WO2008070758A1

WO2008070758A1 - Chemokine receptor binding compounds

Info

Publication number: WO2008070758A1
Application number: PCT/US2007/086588
Authority: WO
Inventors: Elyse Bourque; Markus Metz; Ian R. Baird; Wen Yang; Gary Bridger; Renato T. Skerlj
Original assignee: Genzyme Corporation
Priority date: 2006-12-06
Filing date: 2007-12-06
Publication date: 2008-06-12
Also published as: EP2088860A4; JP2010512340A; AR064181A1; EP2088860A1

Abstract

Compounds that modulate the activity of chemokine receptors, in particular CCR5, are disclosed.

Description

CHEMOKINE RECEPTOR BINDING COMPOUNDS

Cross-Reference to Related Application

This application claims benefit of U.S. provisional application Serial Number 60/873,121 filed 6 December 2005 which is incorporated herein by reference in its entirety.

Technical Field

This invention generally relates to novel compounds, pharmaceutical compositions and their use. More specifically, these novel compounds are modulators of chemokine receptor activity, in particular modulators of chemokine receptor CCR5, further demonstrate protective effects against infection in target cells by a human immunodeficiency virus (HIV). In another aspect, the compounds in the present invention are useful in the treatment and prevention of various inflammatory and autoimmune diseases.

Background of the Invention Approximately 40 human chemokines have been described that function at least in part, by modulating a complex and overlapping set of biological activities important for the movement of lymphoid cells and extravasation and tissue infiltration of leukocytes in response to inciting agents (See, for example: Ponath, P., Exp. Opin. Invest. Drugs (1998) 7:1-18). These chemotacύc cytokines, or chemokines, constitute a family of proteins, approximately 8-10 kDa in size, that are released by a wide variety of cells, to attract macrophages, T cells, eosinophils, basophils, and neutrophils to sites of inflammation and also play a role in the maturation of cells of the immune system. Chemokines appear to share a common structural motif that consists of 4 conserved cysteines involved in maintaining tertiary structure. There are two major subfamilies of chemokines: the "CC" or β-chemokines and the "CXC" or α-chemokines, depending on whether the first two cysteines are separated by a single amino acid, i.e., CXC or are adjacent, i.e., CC.

These chemokines bind specifically to cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane proteins which are referred to as "chemokine receptors", and mediate biological activity through these receptors. The chemokine receptor is classified based upon the chemokine that constitutes the receptor's natural ligand. Chemokine receptors of the β-chemokines are designated "CCR"; while those of the α-chemokines are designated "CXCR." These chemokine receptors include but are not limited to CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CXCR3 and CXCR4 (see for a complete review, Murphy, et al. Pharmacol. Rev. (2000) 52:145-176).

Chemokines are considered to be principal mediators in the initiation and maintenance of inflammation (see Chemokines in Disease published by Humana Press (1999), Edited by C. Herbert; Murdoch, et al, Blood (2000) 95:3032-3043). 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 re-endothelialization after injury (Gupta, et al. , /. Biolog. Chem. (1998) 7:4282-4287). Both chemokine receptors CXCR4 and CCR5 have been implicated in the etiology of infection by human immunodeficiency virus (HIV).

In most instances, HIV initially binds via its gpl20 envelope protein to the CD4 receptor of the target cell. A conformational change appears to take place in the gpl20 which results in its subsequent binding to a chemokine receptor, such as CCR5 (Wyatt, et al., Science (1998) 280:1884-1888). HIV-I isolates arising subsequently in the infection bind to the CXCR4 chemokine receptor. The observed binding of another related retrovirus, feline immunodeficiency virus, to a chemokine receptor without needing to bind first to the CD4 receptor, suggests that chemokine receptors may be the primordial obligate receptors for immunodeficiency retroviruses.

Following the initial binding by HIV to CD4, virus -cell fusion results, which is mediated by members of the chemokine receptor family, with different members serving as fusion cofactors for macrophage-tropic (M-tropic) and T cell line-tropic (T-tropic) isolates of HIV-I (Carroll, et al, Science (1997) 276:273-276; Feng, et al, Science (1996) 272:872-877; Bleul, et al, Nature (1996) 382:829-833; Oberlin, et al, Nature (1996) 382:833-835; Cocchi, et al, Science (1995) 270:1811-1815; Dragic, et al, Nature (1996) 381:667-673; Deng, et al, Nature (1996) 381:661-666; Alkhatib, et al, Science (1996) 272: 1955-1958). During the course of infection within a patient, it appears that a majority of HIV particles shift from the M-tropic to the more aggressive pathogenic T-tropic viral phenotype (Miedema, et al, Immune. Rev. (1994) 140:35; Blaak, et al, Proc. Natl. Acad. ScL (2000) 97:1269-1274; Simmonds, et al, J. Virol. (1996) 70:8355-8360; Tersmette, et al, J. Virol. (1988) 62:2026-2032; Connor, R. I., et al, J. Virol. (1994) 68:4400-4408; Schuitemaker, et al, J. Virol. (1992) 66:1354-1360). The M-tropic viral phenotype correlates with the virus' ability to enter the cell following binding of the CCR5 receptor, while the T-tropic viral phenotype correlates with viral entry into the cell following binding and membrane fusion with the CXCR4 receptor. Clinically, observations suggest that patients who possess genetic mutations in the CCR5 or CXCR4 appear resistant or less susceptible to HIV infection (Liu, et al, Cell (1996) 86:367-377; Samson, et al, Nature (1996) 382:722-725; Michael, et al, Nature Med. (1997) 3:338-340; Michael, et al, J. Virol. (1998)72:6040- 6047; Obrien, et al, Lancet (1997) 349:1219; Zhang, et al, AIDS Res. Hum. Retroviruses (1997) 13:1357-1366; Rana, et al, J. Virol. (1997) 71:3219-3227; Theodorou, et al, Lancet (1997) 349: 1219-1220).

Despite the number of chemokine receptors which have been reported to mediate HIV entry into cells, CCR5 and CXCR4 appear to be the only physiologically relevant coreceptors used by a wide variety of primary clinical HIV-I strains (Zhang, et al, J. Virol. (1998) 72:9307-9312; Zhang, et al, J. Virol. (1999) 73:3443-3448; Simmonds, et al, J. Virol. (1988) 72:8453-8457). Fusion and entry of T-tropic viruses that use CXCR4 are inhibited by the natural CXC-chemokine stromal cell-derived factor- 1 (SDF-I). On the other hand, fusion and entry of M-tropic viruses that use CCR5 are inhibited by the natural CC-chemokines namely, Regulated on Activation Normal T-cell Expressed and Secreted (RANTES or CCL5) and Macrophage Inflammatory proteins (MIP-I alpha and MIP-I beta or CCL3 and CCL4, respectively). SDF-I is known as CXCL12 or Pre B-cell stimulating factor (PBSF).

However, the binding of chemokine receptors to their natural ligands appears to serve a more evolutionary and central role than only as mediators of HIV infection. The binding of the natural ligand, PBSF/SDF-1 to the CXCR4 chemokine receptor provides an important signaling mechanism. CXCR4 or SDF-I knock-out mice exhibit cerebellar, cardiac and gastrointestinal tract abnormalities and die in utero (Zou, et al, Nature (1998) 393:591-594; Tachibana, et al, Nature (1998) 393:591-594; Nagasawa, et al, Nature (1996) 382:635-638). CXCR4-deficient mice also display hematopoietic defects (Nagasawa, et al, Nature (1996) 382:635-638). Furthermore, the migration of CXCR4 expressing leukocytes and hematopoietic progenitors to SDF-I appears to be important for maintaining B-cell lineage and localization of CD34⁺ progenitor cells in bone marrow (Bleul, et al, J. Exp. Med. (1998) 187:753-762; Viardot, et al, Ann. Hematol. (1998) 77:195-197; Auiti, et al, J. Exp. Med. (1997) 185:111-120; Peled, et al, Science (1999) 283:845-848; Qing, et al, Immunity (1999) 10:463-471; Lataillade, et al, Blood (1999) 95:756-768; Ishii, et al, J. Immunol. (1999) 163:3612-3620; Maekawa, et al., Internal Medicine (2000) 39:90-100; Fedyk, et al, J. Leukocyte Biol.

(1999) 66:667-673; Peled, et al, Blood (2000) 95:3289-3296).

The signal provided by SDF- 1 on binding to CXCR4 may also play an important role in tumor cell proliferation and regulation of angiogenesis associated with tumor growth (See Chemokines and Cancer, published by Humana Press (1999); Edited by B. J. Rollins; Arenburg, et al, J. Leukocyte Biol. (1997) 62:554-562; Moore, et al, J. Invest. Med. (1998) 46:113-120; Moore, et al, Trends cardiovasc. Med. (1998) 8:51-58; Seghal, et al, J. Surg. Oncol. (1998) 69:99-104). Known angiogenic growth factors VEG-F and bFGF, up-regulated levels of CXCR4 in endothelial cells, and SDF-I can induce neovascularization in vivo (Salcedo, et al, Am. J. Pathol. (1999) 154:1125- 1135). Furthermore, leukemia cells that express CXCR4 migrate and adhere to lymph nodes and bone marrow stromal cells that express SDF-I (Burger, et al, Blood (1999) 94:3658-3667; Arai, et al, Eur. J. Haematol. (2000) 64:323-332; Bradstock, et al, Leukemia (2000) 14:882-888).

The binding of SDF- 1 to CXCR4 has also been implicated in the pathogenesis of atherosclerosis (Abi-Younes, et al, Circ. Res. (2000) 86:131-138), renal allograft rejection (Eitner, et al, Transplantation (1998) 66:1551-1557), asthma and allergic airway inflammation (Yssel, et al, Clinical and Experimental Allergy (1998) 28: 104- 109; Nagase, H, et al, J. Immunol. (2000) 164:5935-5943; Gonzalo, et al, J. Immunol.

(2000) 165:499-508), Alzheimer's disease (Xia, et al, J. Neurovirology (1999) 5:32-41) and arthritis (Nanki, et al, J. Immunol. (2000) 164:5010-5014).

Platelets have also been shown to secrete the chemokine RANTES upon activation, and that the presence of RANTES on the endothelium promotes the arrest of monocytes on the inflamed endothelium, an important step in atherogenesis as the conversion of macrophages into foam cells in the subendothelium is a central process in atheroma formation (Tan, et al, Expert Opin. Investig. Drugs (2003) 12:1765-1776). Hence, the inhibition or prevention of the binding of RANTES, directly or indirectly, to the CCR5 receptor could potentially attenuate the development of atherosclerosis. For example, Met- RANTES has also been shown to inhibit the binding of monocytes to the activated endothelium (Tan, et al, supra).

In attempting to better understand the relationship between chemokines and their receptors, recent experiments to block the fusion, entry and replication of HIV via the CXCR4 chemokine receptor were carried out through the use of monoclonal antibodies or small molecules that appear to suggest a useful therapeutic strategy (Schols, et al, J. Exp. Med. (1997) 186:1383-1388; Schols, et al., Antiviral Research (1997) 35:147-156; Bridger, et al., J. Med. Chem. (1999) 42:3971-3981; and Bridger, et al, "Bicyclam Derivatives as HIV Inhibitors" in Advances in Antiviral Drug Design, Volume 3, p. 161- 229, Published by JAI press (1999), Edited by E. De Clercq). Small molecules, such as bicyclams, appear to specifically bind to CXCR4 and not CCR5 (Donzella, et al, Nature Medicine (1998) 4:72-77). These experiments demonstrated interference with HIV entry and membrane fusion into the target cell in vitro.

Bicyclams were also shown to inhibit fusion and replication of feline immunodeficiency virus (FIV) that uses CXCR4 for entry (Egberink, et al, J. Virol. (1999) 73:6346-6352). CCR5 blocking agents include monoclonal antibodies, some which selectively block HIV coreceptor activity but not chemokine binding, and chemokine derivatives, such as truncated versions of RANTES, Met-RANTES, and AOP-RANTES and the viral chemokine KSHV vMIP-II, all which block both chemokine and HIV interaction with CCR5 but are not selective (reviewed by Murphy, et al, Pharmacol. Rev. (2000) 52:145-176).

Additional experiments have shown that the bicyclam dose-dependently inhibits binding of 1251-labeled SDF-I to CXCR4 and the signal transduction (indicated by an increase in intracellular calcium) in response to SDF-I. Thus, the bicyclam also functioned as an antagonist to the signal transduction resulting from the binding of stromal derived factor or SDF- lα, the natural chemokine to CXCR4. Bicyclams also inhibited HIV gpl20 (envelope) -induced apoptosis in non-HIV infected cells (Blanco, et al, Antimicrobial Agents and Chemother. (2000) 44:51-56).

Passive immunization with anti-MIP-1 alpha has been shown to delay the onset and reduce the severity of collagen-induced-arthritis (CIA) in mice, where the CIA model is an established murine model representing human rheumatoid arthritis (Szekanecz, Z., et al, AP, Seminars in Immunology, 15(2003), p.15-21). Other studies have also shown that agents that block the CCR5 receptor may provide a rational approach to the treatment of multiple sclerosis. Administration of anti-MIP-1 alpha antiserum has been shown to prevent CNS infiltration by PBMC in mice with experimental allergic encephalomyelitis, a rodent model of multiple sclerosis (Balashov, K.E., et al, Proc. Natl. Acad. Sci. USA (1999) 96:6873-6878).

Other studies involving chronic rejection of transplanted hearts or cardiac allograft vasculopathy (CAV) and acute renal allograft rejection have shown that blocking chemokine receptors such as CCR5 may provide unique therapeutic approaches in the treatment or prevention of such diseases (Yun, J. J., et al, Circulation (2004) 109:932-937, Panzer, U., et al, Transplantation (2004) 78:1341-1350). For example, antagonism of the chemokine receptors CCRl and CCR5 with Met-RANTES attenuated CAV development by reducing mononuclear cell recruitment to the transplanted heart. Met-CCL5, an antagonist of CCRl and CCR5, had been tested and shown to inhibit the growth of breast tumors (Robinson, S. C, et al, Cancer Res. (2003) 63:8360-8365).

Chemokines, as indicated above, play an important role and are implicated in a wide variety of human disease such as in autoimmune disease, allograft rejection, infection, allergies, neoplasia, and vascular abnormalities. In addition to its contributory role in HIV infection, the chemokine receptor CCR5 has been associated with diseases such as the inflammatory demyelinating diseases of the central nervous system, including multiple sclerosis and experimental autoimmune encephalomyelitis, rheumatoid arthritis, intestinal inflammation, allograft rejection, asthma, and cardiovascular disease (reviewed in Gerard, et al., Natl. Immunol. (2001) 2:108-115, and Luster, A., N. Eng. J. Med. (1998) 338:436-445). The CCR5 receptor is expressed on T- lymphocytes, and macrophages and reports of CCR5 on neurons, astrocytes, capillary endothelial cells, epithelium, vascular smooth muscle, and fibroblast have been published. The natural ligands that bind to the CCR5 receptor, in addition to RAΝTES and MIP-I alpha/beta, are monocyte chemoattractant protein 2 (MCP-2 or CCL8).

U.S. Pat. Νos. 5,583,131; 5,698,546; 5,817,807; 5,021,409; and 6,001,826 which are incorporated herein in their entirety by reference, disclose cyclic compounds that are active against HIV-I and HIV-2 in in vitro tests. It was subsequently discovered and further disclosed in PCT WO 02/34745 that these compounds exhibit anti-HIV activity by binding to the chemokine receptor CXCR4 and/or CCR5 expressed on the surface of certain cells of the immune system. This competitive binding thereby protects these target cells from infection by HIV which utilize the CXCR4 receptor for entry. In addition, these compounds antagonize the binding, signaling and chemotactic effects of the natural ligand for CXCR4, the chemokine stromal cell-derived factor lα (SDF-I). Furthermore, these compounds demonstrate protective effects against HIV infection of target cells by binding in vitro to the CCR5 receptor.

Additionally, U.S. Pat. No. 6,365,583 discloses that these cyclic polyamine antiviral agents described in the above-mentioned patents/patent applications have the effect of enhancing production of white blood cells as well as exhibiting antiviral properties. Thus, these agents are useful for controlling the side-effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, as well as combating bacterial infections in leukemia. PCT WO 00/56729, PCT WO 02/22600, PCT WO 02/22599, and PCT

WO 02/34745 describe a series of heterocyclic compounds 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. This competitive binding thereby protects these target cells from infection by HIV which utilize the CXCR4 or CCR5 receptors for entry. In addition, these compounds antagonize the binding, signaling and chemotactic effects of the natural ligand for CXCR4, the chemokine stromal cell-derived factor lα (SDF-I) and/or the natural ligand for CCR5, the chemokine RANTES.

The chemokine receptor, CXCR4 has been found to be associated with the vascularization of the gastrointestinal tract (Tachibana, et ah, Nature (1998) 393:591- 594) as well as in hematopoiesis and cerebellar development (Zou, et al, Nature (1998) 393:591-594). Interference with any of these important functions served by the binding of pre-B-cell growth- stimulating factor/stromal derived factor (PBSF/SDF-1) to the CXCR4 chemokine receptor results in lethal deficiencies in vascular development, hematopoiesis and cardiogenesis. Similarly, fetal cerebellar development appears to rely upon the effective functioning of CXCR4 in neuronal cell migration and patterning in the central nervous system. This G-protein-coupled chemokine receptor appears to play an important role in ensuring the necessary patterns of migration of granule cells in the cerebellar anlage.

Herein, we disclose compounds that have unique chemical attributes and that exhibit protective effects against HIV infection of target cells by binding to chemokine receptor CCR5. In addition, these compounds antagonize the binding, signaling and chemotactic effects of the natural ligand for CCR5, the chemokine RANTES.

Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this application are hereby incorporated in their entirety by reference herein. Disclosure of the Invention

The present invention provides novel compounds that modulate chemokine receptors, in particular CCR5 receptors, and interfere with the binding of the natural ligand thereto. The compounds of the present invention are useful as agents demonstrating protective effects on target cells from HIV infection. The compounds of the present invention are useful for the treatment and prevention of inflammatory and autoimmune diseases. The invention compounds act as antagonists or agonists of chemokine receptors and are useful as agents capable of reconstituting the immune system by increasing the level of CD4⁺ cells; as antagonists to apoptosis in immune cells, such as CD8⁺ cells, and neuronal cells; and as antagonists to migration of human bone marrow B lineage cells to stromal-derived factor 1.

In one aspect, the invention provides a compound of formula (1)

/ Ar¹

wherein each Ar¹ and Ar² is independently an optionally substituted carbocyclic or heterocyclic aromatic system; each Y is independently O, S or CHCN;

Z = H or alkyl or is CH₂ coupled to X;

X = O and k is 0 or 1 ; or X = N or CH and k is 1-2; if X = O, and Z is CH₂ coupled to X, k = 0; if X = N or CH, and Z is CH₂ coupled to X, k = 1 ;

R¹ is H or a non-interfering substituent, but only one R¹ is a non-interfering substituent other than H or alkyl; R²-R⁴ are non-interfering substituents other than H; each m or 1 is independently an integer of 0-4; j is 0 or 1 ; and each n is independently 1-2; or a pharmaceutically acceptable salt or conjugate thereof.

The optional substituents included in the definitions of R^:-R⁴ may be alkyl, alkenyl or alkynyl, including the straight chain, branched chain or cyclic forms thereof, or may be aromatic systems, each optionally containing one or more heteroatoms selected from O, N and S and optionally substituted by halo and/or other inorganic substituents and/or comprising organic functional groups, such as carboxylic acids, carboxylic esters, carboxylic amides, substituted amino groups, and the like. Inorganic substituents include =0, =N0H, NH₂ and oxidized forms thereof, SH and oxidized forms thereof, and like. As noted, R¹ may also be H.

Ar¹ and Ar² are aromatic systems of 5-12 ring members including heterocyclic ring members. Ar¹ and Ar² may also be substituted by the non-interfering substituents as defined above but cannot include more than one additional aromatic system. The non-interfering substituent itself may be an inorganic moiety such as OH, NH₂ and/or an oxidized form thereof, SH and/or an oxidized form thereof, or oxidized forms of phosphorus.

The non- interfering substituents included in R¹ -R⁴ may also themselves include aryl or heteroaryl systems as defined above. The systems included may themselves bear substituents as outlined above, other than including additional aromatic systems.

By "non-interfering substituent" is meant a substituent that does not destroy the ability of the compound to modulate at least the CCR5 chemokine receptor. Assay methods for modulating the CCR5 receptor are well known in the art, and the compounds containing any particular set of non-interfering substituents may readily be tested.

The present invention also provides pharmaceutical compositions comprising one or more compounds having formula (1), and a pharmaceutically acceptable carrier. The present invention also provides methods for treating a CCR5 mediated disease in a cell, tissue or organ, comprising contacting one or more compounds having formula (1) with the system, thereby treating a CCR5-mediated disease. The present invention also provides methods for treating a CCR5 mediated disease in a human or animal subject, comprising administering one or more compounds having formula (1) with the subject, thereby treating a CCR5 -mediated disease. Examples of CCR5 -mediated diseases that may be treated using the compounds of the present invention include but are not limited to HIV, an inflammatory demyelinating disease of the central nervous system, an autoimmune disease, multiple sclerosis, experimental autoimmune encephalomyelitis, psoriatic or rheumatoid arthritis, intestinal inflammation, allograft rejection, asthma, cardiovascular disease, atherosclerosis, allergic disease, allergic rhinitis, dermatitis, conjunctivitis, hypersensitivity lung disease, hypersensitivity pneumonitis, eosinophilic pneumonia, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis, dermatomyositis, systemic anaphylaxis, myastenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune thyroiditis, graft rejection, allograft rejection, graft- versus-host disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, spondyloarthropathy, scleroderma; psoriasis, inflammatory dermatosis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis, eosinophilic myotis, eosiniphilic fasciitis, tumor or cancer.

The compounds of formula (1) may form hydrates or solvates, and may be in any stereoisomeric forms and mixtures of stereoisomeric forms thereof. Racemate compounds may be separated into individual isomers using known separation and purification methods. Individual optical isomers and a mixture thereof, are included in the scope of the present invention. The compounds of the invention may also be in the form of pharmaceutically acceptable salts or conjugates, such as PEGylated forms, or can be provided in a form coupled to targeting agents or additional desired moieties.

Modes of Carrying Out the Invention In one aspect, the invention provides compounds having formula (1) described above, which are modulators of chemokine receptors.

In more detail, the compounds may bind chemokine receptors and interfere with the binding of the natural ligand thereto, and demonstrate protective effects on target cells from HIV infection. The compounds are useful as antagonists or agonists of chemokine receptors, and are thus capable of reconstituting the immune system by increasing the level of CD4⁺ cells; as antagonist agents of apoptosis in immune cells, such as CD8⁺ cells and neuronal cells; as antagonist agents of migration of human bone marrow B lineage cells to stromal-derived factor 1. Chemokine antagonists that interfere in the binding of a chemokine to its receptor are useful to reconstitute the immune system by increasing the level of CD4⁺ cells (Biard-Piechaczyk, et al, Immunol. Lett. (1999) 70:1-3); as antagonist agents of apoptosis in immune cells, such as CD8⁺ cells (Herbin, et al, Nature (1998) 395:189- 193), and as antagonist agents of apoptosis in neuronal cells (Ohagen, et al, J. of Virol. (1999) 73:897-906; and Hesselgesser, et al, Curr. Biol. (1998) 8:595-598). Chemokine receptor antagonist agents also inhibit the migration of human bone marrow B lineage cells to stromal-derived factor 1 (See, e.g., Fedyk, E., et al, J of Leukocyte Biol. (1999) 66:667-783). The invention includes pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of formula (1) along with at least one excipient, and methods of treating diseases of the human body or the bodies of other mammals with such compositions. As used herein, the term "therapeutically effective amount" refers to the amount of one or more compounds of formula (1) that will elicit a desired response of a cell, tissue, organ, system, animal or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician.

The invention provides a method for blocking or interfering with the binding by a chemokine receptor with its natural ligand, comprising contacting of the chemokine receptor with an effective amount of the one or more compounds of formula (1). The present invention also provides methods of protecting target cells possessing chemokine receptors, which binding to a pathogenic agent results in disease or pathology, comprising administering to a mammalian subject a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds of formula (1). The invention provides the use of a compound of formula (1) in the manufacture of a medicament for the treatment of a disease in which blocking or interfering with binding of a chemokine receptor with its natural ligand is advantageous. The compound is formulated into a composition in an amount corresponding to a therapeutically effective amount of a compound of formula (1).

The Invention Compounds

The invention compounds are described by formula (1). Formulas (2)-(5) represent specific embodiments of formula (1). As noted above, compounds of formula (1) have the structure:

Z = H or alkyl or is CH₂ coupled to X;

X = O and k is 0 or 1 ; or

X = N or CH and k is 1-2; if X = O, and Z is CH₂ coupled to X, k = 0; if X = N or CH, and Z is CH₂ coupled to X, k = 1 ;

R¹ is H or a non-interfering substituent, but only one R¹ is a non-interfering substituent other than H or alkyl;

R²-R⁴ are non-interfering substituents other than H; each m or 1 is independently an integer of 0-4; j is 0 or 1; and each n is independently 1-2; or a pharmaceutically acceptable salt or conjugate thereof.

As used herein, the terms alkyl, alkenyl and alkynyl include straight-chain, branched-chain and cyclic monovalent hydrocarbyl radicals, and combinations of these, which contain only C and H when they are unsubstituted. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl, and the like. Typically, these substituents include up to 10 carbon atoms, or up to 8 carbon atoms or up to 6 carbon atoms or up to 4 carbon atoms.

Where an alkyl, alkenyl or alkynyl group is described as Optionally substituted', it can be unsubstituted or it can be substituted with one or more substituents including but not limited to substituents selected from the group consisting of OR, NR₂, NROR, NRNR₂, SR, SO₂, SOR, SO₂R, SO₂NR₂, NRSO₂, NRCONR₂, NRCOOR, NRCOR, CN, COOR, CONR₂, 0OCR, COR, NO₂, =0 and =N0R, wherein each R is independently H or alkyl (1-8C). Heteroalkyl, heteroalkenyl or heteroalkynyl are defined in a manner similar to alkyl, alkenyl and alkynyl except that they include one or more heteroatoms selected from N, O and S in place of one or more carbon atoms of the alkyl, alkenyl or alkynyl group. No more than two contiguous carbon atoms are replaced by heteroatoms. Where N is present, it is understood that it is trivalent and must be suitably substituted according to commonly understood principles of chemical stability.

Halo refers to any of the halogens, typically including F, Cl, Br and I.

The term aromatic refers either to a polyunsaturated, aromatic hydrocarbon substituent containing at least one aromatic ring that does not have a heteroatom as a ring member, or to a heteroaromatic substituent which is an aromatic group containing at least one heteroatom as a ring member. More than one heteroatom may be present as ring members in a heteroaryl group, provided that not more than two contiguous ring atoms are heteroatoms. The aromatic structures encompass compounds having monocyclic, bicyclic or multiple ring systems, and thus they may include a mixture of aryl and heteroaryl groups. At least one ring system must be aromatic or heteroaromatic. The number of ring members is typically 5-12.

Exemplary non- limiting substituents of aromatic or heteroaromatic systems include cyclic or acyclic alkyl, alkenyl, alkynyl, halogen, CN, CHO, CF₃, OCF₃, NO₂, OH, NHC(0)(Ci_6 acyclic or C₃_₆ cyclic alkyl), NHC(O)CF₃, NHSO₂(Ci_₆ alkyl), NHC(O)NH₂, NHC(0)(Ci_6 alkyl), C(O)NH₂, C(O)NHC₆H₅, C(O)C₆H₄C(O)OH, C(0)N(0Ci_6 alkyl)(Ci_₆ alkyl), C(O)NHCH₂C(O)O(Ci_₆ alkyl), C(O)(C_1-6 alkyl), C(O)O(Ci_6 alkyl), C(O)(non-aromatic heterocyclic ring), OC(O)(Ci_₆ alkyl), O(Ci_6 alkyl), O(Ci_₆ alkyl)O(Ci_₆ alkyl), O(Ci_₆ alkyl)C(O)OH, OC₆H₄C(O)OH, OC₆H₄C(O)NH₂, O(Ci_₆ alkyl)C(O)O(Ci_₆ alkyl), O(Ci_₆ alkyl)C(O)NH₂, O(Ci_₆ alkyl)C(O)NHNH₂, OSO₂(Ci_₆ alkyl), 0C(0)0(Ci_₆ alkyl), 0C(0)N(Ci_₆ alkyl)₂, OC(O)(heteroaryl), COOH, C(0)NH(Ci_₆ alkyl), C(O)N(Ci_₆ alkyl)₂, S(Ci_₆ alkyl), CH=NOH, CH=N0(Ci_₆ alkyl), CH=N(Ci_₆ alkyl), (C_1-6 alkyl)C=NOH, (C_1-6 alkyl)C=NO(Ci_₆ alkyl), (C_1-6 alkyl)C=N(Ci_₆ alkyl), (C_1-6 alkyl)C₆H₄C(O)OH, (C_1-6 alkyl)NHC(O)(Ci_₆ alkyl), CH=CHC(0)0(Ci_₆ alkyl), CH=CHC(O)OH, SO_nR⁶ where n is 1 or 2.

The term "inorganic substituent" refers to substituents that do not contain carbon. Examples of inorganic substituents include but are not limited to nitro, halogen, azido, and groups such as sulfonates, sulfinates, phosphates, and phosphonates, as either their acid forms or as simple C1-C4 esters, e.g., a dimethyl phosphonate. Specific embodiments of formula (1) are represented by formulas (2)-(5):

In formulas (2)-(5), X, Y, Z, Ar¹, Ar², and R¹ -R⁴ are as defined with respect to formula (1), as are j-n. In preferred forms of formula (2) or (3), R¹, when X is N, is H, alkyl or cycloalkyl, optionally substituted by a single substituent; R³ is alkyl, preferably methyl, when j is 1. Particularly preferred are compounds of formula (2) or (3) are those wherein 1 and m are 0 and Ar¹ is unsubstituted phenyl. Preferred forms of formulas (4) and (5) are those wherein R¹ is alkyl, alkoxy, cycloalkyl, alkoxyalkoxy, or an oxidized 5-membered ring. More preferred embodiments of R¹ are methyl, methoxy, 2-oxo-oxazolidine, 2-methoxyethoxy, and cyclopropyl. If R¹ is as described above, the remaining embodiments of R¹ in formula (4) or (5) permitted when X is N or CH are H or alkyl, preferably H. Preferred embodiments of X are N or CH, and of Y are O or CHCN. Preferably R³ is alkyl, preferably methyl, and j is 0 or 1. Ar¹ is preferably monovalent thiophene. In formulas (3) and (4), preferably one n is 1 and the other is 2, but it is emphasized that embodiments wherein both n are 1 are included within the scope of the invention.

Exemplary embodiments of Ar¹ and Ar² include phenyl, pyridinyl, thiazolyl, oxazolyl, pyrimidinyl, indolyl, indolinyl, imidazolyl, benzimidazolyl, theophyl, isoindolinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, benzofuranyl, 2,3-dihydroxybenzofuranyl, phthalanyl, and the like.

Exemplary embodiments of the invention compounds are set forth in Table 1:

Table 1 Example Structure and Name

4-[4-((R)-3-Cyclohexyl-2-oxo-5-phenyl-imidazolidin-l-yl)-[l,4'] bipiperidinyl-l'-carbonyl] -benzoic acid methyl ester Example Structure and Name

4-[4-((R)-3-Cyclohexyl-2-oxo-5-phenyl-imidazolidin-l-yl)- [ 1 ,4']bipiperidinyl- 1 '-carbonyl] -benzoic acid

(R)-l-Cyclohexyl-3-[l'-(4,6-dimethyl-pyrimidine-5-carbonyl)-4'-methyl- [l,4']bipiperidinyl-4-yl]-4-phenyl-imidazolidin-2-one

(R)-3-[l'-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-4'-methyl-

[ 1 ,4']bipiperidinyl-4-yl] - 1 -cyclohexyM-phenyl-imidazolidin^-one

(R)-3-[l'-(4,6-Dimethyl-pyrimidine-5-carbonyl)-4'-methyl- [l,4']bipiperidinyl-4-yl]-4-phenyl-oxazolidin-2-one Example Structure and Name

(R)-3-[r-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-4'-methyl- [ 1 ,4']bipiperidinyl-4-yl] -4-phenyl-oxazolidin-2-one

(R)-l-fer?-Butyl-3-[l'-(4,6-dimethyl-pyrimidine-5-carbonyl)-4'-methyl- [ 1 ,4']bipiperidinyl-4-yl] -4-phenyl-imidazolidin-2-one

(^-l-fert-butyl-S-fl'-Co-chloro^^-dimethyl-pyridine-S-carbonyl)^'- methyl- [ 1 ,4']bipiperidinyl-4-yl] -4-phenyl-imidazolidin-2-one

(R)-l-[l'-(4,6-Dimethyl-pyrimidine-5-carbonyl)-4'-methyl- [ 1 ,4']bipiperidinyl-4-yl] -5 -phenyl-imidazolidin-2-one Example Structure and Name

(RH-[r<6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-4'-metriyl- [l,4']bipiperidinyl-4-yl]-5-phenyl-imidazolidin-2-one

(R)-3-[l'-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-4'-methyl- [ 1 ,4']bipiperidinyl-4-yl] - 1 -methyl-4-phenyl-imidazolidin-2-one

l-fl'-Cό-Chloro^^-dimethyl-pyridine-S-carbony^^'-methyl-

[l,4']bipiperidinyl-4-yl]-3-methoxy-l-thiophen-3-ylmethyl-urea

N-[l'-(6-Cyano-2,4-dimethyl-l-oxy-pyridine-3-carbonyl)-4'-methyl- [l,4']bipiperidinyl-4-yl]-2-(2-oxo-oxazolidin-3-yl)-N-thiophen-3- ylmethyl- acetamide Example Structure and Name

N-[l'-(6-Cyano-2,4-dimethyl-pyridine-3-carbonyl)-4'-methyl-

[l,4']bipiperidmyl-4-yl]-2-(2-oxo-oxazolidm-3-yl)-N-thiophen-3- ylmethyl- acetamide

N-[r-(6-Chloro-2,4-dimethyl-l-oxy-pyridine-3-carbonyl)-4'-methyl- [l,4']bipiperidinyl-4-yl]-2-(2-oxo-oxazolidin-3-yl)-N-thiophen-3- ylmethyl-acetamide

l-[l'-(2,6-Dichloro-4-methyl-l-oxy-pyridine-3-carbonyl)-4'-methyl-

[l,4']bipiperidinyl-4-yl]-3-(2-methoxyethoxy)-l-thiophen-3-ylmethyl- urea

l-[r-(6-Cyano-2,4-dimethyl-l-oxy-pyridine-3-carbonyl)-4'-methyl-

[ 1 ,4']bipiperidinyl-4-yl] -3 -(2-methoxyethoxy)- 1 -thiophen-3 -ylmethyl- urea Example Structure and Name

l-[l'-(2,6-Dichloro-4-methyl-l-oxy-pyridine-3-carbonyl)-4'-methyl- [ 1 ,4']bipiperidinyl-4-yl]-3-methoxy- 1 -thiophen-3-ylmethyl-urea

l-fl'-Co-Cyano^^-dimethyl-pyridine-S-carbony^^'-methyl-

[ 1 ,4']bipiperidinyl-4-yl] -3 -methoxy- 1 -thiophen-3 -ylmethyl-urea

l-[l'-(6-Cyano-2,4-dimethyl-l-oxy-pyridine-3-carbonyl)-4'-methyl- [l,4']bipiperidinyl-4-yl]-3-methoxy-l-thiophen-3-ylmethyl-urea

l-fl'-Cό-Chloro^^-dimethyl-l-oxy-pyridine-S-carbony^^'-methyl- [l,4']bipiperidinyl-4-yl]-3-methoxy-l-thiophen-3-ylmethyl-urea Example Structure and Name

5-[4-(3-Methoxy-l-thiophen-3-ylmethyl-ureido)-4'-methyl-

[l,4']bipiperidinyl-l'-carbonyl]-4,6-dimethyl-pyridine-2-carboxylic acid isopropylamide

S-IS-fl'-Cό-Chloro^^-dimethyl-pyridine-S-carbony^^'-methyl-

[l,4']bipiperidinyl-4-yl]-3-thiophen-3-ylmethyl-ureido}-pentanoic acid methyl ester

5-{3-[l'-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-4'-methyl-

[l,4']bipiperidinyl-4-yl]-3-thiophen-3-ylmethyl-ureido}-pentanoic acid

3-{[l'-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-4'-methyl-

[l,4']bipiperidinyl-4-yl]-thiophen-3-ylmethyl-amino}-3-methylamino- acrylonitrile Example Structure and Name

3-{ [l'-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-4'-methyl- [l,4']bipiperidinyl-4-yl]-thiophen-3-ylmethyl-amino}-3- cyclopropylamino-acrylonitrile

l-{ l-[l-(6-Cyano-2,4-dimethyl-pyridine-3-carbonyl)-azetidin-3-yl]- piperidin-4-yl } -3 -methoxy- 1 -thiophen-3 -ylmethyl-urea

5-{3-[4-(3-Methoxy-l-thiophen-3-ylmethyl-ureido)-piperidin-l-yl]- azetidine-l-carbonyl}-4,6-dimethyl-pyridine-2-carboxylic acid isopropylamide

5- { 3- [4-(3-Methoxy- 1 -thiophen-3-ylmethyl-ureido)-piperidin- 1 -yl]- azetidine-l-carbonyl}-4,6-dimethyl-pyridine-2-carboxylic acid isobutyl- amide

99 Example Structure and Name

5-{3-[4-(3-Methoxy-l-thiophen-3-ylmethyl-ureido)-piperidin-l-yl]- azetidine-l-carbonylj^ό-dimethyl-pyridine^-carboxylic acid (3- methyl-butyl)-amide

N-{ l-[l-(6-Cyano-2,4-dimethyl-pyridine-3-carbonyl)-azetidin-3-yl]- piperidin-4-yl}-2-(2-oxo-oxazolidin-3-yl)-N-thiophen-3-ylmethyl- acetamide

The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts that are non-toxic. The term "pharmaceutically acceptable salt" as used herein means an active ingredient comprising compounds of the invention used in the form of a salt thereof, particularly where the salt form confers on the active ingredient improved pharmacokinetic properties as compared to the free form of the active ingredient or other previously disclosed salt form. The term "pharmaceutically acceptable salt" encompasses all acceptable salts including but not limited to acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartarate, mesylate, borate, methylbromide, bromide, methylnitrite, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, Ν-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutame, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydradamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like.

Pharmaceutically acceptable salts of the compounds of the present invention can be used as a dosage for modifying solubility or hydrolysis characteristics, or can be used in sustained release or pro-drug formulations. Also, pharmaceutically acceptable salts of the compounds of this invention may include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.

All of the compounds of the invention contain at least one chiral center. The invention includes mixtures of stereoisomers, individual stereoisomers, and enantiomeric mixtures, and mixtures of multiple stereoisomers. In short, the compound may be supplied in any desired degree of chiral purity. However, preferred forms of compounds of formulas (2) and (3) are those wherein Ar¹ is substituted at the chiral carbon in the S-configuration.

The compounds may also be supplied coupled to, e.g., PEG, PEO, targeting agents such as antibodies or ligands specific for receptors or other targets.

Utility and Administration

In one aspect, the invention is directed to compounds of formula (1) that modulates chemokine receptor activity. Chemokine receptors include but are not limited to CCRl, CCR2, CCR3, CCR4, CCR5, CXCR3, and CXCR4.

In one embodiment, the invention provides compounds of formula (1) that may demonstrate protective effects on target cells from HIV infection by binding specifically to the chemokine receptor, thus affecting the binding of a natural ligand to the CCR5 and/or CXCR4 of a target cell.

In another embodiment, the compounds of the present invention may be useful as agents which affect chemokine receptors, such as CCRl, CCR2, CCR3, CCR4, CCR5, CXCR3, CXCR4 where such chemokine receptors have been correlated as being important mediators of many inflammatory as well as immunoregulatory diseases.

Other diseases that are also implicated with chemokines as mediators include angiogenesis, and tumorigenesis such as brain, and breast tumors. Thus, a compound that modulates the activity of such chemokine receptors is useful for the treatment or prevention of such diseases.

As used herein, the terms "modulators and/or modulation" encompass antagonist/antagonism, agonist/agonism, partial antagonist/partial antagonism, and or partial agonist/partial agonism, i.e., inhibitors, and activators. The compounds of formula (1) described herein may possess biological activity such that they are able to modulate CCR5 chemokine receptor activity and consequent or associated pathogenic processes subsequently mediated by the CCR5 receptor and its natural ligands.

In one embodiment, compounds of formula (1) demonstrate a protective effect against HIV infection by inhibiting the binding of HIV to a chemokine receptor of a target cell such as CCR5 and/or CXCR4. Such modulation is obtained by a method which comprises contacting a target cell with an effective amount of the compound to inhibit the binding of the virus to the chemokine receptor. As used herein, the terms "modulation and/or modulation" encompass modulating activity in all types and subtypes of CCR5 receptors of a target cell, in any tissues of a particular patient where they are found, and in any cell components comprising those tissues that the target cell may be located.

Compounds that inhibit chemokine receptor activity and function may be used for the treatment of diseases that are associated with inflammation, including but not limited to, inflammatory or allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-type hypersensitivity, atherosclerosis, interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, graft rejection, including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myotis, eosiniphilic fasciitis; and cancers. In addition, compounds that activate or promote chemokine receptor function are used for the treatment of diseases associated with immunosuppression, such as in individuals undergoing chemotherapy, radiation therapy, enhanced wound healing and burn treatment, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy) or combination of conventional drugs used in the treatment of autoimmune diseases and graft/transplantation rejection, which causes immunosuppression; or immunosuppression due to congenital deficiency in receptor function or other causes. Compounds that activate or promote chemokine receptor function are also used for the treatment of infectious diseases, such as parasitic diseases, including but not limited to helminth infections, such as nematodes (round worms); Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis; trematodes; visceral worms, visceral larva migtrans (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larva migrans (Ancylostona braziliense, Ancylostoma caninum); the malaria-causing protozoan Plasmodium vivax, Human cytomegalovirus, Herpesvirus saimiri, and Kaposi's sarcoma herpesvirus, also known as human herpesvirus 8, and poxvirus Moluscum contagiosum.

Compounds of the present invention may be used in combination with any other active agents or pharmaceutical compositions where such combined therapy is useful to modulate chemokine receptor activity and thereby prevent and treat inflammatory and immunoregulatory diseases.

Furthermore, the compounds may be used in combination with one or more agents useful in the prevention or treatment of HIV. Examples of such agents include:

(1) nucleotide reverse transcriptase inhibitor such as tenofovir disoproxil fumarate; lamivudine/zidovudine; abacavir/lamivudine/zidovudine; emtricitabine; amdoxovir; alovudine; DPC-817; SPD-756; SPD-754; GS7340; ACH-126,443 (beta)-L-F d4C; didanosine, zalcitabine, stavudine, adefovir, adefovir dipivoxil, fozivudine todoxil, etc.;

(2) non-nucleotide reverse transcriptase inhibitor (including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, TMC-125; DPC-083; capravarine; calanolide A; SJ-3366 series, etc.; (3) protease inhibitors such as saquinavir, lopinavir/ritonavir, atazanavir, fosamprenavir, tipranavir, TMC- 114, DPC-684, indinavir, nelfinavir, amprenavir, palinavir, lasinavir, etc.;

(4) entry inhibitors such as T-20; T-1249; PRO-542; PRO-MO; TNX-355; BMS-806 series; and 5-Helix;

(5) CCR5-receptor inhibitors such as Sch-C (or SCH351125); Sch-D (or SCH350634); TAK779; UK 427,857 and TAK 449; or CXCR4- receptor inhibitors such as T22, T134, T140, 18 amino acid analogs of polyphemusin II, ALX40-4C, ALK40- 4C, AMD3100 and AMD070; (6) Integrase inhibitors such as L-870,810; GW-810781 (S-1360); and

(7) Budding inhibitors such as PA-344; and PA-457.

Combinations of compounds of the present invention with HIV agents are not limited to the above examples, but include the combination with any agent useful for the treatment of HIV. Combinations the compounds of the invention and other HIV agents may be administered separately or in conjunction. The administration of one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).

The compounds according to the present invention may be administered by oral, intramuscular, intraperitoneal, intravenous, intracisternal injection or infusion, subcutaneous injection, transdermal or transmucosal administration or by implant. They may also be administered by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

The compounds of the invention may be used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats, and monkeys. However, compounds of the invention can also be used in other species, such as avian species (e.g., chickens). The compounds of the invention may also be effective for use in humans. The term "subject" or alternatively referred to herein as "patient" is intended to be referred to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. However, the compounds, methods and pharmaceutical compositions of the present invention may be used in the treatment of animals.

The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of compound of formula (1). The compounds may be administered alone or as a mixture with a pharmaceutically acceptable carrier (e.g., solid formulations such as tablets, capsules, granules, powders, etc.; liquid formulations such as syrups, injections, etc.). The compounds may be administered orally or non-orally. Examples of non-oral formulations include injections, drops, suppositories, pessaryies. In the treatment or prevention of conditions which require chemokine receptor modulation, an appropriate dosage level will generally be about 0.01 to 500 mg per kg subject body weight per day, and can be administered in singe or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day. It will be understood that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound used, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the patient undergoing therapy. In another aspect of the present invention, a compound of formula (1) may be used in screening assays for compounds which modulate the activity of chemokine receptors, preferably CCR5 receptors. The ability of a test compound to inhibit gpl20 and CD4/CCR5 -dependent cell-cell fusion may be measured using a cell fusion assay known in the art. The compounds of formula (1) as disclosed herein may be useful for isolating receptor mutants, which can then be made into screening tools for the discovery of even more potent compounds, following procedures described herein and procedures known in the art. The compounds of formula (1) may also be useful in establishing or characterizing the binding sites of other ligands, including compounds other than those of formula (1) to chemokine receptors, e.g., by competitive inhibition. The compounds of the present invention may also be useful for the evaluation of putative specific modulators of various chemokine receptors. As appreciated in the art, thorough evaluation of specific agonists and antagonists of the above chemokine receptors has been hampered by the lack of availability of non-peptidyl (metabolically resistant) compounds with high binding affinity for these receptors. Thus, the compounds of this invention are commercial products to be sold for these purposes.

The invention is further described by means of examples, but not in any limiting sense. EXPERIMENTAL

The following examples are offered to illustrate but not to limit the invention. Compounds of the invention are often readily prepared by known methods: some methods for making compounds and intermediates of the invention are described in a co-pending application by Bridger, et al., which is U.S. Serial Number 11/505,669, filed 16 August 2006.

General Procedures

General procedure A: Reductive Amination with NaBH(OAc)₃

To a stirred solution of the amine (1 equivalent) in CH₂CI₂ (concentration -0.2 M) at room temperature were added the carbonyl compound (1-2 equivalents), glacial AcOH (0-2 equivalents) and sodium triacetoxyborohydride (NaBH(OAc)₃) (-1.5-3 equivalents) and the resultant solution was stirred at room temperature. In a standard workup, the reaction mixture was poured into either saturated aqueous NaHCO₃ or IN NaOH. The phases were separated and the aqueous extracted with CH₂CI₂. The combined organic extracts were dried (Na₂SO₄ or MgSO₄), filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel or by recrystallization.

General Procedure B: BOC deprotection with TFA The BOC-protected amine was dissolved in CH₂CI₂ (-4 mL/mmol) and trifluoroacetic acid (TFA) (-2 mL/mmol) was added. The mixture was stirred at room temperature for 0.5-5 hours. In a standard work-up, the mixture was neutralized with saturated aqueous NaHCO₃ or IN NaOH and the aqueous extracted with CH₂CI₂. The combined extracts were dried (Na₂SO₄ or MgSO₄), filtered and concentrated under reduced pressure. The crude material was used in the next reaction as is or was purified by flash column chromatography on silica gel.

General Procedure C: EDCI coupling

To a stirred solution of a primary or secondary amine (1 equivalent), a carboxylic acid (1.1-2.0 equivalents), 1-hydroxy-benzotriazole hydrate (HOBT) (1.1-2.0 equivalents) and diisopropylethylamine (DIPEA) or N-methylmorpholine (ΝMM) (1.5-3 equivalents) in CH₂Cl₂ or DMF (concentration -0.05-1.5M) was added l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (1.1-2.0 equivalents). The solution was stirred at room temperature for 1-3 days and concentrated in vacuo. In a standard work-up, the mixture was diluted with CH₂Cl₂ or EtOAc and washed consecutively with saturated aqueous NaHCU₃ and brine. The organic layer was dried (Na₂SO₄ or MgSO₄), filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography or by radial chromatography on silica gel.

Intermediates

(R)-l-Cvclohexyl-4-phenyl-3-piperidin-4-yl-imidazolidin-2-one

(R)-l-fery-Butyl-4-phenyl-3-piperidin-4-yl-imidazolidin-2-one

(R)-2-Amino-2-phenyl-ethanol

2-((R)-2-Amino-2-phenyl-ethyl)-isoindole-l,3-dione

(2-Oxo-oxazolidin-3-yl)-acetic acid

Example 1

COMPOUND 1:

4- F4-((R)-3 -Cyclohexyl^-oxo-S -phenyl-imidazolidin- 1 -yl) - F 1 ,41 bipiperidinyl-l'-carbonyll -benzoic acid methyl ester

A solution of (R)-l-cyclohexyl-4-phenyl-3-piperidin-4-yl-imidazolidin-2-one (172 mg, 0.53 mmol), l-Boc-4-piperidone (210 mg, 1.05 mmol), NaBH₃CN (100 mg, 1.59 mmol) and glacial AcOH (8 drops) in MeOH (2.5 niL) was stirred at 60⁰C for 16 hours. Standard work-up and purification gave

4-((R)-3-cyclohexyl-2-oxo-5-phenyl-imidazolidin-l-yl)-[l,4']bipiperidinyl-l'-carboxylic acid tert-buty\ ester as a mixture with the corresponding 4-piperidinol (285 mg). Following general procedure B, the above material gave (R)-3-[l,4']bipiperidinyl-4-yl-l-cyclohexyl-4-phenyl-imidazolidin-2-one as an off-white solid (89.6 mg, 42% over 2 steps).

Following general procedure C: a solution of the piperidine (89.6 mg, 0.22 mmol), mono-methyl terephthalate (49 mg, 0.27 mmol), EDCI (58 mg, 0.30 mmol), HOBT (45 mg, 0.33 mmol) and NMM (50 μL, 0.45 mmol) in DMF (1.5 niL) was stirred at room temperature for 19.5 hours. Standard work-up and purification gave

COMPOUND 1 as an off-white foam (69.6 mg, 56%). ¹H NMR (CDCl₃) δ 0.93-1.09 (m, IH), 1.14-1.54 (m, 8H), 1.59-1.93 (m, 9H), 2.03-2.29 (m, 2H), 2.41-2.52 (m, IH), 2.66-2.81 (m, 2H), 2.87-3.00 (m, 2H), 3.03 (dd, IH, / = 8.3, 7.1 Hz), 3.59-3.82 (m, 3H), 3.64 (t, IH, / = 9.3 Hz), 3.93 (s, 3H), 4.57 (dd, IH, / = 8.9, 6.7 Hz), 4.66-4.77 (m, IH), 7.24-7.36 (m, 5H), 7.42 (d, 2H, / = 8.3 Hz), 8.05 (d, 2H, / = 8.3 Hz); ES-MS m/z 573 (M+H). Example 2

COMPOUND 2: 4-r4-((R)-3-Cvclohexyl-2-oxo-5-phenyl-imidazolidin-l-yl)- r 1 ,4'lbipiperidinyl- 1 '-carbonyll -benzoic acid A solution of COMPOUND 1 (57 mg, 0.10 mmol) and 1OM NaOH (0.20 mL,

2.0 mmol) in MeOH (2.0 mL) was stirred at 60 ⁰C for 3 hours. Once cooled, the reaction was diluted with H₂O (10 mL), the pH was adjusted to 5 and the resulting mixture was extracted with CH₂CI₂ (25 mL x 3). The organic solution was dried (Na₂SO₄), filtered and concentrated under reduced pressure, giving COMPOUND 2 as a pale yellow solid (52 mg, 94%). ¹H NMR (CDCl₃) δ 1.04-1.19 (m, IH), 1.27-1.50 (m, 4H), 1.55-2.19 (m, 12H), 2.26-2.42 (m, IH), 2.73-3.00 (m, 3H), 3.04-3.50 (m, 4H), 3.11 (dd, IH, / = 8.7, 7.2 Hz), 3.55-3.83 (m, 3H), 3.77 (t, IH, / = 9.2 Hz), 4.68-4.80 (m, IH), 4.73 (dd, IH, / = 9.5, 7.1 Hz), 7.28-7.40 (m, 5H), 7.43 (d, 2H, / = 8.1 Hz), 8.03 (d, 2H, / = 8.1 Hz); ES-MS m/z 559 (M+H).

Example 3

COMPOUND 3: (R)-l-Cvclohexyl-3-n'-(4.6-dimethyl- pyrimidine-5-carbonyl)-4'-methyl-ri,4'lbipiperidinyl-4-yll-4-phenyl-imidazolidin-2-one To a solution of (R)-l-cyclohexyl-4-phenyl-3-piperidin-4-yl-imidazolidin-2-one (302 mg, 0.922 mmol) and l-Boc-4-piperidone (184 mg, 0.923 mmol) in CH₂Cl₂ (2 mL) was added titanium(IV) isopropoxide (0.27 mL, 0.92 mmol) and the mixture was stirred at room temperature for 48 hours. Diethylaluminum cyanide (1.0M in toluene, 1.1 mL, 1.1 mmol) was added and the mixture stirred for an additional 20 hours. Standard work-up afforded a pale yellow solid (510 mg).

To a solution of the above nitrile in THF (5 mL) cooled to 0⁰C was added

MgMeBr (3.0M in ether, 1.6 mL, 4.8 mmol) dropwise. The mixture was stirred at 0 ⁰C for 1 hour and at room temperature overnight. The reaction was quenched with saturated aqueous NH₄Cl and standard work-up followed by purification afforded

4-((R)-3-cyclohexyl-2-oxo-5-phenyl- imidazolidin-l-yl)-4'-methyl-[l,4']bipiperidinyl-l'-carboxylic acid tert-butyl ester (260 mg, 54% over 2 steps). Following general procedure B, the above carbamate (260 mg, 0.496 mmol) afforded

(R)-l-cyclohexyl-3-(4'-methyl-[l,4']bipiperidinyl-4-yl)-4-phenyl-imidazolidin-2-one

(180 mg, 85%).

Following general procedure C: a solution of the above amine (60 mg, 0.14 mmol), 4,6-dimethyl-pyrimidine-5-carboxylic acid (30 mg, 0.20 mmol), EDCI (33 mg,

0.17 mmol), HOBT (23 mg, 0.17 mmol) and DIPEA (0.09 mL, 0.5 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 3 as a white foam (55 mg, 70%). ¹H NMR (CDCl₃) δ 0.84 (s,

3H), 0.98-2.12 (m, 19H), 2.40, 2.43, 2.44, 2.45 (s, 6H), 2.55-2.61 (m, IH), 2.71-2.98 (m, 3H), 3.02-3.52 (m, 4H), 3.62 (td, IH, / = 9.3, 1.8 Hz), 3.75 (br t, IH, / = 11.1 Hz),

4.12-4.25 (m, IH), 4.52-4.58 (m, IH), 7.28-7.35 (m, 5H), 8.92, 8.93 (s, IH); ES-MS m/z

559 (M+H).

Example 4

COMPOUND 4:

(R)-3-rr-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-4'-methyl- r 1 ,4'lbipiperidinyl-4- yll - 1 -cyclohexyl-4-phenyl-imidazolidin-2-one

Following general procedure C: a solution of (R)-l-cyclohexyl-3-(4'-methyl- [l,4']bipiperidinyl-4-yl)-4-phenyl-imidazolidin-2-one (see EXAMPLE 3) (60 mg, 0.14 mmol), 6-chloro-2,4-dimethyl-nicotinic acid (34 mg, 0.15 mmol), EDCI (33 mg, 0.17 mmol), HOBT (23 mg, 0.17 mmol) and DIPEA (0.09 mL, 0.5 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 4 as a white foam (60 mg, 72%). ¹H NMR (CDCl₃) δ 0.83 (s, 3H), 0.94-2.11 (m, 19H), 2.18, 2.21, 2.22, 2.23 (s, 3H), 2.37, 2.41, 2.42, 2.43 (s, 3H),

2.52-2.61 (m, IH), 2.70-2.94 (m, 3H), 3.02-3.52 (m, IH), 3.58-3.64 (m, IH), 3.74 (br t, IH, / = 11.4 Hz), 4.08-4.22 (m, IH), 4.50-4.57 (m, IH), 7.00-7.02 (m, IH), 7.28-7.33 (m, 5H); ES-MS m/z 592 (M+H).

Example 5

COMPOUND 5: (R)-3-n'-(4,6-Dimethyl-pyrimidine-5-carbonyl)-4'-methyl- ri,4'lbipiperidinyl-4-yll-4-phenyl-oxazolidin-2-one

To a solution of l,4-dioxa-8-aza-spiro[4.5]decane (2.99 g, 20.9 mmol) and l-Boc-4-piperidone (4.16 g, 20.9 mmol) in CH₂Cl₂ (40 mL) was added titanium (IV) isopropoxide (6.1 mL, 20.8 mmol) and the mixture was stirred at room temperature for 20 hours. Diethylaluminum cyanide (1.0M in toluene, 25 mL, 25 mmol) was added and the mixture stirred for an additional 20 hours. Standard work-up afforded the crude bipiperidine.

To a solution of the crude nitrile in THF (90 mL) cooled to 0 ⁰C was added MgMeBr (3.0 M in ether, 35 mL, 105 mmol) dropwise. The mixture was stirred at 0⁰C for 1 hour and at room temperature overnight. The reaction was quenched with saturated aqueous NH₄Cl and standard work-up followed by purification afforded 4-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methyl-piperidine-l-carboxylic acid fe?t-butyl ester (5.88 g, 82% over 2 steps). A solution of the above carbamate (5.88 g, 17.3 mmol) in THF (20 mL) and cone. HCl (25 mL) was stirred at room temperature for 20 hours. Basic work-up afforded the intermediate amine which was subsequently treated with BOC₂O (3.72 g, 17.0 mmol). Standard work-up and purification afforded 4'-methyl-4-oxo-[l,4']bipiperidinyl-l'-carboxylic acid tert-buty\ ester (2.49 g, 49% over 2 steps).

Following general procedure A: a mixture of (R)-2-amino-2-phenyl-ethanol (88 mg, 0.64 mmol), the above ketone (190 mg, 0.64 mmol) and NaBH(OAc)₃ (157 mg, 0.74 mmol) in CH₂Cl₂ (3 mL) was stirred at room temperature overnight. Standard work-up and purification afforded

4-((R)-2-hydroxy-l-phenyl-ethylamino)-4'-methyl-[l,4']bipiperidinyl-l'-carboxylic acid fe?t-butyl ester (165 mg, 62%).

To a solution of the above amino-alcohol (165 mg, 0.395 mmol) and pyridine (0.08 mL, 0.99 mmol) in CH₂Cl₂ (3 mL) cooled to 0⁰C was added triphosgene (59 mg, 0.20 mmol) and the mixture was stirred at 0 ⁰C for 30 minutes and at room temperature for 2 hours. Standard work-up and purification afforded

4'-methyl-4-((R)-2-oxo-4-phenyl-oxazolidin-3 -yl)- [ 1 ,4']bipiperidinyl- 1 '-carboxylic acid tert-butyl ester (160 mg, 91%). Following general procedure B, the above carbamate (160 mg, 0.360 mmol) afforded (R)-3-(4'-methyl-[l,4']bipiperidinyl-4-yl)-4-phenyl-oxazolidin-2-one (120 mg, 97%).

Following general procedure C: a solution of the above amine (60 mg, 0.17 mmol), 4,6-dimethyl-pyrimidine-5-carboxylic acid (90%, 33 mg, 0.20 mmol), EDCI (41 mg, 0.21 mmol), HOBT (29 mg, 0.21 mmol) and DIPEA (0.11 mL, 0.63 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 5 as a white solid (30 mg, 37%). ¹H NMR (CDCl₃) δ 0.85 (m, 3H), 1.13-1.41 (m, 3H), 1.52-2.12 (m, 7H), 2.40, 2.43 (s, 6H), 2.59-2.64 (m, IH), 2.74-2.95 (m, 2H), 3.10-3.50 (m, 3H), 4.05-4.22 (m, 2H), 4.57 (td, IH, / = 9.0, 2.1 Hz), 4.76-4.82 (m, IH), 7.30-7.39 (m, 5H), 8.91, 8.92 (s, IH); ES-MS m/z 478 (M+H).

Example 6

COMPOUND 6: (R)-3-n'-(6-Chloro-2,4-dimethyl-pyridine-3- carbonyl)-4'-methyl-ri,4'lbipiperidinyl-4-yll-4-phenyl-oxazolidin-2-one Following general procedure C: a solution of

(R)-3-(4'-methyl-[l,4']bipiperidinyl-4-yl)-4-phenyl-oxazolidin-2-one (see EXAMPLE 5) (60 mg, 0.17 mmol), 6-chloro-2,4-dimethyl-nicotinic acid (43 mg, 0.19 mmol), EDCI (41 mg, 0.21 mmol), HOBT (29 mg, 0.21 mmol) and DIPEA (0.11 niL, 0.63 mmol) in CH₂CI₂ (2 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 6 as a white solid (26 mg, 30%). ¹H NMR (CDCl₃) δ 0.83 (s, 3H), 1.05-2.13 (m, 10H), 2.19, 2.22 (s, 3H), 2.37, 2.42 (s, 3H), 2.57-2.65 (m, IH), 2.74-2.96 (m, 2H), 3.05-3.55 (m, 3H), 4.05-4.18 (m, 2H), 4.57 (td, IH, / = 8.4, 1.5 Hz), 4.76-4.82 (m, IH), 7.01-7.03 (m, IH), 7.30-7.39 (m, 5H); ES-MS m/z 511 (M+H).

Example 7

COMPOUND 7: (R)-l-fery-Butyl-3-n'-(4,6-dimethyl-pyrimidine-5-carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-4-phenyl-imidazolidin-2-one

To a solution of (R)-l-fer?-butyl-4-phenyl-3-piperidin-4-yl-imidazolidin-2-one (200 mg, 0.663 mmol) and l-Boc-4-piperidone (133 mg, 0.668 mmol) in CH₂Cl₂ (2 mL) was added titanium(IV) isopropoxide (0.20 mL, 0.68 mmol) and the mixture was stirred at room temperature for 48 hours. Diethylaluminum cyanide (1.0M in toluene, 0.8 mL, 0.8 mmol) was added and the mixture stirred for an additional 20 hours. Standard work-up afforded the intermediate nitrile. To a solution of the above nitrile in THF (3 mL) cooled to 0⁰C was added

MgMeBr (3.0 M in ether, 2.0 mL, 6.0 mmol) dropwise. The mixture was stirred at 0⁰C for 1 hour and at room temperature overnight. The reaction was quenched with saturated aqueous NH₄Cl and standard work-up followed by purification to afford 4-((R)-3-fe?t-butyl-2-oxo-5-phenyl- imidazolidin-l-yl)-4'-methyl-[l,4']bipiperidinyl-l'-carboxylic acid

ester (250 mg, 76% over 2 steps).

Following general procedure B, the above carbamate (250 mg, 0.501 mmol) afforded (R)-l-fer?-butyl-3-(4'-methyl-[l,4']bipiperidinyl-4-yl)-4-phenyl-imidazolidin- 2-one (150 mg, 75%). Following general procedure C: a solution of the above amine (80 mg, 0.20 mmol), 4,6-dimethyl-pyrimidine-5-carboxylic acid (90%, 41 mg, 0.24 mmol), EDCI (46 mg, 0.24 mmol), HOBT (33 mg, 0.24 mmol) and DIPEA (0.12 niL, 0.69 mmol) in CH₂CI₂ (3 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 7 as a white foam (47 mg, 44%). ¹H NMR (CDCl₃) δ 0.82 (s, 3H), 1.06-2.09 (m, 10H), 1.33 (s, 9H), 2.38, 2.42 (s, 6H), 2.54-2.59 (m, IH), 2.69-2.92 (m, 2H), 3.03-3.49 (m, 4H), 3.63 (td, IH, / = 9.0, 1.8 Hz), 4.07-4.22 (m, IH), 4.43-4.49 (m, m), 7.27-7.35 (m, 5H), 8.90, 8.91 (s, IH); ES-MS m/z 533 (M+H).

Example 8

COMPOUND 8: (R)-l-fery-butyl-3-n'-(6-chloro-2,4-dimethyl-pyridine-

3-carbonyl)-4'-methyl-ri,4'lbipiperidinyl-4-yll-4-phenyl-imidazolidin-2-one

Following general procedure C: a solution of (R)-l-fe?t-butyl-3-(4'-methyl- [l,4']bipiperidinyl-4-yl)-4-phenyl-imidazolidin-2-one (see EXAMPLE 8) (74 mg, 0.19 mmol), 6-chloro-2,4-dimethyl-nicotinic acid (45 mg, 0.20 mmol), EDCI (43 mg, 0.22 mmol), HOBT (30 mg, 0.22 mmol) and DIPEA (0.11 mL, 0.63 mmol) in CH₂Cl₂ (3 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 8 as a white foam (50 mg, 46%). ¹H NMR (CDCl₃) δ 0.82 (s, 3H), 0.99-2.11 (m, 10H), 1.34 (s, 9H), 2.19, 2.22, 2.23 (s, 3H), 2.37, 2.41, 2.42, 2.43 (s, 3H), 2.53-2.60 (m, IH), 2.70-2.95 (m, 2H), 3.03-3.56 (m, 4H), 3.60-3.67 (m, IH), 4.05-4.21 (m, IH), 4.43-4.50 (m, IH), 7.00-7.03 (m, IH), 7.27-7.35 (m, 5H); ES-MS m/z 566 (M+H). Example 9

COMPOUND 9: (R)-I-F r-(4.6-Dimethyl-pyrimidine-5-carbonyl)-4'-methyl- r 1 ,4'lbipiperidinyl-4-yll -5 -phenyl-imidazolidin-2-one Following general procedure A: a mixture of 2-((R)-2-amino-2-phenyl-ethyl)- isoindole-l,3-dione (1.35 g, 5.07 mmol), 4'-methyl-4-oxo-[l,4']bipiperidinyl-l'- carboxylic acid tert-buty\ ester (1.503 g, 5.070 mmol) and NaBH(OAc)₃ (1.32 g, 6.23 mmol) in CH₂Cl₂ (20 mL) was stirred at room temperature overnight. Standard work-up and purification afforded the secondary amine. Subsequent treatment of the diamine with hydrazine hydrate (0.25 mL, 5.1 mmol) in EtOH afforded

4-((R)-2-amino-l-phenyl-ethylamino)-4'-methyl-[l,4']bipiperidinyl-l'-carboxylic acid fe?t-butyl ester (810 mg, 39% over 2 steps) following standard work-up and purification.

To a solution of the diamine (176 mg, 0.422 mmol) in DMF (3 mL) was added CDI (76 mg, 0.47 mmol) and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. Standard work-up and purification afforded 4'-methyl-4-((R)-2-oxo-5-phenyl-imidazolidin-l-yl)-[l,4']bipiperidinyl-l'-carboxylic acid tert-butyl ester (194 mg, quant).

Following general procedure B, the above carbamate (100 mg, 0.226 mmol) afforded (R)-l-(4'-methyl-[l,4']bipiperidinyl-4-yl)-5-phenyl-imidazolidin-2-one (65 mg, 84%).

Following general procedure C: a solution of the above amine (30 mg, 0.088 mmol), 4,6-dimethyl-pyrimidine-5-carboxylic acid (90%, 18 mg, 0.11 mmol), EDCI (20 mg, 0.10 mmol), HOBT (14 mg, 0.10 mmol) and DIPEA (0.06 mL, 0.3 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 9 as a white foam (24 mg, 57%). ¹H NMR (CDCl₃) δ 0.85 (s, 3H), 1.07-2.15 (m, 8H), 2.39, 2.43 (s, 6H), 2.56-2.64 (m, IH), 2.74-2.94 (m, 3H), 3.10-3.57 (m, 4H), 3.71-3.78 (m, IH), 4.05-4.19 (m, IH), 4.69-4.84 (m, 2H), 7.29-7.38 (m, 5H), 8.91, 8.92 (s, IH); ES-MS m/z 477 (M+H). Example 10

COMPOUND 10: (R)-l-n'-(6-Chloro-2.4-dimethyl-pyridine-3-carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-5-phenyl-imidazolidin-2-one Following general procedure C: a solution of

(R)-l-(4'-methyl-[l,4']bipiperidinyl-4-yl)-5-phenyl-imidazolidin-2-one (see EXAMPLE 9) (30 mg, 0.088 mmol), 6-chloro-2,4-dimethyl-nicotinic acid (24 mg, 0.11 mmol), EDCI (20 mg, 0.10 mmol), HOBT (14 mg, 0.10 mmol) and DIPEA (0.06 mL, 0.3 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 10 as a white foam (35 mg, 78%). ¹H NMR (CDCl₃) δ 0.85 (s, 3H), 1.12-2.13 (m, 9H), 2.20, 2.24, 2.25 (s, 3H), 2.39, 2.44, 2.45 (s, 3H), 2.55-2.93 (m, 3H), 3.06-3.63 (m, 4H), 3.71-3.78 (m, 4H), 3.71-3.78 (m, IH), 4.05-4.22 (m, IH), 4.37-4.41 (m, IH), 4.70-4.77 (m, IH), 7.02-7.04 (m, IH), 7.30-7.40 (m, 5H); ES-MS m/z 510 (M+H).

Example 11

COMPOUND 11: (R)-3-n'-(6-Chloro-2.4-dimethyl-pyridine-3-carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-l-methyl-4-phenyl-imidazolidin-2-one

To a solution of 4'-methyl-4-((R)-2-oxo-5-phenyl-imidazolidin-l-yl)- [l,4']bipiperidinyl-l'-carboxylic acid fe?t-butyl ester (see EXAMPLE 9) (92 mg, 0.21 mmol) in DMF (2 mL) cooled to 0⁰C was added NaH (60%, 17 mg, 0.42 mmol). After stirring for 5 minutes, MeI (0.03 mL, 0.5 mmol) was added and the mixture was warmed to room temperature over for 30 minutes and stirred for an additional 60 minutes at room temperature. Aqueous work-up and purification afforded 4'-methyl-4-((R)-3-methyl-2-oxo-5-phenyl-imidazolidin-l-yl)-[l,4']bipiperidinyl-l'- carboxylic acid tert-buty\ ester (85 mg, 0.89 mmol).

Following general procedure B, the above carbamate (85 mg, 0.19 mmol) afforded (R)-l-methyl-3-(4'-methyl-[l,4']bipiperidinyl-4-yl)-4-phenyl- imidazolidin-2-one (55 mg, 81%).

Following general procedure C: a solution of the above amine (55 mg, 0.15 mmol), 6-chloro-2,4-dimethyl-nicotinic acid (42 mg, 0.19 mmol), EDCI (37 mg, 0.19 mmol), HOBT (26 mg, 0.19 mmol) and DIPEA (0.10 mL, 0.57 mmol) in CH₂Cl₂ (3 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 11 as a white foam (50 mg, 64%). ¹H NMR (CDCl₃) δ 0.82 (s, 3H), 1.03-2.12 (m, 10H), 2.19, 2.22 (s, 3H), 2.37, 2.41, 2.42, 2.43 (s, 3H), 2.53-2.62 (m, IH), 2.71-2.96 (m, 5H), 3.02-3.56 (m, 4H), 3.62 (t, IH, / = 9.0 Hz), 4.07-7.21 (m, IH), 4.53-4.60 (m, IH), 7.01-7.02 (m, IH), 7.28-7.35 (m, 5H); ES-MS m/z 524 (M+H).

Example 12

COMPOUND 12: l-n'-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-

4'-methyl-ri,4'lbipiperidinyl-4-yll-3-methoxy-l-thiophen-3-ylmethyl-urea

Following general procedure A: a mixture of C-thiophen-3-yl-methylamine

(74 mg, 0.65 mmol), 4'-methyl-4-oxo-[l,4']bipiperidinyl-l'-carboxylic acid fe?t-butyl ester (176 mg, 0.594 mmol) and NaBH(OAc)₃ (158 mg, 0.745 mmol) in CH₂Cl₂ (3 mL) was stirred at room temperature overnight. Standard work-up and purification afforded

4'-methyl-4-[(thiophen-3-ylmethyl)-amino]-[l,4']bipiperidinyl-l'-carboxylic acid fe?t-butyl ester (240 mg, quant).

A solution of the above amine (240 mg, 0.610 mmol), N-(4-nitrophenoxycarbonyl)methoxylamine (155 mg, 0.731 mmol) and DIPEA

(0.13 mL, 0.75 mmol) in CH₂Cl₂ (3 mL) was stirred at room temperature for 90 minutes.

Standard work-up and purification afforded the desired intermediate. Following general procedure B, the intermediate gave 3-methoxy-l-(4'-methyl-[l,4']bipiperidinyl-4-yl)-l-thiophen-3-ylmethyl-urea (88 mg, 39% over 2 steps).

Following general procedure C: a solution of the above amine (44 mg, 0.12 mmol), 6-chloro-2,4-dimethyl-nicotinic acid (40 mg, 0.18 mmol), EDCI (35 mg, 0.18 mmol), HOBT (25 mg, 0.18 mmol) and DIPEA (0.08 mL, 0.46 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 12 as a white foam (50 mg, 78%). ¹H NMR (CDCl₃) δ 0.92, 0.93 (s, 3H), 1.18-1.97 (m, 8H), 2.16-2.27 (m, 5H), 2.41, 2.44 (s, 3H), 2.79-2.85 (m, IH), 2.93-3.00 (m, 2H), 3.21-3.32 (m, IH), 3.39-3.48 (m, IH), 3.63 (s, 3H), 4.05-4.27 (m, 2H), 4.30 (s, 2H), 6.96 (d, IH, / = 4.8 Hz), 7.02 (d, IH, / = 4.8 Hz), 7.09-7.11 (m, 2H), 7.35 (dd, IH, / = 5.1, 3.0 Hz); ES-MS m/z 534 (M+H).

Example 13

COMPOUND 13: N-n'-(6-Cvano-2,4-dimethyl-l-oxy-pyridine-3-carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-2-(2-oxo-oxazolidin-3-yl)-N-thiophen- 3-ylmethyl-acetamide

Following general procedure C: a solution of 4'-methyl-4-[(thiophen- 3-ylmethyl)-amino]-[l,4']bipiperidinyl-l'-carboxylic acid fe?t-butyl ester (see EXAMPLE 12) (266 mg, 0.677 mmol), (2-oxo-oxazolidin-3-yl)-acetic acid (108 mg, 0.745 mmol), EDCI (143 mg, 0.746 mmol), HOBT (100 mg, 0.740 mmol) and DIPEA (0.20 mL, 1.1 mmol) in DMF (10 mL) was stirred at room temperature overnight. Standard work-up and purification afforded the desired carbamate. Following general procedure B, the above carbamate afforded N-(4'-methyl-[ l,4']bipiperidinyl-4-yl)-2- (2-oxo-oxazolidin-3-yl)-N-thiophen-3-ylmethyl-acetamide (170 mg, 60% over 2 steps). Following general procedure C: a solution of the above amine (59 mg,

0.14 mmol), 6-cyano-2,4-dimethyl-l-oxy-nicotinic acid (30 mg, 0.16 mmol), EDCI (30 mg, 0.16 mmol), HOBT (21 mg, 0.16 mmol) and DIPEA (0.04 mL, 0.2 mmol) in DMF (6 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 13 as a white foam (31 mg, 37%). ¹H NMR (CDCl₃) δ 0.98 (br s, 3H), 1.25-2.31 (m, 14H), 2.43 (s, 3H), 2.80-3.06 (m, 2H), 3.27-3.59 (m, 2H), 3.67-3.80 (m, 2H), 4.00-4.17 (m, 3H), 4.32-4.55 (m, 5H), 6.96-7.01 (m, IH), 7.10 (br s, IH), 7.23, 7.36 (br s, IH), 7.40 (br s, IH); ES-MS m/z 595 (M+H).

Example 14

COMPOUND 14:

N-rr-(6-Cvano-2,4-dimethyl-pyridine-3-carbonyl)-4'-methyl-ri,4'lbipiperidinyl-4-yll- 2-(2-oxo-oxazolidin-3-yl)-N-thiophen-3-ylmethyl-acetamide

Following general procedure C: a solution of N-(4'-methyl-[l,4']bipiperidinyl- 4-yl)-2-(2-oxo-oxazolidin-3-yl)-N-thiophen-3-ylmethyl-acetamide (see EXAMPLE 13) (48 mg, 0.11 mmol), 6-cyano-2,4-dimethyl-nicotinic acid (22 mg, 0.13 mmol), EDCI (24 mg, 0.13 mmol), HOBT (17 mg, 0.13 mmol) and DIPEA (0.033 niL, 0.19 mmol) in DMF (6 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 14 as a white foam (27 mg, 41%). ¹H NMR (CDCl₃) δ 0.97 (br s, 3H), 1.29-2.34 (m, 14H), 2.50 (s, 3H), 2.81-3.07 (m, 2H),

3.22-3.58 (m, 2H), 3.67-3.80 (m, 2H), 3.99-4.17 (m, 3H), 4.33-4.55 (m, 5H), 6.98-7.00 (m, IH), 7.11 (br s, IH), 7.23, 7.36 (br s, IH), 7.40 (br s, IH); ES-MS m/z 579 (M+H).

Example 15

COMPOUND 15: N-n'-(6-Chloro-2,4-dimethyl-l-oxy-pyridine-3-carbonyl)-

4'-methyl-ri,4'lbipiperidinyl-4-yll-2-(2-oxo-oxazolidin-3-yl)-N-thiophen- 3-ylmethyl-acetamide Following general procedure C: a solution of

N-(4'-methyl-[l,4']bipiperidinyl-4-yl)-2-(2-oxo-oxazolidin-3-yl)-N-thiophen-3-ylmethyl- acetamide (see EXAMPLE 13) (57 mg, 0.14 mmol), 6-chloro-2,4-dimethyl-l-oxy- nicotinic acid (30 mg, 0.15 mmol), EDCI (29 mg, 0.15 mmol), HOBT (20 mg, 0.15 mmol) and DIPEA (0.039 niL, 0.22 mmol) in DMF (6 niL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 15 as a white foam (10 mg, 12%). ¹H NMR (CDCl₃) δ 0.96 (br s, 3H), 1.26-2.54 (m, 17H), 2.76-3.59 (m, 4H), 3.68-3.84 (m, 2H), 4.00-4.19 (m, 3H), 4.34-4.58 (m, 5H), 7.00 (s, IH), 7.11 (s, IH), 7.22-7.38 (m, 2H); ES-MS m/z 604 (M+H).

Example 16

COMPOUND 16: l-rr-(2,6-Dichloro-4-methyl-l-oxy-pyridine-3-carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-3-(2-methoxyethoxy)-l-thiophen-3-ylmethyl-urea

To a solution of N-hydroxy phthalimide (4.50 g, 27.6 mmol) and Et₃N (7.7 mL, 55 mmol) in DMF (18 mL) was added 2-bromo ethyl methyl ether (3.9 mL, 41.5 mmol). The mixture was stirred at room temperature for 72 hours. Standard work-up afforded the phthalimide intermediate.

To a solution of the above intermediate in CH₂Cl₂ (30 mL) was added methyl hydrazine (1.47 mL, 27.6 mmol) and the mixture was stirred at room temperature overnight. The mixture was filtered, the solid was rinsed with Et₂O and the combined filtrate was concentrated under reduced pressure to afford the desired amine.

To a solution of 4-nitrochloroformate (5.82 g, 28.8 mmol) in CH₂Cl₂ (15 mL) was added NaHCO₃ (15 mL) and the mixture cooled to 0 ⁰C. The above amine was added and the mixture stirred at 0 ⁰C for 30 minutes and at room temperature for 30 minutes. Standard work-up and purification afforded (2-methoxyethoxy)-carbamic acid 4-nitro-phenyl ester (4.24 g, 60% over 3 steps).

A solution of 4'-methyl-4-[(thiophen-3-ylmethyl)-amino]-[l,4']bipiperidinyl- l'-carboxylic acid fe?t-butyl ester (see EXAMPLE 12) (190 mg, 0.483 mmol), the above nitrophenyl carbamate (149 mg, 0.581 mmol) and DIPEA (0.126 mL, 0.723 mmol) in CH₂Cl₂ (6 mL) was stirred at room temperature overnight. Standard work-up afforded the crude carbamate. Following general procedure B, the carbamate gave 3-(2-methoxyethoxy)-l-(4'-methyl-[l,4']bipiperidinyl-4-yl)-l-thiophen-3-ylmethyl-urea (183 mg, 92% over 2 steps). Following general procedure C: a solution of the above amine (91 mg, 0.22 mmol), 2,6-dichloro-4-methyl-l-oxy-nicotinic acid (54 mg, 0.24 mmol), EDCI (47 mg, 0.25 mmol), HOBT (33 mg, 0.24 mmol) and DIPEA (0.064 mL, 0.37 mmol) in DMF (8 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 16 as a pale yellow foam (27 mg, 20%). ¹H NMR (CDCl₃) δ 0.97-2.41 (m, 19H), 2.95-3.15 (m, 2H), 3.29 (s, 3H), 3.31-3.48 (m, IH), 3.53-3.57 (m, 2H), 3.96-4.00 (m, 2H), 4.28-4.39 (m, 3H), 6.96-6.97 (m, IH), 7.10-7.11 (m, IH), 7.32-7.36 (m, 2H), 7.43 (br s, IH); ES-MS m/z 614 (M+H).

COMPOUND 17: l-n'-(6-Cvano-2,4-dimethyl-l-oxy-pyridine-3-carbonyl)-

4'-methyl-ri,4'lbipiperidinyl-4-yll-3-(2-methoxyethoxy)-l-thiophen-3-ylmethyl-urea

Following general procedure C: a solution of 3-(2-methoxyethoxy)-l-(4'-methyl- [l,4']bipiperidinyl-4-yl)-l-thiophen-3-ylmethyl-urea (see EXAMPLE 16) (92 mg, 0.22 mmol), 6-cyano-2,4-dimethyl-l-oxy-nicotinic acid (47 mg, 0.25 mmol), EDCI (47 mg, 0.25 mmol), HOBT (33 mg, 0.24 mmol) and DIPEA (0.064 mL, 0.37 mmol) in DMF (8 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 17 as a white foam (65 mg, 50%). ¹H NMR (CDCl₃) δ 0.97-2.44 (m, 22H), 2.92-3.03 (m, 2H), 3.28-3.39 (m, 4H), 3.53-3.56 (m, 2H), 3.96-3.99 (m, 2H), 4.22-4.35 (m, 3H), 6.95-6.98 (m, IH), 7.09-7.11 (m, IH), 7.33-7.40 (m, 3H); ES-MS m/z 585 (M+H). Example 18

COMPOUND 18 : 1-Fl '-(2.6-Dichloro-4-methyl- 1 -oxy-pyridine-3 -carbonylV 4'-methyl-ri,4'lbipiperidinyl-4-yll-3-methoxy-l-thiophen-3-ylmethyl-urea Following general procedure C: a solution of 3-methoxy-l-(4'-methyl-

[l,4']bipiperidinyl-4-yl)-l-thiophen-3-ylmethyl-urea (see EXAMPLE 12) (79 mg, 0.20 mmol), 2,6-dichloro-4-methyl-nicotinic acid (55 mg, 0.25 mmol), EDCI (47 mg, 0.25 mmol), HOBT (33 mg, 0.24 mmol) and DIPEA (0.086 niL, 0.49 mmol) in DMF (6 niL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 18 as a white foam (8 mg, 7%). ¹H NMR (CDCl₃) δ 0.96 (br s, 3H),

1.25-2.04 (m, 10H), 2.29 (br s, 3H), 2.80-3.05 (m, 3H), 3.34-3.47 (m, 2H), 3.66 (s, 3H), 4.04-4.27 (m, 2H), 4.33 (br s, 2H), 6.98 (d, IH, / = 5.1 Hz), 7.07-7.17 (m, 2H), 7.31-7.38 (m, 2H); ES-MS m/z 570 (M+H).

Example 19

COMPOUND 19: l-n'-(6-Cvano-2.4-dimethyl-pyridine-3-carbonyl)-4'-methyl- ri,4'lbipiperidinyl-4-yll-3-methoxy-l-thiophen-3-ylmethyl-urea

Following general procedure C: a solution of 3-methoxy-l-(4'-methyl- [l,4']bipiperidinyl-4-yl)-l-thiophen-3-ylmethyl-urea (see EXAMPLE 12) (350 mg, 0.956 mmol), 6-cyano-2,4-dimethyl-nicotinic acid (190 mg, 1.08 mmol), EDCI (210 mg, 1.10 mmol), HOBT (150 mg, 1.11 mmol) and DIPEA (0.29 mL, 1.7 mmol) in DMF (15 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 19 as a white foam (87 mg, 17%). ¹H NMR (CDCl₃) δ 0.88-0.94 (m, 3H), 1.17-2.24 (m, 10H), 2.28, 2.32 (s, 3H), 2.48-2.53 (s, 3H), 2.72-2.77 (m, IH), 2.86-2.96 (m, 2H), 3.23-3.48 (m, 3H), 3.65, 3.69, 3.83 (s, 3H), 4.24-4.30 (m, 3H), 6.97, 7.04 (d, IH, / = 4.8 Hz), 7.07, 7.17 (br s, IH), 7.33-7.40 (m, 2H), 7.26-7.29 (m, IH); ES-MS m/z 525 (M+H).

Example 20

COMPOUND 20: l-n'-(6-Cvano-2,4-dimethyl-l-oxy-pyridine-3-carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-3-methoxy-l-thiophen-3-ylmethyl-urea

Following general procedure C: a solution of 3-methoxy-l-(4'-methyl- [l,4']bipiperidinyl-4-yl)-l-thiophen-3-ylmethyl-urea (see EXAMPLE 12) (100 mg, 0.273 mmol), 6-cyano-2,4-dimethyl-l-oxy-nicotinic acid (60 mg, 0.31 mmol), EDCI (60 mg, 0.31 mmol), HOBT (42 mg, 0.31 mmol) and DIPEA (0.082 mL, 0.47 mmol) in DMF (8 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 20 as a white foam (31 mg, 21%). ¹H NMR (CDCl₃) δ 0.95 (br s, 3H), 1.20-1.98 (m, 8H), 2.20-2.27 (m, 5H), 2.41, 2.43 (s, 3H), 2.79-2.98 (m, 3H), 3.28-3.46 (m, 2H), 3.64 (s, 3H), 4.07-4.29 (m, 2H), 4.31 (s, 2H), 6.97 (d, IH, / = 4.8 Hz), 7.11 (br s, 2H), 7.35-7.40 (m, 2H); ES-MS m/z 541 (M+H).

Example 21

COMPOUND 21 : 1 - [ 1 '-(6-Chloro-2,4-dimethyl- 1 -oxy-pyridine-3 -carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-3-methoxy-l-thiophen-3-ylmethyl-urea

Following general procedure C: a solution of 3-methoxy-l-(4'-methyl- [l,4']bipiperidinyl-4-yl)-l-thiophen-3-ylmethyl-urea (see EXAMPLE 12) (100 mg, 0.273 mmol), 6-chloro-2,4-dimethyl-l-oxy-nicotinic acid (63 mg, 0.31 mmol), EDCI (60 mg, 0.31 mmol), HOBT (42 mg, 0.31 mmol) and DIPEA (0.082 niL, 0.47 mmol) in DMF (8 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 21 as a white foam (17 mg, 11%). ¹H NMR (CDCl₃) δ 0.94 (br s, 3H), 1.70-2.01 (m, 9H), 2.20-2.28 (m, 4H), 2.47-2.48 (m, 3H), 2.79-3.01 (m, 3H), 3.25-3.50 (m, 2H), 3.65 (s, 3H), 4.03-4.28 (m, 2H), 4.32 (s, 2H), 6.97 (d, IH, / = 4.8 Hz), 7.08-7.12 (m, 2H), 7.34-7.37 (m, IH); ES-MS m/z 550 (M+H).

Example 22

COMPOUND 22: 5-r4-(3-Methoxy-l-thiophen-3-ylmethyl-ureido)-4'-methyl- ri,4'lbipiperidinyl-r-carbonyll-4,6-dimethyl-pyridine-2-carboxylic acid isopropylamide

A solution of COMPOUND 19 (55 mg, 0.10 mmol) in MeOH (4 mL) and ION NaOH (1 mL) was heated at 100 ⁰C for 2 hours. The mixture was concentrated under reduced pressure and dry loaded onto a silica gel column (8:1:1, CH₃CN/MeOH/NH₄OH) to afford 5-[4-(3-methoxy-l-thiophen-3-ylmethyl-ureido)-4'-methyl-[l,4']bipiperidinyl-l'-carbony l]-4,6-dimethyl-pyridine-2-carboxylic acid (31 mg, 54%).

Following general procedure C: a solution of the above acid (31 mg, 0.057 mmol), isopropylamine (0.008 mL, 0.09 mmol), EDCI (12 mg, 0.063 mmol), HOBT (8 mg, 0.06 mmol) and DIPEA (0.015 mL, 0.086 mmol) in DMF (3 mL) was stirred at room temperature overnight. Standard work-up and purification afforded

COMPOUND 22 as a white foam (19 mg, 57%). ¹H NMR (CDCl₃) δ 0.94 (s, 3H), 1.24-1.98 (m, 14H), 2.18-2.32 (m, 5H), 2.47-2.50 (m, 3H), 2.80-3.01 (m, 3H), 3.21-3.30 (m, IH), 3.41-3.53 (m, IH), 3.65 (s, 3H), 4.07-4.32 (m, 5H), 6.96-6.99 (m, IH), 7.07 (s, IH), 7.12 (s, IH), 7.37 (dd, IH, / = 4.8, 2.7 Hz), 7.82-7.88 (m, 2H); ES-MS m/z 585 (M+H). Example 23

COMPOUND 23: 5-(3-n'-(6-Chloro-2.4-dimethyl-pyridine-3-carbonyl)-4'- methyl- [ 1 ,4'1bipiperidinyl-4-vH-3-thiophen-3-ylmethyl-ιireido j -pentanoic acid methyl ester

Following general procedure B, 4'-methyl-4-[(thiophen-3-ylmethyl)-amino]- [l,4']bipiperidinyl-l'-carboxylic acid tert-buty\ ester (see EXAMPLE 12) gave (4'-methyl-[l,4']bipiperidinyl-4-yl)-thiophen-3-ylmethyl-amine.

Following general procedure C: a solution of the above piperidine (360 mg, 1.23 mmol), 6-chloro-2,4-dimethyl-nicotinic acid (250 mg, 1.35 mmol), EDCI (260 mg, 1.36 mmol), HOBT (180 mg, 1.33 mmol) and DIPEA (0.35 mL, 2.0 mmol) in CH₂Cl₂ (20 mL) was stirred at room temperature overnight. Standard work-up and purification afforded (6-chloro-2,4-dimethyl-pyridin-3-yl)-{4'-methyl-4-[(thiophen-3-ylmethyl)- amino]-[l,4']bipiperidinyl-l'-yl}-methanone (400 mg, 71%). A solution of 5 -amino valeric acid (235 mg, 2.00 mmol) and cone. HCl (few drops) in 2,2-dimethoxypropane was refluxed overnight. The mixture was concentrated under reduced pressure to afford the crude ester. To a solution of the above amine and DIPEA (0.70 mL, 4.0 mmol) in CH₂Cl₂ (13 mL) cooled to 0 ⁰C was added 4-nitrophenyl chloroformate (363 mg, 1.80 mmol) was added slowly. The mixture was stirred for 1 hour and allowed to warm to room temperature. Aqueous work-up and purification afforded 5-(4-nitro-phenoxycarbonylamino)-pentanoic acid methyl ester (157 mg, 26% over 2 steps).

A solution of the above phenylcarbamate (95 mg, 0.33 mmol), the above amide (121 mg, 0.263 mmol) and DIPEA (0.069 mL, 0.40 mmol) in CH₂Cl₂ (5 mL) was stirred at room temperature overnight. Standard work-up and purification afforded

COMPOUND 23 as a white foam (70 mg, 43%). ¹H NMR (CDCl₃) δ 0.93, 0.94 (s, 3H), 1.18-1.82 (m, 10H), 1.95 (br d, IH, / = 13.5 Hz), 2.18-2.27 (m, 7H), 2.42, 2.46 (s, 3H), 2.80-2.84 (m, IH), 2.94-2.99 (m, 2H), 3.12-3.18 (m, 2H), 3.23-3.35 (m, IH), 3.41-3.50 (m, IH), 3.65 (s, 3H), 4.07-4.15 (m, IH), 4.26-4.40 (m, 4H), 6.98 (d, IH, / = 4.8 Hz), 7.03 (d, IH, / = 4.2 Hz), 7.11-7.12 (m, IH), 7.34 (dd, IH, / = 5.1, 3.0 Hz); ES-MS m/z 618 (M+H).

Example 24

COMPOUND 24:

5-{3-rr-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-4'-methyl-ri,4'lbipiperidinyl- 4- yll -3 -thiophen-3 - ylmethyl-ureido j -pentanoic acid

A solution of COMPOUND 23 (52 mg, 0.084 mmol) in MeOH (4 mL) and IN NaOH (1 mL) was heated at 50⁰C for 2 hours. The mixture was concentrated under reduced pressure and the pH was adjusted to ~3 with HCl. The aqueous was extracted with CH₂CI₂ (6 x 15 mL) and the combined organic extracts were dried (Na₂SO₄), filtered and concentrated under reduced pressure to afford COMPOUND 24 as a white foam (36 mg, 71%). ¹H NMR (CDCl₃) δ 0.91-3.68 (m, 30H), 4.41-4.96 (m, 6H), 6.91-7.11 (m, 3H), 7.27-7.32 (m, IH), 11.97 (br s, IH); ES-MS m/z 604 (M+H).

Example 25

COMPOUND 25: 3-( n'-(6-Chloro-2.4-dimethyl-pyridine-3-carbonyl)-4'- methyl-ri,4'lbipiperidinyl-4-yll-thiophen-3-ylmethyl-aminol-3-methylamino- acrylonitrile To a solution of (6-chloro-2,4-dimethyl-pyridin-3-yl)-{4'-methyl-4-[(thiophen-

3-ylmethyl)-amino]-[l,4']bipiperidinyl-l'-yl}-methanone (see EXAMPLE 23) (55 mg, 0.12 mmol), S-methyl N-cyano-N'-methyl-carbamimidothiolate (31 mg, 0.24 mmol) and Et₃N (0.083 mL, 0.60 mmol) in DMF (5 mL) was added AgOTf (61 mg, 0.24 mmol) slowly. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, CH₂CI₂ was added, the mixture was sonicated and the yellow precipitate was filtered. The filtrate was quenched with saturated aqueous NaHCO₃ and extracted with CH₂CI₂ (3 x 30 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated under reduced pressure. The crude material was purified to afford COMPOUND 25 as a white foam (25 mg, 38%). ¹H NMR (CDCl₃) δ 0.95, 0.96 (s, 3H), 1.21-1.97 (m, 7H), 2.19-2.30 (m, 5H), 2.42, 2.45 (s, 3H), 2.80-2.88 (m, IH), 2.94-3.02 (m, 2H), 3.08 (d, 3H, / = 4.8 Hz), 3.21-3.33 (m, IH), 3.44-3.55 (m, IH), 4.03-4.10 (m, IH), 4.35-4.44 (m, 3H), 4.75-4.80 (m, IH), 6.96 (d, IH, / = 4.8 Hz), 7.03 (d, IH, / = 5.4 Hz), 7.09-7.11 (m, IH), 7.41 (dd, IH, / = 4.8, 3.0 Hz); ES-MS m/z 542 (M+H).

Example 26

COMPOUND 26: 3-{ rr-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-4'-methyl-ri,4'lbipiperidinyl-4-yll- thiophen-S-ylmethyl-aminoj-S-cyclopropylamino-acrylonitrile

To a solution of (6-chloro-2,4-dimethyl-pyridin-3-yl)-{4'-methyl-4-[(thiophen- 3-ylmethyl)-amino]-[l,4']bipiperidinyl-r-yl}-methanone (see EXAMPLE 23) (68 mg, 0.15 mmol), 5-methyl N-cyano-/V-cyclopropyl-carbamimidothiolate (46 mg, 0.30 mmol) and Et₃N (0.10 mL, 0.74 mmol) in DMF (5 mL) was added AgOTf (76 mg, 0.30 mmol) slowly. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, CH₂Cl₂ was added, the mixture was sonicated and the yellow precipitate was filtered. The filtrate was quenched with saturated aqueous NaHCO₃ and extracted with CH₂Cl₂ (3 x 30 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated under reduced pressure. The crude material was purified to afford COMPOUND 26 as a white foam (72 mg, 84%). ¹H NMR (CDCl₃) δ 0.32-0.37 (m, 2H), 0.81-0.88 (m, 2H), 0.95 (s, 3H), 1.17-1.95 (m, 7H), 2.17-2.29 (m, 5H), 2.41-2.45 (s, 3H), 2.80-2.88 (m, IH), 2.94-3.03 (m, 3H), 3.21-3.31 (m, IH), 3.43-3.51 (m, IH), 4.03-4.10 (m, IH), 4.31-4.47 (m, 3H), 5.10 (br s, IH), 6.90-6.92 (m, IH), 7.03 (d, IH, / = 6.6 Hz), 7.06-7.08 (m, IH), 7.39 (dd, IH, / = 4.5, 2.7 Hz); ES-MS mJz 568 (M+H).

Example 27

COMPOUND 27: l-{ l-ri-(6-Cyano-2,4-dimethyl-pyridine-3-carbonyl)- azetidin-3-yll-piperidin-4-ylj-3-methoxy-l-thiophen-3-ylmethyl-urea

A solution of 3-amino-azetidine-l-carboxylic acid tert-buty\ ester (800 mg, 4.64 mmol) and N-methyl-ethyl piperidine iodide salt (2.50 g, 9.29 mmol) in EtOH (5 mL) and H₂O (5 mL) was heated to reflux for 3 hours. Standard work-up and purification afforded 3-(4-oxo-piperidin-l-yl)-azetidine-l-carboxylic acid tert-buty\ ester (806 mg, 68%).

Following general procedure A: to a solution of the above ketone (800 mg, 3.15 mmol), 3-aminomethyl thiophene (339 mg, 3.00 mmol) and AcOH (0.17 mL, 3.0 mmol) in CH₂Cl₂ (10 mL) was added NaBH(OAc)₃ (890 mg, 4.20 mmol) and the mixture stirred at room temperature overnight. Standard work-up afforded

3- {4-[(thiophen-3-ylmethyl)-amino]-piperidin- 1-yl} -azetidine- 1-carboxylic acid fe?t-butyl ester (1.09 g, quant.).

A solution of the above amine (580 mg, 1.65 mmol),

N-(4-nitrophenoxycarbonyl)methoxylamine (420 mg, 1.98 mmol) and DIPEA (0.57 mL, 5.9 mmol) in CH₂Cl₂ (8 mL) was stirred at room temperature overnight. Standard work-up afforded the desired crude carbamate. A solution of the carbamate in THF (20 mL) and 4N HCl (7 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, diluted with H₂O (10 mL) and extracted with Et₂O (2 x 30 mL). The aqueous was basified with ION NaOH to pH~13 and extracted with CH₂Cl₂ (4 x 30 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated under reduced pressure to afforded l-(l-azetidin-3-yl-piperidin-4-yl)- 3-methoxy-l-thiophen-3-ylmethyl-urea (480 mg, 90% over 2 steps).

Following general procedure C: a solution of the above azetidine (237 mg, 0.731 mmol), 6-cyano-2,4-dimethyl-nicotinic acid (150 mg, 0.852 mmol), EDCI (154 mg, 0.803 mmol), HOBT (109 mg, 0.807 mmol) and DIPEA (0.25 niL, 1.4 mmol) in DMF (10 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 27 as a white foam (165 mg, 47%). ¹H NMR (CDCl₃) δ 1.60-1.85 (m, 4H), 1.92-2.06 (m, 2H), 2.35 (s, 3H), 2.54, 2.55 (s, 3H), 2.71 (br d, IH, / = 10.8 Hz), 2.87 (br d, IH, / = 11.1 Hz), 3.19-3.26 (m, IH), 3.56-3.77 (m, 5H), 3.98-4.03 (m, IH), 4.22-4.38 (m, 4H), 6.94-6.96 (m, IH), 7.08-7.12 (m, 2H), 7.36-7.39 (m, 2H); ES-MS m/z 483 (M+H).

Example 28

COMPOUND 28: 5-{3-r4-(3-Methoxy-l-thiophen-3-ylmethyl-ureido)- piperidin- 1 - yli -azetidine- 1 -carbonyl j -4,6-dimethyl-pyridine-2-carboxylic acid isopropylamide

A solution of COMPOUND 27 (162 mg, 0.336 mmol) in EtOH (8 mL) and ION NaOH (1 mL) was stirred at 100⁰C for 45 minutes. Purification afforded 5-{3-[4-(3-methoxy-l-thiophen-3-ylmethyl-ureido)-piperidin-l-yl]-azetidine-l- carbonyl}-4,6-dimethyl-pyridine-2-carboxylic acid (138 mg, 82%).

Following general procedure C: a solution of the above acid (43 mg, 0.086 mmol), isopropylamine (8 μL, 0.09 mmol), EDCI (18 mg, 0.094 mmol), HOBT (13 mg, 0.096 mmol) and DIPEA (0.025 mL, 0.14 mmol) in DMF (4 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 28 as a white foam (23 mg, 49%). ¹H NMR (CDCl₃) δ 1.27, 1.29 (d, 6H, / = 3.0 Hz), 1.61-1.83 (m, 4H), 1.90-2.04 (m, 2H), 2.34 (s, 3H), 2.51, 2.52 (s, 3H), 2.69 (d, IH, / = 10.5 Hz), 2.87 (d, IH, / = 10.5 Hz), 3.16-3.24 (m, IH), 3.53-3.72 (m, 5H), 3.96-4.02 (m, IH), 4.19-4.38 (m, 5H), 6.95 (d, IH, / = 4.5 Hz), 7.10 (br s, 2H), 7.35-7.38 (m, IH), 7.83 (d, IH, / = 8.4 Hz), 7.87 (s, IH); ES-MS m/z 543 (M+H). Example 29

COMPOUND 29:

5-{3-r4-(3-Methoxy-l-thiophen-3-ylmethyl-ureido)-piperidin-l-yll-azetidine-l- carbonylj-4,6-dimethyl-pyridine-2-carboxylic acid isobutyl- amide

Following general procedure C: a solution of 5-{3-[4-(3-methoxy-l-thiophen- 3-ylmethyl-ureido)-piperidin-l-yl]-azetidine-l-carbonyl}-4,6-dimethyl- pyridine-2-carboxylic acid (see EXAMPLE 28) (45 mg, 0.090 mmol), isobutylamine (10 μL, 0.10 mmol), EDCI (19 mg, 0.099 mmol), HOBT (13 mg, 0.096 mmol) and DIPEA (0.026 niL, 0.15 mmol) in DMF (4 niL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 29 as a white foam (25 mg, 50%). ¹H NMR (CDCl₃) δ 0.98 (d, 6H, / = 6.6 Hz), 1.57-2.04 (m, 7H), 2.35 (s, 3H), 2.52 (s, 3H), 2.70 (br d, IH, / = 11.1 Hz), 2.87 (br d, IH, / = 11.1 Hz), 3.17-3.36 (m, 3H), 3.54-3.74 (m, 5H), 3.96-4.03 (m, IH), 4.22-4.38 (m, 4H), 6.95 (d, IH, / = 5.1 Hz), 7.08-7.11 (m, 2H), 7.37 (dd, IH, / = 4.8, 2.7 Hz), 7.88 (s, IH), 8.10 (t, IH, J = 6.0 Hz); ES-MS mJz 557 (M+H).

Example 30

COMPOUND 30: 5-(3-r4-(3-Methoxy-l-thiophen-3-ylmethyl-ureidoV piperidin- 1 - yli -azetidine- 1 -carbonyl j -4,6-dimethyl-pyridine-2-carboxylic acid (3-methyl-butvD-amide

Following general procedure C: a solution of 5-{3-[4-(3-methoxy-l-thiophen- 3-ylmethyl-ureido)-piperidin-l-yl]-azetidine-l-carbonyl}-4,6-dimethyl-pyridine-2- carboxylic acid (see EXAMPLE 28) (45 mg, 0.090 mmol), isopentylamine (12 μL, 0.10 mmol), EDCI (19 mg, 0.099 mmol), HOBT (13 mg, 0.096 mmol) and DIPEA (0.026 mL, 0.15 mmol) in DMF (4 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 30 as a white foam (26 mg, 51%). ¹H NMR (CDCl₃) δ 0.95 (d, 6H, / = 6.9 Hz), 1.49-1.56 (m, 2H), 1.62-1.83 (m, 5H), 1.91-2.04 (m, 2H), 2.34 (s, 3H), 2.51 (s, 3H), 2.70 (br d, IH, / = 11.4 Hz), 2.87 (br d, IH, / = 10.2 Hz), 3.16-3.25 (m, IH), 3.40-3.73 (m, 7H), 3.96-4.02 (m, IH), 4.22-4.38 (m, 4H), 6.95 (d, IH, / = 5.1 Hz), 7.09-7.12 (m, 2H), 7.36 (dd, IH, / = 4.5, 3.3 Hz), 7.87 (s, IH), 7.97 (t, IH, / = 5.7 Hz); ES-MS m/z 571 (M+H).

Example 31

COMPOUND 31: N-{ l-ri-(6-Cvano-2,4-dimethyl-pyridine-3-carbonyl)- azetidin-3-yll-piperidin-4-yl)-2-(2-oxo-oxazolidin-3-yl)-N-thiophen-3-ylmethyl- acetamide

Following general procedure C: a solution of 3-{4-[(thiophen-3-ylmethyl)- amino]-piperidin-l-yl}-azetidine-l-carboxylic acid fe?t-butyl ester (see EXAMPLE 27) (156 mg, 0.444 mmol), (2-oxo-oxazolidin-3-yl)-acetic acid (71 mg, 0.49 mmol), EDCI (94 mg, 0.49 mmol), HOBT (66 mg, 0.49 mmol) and DIPEA (0.13 mL, 0.75 mmol) in DMF (6 mL) was stirred at room temperature overnight. Standard work-up gave the crude carbamate. Following general procedure B, the carbamate gave N-(l-azetidin- 3-yl-piperidin-4-yl)-2-(2-oxo-oxazolidin-3-yl)-N-thiophen-3-ylmethyl-acetamide (67 mg, 40% over 2 steps).

Following general procedure C: a solution of the above amine (67 mg, 0.18 mmol), 6-cyano-2,4-dimethyl-nicotinic acid (34 mg, 0.19 mmol), EDCI (37 mg, 0.19 mmol), HOBT (26 mg, 0.19 mmol) and DIPEA (0.051 mL, 0.29 mmol) in DMF (6 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 31 as a white foam (45 mg, 47%). ¹H NMR (CDCl₃) δ 1.66-1.97 (m, 7H), 2.33-2.37 (m, 3H), 2.53-2.56 (m, 3H), 2.70 (br s, IH), 2.83-2.90 (m, IH), 3.22 (br s, IH), 3.57-3.79 (m, 4H), 4.02-4.35 (m, 8H), 6.95-6.99 (m, IH), 7.09 (br s, IH), 7.22, 7.36 (br s, IH), 7.39 (br s, IH); ES-MS m/z 537 (M+H). Example 32 Cell fusion assay

The assay measures the ability of a test compound to inhibit gpl20 and CD4/CCR5 -dependent cell-cell fusion. The assay uses two cell lines, 1) CHO-tat cell line that expresses the viral gpl20 from a R5 using virus (JR-FL) and the HIV tat proteins, 2) P4-CCR5 cell line that expresses human CD4 and CCR5 on the surface and carries a β-galactosidase construct under the control of the retroviral promoter LTR. Once fusion of these two cell lines occurs, the tat protein from the CHO cell line trans-activates the reporter gene β-galactosidase in the P4-CCR5 cell line. In a 96 well format, 1 x 10⁴ cells of each cell line are plated per well in the presence or absence of test compound. The cells are then incubated at 37°C, 5% CO₂ for 18-24 hours. The β-galactosidase activity in each well is measured by the addition of a luminescence substrate (Gal-Screen substrate, Applied Biosystems) and luminescence monitored with a Victor 2 plate reader (Wallac). The ability of test compounds to inhibit fusion is indicated by a decrease in β-galactosidase activity. Results are reported as the concentration of test compound required to inhibit 50% of the β-galactosidase activity in the test controls.

When tested in the assay described above, many compounds of the invention exhibited IC₅₀' s in the range of 0.01 nM to 100 nM.

Example 33

Assay for inhibition of RANTES binding to HEK293F.CCR5 cells

For the competition binding studies, a concentration range of antagonist was incubated for 45 minutes at room temperature in binding buffer (50 mM HEPES, 5 mM MgCl₂, 1 mM CaCl₂, 0.2% BSA pH 7.4) with 8 μg of HEK293F.CCR5 cell membrane and 50 pM ¹²⁵I-RANTES (Perkin Elmer, 81400 GBq/mmol) in Milipore GF-B filter plates. Unbound ¹²⁵I-RANTES was removed by washing with cold 50 mM HEPES, 0.5 M NaCl pH 7.4. Compounds were tested at a concentration range of 10,000 - 0.6 nM. The 50% inhibitory concentration (IC₅₀ value) was defined as the concentration of test compound required to inhibit RANTES binding by 50% relative to untested controls.

When tested in the assay described above, many compounds of the invention exhibited ICso's in the range of 1 nM to 500 nM. Example 34 Assay for inhibition of HIV-I using PBMC and R5

Performed as described in literature (Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. Schols, D., et ah, J. Exp. Med. (1997) 186:1383-1388).

The method was as follows:

PBMC from healthy donors were isolated by density gradient centrifugation and stimulated with PHA at 1 μg/ml (Sigma Chemical Co., Bornem, Belgium) for 3 days at 37°C. The activated cells (PHA-stimulated blasts) were washed three times with PBS, and viral infections were performed. The cells were seeded in 48-well plates (5 x 10⁵ cells per well in 200 μL culture medium) and pre-incubated for 15 min with compounds at different concentrations. Then 500 pg p24 viral Ag/well of CCR5-using viruses was added. The HIV-I R5 strains BaL, SF-162, ADA, and JR-FL were all obtained through the Medical Research Council AIDS reagent project (Herts, UK). HIV-infected or mock- infected PHA-stimulated blasts were then further cultured in the presence of 25 U/ml of IL-2 and supernatant was collected at days 8-10, and HIV-I core antigen in the culture supernatant was analyzed by the p24 Ag ELISA kit from DuPont-Merck Pharmaceutical Co. (Wilmington, DE).

When tested in the assay described above, many compounds of the invention exhibited IC₅₀' s in the range of 0.01 nM to 50 μM.

Claims

1. A compound of the formula:

Z = H or alkyl or is CH₂ coupled to X;

X = O and k is 0 or 1 ; or

R²-R⁴ are non-interfering substituents other than H; each m or 1 is independently an integer of 0-4; j is 0 or 1 ; and each n is independently 1-2; or a pharmaceutically acceptable salt or conjugate thereof.

2. The compound of claim 1, which is of the formula:

wherein X, R¹ -R⁴, Ar¹, Ar² and j-n are as defined in claim 1, or a pharmaceutically acceptable salt or conjugate thereof.

3. The compound of claim 2, which is of formula (2)

or a pharmaceutically acceptable salt or conjugate thereof.

4. The compound of claim 3, wherein when X is N, R¹ is H, alkyl or cycloalkyl optionally substituted by a single substituent; R³ is alkyl when j is 1 ; 1 and m are 0; and Ar¹ is unsubstituted phenyl; or a pharmaceutically acceptable salt or conjugate thereof.

5. The compound of claim 2, which is of formula (3)

or a pharmaceutically acceptable salt or conjugate thereof.

6. The compound of claim 5, wherein when X is N, R¹ is H, alkyl or cycloalkyl optionally substituted by a single substituent;

R³ is alkyl when j is 1 ; 1 and m are 0; and Ar¹ is unsubstituted phenyl; and one n is 1 and the other is 2 or both n are 1; or a pharmaceutically acceptable salt or conjugate thereof.

7. The compound of claim 1, which is of formulas (4) or (5)

wherein X and Y are as defined in claim 1; ZZ iiss HH oorr aallkkyyll,, aanndd AArr¹¹,, AArr²²,, RR¹¹ --RR⁴⁴ aanndd jj--nn are defined in claim 1; or a pharmaceutically acceptable salt or conjugate thereof.

The compound of claim 7, which is of formula (4)

or a pharmaceutically acceptable salt or conjugate thereof.

9. The compound of claim 8, wherein when X is N or CH, one R > 1 : is, alkyl, alkoxy, cycloalkyl, alkyloxyalkyloxy or an oxidized 5-membered ring, and the other R¹ is H or alkyl;

Ar¹ is monovalent thiophene;

R³ is methyl when j is 1 ; and one n is 1 and the other n is 2, or both n are equal to 1 ; and

Y is =0 or CHCN; or a pharmaceutically acceptable salt or conjugate thereof.

10. The compound of claim 7, which is of formula (5)

or a pharmaceutically acceptable salt or conjugate thereof.

11. The compound of claim 10, wherein when X is N or CH, one R¹ is alkyl, alkoxy, cycloalkyl, alkyloxyalkyloxy or an oxidized 5-membered ring, and the other R¹ is H or alkyl;

Ar¹ is monovalent thiophene; R³ is methyl when j is 1 ; and Y is =0 or CHCN; or or a pharmaceutically acceptable salt or conjugate thereof.

12. The compound of claim 1, which is of formulas (1)-(31) in Table 1.

13. A pharmaceutical composition comprising the compound of any of claims 1-12 and at least one pharmaceutically acceptable carrier.

14. Use of the compound of any of claims 1-12 to prepare a medicament for use in a method to treat a condition modulated by the CCR5 receptor.

15. The use of claim 1 wherein said condition is HIV.