METHOD OF TREATING CXCR3 MEDIATED DISEASES USING HETEROCYCLIC SUBSTITUTED PIPERAZINES

Field of the Invention

The present invention relates to methods of treating CXCR3 mediated diseases using CXCR3 antagonists, such as those of Formula 1 , as disclosed herein. Such diseases include, for example, chronic obstructive pulmonary disease (COPD), asthma, sarcoidosis, systemic lupus erythematosus (SLE), alkylosing spondylitis, fibrotic diseases, pulmonary fibrosis, alopecia areata, scleroderma, lichen planus erythematosus, discoid lupus erythematosus, dermatomyositis, Behcet's disease, Wegener's disease, atopic dermatitis, and graft-vs-host disease (GVHD).

BACKGROUND OF THE INVENTION

Chemokines constitute a family of cytokines that are produced in inflammation and regulate leukocyte recruitment (Baggiolini, M. et ai, Adv. Immunol., 55: 97-179 (1994); Springer, T. A., Annual Rev. Physio., 57: 827-872 (1995); and Schall, T. J. and K. B. Bacon, Curr. Opin. Immunol, 6: 865-873 (1994)). Chemokines are capable of selectively inducing chemotaxis of the formed elements of the blood (other than red blood cells), including leukocytes such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells, and lymphocytes, such as T cells and B cells. In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca ²⁺ ]O ₁ granule exocytosis, integrin upregulation, formation of bioactive lipids (e. g., leukotrienes) and respiratory burst, associated with leukocyte activation. Thus, the chemokines are early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.

Chemokines are related in primary structure and share four conserved cysteines, which form disulfide bonds. Based upon this conserved cysteine

motif, the family can be divided into distinct branches, including the C-X-C chemokines (α-chemokines) in which the first two conserved cysteines are separated by an intervening residue (e. g., IL-8, IP-10, Mig, I-TAC, PF4, ENA-78, GCP-2, GROα, GROβ, GROδ, NAP-2, NAP-4), and the C-C chemokines (β-chemokines), in which the first two conserved cysteines are adjacent residues (e. g., MIP-1α, MIP-1 β, RANTES, MCP-1 , MCP-2, MCP-3, I-309) (Baggiolini, M. and Dahinden, C. A., Immunology Today, 15 : 127-133 (1994)). Most CXC-chemokines attract neutrophil leukocytes. For example, the CXC-chemokines interleukin-8 (IL-8), GRO alpha (GROα), and neutrophil-activating peptide 2 (NAP-2) are potent chemoattractants and activators of neutrophils. The CXC-chemokines designated Mig (monokine induced by gamma interferon) and IP-10 (interferon-gamma inducible 10 kDa protein) are particularly active in inducing chemotaxis of activated peripheral blood lymphocytes. 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 human monocyte chemotactic proteins 1-3 (MCP-1 , MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), and the macrophage inflammatory proteins 1 α and 1 β (MIP-1 α and MIP-1 β) 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 the CXC-chemokines IP-10 and Mig has 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 and has been shown to be restrictively expressed in activated T cells, preferentially human Th1 cells. On binding of the appropriate ligand, chemokine receptors transduce an intracellular signal through the associated G-protein resulting in a rapid increase in intracellular calcium concentration.

The CXCR3 receptor mediates Ca ²⁺ (calcium ion) mobilization and chemotaxis in response to IP-10 and Mig. CXCR3 expressing cells show no

significant response to the CXC-chemokines IL-8, GROα, NAP-2, GCP-2 (granulocyte chemotactic protein-2), ENA78 (epithelial-derived neutrophil-activating peptide 78), PF4 (platelet factor 4), or the CC-chemokines MCP-1 , MCP-2, MCP-3, MCP-4, MIP-Ia, MIP-1β, RANTES, I309, eotaxin or lymphotactin. Moreover, a third ligand for CXCR3, I-TAC (Interferon-inducible T cell Alpha Chemoattractant), has also been found to bind to the receptor with high affinity and mediate functional responses (Cole, K. E. et al., J. Exp. Med., 187: 2009-2021 (1998)).

The restricted expression of human CXCR3 in activated T lymphocytes and the ligand selectivity of CXCR3 are noteworthy. The human receptor is highly expressed in IL-2 activated T lymphocytes, but was not detected in resting T lymphocytes, monocytes or granulocytes (Qin, S. et al., J. Clin. Invest., 101 : 746-754 (1998)). Additional studies of receptor distribution indicate that it is mostly CD3 ⁺ cells that express CXCR3, including cells which are CD95\ CD45RO ⁺ , and CD45RA ^|OW , a phenotype consistent with previous activation, although a proportion of CD20 ⁺ (B) cells and CD56 ⁺ (NK) cells also express this receptor. The selective expression in activated T lymphocytes is of interest, because other receptors for chemokines which have been reported to attract lymphocytes (e. g., MCP-1 , MCP-2, MCP-3, MIP-1 α, MIP-1 β, 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 and I-TAC. Although these belong to the CXC-subfamily, in contrast to IL-8 and other CXC-chemokines which 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 (NK) cells (Taub, D. D. et al., J Exp. Med., 177: 18090-1814 (1993); Taub, D. D. er a/., J. Immunol., 155: 3877-3888 (1995); Cole, K. E. et al., J. Exp. Med., 187: 2009-2021 (1998)). (NK cells are large granular lymphocytes, which lack a specific T cell receptor for antigen recognition, but possess cytolytic activity

against cells such as tumor cells and virally infected cells.) Consistently, IP-10, Mig and I-TAC lack the ELR motif, an essential binding epitope in those CXC-chemokines that efficiently induce neutrophil chemotaxis (Clark-Lewis, I. er a/., J. Biol. Chem. 266: 23128-23134 (1991 ); Hebert, C. A. et al., J. Biol. Chem., 266 : 18989-18994 (1991 ); and Clark-Lewis, 1. et ai, Proc. Natl. Acad. Sci. USA, 90 : 3574-3577 (1993)). In addition, both recombinant human Mig and recombinant human IP-10 have been reported to induce calcium flux in tumor infiltrating lymphocytes (TIL) (Liao, F. et al., J Exp. Med, 182: 1301-1314 (1995)). While IP-10 has been reported to induce chemotaxis of monocytes in vitro (Taub, D. D. et ai, J. Exp. Med., 177: 1809-1814 (1993), the receptor responsible has not been identified), human Mig and I-TAC appear 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)). IP-10 expression is induced in a variety of tissues in inflammatory conditions such as psoriasis, fixed drug eruptions, cutaneous delayed-type hypersensitivity responses and tuberculoid leprosy as well as tumors and in animal model studies, for example, experimental glomerulonephritis, and experimental allergic encephalomyelitis. IP-10 has a potent in vivo antitumor effect that is T cell dependent, 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 NK cell recruitment and degranulation (in tumor cell destruction, for example) (Luster, A. D. and P. Leder, J. Exp. Med., 178: 1057-1065 (1993); Luster, A. D. et al., J Exp. Med. 182: 219-231 (1995); Angiolillo, A. L. et al., J. Exp. Med., 182: 155-162 (1995); Taub, D. D. et al., J. Immunol., 155: 3877-3888 (1995)). The expression patterns of IP-10, Mig and I-TAC are also distinct from that of other CXC chemokines in that expression of each is induced by interferon-gamma (IFNδ), while the expression of IL-8 is down-regulated by IFNδ (Luster, A. D. et al., Nature, 315 : 672-676 (1985); Farber, J. M., Proc. Natl. Acad. Sci. USA, 87 : 5238-5242 (1990); Farber, J. M., 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. CHn. Invest, 87 : 463-469

(1991 ); GaIy, A. H. M. and H. Spits, J. Immunol., 147: 3823-3830 (1991 ); Cole, K. E. et al., J. Exp. Med., 187 : 2009-2021 (1998)).

Chemokines are recognized as the long-sought mediators for the recruitment of lymphocytes. Several CC-chemokines were found to elicit lymphocyte chemotaxis (Loetscher, P. et ai, FASEB J., 8: 1055-1060 (1994)), however, they are also active on granulocytes and monocytes (Uguccioni, M. et ai, Eur. J. Immunol., 25 : 64-68 (1995); Baggiolini, M. and C. A. Dahinden, Immunol. Today, 15 : 127-133 (1994)). The situation is different for IP-10, Mig and I-TAC, which are selective in their action on lymphocytes, including activated T lymphocytes and NK cells, and which bind CXCR3, a receptor which does not recognize numerous other chemokines and which displays a selective pattern of expression.

In view of these observations, it is reasonable to conclude that the formation of the 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 CXCR3 expression. Lymphocytes, particularly T lymphocytes, bearing a CXCR3 receptor as a result of activation can be recruited into inflammatory lesions, sites of infection and/or tumors by IP-10, Mig and/or I-TAC, which 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. Accordingly, activated and effector T cells have been implicated in a number of disease states such as graft-rejection, inflammation, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis) and psoriasis. Thus, CXCR3 represents a promising target for the development of novel therapeutics.

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 having the formula:

An illustrative compound of that series is:

Reference is also made to PCT Publication No. WO 99/20606 (Applicant: J. Uriach & CIA. S.A., Published April 29, 1999) which discloses piperazines as platelet aggregation inhibitors having the formula:

Reference is also made to US Patent Application No. US 2002/0018776 A1 (Applicant: Hancock, et al. Published February 14, 2002) which discloses methods of treating graft rejection.

Reference is also made to PCT Publication No. WO 03/098185 A2 (Applicant: Renovar, Inc., Published November 27, 2003) which discloses methods of diagnosing and predicting organ transplant rejection by detection of chemokines, for example, CXCR3 and CCL chemokines in urine. Reference is also made to PCT Publication No. WO 03/082335 A1

(Applicant: Sumitomo Pharmaceuticals Co. Ltd., Published October 9, 2003) which discloses methods of screening a CXCR3 ligand and methods of

diagnosing type 2 diabetes by detecting the expression dose of a CXCR3 ligand in a biological sample.

Reference is also made to PCT Publication No. WO 02/085861 (Applicant: Millennium Pharmaceuticals, Inc. Published October 31 , 2002) which discloses imidazolidine compounds and their use as CXCR3 antagonists having the formula:

An illustrative compound of that 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 that series is:

Reference is also made to US Patent Application No. US 2003/0055054 A1 (Applicant: Medina et al, Published March 20, 2003) and related patent US 6 794 379 B2 ((Applicant: Medina et al, Published September 21 , 2004) which discloses compounds with CXCR3 activity having the formula:

An illustrative compound of that 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 chemokine receptor modulators having the formula:

Reference is also made to PCT Publication WO 03/070242 A1 (Applicant: CELLTECH R& D limited, Published August28, 2003) which discloses compounds useful as "chemokine receptor inhibitors for the treatment of inflammatory diseases" having 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 February 19 ^th 2004) which discloses pyridine derivatives, processes for their preparation and their use in the modulation of autoimmune disease having the formula:

where R ³ 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 CXCR3 activity. For example, there is a need for new treatments and therapies for 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 and zenograft rejections for example) as well as infectious diseases, cancers and tumors, fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, type I diabetes, viral meningitis and tuberculoid leprosy.

There is a need for methods of treatment or prevention or amelioration of one or more symptoms of diseases and conditions associated with CXCR3. There is a need for methods for modulating CXCR3 activity using the compounds provided herein.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a method of treating a CXCR3 chemokine receptor mediated disease selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, sarcoidosis, systemic lupus erythematosus (SLE), alkylosing spondylitis, fibrotic diseases, pulmonary fibrosis, alopecia areata, scleroderma, lichen planus erythematosus, discoid lupus erythematosus, dermatomyositis, Behcet's disease, Wegener's disease, atopic dermatitis, and graft-vs-host disease (GVHD) in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound having the general structure shown in Formula 1 :

Formula 1 or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:

G represents a 5-membered heteroaryl or heterocyclenyl ring containing at least one -C=N- moiety as part of said heteroaryl or heterocyclenyl ring, said heteroaryl or heterocyclenyl ring optionally additionally containing one or more moieties selected from the group consisting of N, N(→O), O, S, S(O) and S(O ₂ ) on the ring, which moieties can be the same or different, each being independently selected, further wherein said heteroaryl or heterocyclenyl ring can be either (i) unsubstituted, or (ii) optionally independently substituted on

one or more ring carbon atoms with one or more R ⁹ substituents, or on one or more ring nitrogen atoms with one or more R ⁸ substituents, wherein said R ⁸ and R ⁹ substituents can be the same or different;

R ³ and R ⁶ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aralkyl, -CN, CF ₃ , haloalkyl, cycloalkyl, halogen, hydroxyalkyl, -N=CH-(R ³¹ ), -C(=O)N(R ³⁰ ) ₂ , -N(R ³⁰ ) _2> -OR ³⁰ , -SO ₂ (R ³¹ ), -N(R ³⁰ )C(=O)N(R ³⁰ ) ₂ and -N(R ³⁰ )C(=O)R ³¹ ; the R ⁸ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(=O)-aryl-halogen, -(CH ₂ ) _q OH, - (CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NH ₂ , -(CH ₂ ) _q NHR ³¹ , -(CH ₂ ) _q C(=O)NHR ³¹ , CH ₂ ) _q C(=O)OR ³¹ , -(CH ₂ ) _q SO ₂ R ³¹ , -(CH ₂ ) _q NSO ₂ R ³¹ , or -(CH ₂ ) _q SO ₂ NHR ³¹ ; the R ⁹ moieties can 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)OR ³⁰ , -C(=O)N(R ³⁰ ) ₂ , -C(=S)N(R ³⁰ ) ₂ , -C(=O)alkyl, -(CH ₂ ) _q OH, - (CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NH ₂ , -(CH ₂ ) _q NHR ³¹ , -(CH ₂ ) _q C(=O)NHR ³¹ , -(CH ₂ ) _q SO ₂ R ³¹ , - (CH ₂ ) _q NSO ₂ R ³¹ , -(CH ₂ ) _q SO ₂ NHR ³¹ , -N(R ³⁰ ) ₂ , -N(R ³⁰ )S(O ₂ )R ³¹ , -N(R ³⁰ ) C(=O)N(R ³⁰ ) _2l -OR ³⁰ , -SO ₂ (R ³¹ ), -SO ₂ N(R ³⁰ ) ₂ , =O and =S; the R ¹⁰ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, alkylaryl, arylalkyl, -CO ₂ H, hydroxyalkyl, -C(=O)N(R ³⁰ ) ₂ , -(CH ₂ ) _q OH, -(CH ₂ ) _q OR ³¹ ,-OR ³⁰ , halogen, =O, and -C(=O)R ³¹ ; the R ¹¹ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, alkylaryl, arylalkyl, carboxamide, CO ₂ H, - (CH ₂ ) _q OH, -(CH ₂ ) _q OR ³¹ , -OR ³⁰ , halogen, = O, and -C(=O)R ³¹ ;

R ¹² moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, -CN, -C(=O)N(R ³⁰ ) ₂ , -(CH ₂ ) _q OH, -(CH ₂ ) _q OR ³¹ and -S(O ₂ )R ³¹ ;

ring D is a five to nine membered cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl ring having 0-4 heteroatoms independently selected from O, S or N, wherein ring D is unsubstituted or optionally substituted with 1-5 independently selected R ²⁰ moieties; the R ²⁰ moieties can 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, -(CH ₂ ) _q OH, -(CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NH ₂ , -(CH ₂ ) _q NHR ³¹ , -(CH ₂ ) _q C(=O)NHR ³¹ , - (CH ₂ ) _q SO ₂ R ³¹ , -(CH ₂ ) _q NSO ₂ R ³¹ , -(CH ₂ ) _q SO ₂ NHR ³¹ , -alkynylC(R ³¹ ) ₂ OR ³¹ , -C(=O)R ³⁰ , -C(=O)N(R ³⁰ ) ₂ , -C(=NR ³⁰ )NHR ³⁰ , -C(=NOH)N(R ³⁰ ) ₂ , - C(=NOR ³¹ )N(R ³⁰ ) ₂ , -C(=O)OR ³⁰ , -N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)R ³¹ , -NHC(=O)N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)OR ³¹ , -N(R ³⁰ )C(=NCN)N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)N(R ³⁰ )SO ₂ (R ³¹ ), -N(R ³⁰ )C(=O)N(R ³⁰ ) ₂ , -N(R ³⁰ )SO ₂ (R ³¹ ), -N(R ³⁰ )S(O) ₂ N(R ³⁰ ) ₂ , -OR ³⁰ , -OC(=O)N(R ³⁰ ) ₂ , -SR ³⁰ , -SO ₂ N(R ³⁰ ) ₂ , -SO ₂ (R ³¹ ), -OSO ₂ (R ³¹ ), and -OSi(R ³⁰ ) ₃ ; or alternatively two R ²⁰ moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0-4 R ²¹ moieties; the R ²¹ moieties can 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, -(CH ₂ ) _q OH, -(CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NH ₂ , -(CH ₂ ) _q NHR ³¹ , -

(CH ₂ ) _q C(=O)NHR ³¹ , -(CH2) _q SO ₂ R ³¹ , -(CH ₂ ) _q NSO ₂ R ³¹ , -(CH ₂ ) _q SO ₂ NHR ³¹ , - alkynylC(R ³¹ ) ₂ OR ³¹ , -C(=O)R ³⁰ , -C(=O)N(R ³⁰ ) ₂ , -C(=NR ³⁰ )NHR ³⁰ , - C(=NOH)N(R ³⁰ ) ₂ , -C(=NOR ³¹ )N(R ³⁰ ) ₂ , -C(=O)OR ³⁰ , -N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)R ³¹ , -NHC(=O)N(R ³⁰ ) _2> -N(R ³⁰ )C(=O)OR ³¹ , -N(R ³⁰ )C(=NCN)N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)N(R ³⁰ )SO ₂ (R ³¹ ), -N(R ³⁰ )C(=O)N(R ³⁰ ) _2l -N(R ³⁰ )SO ₂ (R ³¹ ),

-N(R ³⁰ )S(O) ₂ N(R ³⁰ ) ₂ , -OR ³⁰ , -OC(=O)N(R ³⁰ ) ₂ , -SR ³⁰ , -SO ₂ N(R ³⁰ ) _2> -SO ₂ (R ³¹ ), -OSO ₂ (R ³¹ ), and -OSi(R ³⁰ ) ₃ ;

Y is selected from the group consisting of a covalent bond, -(CR ¹³ R ¹ V, -CHR ¹³ C(=O)-, -(CHR ¹³ ) _r O-, -(CHR ¹³ ) _r N(R ³⁰ )-, -C(=O)-, -C(=O)-(CHR ¹³ )-, -C(=O)-(CHR ¹³ ) _r -, -C(=NR ³⁰ )-, -C(=N-OR ³⁰ )-, -CH(C(=O)NHR ³⁰ )-, CH-heteroaryl-, -C(R ¹³ R ¹³ ) _r C(R ¹³ )=C(R ¹³ )-, -(CHR ¹³ ) _r C(=O)- and -(CHR ¹³ ) _r N(H)C(=O)-; or alternatively Y is cycloalkyl, heterocyclenyl, or heterocyclyl wherein the cycloalkyl, heterocyclenyl, or heterocyclyl is fused with ring D; the R ¹³ moieties can 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, -CO ₂ H, -C(=O)OR ³¹ , -C(=O)R ³⁰ , -C(=O)N(R ³⁰ ) ₂ , -(CHR ³⁰ ) _q OH, -(CHR ³⁰ ) _q OR ³¹ , -(CHR ³⁰ ) _q NH ₂ , -(CH R ³⁰ ) _q NHR ³¹ , -(CH ₂ ) _q C(=O)NHR ³¹ , -(CH ₂ ) _q SO ₂ R ³¹ , -(CH ₂ ) _q NSO ₂ R ³¹ , - (CH ₂ ) _q SO ₂ NHR ³¹ , -NH ₂ , -N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)N(R ³⁰ ) ₂ , -N(R ³⁰ )SO ₂ (R ³¹ ), -OH, -SO ₂ (R ³¹ ); the R ³⁰ moieties can be the same or different, each being independently selected from the group consisting of H ₁ alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, -cycloalkylalkyl, CN, -(CH ₂ ) _q OH, -(CH ₂ ) _q Oalkyl, -(CH ₂ ) _q Oalkylaryl, -(CH ₂ ) _q Oaryl, -(CH ₂ ) _q Oaralkyl, -(CH ₂ ) _q Ocycloalkyl, -(CH ₂ ) _q NH ₂₎ -(CH ₂ ) _q NHalkyl, - (CH ₂ ) _q N(alkyl) ₂ , -(CH ₂ ) _q NHalkylaryl, -(CH ₂ ) _q NHaryl, -(CH ₂ ) _q NHaralkyl, - (CH ₂ ) _q NHcycloalkyl, -(CH ₂ ) _q C(=O)O-alkyl, -(CH ₂ ) _q C(=O)NHalkyl, - (CH ₂ ) _q C(=O)N(alkyl) ₂ , -(CH ₂ ) _q C(=O)NHalkylaryl, -(CH ₂ ) _q C(=O)NHaryl, - (CH ₂ ) _q C(=O)NHaralkyl, -(CH ₂ ) _q C(=O)NHcycloalkyl, -(CH ₂ ) _q SO ₂ alkyl, -

(CH ₂ ) _q SO ₂ alkylaryl, -(CH ₂ ) _q SO ₂ aryl, -(CH ₂ ) _q SO ₂ aralkyl, -(CH ₂ ) _q SO ₂ cycloalkyl, -

(CH ₂ ) _q NSO ₂ alkyl, -(CH ₂ ) _q NSO ₂ alkylaryl, -(CH ₂ ) _q NS0 ₂ aryl, -(CH ₂ ) _q NSO ₂ aralkyl, -(CH ₂ ) _q NSO ₂ cycloalkyl, -(CH ₂ ) _q SO ₂ NHalkyl, -(CH ₂ ) _q SO ₂ NHalkylaryl, - (CH ₂ ) _q SO ₂ NHaryl, -(CH ₂ ) _q SO ₂ NHaralkyl, -(CH ₂ ) _q SO ₂ NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl; the R ³¹ moieties can be the same or different, each being independently selected from the group consisting of alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, - (CH ₂ ) _q OH, -(CH ₂ ) _q Oalkyl, -(CH ₂ ) _q Oalkylaryl, -(CH ₂ ) _q Oaryl, -(CH ₂ ) _q Oaralkyl, - (CH ₂ ) _q Ocycloalkyl, -(CH ₂ ) _q NH ₂ , -(CH ₂ ) _q NHalkyl, -(CH ₂ ) _q N(alkyl) ₂ , - (CH ₂ ) _q NHalkylaryl, -(CH ₂ ) _q NHaryl, -(CH ₂ ) _q NHaralkyl, -(CH ₂ ) _q NHcycloalkyl, - (CH ₂ ) _q C(=O)NHalkyl, -(CH ₂ ) _q C(=O)N(alkyl) ₂ , -(CH ₂ ) _q C(=O)NHalkylaryl, - (CH ₂ ) _q C(=O)NHaryl, -(CH ₂ ) _q C(=O)NHaralkyl, -(CH ₂ ) _q C(=O)NHcycloalkyl, - (CH ₂ ) _q SO ₂ alkyl, -(CH ₂ ) _q SO ₂ alkylaryl, -(CH ₂ ) _q SO ₂ aryl, -(CH ₂ ) _q SO ₂ aralkyl, - (CH ₂ ) _q SO ₂ cycloalkyl, -(CH ₂ ) _q NSO ₂ alkyl, -(CH ₂ ) _q NSO ₂ alkylaryl, - (CH ₂ ) _q NSO ₂ aryl, -(CH ₂ ) _q NS0 ₂ aralkyl, -(CH ₂ ) _q NS0 ₂ cycloalkyl. - (CH ₂ ) _q SO ₂ NHalkyl, -(CH ₂ ) _q SO ₂ NHalkylaryl, -(CH ₂ ) _q SO ₂ NHaryl, -

(CH ₂ ) _q SO ₂ NHaralkyl, -(CH ₂ ) _q SO ₂ NHcycloalkyl, heterocyclenyl, heterocyclyl, and hetroaryl; m is 0 to 4; n is 0 to 4; each q can be the same or different, each being 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 a nitrogen is substituted by two alkyl groups, said two alkyl groups may be optionally joined to each other to form a ring.

The compounds of Formula 1 , its method of preparation, and its uses are disclosed in International Publication WO 2006/088837, published August 24, 2006, and U.S. Patent Publication US 2006/0276479 published December 7, 2006. The present invention also provides a method of treating a CXCR3 chemokine receptor mediated disease selected from the group consisting of

chronic obstructive pulmonary disease (COPD), asthma, sarcoidosis, systemic lupus erythematosus (SLE), alkylosing spondylitis, fibrotic diseases, pulmonary fibrosis, alopecia areata, scleroderma, lichen planus erythematosus, discoid lupus erythematosus, dermatomyositis, Behcet's disease, Wegener's disease, atopic dermatitis, and graft-vs-host disease (GVHD) in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of the formula

or a pharmaceutically acceptable salt, or solvate thereof. In one embodiment, the pharmaceutically acceptable salt is a mesylate salt of this compound.

The compound of formula

its method of preparation, and uses are also disclosed in disclosed in International Publication WO 2006/088837, published August 24, 2006, and U.S. Patent Publication US 2006/0276479 published December 7, 2006.

A further feature of the invention provides a method of treating a CXCR3 mediated disease as set forth above comprising administering to a patient in need thereof a pharmaceutical composition containing as active ingredient at least one compound of Formula 1 together with at least one pharmaceutically acceptable carrier or excipient.

A further feature of the invention provides a method of treating a CXCR3 mediated disease as set forth above comprising administering to a patient in need of such treatment, 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: disease modifying antirheumatic drugs; nonsteroidal antiinflammatory drugs; COX-2 selective inhibitors; COX-1 inhibitors; immunosuppressives; steroids; PDE IV inhibitors, anti-TNF-α compounds, TNF-alpha-convertase inhibitors, cytokine inhibitors, MMP inhibitors, corticosteroids, glucocorticoids, chemokine inhibitors, CB2-selective inhibitors, p38 inhibitors, biological response modifiers; anti-inflammatory agents and therapeutics.

DETAILED DESCRIPTION OF THE INVENTION The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl," "alkoxy," etc.

As used above, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

"Acyl" means an H-C(=O)-, alkyl-C(=O)-, alkenyl-C(=O)-, alkynyl-C(=O)-, cycloalkyl-C(=O)-, cycloalkenyl-C(=O)-, or cycloalkynyl-C(=O)- group in which the various groups are as previously described. The bond to the parent moiety 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 straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 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 by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, aryl, aryloxy, cycloalkyl, cycloalkenyl, cyano, heteroaryl, heterocyclyl, amino, aminosulfonyl, halo, carboxyl, carboxyalkyl (non-limiting example(s) include ester), alkoxycarbonyl, hydroxyalkyl, carbonyl (non-limiting example(s) include ketone), -C(=O)heterocyclyl, formyl (non-limiting example(s) include aldehyde), carboxamido (i.e amido, -C(=O)NH ₂ ), -C(=O)N(alkyl) ₂ , -C(=O)NH(alkyl), -C(=O)N(cycloalkyl) ₂ , -C(=O)NH(cycloalkyl), -NHC(=O)alkyl, urea (e.g -NH(C=O)NH ₂ , -NH(C=O)NH(alkyl), -NH(C=O)NH(alkyl) ₂ , -NH(C=O)NH(heteroaryl), -NH(C=O)NH(heterocyclyl)), guanidinyl, -NHC(=NCN)NH ₂ , -NHC(=NCN)N(alkyl) ₂ , carbamoyl (i.e -CO ₂ NH ₂ ), NHC(=O)Oalkyl, -CO ₂ N(alkyl) ₂ , -NHC(=O))NH-S(O) ₂ alkyl, -NHC(=O)N(alkyl) ₂ -S(O) ₂ alkyl, -NH-S(O) ₂ alkyl, -NH-S(O) ₂ heteroaryl, -N(alkyl)-S(O) ₂ alkyl, -NH-S(O) ₂ aryl, -N(alkyl)-S(O) ₂ aryl, -NH-S(O) ₂ NH ₂ , -NH-S(O) ₂ NHalkyl, -NH-S(O) ₂ N(alkyl) ₂ , alkylthiocarboxy, -S(O) ₂ alkyl , -S(O) ₂ aryl, -OS(O) ₂ alkyl, -OS(O) ₂ aryl, sulfonyl urea (non-limiting example(s) 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 straight 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 straight or branched. The alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, 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 example(s) include ester), alkoxycarbonyl, hydroxyalkyl, carbonyl (non-limiting example(s) include ketone), -C(=O)heterocyclyl, formyl, carboxamido (i.e amido, -C(=O)NH ₂₎ -C(=O)N(alkyl) ₂ , -C(=O)NH(alkyl), -C(=O)N(cycloalkyl) ₂ , -C(=O)NH(cycloalkyl)), -NHC(=O)alkyl, amidinyl, hydrazidyl, hydroxamate, -NHC(=O)H, -NHC(=O)alkyl, urea (e.g -NH(C=O)NH ₂ , -NH(C=O)NH(alkyl), -NH(C=O)NH(alkyl) ₂ ,

-NH(C=O)NH(heteroaryl), -NH(C=O)NH(heterocyclyl)), guanidinyl, -NHC(=NCN)NH ₂ , -NHC(=NCN)N(alkyl) ₂₎ carbamoyl (i.e -CO ₂ NH ₂ ), -NHC(=O)Oalkyl, -CO ₂ N(alkyl) ₂ , -NHC(=O)NH-S(O) ₂ alkyl, -NHC(=O)N(alkyl)-S(O) ₂ alkyl, -NH-S(O) ₂ alkyl, -NH-S(O) ₂ heteroaryl, -N(alkyl)-S(O) ₂ alkyl, -NH-S(O) ₂ aryl, -N(alkyl)-S(O) ₂ aryl, -NH-S(O) ₂ NH ₂ , -NH-S(O) ₂ NHalkyl, -NH-S(O) ₂ N(alkyl) ₂ , thio, alkylthio, alkylthiocarboxy, -S(O)alkyl, -S(O) ₂ alkyl , -S(O) ₂ aryl, -OS(O) ₂ alkyl, -OS(O) ₂ aryl, sulfonyl urea (non-limiting example(s) 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 alkyl-heteroaryl- group wherein the alkyl is as previously described and the bond to the parent moiety is through the heteroaryl group.

"Alkylamino" means an -NH2 or -NH ₃ + group in which one or more of the hydrogen atoms on the nitrogen is replaced by an alkyl group as defined above. The bond to the parent is through the nitrogen.

"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as described herein. Preferred alkylaryls comprise a lower alkyl group. Non-limiting examples of suitable alkylaryl groups include o-tolyl, p-tolyl and xylyl. The bond to the parent moiety is through the aryl.

"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 bond to the parent moiety is through the sulfur. "Alkylthiocarboxy" means an alkyl-S-C(=O)O- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the carboxy.

"Alkylsulfonyl" means an alkyl-S(O) ₂ - group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

"Alkylsulfinyl" means an alkyl-S(O)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfinyl.

"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 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 alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight 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 by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxyl, 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 example(s) include ketone), -C(=O)heterocyclyl, carboxamido (i.e amido, -C(=O)NH ₂ ), -C(=O)N(alkyl) ₂ , -C(=O)NH(alkyl), -C(=O)N(cycloalkyl) _2, -C(=O)NH(cycloalkyl), alkylC(=O)NH-, -NHC(=O)alkyl, urea (e.g -NH(C=O)NH ₂ ), -NH(C=O)NH(alkyl), -NH(C=O)NH(alkyl) ₂ , -NH(C=O)NH(heteroaryl), -NH(C=O)NH(heterocyclyl), -S(O) ₂ alkyl, and -S(O) ₂ aryl.-

"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 bond to the parent moiety is through the ether oxygen.

"Alkoxycarbonyl" means an alkyl-O-C(=O)- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Aminoalkyl" means an amine-alkyl- group in which alkyl is as previously defined. Preferred aminoalkyls contain lower alkyl. Non-limiting examples of suitable aminoalkyl groups include aminomethyl and 2-Dimethlylamino-2-ethyl. The bond to the parent moiety is through the alkyl. "Amidinyl" means -C(=NR)NHR group. The R groups are defined as H, alkyl, alkylaryl, heteroaryl, hydroxyl, alkoxy, amino, ester, -NHSO ₂ alkyl, -NHSO ₂ Aryl, -NHC(=O)NHalkyl, and -NHalkyl. The bond to the parent moiety is through the carbon.

"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the 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 bond to the parent moiety is through the alkyl.

"Aralkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl group. Non-limiting examples of suitable aralkenyl groups include

2-phenethenyl and 2-naphthylethenyl. The bond to the parent moiety is through the alkenyl.

"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.

"Aralkoxy" means an aralkyl-O- group in which the aralkyl group is as described above. The bond to the parent moiety is through the oxygen group.

"Aralkoxycarbonyl" means an aralkyl-O-C(=O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Aroyl" means an aryl-C(=O)- group in which the aryl group is as previously described. The bond to the parent moiety 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 about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can 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 bond to the parent moiety is through the ether oxygen. "Arylsulfonyl" means an aryl-S(O) ₂ - group. The bond to the parent moiety is through the sulfonyl.

"Arylsulfinyl" means an aryl-S(O)- group. The bond to the parent moiety is through the sulfinyl.

"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 bond to the parent moiety is through the sulfur.

"Carboxyalkyl" means an alkyl-C(=O)O- group. The bond to the parent moiety is through the carboxy.

Carbamates and urea substituents refer to 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 about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can 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, norbornyl, adamantyl and the like.

"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond.

Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can 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. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl. The term "cycloalkenyl" additionally means moieties such as cyclobutenedione, cyclopentenone, cyclopentenedione and the like.

"Halogen" (or halo) means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.

"Haloalkyl" means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above. Non-limiting examples include trifluoromethyl, 2,2,2-trifluoroethyl, 2- chloropropyl and alike. "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably 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 about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by 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 heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. The nitrogen or sulfur atom of the heteroaryl can be optionally oxidized to the corresponding 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, 1 ,2,4-triazinyl, benzothiazolyl and the like.

"Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably 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 atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non- limiting examples of suitable heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6- tetrahydropyridinyl, 1 ,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2- imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. Heterocyclenyl also includes rings wherein =O replaces two available hydrogens on the same carbon atom (i.e., heterocyclenyl includes rings having a carbonyl group in the ring). An example of such a heterocyclenyl ring is pyrrolidinone:

.

"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably 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. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), - N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by 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 can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. Heterocyclyl also includes rings wherein =O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). An example of such a heterocyclyl ring is pyrrolidone:

"Heteroaralkyl" means a heteroaryl-alkyl- group in which the 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 bond to the parent moiety is through the alkyl.

"Heteroaralkenyl" means an heteroaryl-alkenyl- group in which the 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 bond to the parent moiety is through the alkenyl. "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. The bond to the parent moiety is through the alkyl. "Hydroxamate" means an alkyl-C(=O)NH-O- group. The bond to the parent moiety is through the oxygen group.

"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkoxyl, 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(aryl) ₂ , -NH(heteroaryl), -N(heteroaryl) ₂ , -NH(heterocyclyl), N(heterocyclyl)2, halo, hydroxy, carboxyl, carboxyalkyl (non-limiting example(s) include ester), cyano, alkoxycarbonyl, hydroxyalkyl, carbonyl (non-limiting example(s) include ketone), -C(=O)heterocyclyl, formyl (non-limiting example(s) include aldehyde), carboxamido (i.e amido, -C(=O)NH ₂ ), -C(=O)N(alkyl) ₂ , -C(=O)NH(alkyl), -C(=O)N(cycloalkyl) ₂ , -C(=O)NH(cycloalkyl), alkylC(=O)NH-, -amidino, hydrazido, hydroxamate, -NHC(=O)H, -NHC(=O)alkyl, urea (e.g -NH(C=O)NH ₂ ), -NH(C=O)NH(alkyl), -NH(C=O)NH(alkyl) ₂ , -NH(C=O)NH(heteroaryl), -NH(C=O)NH(heterocyclyl), guanidinyl, -NHC(=NCN)NH ₂₎ -NHC(=NCN)N(alkyl) ₂ , carbamoyl (i.e -CO ₂ NH ₂ ), -NHC(=O)Oalkyl, -CO ₂ N(alkyl) ₂ , -NHC(=O)NH-S(O) ₂ alkyl, -NHC(=O)N(alkyl) ₂ -S(O) ₂ alkyl, -NH-S(O) ₂ alkyl, -NH-S(O) ₂ heteroaryl, -N(alkyl)-S(O) ₂ alkyl, -NH-S(O) ₂ aryl, -N(alkyl)-S(O) ₂ aryl, -NH-S(O) ₂ NH ₂ ,

-NH-S(O) ₂ NHalkyl, -NH-S(O) ₂ N(alkyl)2,thio, alkylthiocarboxy, -S(O) ₂ alkyl , -S(O) ₂ aryl, -OS(O) ₂ alkyl, -OS(O) ₂ aryl, sulfonyl urea (non-limiting example(s) include -NHC(=S)NHalkyl) and OSi(alkyl) ₃ .

"Spiroalkyl" means an alkylene group wherein two carbon atoms of an alkyl group are attached to one carbon atom of a parent 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 can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein.

"Ring system substituent" also means a cyclic ring of 3 to 7 ring atoms of which may contain 1 or 2 heteroatoms, attached to an aryl, heteroaryl, or heterocyclyl ring by simultaneously substituting two ring hydrogen atoms on said aryl, heteroaryl, heterocyclyl ring. Non-limiting examples include:

and the like.

The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties, in available position or positions.

With reference to the number of moieties (non-limiting example(s) include, substituents, groups or rings) in a compound, unless otherwise defined, the phrases "one or more" and "at least one" mean that, there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is well 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 product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The straight line as a bond generally indicates a mixture of, or either of, the possible isomers, non-limiting example(s) include, containing (R)- and (S)- stereochemistry. For example,

means containing both and

A dashed line ( ) represents an optional bond.

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of the substitutable ring atoms, non limiting examples include carbon, nitrogen and sulfur ring atoms.

As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:

represents

It should also be noted that any heteroatom with unsatisfied valences in the text, schemes, examples, structural formulae, and any Tables herein is assumed 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 employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula 1 or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery 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 thereto.

"Metabolic conjugates", for example, glucuronides and sulfates which can undergo reversible conversion to compounds of Formula 1 are contemplated in this application.

"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective to antagonize CXCR3 and thus produce the desired therapeutic effect in a suitable patient.

"Mammal" means humans and other mammalian animals.

"Patient" includes both human 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 bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H ₂ O. In

general, the solvated forms are equivalent to the unsolvated forms and are intended to be encompassed within the scope of this invention.

The compounds of Formula 1 form salts which are also within the scope of this invention. Reference to a compound of Formula 1 herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic 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 both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (non-limiting example(s) include, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula 1 may be formed, for example, by reacting a compound of Formula 1 with an amount of acid or 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 from basic (or acidic) 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 & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference thereto.

Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,

glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, 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(dehydroabietyl)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. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (non-limiting example(s) include methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (non-limiting example(s) include dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (non-limiting example(s) include decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (non-limiting example(s) include benzyl and phenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for puφoses of the invention.

Pharmaceutically acceptable esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example,

methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C _1-4 alkyl, or C _1-4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C _1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C _6-24 )acyl glycerol.

Compounds of Formula 1 , and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms 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 on various 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. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate" "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.

It should also be noted that throughout the specification and Claims appended hereto any formula, compound, moiety or chemical illustration with unsatisfied valences is assumed to have the hydrogen atom to satisfy the valences unless the context indicates a bond.

In one embodiment, the present invention discloses treating a CXCR3 chemokine receptor mediated disease as set forth above utilizing at least one compound of Formula 1 , or a pharmaceutically acceptable derivative thereof, where the various definitions are given above. Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , G represents a dihydroimidazole, imidazole, dihydrooxazole, oxazole, dihydrooxadiazole, oxadiazole, triazole, or tetrazole ring.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , ring G is selected from the group consisting of:

wherein — is a single bond or double bond.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 R ³ is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, -N(R ³⁰ ) ₂ , -OR ³⁰ and -CF ₃ .

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , R ³ is selected from the group consisting of H, -CH ₃ , - CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , cyclopropyl, -F, -Cl, OCH ₃ , OCF ₃ and CF ₃ .

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , R ⁶ is selected from the group consisting of H, alkyl, halogen, hydroxyalkyl, -CN, -N(R ³⁰ ) ₂ , -OR ³⁰ , -N=CH-alkyl, -NR ³⁰ C(=O)alkyl, and -NR ³⁰ C(=O)N(R ³⁰ ) ₂ .

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , R ⁶ is selected from the group consisting of H, alkyl, halogen, hydroxyalkyl, -CN, -N(R ³⁰ ) ₂ , -OR ³⁰ , -N=CH-alkyl, and - NR ³⁰ C(=O)alkyl.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , R ⁶ is selected from the group consisting of H, -NH ₂ , - NHC(=O)CH ₃ , -NHC(=O)N(CH ₃ ) ₂ , -CH ₃ , -CN and -F. Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , R ⁸ is selected from the group consisting of H, alkyl, alkenyl, arylalkyl, cycloalkyl, -(CH ₂ ) _q OH, -(CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NH ₂ , - (CH ₂ ) _q NHR ³¹ , -(CH ₂ ) _q C(=O)NHR ³¹ , -(CH ₂ ) _q SO ₂ R ³¹ , -(CH ₂ ) _q NSO ₂ R ³¹ , - (CH ₂ ) _q SO ₂ NHR ³¹ , and -C(=O)-aryl-halogen. Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , the R ⁹ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, -C(=O)N(H)R ³⁰ , -C(=O)OR ³⁰ , -C(=O)alkyl, -(CH ₂ ) _q OH, -(CH ₂ ) _q OR ³¹ , - (CH ₂ ) _q NH ₂ , -(CH ₂ ) _q NHR ³¹ , -N(H)R ³⁰ , -N(H)S(O ₂ )R ³¹ , -N(H) C(=O)NH(R ³⁰ ), - OR ³⁰ -SO ₂ (R ³¹ ), and -SO ₂ N(H)R ³⁰ .

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , the R ⁹ moieties can be the same or different, each being independently selected from the group consisting of H, -OH, cyclopropyl, -CF ₃ , -CH ₃ , -CH ₂ OH, -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH ₂ CH ₂ OCH ₃ , -C(=O)OCH ₃₎ -C(=O)OCH ₂ CH ₃ , -CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHSO ₂ CH ₃ ,

-CH ₂ CH ₂ SO ₂ CH ₃ , -C(=O)NH ₂ , -C(=O)N(H)CH ₂ CH ₂ OH, -CH ₂ N(H)C(=O)CF ₃ ,

-C(=O)N(H)-cyclopropyl, -C(=O)N(H)CH ₂ CF ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -N(H)CH ₂ CH ₃ , -N(H)-cyclopropyl-CH ₃ , -N(H)CH(CH ₃ ) ₂ , -N(H)CH ₂ CH ₂ CH ₃ , -N(H)CH ₂ C(=O)OCH ₃ , -N(H)CH ₂ C(=O)OCH ₂ CH ₃ , -N(H)CH ₂ C(O)NH- cyclopropyl, -N(H)CH ₂ CH ₂ OH, -N(H)CH ₂ CH ₂ NH ₂ , -N(H)CH ₂ CH ₂ NHSO ₂ CH ₃ , -N(H)CH ₂ CH ₂ SO ₂ CH ₃ , -N(H)C(=O)N(H)CH ₂ CH ₃₎ -N(H)CH ₂ C(=O)NH ₂ , -OCH ₃ , -N(CH ₂ CH ₃ )S(=O) ₂ -phenyl-alkyl, -N(H)S(=O) ₂ -alkyl, =S and =O.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , the R ⁹ moieties can be the same or different, each being independently selected from the group consisting of H, -OH, -CF ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , cyclopropyl, -C(=O)OCH ₃ , -C(=O)OCH ₂ CH _3,

-CH ₂ CH ₂ OH ₁ -CH ₂ CH ₂ NH ₂ , -NH ₂ , -NHCH ₃ , -N(H)CH ₂ CH ₃ , -N(H)CH(CH ₃ ) ₂ , -N(H)CH ₂ CH ₂ CH ₃ , -N(H)-cyclopropyl-CH ₃ , -N(H)CH ₂ C(=O)OCH ₃ , -N(H)CH ₂ C(=O)OCH ₂ CH ₃ , -N(H)CH ₂ C(=O)NHCH ₃ , -N(H)CH ₂ C(=O)NH- cyclopropyl, -N(H)CH ₂ CH ₂ OH, -N(CH ₂ CH ₃ )S(=O) ₂ -phenyl-alkyl, and -N(H)S(=O) ₂ -alkyl.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , R ¹⁰ is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , R ¹⁰ is selected from the group consisting of -CH ₃ , - CH ₂ CH ₃ and -CH ₂ CH ₂ CH ₃ , and m is O - 2.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , R ¹¹ is selected from the group consisting of H, alkyl, hydroxyalkyl and carbonyl. Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , R ¹¹ is H Or -CH ₃ .

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , R ¹² is selected from the group consisting of H, CN, - C(=O)N(R ³⁰ ) ₂ and alkyl.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , R ¹² is selected from the group consisting of H, -CH ₃ , CN and -CH ₂ CH ₃ .

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , the ring atoms of ring D are independently C, N, O and S, and substituted by 0-4 R ²⁰ moieties.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , the ring atoms of ring D are independently C or N and substituted by 0-4 R ²⁰ moieties. Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , ring D is a 5 to 6 membered aryl, heteroaryl, heterocyclenyl, or heterocyclyl ring and substituted by 0-4 R ²⁰ moieties.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , the R ²⁰ moieties can 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, trifluromethyl, trifluoromethoxy, -(CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NHR ³¹ , - (CH ₂ ) _q C(=O)NHR ³¹ , -(CH ₂ ) _q SO ₂ R ³¹ , -(CH ₂ ) _q NSO ₂ R ³¹ , -(CH ₂ ) _q SO ₂ NHR ³¹ , - alkynylC(R ³¹ ) ₂ OR ³¹ , -C(=O)R ³⁰ , -C(=O)N(R ³⁰ ) ₂ , -C(=O)OR ³⁰ , -N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)R ³¹ , -NHC(=O)N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)OR ³¹ , -N(R ³⁰ )C(=NCN)N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)N(R ³⁰ ) _2> -N(R ³⁰ )SO ₂ (R ³¹ ), -N(R ³⁰ )SO ₂ N(R ³⁰ ) ₂ , -OR ³⁰ , -OC(=O)N(R ³⁰ ) ₂ , -SR ³⁰ , -SO ₂ N(R ³⁰ ) _2, -SO ₂ (R ³¹ ), -OSO ₂ (R ³¹ ), and -OSi(R ³⁰ ) ₃ .

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , the R ²⁰ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH ₃ , CF ₃ , OCF ₃ , -(CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NHR ³¹ , - (CH ₂ ) _q C(=O)NHR ³¹ , -(CH ₂ ) _q SO ₂ R ³¹ , -(CH ₂ ) _q NSO ₂ R ³¹ , -(CH ₂ ) _q SO ₂ NHR ³¹ , - alkynylC(R ³¹ ) ₂ OR ³¹ , -C(=O)R ³⁰ , -C(=O)OR ³⁰ , -N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)R ³¹ ,

-NHC(=O)N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)OR ³¹ , -N(R ³⁰ )C(=NCN)N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)N(R ³⁰ ) ₂ , -OR ³⁰ , -OC(=O)N(R ³⁰ ) ₂ , and -OSO ₂ (R ³¹ ).

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , two R ²⁰ moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0 to 4 R ²¹ moieties.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , the R ²⁰ moieties can be the same or different, each being independently selected from the group consisting of H, -CN, -CH ₃ , - CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , cyclopropyl, -CF ₃ , -CH ₂ OH, -CH ₂ -S(=O) ₂ CH ₃ , -C(=O)H, -CO ₂ H, -CO ₂ CH ₃ , -NH ₂ , -N(H)CH ₃ , - N(H)S(=O) ₂ CH ₃ , -OCF ₃ , -OH, F, Cl, Br, -C(=NOH)NH ₂ , -OCH ₂ CH ₂ S(O ₂ )CH ₃ , -C(=O)NH _2>

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , the R ²¹ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro, and trifluoromethoxy.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , Y is selected from the group consisting of -(CHR ¹³ ) _r -, -(CR ¹³ R ¹³ ) _r -, -C(=O)-, -CHR ¹³ C(=O)-, and -(CHR ¹³ ) _r C(=O). Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , Y is selected from the group consisting of: -(CHR ¹³ ) _r -, -(CR ¹³ R ¹³ ) _r -, -C(=O)- and -CHR ¹³ C(=O)-.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , Y is selected from the group consisting of: -CH ₂ -,

-CH ₂ CH ₂ -, -CH(CH ₃ )-, -CH ₂ CH ₂ O-, -CH(CH ₂ OH)-, -CH(CH ₂ OCH ₂ -phenyl)-, -C(=O)-, -C(=O)CH ₂ - and -CH(C=O)O-alkyl-.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , m is 0-2. Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , n is 0-2.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , q is 1 or 2.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , r is 1 or 2.

Another embodiment of the present invention refers to those methods, wherein, in Formula 1 , ring G is selected from the group consisting of:

is a single bond or a double bond; R ³ is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, -N(R ³⁰ ) _2, -OR ³⁰ and -CF ₃ ;

R ⁶ is selected from the group consisting of H, alkyl, halogen, hydroxyalkyl, -CN, -N(R ³⁰ ) ₂ , -OR ³⁰ , -N=CH-alkyl, -NR ³⁰ C(=O)alkyl, and - NR ³⁰ C(=O)N(R ³⁰ ) ₂ ;

R ⁹ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, -C(=O)N(H)R ³⁰ , - C(=O)OR ³⁰ , -C(=O)alkyl, -(CH ₂ ) _q OH, -(CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NH _2> -(CH ₂ ) _q NHR ³¹ , -N(H)R ³⁰ , -N(H)S(O ₂ )R ³¹ , -N(H) C(=O)NH(R ³⁰ ), -OR ³⁰ -SO ₂ (R ³¹ ), and -SO ₂ N(H)R ³⁰ ;

R ¹⁰ is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl;

R ¹¹ is selected from the group consisting of: H, alkyl, hydroxyalkyl, and carbonyl;

R ¹² is selected from the group consisting of H, CN, -C(=O)N(R ³⁰ ) ₂ and alkyl; ring D is a 5 to 6 membered aryl, heteroaryl, heterocyclenyl, or heterocyclyl ring and substituted by 0-4 R ²⁰ moieties; the R ²⁰ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, amino, halogen, CN, CH ₃ , CF ₃ , OCF ₃ , -(CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NHR ³¹ , -(CH ₂ ) _q C(=O)NHR ³¹ , - (CH ₂ ) _q SO ₂ R ³¹ , -(CH ₂ ) _q NSO ₂ R ³¹ , -(CH ₂ ) _q SO ₂ NHR ³¹ , -alkynylC(R ³¹ ) ₂ OR ³¹ , -C(=O)R ³⁰ , -C(=O)OR ³⁰ , -N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)R ³¹ , -NHC(=O)N(R ³⁰ ) ₂₎ -N(R ³⁰ )C(=O)OR ³¹ , -N(R ³⁰ )C(=NCN)N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)N(R ³⁰ ) ₂ , -N(R ³⁰ )SO ₂ (R ³¹ ), -OR ³⁰ , -OC(=O)N(R ³⁰ ) ₂ ,

alternatively, two R ²⁰ moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0 to 4 R ²¹ moieties;

the R ²¹ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro, and trifluoromethoxy; Y is selected from the group consisting of -CH ₂ -, -CH ₂ CH ₂ -, -CH(CH ₃ )-,

-CH ₂ CH ₂ O-, -CH(CH ₂ OH)-, -CH(CH ₂ OCH ₂ -phenyl)-, -C(=O)-, -C(=O)CH ₂ - and -CH(C=O)O-alkyl-; m is 0-2; n is 0-2; q is 1 or 2; and r is 1 or 2.

Another embodiment of the present invention refers to those methods, wherein, the compound of Formula 1 is represented by structural Formulae 2- 11 :

Formula 2

Formula 5

Formula 6

Formula 7

Formula 8

Formula 9

Formula 10

Formula 11 wherein: the R ⁸ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, arylalkyl, cycloalkyl, - (CH ₂ ) _q OH, -(CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NH ₂ , -(CH ₂ ) _q NHR ³¹ , -(CH ₂ ) _q C(=O)NHR ³¹ , - (CH ₂ ) _q SO ₂ R ³¹ , -(CH ₂ ) _q NSO ₂ R ³¹ , -(CH ₂ ) _q SO ₂ NHR ³¹ , and -C(=O)-aryl-halogen; the R ⁹ moieties can be the same or different, each being independently selected from the group consisting of of H, alkyl, cycloalkyl, -C(=O)N(H)R ³⁰ , - C(=O)OR ³⁰ , -C(=O)alkyl, -(Cη ₂ ) _q OH, -(CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NH _2> -(CH ₂ ) _q NHR ³¹ , -N(H)R ³⁰ , -N(H)S(O ₂ )R ³¹ , -N(H) C(=O)NH(R ³⁰ ), -OR ³⁰ -SO ₂ (R ³¹ ), and -SO ₂ N(H)R ³⁰ ;

L is C or N; in Formula 4 is a single bond or a double bond; X in formula 9 is N, O, or S; p is 0 to 4; and m, n, q, R ¹⁰ , R ¹¹ , R ¹² , R ²⁰ and Y are as defined in Claim 1. Another embodiment of the present invention refers to those methods, wherein, in formulae 2-11 , R ³ is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, -N(R ³⁰ ) ₂ , -OR ³⁰ and -CF ₃ .

Another embodiment of the present invention refers to those methods, wherein, in formulae 2-11 , R ⁶ is selected from the group consisting of H, alkyl, halogen, hydroxyalkyl, -CN, -N(R ³⁰ ) ₂ , -OR ³⁰ , -N=CH-alkyl, -NR ³⁰ C(=O)alkyl, and -NR ³⁰ C(=O)N(R ³⁰ ) ₂ . Another embodiment of the present invention refers to those methods, wherein, in formulae 2-11 , R ⁹ moieties are the same or different, each being independently selected from the group consisting of H ₁ -OH, cyclopropyl, -CF ₃ , -CH ₃ , -CH ₂ OH, -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH ₂ CH ₂ OCH ₃ , -C(=O)OCH ₃ , -C(=O)OCH ₂ CH ₃ , -CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHSO ₂ CH ₃ , -CH ₂ CH ₂ SO ₂ CH ₃ , -C(=O)NH ₂ , -C(=O)N(H)CH ₂ CH ₂ OH, -CH ₂ N(H)C(=O)CF ₃₎ -C(=O)N(H)-cyclopropyl, -C(=O)N(H)CH ₂ CF ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -N(H)CH ₂ CH ₃ , -N(H)-cyclopropyl-CH ₃ , -N(H)CH(CH ₃ ) ₂ , -N(H)CH ₂ CH ₂ CH ₃ , -N(H)CH ₂ C(=O)OCH ₃ , -N(H)CH ₂ C(=O)OCH ₂ CH ₃ , -N(H)CH ₂ C(O)NH- cyclopropyl, -N(H)CH ₂ CH ₂ OH, -N(H)CH ₂ CH ₂ NH ₂ , -N(H)CH ₂ CH ₂ NHSO ₂ CH ₃ , -N(H)CH ₂ CH ₂ SO ₂ CH ₃ , -N(H)C(=O)N(H)CH ₂ CH ₃ , -N(H)CH ₂ C(=O)NH ₂ , -OCH ₃ , -N(CH ₂ CH ₃ )S(=O) ₂ -phenyl-alkyl, -N(H)S(=O) ₂ -alkyl, =S and =O.

Another embodiment of the present invention refers to those methods, wherein, in formulae 2-11 , R ¹⁰ is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl. Another embodiment of the present invention refers to those methods, wherein, in formulae 2-11 , R ¹¹ is selected from the group consisting of: of H, alkyl, hydroxyalkyl and carbonyl.

Another embodiment of the present invention refers to those methods, wherein, in formulae 2-11 , R ¹² is selected from the group consisting of H, -CH ₃ , CN or -CH ₂ CH ₃ .

Another embodiment of the present invention refers to those methods, wherein, in formulae 2-11 , the R ²⁰ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, amino, halogen, CN, CH ₃ , CF ₃ , OCF ₃ , -(CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NHR ³¹ , - (CH ₂ ) _q C(=O)NHR ³¹ , -(CH ₂ ) _q SO ₂ R ³¹ , -(CH ₂ ) _q NSO ₂ R ³¹ , -(CH ₂ ) _q SO ₂ NHR ³¹ , - alkynylC(R ³¹ ) ₂ OR ³¹ , -C(=O)R ³⁰ , -C(=O)OR ³⁰ , -N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)R ³¹ ,

-NHC(=O)N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)OR ³¹ , -N(R ³⁰ )C(=NCN)N(R ³⁰ ) ₂₎ -N(R ³⁰ )C(=O)N(R ³⁰ ) ₂ , -N(R ³⁰ )SO ₂ (R ³¹ ), -OR ³⁰ , -OC(=O)N(R ³⁰ ) ₂₎

alternatively, two R ²⁰ moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0 to 4 R ²¹ moieties; and the R ²¹ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro, and trifluoromethoxy.

Another embodiment of the present invention refers to those methods, wherein, in formulae 2-11 , the R ²⁰ moieties can be the same or different, each being independently selected from the group consisting of H, -CN, -CH ₃ , - CH ₂ CH ₃ , -CH(CH ₃ ) _2l cyclopropyl, -CF ₃ , -CH ₂ OH, -CH ₂ -S(=O) ₂ CH ₃ , -C(=O)H, -CO ₂ H, -CO ₂ CH ₃ , -NH ₂ , -N(H)CH ₃ , - N(H)S(=O) ₂ CH ₃ , -OCF ₃ , -OH, F, Cl, Br, -C(=NOH)NH ₂ , -OCH ₂ CH ₂ S(O ₂ )CH ₃ , -C(=O)NH ₂ ,

and or alternatively, two

R ²⁰ moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl ring is fused to ring D and the fused ring is optionally substituted with O to 4 R ²¹ moieties; the R ²¹ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy,

alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro, and trifluoromethoxy.

Another embodiment of the present invention refers to those methods, wherein, in the above-shown Formulae 2-11 , L is carbon. Another embodiment of the present invention refers to those methods, wherein, in the above-shown Formulae 2-11 , L is nitrogen.

Another embodiment of the present invention refers to those methods, wherein, in the above-shown Formulae 2-11 , Y is selected from the group consisting of: -CH ₂ -, -CH ₂ CH ₂ -, -CH(CH ₃ )-, -CH ₂ CH ₂ O-, -CH(CH ₂ OH)-, -CH(CH ₂ OCH ₂ -phenyl)-, -C(=O)-, -C(=O)CH ₂ - and -CH(C=O)O-alkyk

Another embodiment of the present invention refers to those methods, wherein, in formulae 2-11 , R ³ is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, -N(R ³⁰ ) ₂ , -OR ³⁰ and -CF ₃ ;

R ⁶ is selected from the group consisting of H, alkyl, halogen, hydroxyalkyl, -CN, -N(R ³⁰ ) ₂ , -OR ³⁰ , -N=CH-alkyl, -NR ³⁰ C(=O)alkyl, and - NR ³⁰ C(=O)N(R ³⁰ ) ₂ ; the R ⁹ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, -C(=O)N(H)R ³⁰ , - C(=O)OR ³⁰ , -C(=O)alkyl, -(CH ₂ ) _q OH, -(CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NH ₂ , -(CH ₂ ) _q NHR ³¹ , -N(H)R ³⁰ , -N(H)S(O ₂ )R ³¹ , -N(H) C(=O)NH(R ³⁰ ), -OR ³⁰ -SO ₂ (R ³¹ ), and -SO ₂ N(H)R ³⁰ ;

R ¹⁰ is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl and carbonyl; the R ²⁰ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, amino, halogen, CN, CH ₃ , CF ₃ , OCF ₃ , -(CH ₂ ) _q OR ³¹ , -(CH ₂ ) _q NHR ³¹ , -(CH ₂ ) _q C(=O)NHR ³¹ , - (CH ₂ ) _q SO ₂ R ³ \ -(CH ₂ ) _q NSO ₂ R ³¹ , -(CH ₂ ) _q SO ₂ NHR ³¹ , -alkynylC(R ³¹ ) ₂ OR ³¹ , -C(=O)R ³⁰ , -C(=O)OR ³⁰ , -N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)R ³¹ , -NHC(=O)N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)OR ³¹ , -N(R ³⁰ )C(=NCN)N(R ³⁰ ) ₂ , -N(R ³⁰ )C(=O)N(R ³⁰ ) ₂ , -N(R ³⁰ )SO ₂ (R ³¹ ), -OR ³⁰ , -OC(=O)N(R ³⁰ ) ₂ ,

alternatively, o R ²⁰ moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0 to 4 R ²¹ moieties; the R ²¹ moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro, and trifluoromethoxy;

Y is selected from the group consisting of -CH ₂ -, -CH ₂ CH ₂ -, -CH(CH ₃ )-, -CH ₂ CH ₂ O-, -CH(CH ₂ OH)-, -CH(CH ₂ OCH ₂ -phenyl)-, -C(=O)-, -C(=O)CH ₂ - and -CH(C=O)O-alkyl-; m is 0-2; n is 0-2; q is 1 or 2; and r is 1 or 2.

Another embodiment of the present invention refers to those methods, wherein, a compound is selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate or ester thereof. The human IC ₅₀ values (in nM) for some of the compounds above have been provided (underneath the structure in paretheses).

Another embodiment of the present invention refers to those methods, wherein, a compound is selected from the list of compounds shown in Table 1 below (or pharmaceutically acceptable salts, solvates or esters thereof). In this Table 1 , the compounds are shown along with their IC ₅₀ ratings. The IC ₅₀ values are rated, "A" for IC ₅₀ values less than about 25 nanomolar (nM), "B" for IC ₅₀ values in the range of from about 25 to about 100 nM and "C" for IC ₅₀

values greater than about 100 nM. For instance, Compound Number 1 has an IC ₅₀ value of 0.2 nM.

Table 1

Another embodiment of the present invention refers to those methods wherein the compound according to Formula 1 is in purified form.

Another embodiment of the present invention refers to those methods wherein the pharmaceutical composition comprises 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.

Another embodiment of the present invention refers to those methods, wherein the pharmaceutical composition, in addition to the compound of Formula 1 , further comprises at least one additional agent, drug, medicament, antibody and/or inhibitor for treating a CXCR3 chemokine receptor mediated disease.

When administering a combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, a compound of Formula 1 and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like). A commercial example of such single dosage unit containing fixed amounts of two different active compounds is VYTORIN ^®

(available from Merck Schering-Plough Pharmaceuticals, Kenilworth, New Jersey).

In yet another embodiment, the present invention discloses 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 suitably selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for 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 may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. 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 noted above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.

Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate 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 polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric 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 addition of sweeteners and pacifiers 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, e.g. nitrogen.

For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions may 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 are 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 containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.

The quantity of the inventive active composition in a unit dose of preparation may be generally varied or adjusted from about 1.0 milligram to about 1 ,000 milligrams, preferably from about 1.0 to about 950 milligrams, more preferably from about 1.0 to about 500 milligrams, and typically from about 1 to about 250 milligrams, according to the particular application. The actual dosage employed may be varied depending upon the patient's age, 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 the administration will be regulated according to the judgment of the attending clinician. A generally recommended daily dosage regimen for oral administration may range from about 1.0 milligram to about 1 ,000 milligrams per day, in single or divided doses. Some useful terms are described below:

Capsule - refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.

Tablet- refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.

Oral gels- refers to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.

Powders for constitution - refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices. Diluent - refers to substances that usually make up the major 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 range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.

Disintegrants - refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include starches; "cold water soluble" modified starches 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 sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.

Binders - refers to substances that bind or "glue" powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can range 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. Lubricant - refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or

die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range 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.

Glidents - materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition can range 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 to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the 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 extent to which the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form 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 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 disclosure, both to materials and

methods, may be practiced. Such modifications, variations and alterations are intended to be within the spirit and scope of the present invention.

As stated earlier, the invention includes tautomers, enantiomers and other stereoisomers of the compounds also. Thus, as one skilled in the art knows, certain imidazole compounds may exist in tautomeric forms. Such variations are contemplated to be within the scope of the invention. Certain compounds of the present invention may exist in multiple crystalline forms or amorphous forms. All physical forms of the current invention are contemplated. Compounds of this invention which contain unnatural proportions of atomic isotopes (i.e. "radiolabeled compounds" ) whether their use is therapeutic, diagnostic or as a research reagent are contemplated under this invention.

Another embodiment of the invention discloses the use of the pharmaceutical compositions disclosed above for treatment of diseases of a CXCR3 chemokine receptor mediated disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to Formula 1 , or a pharmaceutically acceptable salt, solvate or ester thereof.

In another embodiment, the method is directed to administering 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 additional agent, drug, medicament, antibody and/or inhibitor for treating a CXCR3 chemokine receptor mediated disease, in combination with a pharmaceutically acceptable carrier. In another embodiment, at least one compound of Formula 1 binds to a

CXCR3 receptor.

The method can 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 medicament selected from the group consisting of: disease modifying antirheumatic drugs; nonsteroidal anti-

inflammatory drugs; COX-2 selective inhibitors; COX-1 inhibitors; immunosuppressives (such as cyclosporins and methotrexate); steroids

(including corticosteroids such as glucorticoids); PDE IV inhibitors, anti-TNF-α compounds, TNF-α-convertase (TACE) inhibitors, MMP inhibitors, cytokine inhibitors, glucocorticoids, other chemokine inhibitors such as CCR2, CCR5, and CXCR2, CB2-selective inhibitors, p38 inhibitors, biological response modifiers; anti-inflammatory agents and therapeutics.

Another embodiment of the present invention refers to those methods wherein the (b) at least one medicament is a chemokine inhibitor. Another embodiment of the present invention refers to those methods wherein the (b) at least one medicament is a chemokine inhibitor, that is a

CXCR2 receptor antagonist or agonist.

Another embodiment of the present invention refers to those methods wherein the CXCR3 chemokine receptor mediated disease is selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, fibrotic diseases, systemic lupus erythematosus (SLE), and graft-vs-host disease (GVHD).

Another embodiment of the present invention refers to those methods wherein the CXCR3 chemokine receptor mediated disease is selected from the group consisting of chronic obstructive pulmonary disease (COPD) and asthma.

Another embodiment of the present invention refers to those methods wherein the CXCR3 chemokine receptor mediated disease is systemic lupus erythematosus (SLE). Another embodiment of the present invention refers to those methods whrerein said CXCR3 chemokine receptor mediated disease is selected from the group consisting of chronic obstructive pulmonary disease (COPD) and asthma, and the treatment method comprises administering concurrently or sequentially with the compound of Formula 1 at least one compound selected from the group consisting of: beta-agonists, muscarinic receptor antagonists,

PDE4 inhibitors and corticosteroids.

Another embodiment of the present invention refers to those methods whrerein said CXCR3 chemokine receptor mediated disease is systemic lupus erythematosus (SLE), and the treatment method comprises administering concurrently or sequentially with the compound of Formula 1 at least one compound selected from the group consisting of: immunosuppressives and corticosteroids.

In another embodiment, the compounds of Formula 1 can be used to treat diseases selected from the group consisting of: pain, acute inflammation, chronic inflammation, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, ischemia reperfusion injury, renal reperfusion injury, glomerulonephritis, Parkinson's disease, Alzheimer's disease, mild cognitive impairment, depression, anxiety, graft vs. host reaction, allograft rejections, acute respiratory distress syndrome, delayed type hypersensitivity reaction, atherosclerosis, cerebral ischemia, osteoarthritis, multiple sclerosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus, meningitis, cystic fibrosis, pre-term labor, cough, pruritis, multi-organ dysfunction, psoriatic arthritis, herpes, encephalitis, traumatic brain injury, CNS tumors, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, ocular inflammation, corneal neovascularization, polymyositis, acne, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia- induced inflammations, hypoxia, pulmonary fibrosis, pulmonary hypertension, peritonitis associated with continuous ambulatory peritoneal dialysis, granulocytic ehrlichiosis, sarcoidosis, small airway disease, ventilation- perfusion mismatching, wheeze, colds, gout, alcoholic liver disease, lupus, periodontitis, cancer, transplant reperfusion injury, early transplantation

rejection, airway hyperreactivity, allergic contact dermatitis, allergic rhinitis, alopecia areata, autoimmune deafness, autoimmune hemolytic syndromes, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, chronic inflammatory demyelinating polyneuropathy, cirrhosis, dermatomyositis, diabetes, drug- induced autoimmunity, endometriosis, fibrotic diseases, gastritis, Goodpasture's syndrome, Graves' disease, Gullain-Barre disease, Hashimoto's thyroiditis, hepatitis-associated autoimmunity, HIV-related autoimmune syndromes and hematologic disorders, hypophytis, interstitial cystitis, juvenile arthritis, Langerhans' cell histiocytes, lichen planus, metal-induced autoimmunity, myocarditis, myositis, neuropathies, nephritic syndrome, optic neuritis, pancreatitis, post-infectious autoimmunity, primary biliary cirrhosis, reactive arthritis, ankylosing spondylitis, Reiter"s syndrome, reperfusion injury, scleritis, scleroderma, secondary hematologic manifestation of autoimmune diseases, silicone implant associated autoimmune disease, Sjogren's syndrome, systemic lupus erythematosus, transverse myelitis, tubulointerstitial nephritis, uveitis, and vitiglio.

While the present invention has been describe 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 such alternatives, medications and variations are intended to fall within the spirit and scope of the present invention.

Each and every document/reference (e.g., patent publication, granted patent or scientific journal article) mentioned in this application is incorporated by reference for all purposes.