MX2008004814A - Substituted heterocyclic compounds with cxcr3 antagonist activity - Google Patents

Abstract

The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having the general structure shown in Formula (1) , or a pharmaceutically acceptable salt, solvate or ester thereof, wherein the various moieties are defined herein. Also disclosed is a method of treating chemokine mediated diseases, such as, palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non-limiting example(s) include, psoriasis), autoimmune diseases (non-limiting example(s) include, rheumatoid arthritis, multiple sclerosis), graft rejection (non-limiting example(s) include, allograft rejection, xenograft rejection), infectious diseases (e.g , tuberculoid leprosy), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, type I diabetes, viral meningitis and tumors using a compound of Formula (1).

Description

HETEROCICLIC COMPOUNDS REPLACED WITH CXCR3 ANTAGONISTIC ACTIVITY FIELD OF THE INVENTION The present invention relates to heterocyclic compounds substituted with CXCR3 antagonist activity, with pharmaceutical compositions containing one or more such antagonists, one or more such antagonists in combination with other compounds with chemokine activity, one or more such antagonists in combination with known immunosuppressive agents (non-limiting examples include Methotrexate, Interferon, Cyclosporin, FK-506 and FTY720), methods for preparing such antagonists and methods for using such antagonists to modulate CXCR3 activity. This invention also describes methods for using such CXCR3 antagonists for treatment (non-limiting examples include palliative, curative and prophylactic therapies) of diseases and conditions wherein CXCR3 has been implicated. Diseases and conditions in which CXCR3 has been implicated include, but are not limited to, inflammatory conditions (psoriasis and inflammatory bowel disease), autoimmune disease (multiple sclerosis, rheumatoid arthritis), fixed rashes from drugs, cutaneous hypersensitivity responses of the type delayed, type I diabetes, viral meningitis and tuberculoid leprosy. CXCR3 antagonist activity has also been indicated as a therapy for the suppression of tumor growth, as well as graft rejection (allograft rejections and xenografts, for example).

BACKGROUND OF THE INVENTION Chemokines constitute a family of cytokines that occur with inflammation and regulate the recruitment of leukocytes (Baggiolini, M. et al., Adv. Immunol., 55: 97-179 (1994); Springer, TA, Annual Rev. Physio., 57: 827-872 (1995); and Schall, TJ and KB Bacon, Curr Opin. Immunol, 6: 865-873 (1994)). Chemokines are capable of selectively inducing the chemotaxis of formed elements of blood (other than red blood cells), including leukocytes, such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells and lymphocytes, such as cells T and B cells. In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in sensitive cells, including changes in cell shape, transient elevations in the concentration of calcium ions ([Ca +] j) intracellular free, exocytosis of the granule, upregulation of the integrin, formation of bioactive lipids (for example, leukotrienes) and respiratory extrusion, associated with the activation of leukocytes. Thus, chemokines are the initial activators of the inflammatory response, causing the release of the inflammatory mediator, chemotaxis and extravasation to sites of infection or inflammation.

The chemokines are related in the primary structure, and share four conserved cysteines, which form disulfide bonds. Based on this conserved cysteine motif, the family can be divided into different branches, including the CXC chemokines (a-chemokines), in which the first two conserved cysteines are separated by an intervening residue (eg, IL-8, IP- 10, Mig, l-TAC, PF4, ENA-78, GCP-2, GROa, GROß, GROd, NAP-2, NAP-4), and the CC chemokines (β-chemokines), in which the first two cysteines conserved are adjacent residues (eg, MIP-1a, MIP-1β, RANTES, MCP-1, MCP-2, MCP-3, I-309) (Baggiolini, M. and Dahinden, CA, Immunology Today, 15: 127-133 (1994)). Most CXC chemokines attract neutrophil leukocytes. For example, the chemokines CXC interleukin-8 (IL-8), alpha GRO (GROa), and peptide 2 that activates neutrophils (NAP-2), are potent chemoattractants and activators of neutrophils. The CXC chemokines designated Mig (monocyte induced by interferon gamma) and IP-10 (protein of 10 kDa inducible by interferon gamma), are particularly active to induce the chemotaxis of activated lymphocytes of the peripheral blood. CC chemokines are generally less selective and can attract a variety of leukocyte cell types, including monocytes, eosinophils, basophils, T lymphocytes and natural killer cells. CC chemokines such as the human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Normal T-regulated with Activation, Expressed and Secreted), and the inflammatory proteins of macrophage 1a and 1β (MIP-1a and MIP-1β), have been characterized as chemoattractants and activators of monocytes or lymphocytes, but do not appear to be chemoattractants for neutrophils. A chemokine receptor that binds to CXC chemokines IP-10 and Mig have been cloned, characterized (Loetscher, M. et al., J. Exp. Med., 184: 963-969 (1996)) and designated CXCR3. CXCR3 is a G-protein coupled receptor with seven transmembrane spanning domains that has been shown to be restrictedly expressed in activated T cells, preferably human Th1 cells. With binding to the appropriate ligand, the chemokine receptors transduce an intracellular signal through the associated G protein, resulting in a rapid increase in intracellular calcium concentration. The CXCR3 receptor mediates the mobilization of Ca2 + (calcium ion) and chemotaxis in response to IP-10 and Mig. Cells expressing CXCR3 do not show a significant response to CXC chemokines IL-8, GROa, NAP-2, GCP-2 (granulocyte chemiotactic protein 2), ENA78 (peptide 78 that activates neutrophils derived from epithelium), PF4 (factor 4 of platelets), or the chemokines CC MCP-1, MCP-2, MCP-3, MCP-4, MIP-la, MIP-1β, RANTES, I309, eotaxin or lymphotactin. In addition, a third ligand for CXCR3, l-TAC (Alpha chemoattractant of T cells inducible by Interferon), has also been found, which binds to the receptor with high affinity and mediates functional responses (Cole, KE et al. , J. Exp. Med., 187: 2009-2021 (1998)). The restricted expression of human CXCR3 in the activated T-cells and the selectivity of the CXCR3 ligand are remarkable. The human receptor is expressed to a large extent in T lymphocytes activated by IL-2, but they are not detected in resting T cells, monocytes or granulocytes (Qin, S. et al., J. Clin. Invest., 101: 746-754 (1998)). Additional studies of the receptor distribution indicate that CD3 + cells are mainly those that express CXCR3, including cells that are CD95 +, CD45RO + and CD45RAl0W, a phenotype consistent with previous activation, although a proportion of CD20 + cells (B) and CD56 + (NK) cells also express this receptor. Selective expression in activated T lymphocytes is of interest, because other receptors for chemokines that have been reported to attract lymphocytes (eg, MCP-1, MCP-2, MCP-3, MIP-1a, MIP- 1ß, RANTES), are also expressed by granulocytes, such as neutrophils, eosinophils and basophils, as well as monocytes. These results suggest that the CXCR3 receptor is involved in the selective recruitment of effector T cells. CXCR3 recognizes unusual CXC chemokines, designated IP-10, Mig e l-TAC. Although these belong to the CXC subfamily, in contrast to IL-8 and other CXC chemokines that are potent chemoattractants for neutrophils, the primary targets of IP-10, Mig and I-TAC are lymphocytes, particularly effector cells such as Activated or stimulated T lymphocytes and natural killer cells (NK) (Taub, DD et al., J Exp. Med., 177: 18090-1814 (1993); Taub, DD et al., J. Immunol., 155 : 3877-3888 (1995); Cole, KE et al., J. Exp. Med., 187: 2009-2021 (1998)). (NK cells are large granular lymphocytes, which lack a specific T receptor for antigen recognition, but have cytolytic activity against cells such as tumor cells and virally infected cells). Consistently, IP-10, Mig e l-TAC lack the ELR motif, an essential binding epitope in those CXC chemokines that efficiently induce neutrophil chemotaxis (Clark-Lewis, I. et al., J Biol. Chem. 266: 23128-23134 (1991), Hebert, CA et al., J. Biol. Chem., 266: 18989-18994 (1991), and Clark-Lewis, 1. et al., Proc. Nati, Acad. Sci. USA, 90: 3574-3577 (1993)). In addition, it has been reported that both recombinant human Mig and recombinant human IP-10 induce calcium flow in lymphocytes that infiltrate the tumor (TIL) (Liao, F. et al., J Exp. Med, 182: 1301-1314 (1995)). Although it has been reported that IP-10 induces the chemotaxis of monocytes in vitro (Taub, DD et al., J. Exp. Med., 177: 1809-1814 (1993), the receptor responsible has not been identified), Mig The human TACs appear to be highly selective, and do not show such an effect (Liao, F. et al., J. Exp. Med., 182: 1301-1314 (1995).; Cole, K. E. et al., J. Exp. Med., 187: 2009-2021 (1998)). The expression of IP-10 is induced in a variety of tissues under inflammatory conditions such as psoriasis, fixed drug eruptions, delayed-type hypersensitivity skin responses and tuberculoid leprosy, as well as tumors and in studies of animal models, for example, glomerulonephritis experimental and experimental allergic encephalomyelitis. IP-10 has a potent antitumor effect in vivo that is dependent on T cells, is reported to be an inhibitor of angiogenesis in vivo and can induce chemotaxis and degranulation of NK cells in vitro, suggesting a role as a mediator of recruitment and degranulation of NK cells (in the destruction of tumor cells, for example) (Luster, AD and P. Leder, J. Exp. Med., 178: 1057-1065 (1993); Luster, AD et al., J Exp. Med. 182: 219-231 (1995), Angiolillo, AL et al., J. Exp. Med., 182: 155-162 (1995), Taub, DD et al., J. Immunol., 155: 3877-3888 (1995)). The expression patterns of IP-10, Mig e l-TAC are also different from those of other CXC chemokines in that the expression of each is induced by interferon gamma (IFNd), whereas the expression of IL-8 is deregulated by IFNd (Luster, AD et al., Nature, 315: 672-676 (1985); Farber, JM, Proc. Nati, Acad. Sci. USA, 87: 5238-5242 (1990); Farber, JM, Biochem. Biophys, Res. Commun., 192 (1): 223-230 (1993), Liao, F. et al., J. Exp. Med., 182: 1301-1314 (1995); Seitz, M. et al, J. Clin Invest, 87: 463-469 (1991); Galy, AHM and H. Spits, J. Immunol., 147: 3823-3830 (1991); Cole, KE et al., J. Exp. Med. , 187: 2009-2021 (1998)). Chemokines are recognized as the mediators long sought for the recruitment of lymphocytes. It was found that several CC chemokines cause lymphocyte chemotaxis (Loetscher, P. et al., FASEB J., 8: 1055-1060 (1994)), however, they are also active in granulocytes and monocytes (Uguccioni, M et al., Eur. J. Immunol., 25-: 64-68 (1995); Baggiolini, M. and CA Dahinden, Immunol. Today, 15: 127-133 (1994)). The situation is different for IP-10, Mig e l-TAC, which are selective in their action on lymphocytes, including activated T lymphocytes and NK cells, and which bind to CXCR3, a receptor that does not recognize numerous other chemokines and that shows a pattern of selective expression. In view of these observations, it is reasonable to conclude that the formation of characteristic infiltrates in inflammatory lesions, such as, for example, delayed-type hypersensitivity lesions, sites of viral infection and certain tumors, is a process mediated via CXCR3 and regulated by the expression of CXCR3. Lymphocytes, particularly T lymphocytes, which carry a CXCR3 receptor as a result of activation, can be recruited in inflammatory lesions, sites of infection and / or tumors by IP-10, Mig and / or I-TAC, which they can be induced locally by interferon gamma. Thus, CXCR3 plays a role in the selective recruitment of lymphocytes, particularly effector cells such as activated or stimulated T lymphocytes. Consequently, activated and effector T cells have been implicated in various disease states, such as graft rejection, inflammation, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and psoriasis. Thus, CXCR3 represents a promising target for the development of novel therapeutic agents. Reference is made to EP1048652A1 (published on November 2, 2000), which refers to aromatic compounds having cyclic amino or salts thereof, which specifically inhibit FXa, exert a potent anticoagulant effect, and so both are useful as medicinal compositions. Reference is made to PCT Publication No. WO 93/10091 (Applicant: Glaxo Group Limited, Published May 27, 1993), which discloses piperidine acetic acid derivatives as inhibitors of fibrinogen-dependent blood platelet aggregation, which They have the formula: An illustrative compound of this series is: Reference is also made to PCT Publication No. WO 99/20606 (Applicant: J. Uriach &CIA, SA, Published on April 29, 1999), which describes piperazines as inhibitors of platelet aggregation, which have the formula: Reference is also made to the U.S. Patent Application. No. US 2002/0018776 A1 (Applicant: Hancock, et al., Published on February 14, 2002), which describes methods for treating graft rejection. Reference is also made to PCT Publication No. WO 03/098185 A2 (Applicant: Renew, Inc., Published on November 27, of the 2003), which describes methods for diagnosing and predicting rejection of organ transplantation by detecting chemokines, for example, CXCR3 and CCL chemokines in the urine. Reference is also made to PCT Publication No. WO 03/082335 A1 (Applicant: Sumitomo Pharmaceuticals Co. Ltd., Published in October 9, 2003), which describes the methods for selecting a CXCR3 ligand and methods for diagnosing type 2 diabetes by detecting the dose of expression of a CXCR3 ligand in a biological sample. Reference is also made to PCT Publication No. WO 02/085861 (Applicant: Millennium Pharmaceuticals, Inc., Published on October 31, 2002), which discloses imidazolidine compounds and their use as CXCR3 antagonists, which have the formula : An illustrative compound of this series is: Reference is also made to PCT Publication No. WO 03/101970 (Applicant: Smithkline Beecham Corporation, Published December 11, 2003), which discloses imidazolium compounds and their use as CXCR3 antagonists, having the formula: An illustrative example of this series is: Reference is also made to the U.S. Patent Application.

No. US 2003/0055054 A1 (Applicant-Medina et al, Published on March 20, 2003) and related patent US 6 794 379 B2 ((Applicant: Medina et al, Published on September 21, 2004), which describe compounds with the activity of CXCR3, which have the formula: An illustrative compound of this series is Reference is also made to US Patent No. 6,124,319 (Applicant: MacCoss et al., Issued September 6, 2000), which discloses compounds useful as modulators of the chemokine receptor, which have the formula: Reference is also made to PCT Publication WO 03/070242 A1 (Applicant: CELLTECH R & D limited, Published on August 28, 2003), which discloses compounds useful as "chemokine receptor inhibitors for the treatment of inflammatory diseases. ", which have the formula: Reference is also made to PCT Publication WO 04/074287 A1, WO 04/074273 A1, WO 04/74278 (Applicant: AstraZeneca R & D, Published on February 19, 2004), which describes pyridine derivatives, processes for their preparation and their use in modulation " of an autoimmune disease, which have the formula: wherein R is phenyl, or a 5 or 6 membered aromatic ring with 1 or more nitrogen atoms. There is a need for compounds that are capable of modulating the activity of CXCR3. For example, there is a need for new treatments and therapies for the diseases and conditions associated with CXCR3, such as inflammatory conditions (psoriasis and inflammatory bowel disease), autoimmune disease (multiple sclerosis, rheumatoid arthritis) and graft rejection (allograft rejections). and xenograft, for example), as well as infectious diseases, cancers and tumors, fixed eruptions by drugs, delayed type hypersensitivity skin responses, type I diabetes, viral meningitis and tuberculoid leprosy. There is a need for methods of treatment or prevention or alleviation of one or more symptoms of the diseases and conditions associated with CXCR3. There is a need for methods to modulate the activity of CXCR3 using the compounds provided herein.

BRIEF DESCRIPTION OF THE INVENTION In many of its embodiments, the present invention deciphers a compound having the general structure shown in Formula 1: Formula 1 or a pharmaceutically acceptable salt, solvate or ester thereof, wherein: G is selected from the group consisting of H, hydroxyl, alkoxy, R2R1N-, R2R1X-C (R14XR15) -, and a 5-membered heteroaryl or heterocyclenyl ring, containing at least one portion -C = N- as part of the heteroaryl or heterocyclenyl ring, the heteroaryl or heterocyclenyl ring also contains optionally one or more portions selected from the group consisting of N, N (OO), O, S, S (O) and S (O2) in the ring, portions which may be the same or different, each being selected independently, further wherein the heteroaryl or heterocyclenyl ring may be (i) unsubstituted, or (ii) optionally and independently substituted on one or more ring carbon atoms with one or more substituents R9, or on one or more nitrogen atoms of the ring with one or more substituents R8, wherein the substituents R8 and R9 may be the same or different; L is O or S; Z is N or CR4; R1 and R2 are independently absent or present, and if present, each is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, carbonyl, cycloalkyl, cycloalkenyl, alkylaryl, arylalkyl, aryl, amino, alkylamino, amidinyl, carboxamido, cyano, hydroxyl, urea, -N = CH, = NCN, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, - (CH2) QN ( R31) 2, - (CH2) qC (= O) NHR31, - (CH2) qS02R31, - (CH2) qNHSO2R31, - (CH2) qSO2NHR31, -C (= S) N (H) alkyl, -N (H) -S (0) 2-alkyl, -N (H) C (= O) N (H) -alkyl, -S (O) 2alkyl, -S (0) 2N (H) alkyl, -S (0) 2N (alkyl) 2, -S (O) 2-aryl, -C (= S) N (H) cycloalkyl, -C (= O) N (H) NH 2, -C (= O) alkyl, -heteroaryl, heterocyclyl and heterocyclyl; or alternatively, when X is N, the N taken together with R1 and R2 forms a heterocyclyl, heteroaryl or -N = C (NH2) 2; the portions R3 and R4 may be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aralkyl, -CN, CF3, haloalkyl, cycloalkyl, halogen, hydroxyalkyl, -N = CH- (R31), -C (= O) N (R30) 2, -N (R30) 2, -OR30, -S02 (R31), -N (R30) C (= O) N (R30) 2 and -N (R30) C (= O) R31; R6 is selected from the group consisting of H, alkyl, arylalkyl, and alkylaryl; X is selected from the group consisting of N, O, alkyl, cycloalkyl, heteroaryl, heterocyclyl, and heterocyclenyl; the R8 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, - (CH2) qC (= 0) NHR31, - (CH2) qS02R31, - (CH2) qNS02R31 and - (CH2) ) qS02NHR31; the R9 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, alkoxy, amidinyl, aryl, cycloalkyl, cyano, heteroaryl, heterocyclyl, hydroxyl, -C (= O) N (R30) 2, -C (= S) N (R30) 2, -C (= O) alkyl, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - ( CH2) qNHR31, - (CH2) qC (= O) NHR31, - (CH2) qS02R31, - (CH2) qNSO2R31, - (CH2) qSO2NHR31, -N (R30) 2, -N (R30) S (O2) R31 , -N (R30) C (= O) N (R30) 2, -OR30, -SO2 (R31), -SO2N (R30) 2, = 0 y = S; the R10 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, alkylaryl, arylalkyl, -CO2H, hydroxyalkyl, -C (= O ) N (R30) 2, - (CH2) qOH, - (CH2) qOR31, -OR30, halogen, = O and -C (= O) R31; the R11 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, alkylaryl, arylalkyl, carboxamide, CO2H, - (CH2) qOH, - (CH2) qOR31, -OR30, halogen, = 0 and -C (= 0) R31; the R12 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, -CN, -C (= O) N (R30) 2, - (CH2) qOH, - (CH2 ) qOR31 and -S (O2) R31; the ring D is a ring of cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl of five to nine members, having 0-4 heteroatoms selected independently of O, S or N, wherein ring D is unsubstituted or optionally substituted with 1-5 R20 portions independently selected; the R20 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, - ( CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, - (CH2) qC (= 0) NHR31, - (CH2) qS02R31, - (CH2) qNSO2R31, - (CH2) qSO2NHR31 , -alkynylC (R31) 2OR31, -C (= 0) R30, -C (= O) N (R30) 2, -C (= NR30) NHR30, -C (= NOH) N (R30) 2, -C (= NOR31) N (R30) 2, -C (= O) OR30, -N (R30) 2, -N (R30) C (= O) R31, -NHC (= O) N (R30) 2, - N (R30) C (= O) OR31, -N (R30) C (= NCN) N (R30) 2, -N (R30) C (= O) N (R30) SO2 (R31), -N (R30) ) C (= O) N (R30) 2, -N (R30) SO2 (R31), -N (R30) S (O) 2N (R 30) 2, -OR30, -OC (= O) N (R30) 2) -SR30, -SO2N (R30) 2, -SO2 (R31), -OSO2 (R31) and -OSi (R30) 3; or alternatively two R20 portions are linked together to form a five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclyl or heteroaryl ring, wherein the aryl, cycloalkyl, heterocyclyl, heterocyclyl or heteroaryl ring of five or six members is fused to ring D and the fused ring is optionally substituted with 0-4 portions R21; the R21 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, carboxamido, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, - (CH2) qC (= 0) NHR31, - (CH2) qSO2R31, - (CH2) qNSO2R31, - (CH2) ) qSO2NHR31, -alkynylC (R31) 2OR31, -C (= O) R30, -C (= O) N (R30) 2) -C (= NR30) NHR30, -C (= NOH) N (R30) 2, -C (= NOR31) N (R30) 2, -C (= 0) OR3 °, -N (R30) 2, -N (R30) C (= O) R31, -NHC (= O) N (R30) 2, -N (R30) C (= O) OR31, -N (R30) C (= NCN) N (R30) 2, -N (R30) C (= O) N (R30) SO2 (R31), -N (R30) C (= O) N (R30) 2, -N (R30) SO2 (R31), -N (R30) S (O) 2N (R30) 2, -OR30, -OC (= O) N (R30) 2, -SR30, -SO2N (R30) 2, -SO2 (R31), -OSO2 (R31) ) and -OSi (R30) 3; Y is selected from the group consisting of - (CR13R3) r-, -CHR13C (= 0) -, - (CHR13) rO-, - (CHR13) rN (R30) -, -C (= O) -, - C (= NR30) -, -C (= N-OR30) -, -CH (C (= 0) NHR30) -, CH-heteroaryl-, -C (R13R13) rC (R13) = C (R13) -, - (CHR13) rC (= 0) - and - (CHR13) rN (H) C (= 0) -; or alternatively Y is cycloalkyl, heterocyclic or heterocyclyl, wherein the cycloalkyl, heterocyclic or heterocyclyl is fused with the D ring; the R13 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocyclenyl, heterocyclyl, spiroalkyl, -CN, -C02H, -C (= O) R30, -C (= O) N (R30) 2, - (CHR30) qOH, - (CHR30) qOR31, - (CHR30) qNH2, - (CHR30) qNHR31, - (CH2) qC (= O NHR31, - (CH2) qSO2R31, - (CH2) qNSO2R31, - (CH2) qSO2NHR31, -NH2, -N (R30) 2, -N (R30) C (= O) N (R30) 2, -N ( R30) SO2 (R31), -OH, OR30, -SO2N (R30) 2, and -SO2 (R31); R14 and R5 are the same or different, each is independently selected from the group consisting of H, alkyl, alkylaryl, heteroaryl, hydroxyl, -CN, alkoxy, alkylamino, -N (H) S (0) 2alkyl, and -N (H) C (= 0) N (H) alkyl; or alternatively R14 and R15 taken together are = O, = S, = NH, = N (alkyl), = N (Oalkyl), = N (OH) or cycloalkyl; the R30 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, - (CH2) qOH, - (CH2) qOalkyl, - (CH2) qOalkylaryl, - (CH2) qOaryl, - (CH2) qOralkyl, - (CH2) qCycloalkyl, - (CH2) qNH2, - (CH2) qNHalkyl , - (CH2) qN (alkyl) 2, - (CH2) qNHalkylaryl, - (CH2) qNHaril, - (CH2) qNHaralkyl, - (CH2) qNHcycloalkyl, - (CH2) qC (= O) NHalkyl, - (CH2) qC (= O) N (alkyl) 2, - (CH2) qC (= O) NHalkylaryl, - (CH2) qC (= O) NHaryl, - (CH2) qC (= O) NHaralkyl, - (CH2) qC ( = O) NHCycloalkyl, - (CH2) qS02alkyl, - (CH2) qS02alkylaryl, - (CH2) qS02aryl, - (CH2) qS02aralkyl, - (CH2) qS02cycloalkyl, - (CH2) qNS02alkyl, - (CH2) qNS02alkylaryl, - (CH2) qNSO2aryl, - (CH2) qNSO2aralkyl, - (CH2) qNSO2cycloalkyl, - (CH2) qSO2NHalkyl, - (CH2) qSO2NHalkylaryl, - (CH2) qSO2NHaril, - (CH2) qSO2NHaralkyl, - (CH2) qSO2NHcycloalkyl, heterocyclenyl, heterocyclyl and heteroaryl; the R31 portions may be the same or different, each being independently selected from the group consisting of alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, - (CH2) qOH, - (CH2) qOalkyl, - (CH2) qOalkylaryl, - (CH2) qOaryl, - (CH2) qOralkyl, - (CH2) qOcycloalkyl, - (CH2) qNH2, - (CH2) qNHalkyl, - (CH2) qN (alkyl) 2, - (CH2) qNHalkylaryl, - (CH2) qNHaril, - (CH2) qNHaralkyl, - (CH2) qNHcycloalkyl, - (CH2) qC (= O) NHalkyl, - (CH2) qC (= O) N (alkyl) 2, - (CH2) qC (= O) NHalkylaryl, - (CH2) qC (= O) NHaryl, - (CH2) qC (= 0) NHaralkyl, - (CH2) qC (= 0) NHcycloalkyl, - (CH2) qS02alkyl, - (CH2) qSO2alkylaryl, - (CH2) qSO2aryl, - (CH2) qSO2aralkyl, - (CH2) qSO2cycloalkyl, - (CH2) qNSO2alkyl, - (CH2) qNSO2alkylaryl, - (CH2) qNSO2aryl, - (CH2) qNSO2aralkyl, - (CH2) qNSO2cycloalkyl, - (CH2) qSO2NHalkyl, - (CH2) qSO2NHalkylaryl, - (CH2) qSO2NHaril, - (CH2) qSO2NHaralkyl, - (CH2) qSO2NHcycloalkyl, heterocyclenyl, heterocyclyl and heteroaryl; m is 0 to 4; n is 0 to 4; each q can be the same or different, each one is independently selected from 1 to 5; and r is 1 to 4; with the proviso that there are no two adjacent double bonds in any ring, and that when one nitrogen is substituted with two alkyl groups, the two alkyl groups may optionally be linked with one another to form a ring.

Where G represents "a 5-membered heteroaryl or heterocyclenyl ring containing at least one portion -C = N-", it means that G represents, non-exclusively, portions such as dihydroimidazole, imidazole, dihydrooxazole, oxazole, dihydrooxadiazole, oxadiazole, dihydrothiazole, thiazole, triazole, tetrazole and the like. These portions may be optionally substituted on the ring carbons with one or more R9 groups as indicated above, or on ring nitrogens with one or more R8 groups as indicated above. A further feature of the invention is a pharmaceutical composition containing as an active ingredient at least one compound of Formula 1, together with at least one pharmaceutically acceptable carrier or excipient The invention provides methods for preparing compounds of Formula 1, as well as methods for treating diseases, for example, the treatment (eg, palliative therapy, curative therapy, prophylactic therapy) of certain diseases and conditions, for example, inflammatory diseases (e.g., psoriasis), autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis) ), graft rejection (eg, allograft rejection, xenograft rejection), infectious diseases and tumors The invention provides a method for treating a chemokine-mediated disease CXCR3 in a patient in need of such treatment, which comprises administering the patient a therapeutically effective amount of at least one compound of Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof. The invention provides methods for treating diseases, for example, the treatment (e.g., palliative therapy, curative therapy, prophylactic therapy) of certain diseases and conditions, such as inflammatory diseases (e.g., psoriasis), autoimmune diseases (e.g., arthritis). rheumatoid, multiple sclerosis), graft rejection (for example, allograft rejection, xenograft rejection), infectious diseases as well as cancers and tumors, drug-induced skin rashes, delayed type hypersensitivity skin responses, type I diabetes, viral meningitis and tuberculoid leprosy, comprising administering: (a) a therapeutically effective amount of at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, concurrently or sequentially with (b) at least a drug selected from the group consisting of: antirheumatic drugs that modify the disease; non-steroidal anti-inflammatory drugs; selective COX-2 inhibitors; COX-1 inhibitors; immunosuppressants; steroids; PDE IV inhibitors, anti-TNF-a compounds, MMP inhibitors, glucocorticoids, other chemokine inhibitors such as CCR2 and CCR5, selective inhibitors of CB2, and other classes of compounds indicated for the treatment of rheumatoid arthritis. The invention also provides a method for modulating (inhibiting or promoting) an inflammatory response in an individual in need of such therapy. The method comprises administering a therapeutically effective amount of a compound (e.g., a small organic molecule) that inhibits or promotes function. of CXCR3 of the mammal and an individual in need thereof. Also disclosed is a method for inhibiting or blocking T cell-mediated chemotaxis in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt, solvate or ester. of the same. Also disclosed is a method for treating an inflammatory bowel disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof. . Also disclosed is a method for treating rejection of a graft in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof. . Also devised is a method for treating multiple sclerosis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: (a) a therapeutically effective amount of at least one compound of Formula 1, or a salt , solvate or pharmaceutically acceptable ester thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone and selective CB2 inhibitors. Also disclosed is a method for treating rheumatoid arthritis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: (a) at least one compound of Formula 1, or a pharmaceutically acceptable salt, solvate or ester acceptable thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: COX-2 inhibitors, COX-1 inhibitors, immunosuppressants, steroids, PDE IV inhibitors, anti-TNF- compounds a, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, caspase inhibitors (ICE) and other classes of compounds indicated for the treatment of rheumatoid arthritis. Also disclosed is a method for treating psoriasis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: a) at least one compound of Formula 1, or a pharmaceutically acceptable salt, solvate or ester of the same, concurrently or sequentially with (b) at least one compound selected from the group consisting of: immunosuppressants, steroids and anti-TNF-a compounds. The invention also provides a method for treating a disease selected from the group consisting of: inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection and psoriasis in a patient in need of such treatment, such method comprises administering to the of the invention is an effective amount of at least one compound of Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof. The invention also provides a method for treating a disease selected from the group consisting of: inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection, psoriasis, fixed rashes by drugs, delayed type hypersensitivity skin responses, type I diabetes, viral meningitis, tuberculoid leprosy, as well as tumors and cancers in a patient in need of such treatment, such method comprises administering to the patient an effective amount of (a) at least one compound according to claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, concurrently or sequentially with (b) ) at least one drug selected from the group consisting of: antirheumatic drugs that modify the disease; non-spheroidal anti-inflammatory drugs; selective COX-2 inhibitors; COX-1 inhibitors; immunosuppressants; steroids; PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, biological response modifiers; anti-inflammatory therapeutic agents and products.

DETAILED DESCRIPTION OF THE INVENTION The terms used herein have their ordinary meaning and the meaning of such terms is independent in each occurrence thereof. However, and despite being indicated otherwise, the following definitions are applied through the specification and the claims. Chemical names, common names and chemical structures can be used interchangeably to describe the same structure. These definitions apply regardless of whether the term is used by itself or in combination with other terms, unless otherwise indicated. Therefore, the definition of "alkyl" is applied to "alkyl", as well as to the "alkyl" portions of "hydroxyalkyl", "haloalkyl", "alkoxy", etc. As used in the foregoing, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings: "Acyl" means a group HC (= 0) -, alkyl-C (= O) -, alkenyl-C (= O) -, alkynyl-C (= 0) -, cycloalkyl-C (= O) -, cycloalkenyl-C (= 0) -, or cycloalkynyl-C (= O) -, in which the various groups are as previously described. The bond to the original portion is through the carbonyl carbon atom. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and cyclohexanoyl.

"Alkenyl" means an aliphatic hydrocarbon group, containing at least one carbon-carbon double bond and which may be linear or branched, and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have from about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. The alkenyl group may be substituted with one or more substituents which may be the same or different, each substituent is independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkenyl, cyano, heteroaryl , heterocyclyl, amino, aminosulfonyl, halo, carboxyl, carboxyalkyl (non-limiting examples include ester), alkoxycarbonyl, hydroxyalkyl, carbonyl (non-limiting examples include ketone), -C (= 0) heterocyclyl, formyl (non-limiting examples include aldehyde), carboxamido (ie, amido, -C (= 0) NH2), -C (= 0) N (alkyl) 2, -C (= 0) NH (alkyl), -C (= O) N ( cycloalkyl) 2, -C (= 0) NH (cycloalkyl), -NHC (= O) alkyl, urea (e.g., -NH (C = O) NH2, -NH (C = O) NH (alkyl), - NH (C = O) NH (alkyl) 2, -NH (C = O) NH (heteroaryl), -NH (C = O) NH (heterocyclyl)), guanidinyl, -NHC (= NCN) NH2, -NHC (= NCN) N (alkyl) 2, carbamoyl (ie, -C02NH2), NHC (= O) Oalkyl, -C02N (alkyl) 2, -NHC (= 0)) NH-S (0) 2alkyl, -NHC (= O) N (alkyl) 2-S (O) 2alkyl, -NH-S (O) 2alkyl, -NH-S (0) 2heteroaryl, -N (alkyl) -S (O) 2alkyl, -NH -S (0) 2-aryl, -N (alkyl) -S (0) 2-aryl, -NH-S (O) 2 NH 2, -NH-S (O) 2 NHC, -NH-S (O) 2 N (alkyl) 2, alkylthiocarboxy, -S (0) 2alkyl, -S (O) 2-propyl, -OS (O) 2alkyl, -OS (O) 2-aryl, sulfonyl urea (non-limiting examples include NHC (= S) NHalkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkyl" means an aliphatic hydrocarbon group which may be linear or branched or a combination thereof, and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain, which may be linear or branched. The alkyl group may be substituted with one or more substituents which may be the same or different, each substituent is independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkenyl, cyano, heteroaryl, heterocyclyl, amino, -NH (alkyl), -N (alkyl) 2, -NH (cycloalkyl), -N (cycloalkyl) 2, -NH (aryl), -N (aryl) 2. -NH (heteroaryl), -N (heteroaryl) 2, -NH (heterocyclyl), N (heterocyclyl) 2, halo, hydroxy, carboxyl, carboxyalkyl (non-limiting examples include ester), alkoxycarbonyl, hydroxyalkyl, carbonyl (examples not limiting agents include ketone), -C (= 0) heterocyclyl, formyl, carboxamido (ie, amido, -C (= 0) NH2, -C (= 0) N (alkyl) 2, -C (= O) NH ( alkyl), -C (= 0) N (cycloalkyl) 2, -C (= 0) NH (cycloalkyl)), -NHC (= O) alkyl, amidinyl, hydrazidyl, hydroxamate, -NHC (= O) H, -NHC (= O) alkyl, urea (eg, -NH (C = O) NH2, -NH (C = O ) NH (alkyl), -NH (C = O) NH (alkyl) 2, -NH (C = O) NH (heteroaryl), -NH (C = 0) NH (heterocyclyl)), guanidinyl, -NHC (= NCN) NH2, -NHC (= NCN) N (alkyl) 2, carbamoyl (ie, -CO2NH2), -NHC (= O) Oalkyl, -CO2N (alkyl) 2, '-NHC (= O) NH-S (O) 2alkyl, -NHC (= O) N (alkyl) -S (O) 2alkyl, -NH-S (O) 2alkyl, -NH-S (O) 2heteroaryl, -N (alkyl) -S (O) 2alkyl, -NH-S (O) 2-aryl, -N (alkyl) -S (O) 2-aryl, -NH-S (O) 2NH 2, -NH-S (O) 2NHalkyl, -NH-S (O) 2N ( alkyl) 2, thio, alkylthio, alkylthiocarboxy, -S (0) alkyl, -S (O) 2alkyl, -S (0) 2 -aryl, -OS (O) 2alkyl, -OS (0) 2-aryl, sulfonyl urea (the examples non-limiting include -NHC (= S) NHalkyl) and OSi (alkyl) 3. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl and cyclopropylmethyl. "Alkylheteroaryl" means an alkylheteroaryl group, wherein the alkyl is as previously described and the bond to the original portion is through the heteroaryl group.

"Alkylamino" means a group -NH2 or -NH3 +, in which one or more of the hydrogen atoms in the nitrogen is replaced by an alkyl group as defined above. The link to the original portion is through nitrogen. "Alkylaryl" means an alkyl-aryl- group in which alkyl and aryl are as deciphered herein. Preferred alkylaryls comprise a lower alkyl group. Non-limiting examples of suitable alkylaryl groups include o-tolyl, p-tolyl and xylil. The link to the original portion is through the aril. "Alkylthio" means an alkyl-S- group, in which the alkyl group is as described herein. Non-limiting examples of suitable alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio. The link to the original portion is through sulfur. "Alkylthiocarboxy" means an alkyl-S-C (= O) O- group. Preferred groups are those in which the alkyl group is lower alkyl. The link to the original portion is through the carboxy. "Alkylsulfonyl" means an alkyl-S (0) 2- group. Preferred groups are those in which the alkyl group is lower alkyl. The link to the original portion is through the sulfonyl. "Alkylsulfinyl" means an alkyl-S (O) - group. Preferred groups are those in which the alkyl group is lower alkyl. The link to the original portion is through sulfinil.

"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be linear and branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have from about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain, which may be linear or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl and decynyl. The alkynyl group may be substituted with one or more substituents which may be the same or different, each substituent is independently selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkenyl, cyano, heteroaryl, heterocyclyl, - NH (alkyl), -N (alkyl) 2, -NH (cycloalkyl), -N (cycloalkyl) 2, -NH (aryl), -N (aryl) 2, -NH (heteroaryl), -N (heteroaryl) 2 , -NH (heterocyclyl), N (heterocyclyl) 2, alkoxycarbonyl, hydroxyalkyl, carbonyl (non-limiting examples include ketone), -C (= O) heterocyclyl, carboxamido (ie, amido, -C (= O) NH2) , -C (= O) N (alkyl) 2, -C (= O) NH (alkyl), -C (= O) N (cycloalkyl) 2, -C (= O) NH (cycloalkyl), alkyIC (= O) NH-, -NHC (= O) alkyl, urea (for example, -NH (C = O) NH2), -NH (C = O ) NH (alkyl), -NH (C = 0) NH (alkyl) 2, -NH (C = O) NH (heteroaryl), -NH (C = O) NH (heterocyclyl), -S (O) 2alkyl and -S (0) 2aryl-. "Alkoxy" means an alkyl-O- group, in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptoxy and methylhydroxy. The link to the original portion is through the oxygen of the ether. "Alkoxycarbonyl" means an alkyl-O-C (= O) - group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The link to the original portion is through the carbonyl. "Aminoalkyl" means an amino-alkyl group, in which the alkyl is as previously defined. Preferred aminoalkyls contain a lower alkyl. Non-limiting examples of suitable aminoalkyl groups include aminomethyl and 2-Dimethylamino-2-ethyl. The link to the original portion is through the alkyl. "Amidinyl" means a group -C (= NR) NHR. The R groups are as defined as H, alkyl, alkylaryl, heteroaryl, hydroxyl, alkoxy, amino, ester, -NHSO2alkyl, -NHSO2Aryl, -NHC (= O) NHalkyl and -NHalkyl. The link to the original portion is through carbon. "Aralkyl" or "arylalkyl" means an aryl-alkyl- group, in which aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group attached to the aryl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The link to the original portion is through the alkyl. "Aralkenyl" means an aryl-alkenyl- group, in which aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl group. Non-limiting examples of suitable aralkenyl groups include 2-phenetenyl and 2-naphthylethenyl. The link to the original portion is through the alkenyl. "Aralkylthio" means an aralkyl-S- group, in which the aralkyl group is as previously described. A non-limiting example of a suitable aralkylthio group is benzylthio. The link to the original portion is through sulfur. "Aralkoxy" means an aralkyl-O- group, in which the aralkyl group is as described above. The link to the original portion is through the oxygen group. "Aralkoxycarbonyl" means an aralkyl-O-C (= O) - group. A non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The link to the original portion is through the carbonyl. "Aroyl" means an aryl-C (= O) - group, in which the aryl group is as previously described. The link to the original portion is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- and 2-naphthoyl.

"Aryl" (sometimes abbreviated "Ar"), means an aromatic monocyclic or multicyclic ring system, comprising from about 6 to about 14 carbon atoms, preferably from about 6 to about 10 carbon atoms. The aryl group may be optionally substituted with one or more "ring system substituents", which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Aryloxy" means an aryl-O- group, in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The link to the original portion is through the oxygen of the ether. "Arylsulfonyl" means an aryl-S (0) 2- group. The link to the original portion is through the sulfonyl. "Arylsulfinyl" means an aryl-S (O) - group. The link to the original portion is through sulfinil. "Arylthio" means an aryl-S- group, in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The link to the original portion is through sulfur. "Carboxyalkyl" means an alkyl-C (= 0) 0- group. The link to the original portion is through the carboxy.

The carbamate and urea substituents refer to the groups with oxygens and nitrogens respectively adjacent an amide; Representative carbamate and urea substituents include the following: "Cycloalkyl" means a non-aromatic mono or multicyclic ring system comprising from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain from about 5 to about 7 ring atoms. The cycloalkyl may be optionally substituted with one or more "ring system substituents", which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalin, norbomyl, adamantyl and the like. "Cycloalkenyl" means a mono or multicyclic non-aromatic ring system comprising from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms, containing at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain from about 5 to about 7 ring atoms. The cycloalkenyl may be optionally substituted with one or more "ring system substituents", which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. A non-limiting example of a suitable multicyclic cycloalkenyl is norbomilenyl. "Halogen" (or halo) means fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are preferred. "Haloalkyl" means an alkyl as defined above, wherein one or more hydrogen atoms in the alkyl are replaced by a halo group defined above. Non-limiting examples include trifluoromethyl, 2,2,2-trifluoroethyl, 2-chloropropyl and the like. "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising from about 5 to about 14 ring atoms, preferably from about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example, nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain from about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted with one or more "ring system substituents", which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the name of the heteroaryl root, means that at least one nitrogen atom, oxygen or sulfur respectively, is present as an atom in the ring. The nitrogen or sulfur atom of the heteroaryl may be optionally oxidized to the N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl. , imidazo [1,2-a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, , 2,4-triazinyl, benzothiazolyl and the like. "Heterocyclenyl" means a partially unsaturated monocyclic or partially unsaturated monocyclic ring system, comprising from about 5 to about 14 ring atoms, preferably from about 5 to about 10 ring atoms, in which one or more of the atoms in the ring is an element other than carbon, for example, nitrogen, oxygen or sulfur, alone or in combination. Preferred heterocyclenyls contain from about 5 to about 6 ring atoms and 1-3 double bonds. Preferred heterocyclenyls also contain at least one -C = N as part of the ring. The "heterocyclenyl" may be optionally substituted with one or more "ring system substituents", which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the name of the heterocyclenyl root means that at least one nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The nitrogen or sulfur atom of the heteroaryl may be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable heterocyclenyls include dihydroimidazole, dihydrooxazole, dihydrooxadiazole, dihydrothiazole, and the like. "Heterocyclyl" (or heterocycloalkyl) means a saturated non-aromatic monocyclic or multicyclic ring system comprising from about 3 to about 10 ring atoms, preferably from about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example, nitrogen, oxygen or sulfur, alone or in combination. Preferred heterocyclyls contain from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the name of the heterocyclyl root means that at least one nitrogen atom, oxygen or sulfur respectively, is present as a ring atom. The heterocyclyl may be optionally substituted with one or more "ring system substituents", which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl may be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclic rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, oxazolidinyl, imidazolidinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. Also included are ring systems comprising from about 3 to about 10 ring atoms; preferably from about 5 to about 10 atoms in the ring, in which one or more of the atoms in the ring system is a non-carbon element, for example, a nitrogen, oxygen or sulfur atom, alone or in combination , and which contains at least one carbon-carbon double bond or a carbon-nitrogen double bond. There are no adjacent oxygen and / or sulfur atoms in the ring system. Non-limiting examples of suitable monocyclic heterocyclic aza groups (ie, azaheterocyclyl), include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1, 4,5,6-tetrahydropyrimidine, dihydro-2-pyrrolinyl, dihydro-3-pyrrolinyl, dihydro-2-imidazolinyl, dihydro-2-pyrazolinyl, dihydro-4,5-trizolyl and the like. Non-limiting examples of suitable oxaheterocyclic groups (ie, oxaheterocyclyl) include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. A non-limiting example of a suitable multicyclic oxaheterocyclic group is 7-oxabicyclo [2.2.1] heptenyl. Non-limiting examples of monocyclic thiaheterocyclic rings (ie, thiaheterocyclyl), include dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heteroaralkyl" means a heteroaryl-alkyl- group in which heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2- (furan-3-yl) ethyl and quinolin- (3-yl) methyl. The link to the original portion is through the alkyl. "Heteroaralkenyl" means a heteroaryl-alkenyl- group, in which heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl group. Non-limiting examples of suitable heteroaralkenyl groups include 2- (pyrid-3-yl) ethenyl and 2- (quinolin-3-yl) ethenyl. The link to the original portion is through the alkenyl. "Hydroxyalkyl" means an HO-alkyl- group, in which the alkyl is as previously defined. Preferred hydroxyalkyls contain a lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. The link to the original portion is through the alkyl. "Hydroxamate" means an alkyl-C (= O) NH-0- group. The link to the original portion is through the oxygen group.

"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system that, for example, replaces a hydrogen available in the ring system. The substituents of the ring system can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkoxy, aryl, aroyl, aryloxy, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, amino, -NH (alkyl), -N (alkyl) 2, -NH (cycloalkyl), -N (cycloalkyl) 2, -NH (aryl), -N (aplo) 2 , -NH (heteroaryl), -N (heteroaryl) 2, -NH (heterocyclyl), N (heterocyclyl) 2, halo, hydroxy, carboxyl, carboxyalkyl (non-limiting examples include ester), cyano, alkoxycarbonyl, hydroxyalkyl, carbonyl ( non-limiting examples include ketone), -C (= O) heterocyclyl, formyl (non-limiting examples include aldehyde), carboxamido (ie, amido, -C (= 0) NH2), -C (= O) N ( alkyl) 2, -C (= O) NH (alkyl), -C (= O) N (cycloalkyl) 2, -C (= O) NH (cycloalkyl), alkyl C (= 0) NH-, -amidino, hydrazido , hydroxamate, -NHC (= 0) H, -NHC (= O) alkyl, urea ( for example, -NH (C = O) NH2), -NH (C = 0) NH (alkyl), -NH (C = 0) NH (alkyl) 2, -NH (C = O) NH (heteroaryl), -NH (C = O) NH (heterocyclyl), guanidinyl, -NHC (= NCN) NH2, -NHC (= NCN) N (alkyl) 2, carbamoyl (ie, -C02NH2), -NHC (= O) Oalkyl, -CO2N (alkyl) 2, -NHC (= O) NH-S (0) 2alkyl, -NHC (= O) N (alkyl) 2-S (0) 2alkyl, -NH-S (O) 2alkyl, -NH-S (0) 2heteroaryl, -N (alkyl) -S (O) 2alkyl, -NH -S (O) 2-aryl, -N (alkyl) -S (0) 2-aryl, -NH-S (0) 2NH2, -NH-S (O) 2NHalkyl, -NH-S (O) 2N (alkyl) 2, thio, alkylthiocarboxy, -S (0) 2alkyl, -S (0) 2aryl, -OS (O) 2alkyl, -OS (O) 2-aryl, sulfonyl urea (non-limiting examples include -NHC (= S) NHalkyl) and OSi (alkyl) 3. "Spiroalkyl" means an alkylene group, wherein two carbon atoms of an alkyl group are attached to a carbon atom of an original molecular group, thereby forming a carbocyclic or heterocyclic ring of three to eleven atoms. Representative structures include examples such as: The spiroalkyl groups of this invention may be optionally substituted with one or more substituents of the ring system, wherein "ring system substituent" is as defined herein. "Ring system substituent" also means a cyclic ring of 3 to 7 ring atoms, which may contain 1 or 2 heteroatoms, attached to an aryl, heteroaryl or heterocyclyl ring, simultaneously replacing two ring hydrogen atoms in the ring. the aryl ring, heteroaryl, heterocyclyl. Non-limiting examples include: and the similar.

The term "optionally substituted" means an optional substitution with the groups, radicals or specified portions, in the position or positions available. With reference to the number of portions (non-limiting examples include, substituents, groups or rings) in a compound, unless defined otherwise, the phrases "one or more" and "at least one" mean that, there may be as many portions as chemically allowed, and the determination of the maximum number of such portions is within the knowledge of those skilled in the art. Preferably, there are one to three substituents, or more preferably, one to two substituents, with at least one in the para position. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any resulting product, directly or indirectly from the combination of the specified ingredients in the specified amounts.

The straight line as a bond generally indicates a mixture of, or any of the possible isomers, non-limiting examples include, which contain stereochemistry (R) and (S). For example, means that it contains a and a A dotted line (- -) represents an optional link. The lines drawn in the ring systems, such as, for example: indicate that the dotted line (link) can be attached to any of the substitutable ring atoms, non-limiting examples include the ring atoms of carbon, nitrogen and sulfur. As is known in the art, a linkage drawn from a particular atom, where no portion is described at the terminal end of the bond, indicates a methyl group linked through that bond to the atom, unless otherwise indicated . For example: represents It should also be noted that any heteroatoms with valences not satisfied in the text, reaction schemes, structural formulas examples and any tables in the present, are supposed to have the hydrogen atom or atoms to satisfy the valences. Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug" as used herein, denotes a compound that is a precursor of the drug, which upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to provide a compound of Formula 1, or a salt and / or solvate thereof. A discussion of the prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Deliver Systems (1987) Volume 14 of the A. C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference. "Metabolic conjugates", for example, glucuronides and sulfates that can undergo reversible conversion to the compounds of Formula 1, are contemplated in this application.

"Effective amount" or "therapeutically effective amount" is intended to describe an amount of compound or composition of the present invention effective to antagonize CXCR3 and thereby produce the desired therapeutic effect in a suitable patient. "Mammal" means humans and other mammalian animals. "Patient" includes both humans and animals. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonds, including hydrogen bonds. In certain cases, the solvent will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystalline lattice of the crystalline solid. "Solvate" covers both solvates in solution phase and isolators. Non-limiting examples of suitable solvates include ethanolates, methanolates and the like. "Hydrate" is a solvate in which the solvent molecule is H2O. In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of this invention. The compounds of Formula 1 form salts that are also within the scope of this invention. The reference to a compound of Formula 1 herein is meant to include references to the salts thereof, unless otherwise indicated. The term "salts", as used herein, denotes acid salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. In addition, when a compound of Formula 1 contains a basic portion, such as, but not limited to a pyridine or imidazole, and an acidic portion, such as, not exclusively a carboxylic acid, zwitterions ("internal salts") can be formed. and are included within the term "salts" as used herein. Pharmaceutically acceptable salts (non-limiting examples include, physiologically acceptable, non-toxic) are preferred, although other salts are also useful. The salts of the compounds of Formula 1 can be formed, for example, by reacting a compound of Formula 1 with an amount of an acid or a base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Acids (and bases), which are generally considered suitable for the formation of pharmaceutically useful salts of basic (or acid) pharmaceutical compounds are discussed, for example, by S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food and Drug Administration, Washington, DC, on its website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Puré and Applied Chemistry, pp. 330-331. These descriptions are incorporated herein by reference.

Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glycoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, iodohydrates, 2-hydroxyethane sulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulphates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulphates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates), undecanoates and the like. Exemplary basic salts include ammonium salts, alkali metal salts, such as sodium, lithium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases ( for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N, N-bis (dehydroabiethyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines , piperazine, phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Groups containing a basic nitrogen can be quaternized with agents such as lower alkyl halides (non-limiting examples include methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (non-limiting examples include dimethyl sulfates) , diethyl, dibutyl and diamyl), long chain halides (non-limiting examples include decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (non-limiting examples include benzyl and phenethyl bromides), and others. All such acid salts and basic salts are intended to be pharmaceutically acceptable salts within the scope of the invention, and all acidic and basic salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention. The pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by the esterification of the hydroxy groups, in which the non-carbonyl portion of the carboxylic acid moiety of the ester grouping are selected of a straight or branched chain alkyl (eg, acetyl, n-propyl, t-butyl or n-butyl), alkoxyalkyl (by way of example, methoxymethyl), aralkyl (eg, benzyl), aryloxyalkyl (eg, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C 1 - alkyl, or C 1-4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (e.g., methanesulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono, di or triphosphate esters. The phosphate esters can be further esterified by, for example, a d.2o alcohol or a reactive derivative thereof, or by a 2,3-dialcylglycerol of (C6.24).

The compounds of Formula 1, and the salts, solvates, esters and prodrugs of the same, can exist in their tautomeric form (for example, as an amide or an ether imine). All of such forms tautomerics are contemplated herein as part of the present invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds, as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons in several substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers and Diastereomeric forms are contemplated within the scope of this invention.

The individual stereoisomers of the compounds of the invention can, for example, being substantially free of other isomers, or they can mix, for example, as racemates or with all the others! stereoisomers or other selected. The chiral centers of this invention may have the S or R configuration as defined by the! Recommendations of the IUPAC of 1974. The use of the terms "salt", "solvate" "prodrug" and the like, is intended to apply equally to salt, solvate, ester and prodrug of the enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds. ' It should also be noted that through the specification and the Claims appended hereto, any formula, compound, portion [or chemical illustration with unfulfilled valences, is assumed to have the hydrogen atom to satisfy the valences, unless the context indicates a link. In one embodiment, the present invention describes compounds of Formula 1, which have CXCR3 antagonist activity, or a pharmaceutically acceptable derivative thereof wherein the various definitions are given above. In another embodiment, L is O (ie, oxygen). In another embodiment, G is R2R1X-C (R4) (R15) -. In another embodiment, where G is R2R X-C (R14) (R15) -, X is N, and R14 and R15 taken together are = O. In another embodiment, wherein G is R2R1X-C (R14) (R15) -, X is N, and R14 and R15 taken together are = O, R1 and R2 are both H; that is, R2R1X-C (R14) (R15) - is H2N- (C = O) -. In another embodiment, G is selected from the group consisting of H, hydroxyl, alkylO- or R R1N. In another embodiment, G of the heteroaryl or heterocyclenyl ring of members containing at least one portion -C = N- as part of the heteroaryl or heterocyclenyl ring, is selected from the group consisting of dihydroimidazole, imidazole, dihydrooxazole, oxazole, dihydrooxadiazole, oxadiazole, triazole and tetrazole. In another embodiment, G is selected from the group consisting of: where ^^ is a single link or a double link. In another modality, G is In another embodiment, R is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, -N (R30) 2, -OR30 and -CF3.

In another embodiment, R3 is selected from the group consisting of H, -CH3, -CH2CH3, cyclopropyl, -F, -Cl, OCH3, OCF3 and CF3. In another embodiment, R3 is selected from the group consisting of H, -Cl and -CH3. In another embodiment, R8 is selected from the group consisting of H, alkyl, alkenyl, arylalkyl, cycloalkyl, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) C? NHR31, - (CH2) qC (= O) NHR31, - (CH2) ) qS02R31, - (CH2) qNSO2R31 and - (CH2) qSO2NHR31. In another embodiment, the R9 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, -C (= O) N (H) R30, -C (= O) alkyl, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, -N (H) R30, -N (H) S (O2) R31, -N (H) C (= O) NH (R30), -OR30-SO2 (R31) and -SO2N (H) R30. In another embodiment, the R9 portions may be the same or different, each being independently selected from the group consisting of H, cyclopropyl, -CF3, -CH3, -CH2OH, -CH2CH2OH, -C (CH3) 2OH, - CH2CH2OCH3, -C (= O) OCH2CH3, -CH2NH2, -CH2CH2NH2, -CH2CH2NHSO2CH3, -CH2CH2SO2CH3, -C (= O) NH2, -C (= O) N (H) CH2CH2OH, -CH2N (H) C (= O) CF3, -C (= O) N (H) -cyclopropyl , -C (= O) N (H) CH2CF3, -NH2, -NHCH3, -N (CH3) 2, -N (H) CH2CH3, -N (H) CH (CH3) 2, -N (H) CH2CH2CH3 , -N (H) CH2C (= O) OCH3, -N (H) CH2CH2OH, -N (H) CH2CH2NH2, -N (H) CH2CH2NHSO2CH3, -N (H) CH2CH2S02CH3, -N (H) C (= 0) N (H) CH2CH3, -N (H) CH2C (= O) NH2, -OCH3, = S y = O .

In another embodiment, the R9 portions may be the same or different, each being independently selected from the group consisting of H, -CF3, -CH3, -CH2CH2OH, -CH2CH2NH2, -NH2, -NHCH3, -N (H) CH2CH3, -N (H) CH (CH3) 2, -N (H) CH2CH2CH3, -N (H) CH2C (0) OCH3 and -N (H) CH2CH2OH. In another embodiment, the R9 portions may be the same or different, each being independently selected from the group consisting of -NH2 and -N (H) CH2CH3. In another embodiment, R10 is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl. In another embodiment, R10 is selected from the group consisting of -CH3, -CH2CH3 and -CH2CH2CH3, and m is 0-2. In another embodiment, R10 is -CH2CH3 and m is 1. In another embodiment, R11 is selected from the group consisting of H, alkyl, hydroxyalkyl and carbonyl. In another embodiment, R11 is H or -CH3. In another embodiment, R 11 is H. In another embodiment, R 12 is selected from the group consisting of H, CN, -C (= O) N (R 30) 2 and alkyl. In another embodiment, R12 is selected from the group consisting of H, -CH3, CN and -CH2CH3. In another embodiment, R12 is H.

In another embodiment, the atoms in the ring of the D ring are independently C or N and are substituted with 0-4 R20 portions. In another embodiment, ring D is an aryl, heteroaryl, heterocyclenyl or heterocyclyl ring of 5 to 6 members and is substituted with 0-4 R20 moieties. In another embodiment, ring D is a 5-6 membered aryl or heteroaryl ring and is substituted with 0-4 R20 moieties. In another embodiment, the aryl ring of the D ring is phenyl and the heteroaryl ring of the D ring is pyrindinyl. In another embodiment, the R20 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylheteroaryl, alkylsulfinyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkoxy, aryl, aryloxy, cyano, cycloalkyl, cycloalkenyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, trifluoromethyl, trifluoromethoxy, - (CH2) qOR31, - (CH2) qNHR31, - (CH2) qC (= 0) NHR31 , - (CH2) qSO2R31, - (CH2) qNSO2R31, - (CH2) qSO2NHR31, -alkynylC (R31) 2OR31, -C (= O) R30, -C (= O) N (R30) 2, -C (= O) OR30, -N (R30) 2, -N (R30) C (= O) R31, -NHC (= O) N (R30) 2, -N (R30) C (= O) OR31, -N (R30) C (= NCN) N (R30) 2, -N (R30) C (= O) N (R30) 2, -N (R30) SO2 (R31), -N (R30) SO2N (R30) 2, -OR30, -OC (= O) N (R30) 2, -SR30, -SO2N (R30) 2, -SO2 (R31), -OSO2 (R31) and -OSi (R30) 3. In another embodiment, the R20 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH3, CF3, OCF3, - (CH2) qOR31, - ( CH2) qNHR31, - (CH2) qC (= 0) NHR31, - (CH2) qSO2R31, - (CH2) C? NS02R31, - (CH2) qSO2NHR31, -alkynylC (R31) 2OR31, -C (= O) R30, -C (= O) OR30, -N (R30) 2l -N (R30) C (= O) R31, -NHC (= O) N (R30) 2) -N (R30) C (= O) OR31, -N (R30) C (= NCN) N (R30) 2, -N (R30) C (= O) N (R30) 2, -OR30, -OC (= O) N (R30) 2 and -OSO2 ( R31). In another embodiment, the R20 portions may be the same or different, each being independently selected from the group consisting of H, halogen and amino. In another modality, Y is selected from the group consisting of: - (C? R13) r-, - (CR13R13) r -, -C (= O) - and -CHR13C (= O) -. In another embodiment, Y is selected from the group consisting of: -CH2-, -CH (CH3) -, -CH (CH2OH) -, -C (= O) - and -CH (CO2alkyl) -. In another embodiment, Y is selected from the group consisting of: -CH2- and -C (= 0) -. In another mode, m is 0-2. In another modality, m is 1. In another modality, n is 0-2. In another modality, n is 0. In another modality, q is 1 or 2. In another modality, r is 1 or 2. In another modality, G is independently selected from the group consisting of R2R1N-C (= O) - Y R3 is selected from the group consisting of H, -Cl and -CH3; R9 is selected from the group consisting of -NH2 and -N (H) CH2CH3; R10 is -CH2CH3; R11 is H; R12 is H; ring D is an aryl or heteroaryl ring of 5 to 6 members and is substituted with 0-4 R20 moieties; the R20 portions may be the same or different, each being independently selected from the group consisting of H, halogen and amino; And it is selected from the group consisting of: -CH2-, and -C (= 0) -; 'm is 1, and n is 0. In another embodiment, the compound of Formula 1 is selected from the group consisting of the following: or a pharmaceutically acceptable salt, solvate or ester thereof.

In another embodiment, the compound is selected from the group it consists of or a pharmaceutically acceptable salt, solvate or ester thereof. In yet another embodiment of the present invention, a compound is selected from the following structures in the following Table 1 (or pharmaceutically acceptable salts, solvates or esters thereof), which are shown together with their Ki classifications. Ki values are classified, "A" for Ki values less than about 25 nanomolar (nM), "B" for Ki values in the range of about 25 to about 100 nM and "C" for values of Ki greater than approximately 100 nM. For example, Compound Number 1 has a Ki of 1.9 nM, and therefore has an "A" rating.

TABLE 1 STRUCTURE Number Classification Ki Composite TO Examples of representative compounds with specific 20 Ki values are shown in Table 2 below: In yet another aspect, the compound according to Formula 1 is in purified form. In another embodiment, this invention provides a pharmaceutical composition comprising at least one compound of Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in combination with at least one pharmaceutically acceptable carrier. In still another embodiment, the invention provides a pharmaceutical composition of Formula 1, further comprising at least one agent, drug, medicament, antibody and / or additional inhibitor for treating a disease mediated by the chemokine receptor CXCR3.

When a combination therapy is administered to a patient in need of such administration, the therapeutic agents in the combination, or a composition or pharmaceutical compositions comprising the therapeutic agents, can be administered in any order, such as, for example, sequentially, concurrent, simultaneous meeting and similar. The amounts of the various active substances in such combination therapy may be different amounts (different dosage amounts) or the same amounts (same dosage amounts). Thus, for non-limiting purposes of illustration, a compound of Formula III and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (eg, a capsule, a tablet and the like). A commercial example of such a single dosage unit containing fixed amounts of two different active compounds is VYTORIN® (available from Merck Schering-Plow Pharmaceuticals, Kenilworth, New Jersey). In yet another embodiment, the present invention describes methods for preparing pharmaceutical compositions comprising the inventive heterocyclic substituted piperazine compounds of Formula 1 as an active ingredient. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier materials selected in a suitable manner with respect to the intended form of administration, i.e., oral tablets, capsules (either filled with solid, filled with semisolid or filled with liquid), powders for the constitution, oral gels, elixirs, dispersible granules, syrups, suspensions and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, sulfate of calcium, talc, mannitol, ethyl alcohol (liquid forms) and the like. In addition, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. The powders and tablets may be comprised from about 5 to about 95 percent of the inventive composition. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes. Among the lubricants, for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride and the like may be mentioned. The disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate. Some of the terms indicated above, namely the disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.

In addition, the compositions of the present invention can be formulated in sustained release form to provide the rate of controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. anti-inflammatory activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymer matrices impregnated with the active components and in the form of tablets or capsules containing such impregnated or encapsulated porous polymer matrices. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or the addition of sweeteners and painkillers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, eg, nitrogen. To prepare suppositories, a low melting point wax, such as a mixture of fatty acid glycerides such as cocoa butter, is first melted, and the active ingredient is homogeneously dispersed therein by agitation or similar mixing. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool and therefore solidify. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be delivered transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and / or emulsions and can be included in a transdermal patch of the matrix or reservoir type, as is conventional in the art for this purpose. Preferably, the compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form.In such form, the preparation is subdivided into suitably sized unit doses, which contain appropriate amounts of the active components, for example, an effective amount to achieve The desired amount of the inventive active composition in a unit dose of preparation may vary or generally range from about 1.0 milligrams to about 1,000 milligrams, preferably from about 1.0 to about 950 milligrams, more preferably about 1.0. to approximately 500 milligrams, and typically from approximately 1 to approximately 250 milligrams, according to the particular application. The actual dosage used may vary depending on the age of the patient, sex, weight and severity of the condition being treated. Such techniques are well known to those skilled in the art. Generally, the human oral dosage form containing the active ingredients can be administered 1 or 2 times per day. The amount and frequency of administration will be regulated according to the judgment of the attending clinician. A daily dosage regimen generally recommended for oral administration may vary from about 1.0 milligrams to about 1,000 milligrams per day, in a single dose or in divided doses. Some useful terms are described below: Capsule - refers to a special container or wrapper made of methyl cellulose, polyvinyl alcohols or gelatins or denatured starch to hold or contain the compositions comprising the active ingredients. Hard shell capsules are typically made from relatively high gel strength bone and pig skin gelatin combinations. The capsule itself may contain small amounts of dyes, opacifying agents, plasticizers and preservatives. Tablet - refers to a compressed or molded dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compressing mixtures or granulations obtained by wet granulation, dry granulation or by compaction. Oral gels - refer to active ingredients dispersed or solubilized in a semi-solid hydrophilic matrix. Powders for the constitution - refers to combinations of powders containing the active ingredients and suitable diluents that can be suspended in water or juice. Diluent - refers to substances that make up and mainly the largest portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can vary from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, most preferably from about 30 to about 60% by weight, even of most preferred way, from about 12 to about 60%. Disintegrants - refer to materials added to the composition to help break it (disintegrate) and release them; medicines. Suitable disintegrants include starches; modified starches "soluble in cold water" such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as croscarmellose sodium; alginates such as alginic acid and sodium alginate; clays such as bentonites and effervescent mixtures. The amount of disintegrant in the composition can vary from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight. Binders - refer to substances that agglutinate or "stick" the powders together and make them cohesive forming granules, thus serving as the "adhesive" in the formulation. The binders add cohesive strength already available in the diluent or filler. Suitable binders include sugars such as sucrose; starches derived from wheat, corn, rice and potatoes; natural gums such as acacia, gelatin and tragacanth; marine algae derivatives such as alginic acid, sodium alginate and calcium and ammonium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone and inorganic compounds such as magnesium aluminum silicate. The amount of the binder in the composition may vary from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably, from about 3 to about 6% by weight. weight. Lubricant - refers to a substance added to the dosage form to allow the tablet, granules, etc., after it has been compressed, to be released from the mold or matrix by reducing friction or wear. Suitable lubricants include metal stearates, such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; waxes with high melting point; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricants are usually added in the last step before compression, since they must be present on the surfaces of the granules and between them and the parts of the tablet press. The amount of lubricant in the composition can vary from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight. Slides - materials that prevent the formation of cake and improve the flow characteristics of the granulations, so that the flow is smooth and uniform. Suitable glidants include silicon dioxide and talc. The amount of glidant in the composition may vary from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2%, by weight. Coloring agents - excipients that provide coloration a; the composition or the dosage form. Such excipients may include food grade dyes and food grade dyes, adsorbed on a suitable adsorbent such as clay or aluminum oxide. The amount of coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%. Bioavailability - refers to the rate and degree to which the ingredient of the active drug or therapeutic portion is absorbed into the systemic circulation of a dosage form administered, as compared to a standard or control. Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of the granulation produced by compaction, or wet methods or other special procedures. Conventional methods for making other forms for administration such as, for example, capsules, suppositories and the like, are also well known. It will be apparent to those skilled in the art that many modifications, variations and alterations to the present description can be practiced, both to the materials and to the methods. Such modifications, variations and alterations are intended to be within the spirit and scope of the present invention. As indicated above, the invention includes tautomers, enantiomers and other stereoisomers of the compounds as well. Thus, as one skilled in the art knows, certain imidazole compounds can exist in tautomeric forms. Such variations are contemplated to be within the scope of the invention. Certain compounds of the present invention can exist in multiple crystalline forms or amorphous forms. All physical forms of the present invention are contemplated. The compounds of this invention may contain unnatural proportions of atomic isotopes (ie, "radiolabelled compounds") whether their use is therapeutic, diagnostic or as a research reagent, are contemplated under this invention. Another embodiment of the invention describes the use of the pharmaceutical compositions described above for the treatment of diseases of a disease mediated by the chemokine receptor CXCR3 in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of minus a compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof. In another embodiment, the method is directed to administer to the patient (a) an effective amount of at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, concurrently or sequentially with (b) ) at least one agent, drug, medicament, antibody and / or additional inhibitor to treat a disease mediated by the chemokine receptor CXCR3, in combination with a pharmaceutically acceptable carrier. In another embodiment, at least one compound of Formula 1 binds to a CXCR3 receptor.

The method may further comprise administering: (a) a therapeutically effective amount of at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, concurrently or sequentially with (b) at least one medication selected from the group consisting of: antirheumatic drugs that modify the disease; non-steroidal anti-inflammatory drugs; selective COX-2 inhibitors; COX-1 inhibitors; immunosuppressants (non-limiting examples include methotrexate, cyclosporin, FK506); steroids; PDE IV inhibitors, anti-TNF-a compounds, TNF-alpha convertase inhibitors, cytokine inhibitors, MMP inhibitors, gi'cocorticoids, chemokine inhibitors, selective inhibitors of CB2, p38 inhibitors, modifiers of the biological response; anti-inflammatory therapeutic agents and products. The disease can be an inflammatory disease. Another embodiment of this invention is directed to a method of inhibiting or blocking chemotaxis mediated by T cells in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of at least one compound according to the Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof. Another embodiment of this invention is directed to a method of treating inflammatory bowel disease in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of at least one compound in accordance with Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof. Another embodiment of this invention is directed to a method of treating or preventing rejection of a graft in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one compound in accordance with Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof. Another embodiment of this invention is directed to a method comprising administering to the patient a therapeutically effective amount of: (a) at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: cyclosporin A, FK-506, FTY720, Interferon beta, rapamycin, mycophenolate, prednisolone, azathioprine, cyclophosphamide and an anti-lymphocyte globulin. Another embodiment of this invention is directed to a method of treating multiple sclerosis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: (a) at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: interferon beta, glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, VLA inhibitors -4 and / or selective CB2 inhibitors. Another embodiment of this invention is directed to a method of treating multiple sclerosis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: a) at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: methotrexate, cyclosporin, leflunimide, sulfasalazine, β-methasone, interferon-β, glatiramer acetate, prednisone, etonercept and infliximab. Another embodiment of this invention is directed to a method of treating rheumatoid arthritis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: (a) at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: COX-2 inhibitors, COX inhibitors, (immunosuppressants, steroids, PDE IV, anti-TNF-α li compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective inhibitors of CB2, caspase inhibitors (ICE) and other classes of compounds indicated for the treatment of rheumatoid arthritis. This invention is directed to a method for treating psoriasis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a) at least one compound according to Formula 1, or a salt, solvate or pharmaceutically acceptable ester thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: immunosuppressants, steroids and omitted anti-TNF-a. Another embodiment of this invention is directed to a method of treating a disease selected from the group consisting of inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection, psoriasis, fixed rashes from drugs, cutaneous hypersensitivity skin responses, delayed type, tuberculoid leprosy, type I diabetes, viral meningitis and tumors in a patient in need of such treatment, such method comprises administering to the patient an effective amount of at least one compound according to Formula 1, or a salt, solvate or pharmaceutically acceptable ester thereof. Another embodiment of this invention is directed to a method of treating a disease selected from the group consisting of inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection, psoriasis, fixed rashes from drugs, cutaneous hypersensitivity skin responses. delayed type, tuberculoid leprosy and cancer in a patient in need of such treatment, such method comprises administering to the patient an effective amount of at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof. Another embodiment of this invention is directed to a method of treating a disease selected from the group consisting of inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection, psoriasis, fixed rashes from drugs, cutaneous hypersensitivity skin responses, delayed type and tuberculoid leprosy, type I diabetes, viral meningitis and cancer in a patient in need of such treatment, such method comprises administering to the patient an effective amount of (a) at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, concurrently or sequentially with (b) at least one medicament selected from the group consisting of: antirheumatic drugs that modify the disease; non-spheroidal anti-inflammatory drugs; selective COX-2 inhibitors; COX-1 inhibitors; immunosuppressants; steroids; PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, biological response modifiers; anti-inflammatory therapeutic agents and products. Another embodiment of the invention describes a method for making the substituted pyrazine compounds described above. Unless indicated otherwise, the following abbreviations have the meanings indicated in the following Examples: DBU = 1, 8-diazabicyclo [5.4.0] undec-7-ene DBN = 1, 5-diazabicyclo [4.3.0jnon-5-ene DMF = N, N-dimethylformamide Et20 = diethyl ether EDCI = 1 - (3-dimethylaminopropyl -3-ethylcarbodiimide HOBT = 1-hydroxybenzotriazole DCC = dicyclohexylcarbodiimide Dibal-H = diisobutylaluminum hydride LAH = lithium aluminum hydride NaBH (OAc) 3 = sodium triacetoxyborohydride NaBH4 = sodium borohydride NaBH3CN = sodium cyanoborohydride LDA = lithium diisopropylamide P-TsOH = p-toluenesulfonic acid m-CPBA = m-chloroperbenzoic acid TMAD = N, N, N ', N'-tetramethylazodicarboxamide CSA = camphorsulfonic acid NaHMDS = sodium hexamethyl disilyllazide THF = tetrahydrofuran HRMS = High Resolution Mass Spectrometry HPLC = High Performance Liquid Chromatography LRMS = Low Resolution Mass Spectrometry nM = nanomolar Ki = Dissociation constant of the substrate / receptor complex pA2 = -logEC50, as defined by J. Hey, Eur. J. Pharmacol., (1995), Vol. 294, 329 -335. Ci / mmol = Curie / mmol (a measure of specific activity) Tr = Trifenylmethyl TRIS = Tris (hydroxymethyl) aminomethane General synthesis The compounds of the present invention can be prepared by several obvious ways to one skilled in the art. Preferred methods include, but are not limited to, the general synthetic methods described herein. One skilled in the art will recognize that a route will be optimal depending on the choice of the substituents attached. In addition, someone with experience in the art will recognize that in some cases, the order of the steps has to be controlled to avoid the incompatibilities of the functional group. One skilled in the art will recognize that a more convergent route (i.e., certain non-linear portions of the molecule or with a pre-assembly) is a more efficient method of assembling the target compounds. The methods for the preparation of the compounds of general formula 1, wherein the variables (R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R30, R31, G, L, Z, X, D, Y, m, n, p and q), are as defined above, are shown in Reaction Schemes 1, 2 and 3 Pr1, Pr2 and Pr3 are protective groups exemplified below . REACTION SCHEME 1 Method A REACTION SCHEME 2 Method B REACTION SCHEME 3 Method C The raw material and reagents used in the preparation of the disclosed compounds are available from commercial suppliers such as Aldrich Chemical Co. (Wisconsin, USA and Acros Organics Co. (New Jersey, USA), or were prepared by known literature methods by those with experience in the art.

The preparation of the arylpiperazine compounds related to the intermediate lll has been reported in WO-03037862 (Nippon Shinyaku). One of skill in the art will recognize that the synthesis of the compounds of formula 1 may require the protection of certain functional groups (ie, the derivation for the purpose of chemical compatibility with a particular reaction condition). A suitable protecting group for a carboxylic acid (Pr1, when R14, R5 = O), is the methyl, ethyl, isopropyl or benzyl ester and the like. A suitable protecting group for an amine (Pr2, Pr3) is methyl, benzyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, phthaloyl, trifluoroacetyl, acetyl and the like. All protecting groups can be linked to, and eliminated by literature methods known to those skilled in the art. One skilled in the art will recognize that the synthesis of the compounds of formula 1 may require the construction of an amide bond. The methods include, but are not limited to, the use of a reactive carboxyl derivative (e.g., acid halide or ester at elevated temperatures), or the use of an acid with coupling reagents (e.g., EDCI, DCC) in the presence of an amine from 0 ° C to 100 ° C. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, DMF and the like. The reaction can be carried out under reduced pressure or in a sealed container.

One skilled in the art will recognize that the synthesis of the compounds of formula 1 may require the construction of an amine linkage. Such a method is, non-exclusively, the reaction of a primary or secondary amine with a reactive carbonyl (eg, aldehyde or ketone) under reductive amination conditions. Suitable reducing agents of the mine intermediate are NaBH 4, NaBH (OAc) 3 and the like from 0 ° C to 100 ° C. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, DMF and the like. Optionally, the reaction can be carried out in the presence of titanium tetraisopropoxide to facilitate the generation of the imine. Another method such is, non-exclusively, the reaction of a primary or secondary amine with a reactive alkylating agent such as alkyl halide, benzyl halide, mesylate, tosylate and the like. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, DMF and the like. The reaction can be carried out under pressure or in a sealed container from 0 ° C to 100 ° C. One skilled in the art will recognize that the synthesis of the compounds of formula 1 may require the reduction of a reducible functional group. Suitable reducing agents include NaBH 4, LAH, diborane and the like at -20 ° C to 100 ° C. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, DMF and the like. One of skill in the art will recognize that the synthesis of the compounds of formula 1 may require the oxidation of a functional group. Suitable oxidizing reagents include oxygen, hydrogen peroxide, m-CPBA and the like at -20 ° C to 100 ° C. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, water and the like. The raw materials and intermediates of a reaction can be isolated and purified if desired using conventional techniques, including, but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

General description of the methods Step A. Amination of 2-Halopyrazine A suitably protected 2-halopyrazine of formula I is reacted with a piperazine of formula II to form a compound of general formula III. Preferably, the reaction is carried out in a solvent such as dioxane in the presence of a base such as potassium carbonate or cesium carbonate.

Step A '. Protection of piperazine amine Optionally, if the 2-halopyrazine of formula I is reacted with unprotected piperazine II (where Pr2 = H), the product of formula III needs to be protected with a suitable amine protecting group described above Step B Sandmver type reaction A suitably protected 2-halopyrazine of formula III is reacted with an alkyl nitrite in the presence of acid to form a compound of general formula IV. Preferably, the reaction is carried out in a solvent such as THF and water. Alternatively, a fully assembled 6-aminopiracine of formula XXI is reacted under the same reaction condition described above, to provide a compound of general formula XVI.

Step C. N-alkylation of 2-pyrazinone A suitably protected 2-pyrazinone of formula IV is reacted with an alkylating agent such as methyl iodide to form an N-alkylated product of general formula V. Preferably, the The reaction is carried out in a solvent such as acetone in the presence of a base such as potassium carbonate or cesium carbonate.

Step D Amidation of an ester A suitably protected alkyl ester of formula V (when R 14, R 15 = O), is reacted with an amine to provide an amide of general formula VI. Preferably, the reaction is carried out in a solvent such as methanol or dioxane in a pressure vessel of ° C to 100 ° C.

Step D '. Formation of the hydrazide A suitably protected alkyl ester of formula XIII (when R14, R15 = O), is reacted with a hydrazide (substituted or unsubstituted), to provide a hydrazide of general formula XIV. Preferably, the reaction is carried out in a polar solvent such as MeOH or EtOH from 25 ° C to 100 ° C.

Step E. Deprotection of the amine protecting group Optionally, if the product of step A is a protected piperazine of structure III, deprotection is required. When Pr2 is benzyl or substituted benzyl, the deprotection can be effected by a reaction under a hydrogen gas pressure in the presence of a catalyst, such as palladium. When Pr2 is ethoxycarbonyl, the deprotection can be effected by reaction with trimethylsilyl iodide. When Pr2 is t-butoxycarbonyl, the deprotection can be carried out with a strong acid such as trifluoroacetic acid.

Step F. Reductive amination A piperazine of structure VII is reacted with a ketone of structure VIII in the presence of a reducing agent with or without titanium tetraisopropoxide, to form a compound of structure VIV, wherein R12 is hydrogen. The general conditions for the reductive amination reaction are described above.

Step G. Deprotection of the amine protecting group Optionally, if the ketone of step F is a protected piperazine of structure VIII, deprotection is required. When Pr3 is benzyl or substituted benzyl, the deprotection can be effected by a reaction under a hydrogen gas pressure, in the presence of a catalyst, such as palladium. When Pr3 is ethoxycarbonyl, the deprotection can be effected by reaction with trimethylsilyl iodide. When Pr3 is t-butoxycarbonyl, the deprotection can be carried out with a strong acid such as trifluoroacetic acid.

Step H. Formation of the amide when Y = C = O A compound of structure X is reacted with reactive carboxyl derivatives (acid halide or ester) or the corresponding acids under the general conditions described above.

Step H. Formation of the amine when Y = CR1 R2 A compound of structure X is reacted with reactive carbonyl derivatives (aldehyde or ketone) under the conditions of reductive amination described above. Other methods include using alkylating agents such as alkyl halide, benzyl halide, mesylate, tosylate or the like. The general conditions were described above.

Step H 'Optionally, the manipulation of a functional group of a compound of structure XI or XVI can be done to provide additional related compounds of structure XI or XVI.

Step I. Suzuki coupling A suitably protected ester of formula XIII, wherein R14 = R15 = O and R3 = Cl, is reacted with an alkylboronic acid in the presence of an appropriate palladium catalyst and ligands under the condition of typical Suzuki coupling. Preferably, the reaction is carried out in a solvent such as DMF or THF in the presence of a base such as potassium carbonate or nodium carbonate from 25 ° C to 100 ° C.

Step J. Formation of the heterocycle portion A suitably protected hydrazide of formula XIV, wherein R14 = R15 = O and Pr3 is an amine protecting group described above, is reacted with an acylating reagent to provide a heterocycle on the presence of a dehydrating agent such as p-toluenesulfonyl chloride. Typically, the reaction is carried out in a solvent such as THF or acetonitrile from 25 ° C to 100 ° C. The compounds of formula 1 can be prepared by the general methods set forth in Reaction Schemes 1, 2 and 3. The synthesis of the specifically exemplified compounds was prepared as described in detail below. The following Examples are provided to further illustrate the present invention. They are for illustrative purposes only; the scope of the invention is not considered to be limited in any way by them.

EXAMPLES EXAMPLE 1 Step A, Method A A round bottom flask was charged with methyl-6-amino-2,3-dichloropiracine 5-carboxylate (Aldrich, 25 g, 112.6 mmol), 2-S-ethyl piperazine (prepared as per Williams et al J. Med. Chem 1996, 39, 1345, 83% active, 15.7 g, 112.7 mmol), cesium carbonate (100 g, 300 mmol) and 1,4-dioxane (400 mL). The flask was equipped with a reflux condenser and heated to 80 ° C. After 12 hours, the reaction was cooled, diluted with CH2Cl2 (-200 mL), and filtered through celite. The filtrate was washed once with water and then concentrated to an oil. The crude product was purified by column chromatography on silica gel (3% to 10% MeOH in CH 2 Cl 2), to give compound A3 (30.8 g, 91%). MS: M + H = 300.

EXAMPLE 2 Step A ', Method A A solution of A3 (19 g, 63 mmol) and triethylamine (26 mL, 189 mmol) in CH2Cl2 (300 mL) was treated with trifluoroacetic anhydride (13 mL, 94 mmol) at 0 ° C. The reaction mixture was stirred for 16 hours at 0 ° C to 25 ° C. The reaction mixture was treated with an aqueous solution of NaHCO3 and stirred for an additional 10 hours at 25 ° C. The organic layers were extracted with CH2Cl2 and the combined organic solution was washed with a brine solution, dried (Na2SO) and concentrated in vacuo. The raw product A4 (24.9 g, 100%) was sufficiently pure to be used in the next step without further purification. MS: M + H = 396.

EXAMPLE 3 Step B, Method A A cold suspension of A4 (3.09 g, 7.8 mmol) in THF (78 mL) was treated with a 50% aqueous solution of H2SO4 (5 mL) and t-butyl nitrite (5 mL). The reaction mixture was stirred for 1 hour at 0 ° C. The reaction mixture was added to a mixture of CH2Cl2 and an aqueous solution of NaHCO3. The mixture was stirred for 0.5 hour and the organic layers were extracted with CH2Cl2. The combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The crude product of formula B1 (3 g, 95%) was used for the next step without further purification. MS: M + H = 395.

EXAMPLE 4 Step C, Method A A mixture of B1 (3 g, 7.8 mmol), cesium carbonate (5 g, 15.3 mmol) and methyl iodide (1.2 mL, 19.2 mmol) in acetone (180 mL) was stirred at 70 ° C for 20 hours. The mixture was concentrated and the residue was dissolved in CH2Cl2. The organic solution was washed with water and with a brine solution, dried (Na2SO4) and concentrated in vacuo to give the crude product of formula C1 (3.2 g, 100%). MS: M + H = 411.

EXAMPLE 5 Step D, Method A A solution of C1 (238 mg, 0.58 mmol) in CH2Cl2 (3 mL) was treated with 7 N NH3 in MeOH (1 mL) at 25 ° C. The reaction mixture was stirred for 4.5 hours and the temperature and then concentrated in vacuo. The residue was dissolved in 7N NH3 in MeOH (5 mL) and the solution was stirred for 17 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (1.5% NH3 7N-MeOH in CH2Cl2) to give a compound of formula E1 (140 mg, 81%).

MS: M + H = 299.

EXAMPLE 6 Step F, Method A A solution of E1 (138 mg, 0.46 mmol) and N-Boc-4-piperidine (137 mg, 0.69 mmol) in 1,2-dichloroethane (4 mL) was treated with NaBH (OAc) 3 (292 mg, 1.38 mmol) at 25 ° C. The reaction mixture was stirred at 60 ° C for 16 hours. To the mixture was added additional NaBH (OAc) 3 (60 mg, 0. 28 mmoles) and the reaction mixture was continued stirring at 60 ° C for 3 hours. The reaction mixture was cooled and added to an aqueous solution of NaHCO 3. The organic layers were extracted with EtOAc and the combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2.5% MeOH in CH 2 Cl 2) to give F1 (105 mg, 47%). MS: M + H = 483.

EXAMPLE 7 Step G, Method A A solution of F1 (92 mg, 0.19 mmol) in CH2Cl2 (2 mL) was treated with trifluoroacetic acid (0.2 mL) at 0 ° C. The reaction mixture was stirred for 3 hours at 0 ° C to 25 ° C. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (2.5% to 10% NH3 7N-MeOH in CH2Cl2) to give G1 (35 mg, 48%). MS: M + H = 383.

EXAMPLE 8 Step H, Method A A solution of G1 (35 mg, 0.091 mmol) in DMF (1 mL) was treated with lithium 2-amino-6-chloronicotinate (19.6 mg, 0.11 mmol, preparation - see below), 1- [3- hydrochloride. (dimethylamino) propyl] -3-ethylcarbodiimide (EDCI, 35 mg, 0.18 mmol) and 1-hydroxybenzotriazole (HOBt, 37 mg, 0.27 mmol) at 25 ° C. The reaction mixture was stirred for 24 hours at the temperature and added to an aqueous solution of NaHCO3. The mixture was stirred for 2 hours and the organic layers were extracted with EtOAc. The combined organic solution was washed with a brine solution, dried (Na 2 SO 4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1.5% NH3 7N-MeOH in CH2Cl2) to give H1 (26 mg, 55%). MS: M + H = 520.

EXAMPLE 9 Step E ', Method B A solution of C1 (1.03 g, 2.5 mmol) in MeOH (70 mL) and water (20 mL) was treated with NaBH (226 mg, 5.95 mmol, added as 4 portions over 23 hours) at 25 ° C. The reaction mixture was stirred for 24 hours at 25 ° C and quenched by the addition of a saturated aqueous solution of NaHCO3 (20 mL). The mixture was stirred for 1 hour at 25 ° C and the organic solvent was evaporated. The aqueous solution was extracted with EtOAc and the combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (3% to 5% MeOH in CH 2 Cl 2) to give E 2 (496 mg, 63%). MS: M + H = 315.

EXAMPLE 10 Step I '. Method B A mixture of F2 (161 mg, 0.32 mmol), methyl boronic acid (30 mg, 0.49 mmol), complex of [1,1 '-bis (diphenylphosphino) ferrocene] -dichloropalladium (ll), with dichloromethane (1: 1) (52 mg, 0.064 mmol) and potassium carbonate (89 mg, 0.64 mmol) in DMF (2 mL) was degassed and stirred at 70 ° C for 20 hours. The reaction mixture was cooled and added to an aqueous solution of NaHCO3. The organic layers were extracted with EtOAc and the combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH in CH 2 Cl 2) to give 11 (115 mg, 75%). MS: M + H = 478.

EXAMPLE 11 Step D ', Method B A compound with the structure of 11 (107 mg, 0.22 mmol) in EtOH (4 mL) was treated with hydrazine (70 μL, 2.2 mmol) and the reaction mixture was stirred at 60 ° C for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (2.5% to 5% MeOH in CH2Cl2) to give D1 (64.2 mg, 60%). MS: M + H = 478.

EXAMPLE 12 Step J, Method B A solution of compound D1 (65 mg, 0.135 mmol) in CH2Cl2 (2 mL) was treated with ethyl isocyanate (13 μL, 0.163 mmol) at 0 ° C. The reaction mixture was stirred at 25 ° C for 1 hour. The reaction mixture was treated with triethylamine (94 μL, 0.675 mmole) and p-toluenesulfonyl chloride (31 mg, 0.162 mmole) at 25 ° C and the mixture was stirred for 20 hours. The reaction mixture was added to an aqueous solution of NaHCO 3 and the organic solution was extracted with CH 2 Cl 2. The combined organic solution was washed with a brine solution, dried (Na 2 SO) and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH in CH2Cl2) to give J1 (26 mg, 36%). MS: M + H = 531.

EXAMPLE 13 Step H ", Method B A solution of compound J1 (26 mg, 0.049 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (0.1 mL) at 25 ° C. The reaction mixture was stirred at the temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residual material was dissolved in DMF (0.6 mL). The solution was treated with triethylamine (20 mL, 0.14 mmol) and the mixture was stirred for 0.25 hours before the addition of lithium 2-amino-6-chloronicotinate (10.5 mg, 0.06 mmol, preparation: see below), hydrochloride 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDCI, 19 mg, 0.1 mmol) and 1-hydroxybenzotriazole (HOBt, 20 mg, 0.15 mmol) at 25 ° C. The reaction mixture was stirred for 7 hours at 25 ° C. The mixture was added to an aqueous solution of NaHCO 3 and the organic layers were extracted with EtOAc. The combined organic solution was washed with a brine solution, dried (Na 2 SO) and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in CH 2 Cl 2) to give H 2 (16.5 mg, 59%). MS: M + H = 437.

EXAMPLE 14 Step J ', Method C A solution of compound D2 (2.26 g, 4.68 mmol) in CH2Cl2 (20 mL) was treated with acetic anhydride (0.58 mL, 6.08 mmol) and triethylamine (1.3 mL, 9.36 mmol) at 0 ° C. The reaction mixture was stirred at 25 ° C for 4 hours. The reaction mixture was added to an aqueous solution of NaHCOs and the organic solution was extracted with CH2Cl2. The combined organic solution was washed with a brine solution, dried (Na 2 SO 4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (3% to 10% MeOH in CH 2 Cl 2) to provide intermediate D 3 (1.9 g, 78%). A solution of intermediate D3 (518 mg, 0.99 mmol) in CH2Cl2 (18 mL) was treated with p-toluenesulfonyl chloride (207 mg, 1.09 mmol) and triethylamine (0.83 mL, 5.94 mmol) at 25 ° C. The reaction mixture was stirred at 25 ° C for 48 hours. The reaction mixture was added to an aqueous solution of NaHCO 3 and the organic solution was extracted with CH 2 Cl 2. The combined organic solution was washed with a brine solution, dried (Na 2 SO) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2.5% NH3 7N-MeOH in CH2Cl2) to give compound J2 (415 mg, 83%). MS: M + H = 507.

EXAMPLE 15 Step G ', Method C A solution of compound J2 (462 mg, 0.91 mmol) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid (1 mL) at 25 ° C. The reaction mixture was stirred at the temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residual material was redissolved in CH2Cl2 (6 mL). The solution was treated with 7N NH3 in MeOH (~1 mL) and the mixture was stirred for 0.5 hours at 0 ° C. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (3% to 10% MeOH in CH 2 Cl 2) to give G 2 (325 mg, 88%). MS: M + H = 407.

EXAMPLE 16 Step H "'Method C A solution of compound G2 (429 mg, 1.05 mmol) in CH2Cl2 (18 mL) and THF (4.5 mL) was treated with triethylamine (0.29 mL, 2.1 mmol) and 4-chlorobenzoyl chloride (0.16 mL, 1.26 mmol) at 0 ° C. The reaction mixture was stirred at the temperature for 1.5 hours. The reaction mixture was added to an aqueous solution of NaHCO3 and the organic solution was extracted with CH2Cl2. The combined organic solution was washed with a brine solution, dried (Na 2 SO) and concentrated m vacuo. The residue was purified by column chromatography on silica gel (1.5% to 5% MeOH in CH2Cl2) to provide compound H3 (565 mg, 99%). MS- M + H = 545.

EXAMPLE 17 Step B ', Method C A cold solution of H3 (hydrochloride salt, 23 mg, 0.039 mmol) in THF (0.5 mL) and water (0.1 mL) was treated with 50% aqueous solution of HBF4 (8 μL) and t-butyl nitrite ( 8 μL). The reaction mixture was stirred for 16 hours at 25 ° C. The reaction mixture was added to the mixture of CH 2 Cl 2 and an aqueous solution of NaHCO 3 -NaOH (5%). The mixture was stirred for 0.5 hour and the organic layers were extracted with CH2Cl2. The combined organic solution was washed with a brine solution, dried (Na 2 SO 4) and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in CH 2 Cl 2) to provide B2 (4.3 mg, 19%). MS: M + H = 546.

Lithium 2-amino-6-chloronicotinate 1. SOCk MeOH A solution of 2,6-dichloronicotinic acid (20.2 g, 0.105 mol) in MeOH (500 mL) was cooled to 0 ° C and pure thionyl chloride (38 mL, 63 g, 0.525 mol) was added over -0.5 hours. The reaction mixture was stirred at 0 ° C for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to 25 ° C, and the reaction allowed to stir for an additional 2 days at 25 ° C. The solvent was removed under reduced pressure to provide a white matte residue. The residue was dissolved in Et20 (-500 mL) and the resulting solution was washed successively with a saturated aqueous solution of NaHCO3 (-300 mL), water (-300 mL) and a brine solution (-300 mL). The organic layer was separated, dried over anhydrous MgSO 4 and filtered. Removal of the solvent under reduced pressure afforded methyl 2,6-dichloronicotinate (21.0 g, 97%) as a white solid. Carried out in duplicate at identical scales in two pressure vessels, methyl 2,6-dichloronicotinate (4.5 g, 22 mmol) was dissolved in an NH3-solution (250 mL, 0.5 M in 1,4-dioxane).; 0.125 moles). The pressure vessels were sealed and heated to (85 ± 5) ° C for 9 days. The two reaction mixtures were allowed to cool to 25 ° C, then combined and concentrated under reduced pressure to give a white solid. Dissolution of the solid in 1: 1 acetone-MeOH (-500 mL), followed by adsorption on silica gel (25 g) and then purification by flash column chromatography (25: 10: 1 hexane-CH2Cl2- Et20), provided 6.08 g (75%) of methyl 2-amino-6-chloronicotinate.

A solution of LiOH »H20 (1.38 g, 33 mmol) in water (33 mL) was added in one portion to a suspension of 2-amino-6-chloronicotinate from methyl (6.08 g, 27 mmol) in MeOH (110 mL). The reaction mixture is stirred at 70 ° C for 24 hours, and gradually became homogeneous. The solvents were removed under reduced pressure, and then, the white solid The resultant was dried under vacuum (<1 mmHg) at a constant weight, obtained . 51 g (95%) of lithium 2-amino-6-chloronicotinate.

Biological examples The inventive compounds can be easily evaluated for activity at CXCR3 receptors, by methods known, such as, for example, Development of the Human CXCR3 (N-delta 4) Union Test.

Cloning and expression of human CXCR3 (N-delta 4) The DNA encoding human CXCR3 was cloned by PCR i using human genomic DNA (Promega, Madison, Wl) as a template.

PCR primers were designed based on the published sequence of the GPR9 (1) human orphan receptor with incorporated i restriction sites, a Kozak consensus sequence, a CD8 leader and a marga! Flag The PCR product was subcloned into the expression vector of mammal pME18Sneo, a derivative of the expression vector SR-alpha (designated as pME18Sneo-hCXCR3 (N-delta 4).

The Ba-F3 IL-3 dependent mouse pro-B cells were transfected by electroporation in 0.4 ml of Dulbecco's PBS containing 4 X 10 6 cells with 20 μg of plasmid DNA pME18Sneo-hCXCR3 (N-delta 4). Cells were pulsed at 400 Volts, 100 OHM, 960 μFd. The transfected cells were under selection with 1 mg / ml of G418 (Life Technologies, Gaithersburg, MD). Ba / F3 clones resistant to G418 were selected for the expression of CXCR3 by specific binding of [125 I] IP-10 (NEN Life Science Products, Boston, MA).

Preparation of the membranes of Ba / F3-hCXCR3 (N-delta 4) The Ba / F3 cells expressing the human CXCR3 (N-delta 4) were granulated and resuspended in the lysis buffer containing 10 mM HEPES, pH 7.5 e Complete® protease inhibitors (1 tablet per 100 ml) (Boehringer Mannheim, Indianapolis, IN) at a cell density of 20 x 106 cells per ml. After 5 minutes of incubation on ice, the cells were transferred to a 4639 cell disruption pump (Parr Instrument, Moline, IL) and 105.46 kgf / cm2 (1, 500 psi) of nitrogen was applied for 30 minutes on ice . Large cell debris was removed by centrifugation at 1,000 x g. The cell membranes in the supernatant were pelleted at 100,000 x g. The membrane was resuspended in the lysis buffer supplemented with 10% sucrose and stored at -80 ° C. The total concentration of the membrane protein was determined by the BCA method of Pierce (Rockford, IL).

Scintillation proximity assay (SPA) of human CXCR3 (N-delta 4) (SPA) For each test site, 2 μg of the membrane was preincubated for 1 hour with 300 μg of SPA beads coated with wheat germ agglutinin (Amersham, Arlington Heights, IL) in the binding buffer (50 mM HEPES, 1 mM CaCl 2, 5 mM MgCl 2, 125 mM NaCl, 0.002% NaN 3, 1.0% BSA) at room temperature. The beads were centrifuged, washed once, resuspended in the binding buffer and transferred to a 96-well Isoplate (Wallac, Gaithersburg, MD). 25 pM of [125 I] IP-10 with the compounds tested in a series of titrations were added to initiate the reaction. After 3 hours of reaction at room temperature, the amount of [125 l] IP-10 bound to the SPA beads was determined with a Wallac 1450 Microbeta counter. The Ki values for the various exemplary compounds of the present invention are given in Table 1 mentioned above. From these values, it would be apparent to the person skilled in the art that the compounds of the invention have excellent utility as CXCR3 antagonists. Although the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All of such alternatives, medications and variations are intended to fall within the spirit and scope of the present invention.

Claims (2)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound that has the general structure shown in the Formula 1 : Formula 1 or a pharmaceutically acceptable salt, solvate or ester thereof, wherein: G is selected from the group consisting of H, hydroxyl, alkoxy, R2R1N-, R2R1X-C (R14XR15) -, and a heteroaryl or heterocyclenyl ring of 5 members, which contains at least one portion -C = N- as part of the heteroaryl or heterocyclic ring, the heteroaryl or heterocyclenyl ring optionally further contains one or more portions selected from the group consisting of N, N (? O), O, S, S (O) and S (02) in the ring, portions which may be the same or different, each is independently selected, in addition where the heteroaryl or heterocyclenyl ring may be (i) not substituted, or (ii) optionally and independently substituted on one or more ring carbon atoms with one or more substituents R9, or on one or more ring nitrogen atoms with one or more substituents R8, wherein substituents R8 and R9 may be the same or different; L is O or S; Z is N or CR4; R1 and R2 are independently absent or present, and if present, each is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, carbonyl, cycloalkyl, cycloalkenyl, alkylaryl, arylalkyl, aryl, amino, alkylamino, amidinyl, carboxamido, cyano, hydroxyl, urea, -N = CH, = NCN, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, - (CH2) qN ( R31) 2, - (CH2) qC (= 0) NHR31, - (CH2) qS02R31, - (CH2) qNHS02R31, - (CH2) qS02NHR31, -C (= S) N (H) alkyl, -N (H) -S (O) 2-alkyl, -N (H) C (= O) N (H) -alkyl, -S (O) 2alkyl, -S (O) 2N (H) alkyl, -S (0) 2N (alkyl) 2, -S (O) 2-aryl, -C (= S) N (H) cycloalkyl, -C (= 0) N (H) NH 2, -C (= O) alkyl, -heteroaryl, heterocyclyl and heterocyclenyl; or alternatively, when X is N, the N taken together with R1 and R2 forms a heterocyclyl, heteroaryl or -N = C (NH2) 2; the portions R3 and R4 may be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aralkyl, -CN, CF3, haloalkyl, cycloalkyl, halogen, hydroxyalkyl, -N = CH- (R31), -C (= O) N (R30) 2, -N (R30) 2, -OR30, -S02 (R31), -N (R30) C (= O) N (R30) 2 and -N (R30) C (= O) R31; R6 is selected from the group consisting of H, alkyl, arylalkyl, and alkylaryl; X is selected from the group consisting of N, O, alkyl, cycloalkyl, heteroaryl, heterocyclyl, and heterocyclenyl; the R8 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, - (CH2) qC (= 0) NHR31, - (CH2) qS02R31, - (CH2) qNS02R31 and - (CH2) qS02NHR31; the R9 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, alkoxy amidinyl, aryl, cycloalkyl, cyano, heteroaryl, heterocyclyl, hydroxyl -C (= O) N (R30) 2, -C (= S) N (R30) 2, -C (= O) alkyl0, - (CH2) qOH, - (CH2) qOR31 - (CH2) qNH2, - (CH2) qNHR31 , - (CH2) qC (= 0) NHR31, - (CH2) qS02R31 - (CH2) qNS02R31, - (CH2) qS02NHR31, -N (R30) 2, -N (R30) S (O2) R31 -N (R30) C (= O) N (R30) 2, -OR30, -S02 (R31), -SO2N (R30) 2, = 0 y = S; the R10 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, alkylaryl, arylalkyl, -C02H, hydroxyalkyl, -C (= O ) N (R30) 2, - (CH2) qOH, - (CH2) qOR31, -OR30, halogen, = O and -C (= 0) R31; the R11 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, alkylaryl, arylalkyl, carboxamide, C02H, - (CH2) qOH, - (CH2) qOR31, -OR30, halogen, = 0 and -C (= 0) R31; the portions R12 may be the same or different, each being independently selected from the group consisting of H, alkyl, -CN, -C (= O) N (R30) 2, - (CH2) q0H, - (CH2 ) q0R31 and -S (02) R31; Ring D is a cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl five to nine members having 0-4 heteroatoms selected independently from O, S or N, wherein ring D is unsubstituted or optionally substituted with 1-5 R20 portions independently selected; R20 portions may be the same or different, each is selected independently from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alquiltiocarboxi, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, - ( CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, - (CH2) qC (= 0) NHR31, - (CH2) qS02R31, - (CH2) qNS02R31, - (CH2) qS02NHR31 , -alkyIC (R31) 2OR31, -C (= 0) R30, -C (= O) N (R30) 2, -C (= NR30) NHR30, -C (= NOH) N (R30) 2, -C (= NOR31) N (R30) 2, -C (= 0) OR30, -N (R30) 2, -N (R30) C (= O) R31, -NHC (= O) N (R30) 2 , -N (R30) C (= O) OR31, -N (R30) C (= NCN) N (R30) 2, -N (R30) C (= O) N (R30) SO2 (R31), -N (R30) C (= O) N (R30) 2 , -N (R30) SO2 (R31), -N (R30) S (O) 2N (R30) 2, -OR30, -OC (= O) N (R30) 2) -SR30, -SO2N (R30) 2 , -S02 (R31), -OS02 (R31) and -OSi (R30) 3; or alternatively two R20 portions are linked together to form a five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclyl or heteroaryl ring, wherein the aryl, cycloalkyl, heterocyclyl, heterocyclyl or heteroaryl ring of five or six members is fused to ring D and the fused ring is optionally substituted with 0-4 portions R21; the R21 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, carboxamido, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, - (CH2) qC (= 0) NHR31, - (CH2) qS02R31, - (CH2) qNS02R31, - (CH2) ) qS02NHR31, -alkynylC (R31) 2OR31, -C (= 0) R30, -C (= O) N (R30) 2) -C (= NR30) NHR30, -C (= NOH) N (R30) 2, -C (= NOR31) N (R30) 2, -C (= O) OR30, -N (R30) 2, -N (R30) C (= O) R31, -NHC (= O) N (R30) 2 , -N (R30) C (= O) OR31, -N (R30) C (= NCN) N (R30) 2, -N (R30) C (= O) N (R30) SO2 (R31), -N (R30) C (= O) N (R30) 2, -N (R30) SO2 (R31), - N (R30) S (O) 2N (R30) 2, -OR30, -OC (= O) N (R30) 2, -SR30, -SO2N (R30) 2, -S02 (R31), -OS02 (R31) and -OSi (R30) 3; Y is selected from the group consisting of - (CR13R13) r, -CHR13C (= 0) -, - (CHR13) rO-, - (CHR13) rN (R30) -, -C (= 0) -, -C ( = NR30) -, -C (= N-OR30) -, -CH (C (= 0) NHR30) -, CH-heteroaryl-, -C (R13R13) rC (R13) = C (R13) -, - ( CHR13) X (= 0) - and - (CHR13) rN (H) C (= 0) -; or alternatively Y is cycloalkyl, heterocyclenyl or heterocyclyl, wherein the cycloalkyl, heterocyclenyl or heterocyclyl is fused with the D ring; the R13 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocyclenyl, heterocyclyl, spiroalkyl, -CN, -C02H, -C (= O) R30, -C (= O) N (R30) 2, - (CHR30) qOH, - (CHR30) qOR31, - (CHR30) qNH2, - (CHR30) qNHR31, - (CH2) qC (= 0 ) NHR31, - (CH2) qS02R31, - (CH2) qNS02R31, - (CH2) qSO2NHR31, -NH2, -N (R30) 2, -N (R30) C (= O) N (R30) 2, -N ( R30) SO2 (R31), -OH, OR30, -SO2N (R30) 2, and -S02 (R31); R14 and R15 are the same or different, each is independently selected from the group consisting of H, alkyl, alkylaryl, heteroaryl, hydroxyl, -CN, alkoxy, alkylamino, -N (H) S (0) 2alkyl and - N (H) C (= 0) N (H) alkyl; or alternatively R14 and R15 taken together are = 0, = S, = NH, = N (alkyl), = N (Oalkyl), = N (OH) or cycloalkyl; the R30 portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, - (CH2) qOH, - (CH2) qOalkyl, - (CH2) qOalkylaryl, - (CH2) qOaryl, - (CH2) qOralkyl, - (CH2) qCycloalkyl, - (CH2) qNH2, - (CH2) qNHalkyl, - (CH2) qN (alkyl) 2, - (CH2) qNHalkylaryl, - ( CH2) qNHaril, - (CH2) qNHaralkyl, - (CH2) qNHcycloalkyl, - (CH2) qC (= O) NHalkyl, - (CH2) qC (= 0) N (alkyl) 2, - (CH2) qC (= O ) NHalkylaryl, - (CH2) qC (= 0) NHaryl, - (CH2) qC (= 0) NHaralkyl, - (CH2) qC (= 0) NHcycloalkyl, - (CH2) qS02alkyl, - (CH2) qS02alkylaryl, - (CH2) qS02aryl, - (CH2) qS02aralkyl, - (CH2) qS02cycloalkyl, - (CH2) qNS02alkyl, - (CH2) qNS02alkylaryl, - (CH2) qNS02aryl, - (CH2) qNS02aralkyl, - (CH2) qNSO2cycloalkyl, - (CH2) qS02NHalkyl, - (CH2) qS02NHalkylaryl, - (CH2) qS02NHaril, - (CH2) qS02NHaralkyl, - (CH2) qS02NHcycloalkyl, heterocyclenyl, heterocyclyl and heteroaryl; the R31 portions may be the same or different, each being independently selected from the group consisting of alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, - (CH2) qOH, - (CH2) qOalkyl, - (CH2) qOalkylaryl, - (CH2) qOaryl, - (CH2) qOralkyl, - (CH2) qCycloalkyl, - (CH2) qNH2, - (CH2) qNHalkyl, - (CH2) qN (alkyl) 2, - (CH2) qNHalkylaryl, - (CH2) qNHaril, - (CH2) qNHaralkyl, - (CH2) qNHcycloalkyl, - (CH2) qC (= 0) NHalkyl, - (CH2) qC (= 0) N (alkyl) 2, - (CH2) qC (= 0) NHalkylaryl, - (CH2) qC (= 0) NHaryl, - (CH2) qC (= O) NHaralkyl, - ( CH2) qC (= 0) NH cycloalkyl, - (CH2) qS02alkyl, - (CH2) qS02alkylaryl, - (CH2) qS02aryl, - (CH2) qS02aralkyl, - (CH2) qS02cycloalkyl, - (CH2) qNS02alkyl, - (CH2) qNS02alkylaryl, - (CH2) qNS02aryl, - (CH2) qNSO2aralkyl, - (CH2) qNS02cycloalkyl, - (CH2) qSO2NHalkyl, - (CH2) qSO2NHalkylaryl, - (CH2) qSO2NHaril, - (CH2) qS02NHaralkyl, - (CH2) qS02NHcycloalkyl, heterocyclenyl, heterocyclyl and heteroaryl; m is 0 to 4; n is 0 to 4; each q can be the same or different, each one is independently selected from 1 to 5; and r is 1 to 4; with the proviso that there are no two adjacent double bonds in any ring, and that when one nitrogen is substituted with two alkyl groups, the two alkyl groups may optionally be linked with one another to form a ring.
2. 2. The compound according to claim 1, further characterized in that L is O. 3 - The compound according to claim 1 or 2, further characterized in that G is R2R1X-C (R14XR15) -. 4. - The compound according to claim 3, further characterized in that X is N, and R14 and R15 taken together are = 0. 5. The compound according to claim 4, further characterized in that R1 and R2 are both H. 6. The compound according to claim 1 or 2, further characterized in that G is selected from the group consisting of H, hydroxyl , alkylO- or R2R1N. 7. The compound according to claim 1 or 2, further characterized in that the 5-membered heteroaryl or heterocyclenyl G ring contains at least one portion -C = N- as part of the heteroaryl or heterocyclenyl ring, is selected from the group which consists of dihydroimidazole, imidazole, dihydrooxazole, oxazole, dihydrooxadiazole, oxadiazole, triazole and tetrazole. 8. The compound according to claim 7, further characterized in that G is selected from the group consisting of: where ^^ is a single link or a double link. 9. The compound according to claim 8, further characterized in that G is 10. The compound according to claim 1 or 2, further characterized in that R3 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, -N (R30) 2, -OR30 and -CF3. 11. The compound according to claim 1 or 2, further characterized in that R3 is selected from the group consisting of H, -CH3, -CH2CH3, cyclopropyl, -F, -Cl, OCH3, OCF3 and CF3. 12. The compound according to claim 11, further characterized in that R3 is selected from the group consisting of H, -Cl and -CH3. 13. The compound according to claim 1 or 2, further characterized in that R8 is selected from the group consisting of H, alkyl, alkenyl, arylalkyl, cycloalkyl, - (CH2) qOH, - (CH2) qOR31, - (CH2 ) qNH2, - (CH2) qNHR31, - (CH2) qC (= 0) NHR31, - (CH2) qS02R31, - (CH2) C1NS02R31 and - (CH2) qS02NHR31. 14. The compound according to claim 1 or 2, further characterized in that the R9 portions can be the same or different, each is independently selected from the group consisting of H, alkyl, cycloalkyl, -C (= 0 ) N (H) R30, -C (= 0) alkyl, - (CH2) qOH, - (CH2) qOR31, - (CH2) c? NH2, - (CH2) qNHR31, -N (H) R30, -N (H) S (02) R31, -N (H) C (= 0) NH (R30), -OR30 -S02 (R31) and -S02N (H) R30. 15. The compound according to claim 1 or 2, further characterized in that the R9 portions can be the same or different, each is independently selected from the group consisting of H, cyclopropyl, -CF3, -CH3, - CH2OH, -CH2CH2OH, -C (CH3) 2 OH, -CH2CH2OCH3, -C (= 0) OCH2CH3, -CH2NH2, -CH2CH2NH2, -CH2CH2NHS02CH3, -CH2CH2S02CH3, -C (= 0) NH2, -C (= 0) N (H) CH2CH2OH, -CH2N (H) C (= 0) CF3, -C (= 0) N (H) -cyclopropyl, -C (= 0) N (H) CH2CF3, -NH2, -NHCH3, -N (CH3) 2, -N (H) CH2CH3, -N (H) CH (CH3) 2, -N (H) CH2CH2CH3, -N (H) CH2C (= 0) OCH3, -N (H) CH2CH2OH, - N (H) CH2CH2NH2, -N (H) CH2CH2NHS02CH3, -N (H) CH2CH2S02CH3, -N (H) C (= 0) N (H) CH2CH3, -N (H) CH2C (= 0) NH2, -OCH3, = S y = 0. 16. The compound according to claim 15, further characterized in that the R9 portions can be the same or different, each is independently selected from the group consisting of H, -CF3, -CH3, -CH2CH2OH, -CH2CH2NH2 , -NH2, -N HCH3, -N (H) CH2CH3, -N (H) CH (CH3) 2, -N (H) CH2CH2CH3, -N (H) CH2C (= 0) OCH3, and -N (H CH2CH2OH. 17. The compound according to claim 16, further characterized in that the R9 portion is selected from the group consisting of -NH2 and -N (H) CH2CH3. 18. The compound according to claim 1 or 2, further characterized in that R10 is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl and carbonyl. 19. The compound according to claim 18, further characterized in that R10 is alkyl, the alkyl is selected from the group consisting of -CH3, -CH2CH3 and -CH2CH2CH3, and m is 0-2. The compound according to claim 19, further characterized in that R10 is -CH2CH3 and m is 1. 21. The compound according to claim 1 or 2, further characterized in that R11 is selected from the group consisting of H, alkyl , hydroxyalkyl and carbonyl. 22. The compound according to claim 21, further characterized in that R11 is H or -CH3. 23 - The compound according to claim 22, further characterized in that R11 is H. 24. The compound according to claim 1 or 2, further characterized in that R12 is selected from the group consisting of H, CN, -C (= O) N (R30) 2 and alkyl. 25. The compound according to claim 24, further characterized in that R12 is selected from the group consisting of H, -CH3, CN and -CH2CH3. 26. The compound according to claim 25, further characterized in that R12 is H. The compound according to claim 1 or 2, further characterized in that the atoms in the ring of the ring D are independently C or N and is substituted with 0-4 R20 portions: 28.- The compound according to claim 1 or 2, further characterized in that ring D is an aryl, heteroaryl, heterocyclenyl or heterocyclyl ring of 5 to 6 members and is substituted with 0-4 R20 portions. 29. The compound according to claim 28, further characterized in that the ring D is a ring of aryl or heteroaryl of 5 to 6 members and substituted with 0-4 portions R20. 30. The compound according to claim 29, further characterized in that the aryl ring is phenyl and the heteroaryl ring is pyrindinyl. 31. The compound according to claim 1 or 2, further characterized in that the R20 portions can be the same or different, each is independently selected from the group consisting of H, alkyl, alkylaryl, alkynyl, alkoxy, alkylamino alkylheteroaryl, alkylsulfinyl, alkoxycarbonyl, aminoalkyl, amidinyl aralkyl, aralkoxy, aryl, aryloxy, cyano, cycloalkyl, cycloalkenyl, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, trifluoromethyl trifluoromethoxy, - (CH2) qOR31, - (CH2) qNHR31, - (CH2) qC (= 0) NHR31 - (CH2) qSO2R31, - (CH2) qNSO2R31, - (CH2) qSO2NHR31, -alkynylC (R31) 2OR31 -C (= O) R30, -C (= O) N (R30) 2, -C (= 0) OR30, -N (R30) 2, -N (R30) C (= O) R31 -NHC (= O) N (R30) 2) -N (R30) C (= O) OR31, -N (R30) C (= NCN) N (R30) 2 -N (R30) C (= O) N (R30) 2, -N (R30) SO2 (R31), -N (R30) SO2N (R30) 2, -OR30 -OC (= O) N (R30) 2) -SR30, -SO2N (R30) 2, -SO2 (R31), -OSO2 (R31) and -OSi (R30) 3. 32. The compound according to claim 1 or 2, further characterized in that the R20 portions can be the same or different, each is independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH3 , CF3, OCF3, - (CH2) qOR31, - (CH2) qNHR31, - (CH2) qC (= 0) NHR31) - (CH2) qS02R31, - (CH2) qNS02R31, - (CH2) qS02NHR31, -alkynyl (R31) ) 2OR31, -C (= 0) R30, -C (= 0) OR30, -N (R30) 2, -N (R30) C (= O) R31, -NHC (= O) N (R30) 2, -N (R30) C (= O) OR31, -N (R30) C (= NCN) N (R30) 2, -N (R30) C (= O) N (R30) 2, -OR30, -OC (= O) N (R30) 2 and -OSO2 ( R31). 33. The compound according to claim 32, further characterized in that the R20 portions can be the same or different, each is independently selected from the group consisting of H, halogen and amino. 34. The compound according to claim 1 or 2, further characterized in that Y is selected from the group consisting of: - (CHR13) r, - (CR13R13) r, -C (= 0) - and -CHR13C (= 0) -. The compound according to claim 1 or 2, further characterized in that Y is selected from the group consisting of: -CH2-, - CH (CH3) -, -CH (CH2OH) -, -C (= 0) - and -CH (C02alkyl) -. 36. The compound according to claim 35, further characterized in that Y is selected from the group consisting of: -CH2- and -C (= O) -. 37. The compound according to claim 1 or 2, further characterized in that m is 0-2. 38.- The compound according to claim 37, further characterized in that m is 1. 39.- The compound according to claim 1 or 2, further characterized in that n is 0-2. 40.- The compound according to claim 1 or 2, further characterized in that n is 0. 41.- The compound according to claim 1 or 2, further characterized in that q is 1 or 2. 42.- The compound of according to claim 1 or 2, further characterized in that r is 1 or 2. 43. The compound according to claim 1 or 2, further characterized in that G is independently selected from the group consisting of R 2r R > 1 ? N-C (= 0) - and R3 is selected from the group consisting of H, -Cl and -CH3; R9 is selected from the group consisting of -NH2 and -N (H) CH2CH3; R10 is -CH2CH3; R11 is H; R12 is H; ring D is an aryl or heteroaryl ring of 5 to 6 members and is substituted with 0-4 R20 moieties; the R20 portions may be the same or different, each being independently selected from the group consisting of H, halogen and amino; And it is selected from the group consisting of: -CH2- and -C (= 0) -; m is 1 and n is 0. 44. The compound according to claim 1, further characterized in that the compound is selected from the group consisting of the following: or a pharmaceutically acceptable salt, solvate or ester thereof. 45.- The compound according to claim 44, further characterized in that the compound is selected from the group consisting of . Y or a pharmaceutically acceptable salt, solvate or ester thereof. 46. The compound according to claim 1, further characterized in that it is in a purified form. 47. A pharmaceutical composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in combination with at least one pharmaceutically acceptable carrier. 48. The pharmaceutical composition according to claim 47, further characterized in that it comprises at least one agent, drug, medicament, antibody and / or additional inhibitor for treating a disease mediated by the chemokine receptor CXCR3. 49.- The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating a disease mediated by the chemokine receptor CXCR3 in a patient in need for such treatment. 50.- The use as claimed in claim 49, wherein the medicament is adapted to be administrable concurrently or sequentially with at least one agent, drug, medicament, antibody and / or additional inhibitor useful for treating a mediated disease. the CXCR3 chemokine receptor, in combination with a pharmaceutically acceptable carrier. 51. The use as claimed in claim 49, wherein the compound binds to a CXCR3 receptor. 52. The use as claimed in claim 49, wherein the medicament is adapted to be administrable concurrently or sequentially with at least one medicament selected from the group consisting of: antirheumatic drugs that modify the disease; non-steroidal anti-inflammatory drugs; selective COX-2 inhibitors; COX-1 inhibitors; immunosuppressants; steroids; PDE IV inhibitors, anti-TNF-a compounds, TNF-alpha convertase inhibitors, cytokine inhibitors, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, p38 inhibitors, response modifiers biological anti-inflammatory therapeutic agents and products. 53 - The use as claimed in claim 49, wherein the disease is an inflammatory disease. 54 - The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for inhibiting or blocking chemotaxis mediated by T cells in a patient in need of such treatment. treatment. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating inflammatory bowel disease in a patient in need of such treatment. 56 - The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, for the preparation of a drug useful to treat or prevent rejection of the graft in a patient in need of such treatment. 57 - The use as claimed in claim 56, wherein the medicament is adapted to be administrable concurrently or sequentially with at least one compound selected from the group consisting of: cyclosporin A, FK-506, FTY720, interferon beta, rapamycin, mycophenolate, prednisolone, azathioprene, cyclophosphamide and an antilymphocyte globulin. The use of: (a) at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof concurrently or sequentially with (b) at least one compound selected from the group consisting of: interferon beta, glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, inhibitors of VLA-4 and selective inhibitors of CB2, for the development of a drug useful to treat multiple sclerosis in a patient in need of such treatment. The use of: a) at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof in a concurrent or sequential manner with (b) at least one compound selected from the group consisting of: methotrexate , cyclosporine, leflunimide, sulfasalazine, β-methasone, interferon β, glatiramer acetate, prednisone, etonercept and infliximab, for the elaboration of a drug useful for treating multiple sclerosis in a patient in need of such treatment. The use of: (a) at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof in a concurrent or sequential manner with (b) at least one compound selected from the group consisting of: COX-2 inhibitors, COX-1 inhibitors, immunosuppressants, steroids, PDE IV inhibitors, anti-TNF-a compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, caspase inhibitors (ICE) ) and other classes of compounds indicated for the treatment of rheumatoid arthritis, for the preparation of a medicament useful for treating rheumatoid arthritis in a patient in need of such treatment. 61 -. 61 - The use of. a) at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof in a concurrent or sequential manner with (b) at least one compound selected from the group consisting of: immunosuppressants, steroids and anti-TNF compounds -a, for the elaboration of a medicine useful for treating psoriasis in a patient in need of such treatment. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating a disease selected from the group consisting of: inflammatory disease, rheumatoid arthritis , multiple sclerosis, inflammatory bowel disease, graft rejection, psoriasis, fixed rashes by drugs, delayed type hypersensitivity skin responses, tuberculoid leprosy and cancer, in a patient in need of such treatment. The use of (a) at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof in a concurrent or sequential manner with (b) at least one medicament selected from the group consisting of: drugs antirheumatics that modify the disease; non-steroidal anti-inflammatory drugs; selective COX-2 inhibitors; COX-1 inhibitors; immunosuppressants; steroids; PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, biological response modifiers; anti-inflammatory therapeutic agents and products, for the preparation of a medicament useful for treating a disease selected from the group consisting of: inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection, psoriasis, fixed rashes by drugs, responses skin conditions of delayed type hypersensitivity and tuberculoid leprosy, type I diabetes, viral meningitis and cancer, in a patient in need of such treatment.