (m, 1H), 2.15-2.33 (m, 2H), 2.38 (s, 3H), 2.39-2, 50 (m, 1H), 2.53 (s, 3H), 3.01-3.08 (t, 2H), 3.79 (d, 1H, J = 12.9 Hz), 3.86 (d , 1H, J = 12.6 Hz), 4.15 (s, 2H), 4.46 (d, 1H, J = 16.5 Hz), 4.64 (d, 1H, J = 16.5 Hz ), 4.79 (t, 1H, blocked by HOD), 6.79 (d, 1H, J = 7.8 Hz), 7.07-7.12 (m, 2H), 7.18 (d, 1H , J = 7.8 Hz), 7.47-7.53 (m, 2H), 7.57-7.62 (m, 2H), 7.74 (d, 1H, J = 6.0 Hz) 7.92 (dd, 1H, J = 7.8, 5.7 Hz), 8.40 (d, 1H, J = 7.2 Hz), 8.48 (d, 1H, J = 6.0 Hz), 8.76 (dd, 1H, J = 5.7, 1.2 Hz); ¹³ C NMR (D ₂ O) δ 17.52, 19.92, 20.49, 20.89, 27.87, 43.36, 50.14, 56.84, 62.98, 113.90, 126 10, 126.72, 127.01, 127.21, 129.39, 129.52, 129.64, 130.57, 135.27, 137.03, 137.43, 139.64, 140.78 , 140.95, 148.24, 150.17, 150.88, 151.79, 157.50, 166.29; ES-MC m / z 531.3 (M + H); elemental analysis: calculated for C ₃₃ H ₃₃ N ₆ O • 3.2HBr • 1.4H ₂ O • 0.5C ₄ H ₁₀ O: C, 49.41; H, 5.21; N, 9.88; Br, 30.05. Found: C, 49.43; H, 5.25; N, 9.85; Br, 29.94.

EXAMPLE 21

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

Preparation of 2,4-Dimethyl-1-hydroxynicotinic Acid Ethyl Ester

To a solution of ethyl 2,4-dimethylpyridin-3-carboxylate (2.0 g, 11.2 mmol) in AcOH (28 ml) was added H ₂ O ₂ (34-37%, 1.1 ml, 11.2 mmol) , and the resulting mixture was heated to 70 ° C for 3 hours. A second aliquot of H ₂ O ₂ (34-37%, 1.1 ml, 11.2 mmol) was added and the mixture was heated to 70 ° C. overnight. The reaction mixture was concentrated under reduced pressure, the resulting syrup was dissolved in CH ₂ Cl ₂ (150 ml) and washed with saturated NaHCO ₃ solution (2 x 25 ml). The aqueous layer was extracted with CH ₂ Cl ₂ (2 x 100 ml), the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated under reduced pressure to obtain the desired N-oxide (2.07 g, 95%).

¹ H NMR (CDCl ₃ ) δ 1.41 (t, 3H, J = 7.2 Hz), 2.30 (s, 3H), 2.49 (s, 3H), 4.44 (q, 2H, J = 7.2 Hz), 6.99 (d, 1H, J = 6.6 Hz), 8.19 (d, 1H, J = 6.6 Hz).

To a solution of the N-oxide obtained above (2.06 g, 10.55 mmol) in EtOH (25 ml) was added a solution of NaOH (844 mg, 21.1 mmol) in H ₂ O (5 ml). The resulting mixture was stirred at 40 ° C for 3 days. The solution was concentrated under reduced pressure. Then, a saturated solution of NaHCO ₃ (10 ml) was added, and the aqueous layer was extracted with CH ₂ Cl ₂ (2 x 100 ml). The aqueous phase was acidified with 10% HCl and concentrated in vacuo. The resulting solid was partially dissolved in CH ₂ Cl ₂ / MeOH (10: 1), filtered and concentrated. N-oxide acid (1.40 g) was used for the next reaction without further purification.

Using General Procedure F: Through a solution of the acid obtained above (46 mg, 0.28 mmol), (4-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8- il) amine (100 mg, 0.25 mmol), NOVT (37 mg, 0.28 mmol) and 4-methylmorpholine (40 μl, 0.38 mmol) in DMF (0.8 ml) was passed N _2. Then was added EDCI (53 mg, 0.28 mmol), and the mixture was stirred at room temperature overnight. Purification of the yellow syrup (140 mg) by silica gel radial chromatography (EtOAc / MeOH / NH ₄ OH, 100: 4: 1) afforded the desired amide (75 mg, 55%) as a yellow foam.

Using General Procedure D: Conversion of the Foam Obtained Above to the Hydrobromide Salt resulted in the compound AMD11036 as a pale yellow solid.

¹ H NMR (D ₂ O) δ 1.80-1.98 (m, 1H), 2.13-2.28 (m, 5H), 2.34 (s, 3H), 2.36-2, 48 (m, 1H), 2.97-3.07 (m, 2H), 3.72 (d, 1H, J = 12.3 Hz), 3.81 (d, 1H, J = 12.3 Hz ), 4.01 (s, 2H), 4.43 (d, 1H, J = 16.5 Hz), 4.61 (d, 1H, J = 16.8 Hz), 4.72-4.79 (m, 1H, blocked by HOD), 6.91 (d, 2H, J = 8.1 Hz), 7.14 (d, 2H, J = 8.1 Hz), 7.39-7.46 (m , 3H), 7.54-7.58 (m, 2H), 7.91 (dd, 1H, J = 7.8, 6.0 Hz), 8.29 (d, 1H, J = 6.9 Hz), 8.38 (d, 1H, J = 8.1 Hz), 8.75 (d, 1H, J = 5.7 Hz); ¹³ C NMR (D ₂ O) δ 14.97, 18.51, 20.49, 20.92, 27.86, 42.94, 50.21, 56.65, 63.16, 113.84, 126 08, 126.63, 126.90, 127.64, 130.50, 135.53, 135.82, 137.28, 139.63, 139.74, 140.92, 143.06, 146.82 , 148.23, 150.90, 151.87, 167.37; ES-MC m / z 547.4 (M + H); elemental analysis: calculated for C ₃₃ H ₃₄ N ₆ O ₂ • 3.0HBr • 2.1H ₂ O • 0.3C ₄ H ₁₀ O: C, 48.36; H, 5.24; N, 9.89; Br, 28.22. Found: C, 48.17; H, 5.41; N, 9.98; Br, 28.48.

EXAMPLE 22

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

Using General Procedure F: Through a solution of 2,4-dimethyl-1-hydroxynicotinic acid (46 mg, 0.28 mmol), (3-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7, 8-tetrahydroquinolin-8-yl) amine (100 mg, 0.25 mmol), HOBT (37 mg, 0.28 mmol) and 4-methylmorpholine (40 μl, 0.38 mmol) in DMF (0.8 ml) N _{2 was} passed _. Then, EDCI (53 mg, 0.28 mmol) was added, and the mixture was stirred at room temperature for 3 days. Purification of yellow syrup (130 mg) by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 5: 1) followed by radial chromatography on silica gel (1 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH , 100: 5: 1) gave the desired amide (81 mg, 59%) as a white foam.

Using General Procedure D: Conversion of the Foam Obtained Above into the Hydrobromide Salt yielded AMD11037 as a white solid.

¹ H NMR (D ₂ O) δ 1.80-1.98 (m, 1H), 2.13-2.35 (m, 8H), 2.36-2.51 (m, 1H), 2, 99-3.07 (m, 2H), 3.77 (d, 1H, J = 12.6 Hz), 3.84 (d, 1H, J = 12.9 Hz), 4.12 (s, 2H ), 4.45 (d, 1H, J = 16.5 Hz), 4.63 (d, 1H, J = 16.5 Hz), 4.79 (m, 1H, blocked by HOD), 6.77 ( d, 1H, J = 7.5 Hz), 7.05-7.10 (m, 2H), 7.16 (d, 1H, J = 7.8 Hz), 7.36 (d, 1H, J = 6.9 Hz), 7.47-7.51 (m, 2H), 7.56-7.60 (m, 2H), 7.91 (dd, 1H, J = 8.1, 6.0 Hz), 8.26 (d, 1H, J = 6.9 Hz), 8.39 (d, 1H, J = 7.8 Hz), 8.74 (d, 1H, J = 4.5 Hz) ; ¹³ C NMR (D ₂ O) δ 14.87, 18.35, 20.48, 20.87, 27.85, 43.25, 50.13, 56.80, 62.95, 113.87, 126 10, 126.72, 126.80, 127.21, 129.29, 129.48, 129.57, 130.54, 135.38, 136.97, 137.53, 139.61, 139.67 , 140.94, 142.35, 146.65, 148.24, 150.88, 151.78, 167.58; ES-MC m / z 547.4 (M + H); elemental analysis: calculated for C ₃₃ H ₃₄ N ₆ O ₂ • 2.9HBr • 2.2H ₂ O • 0.2C ₄ H ₁₀ O: C, 48.57; H, 5.22; N, 10.06; Br, 27.73. Found: C, 48.65; H, 5.46; N, 10.26; Br, 27.60.

EXAMPLE 23

AMD11084: Preparation of 3 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzylamide 4,6-dimethylpyrimidine-5-carboxylic acid

Preparation of 4,6-dimethylpyrimidine-5-carboxylic acid ethyl ester

A solution of ethyl diacetoacetate (8.04 g, 46.7 mmol) and Cs ₂ CO ₃ (15.93 g, 48.9 mmol) in CH ₃ CN (82 ml) was cooled to 0 ° C. Then methyl trifluoromethanesulfonate (5.3 ml, 46.8 mmol) was added dropwise, after completion of the addition, the ice bath was removed, and the mixture was stirred at room temperature for 3 hours. The mixture was filtered and the salts washed with Et ₂ O (2 x 20 ml). Et ₂ O (30 ml) was added to the filtrate, the mixture was filtered, and the salts were washed with Et ₂ O (2 x 40 ml). The combined filtrate was concentrated to half volume, cooled to 0 ° C in an ice bath, washed with chilled 2N NaOH solution (pH 11). The organic layer was dried (MgSO ₄ ), filtered and concentrated under reduced pressure to a yellow suspension. Then CH ₂ Cl ₂ (100 ml) was added and the mixture was refrigerated overnight. The resulting mixture was filtered, and the solid was washed with chilled CH ₂ Cl ₂ . The filtrate was concentrated under reduced pressure to obtain the product as a yellow liquid (9.6 g), which was used in the next reaction without further purification.

A solution of the ethyl ester obtained above (3.19 g, 17.13 mmol), sodium ethoxide (21% by weight solution in EtOH, 6.4 ml, 17.14 mmol) and formamidine acetate (1.78 g, 17.09 mmol ) in EtOH (30 ml) was refluxed for 4 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Then CH ₂ Cl ₂ (200 ml) and H ₂ O (15 ml) were added, the phases were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 x 50 ml). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification of the crude product as an orange syrup by silica gel column chromatography (hexanes / EtOAc, 6: 1) afforded the desired pyrimidine (2.23 g, 30% from two steps) as a yellow syrup.

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

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

Using the General Method F: Through a solution of 4,6-dimethylpyrimidine-5-carboxylic acid obtained above (according to the procedure described in patent application PCT / US00 / 11632) (42 mg, 0.28 mmol), (3-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (100 mg, 0.25 mmol), NOVT (38 mg, 0.28 mmol) and 4-methylmorpholine (40 μl, 0.38 mmol) in DMF (0.8 ml) was passed N _2. Then, EDCI (54 mg, 0.28 mmol) was added, and the mixture was stirred at room temperature overnight. Purification of colorless syrup (150 mg) by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 2: 1) followed by radial chromatography on silica gel (1 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH , 100: 2: 1) afforded the compound AMD11084 (80 mg, 60%) as a white foam.

¹ H NMR (CDCl ₃ ) δ 1.64-1.77 (m, 1H), 1.91-2.08 (m, 2H), 2.18-2.34 (m, 1H), 2.37 (s, 6H), 2.69-2.91 (m, 2H), 3.73 (s, 2H), 3.80 (d, 1H, J = 16.5 Hz), 4.00 (d, 1H, J = 16.5 Hz), 4.07-4.13 (m, 1H), 4.69 (d, 2H, J = 5.7 Hz), 6.53 (t, 1H, J = 5 , 7 Hz), 6.96-7.10 (m, 3H), 7.16-7.22 (m, 2H), 7.29-7.31 (m, 2H), 7.40-7, 45 (m, 3H), 8.64 (d, 1H, J = 3.6 Hz), 8.81 (s, 1H); ^I3 C NMR (CDCl ₃ ) δ 21.71, 22.28, 24.38, 29.55, 44.29, 49.22, 55.11, 61.90, 111.12, 118.82, 121, 68, 122.78, 127.32, 128.67, 129.09, 129.24, 130.48, 135.22, 137.66, 137.83, 140.30, 147.22, 156.42, 157.60, 157.91, 163.43, 166.96; ES-MS m / z 532.4 (M + H); elemental analysis: calculated for C ₃₂ H ₃₃ N ₇ O • 0.4CH ₂ Cl ₂ : C, 68.80; H, 6.02; N, 17.33. Found: C, 68.56; H, 6.09; N, 17.34.

EXAMPLE 24

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

Using a General Coupling Method Using EDCI F: Reaction of (4-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (120 mg, 0.30 mmol ), 2,6-dimethylbenzoic acid (50 mg, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), 4-methylmorpholine (49 μl, 0.45 mmol) and EDCI (63 mg, 0 , 33 mmol) for 4 hours at room temperature, followed by silica gel column chromatography (EtOAc / MeOH / NH ₄ OH, 199: 1: 1) to give the desired product (120 mg, 77%) as a white foam.

Using a General HBr D Salt Formation Technique: Conversion of the above foam into a hydrobromide salt yields AMD9794 as a white powder.

¹ H NMR (300 MHz, D ₂ O) δ 1.90-1.94 (m, 1H), 2.15 (s, 6H), 2.18-2.26 (m, 2H), 2.41 (br, 2H), 3.00-3.05 (m, 2H), 3.66 (d, 1H, J = 12.3 Hz), 3.77 (d, 1H, J = 12.6 Hz) 4.01-4.07 (m, 2H), 4.41 (d, 1H, J = 16.5 Hz), 4.50 (d, 1H, J = 16.8 Hz), 4.72- 4.75 (m, 1H), 6.92 (d, 2H, J = 7.5 Hz), 7.09-7.14 (m, 4H), 7.23-7.28 (m, 3H) 7.52 (dd, 1H, J = 5.7, 3.3 Hz), 7.91-7.96 (t, 1H), 8.40 (d, 1H, J = 7.8 Hz), 8.76 (d, 1H, J = 5.4 Hz); ¹³ C NMR (75.5 MHz, D ₂ O) δ 18.68 (2C), 20.47, 20.94, 27.85, 42.75, 50.20, 56.63, 63.17, 113 79, 126.11, 126.48, 127.87, 129.83, 130.45, 134.60, 135.61, 136.34, 137.74, 139.63, 140.90, 148.25 150.83, 151.89, 173.13; ES-MC m / z 530 (M + H); elemental analysis: calculated for C ₃₄ H ₃₅ N ₅ O • 0.1C ₄ H ₁₀ O • 1.5H ₂ O • 2.1HBr: C, 56.29; H, 5.64; N, 9.54; Br, 22.86. Found: C, 56.47; H, 5.62; N, 9.52; Br, 22.68.

EXAMPLE 25

AMD9842: Preparation of N- (4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) -3,5-dichloroisonicotinamide

Using a General Procedure for Conducting a Coupling Reaction Using EDCI F: Reaction (4-Aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (105 mg, 0 , 26 mmol), 3,5-dichloroisonicotinic acid (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (36 mg, 0.26 mmol), 4-methylmorpholine (100 μl, 0.89 mmol) and EDCI (51 mg, 0.26 mmol) for 2 days at room temperature followed by silica gel column chromatography (MeOH-NH ₄ OH-CH ₂ Cl ₂ , 1: 1: 98) yielded compound AMD9842 (42 mg, 28%) in the form of a white foam.

¹ H NMR (CDCl ₃ ) δ 1.68-1.74 (m, 1H), 1.94-2.05 (m, 2H), 2.16-2.25 (m, 1H), 2.69 -2.75 (m, 1H), 2.81-2.88 (m, 1H), 3.70 (s, 2H), 3.78-3.83 (m, 1H), 4.03-4 09 (m, 2H), 5.54 (dd, 2H, J = 4.5, 4.5 Hz), 7.02-7.12 (m, 3H), 7.17-7.21 (m , 3H), 7.34 (d, 2H, J = 8.1 Hz), 7.44 (d, 2H, J = 7.5 Hz), 7.50 (d, 1H, J = 7.8 Hz ), 8.31-8.35 (m, 2H), 8.68 (d, 1H, J = 3.9 Hz); ¹³ C NMR (CDCl ₃ ) δ 21.76, 23.87, 29.59, 44.13, 48.78, 54.26, 61.05, 111.30, 118.84, 121.62, 122, 06, 122.74, 128.61, 129.43, 133.96, 135.16, 136.24, 137.72, 139.41, 142.90, 144.35, 147.31, 147.72, 156.49, 157.64, 162.39; ES-MC m / z 571.6 (M + H); elemental analysis: calculated for (C ₃₁ H ₂₈ N ₆ Cl ₂ O) • 0.5 (CH ₂ Cl ₂ ) • 0.5 (H ₂ O): C, 60.73; H, 4.85; N, 13.49; Cl, 17.07. Found: C, 60.60; H, 4.96; N, 13.13; Cl, 17.46.

EXAMPLE 26

AMD11034: Preparation of N- (3,5-Dichloroisonicotinamide) -N ^′ - (1H-benzimidazol-2-ylmethyl) -N ^′ - (S) -5,6,7,8-tetrahydroquinolin-8-yl-1,4 -benzene dimethanamine (hydrochloride salt)

Preparation of 3,5-Dichloro-N- (4-formylbenzyl) isonicotinamide

To a stirred, cooled (0 ° C.) solution of 4-cyanobenzaldehyde (3.47 g, 26.5 mmol) in anhydrous THF (150 ml), LAH (6.0 g, 160 mmol) was added in portions. The suspension was stirred in an atmosphere of N ₂ at 60 ° C for 24 hours. After cooling to room temperature, the reaction was gradually quenched with distilled water (6 ml), then 15% (w / v) NaOH (6 ml), then with distilled water (18 ml). The mixture was stirred for 20 minutes, diluted with diethyl ether (200 ml), and the white flocculent precipitate was removed by filtration. The filtrate was dried (MgSO ₄ ) and concentrated in vacuo. The resulting amino alcohol (2.78 g) was used in the next reaction without further purification.

To a solution of the above amine (1.75 g, 12.8 mmol) in DMF (13 ml) was added 3,5-dichloroisonicotinic acid (2.04 g, 10.6 mmol), 1-ethyl-3- hydrochloride (3 dimethylaminopropyl) carbodiimide (4.03 g, 21.0 mmol), 1-hydroxybenzotriazole (2.84 g, 21.0 mmol), 4-methylmorpholine (7.9 ml, 71.8 mmol). The reaction mixture was stirred at 50 ° C. under N ₂ for 65 hours, then concentrated in vacuo. The residue was partitioned between chloroform (100 ml) and saturated NH ₄ Cl solution (100 ml). The aqueous layer was extracted with chloroform (2 x 100 ml), the combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The obtained orange oil (6.84 g) was purified by flash chromatography on a silica gel column (5 cm inner diameter, 140 g silica gel, 5% MeOH / CH ₂ Cl ₂ ) to obtain the desired alcohol (1.33 g, 30% from two stages).

The alcohol obtained above (1.33 g, 68 mmol) in 10% MeOH / CH ₂ Cl ₂ (50 ml) was treated with MnO ₂ (5.9 g, 68 mmol) and refluxed under N ₂ for 32 hours . The resulting suspension was cooled, filtered and concentrated in vacuo to give the pure title compound (1.20 g, 91%).

¹ H NMR (CDCl ₃ ) δ 4.79 (d, 2H, J = 6.1 Hz), 6.13 (br, 1H), 7.59 (d, 2H, J = 8.3 Hz), 7 90 (d, 2H, J = 8.3 Hz), 8.56 (s, 2H), 10.03 (s, 1H).

Using General Procedure B: The 3,5-dichloro-N- (4-formylbenzyl) isonicotinamide (1.28 g, 4.1 mmol) obtained above was reacted with S- (5,6,7,8-tetrahydroquinolin-8- il) amine (0.80 g, 5.4 mmol) and NaBH (OAc) ₃ (2.65 g, 12.5 mmol) in dichloromethane (80 ml). Flash chromatography (5 cm inner diameter of the column, 80 g of silica gel, 5% MeOH / CH ₂ Cl ₂ ) yielded a pure pale yellow solid (1.74 g, 95%).

To a solution of the above amine (1.74 g, 3.9 mmol) in a mixture of acetonitrile (40 ml) and chloroform (10 ml) was added diisopropylethylamine (1 ml, 5.8 mmol), 1-boc-2-chloromethylbenzimidazole (1 35 g, 5.0 mmol) and potassium iodide (66 mg, 0.40 mmol). The mixture was stirred under N ₂ at 60 ° C for 16 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between dichloromethane (100 ml) and brine (100 ml). The separated organic layer was dried (MgSO ₄ ), concentrated to a brown oil (3.5 g) and purified by flash chromatography (column, 5 cm inner diameter, 100 g silica gel, eluting with CH ₂ Cl ₂ to remove unreacted chloride, then 5% MeOH / CH ₂ Cl ₂ to isolate the desired product) to give the pure desired boc-protected amine as a foamy pale yellow solid (2.36 g, 89%).

The above amine (2.32 g, 3.45 mmol) was dissolved in glacial acetic acid (10 ml) and gaseous HCl was passed through the stirred solution for 10 minutes. The solution was allowed to stir at room temperature for an additional 30 minutes, then diluted with glacial acetic acid (10 ml) and gradually dropwise poured into diethyl ether (500 ml) with vigorous stirring. The resulting suspension was filtered through a filter with a porous glass plate with suction, the filter cake was washed with diethyl ether (100 ml) and dried in a vacuum oven at 40 ° C for 65 hours to obtain AMD11034 as a white solid (2.05 g, 88%).

¹ H NMR (D ₂ O) δ 1.81-1.95 (m, 1H), 2.19-2.36 (m, 2H), 2.41-2.49 (m, 1H), 2, 97-3.11 (m, 2H), 3.77-3.84 (m, 2H), 4.10 (s, 2H), 4.43 (d, 1H, J = 16.3 Hz), 4 60 (d, 1H, J = 16.3 Hz), 4.68-4.78 (m, 1H), 6.95 (d, 2H, J = 7.8 Hz), 7.14 (d, 2H, J = 7.8 Hz), 7.42-7.46 (m, 2H), 7.56-7.59 (m, 2H), 7.90 (t, 1H, J = 5.7 Hz ), 8.37 (d, 1H, J = 7.8 Hz), 8.58 (s, 2H), 8.72 (d, 1H, J = 5.7 Hz); ¹³ C NMR (D ₂ O) δ 20.48, 20.87, 27.83, 42.74, 50.26, 56.61, 63.18, 113.85 (2 carbon), 126.02, 126 60 (2 carbon), 127.46 (2 carbon), 129.12, 130.35 (2 carbon), 130.64, 135.74, 137.15, 139.60, 10 140.86, 147, 79 (2 carbon), 148.12, 150.98, 151.91; ES-MC m / z 571 (M + H); elemental analysis: calculated for C ₃₁ H ₂₈ N ₆ Cl ₂ O • 2.0HCl • 1.8H ₂ O: C, 55.01; H, 5.00; N, 12.42; Cl, 20.95. Found: C, 55.11; H, 4.90; N, 12.36; Cl, 20.86.

The enantiomeric purity of AMD11034 was determined as 100% chiral chromatography using the following conditions: Equipment: Hewlett Packard 1100 HPLC (VWD2); Column: Chiralpak AD, 0.46 cm x 25 cm; Mobile phase: A: 90:10 hexanes / isopropanol with 0.1% DEA, B: isopropanol; Balancing: 97% A, 3% B; Total expiration time: 25 min; Flow rate: 2.0 ml / min; Temperature: 5 ° C; Detector: UV @ 254 nm; Injection volume: 10 μl.

Retention time for S enantiomer = 13.0 min.

Retention time for R enantiomer = 15.5 min.

EXAMPLE 27

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

The interaction of 3,5-dibromisonicotinic acid (73 mg, 0.26 mmol), thionyl chloride (2 ml) at reflux for 1 hour, subsequent interaction of the corresponding acyl chloride, (4-aminomethylbenzyl) - (1H-benzimidazole) - ( 5,6,7,8-tetrahydroquinolin-8-yl) amine (103 mg, 0.26 mmol), Et ₃ 3N (0.50 ml, 3.46 mmol) and a catalytic amount of DMAP for 3 hours at room temperature yielded the crude product as a yellow oil. The crude material was purified by silica gel column chromatography (CH ₂ Cl ₂ -MeOH-NH ₄ OH, 98: 1: 1) to give the title compound (67 mg, 39%) as a white foam.

Using General Procedure D: Conversion of the above foam (67 mg, 0.10 mmol) into a hydrobromide salt using an acetic acid / HBr solution, followed by reprecipitation of the salt from diethyl ether, afforded AMD9853 as a white solid.

¹ H NMR (CD ₃ OD) δ 1.96 (br, 1H), 2.25-2.37 (m, 2H), 2.45 (br, 1H), 3.06 (br, 2H), 3 , 80-3.85 (m, 2H), 4.18 (br, 2H), 4.47 (d, 1H, J = 16.2 Hz), 4.68 (d, 1H, J = 16.2 Hz), 4.77-4.82 (m, 1H), 7.13 (d, 2H, J = 7.5 Hz), 7.45 (d, 2H, J = 7.8 Hz), 7, 55-7.58 (t, 2H), 7.76-7.79 (m, 2H), 7.93-7.97 (m, 1H), 8.40 (d, 1H, J = 7.8 Hz), 8.70 (s, 2H), 8.94 (d, 1H, J = 5.4 Hz); ¹³ C NMR (CD ₃ OD) δ 21.97, 29.24, 43.94, 50.85, 57.71, 62.75, 115.28, 119.66, 127.21, 128.02, 129 , 16, 131.94, 132.28, 136.55, 139.46, 141.64, 141.89, 148.53, 149.24, 151.84, 152.19, 152.93, 166.75 ; ES-MC m / z 661.3 (M + H); elemental analysis: calculated for (C ₃₁ H ₂₈ Br ₂ N ₆ O) • 2.0 (HBr) • 1.3H ₂ O: C, 43.61; H, 3.86; N, 9.84; Br, 38.37. Found: C, 43.69; H, 3.80; N, 9.70; Br, 38.22.

EXAMPLE 28

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

Using a General Coupling Method Using EDCI F: Reaction of (4-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (100 mg, 0.25 mmol ), 2-chloro-6-aminobenzoic acid (43 mg, 0.25 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), 4-methylmorpholine (38 μl, 0.35 mmol) and EDCI (48 mg 0.25 mmol) for 4 hours at room temperature followed by silica gel column chromatography (EtOAc / MeOH / NH ₄ OH, 199: 1: 1) to give AMD9862 (90 mg, 65%) as a white foam .

¹ H NMR (300 MHz, CD ₃ OD) δ 1.66-1.69 (m, 1H), 2.01-2.09 (m, 2H), 2.25 (br, 1H), 2.78 -2.89 (m, 2H), 3.55-3.65 (m, 2H), 3.97 (d, 1H, J = 15.3 Hz), 4.08-4.13 (m, 2H) ), 4.37 (s, 2H), 6.85 (d, 2H, J = 7.8 Hz), 7.22-7.29 (m, 3H), 7.36 (d, 2H, J = 8.1 Hz), 7.43-7.47 (m, 1H), 7.50 (d, 2H, J = 8.1 Hz), 7.62-7.65 (m, 2H), 7, 75 (d, 1H, J = 7.8 Hz), 8.79-8.81 (m, 1H); ¹³ C NMR (75.5 MHz, CD ₃ OD) δ 22.83, 24.34, 30.62, 44.55, 51.36, 56.17, 63.17, 115.72, 119.07, 123.04, 123.51, 124.05, 128.92, 130.79, 132.13, 132.70, 137.39, 138.62, 139.54, 139.63, 148.36, 148, 76, 156.41, 158.27, 169.43; ES-MC m / z 551 (M + H); elemental analysis: calculated for C ₃₂ H ₃₁ ClN ₆ O • 0.8 (H ₂ O): C, 67.97; H, 5.81; N, 14.86; Cl, 6.27. Found: C, 68.07; H, 5.87; N, 14.87; Cl, 6.42.

EXAMPLE 29

AMD11028: Preparation of 4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzylamide 4,6-dimethylpyrimidine-5-carboxylic acid

Use of a General Procedure for Conducting a Coupling Reaction Using EDCI F: Reaction of (4-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (100 mg, 0 , 25 mmol), 4,6-dimethylpyrimidine-5-carboxylic acid (42 mg, 0.28 mmol), 1-hydroxybenzotriazole (38 mg, 0.28 mmol), 4-methylmorpholine (39 μl, 0.35 mmol) and EDCI (54 mg, 0.28 mmol) for 24 hours at room temperature followed by silica gel column chromatography (EtOAc / MeOH / NH ₄ OH, 98: 1: 1) to give compound AMD11028 (101 mg, 76% ) in the form of a white foam.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.71-1.98 (m, 1H), 2.02-2.05 (m, 2H), 2.24-2.35 (m, 1H), 2.41 (s, 6H), 2.70-2.86 (m, 2H), 3.70 (s, 2H), 3.84 (d, 1H, J = 16.5 Hz), 4.03 -4.11 (m, 2H), 4.47-4.50 (m, 2H), 6.54-6.57 (m, 1H), 7.07 (br 2H), 7.14 (d, 2H, J = 7.8 Hz), 7.17-7.27 (m, 1H), 7.35 (d, 2H, J = 7.8 Hz), 7.43-7.46 (m, 3H ), 8.68 (d, 1H, J = 3.0 Hz), 8.83 (s, 1H); ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 21.74, 22.36, 23.99, 29.59, 44.18, 48.97, 54.36, 61.36, 111.30, 118 85, 121.85, 122.77, 128.48, 129.67, 130.48, 135.22, 136.42, 137.79, 139.51, 147.28, 156.48, 157.60 , 157.93, 163.47, 167.01; ES-MC m / z 532 (M + H); elemental analysis: calculated for C ₃₂ H ₃₃ N ₇ O • 1.6H ₂ O: C, 68.58; H, 6.51; N, 17.49. Found: C, 68.64; H, 6.44; N, 17.64.

EXAMPLE 30

AMD9593: Preparation of 1- (4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) -3-phenylurea (hydrobromide salt)

To a cooled (0 ° C) solution of (4-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (0.136 g, 0.34 mmol) in Phenyl isocyanate (41 μl, 0.38 mmol) was added CH ₂ Cl ₂ (3.5 ml), and the resulting solution was stirred for 50 minutes. The cooling bath was removed and the mixture was concentrated under reduced pressure. Purification of the crude material by silica gel column chromatography (CH ₂ Cl ₂ —CH ₃ OH — NH ₄ OH, 25: 1: 1) afforded the free base of the title compound (0.127 g, 72%) as a white solid.

Using General Procedure D: Conversion of the free base (127 mg) to the hydrobromide salt, followed by reprecipitation of the intermediate solid from methanol / ether, gave AMD9593 (139 mg) as a white solid.

¹ H NMR (D ₂ O) δ 1.79-1.93 (m, 1H), 2.16-2.28 (m, 2H), 2.35-2.42 (m, 1H), 3, 00 (ss, 2H), 3.65 (d, 1H, J = 12.3 Hz), 3.73 (d, 1H, J = 12.3 Hz), 3.79 (s, 2H) 4.38 (d, 1H, J = 16.5 Hz), 4.62 (d, 1H, J = 16.5 Hz), 4.66-4.71 (m, 1H), 6.84 (d, 2H, J = 7.8 Hz), 7.05 (d, 2H, J = 7.8 Hz), 7.09-7.14 (t, 1H), 7.25 (d, 2H, J = 7.8 Hz), 7.32-7.40 (m, 4H), 7.50 (bs, 2H), 7.87 (dd, 2H, J = 6.6, 6.9 Hz), 8.34 (d , 1H, J = 7.8 Hz); 8.69 (d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 20.44, 20.80, 27.79, 42.77, 50.25, 56.49, 63.07, 113.68, 121.31, 124.32, 126 , 00, 126.56, 127.33, 129.70, 130.22, 130.45, 135.09, 138.56, 139.51, 140.81, 148.14, 150.91, 151.74 , 158.00; ES-MC m / z 517 (M + H); elemental analysis: calculated for C ₃₂ H ₃₂ N ₆ O • 2.3HBr • 1.4H ₂ O: C, 52.80; H, 5.14; N, 11.54; Br, 25.25. Found: C, 52.76; H, 5.19; N, 11.30; Br, 25.30.

EXAMPLE 31

AMD9594: Preparation of 1- (4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) -3-benzylurea (hydrobromide salt)

To a cooled (0 ° C) solution of (4-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (0.130 g, 0.33 mmol) in Benzyl isocyanate (45 μl, 0.36 mmol) was added CH ₂ Cl ₂ (3.5 ml), and the resulting solution was stirred for 100 minutes. The cooling bath was removed and the mixture was concentrated under reduced pressure. Purification of the crude material by silica gel column chromatography (CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH, 25: 1: 1) followed by radial chromatography on silica gel (1 mm plate, CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH , 25: 1: 1) gave the free base of the title compound (0.047 g, 28%) as a white solid.

Using General Procedure D: Conversion of the free base (47 mg) to the hydrobromide salt, followed by reprecipitation of the intermediate solid from methanol / ether, afforded AMD9594 (49 mg) as a white solid.

¹ H NMR (D ₂ O) δ 1.79-1.96 (m, 1H), 2.18-2.30 (m, 2H), 2.38 (ss, 1H), 3.00 (ss, 2H), 3.66-3.75 (m, 4H), 4.25 (s, 2H), 4.40 (d, 1H, J = 16.5 Hz), 4.57 (d, 1H, J = 16.5 Hz), 4.68-4.73 (m, 1H), 6.76 (d, 2H, J = 7.5 Hz), 7.03 (d, 2H, J = 7.5 Hz ), 7.24-7.51 (m, 9H), 7.87 (dd, 1H, J = 7.2, 6.3 Hz), 8.34 (d, 1H, J = 7.8 Hz) 8.67 (d, 1H, J = 5.4 Hz); ^I3 C NMR (D ₂ O) δ 20.45, 20.78, 27.98, 42.92, 43.78, 50.24, 56.48, 63.01, 113.75, 125.98, 126 , 58, 127.00, 127.26, 127.62, 129.13, 130.15, 130.48, 135.02, 139.50, 139.70, 139.90, 140.80, 148.11 150.93, 151.76, 160.44; ES-MC m / z 531 (M + H); elemental analysis: calculated for C ₃₂ H ₃₄ N ₆ O • 2.5HBr • 3.0H ₂ O: C, 50.36; H, 5.44; N, 10.68; Br, 25.38. Found: C, 50.19; H, 5.26; N, 10.41; Br, 25.56.

EXAMPLE 32

AMD9547: Preparation of 6- (4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) -6,7-dihydropyrrolo [3, 4-b] pyridin-5-one (hydrobromide salt)

Preparation of 3-Carboethoxy-2-pyridinecarboxaldehyde

To a stirred solution of 2-methylnicotinate (1.657 g, 10.0 mmol) in a mixture of 1,4-dioxane (10 ml) and water (1 ml) was added selenium dioxide (1.568 g, 14.1 mmol), and the resulting mixture was boiled with reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes / ethyl acetate, 3: 1) to obtain the title compound (0.90 g, 50%) as a yellow oil.

¹ H NMR (CDCl ₃ ) δ 1.41 (t, 3H, J = 7.5 Hz), 4.45 (q, 2H; J = 7.5 Hz), 7.56 (dd, 1H, J = 6.0, 6.0 Hz), 8.11 (dd, 1H, J = 6.0, 1.0 Hz), 8.87 (dd, 1H, J = 6.0, 1.0 Hz), 10.34 (s, 1H).

Using General Procedure B: Reaction of 3-carboethoxy-2-pyridinecarboxaldehyde (0.210 g, 1.17 mmol) and (4-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinoline- 8-yl) amine (0.472 g, 1.18 mmol) with NaBH (OAc) ₃ (0.507 g, 2.39 mmol) in CH ₂ Cl ₂ (12 ml) for 75 minutes, followed by purification of the crude material by column chromatography on silica gel (CH ₂ Cl ₂ —CH ₃ OH-NH ₄ OH, 40: 1: 1) and then by radial chromatography on silica gel (2 mm plate, CH ₂ Cl ₂ —CH ₃ OH-NH ₄ OH, 100: 1: 1 ) resulted in the free base of the title compound (0.396 g, 65%) as white wow solid.

Using General Procedure D: Conversion of the free base (56 mg) to the hydrobromide salt, followed by reprecipitation of the intermediate solid from methanol / ether, afforded AMD9547 (61 mg) as a white solid.

¹ H NMR (D ₂ O) δ 1.81-1.95 (m, 1H), 2.19-2.32 (m, 2H), 2.40-2.46 (m, 1H), 3, 03 (br, 2H), 3.70 (d, 1H, J = 12.6 Hz), 3.80 (d, 1H, J = 12.6 Hz) 4.14 (d, 2H, J = 3, 3 Hz) 4.31 (s, 2H), 4.44 (d, 1H, J = 16.8 Hz), 4.62 (d, 1H, J = 16.8 Hz), 4.73-4, 80 (m, 1H, blocked by HOD), 6.92-6.98 (m, 4H), 7.16 (d, 2H, J = 8.1 Hz), 7.39 (dd, 2H, J = 3 0, 6.0 Hz), 7.77 (dd, 1H, J = 5.4, 7.8 Hz), 7.92 (dd, 1H, J = 5.4, 7.8 Hz), 8 32 (d, 1H, J = 7.8 Hz), 8.39 (d, 1H, J = 7.8 Hz), 8.76 (d, 1H, J = 5.7 Hz), 8.82 (d, 1H, J = 5.1Hz); ¹³ C NMR (D ₂ O) δ 20.44, 20.97, 27.85, 45.99, 50.42, 51.23, 56.73, 63.50, 113.41, 125.30, 126 , 10, 127.59, 128.66, 130.23, 130.68, 135.30, 135.83, 136.11, 139.65, 141.02, 148.28, 150.66, 150.84 , 152.02, 160.43, 167.55; ES-MC m / z 515 (M + H); elemental analysis: calculated for C ₃₂ H ₃₀ N ₆ O • 3.1HBr • 2.8H ₂ O: C, 47.11; H, 4.78; N, 10.30; Br, 30.36. Found: C, 46.98; H, 4.60; N, 10.07; Br, 30.65.

EXAMPLE 33

AMD9933: Preparation of N- (4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-7-yl) amino] methyl} benzyl) -3,5-dichloroisonicotinamide

Preparation of {4 - [(5,6,7,8-tetrahydroquinolin-7-ylamino) methyl] benzyl} carbamic acid tert-butyl ester

Using General Procedure B: Reaction of (4-formylbenzyl) carbamic acid tert-butyl ester (356 mg, 1.51 mmol), 5,6,7,8-tetrahydroquinolin-7-ylamine (224 mg, 1.51 mmol) in anhydrous MeOH (5 ml) at room temperature overnight under N ₂ atmosphere and stirring for 2 minutes after adding sodium borohydride (115 mg, 3.00 mmol), as well as subsequent purification of the crude material by silica gel chromatography (CH ₃ OH- NH ₃ H ₂ O-CH ₂ Cl ₂ , 2: 2: 96) afforded the title compound (556 mg, 100%) as a white foam.

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

{4 - [(5,6,7,8-tetrahydroquinolin-7-ylamino) methyl] benzyl} carbamic acid tert-butyl ester (88 mg, 0.24 mmol), 2-chloromethylbenzimidazole-1-carboxylic tert-butyl ester acids (80 mg, 0.30 mmol), DIPEA (0.10 ml, 0.54 mmol) and KI (19 mg, 0.11 mmol) were heated at 80 ° C in CH ₃ CN (1.5 ml) in for 2 hours in an atmosphere of N ₂ , then the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, washed with NH ₄ Cl (aqueous solution), NaCl (aqueous solution) and dried (MgSO ₄ ). Evaporation of the solvent and purification of the residue by silica gel flash chromatography (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 1: 1: 98) afforded the title compound (80 mg, 56%) as a white foam .

Preparation of (4-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-7-yl) amine

To a stirred solution of tert-butyl ether 2 - {[[4- (tert-butoxycarbonylaminomethyl) benzyl] - (5,6,7,8-tetrahydroquinolin-7-yl) amino] methyl} benzimidazole-1-carboxylic acid (120 mg , 0.20 mmol) in anhydrous CH ₂ Cl ₂ (1 ml) was added TFA (1 ml). The solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, dissolved using MeOH and NaHCO _{3 was} added. The mixture was stirred for 20 minutes, diluted with CH ₂ Cl ₂ , filtered through celite. The crude product was purified by flash chromatography on silica gel (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 2: 2: 96), resulting in the title compound (71 mg, 89%) as a white foam .

Using a General Coupling Method Using EDCI F: Reaction of (4-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-7-yl) amine (71 mg, 0.18 mmol ), 3,5-dichloroisonicotinic acid (75%, 48 mg, 0.18 mmol), 1-hydroxybenzotriazole (25 mg, 0.18 mmol), 4-methylmorpholine (60 μl, 0.53 mmol) and EDCI (34 mg, 0.18 mmol) for 2 days at 50 ° C followed by column chromatography on silica gel (MeOH-NH ₄ OH-CH ₂ Cl ₂ , 1: 1: 98) yielded compound AMD9933 (29 mg, 28% ) in the form of a white powder.

¹ H NMR (CDCl ₃ ) δ 1.72 (br, 1H), 2.18-2.24 (m, 1H), 2.74-2.92 (t, 2H), 3.02-3.19 (t, 3H), 3.70 (d, 1H, J = 13.5 Hz), 3.83 (d, 1H, J = 13.5 Hz), 3.94-4.05 (t, 2H) 4.57 (d, 2H, J = 5.4 Hz), 6.47 (br, 1H), 7.00-7.08 (t, 3H), 7.21-7.36 (t, 6H) ), 7.56-7.59 (t, 1H), 8.31 (d, 1H, J = 3.3 Hz), 8.48 (s, 2H), 9.59 (s, 1H); ¹³ C NMR (CDCl ₃ ) δ 24.73, 28.40, 35.98, 43.92, 49.16, 55.11, 57.07, 110.99, 119.39, 121.76, 122, 20, 122.85, 128.55, 129.41, 131.78, 133.85, 136.51, 136.95, 139.03, 142.88, 143.55, 147.26, 147.91, 154.08, 156.03, 162.48; ES-MC m / z 571.2 (M + H); elemental analysis: calculated for (C ₃₁ H ₂₈ N ₆ Cl ₂ O) • 0.1 (CH ₂ Cl ₂ ) • 0.3 (H ₂ O): C, 63.81; H, 4.96; N, 14.36; Cl, 13.32. Found: C, 63.85; H, 5.02; N, 14.24; Cl, 13.47.

EXAMPLE 34

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

Preparation of (4 - {[(2-nitrobenzenesulfonyl) - (5,6,7,8-tetrahydroquinolin-7-yl) amino] methyl} benzyl) carbamic acid tert-butyl ester

Reaction of tert-butyl ester {4 - [(5,6,7,8-tetrahydroquinolin-7-ylamino) methyl] benzyl} carbamic acid (98 mg, 0.27 mmol), NsCl (67 mg, 0.29 mmol) , DIPEA (0.10 ml, 0.54 mmol) in anhydrous CH ₂ Cl ₂ for 3 hours at room temperature followed by silica gel column chromatography (MeOH-NH ₄ OH-CH ₂ Cl ₂ , 1: 1: 98) yielded the title compound (70 mg, 47%) as a yellow foam.

Preparation of N- (4-aminomethylbenzyl) -2-nitro-N- (5,6,7,8-tetrahydroquinolin-7-yl) benzenesulfamide

To a stirred solution of tert-butyl ether (4 - {[(2-nitrobenzenesulfonyl) - (5,6,7,8-tetrahydroquinolin-7-yl) amino] methyl} benzyl) carbamic acid (160 mg, 0.29 mmol) in anhydrous CH ₂ Cl ₂ (2 ml), TFA (2 ml) was added. The solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, MeOH was dissolved and NaHCO _{3 was} added. The mixture was stirred for 20 minutes, diluted with CH ₂ Cl ₂ , filtered through celite. The crude product was purified by flash chromatography on silica gel (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 1: 1: 98), which afforded the title compound (75 mg, 57%) as a white foam .

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

Using a General Procedure for Conducting a Coupling Reaction Using EDCI F: Reaction of N- (4-aminomethylbenzyl) -2-nitro-N- (5,6,7,8-tetrahydroquinolin-7-yl) benzene sulfamide (75 mg, 0.17 mmol), 3,5-dichloroisonicotinic acid (75%, 55 mg, 0.22 mmol), 1-hydroxybenzotriazole (23 mg, 0.17 mmol), 4-methylmorpholine (100 μl, 0.89 mmol) and EDCI ( 32 mg, 0.17 mmol) for two days at 50 ° C followed by column chromatography on silica gel (MeOH-NH ₄ OH-CH ₂ Cl ₂ , 1: 1: 98) gave the title compound (42 mg , 40%) as a yellow foam.

Using the general procedure for removing the nosyl-protective group C: Reaction of 3,5-dichloro-N- (4 - {[((2-nitrobenzenesulfonyl) - (5,6,7,8-tetrahydroquinolin-7-yl) amino] methyl} benzyl ) isonicotinamide (42 mg, 0.07 mmol), thiophenol (0.10 ml, 0.97 mmol) and K ₂ CO ₃ (269 mg, 1.95 mmol) in DMF (2 ml) at room temperature under N ₂ followed by purification of the crude material by silica gel chromatography (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 2: 2: 96) to give AMD9958 (15 mg, 51%) as a white foam.

¹ H NMR (CDCl ₃ ) δ 1.57-1.70 (m, 2H), 2.01-2.06 (m, 1H), 2.60-2.89 (m, 3H), 3.00 -3.13 (m, 2H), 3.83 (s, 2H), 4.66 (d, 2H, J = 5.7 Hz), 7.00 (dd, 2H, J = 4.8, 7 5 Hz), 7.30-7.37 (m, 5H), 8.23 (d, 1H, J = 3.9 Hz), 8.46 (s, 2H); ¹³ C NMR (CDCl ₃ ) δ 26.48, 28.80, 39.42, 43.70, 50.69, 52.39, 121.16, 127.68, 128.27, 128.55, 129, 02, 131.47, 135.75, 136.46, 140.19, 142.35, 146.79, 147.65, 155.51, 162.04; ES-MC m / z 441.5 (M + H); elemental analysis calculated for (C ₂₃ H ₂₂ N ₄ Cl ₂ O) • 0.5 (CH ₄ O): C, 61.71; H, 5.29; N, 12.25. Found: C, 61.71; H, 5.24; N, 12.24.

EXAMPLE 35

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

Preparation of 2- (4-aminomethylphenyl) ethanol

To a stirred solution of NH ₃ / EtOH (170 ml) was added (4-bromomethylphenyl) acetic acid (1.61 g, 7.01 mmol). The solution was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and redissolved in anhydrous THF (10 ml). BH ₃ .Me ₂ S was added to the solution, and the mixture was stirred for 1 hour at 70 ° C. and at room temperature for 2 days. The reaction mixture was concentrated in vacuo, 6N HCl (10 ml) was added and the mixture was stirred at 70 ° C for 1 hour. Then water (20 ml) was added and the solution was neutralized with 1N NaOH to pH ~ 7. The solution was concentrated to dryness under high vacuum, washed with MeOH / CH ₂ Cl ₂ and filtered. The crude product was purified by flash chromatography on silica gel (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 5: 3: 92) to give the title compound (820 mg, 77%) as a white foam.

Preparation of 3,5-Dichloro-N- [4- (2-hydroxyethyl) benzyl] isonicotinamide

Using a General Coupling Method Using EDCI F: Reaction of 2- (4-aminomethylphenyl) ethanol (306 mg, 2.03 mmol), 3,5-dichloroisonicotinic acid (385 mg, 2.03 mmol), 1-hydroxybenzotriazole (301 mg , 2.22 mmol), 4-methylmorpholine (0.50 ml, 4.45 mmol) and EDCI (426 mg, 2.22 mmol) in anhydrous DMF (5 ml) overnight at room temperature and overnight at 40 ° C. followed by silica gel column chromatography (MeOH-NH ₄ OH-CH ₂ Cl ₂ , 2: 2: 96) afforded the title compound (291 mg, 44%) as a white foam.

Preparation of 3,5-Dichloro-N- [4- (2-oxoethyl) benzyl] isonicotinamide

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

Obtaining tert-butyl ether 2 - {[[2- (4 - {[(3,5-dichloropyridin-4-carbonyl) amino] methyl} phenyl) ethyl] - (5,6,7,8-tetrahydroquinoline-8- il) amino] methyl} benzimidazole-1-carboxylic acid

Using the general reductive amination procedure B: Reaction of tert-butyl ether 2 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzimidazole-1-carboxylic acid (74 mg, 0.20 mmol), 3, 5-dichloro-N- [4- (2-oxoethyl) benzyl] isonicotinamide (53 mg, 0.16 mmol) and NaBH (OAc) ₃ (44 mg, 0.20 mmol) overnight at room temperature followed by a column silica gel chromatography (CH ₂ Cl ₂ -MeOH-NH ₄ OH, 98: 1: 1) afforded the title compound (99 mg, 88%) as a white foam.

To a stirred solution of tert-butyl ether 2 - {[[2- (4 - {[(3,5-dichloropyridin-4-carbonyl) amino] methyl} phenyl) ethyl] - (5,6,7,8-tetrahydroquinoline- 8-yl) amino] methyl} benzimidazole-1-carboxylic acid (99 mg, 0.14 mmol) in anhydrous CH ₂ Cl ₂ (1 ml), TFA (1 ml) was added. The solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, dissolved in MeOH and NaHCO _{3 was} added. The mixture was stirred for 20 minutes, diluted with CH ₂ Cl ₂ , filtered through celite. The crude product was purified by flash chromatography on silica gel (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 2: 2: 96) to give AMD11072 (50 mg, 59%) as a light yellow foam.

¹ H NMR (CDCl ₃ ) δ 1.67-1.73 (m, 1H), 1.84-1.95 (m, 1H), 2.01-2.05 (m, 1H), 2.17 -2.24 (m, 1H), 2.65-3.02 (m, 6H), 3.99-4.14 (m, 3H), 4.61 (d, 2H, J = 5.7 Hz ), 6.13 (br, 1H), 6.99 (d, 2H, J = 7.8 Hz), 7.06-7.17 (m, 5H), 7.38-7.44 (m, 2H), 7.61 (d, 1H, J = 8.1 Hz), 8.52 (br, 3H); ¹³ C NMR (CDCl ₃ ) δ 21.79, 24.64, 29.51, 35.64, 43.87, 49.72, 52.89, 62.70, 114.04, 118.22, 121, 99, 122.67, 127.78, 128.29, 129.43, 134.98, 135.34, 137.87, 139.86, 142.94, 146.89, 147.84, 156.88, 157.54, 162.54; ES-MC m / z 585.5 (M + H); elemental analysis: calculated for (C ₃₂ H ₃₀ N ₆ Cl ₂ O) • 0.3 (CH ₂ Cl ₂ ) • 0.3 (H ₂ O): C, 62.94; H, 5.10; N, 13.63; Cl, 14.95. Found: C, 63.17; H, 5.14; N, 13.68; Cl, 14.64.

EXAMPLE 36

AMD9702: 3 - {[(1H-Benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzylamide pyridine-2-carboxylic acid (hydrobromide salt)

Using a General Coupling Method Using EDCI F: Reaction of (3-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (133 mg, 0.33 mmol ), picolinic acid (40 mg, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), DIPEA (100 μl, 0.57 mmol) and EDCI (64 mg, 0.33 mmol) in anhydrous DMF (3 ml) for 3 days at room temperature, followed by purification of the crude material by silica gel chromatography (CH ₃ OH-NH ₃ H ₂ O-CH ₂ Cl ₂ , 2: 2: 96) afforded the title compound ( 158 mg, 94%) as a white foam.

Using General Procedure D: Conversion of the above foam (158 mg, 0.31 mmol) into a hydrobromide salt using an acetic acid / HBr solution, followed by reprecipitation of the salt from diethyl ether, gave AMD9702 as a white solid.

¹ H NMR (D ₂ O) δ 1.75-1.89 (m, 1H), 2.14-2.25 (m, 2H), 2.36 (br, 1H), 2.97-3, 04 (m, 2H), 3.67-3.75 (m, 2H), 4.18 (s, 2H), 4.37 (d, 1H, J = 16.2 Hz), 4.55 (d , 1H, J = 16.2 Hz), 4.67-4.72 (m, 1H), 6.73 (d, 1H, J = 7.2 Hz), 6.94-7.08 (m, 3H), 7.36-7.39 (m, 2H), 7.47-7.50 (m, 2H), 7.82-7.90 (m, 2H), 8.16 (d, 1H, J = 7.8 Hz), 8.29-8.34 (m, 2H), 8.65 (d, 1H, J = 5.7 Hz), 8.73 (d, 1H); ¹³ C NMR (D ₂ O) δ 18.36, 18.74, 25.75, 41.20, 48.00, 54.57, 60.66, 111.72, 122.17, 123.99, 124 , 53, 125.21, 126.79, 127.13, 127.31, 128.32, 134.67, 135.79, 137.49, 138.72, 141.85, 143.48, 144.06 , 146.11, 148.69, 149.54, 161.17; ES-MC m / z 503.3 (M + H); elemental analysis: calculated for (C ₃₁ H ₂₉ N ₅ O) • 2.7 (HBr) • 1.7 (H ₂ O) • 0.2 (C ₄ H ₁₀ O): C, 49.83; H, 5.01; N, 10.96; Br, 28.15. Found: C, 49.75; H, 4.77; N, 10.89; Br, 28.30.

EXAMPLE 37

AMD9788: Preparation of N- (3 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) -2,6-dichloroisonicotinamide

Using a General Procedure for Conducting a Coupling Reaction Using EDCI F: Reaction of (3-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (94 mg, 0 24 mmol), 2,6-dichloroisonicotinic acid (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol), 4-methylmorphiline (40 μl, 0.36 mmol) and EDCI (50 mg, 0.26 mmol) for 24 hours at room temperature followed by silica gel column chromatography (EtOAc / MeOH / NH ₄ OH, 199: 1: 1) to give AMD9788 (87 mg, 59%) as white foam.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.74-1.83 (m, 1H), 1.98-2.06 (m, 2H), 2.27-2.28 (m, 1H), 2.72-2.84 (m, 2H), 3.74 (s, 2H), 3.88 (d, 1H, J = 18.0 Hz), 4.08 (d, 1H, J = 18, 0 Hz), 4.13-4.16 (m, 1H), 4.43 (dd, 1H, J = 15.0, 3.0 Hz), 4.56 (dd, 1H, J = 15.0 , 6.0 Hz), 7.03-7.37 (m, 10H), 7.44 (s, 1H), 7.65 (s, 2H), 8.60-8.62 (m, 1H) ; ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 14.85, 21.94, 24.35, 37.14, 44.78, 49.25, 54.67, 61.32, 112.37, 118 95, 121.89, 122.34, 123.01, 127.43, 128.45, 128.97, 129.19, 135.48, 138.08, 138.14, 140.43, 147.42 , 147.69, 151.66, 156.54, 157.73, 163.68; ES-MC m / z 573 (M + H); elemental analysis: calculated for C ₃₁ H ₂₈ N ₆ Cl ₂ O • 1.0CH ₂ Cl ₂ • 0.4H ₂ O: C, 57.92; H, 4.68; N, 12.66; Cl, 21.37. Found: C, 58.08; H, 4.60; N, 12.63; Cl, 21.20.

EXAMPLE 38

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

Using a General Coupling Method Using EDCI F: Reaction of (3-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (120 mg, 0.30 mmol ), 2,6-dimethylbenzoic acid (50 mg, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), 4-methylmorphiline (49 μl, 0.45 mmol) and EDCI (63 mg, 0 , 33 mmol) for 4 hours at room temperature, followed by silica gel column chromatography (EtOAc / MeOH / NH ₄ OH, 199: 1: 1) to give the desired product (89 mg, 56%) as a white foam.

Using a General Method for the Formation of HBr Salt D: Conversion of the resulting foam into a hydrobromide salt resulted in the compound AMD9795 as a white powder.

¹ H NMR (300 MHz, D ₂ O) δ 1.92-2.09 (m, 1H), 2.13 (s, 6H), 2.20-2.33 (t, 2H), 2.46 -2.49 (t, 1H), 3.02-3.08 (m, 2H), 3.77-3.88 (m, 2H), 4.14 (s, 2H), 4.47 (d) , 1H, J = 16.5 Hz), 4.66 (d, 1H, 7 = 16.2 Hz), 4.76-4.81 (t, 1H), 6.92 (d, 1H, J = 7.5 Hz), 7.09-7.12 (t, 4H), 7.16-7.19 (t, 1H), 7.24-7.29 (m, 1H), 7.42-7 50 (m, 2H), 7.58-7.63 (m, 2H), 7.94 (dd, 1H, J = 7.5, 6.0 Hz), 8.42 (d, 1H, J = 7.8 Hz), 8.75 (d, 1H, J = 5.4 Hz); ¹³ C NMR (75.5 MHz, D ₂ O) 18.55 (2C), 20.47, 20.85, 27.84, 43.00, 50.16, 56.80, 62.94, 113, 83, 126.11, 126.76, 127.37, 127.84, 129.17, 129.38, 129.79, 130.55, 134.59, 136.85, 138.12, 139.58, 140.96, 148.24, 150.92, 151.81; ES-MC m / z 530 (M + H); elemental analysis: calculated for C ₃₄ H ₃₅ N ₅ O • 2.2HBr • 1.2H ₂ O: C, 55.99; H, 5.47; N, 9.60; Br, 24.10. Found: C, 55.80; H, 5.50; N, 9.53; Br, 24.26.

EXAMPLE 39

AMD9836: Preparation of N- (3 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) -3,5-dibromisonicotinamide (hydrobromide salt )

Reaction of 3,5-dibromisonicotinic acid (73 mg, 0.26 mmol), oxalyl chloride (1 ml) under reflux for 1 hour, subsequent reaction of the corresponding acyl chloride, (3-aminomethylbenzyl) - (1H-benzimidazole-2- ilmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (103 mg, 0.26 mmol), DIPEA (0.30 ml, 1.70 mmol) and a catalytic amount of DMAP for 3 hours at room temperature yielded a crude yellow oil. The crude product was purified by silica gel column chromatography (EtOAc-MeOH-NH ₄ OH, 199: 1: 1) to obtain the title compound (60 mg, 35%) as a white foam.

Using General Procedure D: Conversion of the resulting foam (60 mg, 0.09 mmol) into a hydrobromide salt using an acetic acid / HBr solution, followed by reprecipitation of the salt from diethyl ether, afforded AMD9836 as a white foam.

¹ H NMR (CD ₃ OD) δ 1.88-1.93 (m, 1H), 2.22-2.35 (m, 2H), 2.44-2.48 (m, 1H), 3, 05-3.09 (m, 2H), 3.80-3.89 (m, 2H), 4.40-4.46 (m, 3H), 4.64 (d, 1H, J = 16.5 Hz), 4.72-4.77 (m, 1H), 6.99-7.07 (m, 2H), 7.28 (d, 1H, J = 6.9 Hz), 7.55 (dd , 2H, J = 3.3, 6.3 Hz), 7.65 (s, 1H), 7.73-7.77 (m, 2H), 7.94 (dd, 1H, J = 6.0 , 7.8 Hz), 8.40 (d, 1H, J = 7.8 Hz), 8.67 (s, 2H), 8.93 (d, 1H, J = 5.7 Hz); ¹³ C NMR (CD ₃ OD) δ 25.22, 25.31, 32.59, 47.62, 54.07, 61.33, 66.00, 118.63, 122.98, 130.57, 131 , 39, 132.35, 133.36, 133.90, 134.59, 135.71, 141.05, 143.19, 145.09, 145.38, 151.80, 152.66, 155.26 155.55, 156.18; ES-MC m / z 661.3 (M + H); elemental analysis: calculated for (C ₃₁ H ₂₈ Br ₂ N ₆ O) • 0.4 (C ₂ H ₄ O ₂ ) • 0.7 (H ₂ O) • 2.1 (HBr): C, 44.06 ; H, 3.85; N, 9.69; Br, 37.79. Found: C, 44.22; H, 3.87; N, 9.75; Br, 37.77.

EXAMPLE 40

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

Using a General Coupling Method Using EDCI F: Reaction of (3-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (100 mg, 0.25 mmol ), 2-chloro-6-aminobenzoic acid (43 mg, 0.25 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), 4-methylmorphiline (38 μl, 0.35 mmol) and EDCI (48 mg 0.25 mmol) for 4 hours at room temperature followed by silica gel column chromatography (EtOAc / MeOH / NH ₄ OH, 199: 1: 1) to give AMD9874 (108 mg, 79%) as a white foam .

¹ H NMR (300 MHz, CD ₃ OD) δ 1.58-1.75 (m, 1H), 2.01-2.12 (t, 2H), 2.18-2.67 (t 1H), 2.73-2.94 (t, 2H), 3.56 (d, 1H, J = 12.9 Hz), 3.64 (d, 1H, J = 13.2 Hz), 3.97-4 15 (t, 3H), 4.20 (s, 2H), 6.64-6.69 (m, 2H), 7.03-7.08 (m, 3H), 7.13 (dd, 2H) , J = 6.0, 3.3 Hz), 7.20-7.28 (m, 2H), 7.37 (br, 1H), 7.42-7.45 (m, 2H), 7, 57 (d, 1H, J = 7.8 Hz); 8.58 (d, 1H, J = 5.4 Hz); ¹³ C NMR (75.5 MHz, CD ₃ OD) δ 22.81, 24.38, 30.60, 44.81, 51.53, 56.52, 63.34, 115.78, 115.95, 119.12, 123.06, 123.65, 124.07, 127.93, 129.57, 129.86, 130.05, 132.16, 132.75, 137.41, 139.49, 139, 62, 140.88, 148.34, 148.85, 156.26, 158.17, 169.44; ES-MC m / z 551 (M + H); elemental analysis: calculated for C ₃₂ H ₃₁ ClN ₆ O • 0.8H ₂ O • 0.7 (C ₄ H ₈ O ₂ ): C, 66.65; H, 6.14; N, 13.40; Cl, 5.65. Found: C, 66.62; H, 6.05; N, 13.28; Cl, 5.76.

EXAMPLE 41

AMD9843: Preparation of N- (3 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) -3,5-dichloroisonicotinamide

Using a General Coupling Method Using EDCI F: Reaction of (3-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (105 mg, 0.26 mmol ), 3,5-dichloroisonicotinic acid (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (36 mg, 0.26 mmol), 4-methylmorphiline (100 μl, 0.89 mmol) and EDCI (51 mg, 0 , 26 mmol) for 2 days at room temperature followed by column chromatography on silica gel (MeOH-NH ₄ OH-CH ₂ Cl ₂ , 1: 1: 98) gave compound AMD9843 (62 mg, 41%) as white foam.

¹ H NMR (CDCl ₃ ) δ 1.65-1.77 (m, 1H), 1.91-2.07 (t, 2H), 2.23-2.28 (m, 1H), 2.70 -2.91 (m, 1H), 3.71 (s, 2H), 3.81 (d, 1H, J = 16.5 Hz), 4.01 (d, 1H, J = 16.5 Hz) 4.05-4.10 (m, 1H), 4.53 (d, 2H, J = 5.7 Hz), 7.02-7.04 (t, 3H), 7.12-7.21 (t, 3H), 7.29-7.35 (m, 2H), 7.42-7.45 (m, 3H), 7.50 (d, 1H, J = 7.8 Hz), 8, 29 (s, 2H); 8.65-8.67 (m, 1H); ¹³ C NMR (CDCl ₃ ) δ 21.72, 24.12, 29.56, 44.23, 49.04, 54.87, 61.48, 121.93, 122.80, 127.50, 128, 54, 129.06, 129.13, 129.40, 135.27, 137.46, 137.92, 140.10, 142.89, 147.17, 147.73, 156.27, 157.48, 162.47; ES-MC m / z 571.6 (M + H); elemental analysis: calculated for (C ₃₁ H ₂₈ N ₆ Cl ₂ O) • 0.2 (CH ₂ Cl ₂ ) • 0.7 (H ₂ O): C, 62.34; H, 5.00; N, 13.98; Cl, 14.16. Found: C, 62.28; H, 4.98; N, 13.58; Cl, 14.20.

EXAMPLE 42

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

Using a General Coupling Method Using EDCI F: Reaction of (2-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (70 mg, 0.18 mmol ), 2,6-dimethylbenzoic acid (29 mg, 0.19 mmol), 1-hydroxybenzotriazole (26 mg, 0.19 mmol), 4-methylmorphiline (27 μl, 0.25 mmol) and EDCI (37 mg, 0 , 19 mmol) for 18 hours at room temperature, followed by silica gel column chromatography (EtOAc / MeOH / NH ₄ OH, 199: 1: 1) to give the desired product (34 mg, 37%) as a white foam.

Using a General Method for the Formation of HBr Salt D: Conversion of the resulting foam into a hydrobromide salt gave compound AMD9849 as a white powder.

¹ H NMR (300 MHz, D ₂ O) δ 1.94-1.98 (m, 1H), 2.08 (s, 6H), 2.23-2.28 (m, 1H), 2.40 -2.48 (t, 2H), 3.06 (br, 2H), 3.94 (d, 1H, J = 12.9 Hz), 4.17 (d, 1H, J = 12.9 Hz) 4.44-4.51 (t, 2H); 4.58-4.66 (m, 2H); 4.81-4.87 (m, 1H); 6.87-6.92 (m, 1H), 6.97-7.01 (m, 1H), 7.04-7.08 (t, 3H), 7.21-7.26 (m, 1H), 7.34 (d, 1H, J = 7.5 Hz), 7.53-7.57 (t, 2H), 7.60-7.65 (t, 2H), 7.91 (dd, 1H, J = 7.8, 6, 0 Hz), 8.41 (d, 1H, J = 7.8 Hz), 8.73 (d, 1H, J = 5.7 Hz); ¹³ C NMR (75.5 MHz, D ₂ O) δ 18.57 (2C), 20.46, 20.73, 27.93, 43.93, 49.60, 53.83, 62.04, 113 , 94, 126.19, 126.82, 127.76, 128.30, 129.24, 129.31, 129.75, 130.59, 131.89, 133.93, 134.50, 136.01 , 136.34, 139.87, 141.06, 148.29, 150.67, 151.32, 173.34; ES-MC m / z 530 (M + H); elemental analysis: calculated for C ₃₄ H ₃₅ N ₅ O • 2.1HBr • 1.4H ₂ O: C, 56.34; H, 5.55; N, 9.66; Br, 23.15. Found: C, 56.48; H, 5.73; N, 9.30; Br, 23.18.

EXAMPLE 43

AMD9981: Preparation of N- (2 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) -3,5-dichloroisonicotinamide

Using a General Coupling Method Using EDCI F: Reaction of (2-aminomethylbenzyl) - (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (70 mg, 0.18 mmol ), 3,5-dichloroisonicotinic acid (75%, 67 mg, 0.26 mmol), 1-hydroxybenzotriazole (24 mg, 0.18 mmol), 4-methylmorphiline (100 μl, 0.89 mmol) and EDCI (37 mg, 0.19 mmol) for 2 days at room temperature followed by silica gel column chromatography (MeOH-NH ₄ OH-CH ₂ Cl ₂ , 1: 1: 98) yielded compound AMD9981 (40 mg, 40%) in the form of a white foam.

¹ H NMR (CDCl ₃ ) δ 1.53-1.77 (m, 2H), 2.02-2.08 (m, 1H), 2.35-2.39 (m, 1H), 2.68 -2.88 (m, 2H), 3.56-3.85 (m, 5H), 4.20 (d, 1H, J = 12.6 Hz), 5.01 (dd, 1H, J = 9 6, 13.2 Hz), 6.75-6.79 (m, 1H), 7.18-7.33 (m, 8H), 7.47 (br, 1H), 7.66 (d, 2H, J = 7.5 Hz), 8.32 (s, 2H), 9.81 (m, 1H); ¹³ C NMR (CDCl ₃ ) δ 20.86, 21.16, 28.87, 40.32, 49.16, 55.17, 58.51, 110.68, 119.37, 122.04, 122, 38, 123.07, 127.85, 128.82, 129.15, 130.47, 132.07, 134.95, 135.39, 138.01, 138.23, 143.38, 145.30, 147.33, 153.38, 157.32, 162.39; ES-MC m / z 571.2 (M + H); elemental analysis calculated for (C ₃₁ H ₂₈ N ₆ Cl ₂ O) • 0.2 (CH ₂ Cl ₂ ): C, 63.68; H, 4.86; N, 14.28; Cl, 14.46. Found: C, 64.00; H, 4.87; N, 14.10; Cl, 14.36.

EXAMPLE 44

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

Preparation of (4-hydroxymethylphenyl) pyridine-2-carboxylic acid amide

Using General Procedure F: Reaction of (4-aminophenyl) methanol (200 mg, 1.63 mmol), picolinic acid (217 mg, 1.79 mmol), 1-hydroxybenzotriazole (242 mg, 1.79 mmol), 4-methylmorpholine (269 μl, 2.45 mmol) and EDCI (343 mg, 1.79 mmol) for 24 hours at room temperature afforded the title compound (342 mg, 92%) as a red solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.70 (d, 2H, J = 3.9 Hz), 7.41 (d, 2H, J = 8.4 Hz), 7.50 (ddd, 1H , J = 7.5, 4.8, 1.3 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.92 (ddd, 1H, J = 7.5, 7.5 4.5 Hz), 8.31 (d, 1H, J = 6.0 Hz), 10.06 (br, 1H).

Preparation of (4-chloromethylphenyl) pyridine-2-carboxylic acid amide

The interaction of (4-hydroxymethylphenyl) amide of pyridine-2-carboxylic acid (342 mg, 1.50 mmol), Et ₃ N (262 μl, 1.80 mmol) and methanesulfonyl chloride (128 μl, 1.65 mmol) for 2 hours at reflux, the title compound (352 mg, 95%) was obtained as a red solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.61 (s, 2H), 7.45 (d, 2H, J = 8.4 Hz), 7.50 (ddd, 1H, J = 7.5, 4.8, 0.9 Hz), 7.80 (d, 2H, J = 8.7 Hz), 7.92 (ddd, 1H, J = 7.8, 7.8, 1.6 Hz), 8.63 (d, 1H, J = 6.0 Hz), 10.08 (br, 1H).

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

General procedure for the substitution of chlorides (I):

A solution of chloride (1.0 equivalent) was added dropwise to a stirred solution of amine (~ 1.5 equivalents) and Hanig base (1.0 equivalents) in anhydrous MeCN (~ 0.2 M) at room temperature under nitrogen atmosphere. The resulting solution was stirred at the indicated temperature (~ 80 ° C) for the specified time. The mixture was diluted with CH ₂ Cl ₂ (100 ml / mmol), filtered through celite and concentrated. The crude material was purified by chromatography.

Using the above procedure I: Reaction of 8-amino-5,6,7,8-tetrahydroquinoline (181 mg, 1.22 mmol), N, N-diisopropylethylamine (142 μl, 0.81 mmol) and (4-chloromethylphenyl) pyridine-2-carboxylic acid amide (200 mg, 0.81 mmol) for 3 hours at 80 ° C followed by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 198: 1: 1) led to compound AMD9409 (106 mg, 36%) as a yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.75-1.85 (m, 2H), 2.00-2.04 (m, 1H), 2.16-2.20 (m, 1H), 2.73-2.81 (m, 3H), 3.82-3.86 (m, 1H), 3.87 (d, 1H, J = 12.0 Hz), 3.98 (d, 1H, J = 15.0 Hz), 7.03 (dd, 1H, J = 7.4, 4.7 Hz), 7.34 (d, 1H, J = 7.5 Hz), 7.41-7, 46 (m, 3H), 7.43 (d, 2H, J = 8.4 Hz), 7.87 (ddd, 1H, J = 7.8, 7.8, 1.7 Hz), 8.27 (d, 1H, J = 7.8 Hz), 8.37 (d, 1H, J = 7.8 Hz), 8.58 (d, 1H, J = 3.3 Hz), 10.00 (bs , 1H); ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 20.09, 29.08, 29.28, 51.86, 57.98, 120.06 (2C), 122.20, 122.75, 126, 79, 129.37 (2C), 132.85, 136.85, 137.25, 138.05, 147.23, 148.34, 150.25, 157.90, 162.28; ES-MC m / z 359 (M + H); elemental analysis: calculated for C ₂₂ H ₂₂ N ₄ O • 0.2H ₂ O: C, 72.99; H, 6.24; N, 15.48. Found: C, 72.98; H, 6.20; N, 15.48.

EXAMPLE 45

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

Using General Procedure B: Reaction (4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] phenyl} pyridine-2-carboxylic acid amide (AMD9409) (67 mg, 0.19 mmol), 1H -benzimidazole-2-carbaldehyde (30 mg, 0.21 mmol) and NaBH (OAc) ₃ (119 mg, 0.50 mmol) for 0.5 hours at 60 ° C, followed by purification of the crude product by silica gel column chromatography ( CH ₂ Cl ₂ / MeOH / NH ₄ OH, 198: 1: 1) afforded the compound AMD9413 (48 mg, 53%) as a white foam.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.62-1.75 (m, 1H), 1.96-2.07 (m, 2H), 2.23-2.30 (m, 1H), 2.68-2.91 (m, 2H), 3.74 (br, 2H), 3.98 (d, 1H, J = 16.8 Hz), 4.09 (m, 1H), 4.19 (d, 1H, J = 16.5 Hz), 7.16-7.20 (m, 3H), 7.41-7.46 (m, 4H), 7.53 (d, 1H, J = 6 , 0 Hz), 7.64-7.67 (m, 3H), 7.87 (ddd, 1H, J = 7.5, 7.5, 1.5 Hz), 8.26 (d, 1H, J = 7.8 Hz), 8.58 (d, 1H, J = 3.9 Hz), 8.70 (d, 1H, J = 3.3 Hz), 9.94 (br, 1H); ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 21.39, 23.41, 29.22, 48.54, 53.54, 60.11, 119.57, 121.50, 122.25, 122 , 36, 126.37, 129.28, 134.71, 135.33, 136.73, 137.21, 137.62, 146.93, 147.93, 149.80, 157.47, 161.84 ; ES-MC m / z 489 (M + H); elemental analysis: calculated for C ₃₀ H ₂₈ N ₆ O • 0.5H ₂ O • 0.3CHCl ₃ : C, 68.23; H, 5.54; N, 15.76. Found: C, 68.06; H, 5.54; N, 15.46.

EXAMPLE 46

AMD9982: Preparation of N- (4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} phenyl) -3,5-dichloroisonicotinamide

Preparation of 3,5-Dichloro-N- (4-hydroxymethylphenyl) isonicotinamide

A suspension of 3,5-dichloroisonicotinic acid (128 mg, 0.667 mmol) in thionyl chloride (2 ml) was refluxed for 2 hours, then concentrated. 4-aminobenzyl alcohol (123 mg, 0.999 mmol) and THF (2.2 ml) were added to the residue, and the mixture was stirred at room temperature for 19 hours. The mixture was filtered and the filtrate was concentrated to give a yellow foam.

¹ H NMR (CD ₃ OD) δ 4.60 (s, 2H), 7.38 (d, 2H, J = 8.7 Hz), 7.63 (d, 2H, J = 8.4 Hz), 8.66 (s, 2H).

Preparation of 3,5-Dichloro-N- (4-formylphenyl) isonicotinamide

A solution of 3,5-dichloro-N- (4-hydroxymethylphenyl) isonicotinamide (125 mg, 0.421 mmol) in CH ₂ Cl ₂ (4.2 ml) was refluxed with a suspension of 85% MnO ₂ (430 mg, 4.20 mmol) for 3 hours. The mixture was filtered and the filtrate was concentrated to give a brown solid.

¹ H NMR (CDCl ₃ ) δ 7.78 (s, 1H), 7.83 (d, 2H, J = 8.7 Hz), 7.94 (d, 2H, J = 8.4 Hz), 8 61 (s, 2H); 9.98 (s, 1H).

Using General Procedure B: For a stirred solution of (1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (76 mg, 0.27 mmol), 3,5-dichloro- N- (4-formylphenyl) isonicotinamide (81 mg, 0.27 mmol) and AcOH (0.016 ml, 0.28 mmol) in THF (3 ml) were added NaBH (OAc) ₃ (175 mg, 0.826 mmol), and the mixture stirred at room temperature for 17.5 hours. The crude material was dissolved in a saturated solution of HBr / AcOH (2 ml) and stirred at room temperature for 15 minutes. The solution was basified with 10N NaOH (aqueous solution) and extracted with CH ₂ Cl ₂ (3 x 15 ml). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. Purification of the crude material by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 400: 5: 1-200: 5: 1) afforded AMD9982 (69 mg, 42%) as a yellow foam.

¹ H NMR (CDCl ₃ ) δ 1.68 (m, 1H), 1.98 (m, 2H), 2.17 (m, 1H), 2.69-2.91 (m, 2H), 3, 63 (d, 1H, J = 17 Hz), 3.67 (d, 1H, J = 17 Hz), 3.87 (d, 1H, J = 17 Hz), 4.03 (m, 1H), 4 09 (d, 1H, J = 17 Hz), 7.19 (m, 3H), 7.29 (d, 2H, J = 8.4 Hz), 7.49 (m, 5H), 8.30 (s, 2H), 8.69 (d, 1H, J = 3 Hz), 10.29 (s, 1H); ¹³ C NMR (CDCl ₃ ) δ 21.31, 24.10, 29.15, 48.10, 53.17, 60.55, 111.13, 118.26, 120.20, 121.50, 121, 81, 122.40, 128.94, 129.13, 134.84, 136.13, 136.61, 137.42, 142.42, 146.79, 147.39, 156.23, 157.24 160.31; ES-MC m / z 557 (M + H) ( ³⁵ Cl), 559 (M + H) ( ³⁷ Cl); elemental analysis: calculated for C ₃₀ H ₂₆ N ₆ Cl ₂ O • 0.2H ₂ O • 0.4CH ₂ Cl ₂ : C, 61.36; H, 4.61; N, 14.12; Cl, 16.68. Found: C, 61.22; H, 4.62; N, 13.86; Cl, 16.80.

EXAMPLE 47

AMD9426: Preparation of 4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzylamide pyridin-2-sulfonic acid

Obtaining 4-hydroxymethylbenzylamide pyridin-2-sulfonic acid

General procedure for the reaction of amines with sulfonyl chlorides J:

To a stirred solution of amine (1.1 equivalents) and Hanig base (1.0 equivalent) in anhydrous CH ₂ Cl ₂ (~ 0.2 M) at room temperature under nitrogen atmosphere was added a solution of sulfonyl chloride (1.0 equivalent). The resulting solution was stirred at room temperature for the indicated time. The mixture was diluted with CH ₂ Cl ₂ (100 ml / mmol), washed with an aqueous solution of NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by chromatography.

Using the above procedure J: Reaction of (4-aminomethylphenyl) methanol (255 mg, 1.86 mmol), N, N-diisopropylethylamine (294 μl, 1.69 mmol) and pyridin-2-sulfonyl chloride (300 mg, 1.69 mmol) for 10 minutes at room temperature, the title compound (400 mg, 85%) was obtained as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.26 (ss, 2H), 4.66 (ss, 2H), 5.28 (ss, 1H), 7.23-7.30 (m, 4H) 7.49-7.51 (m, 1H), 7.90-7.92 (m, 1H), 7.99 (d, 1H, J = 4.8 Hz), 8.68 (d, 1H) , J = 4.5 Hz).

Obtaining 4-chloromethylbenzylamide pyridin-2-sulfonic acid

Reaction of 4-hydroxymethylbenzylamide pyridin-2-sulfonic acid (140 mg, 0.50 mmol), Et ₃ N (88 μl, 0.60 mmol) and MsCl (47 μl, 0.60 mmol) for 2 hours under reflux a refrigerator, followed by silica gel column chromatography (CHCl ₂ / MeOH, 99: 1), afforded the title compound (67 mg, 45%) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.28 (d, 2H, J = 6.0 Hz), 4.54 (s, 2H), 5.17 (ss, 1H), 7.23-7 49 (m, 4H), 7.47-7.52 (m, 1H), 7.88 (ddd, 1H, J = 7.5, 7.5, 1.7 Hz), 7.97 (d , 2H, J = 7.5 Hz); 8.69 (d, 1H, J = 4.8 Hz); ES-MC m / z 319 (M + Na).

Preparation of 4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzylamide pyridin-2-sulfonic acid

Reaction between 8-amino-5,6,7,8-tetrahydroquinoline (200 mg, 1.35 mmol), N, N-diisopropylethylamine (157 μl, 0.90 mmol) and 4-chloromethylbenzylamide pyridine-2-sulfonic acid (266 mg , 0.90 mmol) for 3 hours at 50 ^° C followed by column chromatography on silica gel to give AMD9426 (150 mg, 41%) as a yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.79 (m, 2H), 1.97-2.03 (m, 1H), 2.12-2.20 (m, 1H), 2.69-2.84 (m, 3H), 3.77-3.81 (m, 2H), 3.92 (d, 1H, J = 12.0 Hz), 4.20 (br, 2H) 7.05 (dd, 1H, J = 7.5, 4.8 Hz), 7.15 (d, 2H, J = 7.8 Hz), 7.25 (d, 2H, J = 7.8 Hz), 7.36 (d, 1H, J = 7.5 Hz), 7.39-7.44 (m, 1H), 7.82 (ddd, 1H, J = 7.8, 7.8, 1.5 Hz), 7.92 (d, 1H, J = 7.8 Hz), 8.36 (d, 1H, J = 3.9 Hz), 8.59 (d, 1H, J = 4, 2 Hz); ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 20.09, 28.94, 29.23, 47.80, 51.75, 57.87, 122.25, 122.63, 126.94, 128 45 (2C), 128.88 (2C), 132.88, 135.25, 137.30, 138.35, 147.68, 147.15, 150.34, 157.75, 157.95, ES -MC m / z 409 (M + H); elemental analysis: calculated for C ₂₂ H ₂₄ N ₄ O ₂ S • 0.2H ₂ O • 0.3CH ₂ Cl ₂ : C, 61.21; H, 5.76; N, 12.80; S, 7.33; O, 8.04. Found: C, 60.82; H, 5.73; N, 12.42; S, 7.30; O, 8.14.

EXAMPLE 48

AMD9429: Preparation of 4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzylamide pyridin-2-sulfonic acid (hydrobromide salt)

Preparation of 4 - ({(5,6,7,8-tetrahydroquinolin-8-yl) - [1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazol-2-ylmethyl] amino} methyl) benzylamide pyridin-2-sulfonic acid

Using General Procedure B: Reaction of 4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] benzylamide pyridin-2-sulfonic acid ( AMD9426) (150 mg, 0.37 mmol), 1- (2- trimethylsilanylethoxymethyl) -1H-benzimidazole-2-carbaldehyde (102 mg, 0.37 mmol) and NaBH (OAc) ₃ (233 mg, 1.10 mmol) for 1 hour at room temperature followed by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 198: 1: 1) afforded the title compound (101 mg, 41%) as a yellow foam.

¹ H NMR (300 MHz, CD ₃ OD) δ 0.00 (s, 9H), 0.75 (dd, 2H, J = 8.1, 8.1 Hz), 1.58-1.75 (m , 2H), 2.22 (br, 2H), 2.66-2.85 (t, 2H), 3.25 (dd, 2H, J = 8.1, 8.1 Hz), 3.66 ( d, 1H, J = 14.1 Hz), 3.78 (d, 1H, J = 14.1 Hz), 4.02 (d, 1H, J = 6.0 Hz), 4.06-4, 16 (m, 1H) 4.20 (br, 2H), 4.81 (br, 1H), 5.68 (d, 1H, J = 12.0 Hz), 5.91 (d, 1H, J = 12.0 Hz), 6.92 (d, 2H, J = 7.8 Hz), 7.06 (dd, 1H, J = 7.5, 4.8 Hz), 7.17-7.23 ( m, 4H), 7.30-7.35 (m, 2H), 7.45 (ddd, 1H, J = 7.5, 4.5, 1.1 Hz), 7.61-7.64 ( t, 1H), 7.87 (ddd, 1H, J = 7.8, 7.8, 1.7 Hz), 7.98 (d, 1H, J = 7.8 Hz), 8.55 (d , 1H, J = 3.6 Hz), 8.68 (d, 1H, J = 3.9 Hz). ES-MC m / z 669 (M + H).

Preparation of 4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzylamide pyridin-2-sulfonic acid

Using General Procedure E: Reaction of 4 - ({(5,6,7,8-tetrahydroquinolin-8-yl) - [1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazol-2-ylmethyl] amino} methyl) benzylamide pyridin- 2-sulfonic acids (100 mg, 0.15 mmol) and 6N HCl (3.9 ml) for 3 hours at 50 ° C followed by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 94: 3 : 3) yielded the title compound (68 mg, 85%) as a white foam.

Using General Procedure D: The resulting product was converted to the corresponding hydrobromide salt to give AMD9429 as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 1.92-2.02 (m, 1H), 2.22-2.41 (m, 3H), 3.04-3.05 (m, 2H) 3.68 (bs, 4H), 4.42 (d, 1H, J = 16.2 Hz), 4.64 (d, 1H, J = 16.5 Hz), 4.77 (dd, 1H, J = 10.2, 6.3 Hz), 6.93 (d, 2H, J = 8.4 Hz), 7.33 (d, 2H, J = 8.1 Hz), 7.53 (dd, 2H, J = 6.3, 3.3 Hz), 7.60 (ddd, 1H, J = 7.5, 4.8, 1.2 Hz), 7.73 (dd, 2H, J = 6, 3, 3.2 Hz), 7.91-7.97 (m, 2H), 8.01-8.07 (m, 1H), 8.39 (d, 1H, J = 7.8 Hz), 8.65-8.67 (m, 1H); 8.92 (d, 1H, J = 5.7 Hz); ¹³ C NMR (75.5 MHz, CD ₃ OD) δ 15.86, 21.94, 29.21, 47.78, 57.69, 62.82, 67.31, 115.22 (2C), 123 70, 127.23, 128.03 (2C), 128.65, 129.10 (2C), 131.80 (2C), 132.24, 136.53, 139.56, 140.73, 141, 58, 141.92, 149.29, 151.08 (2C), 152.21, 152.92, 159.36. ES-MC m / z 539 (M + H). Elemental analysis: calculated for C ₃₀ H ₃₀ N ₆ O ₂ S • 2.2HBr • 1.9H ₂ O: C, 47.99; H, 4.83; N, 11.19; O, 8.31; Br, 23.41; S, 4.27. Found: C, 43.35; H, 4.92; N, 11.13; O, 8.35; Br, 23.27; S, 4.22.

EXAMPLE 49

AMD9830: Preparation of N- (4 - {[(1-benzenesulfonyl-1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) benzenesulfamide

Solution N ^′ - (1H-benzimidazol-2-ylmethyl) -N ^′ - (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine (302 mg, 0.760 mmol), benzenesulfonyl chloride (0, 12 ml, 0.94 mmol) and Et ₃ N (0.15 ml, 1.1 mmol) in CH ₂ Cl ₂ (7.5 ml) were refluxed for 17 hours, then concentrated in vacuo. The residue was partitioned between saturated NaHCO ₃ (aq) (15 ml) and EtOAc (20 ml). The aqueous phase was extracted with EtOAc (20 ml), the combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification of the crude product by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 400: 5: 1) gave compound AMD9830 (229 mg, 71%) as a yellow foam.

¹ H NMR (CDCl ₃ ) δ 1.64-2.03 (m, 3H), 2.37 (m, 1H), 2.66-2.84 (m, 2H), 3.76-3.89 (m, 4H), 4.06 (m, 1H), 4.41 (dd, 1H, J = 9.6, 6.0 Hz), 4.66 (d, 1H, J = 15 Hz), 4 79 (d, 1H, J = 15 Hz), 6.76 (d, 2H, J = 8.1 Hz), 7.07 (m, 1H), 7.18 (d, 2H, J = 8, 1 Hz), 7.27 (m, 2H), 7.41 (m, 3H), 7.55 (m, 5H), 7.84 (m, 3H), 7.96 (m, 2H), 8 48 (m, 1H); ¹³ C NMR (CDCl ₃ ) δ 20.15, 27.15, 27.55, 45.30, 51.78, 53.32, 61.49, 111.81, 118.60, 119.84, 122, 59, 123.06, 125.43, 125.60, 127.06, 127.47, 127.76, 131.01, 131.24, 131.92, 132.55, 132.69, 134.81, 136.75, 138.13, 139.21, 140.14, 145.11, 151.74, 156.99; ES-MC m / z 678 (M + H); elemental analysis: calculated for C ₃₇ H ₃₅ N ₅ S ₂ O ₄ • 0.5H ₂ O: C, 64.70; H, 5.28; N, 10.20. Found: C, 64.65; H, 5.11; N, 10.08.

EXAMPLE 50

AMD9831: Preparation of N- (4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) -N-methylbenzenesulfamide

Preparation of 4-methylaminomethylbenzoic Acid Methyl Ester

A mixture of methyl (4-bromomethyl) benzoate (600 mg, 2.62 mmol), methylamine (2.0 M / MeOH, 6.5 ml, 13 mmol), potassium iodide (cat.) And N, N-diisopropylethylamine (0 , 46 ml, 2.64 mmol) was heated to 40 ° C in CH ₃ CN in a sealed vessel for 17 hours, then concentrated in vacuo. The residue was partitioned between saturated NaHCO ₃ (aqueous solution) and CH ₂ Cl ₂ (20 ml), and the aqueous phase was extracted with CH ₂ Cl ₂ (20 ml). The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification of the crude product by silica gel column chromatography (20% EtOAc / Hexanes, then CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 5: 1) gave a colorless oil (262 mg, 56%).

¹ H NMR (CDCl ₃ ) δ 2.46 (s, 3H), 3.81 (s, 2H), 3.91 (s, 3H), 7.39 (d, 2H, J = 8.1 Hz) 8.00 (d, 2H, J = 8.1 Hz).

N- (4-hydroxymethylbenzyl) -N-methylbenzenesulfamide

A solution of 4-methylaminomethylbenzoic acid methyl ester (262 mg, 1.46 mmol), benzenesulfonyl chloride (0.22 ml, 1.7 mmol) and Et ₃ N (0.29 ml, 2.1 mmol) in CH ₂ Cl ₂ ( 15 ml) was refluxed for 15 hours, then concentrated in vacuo. The residue was partitioned between saturated NaHCO ₃ (aqueous solution) (20 ml) and EtOAc (20 ml), and the aqueous phase was extracted with EtOAc (20 ml). The combined organic phases were washed with saturated NaHCO ₃ (aq) (15 ml) and brine (10 ml), then dried (MgSO ₄ ), filtered and concentrated in vacuo to give tan crystals (672 mg).

To a solution of the above ester (672 mg) in THF (2.9 ml) was added diisobutylaluminum hydride (1.0 M / THF, 8.8 ml, 8.8 mmol) at 0 ° C., and the solution was stirred at room temperature for 30 minutes. MeOH (4 ml) was added to the solution, and the solution was acidified (pH 2) with 10% HCl (aqueous solution). The mixture was basified with 1 N NaOH (aqueous solution) and extracted with EtOAc (2 x 20 ml). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification of the crude product by silica gel column chromatography (40% EtOAc / Hexanes) gave colorless crystals (258 mg, 61%).

¹ H NMR (CDCl ₃ ) δ 1.66 (t, 1H, J = 6.0 Hz), 2.60 (s, 3H), 4.15 (s, 2H), 4.70 (d, 2H, J = 6.0 Hz), 7.33 (m, 4H), 7.54-7.66 (m, 3H), 7.85 (m, 2H).

N- (4-formylbenzyl) -N-methylbenzenesulfamide

A solution of N- (4-hydroxymethylbenzyl) -N-methylbenzenesulfamide (258 mg, 0.885 mmol) in CH ₂ Cl ₂ (9 ml) was stirred at room temperature with a suspension of 85% MnO ₂ (900 mg, 8.8 mmol) for 63 hours. The mixture was filtered through celite, and the solvent from the filtrate was removed under reduced pressure to obtain a colorless solid.

¹ H NMR (CDCl ₃ ) δ 2.65 (s, 3H), 4.24 (s, 2H), 7.50 (d, 2H, J = 8.1 Hz), 7.56-7.68 ( m, 3H), 7.87 (m, 4H), 10.02 (s, 1H).

Using General Procedure B: To a stirred solution of (1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amine (130 mg, 0.343 mmol), N- (4-Formylbenzyl) -N-methylbenzenesulfamide (109 mg, 0.377 mmol) and AcOH (0.020 ml, 0.35 mmol) in THF (3.5 ml) was added NaBH (OAc) ₃ (218 mg, 1.03 mmol) and the mixture was stirred at room temperature for 20 hours. Purification of the crude material by silica gel column chromatography (40% EtOAc / Hexanes) gave the product as a colorless oil (41 mg).

A solution of the above oil (41 mg, 0.063 mmol) in a mixture of TFA / CH ₂ Cl ₂ , 3: 1 (4 ml) was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was partitioned between CH ₂ Cl ₂ (10 ml) and 1 N NaOH (aqueous solution) (15 ml), and the aqueous phase was extracted with CH ₂ Cl ₂ (2 x 10 ml). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give AMD9831 (33 mg, 16%) as a colorless foam.

¹ H NMR (CDCl ₃ ) δ 1.69 (m, 1H), 2.02 (m, 2H), 2.26 (m, 1H), 2.51 (s, 3H), 2.69-2, 91 (m, 2H), 3.73 (s, 2H), 3.95 (d, 1H, J = 17 Hz), 4.05 (s, 2H), 4.09 (m, 1H), 4, 18 (d, 1H, J = 17 Hz), 7.17 (m, 5H), 7.37 (d, 2H, J = 8.1 Hz), 7.43 (d, 1H, J = 6.6 Hz), 7.49-7.61 (m, 5H), 7.80 (m, 2H), 8.69 (m, 1H); ¹³ C NMR (CDCl ₃ ) δ 21.77, 23.84, 29.61, 34.71, 49.05, 54.15, 60.81, 121.87, 122.69, 127.79, 128, 68, 129.25, 129.48, 133.00, 134.85, 135.14, 137.66, 137.86, 139.57, 147.33, 156.54, 157.75; ES-MC m / z 552 (M + H); elemental analysis: calculated for C ₃₂ H ₃₃ N ₅ SO ₂ • 0.2H ₂ O • 0.4C ₄ H ₈ O ₂ : C, 68.34; H, 6.25; N, 11.86. Found: C, 68.31; H, 6.33; N, 11.86.

EXAMPLE 51

AMD9845: Preparation of N- (4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) benzene sulfamide

Solution N- (4 - {[(1-benzenesulfonyl-1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) benzenesulfamide (AMD9830) (161 mg , 0.234 mmol) in a saturated solution of HBr / AcOH (3 ml) was stirred at room temperature for 3.5 hours, then diethyl ether (20 ml) was added to obtain a colorless precipitate. The supernatant was decanted and the residue was partitioned between CH ₂ Cl ₂ (10 ml) and saturated NaHCO ₃ (aqueous solution) (15 ml). The main aqueous phase was extracted with CH ₂ Cl ₂ (10 ml), and the combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification of the crude material by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 500: 5: 1) gave compound AMD9845 (59 mg, 44%) as a yellow foam.

¹ H NMR (CDCl ₃ ) δ 1.68 (m, 1H), 1.99 (m, 2H), 2.24 (m, 1H), 2.67-2.91 (m, 2H), 3, 68 (s, 2H), 3.86 (d, 1H, J = 17 Hz), 4.05 (m, 3H), 4.14 (d, 1H, J = 17 Hz), 4.87 (m, 1H), 7.01 (d, 2H, J = 7.8 Hz), 7.18 (t, 3H), 7.28 (t, 2H), 7.37-7.60 (t, 6H), 7.80 (t, 2H); 8.68 (t, 1H); ¹³ C NMR (CDCl ₃ ) δ 22.08, 24.18, 29.90, 47.66, 49.21, 54.47, 61.26, 122.30, 123.03, 127.75, 128, 54, 129.65, 129.73, 133.29, 135.47, 135.74, 138.01, 139.87, 140.65, 147.63, 156.87, 158.03; ES-MC m / z 538 (M + H); elemental analysis: calculated for C ₃₁ H ₃₁ N ₅ SO ₂ • 0.46CH ₂ Cl ₂ : C, 65.52; H, 5.58; N, 12.14. Found: C, 65.56; H, 5.60; N, 12.09.

EXAMPLE 52

AMD9436: Preparation of {4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] phenyl} pyridin-2-sulfonic acid amide (hydrobromide salt)

Preparation of (4-hydroxymethylphenyl) pyridin-2-sulfonic acid amide

The interaction of (4-aminophenyl) methanol (249 mg, 2.03 mmol), N, N-diisopropylethylamine (294 μl, 1.69 mmol) and pyridine-2-sulfonyl chloride (300 mg, 1.69 mmol) for 1 hour at room temperature, followed by silica gel column chromatography (CH ₂ Cl ₂ / MeOH, 194: 3), the title compound (210 mg, 47%) was obtained as a red solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.60 (d, 2H, J = 6.0 Hz), 7.07 (br, 1H), 7.15 (d, 2H, J = 8.4 Hz ), 7.23 (d, 2H, J = 8.7 Hz), 7.44-7.48 (m, 1H), 7.83 (ddd, 1H, J = 7.5, 7.5, 1 8 Hz), 7.89 (d, 1H, J = 7.8 Hz), 8.72 (d, 1H, J = 4.5 Hz).

Preparation of (4-formylphenyl) pyridin-2-sulfonic acid amide

To a stirred solution of (4-hydroxymethylphenyl) pyridine-2-sulfonic acid amide (200 mg, 0.76 mmol) and pyridine (612 μl) in anhydrous CH ₂ Cl ₂ (3 ml) was added Dess Martin periodan (450 mg, 1, 06 mmol). The resulting solution was stirred at room temperature for 1 hour. The mixture was diluted with 100 ml of CH ₂ Cl ₂ , filtered through celite and concentrated. The crude material was purified by recrystallization from chilled CH ₂ Cl ₂ to give the title compound (120 mg, 60%) as a yellow powder.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.34 (d, 2H, J = 8.4 Hz), 7.49-7.50 (m, 1H), 7.74 (br, 1H), 7 75 (d, 2H, J = 8.4 Hz), 7.89-7.70 (m, 1H), 8.03 (d, 1H, J = 8.1 Hz), 8.70 (d, 1H, J = 4.2 Hz), 9.87 (s, 1H).

Preparation of {4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] phenyl} pyridin-2-sulfonic acid amide

Using General Procedure B: Reaction of 5,6,7,8-tetrahydroquinolin-8-ylamine (68 mg, 0.46 mmol), (4-formylphenyl) amide (120 mg, 0.46 mmol) and NaBH (OAc) ₃ (291 mg, 1.37 mmol) for 1 hour at room temperature, followed by purification of the crude product by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 98: 1: 1) to give the title compound (121 mg, 67%) as a white foam.

Using General Procedure D: The foam obtained above was converted to the corresponding hydrobromide salt to give AMD9436 as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 1.86-2.00 (m, 2H), 2.11-2.15 (m, 1H), 2.43-2.49 (m, 1H) , 2.88-2.90 (m, 2H), 4.20 (d, 1H, J = 13.2 Hz), 4.32 (d, 1H, J = 12.9 Hz), 4.40 ( dd, 1H, J = 9.6, 4.8 Hz), 7.29 (d, 2H, J = 8.4 Hz), 7.35 (dd, 1H, J = 7.8, 4.8 Hz ), 7.42 (d, 2H, J = 8.7 Hz), 7.53-7.59 (m, 1H), 7.67 (d, 1H, J = 7.5 Hz), 7.95 7.99 (m, 2H), 8.50 (d, 1H, J = 4.5 Hz), 8.62 (d, 1H, J = 3.9 Hz); ¹³ C NMR (75.5 MHz, CD ₃ OD) δ 20.34, 26.35, 28.67, 57.32, 122.43 (2C), 124.35, 126.69, 128.64, 128 89, 132.57 (2C), 137.67, 140.17, 140.73, 143.04, 146.85, 149.31, 151.52, 158.47; ES-MC m / z 395 (M + H); elemental analysis: calculated for C ₂₁ H ₂₂ N ₄ O ₂ S • 2.0HBr • 1.5H ₂ O: C, 43.24; H, 4.67; N, 9.60; O, 9.60; S, 5.50; Br 27.40. Found: C, 42.89; H, 4.77; N, 9.63; O, 9.33; S, 5.42; Br, 27.50.

EXAMPLE 53

AMD9444: Preparation of (4 - {[(1H-benzimidazol-2-ylmethyl) - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} phenyl) pyridin-2-sulfonic acid amide

Using General Procedure B: Reaction of {4 - [(5,6,7,8-tetrahydroquinolin-8-ylamino) methyl] phenyl} pyridin-2-sulfonic acid amide (hydrobromide salt) (AMD9436) (82 mg, 0.21 mmol ), 1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazole-2-carbaldehyde (57 mg, 0.21 mmol) and NaBH (OAc) ₃ (132 mg, 0.62 mmol) for 1 hour at room temperature followed by purification of the crude product by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 198: 1: 1) gave [4 - ({(5,6,7,8-tetrahydroquinolin-8-yl) - [ 1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazol-2-ylmethyl] amino} methyl) fe yl] -amide pyridine-2-sulfonic acid (72 mg, 41%) as a yellow foam.

Using General Procedure E: Reaction of the above Compound (72 mg, 0.11 mmol) with 6 N HCl (2.0 ml) for 3 hours at 50 ° C. followed by silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 194: 3: 3) afforded the title compound (41 mg, 71%) as a white foam.

Using General Procedure D: Conversion of the Product Above into the Corresponding Hydrobromide Salt Produced AMD9444 as a White Solid

¹ H NMR (300 MHz, CD ₃ OD) δ 1.88-1.90 (m, 1H), 2.18-2.24 (t, 2H), 2.35-2.36 (m, 1H) 3.00-3.01 (t, 2H), 3.70 (d, 1H, J = 12.9 Hz), 3.76 (d, 1H, J = 12.9 Hz), 4.38 ( d, 1H, J = 16.2 Hz), 4.59 (d, 1H, J = 16.2 Hz), 4.64-4.73 (m, 1H), 6.87 (d, 2H, J = 8.4 Hz), 7.30 (d, 2H, J = 8.4 Hz), 7.51-7.56 (t, 3H), 7.72 (dd, 2H, J = 6.0, 3.0 Hz), 7.84-7.91 (t, 2H), 7.92-7.98 (m, 1H), 8.33 (d, 1H, J = 7.8 Hz), 8, 59 (d, 1H, J = 4.5 Hz), 8.86 (d, 1H, J = 4.5 Hz); ¹³ C NMR (75.5 MHz, CD ₃ OD) δ 15.84, 21.90, 29.17, 50.61, 57.21, 62.46, 115.19 (2C), 121.77 (2C ), 124.09, 127.11, 128.09 (2C), 128.77, 132.28 (2C), 133.15, 139.16, 140.07, 141.57, 141.81, 149, 10, 151.46, 152.87; ES-MC m / z 525 (M + H); elemental analysis: calculated for C ₂₉ H ₂₈ N ₆ O ₂ S • 2.2HBr • 1.5H ₂ O • 0.3C ₄ H ₁₀ O: C, 48.24; H, 4.85; N, 11.18; O, 8.09; Br, 23.38; S, 4.26. Found: C, 48.44; H, 4.85; N, 11.18; O, 8.22; Br, 23.08; S, 4.34.

EXAMPLE 54

AMD 9541: Preparation of 4 - {[cis-2 - [(N-pyridin-2-ylmethyl) amino] cyclohexyl] aminomethyl} benzylamide pyridine-2-carboxylic acid (hydrobromide salt)

Obtaining 4-hydroxymethylbenzylamide pyridine-2-carboxylic acid

Using General Procedure F: To a stirred solution of 4-aminomethylbenzyl alcohol (203 mg, 1.48 mmol) in DMF (3 ml) was added picolinic acid (198 mg, 1.61 mmol), 1-hydroxybenzotriazole (213 mg, 1.58 mmol), N, N-diisopropylethylamine (0.39 ml, 2.24 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl (EDC) (315 mg, 1.64 mmol), and the mixture was stirred for nights at room temperature. Standard work-up afforded the title compound (340 mg, 95%) as a yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.67 (d, 2H, J = 6.0 Hz), 4.69 (s, 2H), 7.36 (br, 4H), 7.43-7 44 (m, 1H), 7.85-7.86 (m, 1H), 8.24 (d, 1H, J = 9.0 Hz), 8.52 (br, 1H), 8.52 ( d, 1H, J = 3.0 Hz); ES-MC m / z 243 (M + H).

Obtaining 4-formylbenzylamide pyridine-2-carboxylic acid

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

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.76 (d, 2H, J = 6.0 Hz), 7.42-7.44 (m, 1H), 7.53 (d, 2H, J = 6.0 Hz), 7.87 (d, 2H, J = 6.0 Hz), 7.85-7.88 (m, 1H), 8.24 (d, 1H, J = 6.0 Hz) 8.55 (br s, 1H); 8.57 (d, 1H; J = 3.0 Hz); 10.00 (s, 1H).

Using General Procedure B: To a solution of cis-1- [N- (tert-butoxycarbonyl)] cyclohexane-1,2-diamine (0.79 g, 3.69 mmol) and 2-pyridinecarboxaldehyde (0.35 ml, 3, 68 mmol) in CH ₂ Cl ₂ (20 ml) was added NaBH (OAc) ₃ (0.036 g, 0.57 mmol), and the mixture was stirred at room temperature overnight. The resulting crude oil was used in the next step without further purification.

¹ H NMR (CDCl ₃ ) δ 1.35-1.51 (m, 4H), 1.44 (s, 9H), 1.54-1.64 (m, 3H), 2.01-2.04 (m, 2H), 2.75-2.79 (m, 1H), 3.66-3.70 (m, 1H), 3.87 (d, 1H, J = 15 Hz), 3.96 ( d, 1H, J = 15 Hz), 5.42 (br, 1H, NH), 7.16 (dd, 1H, J = 9.6 Hz), 7.30 (d, 1H, J = 9 Hz) 7.61 (td, 1H, J = 9.3 Hz); 8.56 (d, 1H, J = 3 Hz).

To a solution of the above oil and N, N-diisopropylethylamine (0.96 ml, 5.52 mmol) in CH ₂ Cl ₂ (10 ml) was added benzyl chloroformate (0.64 ml, 4.48 mmol), and the mixture was stirred at room temperature. temperature for 3 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (15 ml) and brine (25 ml), and the phases were separated. The aqueous phase was washed with CH ₂ Cl ₂ (2 x 20 ml), and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification of the crude product by silica gel flash chromatography (CH ₂ Cl ₂ / MeOH, 97: 3) afforded di-protected diamine (1.44 g, 89% from two steps) as an orange oil.

Removal of the Boc-protecting group: The above oil (1.44 g, 3.28 mmol) was dissolved in CH ₂ Cl ₂ (2 ml), treated with trifluoroacetic acid (2 ml) and the mixture was stirred overnight. Conventional work-up gave an orange oil (1.17 g), which was used in the next reaction without further purification.

Using General Procedure B: To a solution of the above oil (187 mg) and pyridine-2-carboxylic acid 4-hydroxymethylbenzylamide (127 mg, 0.53 mmol) in CH ₂ Cl ₂ (6 ml) was added NaBH (OAc) ₃ (170 mg, 0.80 mmol), and the mixture was stirred at room temperature overnight. Purification of the crude material by silica gel flash chromatography (CH ₂ Cl ₂ / MeOH, 96: 4, then 90:10) afforded the desired protected amine (150 mg, 50% from two steps) as a pale yellow foam.

Removal of the Cbz group: To a solution of the foam obtained above (150 mg, 0.27 mmol) in MeOH (5 ml) was added palladium on activated carbon (10%, 34 mg), and the mixture was hydrogenated (1 atmosphere) at room temperature during the night. The reaction mixture was filtered through celite, and the squeezed precipitate was washed with methanol. The combined filtrates were evaporated under reduced pressure, and the resulting clear oil was purified by silica gel radial chromatography (1 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 2: 1) to give the free amine (45 mg, 39%) in as a clear oil.

Using General Procedure D: The free base obtained above (33 mg, 0.077 mmol) was converted to the hydrobromide salt to give AMD9541 (70 mg) as a white solid.

¹ H NMR (D ₂ O) δ 1.39-1.56 (m, 4H), 1.62-1.75 (m, 2H), 1.92-1.97 (m, 2H), 3, 27-3.31 (m, 1H), 3.42-3.46 (m, 1H), 3.90 (d, 1H, J = 17.4 Hz), 4.20 (d, 1H, J = 13.5 Hz), 4.33 (d, 1H, J = 13.5 Hz), 4.41 (d, 1H, J = 17.4 Hz), 4.59 (s, 2H), 7.35 (d, 2H, J = 8.1 Hz), 7.42 (d, 2H, J = 8.1 Hz), 7.85-7.90 (m, 2H), 8.11-8.13 ( bm, 1H), 8.40-8.47 (m, 2H), 8.56-8.63 (m, 2H), 8.82-8.87 (bm, 1H); ¹³ C NMR (D ₂ O) δ 19.63, 23.45, 24.83, 27.17, 44.41, 48.33, 49.12, 54.52, 58.88, 125.63, 126 66, 126.85, 129.15 (2 carbon), 130.42, 131.33 (2 carbon), 139.69, 141.47, 144.55, 145.00, 147.16, 147.45 (2 carbon), 155.72, 162.53; ES-MC m / z 430 (M + H).

EXAMPLE 55

Inhibition of chemokine-induced Ca intake measured by FLIPR (molecular devices)

Reagents:

Dye Used: Fluo-3, AM (Molecular Probes F-1241) was dissolved in anhydrous DMSO and stored frozen in aliquots. To increase the solubility of the dye in the medium used, 10% (w / v) pluronic acid (Molecular Probes F-127) was added to the Fluo-3 stock solution immediately before use.

Receipt Buffer:

HBSS + 20 mM Hepes

Buffer + 0.2% BSA, pH 7.4. HBSS 10x [(w / v Phenol Red and Sodium Bicarbonate (Gibco 14065-049)]; Hepes buffer 1 M (Gibco 15630-056), BSA (Sigma A3675). The intake buffer was vacuum filtered and stored in a refrigerator for 5 days maximum Before use in the experiment, the buffer was heated at 37 ° C in a water bath.

Antagonists:

Test compounds were diluted in an intake buffer at the desired concentration and added to 4 wells of a black microplate (4 parallel measurements per compound). The following control wells were used: 100% response control (no inhibition), addition buffer was added; 100% inhibition control: chemokine was added at a concentration that is 5 times higher than the concentration required to induce Ca intake.

Preparation of an agonist tablet (chemokine)

Chemokines were diluted in an intake buffer to concentrations that are 4 times higher than the required concentrations to stimulate cells (i.e. 2.5 nM for SDF-1α and 0.6 nM for RANTES). Chemokines were added to untreated 96-well Sero well compound plates (International Medical, Sterilin code 611F96). Negative control wells (baseline monitoring) were supplemented with an entry buffer instead of chemokine. As a positive control to test staining efficacy, 20 μM digitonin (final concentration) was also included. The agonist plate was incubated in FLIPR (37 ° C) for 15-30 minutes.

Protocol for measuring the inhibition of SDF-1α-induced Ca intake in SUP-T1 cells upon cell loading.

SUP-T1 cells were centrifuged at room temperature (RT) and resuspended in the medium used (RPMI-1640 containing 2% FBS and 4 μM Fluo-3, AM). Cells were incubated at room temperature for 45 minutes, then washed twice in the buffer of receipt, then incubated in the buffer of receipt at room temperature for 10 minutes. Cells were centrifuged and resuspended in an entry buffer at a density of 3x10 ⁶ cells per ml. An aliquot of a 100 μl cell suspension (3x10 ⁵ cells) was added to each well of a black microplate (Costar 3603), which already contained 50 μl of a solution of the test compound (at concentrations that are 3 times higher than the desired final concentration of the compound). Then the microplate was carefully centrifuged at room temperature. The uniform distribution of cells at the bottom of the wells of the microplate was then confirmed with a microscope and the microplate was incubated in FLIPR (37 ° C) for 10 minutes prior to testing.

Fluorescence measurements as a function of time on FLIPR

The FLIPR settings (camera exposure time and laser power) were set so as to obtain initial fluorescence values between 8000 and 10000 units. After checking a 20 second baseline, an agonist (chemokine) (50 μl) was added using a black pipette tip pipettor. Fluorescence was measured simultaneously in all wells of the microplate every 2 seconds (first 2 minutes) and after that every 6 seconds (additional 2 minutes). The average Ca intake measured in each series of 4 identical wells (one test compound) was calculated using the FLIPR program.

The compounds of the present invention were tested for the inhibition of SDF-1α-induced uptake of Ca into SUP-T1 cells using the method described above. Illustrated compounds showed inhibition. The following compounds inhibited SDF-1α-induced Ca intake by more than 20% at 20 μg / ml:

Example numbers: 2, 4, 11, 17, 45, 48.

EXAMPLE 56

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

A study of the inhibition of HIV-1 NL4.3 (or III _B , use of CXCR4) replication was performed as previously described (Bridger et al. J. Med. Chem. 1999, 42, 3971-3981; De Clercq et al. Proc. Natl. Acad. Sci, 1992, 89, 5286-5290; De Clercq et al. Antimicrob. Agents Chemother. 1994, 38, 668-674; Bridger et al, J. Med. Chem. 1995, 38, 366-378; Schols et al, J. Exp. Med., 1997, 186, 1383-1388). At the same time, anti-HIV activity and cytotoxicity were measured. They were based on the survival rate of MT-4 cells that were infected with HIV in the presence of various concentrations of test compounds. After MT-4 cells proliferated for 5 days, a number of viable cells were quantified using the tetrazolium-based colorimetric method using 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) in 96 well plates. In all experiments, the introduction of the virus (multiplicity of virus infection, MOI) was 0.01, or 100 times higher than the infectious dose of 50% cell culture (CCID ₅₀ ). An EC ₅₀ value was defined as the concentration required to protect 50% of virus-infected cells against viral cytopathology.

When the compounds of the present invention were tested for inhibition of HIV-1 NL4.3 or III _B replication in MT-4 cells, all compounds showed inhibitory activity. The following compounds showed EC ₅₀ values of less than 20 μg / ml:

Example numbers: 2, 4, 11, 17, 45, 48, 53.

EXAMPLE 57

A study of the inhibition of HIV-1 (BaL) replication in PBMC ^′

When the compounds of the present invention were tested for inhibition of HIV-1 Bal (using CCR5) replication in RNA-stimulated PBMCs (mononuclear peripheral blood cells) using the expression of viral p24 antigen (De Clercq et al. Antimicrob. Agents Chemother., 1994, 38 , 668-674; Schols et al. J. Exp. Med., 1997, 186, 1383-1388), all showed inhibitory activity. The following compounds showed EC ₅₀ values of less than 20 μg / ml:

Example numbers: 2, 4, 11, 16, 17, 48, 53.

The following compounds were also prepared by the above procedures:

one.

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

2.

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

3.

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

four.

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

5.

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

6.

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

7.

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

8.

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

9.

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

10.

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

eleven.

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

12.

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

13.

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

fourteen.

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

fifteen.

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

16.

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

17.

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

eighteen.

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

19.

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

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

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

twenty.

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

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

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

21.

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

22.

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

23.

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

24.

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

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

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

25.

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

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

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

26.

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

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

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

27.

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

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

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

28.

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

29.

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

thirty.

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

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

31.

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

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

32.

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

33.

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

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

34.

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

35.

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

36.

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

37.

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

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

38.

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

39.

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

40.

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

41.

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

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

42.

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

43.

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

44.

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

45.

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

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

46.

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

47.

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

48.

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

49.

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

fifty.

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

51.

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

52.

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

53.

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

54.

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

55.

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

56.

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

57.

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

58.

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

59.

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

60.

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

61.

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

62.

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

63.

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

64.

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

65.

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

66.

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

67.

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

68.

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

69.

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

70.

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

71.

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

72.

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

73.

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

74.

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

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

75.

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

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

76.

N- (4 - {[{2 - [(1H-benzimidazol-2-ylmethyl) amino] ethyl} - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) -3.5 dichloroisonicotinamide

77.

N- (3 - {[{2 - [(1H-benzimidazol-2-ylmethyl) amino] ethyl} - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzyl) -3.5 dichloroisonicotinamide

78.

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

79.

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

80.

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

81.

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

82.

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

83.

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

84.

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

85.

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

86.

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

87.

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

88.

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

89.

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

90.

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

91.

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

92.

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

93.

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

94.

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

95.

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

96.

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

97.

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

98.

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

99.

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

one hundred.

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

101.

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

102.

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

103.

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

104.

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

105.

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

106.

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

107.

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

108.

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

109.

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

110.

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

111.

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

112.

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

113.

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

114.

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

115.

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

116.

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

117

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

118.

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

119.

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

120.

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

121.

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

122.

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

123.

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

124.

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

125.

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

126.

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

127.

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

128.

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

129.

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

130.

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

131.

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

132.

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

133.

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

134.

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

135.

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

136.

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

137.

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

138.

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

139.

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

140.

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

141.

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

142.

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

143.

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

144.

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

145.

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

146.

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

147.

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

148.

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

149.

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

150.

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

151.

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

152.

4 - {[piperidin-4-yl- (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzylamide 4,6-dimethylpyrimidine-5-carboxylic acid

153.

3 - {[piperidin-4-yl- (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzylamide 4,6-dimethylpyrimidine-5-carboxylic acid

154.

4 - {[piperidin-3-yl- (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzylamide 4,6-dimethylpyrimidine-5-carboxylic acid

155.

3 - {[piperidin-3-yl- (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzylamide 4,6-dimethylpyrimidine-5-carboxylic acid

156.

4 - {[[2- (1H-benzimidazol-2-yl) ethyl] - (5,6,7,8-tetrahydroquinolin-8-yl) amino] methyl} benzylamide 4,6-dimethylpyrimidine-5-carboxylic acid

157.

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

158.

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

159.

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

160.

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

161.

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

162.

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

163.

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

164.

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

165.

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

166.

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

167.

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

168.

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

169.

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

170.

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

171.

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

172.

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

173.

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

174.

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

175.

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

176.

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

177.

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

178.

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

179.

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

180.

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

181.

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

182.

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

183.

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

184.

N- (4 - {[(1H-benzimidazol-2-ylmethyl) - (3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-yl) amino] methyl} benzyl) -3.5 dichloroisonicotinamide

185.

N- (3 - {[(1H-benzimidazol-2-ylmethyl) - (3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-yl) amino] methyl} benzyl) -3.5 dichloroisonicotinamide

186.

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

187.

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

188.

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

189.

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

190.

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

191.

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

192.

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

193.

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

194.

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

195.

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

196.

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

197.

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

198.

N- (4 - {[[2- (1H-benzimidazol-2-yl) ethyl] - (3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-yl) amino] methyl} benzyl ) -3,5-dichloroisonicotinamide

199.

N- (3 - {[[2- (1H-benzimidazol-2-yl) ethyl] - (3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-yl) amino] methyl} benzyl ) -3,5-dichloroisonicotinamide

200.

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

201.

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

202.

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

203.

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

204.

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

205.

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

206.

N- (4 - {[{2 - [(1H-benzimidazol-2-ylmethyl) amino] ethyl} - (3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-yl) amino] methyl} benzyl) -3,5-dichloroisonicotinamide

207.

N- (3 - {[{2 - [(1H-benzimidazol-2-ylmethyl) amino] ethyl} - (3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-yl) amino] methyl} benzyl) -3,5-dichloroisonicotinamide

208.

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

209.

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

Claims (17)

1. The compound of formula (1)

and its salts, where X is an unsubstituted monocyclic (5-6 membered) ring system containing N; or X is a fused bicyclic (9-12 membered) ring system containing N, which may be substituted with the substituent —SO ₂ phenyl; Z represents H or means a fused bicyclic (9-12 membered) unsubstituted or substituted ring system containing at least one heteroatom, N; Ar represents an unsubstituted phenyl ring; each of L ¹ , L ² and L ³ independently represents a bond, CO, SO ₂ or CH ₂ , where at least one of L ² and L ³ must include CO or SO ₂ ; L ² and L ^{3 may} also independently represent CONH or CONHCH ₂ ; n is 0, 1 or 2; each R ¹ and R ² independently represents an H atom or a straight chain of (1-6C) alkyl; and Y includes at least one substituted or unsubstituted phenyl ring or a 5-6 membered heteroaromatic ring containing at least one N heteroatom; where optional substituents selected from the group consisting of halogen, alkyl, —COOH, —OH and —NH ₂ ; or Y represents 6,7-dihydro-pyrrolo [3,4-b] pyridin-5-one; where the nitrogen in the ring, optionally, can be oxidized; provided that excluded N- (2-pyridylmethyl) -4- (2-aminophenyl) aminocarbonylbenzylamine and N- (3-pyridylmethyl) -4- (2-aminophenyl) aminocarbonylbenzylamine. 2. The compound according to claim 1, where Z is tetrahydroquinoline. 3. The compound according to claim 1, where L ¹ means alkylene, as defined in claim 1, CO or SO ₂ and X means benzimidazole or an unsubstituted monocyclic (5-6 membered) ring system containing at least one heteroatom selected from N. 4. The compound according to claim 3, where X is an optionally substituted imidazole. 5. The compound according to claim 1, where Z is hydrogen. 6. The compound according to claim 1, where Y is an optionally substituted imidazole, pyridine, pyrimidine or phenyl, where the nitrogen in the ring, optionally, can be oxidized. 7. The compound according to claim 1, having the formula

or formula

where l is 0-3 and R 'is OH, F, Cl, Br, NH ₂ or Me; each of Z ¹ , Z ² and Z ³ independently means CH, CR 'or N, where only two of these Z ¹ , Z ² and Z ³ can mean N; and L ² and L ³ are as defined in claim 1. 8. The compound according to claim 7, where all of Z ¹ , Z ² and Z ³ represent CH or CR '. 9. The compound according to claim 7, where Z ³ means N and L ³ means WITH. 10. The compound of claim 8 or 9, where one of L ² and L ³ means SO ₂ and the other represents a bond or CH ₂ . 11. The compound of claim 8 or 9, where one of L ² and L ³ means CO and the other represents a bond or CH ₂ . 12. A pharmaceutical composition for treating conditions that are regulated by the chemokine receptor CXCR4 or CCR5, containing an effective amount of at least one compound according to claims 1-11. 13. The use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of conditions that are regulated by the chemokine receptor CXCR4 or CCR5. 14. The use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of HIV or FIV-infected patients. 15. The use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of conditions regulated by a chemokine receptor in a mammalian subject. Priority posting: 09/15/2000 according to claim 1, by all indications, except X, means a fused bicyclic (9-12 membered) ring system containing N, which may be substituted with the substituent -SO ₂ -phenyl; L ² and L ³ independently represent CONH or CONHCH ₂ ; Y represents 6,7-dihydro-pyrrolo [3,4-b] pyridin-5-one; Claim 6 in all respects except Y means pyrimidine; Claim 7 in all respects except Z ¹ , Z ² and Z ³ each independently means CH or CR '; two of Z ¹ , Z ² and Z ³ may mean N; paragraphs 2, 3, 5, 12-15 in all respects; 09/17/2001 according to claim 1, when X is a fused bicyclic (9-12 membered) ring system containing N, which may be substituted with the substituent -SO ₂ -phenyl; L ² and L ³ independently represent CONH or CONHCH ₂ ; Y represents 6,7-dihydro-pyrrolo [3,4-b] pyridin-5-one; claim 6, when Y is pyrimidine; claim 7, when Z ¹ , Z ² and Z ³ each independently means CH or CR '; two of Z ¹ , Z ² and Z ³ may mean N; pp. 4, 8-11 by all indications.