JP2010512340A - Chemokine receptor binding compound - Google Patents

Abstract

  Disclosed are compounds that modulate the activity of chemokine receptors, particularly CCR5.

Description

CROSS-REFERENCE <br/> TO RELATED APPLICATIONS This application was filed on December 6, 2005, which claims the benefit of U.S. Provisional Application No. 60 / 873,121, its entirety by reference the Incorporated herein by reference.
TECHNICAL FIELD The present invention relates generally to novel compounds, pharmaceutical compositions, and uses thereof. More specifically, these novel compounds are modulators of chemokine receptor activity, particularly modulators of the chemokine receptor CCR5, and further show a protective effect against infection of target cells by human immunodeficiency virus (HIV). In another embodiment, the compounds of the invention are useful for the treatment and prevention of various inflammatory and autoimmune diseases.

  About 40 that function at least in part by regulating the complex and regulating a series of complex and overlapping biological activities important for lymphoid cell and extravasation motility and leukocyte tissue infiltration. Human chemokines have been described. (See Ponath, P., Exp. Opin Invest. Drugs (1998) 7: 1-18). These chemotactic cytokines, or chemokines, are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils, and neutrophils to the site of inflammation, about 8 to It constitutes a family of 10 kDa proteins and plays a role in cell ripening of the immune system. Chemokines are thought to share a common structural motif consisting of four conserved cysteines involved in maintaining tertiary structure. There are two major chemokine subfamilies, “CC” or β-chemokines and “CXC” or α-chemokines, but the first two cysteines are separated by a single amino acid, ie CXC, or It depends on whether it is adjacent, ie CC.

  These chemokines specifically bind to cell surface receptors belonging to a family of G protein-coupled 7 transmembrane proteins called “chemokine receptors” and mediate biological activity through these receptors. Chemokine receptors are classified based on the chemokines that make up the natural ligand of the receptor. The chemokine receptors for β-chemokines are termed “CCR” and those for α-chemokines are termed “CXCR”. These chemokine receptors include, but are not limited to, CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CXCR3 and CXCR4 (for a complete review, see Murphy, et al. Pharmacol. Rev. (2000) 52: 145-176).

  Chemokines are thought to be major mediators in the initiation and maintenance of inflammation (Chemokines in Disease; Humana Press (1999), edited by C. Herbert; Murdoch, et al., Blood (2000) 95: 3032-). (See 3043). More specifically, it has been discovered that chemokines 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., J. Biolog. Chem (1998) 7: 4282-4287). Both chemokine receptors CXCR4 and CCR5 are involved in the cause of infection by human immunodeficiency virus (HIV).

  In most cases, HIV first binds to the CD4 receptor of the target cell via the gp120 coat protein. Conformational changes are thought to occur in gp120, resulting in subsequent binding to chemokine receptors such as CCR5 (Wyatt, et al., Science (1998) 280: 1884-1888). Subsequent HIV-1 isolates resulting from infection bind to the CXCR4 chemokine receptor. The observed binding of feline immunodeficiency virus, another related retrovirus to the chemokine receptor, which does not need to bind to the CD4 receptor first, indicates that the chemokine receptor is fundamental and absolute to the immunodeficiency retrovirus. This suggests that it may be a typical receptor.

  After initial binding to CD4 by HIV, different members of the chemokine receptor family that act as fusion cofactors for HIV-1 macrophage-tropic (M-tropic) and T-cell (T-tropic) isolates. Virus-cell fusion occurs mediated by members (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. (19 6) 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, most HIV particles change from M-tropic to the more aggressive pathogen T-tropic virus phenotype (Miedema, et al., Immun. Rev. (1994) 140: 35). Blaak, et al., Proc. Natl. Acad. Sci. (2000) 97: 1269-1274; Simmonds, et al., J. Virol. (1996) 70: 8355-8360, Tersmette, et al., J. Virol. (1998) 62: 2026-2032; Connor, RI et al., J. Virol. (1994) 68: 4400-4408; Schuitemaker, et al., J. Virol (1992) 66: 1354. -1360). The M-tropic virus phenotype correlates with the ability of the virus to enter the cell after binding of the CCR5 receptor, whereas the T-tropic virus phenotype is the virus into the cell after binding and membrane fusion with the CXCR4 receptor. Correlate with intrusion. Clinically, findings suggest that patients who possess genetic mutations in CCR5 or CXCR4 are considered 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; , J.V irol. (1997) 71: 3219-3227; Theodorou, et al., Lancet (1997) 349: 1219-1220).

  Despite numerous reports of such chemokine receptors mediating HIV entry into cells, CCR5 and CXCR4 are the only physiologically used by a wide variety of HIV-1 strains. It is considered to be a well-related co-receptor (Zhang, et al., J. Virol. (1998) 72: 9307-9912; Zhang, et al., J. Virol. (1999) 73: 3443- 3448; Simmonds, et al., J. Virol. (1988) 72: 8453-8457). T tropic virus fusion and entry using CXCR4 is inhibited by native CXC-chemokine stromal cell derived factor 1 (SDF-1). On the other hand, the fusion and invasion of M-tropic viruses using CCR5 is a natural CC chemokine, a substance that is regulated when normal T cells are expressed and secreted (RANTES or CCL5), and a macrophage inflammatory protein (MIP-1α, respectively). And is inhibited by MIP-1β or CCL3 and 4). SDF-1 is known as CXCL12 or pre-B cell stimulating factor (PBSF).

  However, the binding of chemokine receptors to their natural ligands is thought to play a more evolutionary and central role only as a mediator of HIV infection. Binding of the natural ligand PBSF / SDF-1 to the CXCR4 chemokine receptor provides an important signaling mechanism. CXCR4 or SDF-1-deficient mice exhibit cerebellar, heart and gastrointestinal 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 exhibit hematopoietic deficiency (Nagazawa, et al., Nature (1996) 382: 635-638). Furthermore, migration of CXCR4 expressing leukocytes and hematopoietic progenitor cells to SDF-1 appears to be important for maintaining the localization of B cell lineage and CD34 + progenitor cells in the bone marrow (Bleul, et atl. , J. Exp. Med. (1998) 187: 753-762; Viadot, et al., Ann. Hematol. (1998) 77: 195-197, Auiti, et al., J. Exp. 185: 111-120; Peled, et al., Science (1999) 283: 845-848; Qing, et al., Immunity (1999) 10: 463-471; Lateladlade, 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 when bound to CXCR4 may also play an important role in the regulation of tumor cell proliferation and angiogenesis associated with tumor growth. (Chemokines and Cancer, Humana Press (1999) publication; edited by BJ Rollins; Arenburg, et al., J. Leukocyte Biol. (1997) 62: 554-562; Moore, et al., J. Invest Med). (1998) 46: 113-120; see 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, CXCR4 upregulation of endothelial cells, and SDF-1 can induce angiogenesis in vivo (Salcedo, et al., Am. J. Pathol. ( 1999) 154: 1125-1135). In addition, leukemia cells expressing CXCR4 migrate and adhere to lymph nodes and bone marrow stromal cells that express SDF-1 (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 shown to cause 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. Neurovirolo. y (1999) 5: 32-41), as well as arthritis 164 (Nanki, et al, J.Immunol (2000..): is involved in 5010-5014).

Platelets are also shown to secrete the chemokine RANTES upon activation, and the presence of ANTES on the endothelium is a key step in atherogenesis because macrophage foam cell transformation in the subendothelium is a central step in atherogenesis It promotes the inhibition of monocytes on inflammatory endothelium (Tan, et al., Expert Opin. Investig. Drugs (2003) 12: 1765-1776). Thus, inhibition or suppression of RANTES binding to direct or indirect CCR5 receptor can potentially debilitate the development of atherosclerosis. For example, Met-RANTES has also been shown to inhibit monocyte binding to the active subendothelium (Tan, et al., Supra).
To better understand the relationship between chemokines and their receptors, monoclonal antibodies that the latest experiments blocking HIV fusion, invasion and replication via the CXCR4 chemokine receptor would suggest a useful therapeutic strategy Or carried out through the use of small molecules (Schole, et al., J. Exp. Med. (1997) 186: 1383-1388; Schole, et al., Annual Research (1997) 35: 147-156; Bridger, et al., J. Med. Chem (1994) 42: 3971-3981; and Bridger, et al., “Bicylam Derivatives as HIV Inhibitors” in Advances in Antibiotic Drug D. sigh, Volume 3, p.161-229, JAI press (1999) publication, E.De Clercq editing). Small molecules such as bicyclam are thought to bind specifically to CXCR4 but not CCR5 (Donzella, et al., Nature Medicine (1998) 4: 72-77). These experiments have demonstrated that they interfere with HIV entry and membrane fusion into target cells in vitro.

  Bicyclam has also been shown to inhibit the fusion and replication of feline immunodeficiency virus (FIV) using CXCR4 for entry (Egbering, et al., J. Virol (1999) 73: 6346-6352). CCR5 blockers include monoclonal antibodies, some of which are not chemokine binding but HIV co-receptor activity, fragments of chemokine derivatives such as RANTES, Met-RANTES and AOP-RANTES, and the viral chemokine KSHVvMIP-II Are not selective and both chemokines and HIV block interference with CCR5 (reviewed by Murphy, et al., Pharmacol. Rev. (2000) 52: 145-176). .

  Further experiments showed that bicyclam inhibits 125I-labeled SDF-1 binding to CXCR4 and signaling (indicated by an increase in intracellular calcium) in a dose-dependent manner in response to SDF-1. . Thus, bicyclam also acted as an antagonist to signal transduction resulting from binding of the natural chemokine stromal factor or SDF-1α to CXCR4. Bicyclam also inhibited the induction of HIV gp120 (jacket) apoptosis in non-HIV infected cells (Blanco, et al., Antimicrobial Agents and Chemother. (2000) 44: 51-56).

  While passive immunization with anti-MIP-1α has been shown to delay the expression of collagen-induced arthritis (CIA) in mice and reduce severity, the CIA model is an established mouse 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 can provide a reasonable approach for the treatment of multiple sclerosis. Administration of anti-MIP-1α antiserum has been shown to prevent CNS infiltration by PBMC in mice with experimental allergic encephalomyelitis, a goblet model of multiple sclerosis (Balashov, K. et al. E., et al., Proc. Natl. Acad. Sci. USA (1999) 96: 6873-6878).

  Other studies including chronic rejection of transplanted hearts or cardiac allograft vasculopathy (CAV) and acute kidney allograft rejection have shown that blockade of chemokine receptors such as CCR5 is the treatment or prevention of such diseases. (Yun, JJ, et al., Circulation (2004) 109: 932-937, Panzer, et al., Transplantation (2004) 78: 1341-). 1350). For example, antagonism of the chemokine receptors CCR1 and CCR5 with Met-RANTES attenuated CAV development by reducing mononuclear cell recruitment to the transplanted heart. Met-CCL5, an antagonist of CCR1 and CCR5 were tested and shown to inhibit mammary tumor growth (Robinson, SC, et al., Cancer Res. (2003) 63: 8360-8365).

  As mentioned above, chemokines played an important role and have been shown in a wide variety of human diseases such as autoimmune diseases, allograft rejection, infections, allergies, tumors, and vascular abnormalities. In addition to a contributing role in HIV infection, the chemokine receptor CCR5 includes multiple sclerosis and experimental autoimmune encephalomyelitis, rheumatoid arthritis, intestinal inflammation, allograft rejection, asthma, and cardiovascular disease It has been implicated in diseases such as inflammatory demyelinating diseases of the central nervous system (Gerrard, et al., Natl. Immunol. (2001) 2: 108-115 and Luster, A., N. Eng. J. Med. (1998) 338: 436-445). CCR5 receptor is expressed on T lymphocytes and macrophages, and reports of CCR5 on neurons, astrocytes, capillary endothelial cells, epithelium, vascular smooth muscle, and fibroblasts have been published. In addition to RANTES and MIP-1α / β, the natural ligand that binds to the CCR5 receptor is monocyte chemotactic protein 2 (MCP-2 or CCL8).

US Pat. Nos. 5,583,131, 5,698,546, 5,817,807, 5,021,409, and US Pat. No. 5,583,131, which are hereby incorporated by reference in their entirety. US Pat. No. 6,001,826 discloses cyclic compounds that are active against HIV-1 and HIV2 in in vitro tests. These compounds were later discovered to exhibit anti-HIV activity by binding to the chemokine receptors CXCR4 and / or CCR5 expressed on the surface of cells of the immune system and were further disclosed in PCT WO 02/34745 . This competitive binding thereby protects these target cells from infection by HIV that utilizes CXCR4 for entry. Furthermore, these compounds antagonize the binding, transmission and chemotaxis effects of the natural ligand to CXCR4 of the chemokine stromal chemokine-derived factor 1α (SDF-1). Furthermore, these compounds demonstrate a protective effect against HIV infection of target cells by binding to the CCR5 receptor in vitro. Furthermore, US Pat. No. 6,365,583 describes the above-mentioned patent / patent It is disclosed that these cyclic polyamine antiviral agents described in the application not only enhance the protection of leukocytes (blood cells), but also have antiviral properties. Thus, these agents are useful not only in controlling the side effects of chemotherapy, enhancing bone marrow transplant success, enhancing wound healing, and treating burns, but also in combating bacterial infections of leukemia.

  PCTWO00 / 56729, PCTWO02 / 22600, PCTWO02 / 22599 and PCTWO02 / 34745 show a series of anti-HIV activities by binding to the chemokine receptors CXCR4 and CCR5 expressed on the surface of cells of the immune system. Heterocyclic compounds are described. This competitive binding thereby protects these target cells from infection by HIV that utilizes CXCR4 or CCR5 for invasion. In addition, these compounds antagonize the binding, transmission and chemotactic effects of the natural ligand for CXCR4 of the chemokine stromal chemokine-derived factor 1α (SDF-1) and / or CCR5 of the chemokine RANTES.

  CXCR4, a chemokine receptor, is known not only for gastrointestinal angiogenesis (Tachibana, et al., Nature (1998) 393: 591-594), but also for hematopoiesis and cerebellar development (Zou, et al., Nature (1998)). 393: 591-594). Interference with any of these important functions provided by the binding of pre-B cell growth stimulating factor / stromal factor (PBSF / SDF-1) to the CXCR4 chemokine receptor is angiogenesis, hematopoiesis and cardiogenesis Cause a fatal defect. Similarly, fetal cerebellar development is thought to depend on the effective function of CXCR4 in nerve cell migration and pattern formation in the central nervous system. This G protein-coupled chemokine receptor is thought to play an important role in ensuring the necessary pattern of cerebellar primordium granule cell migration.

  Disclosed herein are compounds that have unique chemical properties and that protect against HIV infection of target cells by binding to the chemokine receptor CCR5. In addition, these compounds antagonize the binding, transmission and chemotactic effects of the natural ligand for CCR5 of 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 regarding dates or explanations regarding the contents of these documents are based on information available to the applicant and do not correspond to the accuracy of the dates and any approval of the contents of these documents. In addition, all documents referenced throughout this application are hereby incorporated by reference in their entirety.

US Pat. No. 5,583,131 US Pat. No. 5,698,546 US Pat. No. 5,817,807 US Pat. No. 5,021,409 US Pat. No. 6,001,826 WO02 / 34745 US Pat. No. 6,365,583 WO00 / 56729 WO02 / 22600 WO02 / 22599 WO02 / 34745

Ponath, P.M. , Exp. Opin Invest. Drugs (1998) 7: 1-18 Murphy, et. al. Pharmacol. Rev. (2000) 52: 145-176 Chemokines in Disease; Humana Press (1999) publication, C.I. Herbert edit Murdoch, et al. , Blood (2000) 95: 3032-3043. Gupta, et al. , J .; Biolog. Chem (1998) 7: 4282-4287. Wyatt, et al. , Science (1998) 280: 1884-1888. 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. Miedema, et al. , Immun. Rev. (1994) 140: 35 Blaak, et al. , Proc. Natl. Acad. Sci. (2000) 97: 1269-1274 Simmonds, et al. , J .; Virol. (1996) 70: 8355-8360 Tersmette, et al. , J .; Virol. (1998) 62: 2026-2032 Connor, R.A. I. et al. , J .; Virol. (1994) 68: 4400-4408 Schuitemaker, et al. , J .; Virol (1992) 66: 1354-1360. 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. Zhang, et al. , J .; Virol. (1998) 72: 9307-9912 Zhang, et al. , J .; Virol. (1999) 73: 3443-3448 Simmonds, et al. , J .; Virol. (1988) 72: 8453-8457 Zou, et al. , Nature (1998) 393: 591-594. Tachibana, et al. , Nature (1998) 393: 591-594. Nagasawa, et al. , Nature (1996) 382: 635-638. Bleul, et al. , J .; Exp. Med. (1998) 187: 753-762 Viadot, 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. Latlaladade, 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 Chemokines and Cancer, Humana Press (1999) publication; J. et al. Rollins editing 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 Salcedo, et al. , Am. J. et al. Pathol. (1999) 154: 1125-1135 Burger, et al. , Blood (1999) 94: 3658-3667. Arai, et al. , Eur. J. et al. Haematol. (2000) 64: 323-332 Bradstock, et al. Leukemia (2000) 14: 882-888. Abi-Younes, et al. , Circ. Res (2000) 86: 131-138 Eitner, et al. , Transplantation (1998) 66: 1551-1557. 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 Xia, et al. , J .; Neurovirology (1999) 5: 32-41. Nanki, et al. , J .; Immunol. (2000) 164: 5010-5014 Tan, et al. , Expert Opin. Investig. Drugs (2003) 12: 1765-1776 Schole, et al. , J .; Exp. Med. (1997) 186: 1383-1388 Schole, et al. , Antiviral Research (1997) 35: 147-156. Bridger, et al. , J .; Med. Chem (1994) 42: 3971-3981. Bridger, et al. "Bicylam Derivatives as HIV Inhibitors" in Advances in Antiviral Drug Design, Volume 3, p. 161-229, JAI press (1999) publication, E.I. Edited by De Clercq Donzella, et al. , Nature Medicine (1998) 4: 72-77. Eggering, et al. , J .; Virol (1999) 73: 6346-6352 Murphy, et al. Pharmacol. Rev. (2000) 52: 145-176 Blanco, et al. , Antimicrobial Agents and Chemother. (2000) 44: 51-56 Szekanecz, Z. et al. , Et al. , AP, Seminars in Immunology, 15 (2003), p. 15-21 Balashov, K.M. E. , Et al. , Proc. Natl. Acad. Sci. USA (1999) 96: 6873-6878 Yun, J .; J. et al. , Et al. , Circulation (2004) 109: 932-937. Panzer, et al. , Transplantation (2004) 78: 1341-1350. Robinson, S.M. C. , Et al. , Cancer Res. (2003) 63: 8360-8365 Gerard, et al. Natl. Immunol. (2001) 2: 108-115 Luster, A.M. , N.M. Eng. J. et al. Med. (1998) 338: 436-445. Tachibana, et al. , Nature (1998) 393: 591-594.

DISCLOSURE OF THE INVENTION The present invention provides novel compounds that modulate chemokine receptors, in particular CCR5 receptors, and interfere with the binding of their natural ligands.

The compounds of the present invention are useful as agents that have a protective effect on target cells from HIV infection. The compounds of the present invention are useful for the treatment and prevention of inflammation and autoimmune diseases. The compound of the present invention acts as an antagonist or agonist of a chemokine receptor, as an agent that enables reconstitution of the immune system by increasing the level of CD4 ⁺ cells, and as an antagonist of apoptosis of immune cells such as CD8 ⁺ cells and nerve cells , And as an antagonist of migration to stromal-derived factor 1 of human bone marrow B lineage cells.

  In one aspect, the present invention provides compounds of formula (1)

Or a pharmaceutically acceptable salt thereof or a conjugate thereof (conjugate),
Where Ar ¹ and Ar ² are independently an optionally substituted carbocyclic or heterocyclic aromatic system;
Each Y is independently O, S, or CHCN;
Z = H or alkyl, or CH ₂ bonded to X;
X = O, k is 0 or 1, or X = N or CH, k is 1-2,
If X = O and Z is CH ₂ bonded to X, then k = 0;
If X = N or CH and Z is CH ₂ bonded to X, then k = 1;
R ¹ is H or a non-interfering substituent, but only one R ¹ is a non-interfering substituent other than H or alkyl;
R ^{2 to} R ⁴ are non-interfering substituents other than H,
Each m or l is independently an integer from 0 to 4;
j is 0 or 1,
Each n is independently 1-2.

Optional substituents included in the definition of R ¹ -R ⁴ can be alkyl, alkenyl or alkynyl, including straight chain, branched chain or cyclic forms thereof, or each is selected from O, N and S; And / or organic functional groups containing one or more heteroatoms optionally substituted by other inorganic substituents and / or carboxylic acids, carboxylic esters, carboxylic amides, substituted amino groups, etc. It can be aromatic, including. Inorganic substituents include ═O, ═NOH, NH ₂ and its oxidized form, SH and its oxidized form, and the like. As described, R ¹ can also be H.

Ar ¹ and Ar ² are 5-12 ring member aromatic systems, including heterocyclic ring members. Ar ¹ and Ar ² can also be substituted with non-interfering substituents as described above, but cannot contain one or more additional aromatic systems. The non-interfering substituents themselves may be inorganic moieties such as OH, NH ₂ and / or oxidized forms thereof, SH and / or oxidized forms thereof, or oxidized forms of phosphorus.

Non-interfering substituents themselves contained in R ¹ to R ⁴ also, as defined above, may comprise an aryl or heteroaryl system. The included system may itself have substituents other than those containing additional aromatic systems, as summarized above.

  “Non-interfering substituents” refers to substituents that do not destroy the ability of the compound to modulate at least the CCR5 chemokine receptor. Measurement methods for modulating the CCR5 receptor are well known in the art, and compounds containing any given series of non-interfering substituents can be readily tested.

  The present invention also provides a pharmaceutical composition comprising one or more compounds having formula (1) and a pharmaceutically acceptable carrier. The invention also includes a method for treating a CCR5-mediated disease of a cell, tissue or organ comprising the step of treating the CCR5-mediated disease by contacting one or more compounds having formula (1) with the system. provide. The present invention also provides a method for treating a CCR5-mediated disease in a human or animal subject comprising the step of treating the CCR5-mediated disease by administering one or more compounds having formula (1) to the subject. .

  Examples of CCR5 mediated diseases that can be treated using the compounds of the present invention include: HIV, central nervous system inflammatory demyelinating disease, autoimmune disease, multiple sclerosis, experimental autoimmune encephalomyelitis, psoriasis or Rheumatoid arthritis, intestinal inflammation, allograft rejection, asthma, cardiovascular disease, atherosclerosis, allergic disease, allergic rhinitis, dermatitis, hypersensitivity lung disease, hypersensitivity pneumonia, 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, myasthenia gravis, juvenile diabetes, glomerulonephritis, autoimmune thyroiditis, graft rejection, allograft rejection, graft-versus-host disease, inflammatory bowel disease, black Disease, ulcerative colitis, spondyloarthritis, scleroderma, psoriasis, inflammatory dermatosis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, hives, eosinophilic myositis, favorable Examples include, but are not limited to, eosinophilic fasciitis, tumor or cancer.

  The compound of formula (1) can form hydrates or solvates and can be any stereoisomeric form and mixtures of the stereoisomeric forms. Racemic compounds can be separated into their individual isomers using known separation and purification methods. The individual optical isomers and mixtures thereof are included within the scope of the present invention. The compounds of the invention can be provided in the form of a pharmaceutically acceptable salt or conjugate, such as a PEGylated form, or in a form that is bound to a target agent or further desired moiety.

  In one aspect, the present invention provides a compound having formula (1) above, which is a modulator of a chemokine receptor.

More particularly, the compounds may bind chemokine receptors, interfere with the binding of their natural ligands and show protective effects on target cells from HIV infection. The compounds are useful as antagonists or agonists of chemokine receptors, and therefore as antagonists of apoptosis of immune cells such as CD8 ⁺ cells and neurons and of migration to human bone marrow B lineage cell stromal factor 1 As an antagonist, it allows reconstitution of the immune system by increasing levels of CD4 ⁺ cells.

Chemokine antagonists that interfere with the binding of chemokines to receptors are as antagonists of apoptosis of immune cells such as CD8 ⁺ cells (Herbin, et al., Nature (1998) 395: 189-193) and of neuronal apoptosis. As antagonists (Ohagen, et al., J. of Virol. (1999) 73: 897-906; and Hesselgersser, et al., Curr. Biol. (1998) 8: 595-598) at the level of CD4 ⁺ cells Increased is useful for reconstitution of the immune system (Biaard-Piechaczzyk, et al., Immunol. Lett. (1999) 70: 1-3). Chemokine receptor antagonists also inhibit migration of human bone marrow B lineage cells into stroma-derived factor 1 (see, eg, Fedyk, E. et al., J of Leukocyte Biol. (1999) 66: 667-783). thing).

  The present invention relates to pharmaceutical compositions containing a therapeutically effective amount of one or more compounds of formula (1) together with at least one excipient, and human compositions or other animals using such compositions. A method for treating a disease of the body. The term “therapeutically effective amount” as used herein elicits the desired response of a cell, tissue, organ, system, animal or human that is sought by a researcher, veterinarian, physician, or other clinician. Refers to the amount of one or more compounds of formula (1).

  The present invention provides a method for inhibiting or interfering with the binding of a chemokine receptor to a natural ligand comprising the step of contacting a chemokine receptor with an effective amount of one or more compounds of formula (1). The present invention relates to a target having a chemokine receptor whose binding to a pathogen results in a disease or pathology comprising administering to a mammalian subject a pharmaceutical composition containing a therapeutically effective amount of one or more compounds of formula (1) A method of protecting cells is also provided.

  The present invention provides the use of a compound of formula (1) in the manufacture of a medicament for the treatment of diseases where it is advantageous to inhibit or interfere with the binding of chemokine receptors to natural ligands. The compound is prepared in the composition in an amount corresponding to a therapeutically effective amount of the compound of formula (1).

Compounds of the invention The compounds of the invention are described in formula (1). Equations (2)-(5) represent a specific embodiment of equation (1).
As mentioned above, the compound of formula (1) has the structure

Have
Wherein each Ar ¹ and Ar ² is independently an optionally substituted carbocyclic or heterocyclic aromatic system;
Each Y is independently O, S, or CHCN;
Z = H or alkyl, or CH ₂ bonded to X;
X = O, k is 0 or 1, or X = N or CH, k is 1-2,
If X = O and Z is CH ₂ bonded to X, then k = 0;
If X = N or CH and Z is CH ₂ bonded to X, then k = 1;
R ¹ is H or a non-interfering substituent, but only one R ¹ is a non-interfering substituent other than H or alkyl;
R ^{2 to} R ⁴ are non-interfering substituents other than H,
Each m or l is independently an integer from 0 to 4;
j is 0 or 1,
Each n is independently 1-2.
Or a pharmaceutically acceptable salt or conjugate thereof.

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

When an alkyl, alkenyl or alkynyl group is described as “optionally substituted” it is unsubstituted or not limited to, OR, NR ₂ , NROR, NRNR ₂ , SR, SO ₂ , SOR , SO ₂ R, SO ₂ NR ₂ , NRSO ₂ , NRCONR ₂ , NRCOOR, NRCOR, CN, COOR, CONR ₂ , OOCR, COR, NO ₂ , ═O and ═NOR (each R is independently H or It can be substituted with one or more substituents, including substituents selected from the group consisting of alkyl (1-8C).

  Heteroalkyl, heteroalkenyl, or heteroalkynyl is an alkyl, except that it contains one or more heteroatoms selected from N, O, and S at one or more carbon atom positions of the alkyl, alkenyl, or alkynyl group. , Alkenyl and alkynyl. Only two adjacent carbon atoms are replaced by heteroatoms. It should be understood that when N is present, it is trivalent and must be appropriately substituted according to the generally understood principles of chemical stability.

  Halo typically refers to any halogen, including F, Cl, Br and I.

  The term aromatic refers to a polyunsaturated aromatic hydrocarbon substituent containing at least one aromatic ring that has no heteroatoms as ring members, or an aromatic containing at least one heteroatom as ring members. Refers to any of the group heteroaromatic substituents. Where two or more adjacent ring atoms are heteroatoms, one or more heteroatoms may exist as ring members of a heteroaryl group. Aromatic structures encompass compounds having monocyclic, bicyclic, or multiple ring systems, and thus may include mixtures of aryls and heteroaryl groups. At least one ring system must be aromatic or heteroaromatic. The number of ring members is typically 5-12.

Non-limiting examples of aromatic or heteroaromatic substituents include cyclic or acyclic alkyl, alkenyl, alkynyl, halogen, CN, CHO, CF ₃ , OCF ₃ , NO ₂ , OH, NHC (O) ( C _1-6 acyclic or C _3-6 cyclic alkyl), NHC (O) CF ₃ , NHSO ₂ (C _1-6 alkyl), NHC (O) NH ₂ , NHC (O) (C _1-6 alkyl) _{, C (O) NH 2,} C (O) NHC 6 H 5, C (O) C 6 H 4 C (O) OH, C (O) N (OC 1-6 _{alkyl) (C 1-6} alkyl) , C (O) NHCH ₂ C (O) O (C _1-6 alkyl), C (O) (C _1-6 alkyl), C (O) O (C _1-6 alkyl), C (O) ( non-aromatic heterocyclic _{ring), OC (O) (C} 1-6 alkyl), _{O (C 1-6} alkyl) O _{(C 1-6} alkyl) _{O (C 1-6} alkyl), _{O (C 1-6 alkyl) C (O) OH, OC} 6 H 4 C (O) OH, OC 6 H 4 C (O) NH ₂ , O (C _1-6 alkyl) C (O) O (C _1-6 alkyl), O (C _1-6 alkyl) C (O) NH ₂ , O (C _1-6 alkyl) C (O) NHNH ₂ , OSO ₂ (C _1-6 alkyl), OC (O) O (C _1-6 alkyl), OC (O) N (C _1-6 alkyl) ₂ , OC (O) (heteroaryl), COOH, C (O) NH (C _1-6 alkyl), C (O) N (C _1-6 alkyl) ₂ , S (C _1-6 alkyl), CH═NOH, CH═NO (C _1-6 alkyl) , CH = _{N (C 1-6 alkyl), (C 1-6} alkyl) _C = _{NOH, (C 1-6} alkyl) _C = NO _{(C 1- Alkyl), (C 1-6} alkyl) _C = _{N (C 1-6 alkyl), (C 1-6 alkyl) C 6 H 4 C (O} ) OH, (C 1-6 alkyl) NHC (O) ( C _1-6 alkyl), CH═CHC (O) O (C _1-6 alkyl), CH═CHC (O) OH, SO _n R ⁶ , wherein n is 1 or 2.

The term “inorganic substituent” means a substituent that does not contain carbon. Examples of inorganic substituents include either nitro, halogen, azide and sulfonic acids, sulfinic acids, phosphoric acids, and phosphonic acids, either in acid form or simple C1-C4 esters such as, for example, dimethyl phosphonate. However, it is not limited to this.
Certain embodiments of formula (1) are represented by formulas (2) to (5)

Is represented by

In the formulas (2) to (5), X, Y, Z, Ar ¹ , Ar ² and R ^{1 to} R ⁴ are defined with respect to the formula (1), and j to n are the same.

In a preferred form of formula (2) or (3), when X is N, R ¹ is H, alkyl or cycloalkyl, optionally substituted with a single substituent, and when j is 1. , R ³ is alkyl, preferably methyl. Particularly preferred are compounds of formula (2) or (3), wherein l and m are 0 and Ar ¹ is unsubstituted phenyl.

Preferred forms of formulas (4) and (5) are those in which R ¹ is an alkyl, alkoxy, cycloalkyl, alkoxyalkoxy, or oxidized 5-membered ring. More preferred embodiments of R ¹ are methyl, methoxy, 2-oxo-oxazolidine, 2-methoxyethoxy, and cyclopropyl. When R ¹ is as described above, the remaining embodiments of R ¹ in formula (4) or (5) are possible when X is N, or CH is H, or alkyl, preferably H. . Preferred embodiments of X are N or CH, and Y is O or CHCN. Preferably R ³ is alkyl, preferably methyl, and j is 0 or 1. Ar ¹ 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 where both n are 1 are also within the scope of the present invention. To do.

Exemplary embodiments Ar ¹ and Ar ² are phenyl, pyridinyl, thiazolyl, oxazolyl, pyrimidinyl, indolyl, indolinyl, imidazolyl, benzimidazolyl, theopherin, isoindolinyl, 1,3-benzodioxolyl, 1,4-benzo Including dioxanyl, benzofuranyl, 2,3-dihydroxybenzofuranyl, fusaranyl and the like.

  Exemplary embodiments of the compounds of the invention are listed in Table 1.

  The compounds of the present invention may be administered in the form of non-toxic pharmaceutically acceptable salts. As used herein, the term “pharmaceutically acceptable salt” refers to pharmacokinetic properties, particularly when the salt is compared to the free active ingredient or other previously disclosed salt forms. It means an active ingredient containing a compound of the present invention used in the form of its salt to give an improved active ingredient. The term “pharmaceutically acceptable salt” refers to acetic acid, lactobionic acid, benzenesulfonate, lauric acid, benzoic acid, malic acid, bicarbonate, maleic acid, bisulfate, mandelic acid, bitartrate, mesylate , Boric acid, methyl bromide, bromide, methyl nitrite, calcium edetic acid, methyl sulfuric acid, cansylic acid, mucolate, carbonic acid, napsylic acid, chloride, nitric acid, clavulanic acid, N-methylglucamine, citric acid , Ammonium salt, dihydrochloride, oleic acid, edetic acid, oxalic acid, edicylic acid, pamoic acid (embonate), esterate, palmitate, esylate, pantothenic acid, fumaric acid, phosphoric acid, diphosphoric acid, glucosuccinic acid, polygalacturo Acid, gluconic acid, salicylic acid, glutamine, stearic acid, glycolylarsanilate, sulfuric acid, hexyl resole Phosphate, diacetate, hydraamine, succinic acid, hydrobromic acid, tannic acid, hydrochloride, tartaric acid, hydroxynaphthoate, teocric acid, tosylate, isothionate, iodide, triethiodide, lactate, pamoic acid Including, but not limited to, valeric acid and the like encompass all acceptable salts.

  The pharmaceutically acceptable salts of the compounds of this invention can be used as dosages for adjusting solubility and hydrolysis properties, or can be used in sustained release or prodrug form. Also, pharmaceutically acceptable salts of the compounds of the present invention include sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and other cations, and ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, Formed from bases such as choline, N, N′-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, and tetraethylammonium hydroxide Can be included.

All of the compounds of the present invention contain at least one chiral center. The present invention includes stereoisomers, mixtures of individual stereoisomers and enantiomeric mixtures, and mixtures of multiple stereoisomers. That is, the compound can be supplied in any desired degree of chiral purity. However, preferred forms of the compounds of formulas (2) and (3) are those in which Ar ¹ is replaced with a chiral carbon of S configuration.

  The compound can be supplied in conjunction with a targeting agent such as, for example, an antibody or ligand specific for PEG, PEO, receptors or other targets.

Utility and Administration In one aspect, the present invention is directed to compounds of formula (1) that modulate chemokine receptor activity. Chemokine receptors include, but are not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CXCR3, and CXCR4.

  In one embodiment, the present invention specifically protects target cells from HIV infection by binding to chemokine receptors and thus affecting the binding of natural ligands to CCR5 and / or CXCR4 of target cells. Provided is a compound of formula (1) which can exhibit an action.

  In another embodiment, the compounds of the present invention may be useful as agents that affect chemokine receptors such as CCR1, CCR2, CCR3, CCR4, CCR5, CXCR3, CXCR4, and such chemokine receptors may be It correlates with important mediators of immunoregulatory diseases as well as many inflammations.

  Other diseases that are also associated with chemokines as mediators include angiogenesis, tumor formation such as the brain, and breast adenoma. Accordingly, compounds that modulate the activity of such chemokine receptors are useful for the treatment or prevention of such diseases.

  As used herein, the term “intermediate and / or modulation” refers to antagonist / antagonism, agonist / receptor activation, partial antagonist / partial antagonism, and / or partial agonist / partial receptor activation. Encloses the action, ie inhibitor and activator. The compounds of formula (1) described herein are capable of modulating CCR5 chemokine receptor activity and the resulting or related pathogenic processes subsequently mediated by CCR5 receptor and its natural ligands. May have active activity.

  In one embodiment, the compound of formula (1) exhibits a protective effect against infection by inhibiting the binding of HIV to chemokine receptors on target cells such as CCR5 and / or CXCR4. Such modulation is obtained by a method comprising contacting a target cell with an effective amount of a compound that inhibits viral binding to a chemokine receptor. As used herein, the term “modulation and / or modulation” refers to any tissue of a particular patient in which the target cell is found, and any cellular component that includes those cells in which the target cell can be located. Encloses modulation of activity in all types and subtypes of the CCR5 receptor.

  Compounds that inhibit chemokine receptor activity and function include asthma, allergic rhinitis, hypersensitivity lung disease, hypersensitivity pneumonia, eosinophilic pneumonia, delayed type hypersensitivity, atherosclerosis, interstitial lung disease (ILD) (Eg, idiopathic pulmonary fibrosis or rheumatoid arthritis-related ILD, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis) or other allergies Disease; systemic anaphylaxis or hypersensitivity reaction, drug allergy, insect sting allergy; rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile diabetes, etc .; thread Graft nephritis, autoimmune thyroiditis, allograft rejection, including graft rejection, graft-versus-host disease; such as Crohn's disease and ulcerative colitis Symptomatic bowel disease; spondyloarthropathy; scleroderma; psoriasis (including T-cell mediated psoriasis) and dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, etc .; blood vessels Can be used to treat inflammation-related diseases including, but not limited to, inflammation (eg, necrosis, skin and hypersensitivity vasculitis); eosinophilic myositis, eosinophilic fasciitis; .

  In addition, compounds that activate or promote chemokine receptor function may include chemotherapy, radiation therapy, enhanced wound healing and burn treatment, therapy for autoimmune diseases, or other drug therapy (eg, corticosteroid therapy), or Diseases related to immunosuppression in individuals receiving linkage between existing drugs used in the treatment of autoimmune diseases and graft / transplant rejection, or congenital defects in receptor function or other causes Used for the treatment of. Compounds that activate or promote chemokine receptor function include, but are not limited to, helminth infections such as linear animals (roundworms); Trichuriasis, helminthiasis, roundworm, helminthiasis, faecal nematosis, trichinosis, filaria Visceral parasitosis, visceral larva migration (eg Toxocara), eosinophilic gastroenteritis (eg Anisaki spp., Phokanema ssp.), Skin larva migration (Ancylostona brazilianse, Ancylostoma) Parasites including the protozoan Plasmodium vivax due to malaria, the human cytomegalovirus, the Herpesvirus saimiri, and the Kaposi's sarcoma herpesvirus known as human herpesvirus 8, and the poxvirus Moluscum contagiosum It can also be used for the treatment of infectious diseases and the like.

  The compounds of the present invention may be combined with any other active agent or pharmaceutical composition where such combination therapy is useful for preventing and treating inflammation and immunomodulatory diseases by modulating chemokine receptor activity. Can be used.

Furthermore, the compounds can be used in combination with one or more agents that are useful in the prevention or treatment of HIV. Examples of such drugs include
(1) Nucleotide reverse transcriptase inhibitors such as tenofovir disoproxil fumarate; lamivudine / dizovudine; abacavir / lamivudine / zidovudine; emtricitabine; amdoxovir; arobudine; DPC-817; SPD-756; SPD-754; CGS7430; -126,443 (β) -L-Fd4; didanosine, sarcitabine, stavudine, adefovir, adefovir dikipivoxil, fodivudine tidoxyl and the like;
(2) Non-nucleotide reverse transcriptase inhibitors such as nevirapine, delavirdine, efavirenz, lobilide, immunocam, oltipraz, TMC-125 (including drugs having antioxidant activity such as immunocam, oltipraz); DPC-083; couplerbilin; calanolide A; SJ-3366 series, etc .;
(3) Protease inhibitors such as saquinavir, pinaviruro / ritonavir, atazanavir, fosamprenavir, tipranavir, TMC-114, DPC-684, indinavir, nelfinavir, amplinavir, parinavir, rasinavir;
(4) Invasion inhibitors such as T-20; T-1249; PRO-542; PRO-140; TNX-355; BMS-806 series; and 5-helix;
(5) CCR5-receptor inhibitors such as Sch-C (or SCH351125); Sch-D (or SCH350634); TAK779; UK427,857 and TAK449; or T22, T134, T140, an 18 amino acid analog of polyphemsin II, CXCR4-receptor inhibitors such as ALX40-4C, ALK40-4C, AMD3100 and AMD070;
(6) integrase inhibitors such as L-870 and 810; GW-810781 (S-1360); and (7) budding inhibitors such as AP-344; and PA-457
including.

  Combinations of HIV agents and compounds of the present invention are not limited to the above examples, but include combinations with any agent useful for the treatment of HIV. The combination of a compound of the invention and the HIV agent can be administered separately or in combination. Administration of one drug can be before, simultaneously with, or after administration of the other drug.

  The compounds according to the invention can be administered orally, intramuscularly, intraperitoneally, intravenously, intracapsular injection or infusion, subcutaneous injection, transdermal or transmucosal administration, or by graft. The compounds can be administered by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes, and contain conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for each route of administration. Can be prepared alone or together in a single dosage unit formulation.

  The compounds of the present invention can be used to treat animals including mice, rats, horses, cows, sheep, dogs, cats, and monkeys. However, the compounds of the present invention can also be used in other species such as birds (eg, chickens). The compounds of the present invention may also be effective for human use. The term referred to herein as “subject” or alternatively “patient” is intended to refer to an animal, preferably a mammal, and most preferably a human that is the subject of treatment, observation or experimentation. However, the compounds, methods and pharmaceutical compositions of the present invention can be used in the treatment of animals.

  The invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of formula (1). The compounds can be administered alone or as a mixture with a pharmaceutically acceptable carrier (eg, tablets, capsules, granules, powders, etc .; liquid formulations such as syrups, injections, etc.). The compound can be administered orally or parenterally. Examples of parenteral formulations include infusions, drops, suppositories, vaginal suppositories.

  In the treatment or prevention of conditions requiring chemokine receptor modulation, suitable dosage levels are generally about 0.01-500 mg / kg / subject body weight / day, administered in single or multiple doses Can be done. Preferably, the dose level will be about 0.1 to about 250 mg / kg / day. The dose level and frequency of administration of a patient are different, the activity of a compound used, the metabolic stability and length of action of the compound, age, weight, overall health, sex, diet, dosage form and time, Understand that it depends on a variety of factors, including elimination rate, drug linkage, severity of certain conditions, and patient treatment experience.

  In another aspect of the invention, the compounds of formula (1) may be used in screening tests for compounds that modulate the activity of chemokine receptors, preferably CCR5 receptors. The ability of a test compound to inhibit gp120 and CD4 / CCR5-dependent cell-cell fusion can be measured using cell fusions well known in the art.

  The compounds of formula (1) disclosed herein may be useful for the separation of receptor variants, which are more powerful according to the processes described herein and processes well known in the art. Can be a screening tool for compound discovery. Compounds of formula (1) may be useful for establishing or characterizing binding of chemokine receptors to sites of other ligands, including compounds other than formula (1), for example by competition inhibition. The compounds of the present invention may also be useful for the evaluation of certain putative mediators of various chemokine receptors. As understood in the art, a complete evaluation of certain agonists and antagonists of the above chemokine receptors is due to the lack of efficacy of non-peptidyl (metabolically resistant) compounds with high binding affinity for these receptors. It is obstructed. Accordingly, the compounds of the present invention are commercial products sold for these purposes.

  The invention is further described by means of examples, but is not meant to be limiting.

The following examples experiment <br/> are not intended to limit the invention, it is intended to illustrate.

  The compounds of the invention are often readily prepared by known methods. Several methods for producing the compounds and intermediates of the invention are described in US 11 / 505,669, filed Aug. 16, 2006, Bridger, et al. , Listed in pending applications.

General process
General Step A: Reductive Amination with NaBH (OAc) _{3 At} room temperature, a stirred solution of CH ₂ Cl ₂ amine (1 equivalent) was added to a carbonyl compound (1 to 2 equivalents), glacial AcOH (0 to 0). 2 equivalents) and sodium triacetoxyborohydride (NaBH (OAc) ₃ ) (about 1.5-3 equivalents) were added and the resulting solution was stirred at room temperature. In a standard workup, the reaction mixture was poured into either saturated aqueous NaHCO ₃ or 1N NaOH. The phases were separated and the aqueous solution was extracted with CH ₂ Cl ₂ . The combined organic extracts were dried (Na ₂ SO ₄ or MgSO ₄ ), filtered and concentrated under reduced pressure. The crude product is purified by flash column chromatography on silica gel or by recrystallization.

General Step B: BOC Deprotection with TFA A BOC protected amine was dissolved in CH ₂ Cl ₂ (about 4 mL / mmol) and trifluoroacetic acid (TFA) (about 2 mL / mmol) was added to a 0.5- Stir for 5 hours at room temperature. In a standard workup, the reaction mixture was neutralized with saturated aqueous NaHCO ₃ or 1N NaOH. The phases were separated and the aqueous solution was extracted with CH ₂ Cl ₂ . The combined extracts were dried (Na ₂ SO ₄ or MgSO ₄ ), filtered and concentrated under reduced pressure. The crude is used as such for the next reaction or purified by flash column chromatography on silica gel.

General Step C: Primary or secondary amine (1 equivalent), carboxylic acid (1.1-2.0 etc.) in EDCI-conjugated CH ₂ Cl ₂ or DMF (concentration about 0.05-1.5 M) Amount), 1-hydroxy-benzotriazole hydrate (HOBT) (1.1-2.0 equivalents), and diisopropylethylamine (DIPEA) or N-methylmorpholine (NMM) (1.5-3 equivalents) To the stirring solution was added 1- [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 standard work-up, the mixture was diluted with CH ₂ Cl ₂ or EtOAc and washed successively with saturated aqueous NaHCO 3 and brine. The organic layer was dried (Na ₂ SO ₄ or MgSO ₄ ), filtered and concentrated under reduced pressure. The crude product is purified by flash column chromatography on silica gel or radial chromatography.

Intermediate

Example 1

Compound 1:
4- [4-((R) -3-cyclohexyl-2-oxo-5-phenyl-imidazolidin-1-yl)-[1,4 ′] bipiperidinyl-1′-carbonyl] -benzoic acid methyl ester MeOH ( (R) -1-cyclohexyl-4-phenyl-3-piperidin-4-yl-imidazolidin-2-one (172 mg, 0.53 mmol), 1-Boc-4-piperidone (210 mg, 2.5 mL) 1.05 mmol), NaBH ₃ CN (100 mg, 1.59 mmol) and glacial AcOH (8 drops) were stirred at 60 ° C. for 16 h. 4-((R) -3-cyclohexyl-2-oxo-5-phenyl-imidazolidin-1-yl)-as a mixture with the corresponding 4-piperidinol (285 mg) with standard workup and purification [1,4 ′] bipiperidinyl-1′-carboxylic acid tert-butyl ester was obtained.

  After general step B, the top material is off-white solid (R) -3- [1,4 ′] bipiperidinyl-4-yl-1-cyclohexyl-4-phenyl-imidazolidin-2-one. Obtained (89.6 mg, 42% by 2 steps).

After general step C, piperidine (89.6 mg, 0.22 mmol), mono-methyl terephthalate (49 mg, 0.27 mmol), EDCI (58 mg, 0.30 mmol), HOBT (45 mg, in DMF (1.5 mL) 0.33 mmol) and NMM (50 μL, 0.45 mmol) were stirred for 19.5 hours at room temperature. Standard work-up and purification gave compound 1 as an off-white foam (69.6 mg, 56%). ¹ H NMR (CDCl ₃ ) δ 0.93-1.09 (m, 1H), 1.14-1.54 (m, 8H), 1.59-1.93 (m, 9H), 2.03- 2.29 (m, 2H), 2.41-2.52 (m, 1H), 2.66-2.81 (m, 2H), 2.87-3.00 (m, 2H), 3. 03 (dd, 1H, J = 8.3, 7.1 Hz), 3.59-3.82 (m, 3H), 3.64 (t, 1H, J = 9.3 Hz), 3.93 (s 3H), 4.57 (dd, 1H, J = 8.9, 6.7 Hz), 4.66-4.77 (m, 1H), 7.24-7.36 (m, 5H), 7 .42 (d, 2H, J = 8.3 Hz), 8.05 (d, 2H, J = 8.3 Hz); ES-MS m / z 573 (M + H).

Example 2

Compound 2: 4- [4-((R) -3-cyclohexyl-2-oxo-5-phenyl-imidazolidin-1-yl)-[1,4 ′] bipiperidinyl-1′-carbonyl] -benzoic acid MeOH A solution of compound 1 (57 mg, 0.10 mmol) and 10M NaOH (0.20 mL, 2.0 mmol) in (2.0 mL) was stirred at 60 ° C. for 3 hours. After cooling, the reaction was diluted with H 2 O (10 mL), the pH was adjusted to 5, and the resulting mixture was extracted with CH ₂ Cl ₂ (25 mL × 3). The organic solution was dried (Na ₂ SO ₄ or MgSO ₄ ), filtered and concentrated under reduced pressure to give light yellow solid Compound 2 (52 mg, 94%). ¹ H NMR (CDCl ₃ ) δ 1.04-1.19 (m, 1H), 1.27-1.50 (m, 4H), 1.55-2.19 (m, 12H), 2.26 -2.42 (m, 1H), 2.73-3.00 (m, 3H), 3.04-3.50 (m, 4H), 3.11 (dd, 1H, J = 8.7, 7.2 Hz), 3.55-3.83 (m, 3H), 3.77 (t, 1H, J = 9.2 Hz), 4.68-4.80 (m, 1H), 4.73 ( dd, 1H, J = 9.5, 7.1 Hz), 7.28-7.40 (m, 5H), 7.43 (d, 2H, J = 8.1 Hz), 8.03 (d, 2H) , J = 8.1 Hz); ES-MS m / z 559 (M + H).

Example 3

Compound 3: (R) -1-cyclohexyl-3- [1 '-(4,6-dimethyl-pyrimidine-5-carbonyl) -4'-methyl- [1,4'] bipiperidinyl-4-yl] -4 - phenyl - imidazolidin-2-CH ₂ Cl ₂ (2mL) solution of (R)-1-cyclohexyl-4-phenyl-3-piperidin-4-yl - imidazolidin-2-one (302 mg, 0.922 mmol ) And 1-Boc-4-piperidone (184 mg, 0.923 mmol) were added titanium (IV) isopropoxide (0.27 mg, 0.92 mmol) and the mixture was stirred for 48 hours at room temperature. Diethylaluminum cyanide (1.0 M in toluene, 1.1 mL, 1.1 mmol) was added and the mixture was stirred for an additional 20 hours. Standard post-treatment produced a light yellow individual (510 mg).

To a solution of the above nitrile in THF (5 mL) cooled to 0 ° C., MgMeBr (3.0 M in ether, 16 mL, 4.8 mmol) was added dropwise. The mixture was stirred for 1 hour at 0 ° C. and stirred overnight at room temperature. The reaction was quenched with saturated aqueous NH ₄ Cl, purified after standard workup and 4-((R) -3-cyclohexyl-2-oxo-5-phenyl-imidazolidin-1-yl) -4 ′. -Methyl- [1,4 '] bipiperidinyl-1'-carboxylic acid tert-butyl ester was produced (260 mg, 54% in 2 steps)
After general step B, the above carbamate (260 mg, 0.496 mmol) was added to (R) -1-cyclohexyl-3- (4′-methyl- [1,4 ′] bipiperidinyl-4-yl) -4-phenyl -Imidazolidin-2-one was produced (180 mg, 85%).

After general step C, the above amine (60 mg, 0.14 mmol), 4,6-dimethyl-pyrimidine-5-carboxylic acid (30 mg, 0.20 mmol), EDCI (33 mg, CH ₂ Cl ₂ (2 mL)). 0.17 mmol) HOBT (23 mg, 0.17 mmol) and DIPEA (0.09 mL, 0.5 mmol) were stirred overnight at room temperature. Standard work-up and purification yielded compound 3 as a white foam (55 mg, 70%). ¹ H NMR (CDCl ₃ ) 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, 1H), 271-2.98 (m, 3H), 3.02-3.52 (m, 4H), 3.62 (td, 1H, J = 9.3, 1.8 Hz), 3.75 (br t, 1H, J = 11.1 Hz), 4.12-4.25 (m, 1H), 4.52-4.58 (m, 1H) 7.28-7.35 (m, 5H), 8.92, 8.93 (s, 1H); ES-MS m / z 559 (M + H).

Example 4

Compound 4: (R) -3- [1 ′-(6-Chloro-2,4-dimethyl-pyridin-3-carbonyl) -4′-methyl- [1,4] bipiperidinyl-4-yl] -1- Cyclohexyl-4-phenyl-midazolidon-2-one After general step C, (R) -1-cyclohexyl-3- (4′-methyl- [1,4 ′] bipiperidinyl- in CH ₂ Cl ₂ (2 mL) 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) were stirred overnight at room temperature. Standard work-up and purification yielded white foam of compound 4 (60 mg, 72%). ¹ H NMR (CDCl ₃ ) 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, 1H), 2.70-2.94 (m, 3H), 3. 02-3.52 (m, 1H), 3.58-3.64 (m, 1H), 3.74 (br t, 1H, J = 11.4 Hz), 4.08-4.22 (m, 1H), 4.50-4.57 (m, 1H), 7.00-7.02 (m, 1H), 7.28-7.33 (m, 5H); ES-MS m / z 592 ( M + H).

Example 5

Compound 5: (R) -3- [1 ′-(4,6-Dimethyl-pyrimidine-5-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyll-4-ylyl] -4-phenyl - oxazolidin-2-one CH ₂ Cl ₂ (40mL) solution of 1,4-dioxa-8-aza - spiro [4.5] decane (2.99 g, 20.9 mmol) and 1-Boc-4-piperidone ( To a solution of 4.16 g, 20.9 mmol) was added titanium (IV) isopropoxide (6.1 mL, 20.8 mmol) and the mixture was stirred for 20 hours at room temperature. Diethylaluminum cyanide (1.0 M in toluene, 25 mL, 25 mmol) was added and the mixture was stirred for an additional 20 hours. Crude bipiperidine was produced with standard workup.

To a solution of the crude nitrile in THF (90 mL) cooled to 0 ° C., MgMeBr (3.0 M in ether, 35 mL, 105 mmol) was added dropwise. The mixture was stirred for 1 hour at 0 ° C. and overnight at room temperature. The reaction was quenched with saturated aqueous NH ₄ Cl and purified after standard workup to give 4- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -4-methyl. -Piperidine-1-carboxylic acid tert-butyl ester was produced (2 steps, 5.88 g, 82%).

A solution of the above carbamate (5.88 g, 17.3 mmol) and concentrated hydrogen chloride in THF (20 mL) was stirred at room temperature for 20 hours. Standard workup yielded an intermediate amine that was subsequently treated with BOC ₂ O (3.72 g, 17.0 mmol). Standard work-up and purification yielded 4′-methyl-4-oxo- [1,4 ′] bipiperidinyl-1′-carboxylic acid tert-butyl ester (2.49 g, 49% by 2 steps).

After general step A: (R) -2-amino-2-phenyl-ethanol (88 mg, 0.64 mmol) in CH ₂ Cl ₂ (3 mL), the above ketone (190 mg, 0.64 mmol) and NaBH (OAc ) ₃ (157 mg, 0.74 mmol) was stirred overnight at room temperature. Standard work-up and purification yields 4- (R) -2-hydroxy-1-phenyl-ethylamino) -4'-methyl- [1,4 '] bipiperidinyl-1'-carboxylic acid tert-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 CH ₂ Cl ₂ (3 mL) cooled to 0 ° C., triphosgene (59 mg, 0.20 mmol). Was added and the mixture was stirred for 30 minutes at 0 ° C. and for 2 hours at room temperature. By standard work-up and purification, 4′-methyl-4-((R) -2-oxo-4-phenyl-oxazolidin-3-yl)-[1,4 ′] bipiperidinyl-1′-carboxylic acid tert- The butyl ester was produced (160 mg, 91%).

  After general step B, the above carbamate (160 mg, 0.360 mmol) was added to (R) -3- (4′-methyl- [1,4 ′] bipiperidinyl-4-yl) -4-phenyl-oxazolidine-2- On was produced (120 mg, 97%).

Following general procedure _{C: CH 2 Cl 2 (2mL} ) solution of the above amine (60mg, 0.17mmol), 4,6- dimethyl - pyrimidine-5-carboxylic acid (90%, 33mg, 0.20mmol) , EDCI A solution of (41 mg, 0.21 mmol), HOBT (29 mg, 0.21 mmol) and DIPEA (0.11 mL, 0.63 mmol) was stirred overnight at room temperature. Standard work-up and purification produced white solid compound 5 (30 mg, 37%).
¹ H NMR (CDCl ₃ ) 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, 1H), 2.74-2.95 (m, 2H), 3.10-3.50 (m, 3H), 4.05-4 .22 (m, 2H), 4.57 (td, 1H, J = 9.0, 2.1 Hz), 4.76-4.82 (m, 1H), 7.30-7.39 (m, 5H), 8.91, 8.92 (s, 1H); ES-MS m / z 478 (M + H).

Example 6

Compound 6: (R) -3- [1 ′-(6-Chloro-2,4-dimethyl-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -4 - phenyl - oxazolidin-2-one following general procedure _{C: CH 2 Cl 2 (2mL} ) solution of (R) -3- (4'- methyl - [1,4 '] 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 mL, 0.63 mmol) were stirred overnight at room temperature. Standard work-up and purification produced white solid Compound 6 (26 mg, 30%). ¹ H NMR (CDCl ₃ ) 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, 1H), 2.74-2.96 (m, 2H), 3.05-3.55 (m, 3H), 4.05-4 .18 (m, 2H), 4.57 (td, 1H, J = 8.4, 1.5 Hz), 4.76-4.82 (m, 1H), 7.01-7.03 (m, 1H), 7.30-7.39 (m, 5H); ES-MS m / z 511 (M + H).

Example 7

Compound 7: (R) -1-tert-butyl-3- [1 ′-(4,6-dimethyl-pyrimidine-5-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -4-phenyl-imidazolidin-2-one (R) -1-tert-butyl-4-phenyl-3-piperidin-4-yl-imidazolidin-2-one (200 mg) in CH ₂ Cl ₂ (2 mL) , 0.663 mmol) and 1-Boc-4-piperidone (133 mg, 0.668 mmol) in solution was added titanium (IV) isopropoxide (0.20 mL, 0.68 mmol) and the mixture was stirred at room temperature for 48 hours. And stirred. Diethylaluminum cyanide (1.0 M in toluene, 0.8 mL, 0.8 mmol) was added and the mixture was stirred for an additional 20 hours. Standard workup produced the intermediate nitrile.

MgMeBr (3.0 M in ether, 2.0 mL, 6.0 mmol) was added dropwise to a solution of nitrile on THF (3 mL) cooled to 0 ° C. The mixture was stirred for 1 hour at 0 ° and stirred overnight at room temperature. The reaction was quenched with saturated aqueous NH ₄ Cl and 4-((R) -3-tert-butyl-2-oxo-5-phenyl-imidazolidin-1-yl) -4 by standard workup and purification. '-Methyl- [1,4'] bipiperidinyl-1'-carboxylic acid tert-butyl ester was produced (250 mg, 76% by 2 steps).

  After general step B: With the above carbamate (250 mg, 0.501 mmol), (R) -1-tert-butyl-3- (4′-methyl- [1,4 ′] bipiperidinyl-4-yl) -4 -Phenyl-imidazolidin-2-one was produced (150 mg, 75%).

Following general procedure _{C: CH 2 Cl 2 (3mL} ) solution of the above amine (80mg, 0.20mmol), 4,6- dimethyl - pyrimidine-5-carboxylic acid (90%, 41mg, 0.24mmol) , EDCI A solution of (46 mg, 0.24 mmol), HOBT (33 mg, 0.24 mmol) and DIPEA (0.12 mL, 0.69 mmol) was stirred overnight at room temperature. Standard workup and purification yielded white foam of compound 7 (47 mg, 44%).
¹ H NMR (CDCl ₃ ) 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, 1H), 2.69-2.92 (m, 2H), 3.03-3.49 (m, 4H), 3.63 (td, 1H, J = 9.0, 1.8 Hz), 4.07-4.22 (m, 1H), 4.43-4.49 (m, 1H), 7.27-7.35 (m, 5H), 8 .90, 8.91 (s, 1H); ES-MS m / z 533 (M + H).

Example 8

Compound 8: (R) -1-tert-butyl-3- [1 ′-(6-chloro-2,4-dimethyl-pyridine-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl- 4-yl] -4-phenyl-imidazolidin-2-one After general step C: (R) -1-tert-butyl-3- (4′-methyl- [1] in CH ₂ Cl ₂ (3 mL). , 4 ′] bipiperidinyl-4-yl) -4-phenyl-imidazolidin-2-one (see Example 8) (74 mg, 0.19 mmol), 6-chloro-2,4-dimethyl-nicotinic acid A solution of (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) was stirred overnight at room temperature. Standard workup and purification yielded white foam of compound 8 (50 mg, 46%). ¹ H NMR (CDCl ₃ ) 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, 1H), 2.70-2.95 (m, 2H), 3.03-3.56 (m, 4H), 3.60-3.67 (m, 1H), 4.05-4.21 (m, 1H), 4.43-4.50 ( m, 1H), 7.00-7.03 (m, 1H), 7.27-7.35 (m, 5H); ES-MS m / z 566 (M + H).

Example 9

Compound 9: (R) -1- [1 ′-(4,6-Dimethyl-pyrimidin-5-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -5-phenyl-imidazo Lysine-2-one After general step A: 2-((R) -2-amino-2-phenyl-ethyl) -isoindole-1,3-dione (1.35 g) in CH ₂ Cl ₂ (20 mL). , 5.07 mmol), 4′-methyl-4-oxo- [1,4 ′] bipiperidinyl-1′-carboxylic acid tert-butyl ester (1.503 g, 5.070 mmol) and NaBH (OAc) ₃ (1. 32 g, 6.23 mmol) was stirred overnight at room temperature. Secondary work-up and purification produced the secondary amine. After standard workup and purification, subsequent treatment of the diamine with hydrazine hydrate (0.25 mL, 5.1 mmol) in EtOH gave 4-((R) -2-amino-1-phenyl-ethyl. Amino) -4′-methyl- [1,4 ′] bipiperidinyl-1′-carboxylic acid tert-butyl ester (810 mg, 39% by 2 steps) was produced.

  To a solution of diamine (176 mg, 0.422 mmol) in DMF (3 mL) was added CDI (76 mg, 0.47 mmol) and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. By standard work-up and purification, 4′-methyl-4-((R) -2-oxo-5-phenyl-imidazolidin-1-yl)-[1,4 ′] bipiperidinyl-1′-carboxylic acid The tert-butyl ester was produced (194 mg, quantum).

  After general step B: (R) -1- (4′-methyl- [1,4 ′] bipiperidinyl-4-yl) -5-phenyl-imidazolidine-2 with the above carbamate (100 mg, 0.226 mmol) -On was produced (65 mg, 84%).

Following general procedure _{C: CH 2 Cl 2 (2mL} ) solution of the above amine (30mg, 0.088mmol), 4,6- dimethyl - pyrimidine-5-carboxylic acid (90%, 18mg, 0.11mmol) , EDCI A solution of (20 mg, 0.10 mmol), HOBT (14 mg, 0.10 mmol) and DIPEA (0.06 mL, 0.3 mmol) was stirred overnight at room temperature. Standard work-up and purification yielded white foam of compound 9 (24 mg, 57%).
¹ H NMR (CDCl ₃ ) δ 0.85 (s, 3H), 1.07-2.15 (m, 8H), 2.39, 2.43 (s, 6H), 2.56-2.64 (M, 1H), 2.74-2.94 (m, 3H), 3.10-3.57 (m, 4H), 3.71-3.78 (m, 1H), 4.05-4 .19 (m, 1H), 4.69-4.84 (m, 2H), 7.29-7.38 (m, 5H), 8.91, 8.92 (s, 1H); ES-MS m / z 477 (M + H).

Example 10

Compound 10: (R) -1- [1 ′-(6-Chloro-2,4-dimethyl-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -5 - phenyl - after imidazolidin-2-one general procedure _{C: CH 2 Cl 2 (2mL} ) solution of (R) -1- (4'- methyl - [1,4 '] 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) were stirred overnight at room temperature. Standard workup and purification yielded white foam of compound 10 (35 mg, 78%). ¹ H NMR (CDCl ₃ ) 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, 1H), 4.05-4.22 (m, 1H), 4.37-4.41 (m, 1H), 4.70-4.77 ( m, 1H), 7.02-7.04 (m, 1H), 7.30-7.40 (m, 5H); ES-MS m / z 510 (M + H).

Example 11

Compound 11: (R) -3- [1 ′-(6-Chloro-2,4-dimethyl-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -1 -Methyl-4-phenyl-imidazolidin-2-one 4'-methyl-4-((R) -2-oxo-5-phenyl-imidazolidine-1- in DMF (2 mL) cooled to 0 ° C Yl)-[1,4 ′] bipiperidinyl-1′-carboxylic acid tert-butyl ester (see Example 9) (92 mg, 0.21 mmol) in a solution of NaH (60%, 17 mg, 0.42 mmol). ) Was added. After stirring for 5 minutes, MeI (0.03 mL, 0.5 mmol) was added and the mixture was allowed to warm to room temperature over 30 minutes and stirred for an additional 60 minutes at room temperature. Aqueous work-up and purification gave 4′-methyl-4-((R) -3-methyl-2-oxo-5-phenyl-imidazolidin-1-yl)-[1,4 ′] bipiperidinyl-1 ′. -Carboxylic acid tert-butyl ester was produced (85 mg, 0.89 mmol).

  After general step B: The above carbamate (85 mg, 0.19 mmol) gives (R) -1-methyl-3- (4′-methyl- [1,4 ′] bipiperidinyl-4-yl) -4-phenyl -Imidazolidin-2-one (55 mg, 81%) was produced.

After general step C: amine above (55 mg, 0.15 mmol), 6-chloro-2,4-dimethyl-nicotinic acid (42 mg, 0.19 mmol), EDCI (37 mg, in CH ₂ Cl ₂ (3 mL). 0.19 mmol), HOBT (26 mg, 0.19 mmol) and DIPEA (0.10 mL, 0.57 mmol) were stirred overnight at room temperature. Standard workup and purification yielded white foam of compound 11 (50 mg, 64%).
¹ H NMR (CDCl ₃ ) 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, 1H), 2.71-2.96 (m, 5H), 3.02-3.56 (m, 4H), 3.62 (t, 1H, J = 9.0 Hz), 4.07-7.21 (m, 1H), 4.53-4.60 (m, 1H), 7.01-7. 02 (m, 1H), 7.28-7.35 (m, 5H); ES-MS m / z 524 (M + H).

Example 12

Compound 12: 1- [1 ′-(6-Chloro-2,4-dimethyl-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -3-methoxy-1 - ylmethyl - after urea general procedure _{a: CH 2 Cl 2 (3mL} ) solution of C- thiophen-3-ylmethyl-amine (74mg, 0.65mmol), 4'- methyl-4-oxo - A mixture of [1,4 ′] bipiperidinyl-1′-carboxylic acid tert-butyl ester (176 mg, 0.594 mmol) and NaBH (OAc) ₃ (158 mg, 0.745 mmol) was stirred overnight at room temperature. Standard workup and purification yielded 4′-methyl-4-[(thiophen-3-ylmethyl) -amino]-[1,4 ′] bipiperidinyl-1′-carboxylic acid tert-butyl ester (240 mg ,quantum).

CH ₂ Cl ₂ (3mL) solution of the above amine (240mg, 0.610mmol), N- ( 4- nitrophenoxy carbonyl) methoxylamine (155 mg, 0.731 mmol) and DIPEA of (0.13 mL, 0.75 mmol) The solution was stirred with the solution for 90 minutes. Standard work-up and purification produced the desired intermediate pair. After general process B: 3-methoxy-1- (4′-methyl- [1,4 ′] bipiperidinyl-4-yl) -1-thiophen-3-ylmethyl-urea was obtained by an intermediate (by two steps). 88 mg, 39%).

After general step C: Amine above (44 mg, 0.12 mmol), 6-chloro-2,4-dimethyl-nicotinic acid (40 mg, 0.18 mmol), EDCI (35 mg) in CH ₂ Cl ₂ (2 mL). , 0.18 mmol), HOBT (25 mg, 0.18 mmol) and DIPEA (0.08 mL, 0.46 mmol) were stirred overnight at room temperature. Standard work-up and purification yielded white foam of compound 12 (50 mg, 78%).
¹ H NMR (CDCl ₃ ) 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, 1H), 2.93-3.00 (m, 2H), 3.21-3.32 (m, 1H), 3 .39-3.48 (m, 1H), 3.63 (s, 3H), 4.05-4.27 (m, 2H), 4.30 (s, 2H), 6.96 (d, 1H) , J = 4.8 Hz), 7.02 (d, 1H, J = 4.8 Hz), 7.09-7.11 (m, 2H), 7.35 (dd, 1H, J = 5.1). 3.0 Hz); ES-MS m / z 534 (M + H).

Example 13

Compound 13: N- [1 ′-(6-Cyano-2,4-dimethyl-1-oxy-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -2 -(2-Oxo-oxazolidine-3-yl) -N-thiophen-3-ylmethyl-acetamide After general step C: 4'-methyl-4-[(thiophen-3-ylmethyl)-in DMF (10 mL) Amino]-[1,4 ′] bipiperidinyl-1′-carboxylic acid tert-butyl ester (see Example 12) (266 mg, 0.677 mmol), (2-oxo-oxazolidine-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 The solution overnight 1mmol), was stirred at room temperature. Standard workup and purification produced the desired carbamate. After general configuration B, the carbamate above gives N- (4′-methyl- [1,4 ′] bipiperidinyl-4-yl) -2- (2-oxo-oxazolidine-3-yl) -N-thiophene- 3-ylmethyl-acetamide was produced (170 mg, 60% by 2 steps).

After general step C: amine above (59 mg, 0.14 mmol), 6-cyano-2,4-dimethyl-1-oxy-nicotinic acid (30 mg, 0.16 mmol), EDCI (30 mg) in DMF (6 mL). , 0.16 mmol), HOBT (21 mg, 0.16 mmol) and DIPEA (0.04 mL, 0.2 mmol) were stirred at room temperature overnight. Standard workup and purification yielded white foam of compound 13 (31 mg, 37%).
¹ H NMR (CDCl ₃ ) δ 0.98 (brs, 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, 1H), 7.10 (brs, 1H), 7.23, 7.36 (brs, 1H), 7.40 (brs, 1H) ES-MS m / z 595 (M + H).

Example 14

Compound 14: N- [1 ′-(6-cyano-2,4-dimethyl-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -2- (2- Oxo-oxazolidin-3-yl) -N-thiophen-3-ylmethyl-acetamide After general step C: N- (4′-methyl- [1,4 ′] bipiperidinyl-4-yl) in DMF (6 mL) 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 mL, 0.19 mmol) The solution of was stirred overnight at room temperature Standard work-up and purification yielded compound 14 as a white foam (27 mg, 41%).
¹ H NMR (CDCl ₃ ) 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, 1H), 7.11 (br s, 1H), 7.23, 7.36 (br s, 1H), 7.40 (br s, 1H) ); ES-MS m / z 579 (M + H).

Example 15

Compound 15: N- [1 ′-(6-Chloro-2,4-dimethyl-1-oxy-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -2 -(2-Oxo-oxazolidine-3-yl) -N-thiophen-3-ylmethyl-acetamide After general step C: N- (4'-methyl- [1,4 '] bipiperidinyl- in DMF (6 mL) 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-1-oxy-nicotinic acid (30 mg, 0.15 mmol), EDCI (29 mg, 0.15 mmol), HOBT (20 mg, 0.15 mmol) and DIPEA (0.03 9 mL, 0.22 mmol) was stirred overnight at room temperature. Standard work-up and purification yielded white foam of compound 15 (10 mg, 12%).
¹ H NMR (CDCl ₃ ) δ 0.96 (br s, 3H), 1.26 to 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, 1H), 7.11 (s, 1H) 7.22-7.38 (m, 2H); ES-MS m / z 604 (M + H).

Example 16

Compound 16: 1- [1 ′-(2,6-Dichloro-4-methyl-1-oxy-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -3 -(2-Methoxyethoxy) -1-thiophen-3-ylmethyl-urea To a solution of N-hydroxyphthalimide (4.50 g, 27.6 mmol) and Et3N (7.7 mL, 55 mmol) in DMF (18 mL) was added 2- Bromoethyl methyl ether (3.9 mL, 41.5 mmol) was added. The mixture was stirred for 72 hours at room temperature. The phthalimide intermediate was produced by standard workup.

To a solution of the above intermediate in CH ₂ Cl ₂ (30 mL) was added methyl hydrazine (1.47 mL, 27.6 mmol) and the mixture was stirred overnight at room temperature. The mixture was filtered, the solid was washed with Et ₂ O, and the combined filtrate was concentrated under reduced pressure to produce the desired amine.

To a solution of 4-nitrochloroformate (5.82 g, 28.8 mmol) in CH ₂ Cl ₂ (15 mL) was added NaHCO ₃ (15 mL) and the mixture was cooled to 0 ° C. The above amine was added and the mixture was stirred for 30 minutes at 0 ° C. and for 30 minutes at room temperature. Standard workup and purification yielded (2-methoxyethoxy) -carbamic acid 4-nitro-phenyl ester (4.24 g, 60% by 3 steps).
4′-methyl-4-[(thiophen-3-ylmethyl) -amino]-[1,4 ′] bipiperidinyl-1′-carboxylic acid tert-butyl ester in CH ₂ Cl ₂ (6 mL) (Example 12 (See) (190 mg, 0.483 mmol), the above solution of nitrophenyl formic acid (149 mg, 0.581 mmol) and DIPEA (0.126 mL, 0.723 mmol) was stirred overnight at room temperature. Treatment yielded crude gizan: after general step B, 3- (2-methoxyethoxy) -1- (4′-methyl- [1,4 ′] bipiperidinyl-4-yl) -1-thiophene with formic acid -3-ylmethyl-urea was obtained (183 mg, 92% by 2 steps).

After general step C, amine above (91 mg, 0.22 mmol), 2,6-dichloro-4-methyl-1-oxy-nicotinic acid (54 mg, 0.24 mmol), EDCI (47 mg) in DMF (8 mL). , 0.25 mmol), HOBT (33 mg, 0.24 mmol) and DIPEA (0.064 mL, 0.37 mmol) were stirred overnight at room temperature. Standard workup and purification yielded pale yellow foam compound 16 (27 mg, 20%). ¹ H NMR (CDCl ₃ ) δ 0.97-2.41 (m, 19H), 2.95-3.15 (m, 2H), 3.29 (s, 3H), 3.31-3.48 (M, 1H), 3.53-3.57 (m, 2H), 3.96-4.00 (m, 2H), 4.28-4.39 (m, 3H), 6.96-6 .97 (m, 1H), 7.10-7.11 (m, 1H), 7.32-7.36 (m, 2H), 7.43 (br s, 1H); ES-MS m / z 614 (M + H).

Example 17

Compound 17: 1- [1 ′-(6-Cyano-2,4-dimethyl-1-oxy-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -3 -(2-Methoxyethoxy) -1-thiophen-3-ylmethyl-urea After general step C: 3- (2-methoxyethoxy) -1- (4'-methyl- [1,4 in DMF (8 mL) '] Bipiperidinyl-4-yl) -1-thiophen-3-ylmethyl-urea (see Example 16) (92 mg, 0.22 mmol), 6-cyano-2,4-dimethyl-1-oxy-nicotine A solution of 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) was added overnight at room temperature. Stir. Standard work-up and purification yielded white foam of compound 17 (65 mg, 50%).
¹ H NMR (CDCl ₃ ) 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, 1H), 7 .09-7.11 (m, 1H), 7.33-7.40 (m, 3H); ES-MS m / z 585 (M + H).

Example 18

Compound 18: 1- [1 ′-(2,6-Dichloro-4-methyl-1-oxy-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -3 -Methoxy-1-thiophen-3-ylmethyl-urea General Step C: 3-Methoxy-1- (4'-methyl- [1,4 '] bipiperidinyl-4-yl) -1-thiophene in DMF (6 mL) -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 mL, 0.49 mmol) were stirred overnight at room temperature. Standard work-up and purification yielded white foam of compound 18 (8 mg, 7%). ¹ H NMR (CDCl ₃ ) 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, 1H, J = 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: 1- [1 ′-(6-Cyano-2,4-dimethyl-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -3-methoxy-1 -Thiophen-3-ylmethyl-urea After general step C: 3-methoxy-1- (4'-methyl- [1,4 '] bipiperidinyl-4-yl) -1-thiophene-3 in DMF (15 mL) -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), A solution of HOBT (150 mg, 1.11 mmol) and DIPEA (0.29 mL, 1.7 mmol) was stirred overnight at room temperature. Standard work-up and purification yielded white foam of compound 19 (87 mg, 17%). ¹ H NMR (CDCl ₃ ) 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, 1H), 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, 1H, J = 4.8 Hz), 7. 07, 7.17 (br s, 1H), 7.33-7.40 (m, 2H), 7.26-7.29 (m, 1H); ES-MS m / z 525 (M + H).

Example 20

Compound 20: 1- [1 ′-(6-Cyano-2,4-dimethyl-1-oxy-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -3 -Methoxy-1-thiophen-3-ylmethyl-urea After general step C: 3-methoxy-1- (4'-methyl- [1,4 '] bipiperidinyl-4-yl) -1 in DMF (8 mL) -Thiophen-3-ylmethyl-urea (see Example 12) (100 mg, 0.273 mmol), 6-cyano-2,4-dimethyl-1-oxy-nicotinic acid (60 mg, 0.31 mmol), EDCI A solution of (60 mg, 0.31 mmol), HOBT (42 mg, 0.31 mmol) and DIPEA (0.082 mL, 0.47 mmol) was stirred overnight at room temperature. Standard workup and purification yielded white foam of compound 20 (31 mg, 21%).
_{^{1 H NMR (CDCl 3) 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, 1H, J = 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-pyridin-3-carbonyl) -4′-methyl- [1,4 ′] bipiperidinyl-4-yl] -3 -Methoxy-1-thiophen-3-ylmethyl-urea After general step C: 3-methoxy-1- (4'-methyl- [1,4 '] bipiperidinyl-4-yl) -1 in DMF (8 mL) -Thiophen-3-ylmethyl-urea (see Example 12) (100 mg, 0.273 mmol), 6-chloro-2,4-dimethyl-1-oxy-nicotinic acid (63 mg, 0.31 mmol), EDCI A solution of (60 mg, 0.31 mmol), HOBT (42 mg, 0.31 mmol) and DIPEA (0.082 mL, 0.47 mmol) was stirred overnight at room temperature. Standard work-up and purification yielded white foam compound 21 (17 mg, 11%).
¹ H NMR (CDCl ₃ ) 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, 1H, J = 4.8 Hz), 7.08-7.12 (m, 2H), 7.34-7.37 ( m, 1H); ES-MS m / z 550 (M + H).

Example 22

Compound 22: 5- [4- (3-Methoxy-1-thiophen-3-ylmethyl-ureido) -4′-methyl- [1,4 ′] bipiperidinyl-1′-carbonyl] -4,6-dimethyl-pyridine 2-Carboxylic acid isopropylamide A solution of compound 19 (55 mg, 0.10 mmol) in MeOH (4 mL) and 10 N NaOH (1 mL) were heated at 100 ° C. for 2 h. The mixture was concentrated under reduced pressure, silica gel column on a dry-filled _{(8: 1: 1, CH} 3 CN / MeOH / NH 4 OH) to give 5- [4- (3-methoxy-1-thiophen-3-ylmethyl -Ureido) -4'-methyl- [1,4 '] bipiperidinyl-1'-carbonyl] -4,6-dimethyl-pyridine-2-carboxylic acid was produced (31 mg, 54%).

After general step C: acid above in DMF (3 mL) (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) were stirred overnight at room temperature. Standard workup and purification yielded white foam of compound 22 (19 mg, 57%).
¹ H NMR (CDCl ₃ ) 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, 1H), 3.41-3.53 (m, 1H), 3.65 (s) 3H), 4.07-4.32 (m, 5H), 6.96-6.99 (m, 1H), 7.07 (s, 1H), 7.12 (s, 1H), 7. 37 (dd, 1H, J = 4.8, 2.7 Hz), 7.82-7.88 (m, 2H); ES-MS m / z 585 (M + H).

Example 23

Compound 23: 5- {3- [1 '-(6-Chloro-2,4-dimethyl-pyridin-3-carbonyl) -4'-methyl- [1,4'] bipiperidinyl-4-yl] -3- Thiophen-3-ylmethyl-ureido} -pentanoic acid methyl ester After general step B, 4′-methyl-4-[(thiophen-3-ylmethyl) -amino]-[1,4 ′] bipiperidinyl-1′-carvone Acid tert-butyl ester (see Example 12) gave (4′-methyl- [1,4 ′] bipiperidinyl-4-yl) -thiophen-3-ylmethyl-amine.

After general step C: Piperidine (360 mg, 1.23 mmol) above, 6-chloro-2,4-dimethyl-nicotinic acid (250 mg, 1.35 mmol), EDCI (260 mg, in CH ₂ Cl ₂ (20 mL)). 1.36 mmol), a solution of HOBT (180 mg, 1.33 mmol) and DIPEA (0.35 mL, 2.0 mmol) was stirred overnight at room temperature. Standard workup and purification gave (6-chloro-2,4-dimethyl-pyridin-3-yl)-{4'-methyl-4-[(thiophen-3-ylmethyl) -amino]-[1, 4 ′] bipiperidinyl-1′-yl} -methanone was produced (400 mg, 71%).

A solution of 5-aminovaleric acid (235 mg, 2.00 mmol) and concentrated HCl (a few drops) in 2,2-dimethoxypropane was refluxed overnight. The mixture was concentrated under reduced pressure to produce the crude ester. To a solution of the above amine and DIPEA (0.70 mL, 4.0 mmol) in CH ₂ Cl ₂ (13 mL) cooled to 0 ° C. was added 4-nitrophenyl chloroformate (363 mg, 1.80 mmol) slowly. The mixture was stirred for 1 hour and allowed to warm to room temperature. Work-up and purification with aqueous solution yielded 5- (4-nitro-phenoxycarbonylamino) -pentanoic acid methyl ester (157 mg, 26% by 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 CH ₂ Cl ₂ (5 mL) overnight at room temperature. And stirred. Standard work-up and purification yielded white foam, compound 23 (70 mg, 43%). ¹ H NMR (CDCl ₃ ) δ 0.93, 0.94 (s, 3H), 1.18-1.82 (m, 10H), 1.95 (br d, 1H, J = 13.5 Hz), 2.18-2.27 (m, 7H), 2.42, 2.46 (s, 3H), 2.80-2.84 (m, 1H), 2.94-2.99 (m, 2H) ), 3.12-3.18 (m, 2H), 3.23-3.35 (m, 1H), 3.41-3.50 (m, 1H), 3.65 (s, 3H), 4.07-4.15 (m, 1H), 4.26-4.40 (m, 4H), 6.98 (d, 1H, J = 4.8 Hz), 7.03 (d, 1H, J = 4.2 Hz), 7.11-7.12 (m, 1H), 7.34 (dd, 1H, J = 5.1, 3.0 Hz); ES-MS m / z 618 (M + H).

Example 24

Compound 24: 5- {3- [1 '-(6-chloro-2,4-dimethyl-pyridin-3-carbonyl) -4'-methyl- [1,4'] bipiperidinyl-4-yl] -3- Thiophen-3-ylmethyl-ureido} -pentanoic acid A solution of compound 23 (52 mg, 0.084 mmol) and 1N NaOH (1 mL) in MeOH (4 mL) was heated at 50 ° C. for 2 hours. The mixture was concentrated under reduced pressure and the pH was adjusted to about 3 with HCl. The aqueous solution was extracted with CH ₂ Cl ₂ (6 × 15 mL) and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to yield white foam compound 24 (36 mg 71%). ¹ H NMR (CDCl ₃ ) δ 0.91-3.68 (m, 30H), 4.41-4.96 (m, 6H), 6.91-7.11 (m, 3H), 7.27 −7.32 (m, 1H), 11.97 (br s, 1H); ES-MS m / z 604 (M + H).

Example 25

Compound 25: 3-{[1 '-(6-Chloro-2,4-dimethyl-pyridin-3-carbonyl) -4'-methyl- [1,4'] bipiperidinyl-4-yl] -thiophen-3- Ilmethyl-amino} -3-methylamino-acrylonitrile (6-Chloro-2,4-dimethyl-pyridin-3-yl)-{4'-methyl-4-[(thiophen-3-ylmethyl) in DMF (5 mL) ) -Amino]-[1,4 ′] bipiperidinyl-1′-yl} -methanone (see Example 23) (55 mg, 0.12 mmol), 5-methyl N-cyano-N′-methyl-carba To a solution of imidothiolate (31 mg, 0.24 mmol) and Et ₃ N (0.083 mL, 0.60 mmol) was slowly added AgOTf (61 mg, 0.24 mmol). The mixture was stirred for 3 hours at room temperature. The mixture was concentrated under reduced pressure, CH ₂ Cl ₂ was added, the mixture was sonicated and the yellow precipitate was filtered. The filtrate was quenched with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ (3 × 30 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude was purified to yield white foam, compound 25 (25 mg, 38%).
¹ H NMR (CDCl ₃ ) 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, 1H), 2.94-3.02 (m, 2H), 3.08 (d, 3H, J = 4.8 Hz) 3.21-3.33 (m, 1H), 3.44-3.55 (m, 1H), 4.03-4.10 (m, 1H), 4.35-4.44 (m, 3H), 4.75-4.80 (m, 1H), 6.96 (d, 1H, J = 4.8 Hz), 7.03 (d, 1H, J = 5.4 Hz), 7.09- 7.11 (m, 1H), 7.41 (dd, 1H, J = 4.8, 3.0 Hz); ES-MS m / z 542 (M + H).

Example 26

Compound 26:
3-{[1 '-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl) -4'-methyl- [1,4'] bipiperidinyl-4-yl] -thiophen-3-ylmethyl-amino } -3-Cyclopropylamino-acrylonitrile (6-Chloro-2,4-dimethyl-pyridin-3-yl)-{4'-methyl-4-[(thiophen-3-ylmethyl)-in DMF (5 mL) Amino]-[1,4 ′] bipiperidinyl-1′-yl} -methanone (see Example 23) (68 mg, 0.15 mmol), 5-methyl N-cyano-N′-cyclopropyl-carbimide thiolate (46 mg, 0.30 mmol) and _Et 3 N _(0.10mL, 0.74mmol) to a solution of was added slowly AgOTf (76mg, 0.30mmol). The mixture was stirred for 3 hours at room temperature. The mixture was concentrated in vacuo, CH ₂ Cl ₂ was added, the mixture was sonicated and the yellow precipitate was filtered. The filtrate was quenched with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ (3 × 30 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude was purified to yield white foam compound 26 (72 mg, 84%).
¹ H NMR (CDCl ₃ ) 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, 1H), 2.94-3 .03 (m, 3H), 3.21-3.31 (m, 1H), 3.43-3.51 (m, 1H), 4.03-4.10 (m, 1H), 4.31 -4.47 (m, 3H), 5.10 (brs, 1H), 6.90-6.92 (m, 1H), 7.03 (d, 1H, J = 6.6 Hz), 7. 06-7.08 (m, 1H), 7.39 (dd, 1H, J = 4.5, 2.7 Hz); ES-MS m / z 568 (M + H).
Example 27

Compound 27: 1- {1- [1- (6-Cyano-2,4-dimethyl-pyridin-3-carbonyl) -azetidin-3-yl] -piperidin-4-yl} -3-methoxy-1-thiophene -3-ylmethyl-urea 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (800 mg, 4.64 mmol) and N-methyl-ethylpiperidine iodide salt (2.50 g, 9. 29 mmol) and H ₂ O (5 mL) was heated at reflux for 3 h. Standard workup and purification yielded 3- (4-oxo-piperidin-1-yl) -azetidine-1-carboxylic acid tert-butyl ester (806 mg, 68%).

Following general procedure _{A: CH 2 Cl 2 (10mL} ) ketone over in (800mg, 3.15mmol), 3- aminomethyl-thiophene (339 mg, 3.00 mmol) and AcOH in (0.17 mL, 3.0 mmol) To the solution was added NaBH (OAc) ₃ (890 mg, 4.20 mmol) and the mixture was stirred overnight at room temperature. Standard workup yielded 3- {4-[(thiophen-3-ylmethyl) -amino] -piperidin-1-yl} -azetidine-1-carboxylic acid tert-butyl ester (1.09 g, quantum ).

CH ₂ Cl ₂ (8mL) solution of the above amine (580mg, 1.65mmol), N- ( 4- nitrophenoxy carbonyl) methoxylamine (420 mg, 1.98 mmol) and DIPEA of (0.57 mL, 5.9 mmol) The solution was stirred overnight at room temperature. Standard work-up produced the desired crude carbamate. A solution of carbamate and 4N HCl (7 mL) in THF (20 mL) was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure, diluted with H ₂ O (10 mL) and extracted with Et ₂ O (2 × 30 mL). The aqueous solution was basified with 10N NaOH to pH ˜13 and extracted with CH ₂ Cl ₂ (4 × 30 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 1- (1-azetidin-3-yl-piperidin-4-yl) -3-methoxy-1-thiophene-3. -Produced ylmethyl-urea (480 mg, 90% by 2 steps).

After general step C: Azetidine (237 mg, 0.731 mmol), 6-cyano-2,4-dimethyl-nicotinic acid (150 mg, 0.852 mmol), EDCI (154 mg, 0.803 mmol) in DMF (10 mL). ), HOBT (109 mg, 0.807 mmol) and DIPEA (0.25 mL, 1.4 mmol) were stirred overnight at room temperature. Standard work-up and purification yielded white foam, compound 27 (165 mg, 47%). ¹ H NMR (CDCl ₃ ) 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 (brd, 1H, J = 10.8 Hz), 2.87 (brd, 1H, J = 11.1 Hz), 3.19-3.26 (m, 1H) 3.56 to 3.77 (m, 5H), 3.98 to 4.03 (m, 1H), 4.22 to 4.38 (m, 4H), 6.94 to 6.96 (m, 1H), 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- [4- (3-Methoxy-1-thiophen-3-ylmethyl-ureido) -piperidin-1-yl] -azetidine-1-carbonyl} -4,6-dimethyl-pyridine-2 Carboxylic acid isopropylamide A solution of compound 27 (162 mg, 0.336 mmol) in EtOH (8 mL) and 10 N NaOH (1 mL) were stirred at 100 ° C. for 45 min. Purification gave 5- {3- [4- (3-methoxy-1-thiophen-3-ylmethyl-ureido) -piperidin-1-yl] -azetidine-1-carbonyl} -4,6-dimethyl-pyridine-2. -Carboxylic acid was produced (138 mg, 82%).

After general step C: acid (43 mg, 0.086 mmol), isopropylamine (8 μL, 0.09 mmol), EDCI (18 mg, 0.094 mmol), HOBT (13 mg, 0.096 mmol) in DMF (4 mL) And a solution of DIPEA (0.025 mL, 0.14 mmol) was stirred overnight at room temperature. Standard workup and purification yielded white foam of compound 28 (23 mg, 49%). ¹ H NMR (CDCl ₃ ) δ 1.27, 1.29 (d, 6H, J = 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, 1H, J = 10.5 Hz), 2.87 (d, 1H, J = 10.5 Hz), 3.16-3.24 (m, 1H), 3.53-3.72 (m, 5H), 3.96-4.02 (m, 1H), 4.19-4. 38 (m, 5H), 6.95 (d, 1H, J = 4.5 Hz), 7.10 (brs, 2H), 7.35-7.38 (m, 1H), 7.83 (d, 1H, J = 8.4 Hz), 7.87 (s, 1H); ES-MS m / z 543 (M + H).

Example 29

Compound 29:
5- {3- [4- (3-Methoxy-1-thiophen-3-ylmethyl-ureido) -piperidin-1-yl] -azetidine-1-carbonyl} -4,6-dimethyl-pyridine-2-carboxylic acid Isobutyl-amide After General Step C: 5- {3- [4- (3-Methoxy-1-thiophen-3-ylmethyl-ureido) -piperidin-1-yl] -azetidine-1-in DMF (4 mL) 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) , A solution of HOBT (13 mg, 0.096 mmol) and DIPEA (0.026 mL, 0.15 mmol) was stirred overnight at room temperature. It was. Standard workup and purification afforded compound 29 as a white foam (25mg, 50%).
¹ H NMR (CDCl ₃ ) δ 0.98 (d, 6H, J = 6.6 Hz), 1.57-2.04 (m, 7H), 2.35 (s, 3H), 2.52 (s 3H), 2.70 (br d, 1H, J = 11.1 Hz), 2.87 (br d, 1H, J = 11.1 Hz), 3.17-3.36 (m, 3H), 3 .54-3.74 (m, 5H), 3.96-4.03 (m, 1H), 4.22-4.38 (m, 4H), 6.95 (d, 1H, J = 5. 1 Hz), 7.08-7.11 (m, 2H), 7.37 (dd, 1H, J = 4.8, 2.7 Hz), 7.88 (s, 1H), 8.10 (t, 1H, J = 6.0 Hz); ES-MS m / z 557 (M + H).

Example 30

Compound 30: 5- {3- [4- (3-Methoxy-1-thiophen-3-ylmethyl-ureido) -piperidin-1-yl] -azetidine-1-carbonyl} -4,6-dimethyl-pyridine-2 -Carboxylic acid (3-methyl-butyl) -amide After general step C: 5- {3- [4- (3-Methoxy-1-thiophen-3-ylmethyl-ureido) -piperidine- in DMF (4 mL) 1-yl] -azetidine-1-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) The solution of was stirred overnight at room temperature. Standard workup and purification yielded compound 30 as a white foam (26 mg, 51%).
¹ H NMR (CDCl ₃ ) δ 0.95 (d, 6H, J = 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 (brd, 1H, J = 11.4 Hz), 2.87 ( br d, 1H, J = 10.2 Hz), 3.16-3.25 (m, 1H), 3.40-3.73 (m, 7H), 3.96-4.02 (m, 1H) 4.22-4.38 (m, 4H), 6.95 (d, 1H, J = 5.1 Hz), 7.09-7.12 (m, 2H), 7.36 (dd, 1H, J = 4.5, 3.3 Hz), 7.87 (s, 1H), 7.97 (t, 1H, J = 5.7 Hz); ES-MS m / z 571 (M + H).
Example 31

Compound 31: N- {1- [1- (6-cyano-2,4-dimethyl-pyridin-3-carbonyl) -azetidin-3-yl] -piperidin-4-yl} -2- (2-oxo- Oxazolidin-3-yl) -N-thiophen-3-ylmethyl-acetamide After general step C: 3- {4-[(thiophen-3-ylmethyl) -amino] -piperidin-1-yl in DMF (6 mL) } -Azetidine-1-carboxylic acid tert-butyl ester (see Example 27) (156 mg, 0.444 mmol), (2-oxo-oxazolidine-3-yl) -acetic acid (71 mg, 0.49 mmol), A solution of EDCI (94 mg, 0.49 mmol), HOBT (66 mg, 0.49 mmol) and DIPEA (0.13 mL, 0.75 mmol) And stirred overnight at room temperature. The standard carbamate gave the crude carbamate. After general procedure B: Carbamate with N- (1-azetidin-3-yl-piperidin-4-yl) -2- (2-oxo-oxazolidine-3-yl) -N-thiophen-3-ylmethyl- Acetamide was obtained (67 mg, 40% by 2 steps).

After general step C: amine above (67 mg, 0.18 mmol), 6-cyano-2,4-dimethyl-nicotinic acid (34 mg, 0.19 mmol), EDCI (37 mg, 0.19 mmol) in DMF (6 mL). ), HOBT (26 mg, 0.19 mmol) and DIPEA (0.051 mL, 0.29 mmol) were stirred overnight at room temperature. Standard workup and purification afforded compound 31 as a white foam (45mg, 47%).
¹ H NMR (CDCl ₃ ) δ 1.66-1.97 (m, 7H), 2.33-3.37 (m, 3H), 2.53-2.56 (m, 3H), 2.70 (Br s, 1H), 2.83-2.90 (m, 1H), 3.22 (br s, 1H), 3.57-3.79 (m, 4H), 4.02-4.35 (M, 8H), 6.95-6.99 (m, 1H), 7.09 (brs, 1H), 7.22, 7.36 (brs, 1H), 7.39 (brs, 1H); ES-MS m / z 537 (M + H).

Example 32
Cell fusion assays <br/> present assay, gp120 and CD4 / CCR5-dependent cell - measures the ability of a test compound to inhibit the cell fusion. This measurement method consists of 1) R5-derived viral gp120 using virus (JR-FL) and CHO-tat cell line expressing HIVtat protein, 2) human CD4 and CCR5 expressed on the surface, retroviral promoter Two cell lines are used, a P4-CCR5 cell line carrying a β-galactosidase construct under the control of the LTR. Once the fusion of these two cell lines occurs, the tat protein from the CHO cell line transactivates the β-galactosidase of the reporter gene of the P4-CCR5 cell line. In a 96-well format, 1 × 10 4 cells of each cell line were seeded per well in the presence or absence of test compound. The cells were then incubated for 18-24 hours at 37 °, 5% CO2. Β-galactosidase activity in each well was measured by the addition of a luminescent substrate (Gal screen substrate, Applied Biosystem) and luminescence monitored with a Victor II plate reader (Wallac). The ability of the test compound to inhibit fusion is represented by a decrease in β-galactosidase activity. Results are reported as the concentration of test compound that required 50% inhibition of β-galactosidase activity in the test control.

When tested with the above assay, many compounds of the present invention exhibited IC ₅₀ in the range of 0.01 nM to 100 nM.

Example 33
HEK293F. In the inhibition assay <br/> competitive binding studies of RANTES to bind to CCR5 cells, a concentration range of antagonists, at room temperature, 45 minutes, binding buffer _{(50mM HEPES, 5mM MgCl 2,} 1mM CaCl 2, 0. 2% BSA, pH 7.4), 8 μg HEK293F. Incubated in Millipore GF-B filter plates with CCR5 cell membrane and 50 pM ¹²⁵ I-RANTES (Perkin Elmer, 81400 GBq / mmol). Unbound ¹²⁵ I-RANTES was removed by washing with cold 50 mM HEPES, 0.5 M NaCl pH 7.4. The compounds were tested in a concentration range of 10,000 to 0.6 nM. The 50% inhibitory concentration (IC ₅₀ value) was defined as the concentration of test compound required for 50% inhibition of RANTES binding relative to the untested control.

When tested with the above assay, many compounds of the present invention exhibited an IC ₅₀ in the range of 1 nM to 500 nM.

Example 34
Inhibition assay of HIV-1 using PBMC and R5 Inhibition of T-tropic HIV strain of selective antagonist of the chemokin receptor, CXCR4. J. Exp. Med. (1997) 186: 1383-1388).

  The method is as follows.

PBMCs from healthy donors were separated by density gradient centrifugation and simulated with PHA at 1 μg / ml (Sigma Chemical Co., Bornem, Belgium) at 37 ° C. for 3 days. Activated cells (PHA-stimulated blasts) were washed 3 times with PBS and virus infection was performed. Cells were seeded in 48-well plates (5 × 10 ⁵ cells per well of 200 μL medium) and pre-incubated with compounds at different concentrations for 15 minutes. Next, 500 pg p24 virus Ag / well of CCR5 using virus was added. HIV-1 R5 lines BaL, SF-162, ADA, and JR-FL were all obtained through the Medical Research Council AIDS Reagents Project (Herts, UK).

  The HIV-infected or mock-infected PHA-stimulated blasts are then further cultured in the presence of 25 U / ml IL-2, and the supernatant is harvested in 8-10 days and cultured supernatant HIV-1 core antigen DuPont-Merck Pharmaceutical Co. (Wilmington, DE) p24 Ag ELISA kit.

When tested with the above assay, many compounds of the present invention exhibited IC ₅₀ in the range of 0.01 nM to ₅₀ μM.

Claims (15)

formula:

A compound of
Wherein each Ar ¹ and Ar ² is independently an optionally substituted carbocyclic or heterocyclic aromatic system;
Each Y is independently O, S, or CHCN;
Z = H or alkyl, or CH ₂ bonded to X;
X = O, k is 0 or 1, or X = N or CH, k is 1-2,
If X = O and Z is CH ₂ bonded to X, then k = 0;
When X = N or CH and Z is CH ₂ bound to X, k = 1;
R ¹ is H or a non-interfering substituent, but only one R ¹ is a non-interfering substituent other than H or alkyl;
R ^{2 to} R ⁴ are non-interfering substituents other than H,
Each m or l is independently an integer from 0 to 4;
j is 0 or 1,
Each n is independently 1-2, a compound, or a pharmaceutically acceptable salt thereof, or a conjugate thereof. formula:

Or

A compound which is
^{Wherein, X, R 1 ~R 4,} Ar 1, Ar 2 and j~n are as defined in claim 1, salts acceptable compound according to claim 1, or as the agent or Conjugates. Formula (2)

The compound according to claim 2, or a pharmaceutically acceptable salt thereof or a conjugate thereof. When X is N, R ¹ is H or alkyl or cycloalkyl optionally substituted with a single substituent;
When j is 1, ^{R 3} is alkyl,
l and m are 0;
The compound according to claim 3, wherein Ar ¹ is unsubstituted phenyl, or a pharmaceutically acceptable salt thereof, or a conjugate thereof. Formula (3)

The compound according to claim 2, or a pharmaceutically acceptable salt thereof or a conjugate thereof. When X is N, R ¹ is H or alkyl or cycloalkyl optionally substituted with a single substituent;
when j is 1, R ³ is alkyl;
l and m are 0;
Ar ¹ is an unsubstituted phenyl,
6. The compound according to claim 5, wherein one n is 1, the other is 2, or both n are 1, or a pharmaceutically acceptable salt thereof or a conjugate thereof. Formula (4) or (5)

Or

A compound which is
In which X and Y are as defined in claim 1;
Z is H or alkyl, Ar ¹ , Ar ² , R ^{1 to} R ⁴ , and j to n are as defined in claim 1, or a pharmaceutically acceptable salt thereof. Salt or conjugate thereof. Formula (4)

The compound according to claim 7, or a pharmaceutically acceptable salt thereof, or a conjugate thereof. X is N or CH, one R ¹ is alkyl, alkoxy, cycloalkyl, alkyloxyalkyloxy or an oxidized 5-membered ring, the other R ¹ is H or alkyl,
Ar ¹ is a monovalent thiophene,
when j is 1, R ³ is methyl;
One n is 1 and the other n is 2, or both n are equal to 1,
The compound according to claim 8, wherein Y is = O or CHCN, or a pharmaceutically acceptable salt thereof, or a conjugate thereof. Formula (5)

The compound according to claim 7, or a pharmaceutically acceptable salt thereof, or a conjugate thereof. When X is N or CH, one R ¹ is alkyl, alkoxy, cycloalkyl, alkyloxyalkyloxy or an oxidized 5-membered ring, the other R ¹ is H or alkyl,
Ar1 is a monovalent thiophene,
when j is 1, R ³ is methyl;
The compound according to claim 10, or a pharmaceutically acceptable salt thereof, or a conjugate thereof, wherein Y is ═O or CHCN.   The compound of Claim 1 which is Formula (1)-(31) of Table 1.   A pharmaceutical composition comprising a compound according to any of claims 1 to 12 and at least one pharmaceutically acceptable carrier.   Use of a compound according to any of claims 1 to 12 for the preparation of a medicament for use in a method for treating a condition modulated by a CCR5 receptor.   2. Use according to claim 1, wherein the condition is HIV.