JP2010535711A - Method for treating CXCR3-mediated diseases using heterocyclic substituted piperazines - Google Patents

Abstract

The application relates to chronic obstructive pulmonary disease (COPD), asthma, sarcoidosis, systemic lupus erythematosus (SLE), ankylosing spondylitis, fibrotic disease, pulmonary fibrosis, in patients in need of treatment. CXCR3 chemokine selected from the group consisting of alopecia areata, scleroderma, lichen planus lupus erythematosus, discoid lupus erythematosus, dermatomyositis, Behcet's disease, Wegener's disease, atopic dermatitis and graft-versus-host disease (GVHD) A method of treating a receptor-mediated disease, wherein at least one compound having the general structure shown in Formula 1 or a pharmaceutically acceptable salt, solvate or ester thereof is administered to a patient in a therapeutically effective amount. A method is disclosed. Various parts in the formula are defined herein.

Description

(Field of 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), ankylosing spondylitis, fibrotic disease, pulmonary fibrosis, alopecia areata, scleroderma, flatness Examples include lichen planus erythematosus, discoid lupus erythematosus, dermatomyositis, Behcet's disease, Wegener's disease, atopic dermatitis and graft-versus-host disease (GVHD).

(Background of the Invention)
Chemokines constitute the cytokine family and are produced during inflammation and regulate leukocyte recruitment (Baggiolini, M. et al., Adv. Immunol., 55: 97-179 (1994); Springer, TA. , Annual Rev. Physio., 57: 827-872 (1995); and Schall, TJ and KB Bacon, Curr. Opin. Immunol, 6: 865-873 (1994)). Chemokines chemotaxis blood components (other than red blood cells) such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells, and white blood cells such as lymphocytes such as T cells and B cells. Sex can be selectively induced. In responsive cells, in addition to chemotaxis stimulation associated with leukocyte activation, changes in cell morphology, temporary increase in intracellular free calcium ion ([Ca ²⁺ ] _i ) concentration, granule exocytosis Other changes, such as upregulation of integrins, formation of bioactive lipids (eg, leukotrienes) and respiratory burst may also be selectively induced by chemokines. Thus, chemokines trigger the initial inflammatory response, causing the release of inflammatory mediators, chemotaxis to the infected or inflammatory site and extravasation.

  Each chemokine is related to primary structure and shares four conserved cysteines that form disulfide bonds. This family is based on this conserved cysteine motif, C—X—C chemokines (α-chemokines) (eg, IL-8, in which the first two conserved cysteines are separated by intervening residues). IP-10, Mig, I-TAC, PF4, ENA-78, GCP-2, GROα, GROβ, GROδ, NAP-2, NAP-4) and the first two conserved cysteines are adjacent residues C-C chemokines (β-chemokines) (eg, MIP-1α, MIP-1β, RANTES, MCP-1, MCP-2, MCP-3, I-309) can be clearly classified into groups such as ( Baggiolini, M. and Dahinden, CA, Immunology Today, 15: 127-133 (1994)). Most CXC-chemokines attract neutrophil leukocytes. For example, CXC-chemokines, interleukin-8 (IL-8), GROalpha (GROα) and neutrophil-activating peptide 2 (NAP) are potent chemoattractants of neutrophils And an activator. CXC-chemokines called Mig (monokines induced by γ-interferon) and IP-10 (interferon-γ-inducible 10 kDa protein) have the effect of inducing chemotaxis of activated peripheral blood lymphocytes.

  CC-chemokines are usually poorly selective and can attract various cell types of leukocytes such as monocytes, eosinophils, basophils, T lymphocytes and natural killer cells. Human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted: expressed and secreted in normal T cells by activation Factor) and CC-chemokines such as macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β) have been characterized as monocyte or lymphocyte chemoattractants and activators, but neutrophils It does not appear to be a chemoattractant for the sphere

  Chemokine receptors that bind CXC-chemokine IP-10 and Mig have been cloned and characterized (Loetscher, M. et al., J. Exp. Med., 184: 963-969 (1996). ), Has been called CXCR3. CXCR3 is a G protein-coupled receptor with a 7-transmembrane domain and has been shown to be restricted to activated T cells, particularly human Th1 cells. Chemokine receptors, when bound by the appropriate ligand, transduce intracellular signals through the associated G protein and rapidly increase the intracellular calcium concentration.

The CXCR3 receptor is involved in Ca ²⁺ (calcium ion) mobilization and chemotaxis in response to IP-10 and Mig. CXCR3-expressing cells are CXC-chemokines IL-8, GROα, NAP-2, GCP-2 (granulocyte chemotactic protein-2), ENA78 (epithelial neutrophil activation peptide 78), PF4 (platelet count). 4 factor) or CC-chemokines MCP-1, MCP-2, MCP-3, MCP-4, MIP-1α, MIP-1β, RANTES, I309, eotaxin or lymphotactin. It has also been clarified that I-TAC (interferon-inducible T cell α chemoattractant), a third ligand for CXCR3, binds to this receptor with high affinity and mediates a functional response. (Cole, KE et al., J. Exp. Med., 187: 2009-2021 (1998)).

It is noted that human CXCR3 expression is restricted to activated T lymphocytes and that CXCR3 has ligand selectivity. This human receptor is highly expressed on IL-2 activated T lymphocytes but not detected on resting T lymphocytes, monocytes or granulocytes (Qin, S. et al., J. Clin. Invest. , 101: 746-754 (1998)). Further studies on receptor distribution show that although CD20 ⁺ (B) and CD56 ⁺ (NK) cells also express CXCR3 at a certain rate, this receptor is mostly expressed previously It has been suggested to be CD3 ⁺ cells, including cells that are CD95 ⁺ , CD45RO ⁺ and CD45RA ^low phenotypes indicating that Other receptors of chemokines that have been reported to attract T lymphocytes (eg, MCP-1, MCP-2, MCP-3, MIP-1α, MIP-1β, RANTES) are neutrophils, eosinophils It is also noted that it is selectively expressed on activated T lymphocytes because it is expressed on monocytes as well as granulocytes such as basophils. From these results, it is considered that the CXCR3 receptor is involved in selective recruitment of effector T cells.

  CXCR3 recognizes an unusual CXC-chemokine called IP-10, Mig and I-TAC. Although these IP-10, Mig and I-TAC belong to the CXC subfamily, they differ from other CXC-chemokines that are potent chemoattractants of IL-8 and neutrophils, and their primary target is lymphocytes In particular, effector cells such as activated or stimulated T lymphocytes and natural killer (NK) cells (Taub, DD et al., J Exp. Med., 177: 18090-1814). (1993); Taub, DD et al., J. Immunol., 155: 3877-3888 (1995); Cole, KE et al., J. Exp. Med., 187: 2009-2021. (1998)). (NK cells are large granular lymphocytes lacking specific T cell receptors for antigen recognition but have cytolytic activity against cells such as tumor cells and virus-infected cells). IP-10, Mig and I-TAC always lack the ELR motif, a binding epitope essential for CXC-chemokines that efficiently induces neutrophil chemotaxis (Clark-Lewis, I. et. al., J. Biol. Chem. 266: 23128-23134 (1991); Hebert, CA et al., J. Biol.Chem., 266: 18989-18994 (1991); and Clark-Lewis, 1 Et al., Proc. 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 efflux in tumor infiltrating lymphocytes (TIL) (Liao, F. et al., J Exp. Med, 182). : 1301-1314 (1995)). Although IP-10 has been reported to induce monocyte chemotaxis in vitro (Taub, DD et al., J. Exp. Med., 177: 1809-1814 (1993), Receptors involved have not been identified), human Mig and I-TAC are highly selective and do not show such action (Liao, F. et al., J. Exp. Med., 182: 1301- 1314 (1995); Cole, KE et al., J. Exp. Med., 187: 2009-2021 (1998)). Expression of IP-10 is induced in various tissues and tumors of inflammatory conditions such as psoriasis, fixed drug eruption, cutaneous delayed type hypersensitivity reaction and tuberculosis leprosy, and in animal model studies, for example, experimental glomerulonephritis And has been induced in experimental allergic encephalomyelitis. With respect to IP-10, it has been reported that it has a strong antitumor effect dependent on T cells in vivo and becomes an inhibitor of angiogenesis, and induces chemotaxis and degranulation of NK cells in vitro. be able to. This suggests a role as a mediator of NK cell mobilization and degranulation (eg, in tumor cell destruction) (Luster, AD and P. Leder, J. Exp. Med., 178: 1057-1065 (1993); Luster, AD et al., J Exp.Med.182: 219-231 (1995); Angiollillo, AL et al., J. Exp.Med., 182: 155-162 (1995); Taub, DD et al., J. Immunol., 155: 3877-3888 (1995)). IP-10, Mig and I-TAC also differ in expression pattern from other CXC chemokines. Expression of other CXC chemokines is induced by interferon gamma (IFNδ), respectively, whereas IL-8 expression is down-regulated by IFNδ (Luster, AD et al., Nature, 315: 672). -676 (1985); Farber, JM, Proc. Natl. Acad. Sci. USA, 87: 5238-5242 (1990); Farber, JM, Biochem. Biophys. Res. Commun., 192 ( 1): 223-230 (1993), Liao, F. et al., J. Exp. Med., 182: 1301-1314 (1995), Seitz, M. et al., J. Clin. 463-469 (1991); Gary, 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 known to have been explored for many years as mediators of lymphocyte recruitment. Some CC-chemokines have been shown to induce lymphocyte chemotaxis (Loetscher, P. et al., FASEB J., 8: 1055-1060 (1994)), but such CC-chemokines are It also acts on granulocytes and monocytes (Uguccioni, M. et al., Eur. J. Immunol., 25: 64-68 (1995); Baggiolini, M. and CA Dahinden, Immunol. Today, 15: 127-133 (1994)). In IP-10, Mig and I-TAC, the situation is different and its action on lymphocytes such as activated T lymphocytes and NK cells is selective. Furthermore, IP-10, Mig and I-TAC do not recognize many other chemokines and bind to the receptor CXCR3 which exhibits a selective expression pattern.

  From the above findings, the formation of characteristic infiltrates of inflammatory lesions such as lesions with delayed type hypersensitivity, viral infection sites and certain tumors is mediated by CXCR3 and controlled by the expression of CXCR3. It is reasonable to conclude that this is a process. Upon activation, lymphocytes with CXCR3 receptor, particularly T lymphocytes, can be induced locally by interferon gamma by inflammatory lesions, infection sites and / or by IP-10, Mig and / or I-TAC. Or may be mobilized to a tumor. Thus, CXCR3 is involved in the selective recruitment of effector cells such as lymphocytes, particularly activated or stimulated T lymphocytes. Thus, many disease states, such as graft rejection, inflammation, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis) and psoriasis, include activated T cells and effector T cells. It has been thought to be related. Thus, CXCR3 is a promising target for the development of new therapeutic agents.

  See U.S. Pat. No. 6,057,056 (Applicant: Glaxo Group Limited, published May 27, 1993) which discloses piperidineacetic acid derivatives as inhibitors of fibrinogen-dependent platelet aggregation having the following formula.

この系列の例示的化合物として下記がある。

Exemplary compounds of this series include:

下記式を持つ、血小板凝集阻害剤としてピペラジンを開示する特許文献２（出願人：Ｊ．Ｕｒｉａｃｈ ＆ ＣＩＡ．Ｓ．Ａ．、１９９９年４月２９日公開）も参照されたい。

See also U.S. Pat. No. 6,057,086 (Applicant: J. Uriach & CIA.SA, published April 29, 1999) which discloses piperazine as a platelet aggregation inhibitor having the following formula.

移植片拒絶反応を処置する方法を開示する特許文献３（出願人：Ｈａｎｃｏｃｋ，ｅｔ ａｌ．２００２年２月１４日公開）も参照されたい。

See also U.S. Pat. No. 6,057,056 (Applicant: Hancock, et al. Published February 14, 2002) which discloses a method for treating graft rejection.

  See also U.S. Patent No. 6,057,028 (Applicant: Renovar, Inc., published Nov. 27, 2003) which discloses a method for diagnosing and predicting organ transplant rejection by detection of chemokines such as CXCR3 and CCL chemokines in urine. I want to be.

  Patent Document 5 discloses a method for screening CXCR3 ligand and a method for diagnosing type 2 diabetes by detecting the expression level of CXCR3 ligand in a biological sample (Applicant: Sumitomo Pharmaceuticals Co. Ltd., October 9, 2003). See also (Japanese).

  See also U.S. Pat. No. 6,099,056 (Applicant: Millennium Pharmaceuticals, Inc., published October 31, 2002) disclosing imidazolidine compounds as CXCR3 antagonists and their use, having the formula:

この系列の例示的化合物として下記がある。

Exemplary compounds of this series include:

下記式を持つ、ＣＸＣＲ３アンタゴニストとしてのイミダゾリウム化合物およびその使用を開示する特許文献７（出願人：Ｓｍｉｔｈｋｌｉｎｅ Ｂｅｅｃｈａｍ Ｃｏｒｐｏｒａｔｉｏｎ、２００３年１２月１１日公開）も参照されたい。

See also U.S. Pat. No. 6,057,056 (Applicant: Smithkline Beecham Corporation, published Dec. 11, 2003) disclosing imidazolium compounds and their use as CXCR3 antagonists having the formula:

この系列の例示的化合物として下記がある。

Exemplary compounds of this series include:

下記式を持つ、ＣＸＣＲ３活性のある化合物を開示する特許文献８（出願人：Ｍｅｄｉｎａ ｅｔ ａｌ、２００３年３月２０日公開）および関連する特許文献９（（出願人：Ｍｅｄｉｎａ ｅｔ ａｌ、２００４年９月２１日公開）も参照されたい。

Patent Document 8 (Applicant: Medina et al, published on March 20, 2003) and related Patent Document 9 ((Applicant: Medina et al, 2004 9) disclosing a compound having the following formula and having CXCR3 activity See also Monday 21st.

この系列の例示的化合物として下記がある。

Exemplary compounds of this series include:

下記式を持つ、ケモカイン受容体修飾物質として有用な化合物を開示する特許文献１０（出願人：ＭａｃＣｏｓｓ ｅｔ ａｌ．、２０００年９月６日発行）も参照されたい。

See also U.S. Pat. No. 6,057,086 (Applicant: MacCoss et al., Issued September 6, 2000) which discloses compounds useful as chemokine receptor modifiers having the formula:

下記式を持つ、「炎症性疾患を処置するケモカイン受容体阻害剤」として有用な化合物を開示する特許文献１１（出願人：ＣＥＬＬＴＥＣＨ Ｒ＆ Ｄ ｌｉｍｉｔｅｄ、２００３年８月２８日公開）も参照されたい。

See also Patent Document 11 (Applicant: CELLTECH R & D limited, published Aug. 28, 2003), which discloses compounds useful as “chemokine receptor inhibitors for treating inflammatory diseases” having the formula:

下記式を持つピリジン誘導体、その調製プロセスおよび自己免疫疾患の調節におけるその使用を開示する特許文献１２、特許文献１３、特許文献１４（出願人：ＡｓｔｒａＺｅｎｅｃａ Ｒ ＆ Ｄ ２００４年２月１９日公開）も参照されたい。式中、Ｒ^３は、フェニル、または１個または複数個の窒素原子を持つ５または６員の芳香環である。

Also disclosed are pyridine derivatives having the following formula, their preparation process and their use in the regulation of autoimmune diseases (Applicant: AstraZeneca R & D published 19 February 2004). Please refer. Wherein R ³ is phenyl or a 5 or 6 membered aromatic ring having one or more nitrogen atoms.

ＣＸＣＲ３の活性を調節できる化合物が求められている。たとえば、炎症状態（乾癬および炎症性腸疾患）、自己免疫疾患（多発性硬化症、関節リウマチ）および移植片拒絶反応（たとえば、同種移植片拒絶および異種移植片拒絶（ｚｅｎｏｇｒａｆｔ ｒｅｊｅｃｔｉｏｎ））のほか、感染症、癌および腫瘍、固定薬疹、皮膚遅延型過敏反応、Ｉ型糖尿病、ウイルス性髄膜炎および類結核型ハンセン病などのＣＸＣＲ３に関連する疾患および症候を対象とした新しい処置および療法が必要である。

There is a need for compounds that can modulate the activity of CXCR3. For example, in addition to inflammatory conditions (psoriasis and inflammatory bowel disease), autoimmune diseases (multiple sclerosis, rheumatoid arthritis) and graft rejection (eg, allograft rejection and xenograft rejection), New treatments and therapies are needed for diseases and symptoms related to CXCR3 such as infections, cancers and tumors, fixed drug eruptions, delayed skin hypersensitivity reactions, type I diabetes, viral meningitis and leprosy tuberculosis It is.

  There is a need for methods of treating, preventing, or alleviating one or more symptoms of diseases and symptoms associated with CXCR3. There is also a need for methods of modulating CXCR3 activity using the compounds described herein.

International Publication No. 93/10091 Pamphlet WO99 / 20606 pamphlet US Patent Application Publication No. 2002/0018776 International Publication No. 03/098185 Pamphlet International Publication No. 03/082335 Pamphlet International Publication No. 02/085861 Pamphlet International Publication No. 03/101970 Pamphlet US Patent Application Publication No. 2003/0055054 US Pat. No. 6,794,379 US Pat. No. 6,124,319 International Publication No. 03/070242 Pamphlet International Publication No. 04/074287 Pamphlet International Publication No. 04/074273 Pamphlet International Publication No. 04/74278 Pamphlet

  In many embodiments thereof, the present invention provides chronic obstructive pulmonary disease (COPD), asthma, sarcoidosis, systemic lupus erythematosus (SLE), ankylosing spondylitis, fibrotic disease, lungs in patients in need of treatment. Selected from the group consisting of fibrosis, alopecia areata, scleroderma, lichen planus lupus erythematosus, discoid lupus erythematosus, dermatomyositis, Behcet's disease, Wegener's disease, atopic dermatitis and graft-versus-host disease (GVHD) A method for treating a CXCR3 chemokine receptor mediated disease, wherein the patient has a therapeutically effective amount of at least one compound having the general structure shown in Formula 1 or a pharmaceutically acceptable salt, solvate or ester thereof: A method is provided comprising administering to.

式中：
Ｇは、５員のヘテロアリール環またはヘテロシクレニル環の一部として少なくとも１つの−Ｃ＝Ｎ−部分を含む前記ヘテロアリール環またはヘテロシクレニル環を表し、前記ヘテロアリール環またはヘテロシクレニル環は任意に、環上にＮ、Ｎ（→Ｏ）、Ｏ、Ｓ、Ｓ（Ｏ）およびＳ（Ｏ_２）からなる群から選択される１つまたは複数の部分をさらに含み、この部分は同一でも異なっていてもよく、各々が独立に選択され、さらに前記ヘテロアリール環またはヘテロシクレニル環は、（ｉ）非置換であっても、あるいは（ｉｉ）任意に独立して１個または複数個の環炭素原子上で１つまたは複数のＲ^９置換基で置換されているか、または１個または複数個の環窒素原子上で１つまたは複数のＲ^８置換基で置換されていてもよく、前記Ｒ^８およびＲ^９置換基は同一でも異なっていてもよく；
Ｒ^３およびＲ^６部分は同一でも異なっていてもよく、各々が独立にＨ、アルキル、アルキルアリール、アラルキル、−ＣＮ、ＣＦ_３、ハロアルキル、シクロアルキル、ハロゲン、ヒドロキシアルキル、−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および−Ｎ（Ｒ^３０）Ｃ（＝Ｏ）Ｒ^３１からなる群から選択され；
Ｒ^８部分は同一でも異なっていてもよく、各々が独立にＨ、アルキル、アルケニル、アルキルアリール、アリールアルキル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−Ｃ（＝Ｏ）−アリール−ハロゲン、−（ＣＨ_２）_ｑＯＨ、−（ＣＨ_２）_ｑＯＲ^３１、−（ＣＨ_２）_ｑＮＨ_２、−（ＣＨ_２）_ｑＮＨＲ^３１、−（ＣＨ_２）_ｑＣ（＝Ｏ）ＮＨＲ^３１、ＣＨ_２）_ｑＣ（＝Ｏ）ＯＲ^３１、−（ＣＨ_２）_ｑＳＯ_２Ｒ^３１、−（ＣＨ_２）_ｑＮＳＯ_２Ｒ^３１または−（ＣＨ_２）_ｑＳＯ_２ＮＨＲ^３１からなる群から選択され；
Ｒ^９部分は同一でも異なっていてもよく、各々が独立にＨ、アルキル、アルケニル、アルキルアリール、アリールアルキル、アルコキシ、アミジニル、アリール、シクロアルキル、シアノ、ヘテロアリール、ヘテロシクリル、ヒドロキシル、

In the formula:
G represents the heteroaryl ring or heterocyclenyl ring containing at least one -C = N- moiety as part of a 5-membered heteroaryl ring or heterocyclenyl ring, wherein the heteroaryl ring or heterocyclenyl ring is optionally on the ring Further includes one or more parts selected from the group consisting of N, N (→ O), O, S, S (O) and S (O ₂ ), which may be the same or different. Each of which is independently selected, and further wherein said heteroaryl or heterocyclenyl ring may be (i) unsubstituted or (ii) optionally independently on one or more ring carbon atoms. or R ⁹ or is substituted with a substituent, or one or on a plurality of ring nitrogen atoms may be substituted by one or more R ⁸ substituents, wherein R ⁸ Contact Fine R ⁹ substituent may be the same or different;
The R ³ and R ⁶ moieties may be the same or different and each is independently 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 ( Selected from the group consisting of R ³⁰ ) ₂ and —N (R ³⁰ ) C (═O) R ³¹ ;
The R ⁸ moieties may be the same or different and each is independently 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 may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, arylalkyl, alkoxy, amidinyl, aryl, cycloalkyl, cyano, heteroaryl, heterocyclyl, hydroxyl,

からなる群から選択され；
Ｒ^１０部分は同一でも異なっていてもよく、各々が独立にＨ、アルキル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、アルキルアリール、アリールアルキル、−ＣＯ_２Ｈ、ヒドロキシアルキル、−Ｃ（＝Ｏ）Ｎ（Ｒ^３０）_２、−（ＣＨ_２）_ｑＯＨ、−（ＣＨ_２）_ｑＯＲ^３１、−ＯＲ^３０、ハロゲン、＝Ｏおよび−Ｃ（＝Ｏ）Ｒ^３１からなる群から選択され；
Ｒ^１１部分は同一でも異なっていてもよく、各々が独立にＨ、アルキル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、ヘテロシクレニル、アルキルアリール、アリールアルキル、カルボキサミド、ＣＯ_２Ｈ、−（ＣＨ_２）_ｑＯＨ、−（ＣＨ_２）_ｑＯＲ^３１、−ＯＲ^３０、ハロゲン、＝Ｏおよび−Ｃ（＝Ｏ）Ｒ^３１からなる群から選択され；
Ｒ^１２部分は同一でも異なっていてもよく、各々が独立にＨ、アルキル、−ＣＮ、−Ｃ（＝Ｏ）Ｎ（Ｒ^３０）_２、−（ＣＨ_２）_ｑＯＨ、−（ＣＨ_２）_ｑＯＲ^３１および−Ｓ（Ｏ_２）Ｒ^３１からなる群から選択され；
環Ｄは、５〜９員のシクロアルキル環、シクロアルケニル環、アリール環、ヘテロアリール環、ヘテロシクレニル環またはヘテロシクリル環であり、Ｏ、ＳまたはＮから独立に選択される０〜４個のヘテロ原子を持ち、環Ｄは、非置換であるか、または任意に、独立に選択された１〜５個のＲ^２０部分で置換されており；
Ｒ^２０部分は同一でも異なっていてもよく、各々が独立にＨ、アルキル、アルケニル、アルキルアリール、アルキニル、アルコキシ、アルキルアミノ、アルキルチオカルボキシ、アルキルヘテロアリール、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルコキシカルボニル、アミノアルキル、アミジニル、アラルキル、アラルケニル、アラルコキシ、アラルコキシカルボニル、アラルキルチオ、アリール、アロイル、アリールオキシ、シアノ、シクロアルキル、シクロアルケニル、ホルミル、グアニジニル、ハロゲン、ハロアルキル、ヘテロアルキル、ヘテロアリール、ヘテロシクリル、ヘテロシクレニル、ヒドロキシアルキル、ヒドロキサマート、ニトロ、トリフルオロメトキシ、

Selected from the group consisting of:
The R ¹⁰ moieties may be the same or different and each is independently H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, alkylaryl, arylalkyl, —CO ₂ H, hydroxyalkyl, —C (═ Selected from the group consisting of 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 may be the same or different and each is independently H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, alkylaryl, arylalkyl, carboxamide, CO ₂ H, — (CH ₂ ) _q Selected from the group consisting of OH, — (CH ₂ ) _q OR ³¹ , —OR ³⁰ , halogen, ═O and —C (═O) R ³¹ ;
The R ¹² moieties may be the same or different and each is independently H, alkyl, —CN, —C (═O) N (R ³⁰ ) ₂ , — (CH ₂ ) _q OH, — (CH ₂ ) _q Selected from the group consisting of OR ³¹ and —S (O ₂ ) R ³¹ ;
Ring D is a 5- to 9-membered cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, heterocyclenyl ring or heterocyclyl ring, and 0 to 4 heteroatoms independently selected from O, S or N And ring D is unsubstituted or optionally substituted with 1 to 5 independently selected R ²⁰ moieties;
The R ²⁰ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, Aminoalkyl, amidinyl, aralkyl, aralkyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, Heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy,

からなる群から選択され；あるいは２個のＲ^２０部分は一緒に結合して、５または６員のアリール環、シクロアルキル環、ヘテロシクリル環、ヘテロシクレニル環またはヘテロアリール環を形成し、前記５または６員のアリール環、シクロアルキル環、ヘテロシクリル環、ヘテロシクレニル環またはヘテロアリール環は環Ｄに縮合し、この縮合環は任意に０〜４個のＲ^２１部分で置換されており；
Ｒ^２１部分は同一でも異なっていてもよく、各々が独立にＨ、アルキル、アルケニル、アルキルアリール、アルキニル、アルコキシ、アルキルアミノ、アルキルチオカルボキシ、アルキルヘテロアリール、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルコキシカルボニル、アミノアルキル、アミジニル、アラルキル、アラルケニル、アラルコキシ、アラルコキシカルボニル、アラルキルチオ、アリール、アロイル、アリールオキシ、カルボキサミド、シアノ、シクロアルキル、シクロアルケニル、ホルミル、グアニジニル、ハロゲン、ハロアルキル、ヘテロアルキル、ヘテロアリール、ヘテロシクリル、ヘテロシクレニル、ヒドロキシアルキル、ヒドロキサマート、ニトロ、トリフルオロメトキシ、

Or two R ²⁰ moieties joined together to form a 5- or 6-membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl or heteroaryl ring, said 5 or 6 A membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl or heteroaryl ring is fused to Ring D, which is optionally substituted with 0 to 4 R ²¹ moieties;
The R ²¹ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, Aminoalkyl, amidinyl, aralkyl, aralkyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, carboxamide, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, Heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy,

からなる群から選択され；
Ｙは、共有結合、−（ＣＲ^１３Ｒ^１３）_ｒ−、−ＣＨＲ^１３Ｃ（＝Ｏ）−、−（ＣＨＲ^１３）_ｒＯ−、−（ＣＨＲ^１３）_ｒＮ（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−ヘテロアリール−、−Ｃ（Ｒ^１３Ｒ^１３）_ｒＣ（Ｒ^１３）＝Ｃ（Ｒ^１３）−、−（ＣＨＲ^１３）_ｒＣ（＝Ｏ）−および−（ＣＨＲ^１３）_ｒＮ（Ｈ）Ｃ（＝Ｏ）−からなる群から選択され；あるいはＹは、シクロアルキル、ヘテロシクレニルまたはヘテロシクリルであり、このシクロアルキル、ヘテロシクレニルまたはヘテロシクリルは、環Ｄと縮合しており；
Ｒ^１３部分は同一でも異なっていてもよく、各々が独立にＨ、アルキル、アルキルアリール、シクロアルキル、アルコキシ、アリール、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、スピロアルキル、

Selected from the group consisting of:
Y is a covalent bond, — (CR ¹³ R ¹³ ) _r —, —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 Selected from the group consisting of C (═O) — and — (CHR ¹³ ) _r N (H) C (═O) —; or Y is cycloalkyl, heterocyclenyl or heterocyclyl, which cycloalkyl, heterocyclenyl or heterocyclyl. Is fused with ring D;
The R ¹³ moieties may be the same or different and each is independently H, alkyl, alkylaryl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocyclenyl, heterocyclyl, spiroalkyl,

からなる群から選択され；
Ｒ^３０部分は同一でも異なっていてもよく、各々が独立にＨ、アルキル、アルキルアリール、アリール、アラルキル、シクロアルキル、−シクロアルキルアルキル、ＣＮ、−（ＣＨ_２）_ｑＯＨ、−（ＣＨ_２）_ｑＯアルキル、−（ＣＨ_２）_ｑＯアルキルアリール、−（ＣＨ_２）_ｑＯアリール、−（ＣＨ_２）_ｑＯアラルキル、−（ＣＨ_２）_ｑＯシクロアルキル、−（ＣＨ_２）_ｑＮＨ_２、−（ＣＨ_２）_ｑＮＨアルキル、−（ＣＨ_２）_ｑＮ（アルキル）_２、−（ＣＨ_２）_ｑＮＨアルキルアリール、−（ＣＨ_２）_ｑＮＨアリール、−（ＣＨ_２）_ｑＮＨアラルキル、−（ＣＨ_２）_ｑＮＨシクロアルキル、−（ＣＨ_２）_ｑＣ（＝Ｏ）Ｏ−アルキル、−（ＣＨ_２）_ｑＣ（＝Ｏ）ＮＨアルキル、−（ＣＨ_２）_ｑＣ（＝Ｏ）Ｎ（アルキル）_２、−（ＣＨ_２）_ｑＣ（＝Ｏ）ＮＨアルキルアリール、−（ＣＨ_２）_ｑＣ（＝Ｏ）ＮＨアリール、−（ＣＨ_２）_ｑＣ（＝Ｏ）ＮＨアラルキル、−（ＣＨ_２）_ｑＣ（＝Ｏ）ＮＨシクロアルキル、−（ＣＨ_２）_ｑＳＯ_２アルキル、−（ＣＨ_２）_ｑＳＯ_２アルキルアリール、−（ＣＨ_２）_ｑＳＯ_２アリール、−（ＣＨ_２）_ｑＳＯ_２アラルキル、−（ＣＨ_２）_ｑＳＯ_２シクロアルキル、−（ＣＨ_２）_ｑＮＳＯ_２アルキル、−（ＣＨ_２）_ｑＮＳＯ_２アルキルアリール、−（ＣＨ_２）_ｑＮＳＯ_２アリール、−（ＣＨ_２）_ｑＮＳＯ_２アラルキル、−（ＣＨ_２）_ｑＮＳＯ_２シクロアルキル、−（ＣＨ_２）_ｑＳＯ_２ＮＨアルキル、−（ＣＨ_２）_ｑＳＯ_２ＮＨアルキルアリール、−（ＣＨ_２）_ｑＳＯ_２ＮＨアリール、−（ＣＨ_２）_ｑＳＯ_２ＮＨアラルキル、−（ＣＨ_２）_ｑＳＯ_２ＮＨシクロアルキル、ヘテロシクレニル、ヘテロシクリルおよびヘテロアリールからなる群から選択され；
Ｒ^３１部分は同一でも異なっていてもよく、各々が独立にアルキル、アルキルアリール、アリール、アラルキル、シクロアルキル、−（ＣＨ_２）_ｑＯＨ、−（ＣＨ_２）_ｑＯアルキル、−（ＣＨ_２）_ｑＯアルキルアリール、−（ＣＨ_２）_ｑＯアリール、−（ＣＨ_２）_ｑＯアラルキル、−（ＣＨ_２）_ｑＯシクロアルキル、−（ＣＨ_２）_ｑＮＨ_２、−（ＣＨ_２）_ｑＮＨアルキル、−（ＣＨ_２）_ｑＮ（アルキル）_２、−（ＣＨ_２）_ｑＮＨアルキルアリール、−（ＣＨ_２）_ｑＮＨアリール、−（ＣＨ_２）_ｑＮＨアラルキル、−（ＣＨ_２）_ｑＮＨシクロアルキル、−（ＣＨ_２）_ｑＣ（＝Ｏ）ＮＨアルキル、−（ＣＨ_２）_ｑＣ（＝Ｏ）Ｎ（アルキル）_２、−（ＣＨ_２）_ｑＣ（＝Ｏ）ＮＨアルキルアリール、−（ＣＨ_２）_ｑＣ（＝Ｏ）ＮＨアリール、−（ＣＨ_２）_ｑＣ（＝Ｏ）ＮＨアラルキル、−（ＣＨ_２）_ｑＣ（＝Ｏ）ＮＨシクロアルキル、−（ＣＨ_２）_ｑＳＯ_２アルキル、−（ＣＨ_２）_ｑＳＯ_２アルキルアリール、−（ＣＨ_２）_ｑＳＯ_２アリール、−（ＣＨ_２）_ｑＳＯ_２アラルキル、−（ＣＨ_２）_ｑＳＯ_２シクロアルキル、−（ＣＨ_２）_ｑＮＳＯ_２アルキル、−（ＣＨ_２）_ｑＮＳＯ_２アルキルアリール、−（ＣＨ_２）_ｑＮＳＯ_２アリール、−（ＣＨ_２）_ｑＮＳＯ_２アラルキル、−（ＣＨ_２）_ｑＮＳＯ_２シクロアルキル、−（ＣＨ_２）_ｑＳＯ_２ＮＨアルキル、−（ＣＨ_２）_ｑＳＯ_２ＮＨアルキルアリール、−（ＣＨ_２）_ｑＳＯ_２ＮＨアリール、−（ＣＨ_２）_ｑＳＯ_２ＮＨアラルキル、−（ＣＨ_２）_ｑＳＯ_２ＮＨシクロアルキル、ヘテロシクレニル、ヘテロシクリルおよびヘテロアリールからなる群から選択され；
ｍは０〜４であり；
ｎは０〜４であり；
ｑは各々同一でも異なっていてもよく、各々が１〜５から独立に選択され；および
ｒは１〜４であり；
ただし、隣接する２個の二重結合はどの環にも存在せず、窒素が２個のアルキル基で置換されている場合、前記２個のアルキル基は任意に互いに結合して環を形成していてもよい。

Selected from the group consisting of:
The R ³⁰ moieties may be the same or different and each is independently H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, -cycloalkylalkyl, CN, — (CH ₂ ) _q OH, — (CH ₂ ). _q O-alkyl, - _{(CH 2) q} O alkylaryl, - _{(CH 2) q} O aryl, - _{(CH 2) q} O aralkyl, - _{(CH 2) q} O _{cycloalkyl, - (CH 2) q NH} 2 , - _{(CH 2)} q NH _{alkyl, - (CH 2) q N} ( _{alkyl) 2, - (CH 2)} q NH alkyl aryl, - _{(CH 2)} q NH aryl, - _{(CH 2)} q NH aralkyl, - _{(CH 2)} q NH _{cycloalkyl, - (CH 2) q C} (= O) O- _{alkyl, - (CH 2) q C} (= O) NH -alkyl, - _{(CH 2) q} (= O) N _{(alkyl) 2, - (CH 2)} q C (= O) NH -alkyl _{aryl, - (CH 2) q C} (= O) NH _{aryl, - (CH 2) q C} (= O) NH aralkyl, — (CH ₂ ) _q C (═O) NH cycloalkyl, — (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 NSO} 2 _{aralkyl, - (CH 2) q NSO} 2 _{cycloalkyl, - (CH 2) q SO} 2 NH _{-alkyl, - (CH 2) q SO} 2 NH -alkyl aryl, _{- (CH 2) q SO 2} NH aryl, _{- (CH 2) q SO 2} NH aralkyl, _{- (CH 2) q SO 2} NH cycloalkyl, heterocyclenyl, is selected from the group consisting of heterocyclyl and heteroaryl;
The R ³¹ moieties may be the same or different and each is independently alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, — (CH ₂ ) _q OH, — (CH ₂ ) _q O alkyl, — (CH ₂ ). _q O alkylaryl, - _{(CH 2) q} O aryl, - _{(CH 2) q} O aralkyl, - _{(CH 2) q} O _{cycloalkyl, - (CH 2) q NH} 2, - (CH 2) q NH alkyl , — (CH ₂ ) _q N (alkyl) ₂ , — (CH ₂ ) _q NH alkylaryl, — (CH ₂ ) _q NH aryl, — (CH ₂ ) _q NH aralkyl, — (CH ₂ ) _q NH cycloalkyl _{, - (CH 2) q C} (= O) NH _{-alkyl, - (CH 2) q C} (= O) N ( _{alkyl) 2, - (CH 2)} q C (= O) NH -alkyl aryl _{- (CH 2) q C (} = O) NH _{aryl, - (CH 2) q C} (= O) NH _{aralkyl, - (CH 2) q C} (= O) NH cycloalkyl, - _{(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 alkyl, - _(CH 2) _q NSO _{2 alkyl, - (CH 2) q NSO} 2 _{alkylaryl, - (CH 2) q NSO} 2 _{aryl, - (CH 2) q NSO} 2 _{aralkyl, - (CH 2) q NSO} 2 cycloalkyl, - (CH _{2) q} SO _{2 NH-alkyl, - (CH 2) q SO} 2 NH -alkyl _{aryl, - (CH 2) q SO} 2 NH _{aryl, - (CH 2) q SO} 2 NH aralkyl _{- (CH 2) q SO 2} NH cycloalkyl, heterocyclenyl, is selected from the group consisting of heterocyclyl and heteroaryl;
m is 0-4;
n is 0-4;
each q may be the same or different and each is independently selected from 1-5; and r is 1-4.
However, two adjacent double bonds do not exist in any ring, and when nitrogen is substituted with two alkyl groups, the two alkyl groups are arbitrarily bonded to each other to form a ring. It may be.

  For compounds of formula 1, their preparation and their use, see WO 2006/088837 published Aug. 24, 2006 and U.S. Patent Application Publication No. 2006/0276479 published Dec. 7, 2006. Is disclosed.

  The present invention further provides chronic obstructive pulmonary disease (COPD), asthma, sarcoidosis, systemic lupus erythematosus (SLE), ankylosing spondylitis, fibrotic disease, pulmonary fibrosis, alopecia areata, scleroderma, lichen planus Needed to treat a CXCR3 chemokine receptor-mediated disease selected from the group consisting of scabies lupus erythematosus, discoid lupus erythematosus, dermatomyositis, Behcet's disease, Wegener's disease, atopic dermatitis and graft-versus-host disease (GVHD) There is also provided a method of treating the above diseases in a patient having a therapeutically effective amount of a compound of formula

またはその薬学的に許容される塩または溶媒和物を上記患者に投与することを含む。一実施形態では、薬学的に許容される塩は、この化合物のメシラート塩である。

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

  Compounds of the following formula, methods for their preparation and use are also disclosed in WO 2006/088837 published Aug. 24, 2006 and U.S. Patent Application Publication No. 2006/0276479 published Dec. 7, 2006. Disclosure and disclosure.

本発明のさらなる特徴は、上記のようなＣＸＣＲ３が関与する疾患を処置する方法であって、それを必要としている患者に、活性成分として少なくとも１種の式１の化合物を含有する医薬組成物を、少なくとも１種の薬学的に許容されるキャリアまたは賦形剤と併用投与することを含む方法を提供する。

A further feature of the present invention is a method of treating a disease involving CXCR3 as described above, wherein a patient in need thereof is provided with a pharmaceutical composition comprising at least one compound of formula 1 as an active ingredient. A method comprising administering in combination with at least one pharmaceutically acceptable carrier or excipient.

  A further feature of the present invention is a method of treating a disease involving CXCR3 as described above, wherein (a) at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate thereof (B) disease-modifying anti-rheumatic agent; non-steroidal anti-inflammatory agent; COX-2 selective inhibitor; COX-1 inhibitor; immunosuppressive drug; steroid; PDE-IV inhibitor , Anti-TNF-α compound, TNF-α-convertase inhibitor, cytokine inhibitor, MMP inhibitor, corticosteroid, glucocorticoid, chemokine inhibitor, CB2 selective inhibitor, p38 inhibitor, biological response modulation A method comprising administering to a patient in need of such treatment in an effective amount with at least one drug selected from the group consisting of anti-inflammatory and therapeutic agents provide.

  The terms used in this specification have their ordinary meanings, and the meanings of the terms are independent each time they are described. However, unless otherwise stated, the following definitions apply in this specification and the claims. In the description of the same structure, a chemical name, a general name, and a chemical structure can be used interchangeably. This definition applies regardless of whether a term is used by itself or in combination with other terms, unless otherwise noted. Thus, the definition of “alkyl” applies not only to “alkyl” but also to “alkyl” moieties such as “hydroxyalkyl”, “haloalkyl”, “alkoxy” and the like.

  As used above, in this specification, the following terms shall be understood to have the following meanings unless otherwise indicated.

  “Acyl” refers to an HC (═O) — group, an alkyl-C (═O) — group, an alkenyl-C (═O) — group, an alkynyl-C (═O) — group, and a cycloalkyl-C. Means a (═O) — group, a cycloalkenyl-C (═O) — group or a cycloalkynyl-C (═O) — group, where the various groups are as previously described. The bond to the parent moiety is through the carbonyl carbon atom. Preferred acyls include 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, which may be straight or branched, 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, 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. Alkenyl groups may be substituted with one or more substituents, which may be the same or different, and each of these substituents is independently alkyl, alkenyl, alkynyl, alkoxyl, aryl, aryloxy, cycloalkyl, cyclo Alkenyl, cyano, heteroaryl, heterocyclyl, amino, aminosulfonyl, halo, carboxyl, carboxyalkyl (including esters as non-limiting examples), alkoxycarbonyl, hydroxyalkyl, carbonyl (including ketones as non-limiting examples) , —C (═O) heterocyclyl, formyl (non-limiting examples include aldehydes), carboxamides (ie, amides, —C (═O) NH ₂ ), —C (═O) N (alkyl) ₂ , -C (= O) NH (alkyl), -C (= O) N (cycloa Alkyl) ₂ , —C (═O) NH (cycloalkyl), —NHC (═O) alkyl, urea (eg, —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 (ie, —CO ₂ NH ₂ ), NHC (═O) O alkyl, —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 NH alkyl, -NH-S (O) ₂ N ( Alkyl) ₂ , alkylthiocarboxy, —S (O) ₂ alkyl, —S (O) ₂ aryl, —OS (O) ₂ alkyl, —OS (O) ₂ aryl, sulfonylurea (non-limiting examples include NHC ( = S) NH alkyl is selected). 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 containing about 1 to about 20 carbon atoms in the chain which may be straight or branched or combinations thereof. 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. Alkyl groups may be substituted with one or more substituents, which may be the same or different, and each of these substituents is independently alkyl, alkenyl, alkynyl, alkoxyl, aryl, aryloxy, cycloalkyl, cyclo Alkenyl, 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) ₂ , N (heterocyclyl) ₂ , halo, hydroxy, carboxyl, carboxyalkyl (non-limiting examples (one or more esters) ), Alkoxycarbonyl, hydroxyalkyl, carbonyl (unlimited) Specific examples include ketones), —C (═O) heterocyclyl, formyl, carboxamide (ie, amide, —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 (eg, —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 _{That, -CO 2 NH 2), -} NHC (= O) O -alkyl, _-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 NH alkyl, —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 (as non-limiting example -NHC (= S) NH Alkyl) and OSi _(alkyl) is selected from the group consisting of _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 Is mentioned.

  “Alkylheteroaryl” means an alkyl-heteroaryl-group in which alkyl is as previously described and the bond to the parent moiety is through the heteroaryl group.

“Alkylamino” means a —NH ₂ or —NH ₃ + group in which one or more hydrogen atoms on the nitrogen is replaced with an alkyl group as defined above. The bond with the parent is a bond through nitrogen.

  “Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are as described herein. Preferred alkylaryls contain 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 a bond through 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 a bond through 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 sulfinyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which may be straight or branched, 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, 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. Alkynyl groups may be substituted with one or more substituents, which may be the same or different, and each substituent is independently alkyl, alkoxyl, aryl, aryloxy, cycloalkyl, cycloalkenyl, cyano, hetero Aryl, 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 (including ketones as non-limiting examples), -C (= O) heterocyclyl, carboxamide (i.e., _{amide, -C (= O) NH 2} ), - C (= O) N ( alkyl _{) 2, -C (= O)} NH ( alkyl), - C (= O) N ( _{cycloalkyl) 2, -C (= O)} NH ( cycloalkyl), alkyl C (= O) NH -, - NHC (═O) alkyl, urea (eg, —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) is selected from _2-alkyl and -S _(O) group consisting of 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 with 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 include lower alkyl. Non-limiting examples of suitable aminoalkyl groups include aminomethyl and 2-dimethylolamino-2-ethyl. The bond to the parent moiety is through an alkyl.

“Amidinyl” refers to the group —C (═NR) NHR. The R group is 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 contain a lower alkyl group attached to an aryl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through an 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 a bond through sulfur.

  “Aralkoxy” means an aralkyl-O— group in which the aralkyl group is as previously described. The bond with the parent moiety is a bond through an 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, 1-naphthoyl and 2-naphthoyl.

  “Aryl” (sometimes abbreviated “Ar”) means monocyclic or polycyclic aromatics containing about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. Means a family ring system. Aryl groups are optionally substituted with one or more “ring system substituents”. The ring system substituents may be the same or different, but 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 with 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 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 a bond through sulfur.

  “Carboxyalkyl” means an alkyl-C (═O) O— group. The bond to the parent moiety is a bond through carboxy.

  Carbamate and urea substituents refer to groups in which oxygen and nitrogen are each adjacent to an amide. Exemplary carbamate and urea substituents include the following.

「シクロアルキル」とは、約３〜約１０個の炭素原子、好ましくは約５〜約１０個の炭素原子を含む単環式または多環式非芳香族環系を意味する。好ましいシクロアルキル環は、約５〜約７個の環原子を含む。シクロアルキルは任意に、１つまたは複数の「環系置換基」で置換されていてもよい。環系置換基は同一でも異なっていてもよいが、上記で定義した通りである。好適な単環式シクロアルキルの非限定的な例として、シクロプロピル、シクロペンチル、シクロヘキシル、シクロヘプチルなどが挙げられる。好適な多環式シクロヘキシルの非限定的な例として、１−デカリン、ノルボルニル、アダマンチルなどが挙げられる。

“Cycloalkyl” means a monocyclic or polycyclic non-aromatic 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. Cycloalkyls may be optionally substituted with one or more “ring system substituents”. The ring system substituents may be the same or different, but are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable polycyclic cyclohexyls include 1-decalin, norbornyl, adamantyl and the like.

  “Cycloalkenyl” means a monocyclic or polycyclic ring containing at least one carbon-carbon double bond and comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Means a non-aromatic ring system. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. A cycloalkenyl may be optionally substituted with one or more “ring system substituents”. The ring system substituents may be the same or different, but are as defined herein. Non-limiting examples of suitable monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl. The term “cycloalkenyl” also refers to moieties such as cyclobutenedione, cyclopentenone, cyclopentenedione, and the like.

  “Halogen” (or halo) means fluorine, chlorine, bromine or iodine. Preference is given to fluorine, chlorine and bromine.

  “Haloalkyl” means an alkyl in which one or more hydrogen atoms on the alkyl as defined above is replaced with a halo group as described above. Non-limiting examples include trifluoromethyl, 2,2,2-trifluoroethyl, 2-chloropropyl, and the like.

  “Heteroaryl” includes about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the ring atoms are other than carbon, such as nitrogen, oxygen Or a monocyclic or polycyclic aromatic ring system that is any one or a combination of two or more of sulfur. Preferred heteroaryls contain about 5 to about 6 ring atoms. “Heteroaryl” may be optionally substituted with one or more “ring system substituents”. The ring system substituents may be the same or different, but 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 heteroaryl 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 Examples thereof include isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like.

  “Heterocyclenyl” includes about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the atoms in the ring system is an element other than carbon, such as nitrogen. A monocyclic or polycyclic non-cyclic group that is any one or a combination of two or more of atoms, oxygen atoms, or sulfur atoms and contains at least one carbon-carbon double bond or carbon-nitrogen double bond Means an aromatic ring system. 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. Heterocyclenyl is optionally substituted with one or more ring system substituents. A “ring system substituent” is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to its 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 further includes rings in which two substitutable hydrogens on the same carbon atom are replaced with ═O (ie, heterocyclenyl includes rings having a carbonyl group in the ring). Examples of such heterocyclenyl rings include the following pyrrolidinones.

「ヘテロシクリル」とは、約３〜約１０個の環原子、好ましくは約５〜約１０個の環原子を含み、環系中の原子の１つまたは複数が炭素以外の元素、たとえば、窒素、酸素または硫黄のいずれか１つまたは２種以上の組み合わせである、飽和の単環式または多環式非芳香族環系を意味する。環系中には隣接する酸素原子および／または硫黄原子は存在しない。好ましいヘテロシクリルは、約５〜約６個の環原子を含む。ヘテロシクリルの語幹名の前の接頭辞アザ、オキサまたはチアは、少なくとも窒素原子、酸素原子または硫黄原子がそれぞれ環原子として存在することを意味する。ヘテロシクリル環中の任意の−ＮＨは、たとえば、−Ｎ（Ｂｏｃ）基、−Ｎ（ＣＢｚ）基、−Ｎ（Ｔｏｓ）基などとして保護されていてもよく、そうした保護も本発明の一部と考えられる。ヘテロシクリルは任意に、１つまたは複数の「環系置換基」で置換されていてもよい。環系置換基は、同一でも異なっていてもよいが、本明細書に定義した通りである。ヘテロシクリルの窒素原子または硫黄原子は任意に対応するＮ−オキシド、Ｓ−オキシドまたはＳ，Ｓ−ジオキシドへと酸化され得る。好適な単環式ヘテロシクリル環の非限定的な例として、ピペリジル、ピロリジニル、ピペラジニル、モルホリニル、チオモルホリニル、チアゾリジニル、１，４−ジオキサニル、テトラヒドロフラニル、テトラヒドロチオフェニル、ラクタム、ラクトンなどが挙げられる。ヘテロシクリルさらに、同一の炭素原子上の置換可能な２個の水素が＝Ｏで置換されている環も含む（すなわち、ヘテロシクリルは、環中にカルボニル基を持つ環を含む）。そうしたヘテロシクリル環の例として下記ピロリドンがある。

“Heterocyclyl” includes about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the atoms in the ring system is an element other than carbon, such as nitrogen, It means a saturated monocyclic or polycyclic non-aromatic ring system that is either one or a combination of two or more of oxygen or sulfur. 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 the heterocyclyl ring may be protected, for example, as a —N (Boc) group, —N (CBz) group, —N (Tos) group, and such protection is also part of the present invention. Conceivable. A heterocyclyl may be optionally substituted with one or more “ring system substituents”. The ring system substituents may be the same or different, but 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 further includes rings in which two substitutable hydrogens on the same carbon atom are replaced with ═O (ie, heterocyclyl includes rings having a carbonyl group in the ring). Examples of such heterocyclyl rings include the following pyrrolidones.

「ヘテロアラルキル」とは、ヘテロアリールおよびアルキルが前に記載した通りであるヘテロアリール−アルキル−基を意味する。好ましいヘテロアラルキルは、低級アルキル基を含む。好適なアラルキル基の非限定的な例として、ピリジルメチル、２−（フラン−３−イル）エチルおよびキノリン−（３−イル）メチルが挙げられる。親部分との結合は、アルキルを介した結合である。

“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 an alkyl.

  “Heteroaralkenyl” means a 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 hydroxyalkyl include lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. The bond to the parent moiety is through an alkyl.

  “Hydroxamate” means an alkyl-C (═O) NH—O— group. The bond with the parent moiety is a bond through an oxygen group.

“Ring system substituent” means a substituent attached to an aromatic or non-aromatic ring system which is substituted, for example, with a substitutable hydrogen on the ring system. The ring system substituents may be the same or different and each is independently H, alkyl, alkenyl, alkynyl, alkoxyl, aryl, aroyl, aryloxy, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, alkylaryl, alkyl Heteroaryl, 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 (esters as non-limiting examples) ), Cyano, alkoki Cycarbonyl, hydroxyalkyl, carbonyl (non-limiting examples are ketones), -C (= O) heterocyclyl, formyl (non-limiting examples are aldehydes), carboxamides (ie, amides, -C (= O) NH ₂ ), —C (═O) N (alkyl) ₂ , —C (═O) NH (alkyl), —C (═O) N (cycloalkyl) ₂ , —C (═O) NH ( Cycloalkyl), alkyl C (═O) NH—, —amidino, hydrazide, hydroxamate, —NHC (═O) H, —NHC (═O) alkyl, urea (eg, —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) ), Guanidini , —NHC (═NCN) NH ₂ , —NHC (═NCN) N (alkyl) ₂ , carbamoyl (ie, —CO ₂ NH ₂ ), —NHC (═O) O alkyl, —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 NH _{-alkyl, -NH-S (O) 2} N ( _{alkyl) 2,} thio, alkylthio carboxy, -S _{(O) 2} alkyl, -S _{(O) 2} aryl, -OS _{(O) 2} alkyl, -OS _{(O) 2} aryl (-NHC Nonlimiting examples (= S) is NH alkyl) sulfonylureas and OSi _(alkyl) is selected from the group consisting of _3.

  “Spiroalkyl” means that two carbon atoms of an alkyl group are bonded to one carbon atom of a parent molecular group to form a carbocyclic or heterocyclic ring of 3 to 11 atoms. An alkylene group. Typical structures include the following examples.

本発明のスピロアルキル基は任意に、１つまたは複数の環系置換基で置換されていてもよい。「環系置換基」は、本明細書に定義されている通りである。

The spiroalkyl groups of the present invention may optionally be substituted with one or more ring system substituents. “Ring system substituents” are as defined herein.

  In addition, a “ring system substituent” is a cyclic ring of 3 to 7 ring atoms that may contain 1 or 2 heteroatoms, including two on the aryl, heteroaryl, heterocyclyl ring A ring ring bonded to the aryl ring, heteroaryl ring, or heterocyclyl ring by simultaneously substituting the ring hydrogen atoms is also meant. Non-limiting examples include:

「任意に置換されている」という語は、置換可能な位置において特定の基、ラジカルまたは部分で任意に置換されていることを意味する。

The term “optionally substituted” means optionally substituted with the specified group, radical or moiety at substitutable positions.

  The terms “one or more” and “at least one” with respect to the number of moieties (substituents, groups or rings as a non-limiting example) in a compound, unless otherwise defined, It means that it may be the same as the number allowed, and the determination of the maximum number of such parts is well within the knowledge of those skilled in the art. The number of substituents is preferably 1 to 3, or more preferably 1 to 2, and at least one is in the para position.

  As used herein, the term “composition” refers to a product that contains a particular component in a particular amount, and any product that is obtained directly or indirectly by combining a particular component in a particular amount. It is intended to encompass things.

  Straight line as a bond

は通常、考えられる異性体の混合物またはその考えられる異性体のいずれかを示し、非限定的な例として、（Ｒ）および（Ｓ）立体化学がある。たとえば、

Usually refers to a mixture of possible isomers or any of the possible isomers, non-limiting examples being (R) and (S) stereochemistry. For example,

破線

Broken line

は、任意の結合を表す。

Represents any bond.

  For example, a line drawn in the ring system as follows indicates that the indicated line (bond) may be bonded to any of the substitutable ring atoms, and is a non-limiting example. As carbon ring atoms, nitrogen ring atoms and sulfur ring atoms.

当該技術分野において周知のように、結合の末端の部分が記載されていない特定の原子から引かれる結合は、その結合を介してその原子にメチル基結合が結合していることを表す。たとえば：

As is well known in the art, a bond drawn from a particular atom for which the terminal portion of the bond is not described indicates that a methyl group bond is attached to the atom through the bond. For example:

また、本明細書の本文、スキーム、例、構造式および任意の表において原子価が不飽和な任意のヘテロ原子については、原子価を飽和するために水素原子を有することが想定される点にも注意すべきである。

In addition, any hetero atom whose valence is unsaturated in the text, scheme, examples, structural formulas and arbitrary tables of the present specification is assumed to have a hydrogen atom to saturate the valence. You should also be careful.

  Also contemplated herein are prodrugs and solvates of the compounds of the invention. The term “prodrug” as used herein refers to a compound of Formula 1 or a salt and / or solvate thereof that, when administered to a subject, is chemically transformed by a metabolic or chemical process. Is a compound that is a drug precursor. For discussion of prodrugs, both are described in T.W. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.M. C. S. Symposium Series, and Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed. , American Pharmaceutical Association and Pergamon Press.

  This application contemplates “metabolic conjugates” such as, for example, glucuronides and sulfates that can be reversibly converted to compounds of Formula 1.

  “Effective amount” or “therapeutically effective amount” shall refer to the amount of a compound or composition of the invention effective to antagonize CXCR3 and thus exert the desired therapeutic effect in a suitable patient.

  “Mammal” means humans and other mammalian animals.

  “Patient” includes both humans and animals.

“Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association includes ionic and covalent bonds of varying strength (including hydrogen bonds). Solvates may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. “Solvate” encompasses both liquid-phase solvates and isolatable solvates. Non-limiting examples of suitable solvates include ethanolate, methanolate and the like. “Hydrate” is a solvate wherein the solvent molecule is H ₂ O. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

  The compounds of formula 1 also form salts that are within the scope of this invention. References herein to a compound of formula 1 are to be understood to include the salts thereof unless otherwise stated. As used herein, the term “salt” refers to acidic salts formed with inorganic and / or organic acids and basic salts formed with inorganic and / or organic bases. Further, when the compound of Formula 1 includes, but is not limited to, a basic moiety such as pyridine or imidazole and an acidic moiety such as, but not limited to, carboxylic acid, amphoteric May form ions (“inner salts”), which are also included in the term “salts” as used herein. Although pharmaceutically acceptable (non-limiting examples are non-toxic, physiologically acceptable) salts are preferred, other salts are useful. A salt of a compound of formula 1 can be reacted, for example, by reacting the compound of formula 1 with an amount (eg, equal amount) of acid or base in a medium in which the salt precipitates or in an aqueous medium, and then lyophilized Can be formed. For acids (and bases) that are generally considered suitable for forming pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds, see, for example, S.A. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; Gould, International J. et al. of Pharmaceuticals (1986) 33 201-217; Anderson et al, The Practice of Medicine Chemistry (1996), Academic Press, New York, in The Orange. and P.M. 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. Such disclosure is incorporated herein by reference.

  Exemplary acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate , Camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, Hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, methylsulfate, 2-naphthalenesulfonate, nicotinic acid Salt, nitrate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, prop Pionate, salicylate, succinate, sulfate, sulfonate (such as those described herein), tartrate, thiocyanate, toluenesulfonate (also called tosylate) undecanoate, etc. .

  Exemplary basic salts include ammonium salts, alkali metal salts (eg, sodium, lithium and potassium salts), alkaline earth metal salts (eg, calcium and magnesium salts), aluminum salts, zinc salts, benzathines, Diethylamine, dicyclohexylamine, hydrabamine (formed by N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, piperazine, phenylcyclohexylamine, Examples thereof include salts with organic bases (for example, organic amines) such as choline and tromethamine, and salts with amino acids (for example, arginine, lysine). For basic nitrogen-containing groups, lower alkyl halides (non-limiting examples include methyl chloride, ethyl chloride, propyl chloride, butyl chloride, methyl bromide, ethyl bromide, propyl bromide, butyl bromide, iodide) Methyl, ethyl iodide, propyl iodide, butyl iodide), dialkyl sulfate (non-limiting examples include dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate), long chain halides (non-limiting Examples include decyl chloride, lauryl chloride, myristyl chloride, stearyl chloride, decyl bromide, lauryl bromide, myristyl bromide, stearyl bromide, decyl iodide, lauryl iodide, myristyl iodide, stearyl iodide), halogen Quaternary with aralkyl bromide (non-limiting examples include benzyl bromide and phenethyl bromide) and other drugs It may be.

  All of these acidic and basic salts are intended to be pharmaceutically acceptable salts within the scope of the present invention, in which all acidic and basic salts are free of the compound. Considered equivalent to type.

The pharmaceutically acceptable esters of this compound are the following groups: (1) Carboxylic acid esters obtained by esterification of hydroxy groups, wherein the non-carbonyl part of the carboxylic acid part of the ester group is linear or branched Chain alkyl (eg acetyl, n-propyl, t-butyl or n-butyl), alkoxyalkyl (eg methoxymethyl), aralkyl (eg benzyl), aryloxyalkyl (eg phenoxymethyl), aryl (eg A carboxylic acid ester optionally selected from halogen, C _1-4 alkyl or phenyl substituted by C _1-4 alkoxy or amino, etc .; (2) sulfones such as alkylsulfonyl or aralkylsulfonyl (eg methanesulfonyl) Acid ester; (3) a Bruno esters (e.g., L- valyl or L- isoleucyl); including (4) phosphonate esters and (5) monophosphate ester, diphosphate ester, or triphosphate ester. The phosphate ester may be further esterified with, for example, C _1-20 alcohol or a reactive derivative thereof, or 2,3-di (C _6-24 ) acylglycerol.

  Compounds of formula 1 and salts, solvates, esters and prodrugs thereof may exist as tautomers (eg, amides or imino ethers). All such tautomers are contemplated herein as part of the present invention.

  All stereoisomers (eg geometric isomers, optical isomers) of this compound (including salts, solvates, esters and prodrugs of this compound, as well as salts of prodrugs, solvates and esters) For example, enantiomeric forms that may exist due to asymmetric carbons on various substituents (may exist without asymmetric carbon), rotamers, atropisomers and diastereoisomers Such stereoisomers and the like are intended to be within the scope of the present invention. Individual stereoisomers of the compounds of the invention may be, for example, substantially free of other isomers, or may be, for example, as racemates or all other stereoisomers or other specific isomers. It may be mixed with a stereoisomer. The configuration of the chiral center of the present invention may be the S or R configuration as defined by the IUPAC 1974 recommendation. When using the terms “salt”, “solvate” “prodrug” and like terms, enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug salts of the compounds of the invention, It is intended to apply to solvates, esters and prodrugs as well.

  In the present specification and claims appended hereto, any formula, compound, moiety or chemical diagram that is unsaturated in valence is saturated unless the context indicates a bond. It is necessary to note that it is assumed to have a hydrogen atom to do so.

  In one embodiment, the present invention relates to a CXCR3 chemokine receptor mediated disease as described above using at least one compound of formula 1 or a pharmaceutically acceptable derivative thereof as set forth above. Disclose to treat.

  Another embodiment of the invention relates to a method wherein G in formula 1 represents a dihydroimidazole ring, imidazole ring, dihydrooxazole ring, oxazole ring, dihydrooxadiazole ring, oxadiazole ring, triazole ring or tetrazole ring. .

  Another embodiment of the present invention is that ring G in formula 1 is

からなる群から選択される方法に関し、式中、

With respect to a method selected from the group consisting of

は、単結合または二重結合である。

Is a single bond or a double bond.

Another embodiment of this invention is a method wherein R ^{3 of} formula 1 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, —N (R ³⁰ ) ₂ , —OR ^30, and —CF _3. About.

Another embodiment of the present invention is that R ^{3 in} formula 1 is H, —CH ₃ , —CH ₂ CH ₃ , —CH (CH ₃ ) ₂ , cyclopropyl, —F, —Cl, OCH ₃ , OCF Relates to a method selected from the group consisting of ₃ and CF ₃ .

Another embodiment of this invention is that R ^{6 in} formula 1 is H, alkyl, halogen, hydroxyalkyl, —CN, —N (R ³⁰ ) ₂ , —OR ³⁰ , —N═CH-alkyl, —NR ^It relates to a process selected from the group consisting of ³⁰ C (═O) alkyl and —NR ³⁰ C (═O) N (R ³⁰ ) ₂ .

Another embodiment of this invention is that R ^{6 in} formula 1 is H, alkyl, halogen, hydroxyalkyl, —CN, —N (R ³⁰ ) ₂ , —OR ³⁰ , —N═CH-alkyl and —NR. ^It relates to a process selected from the group consisting of ³⁰ C (═O) alkyl.

Another embodiment of the present invention is that R ^{6 in} formula 1 is H, —NH ₂ , —NHC (═O) CH ₃ , —NHC (═O) N (CH ₃ ) ₂ , —CH ₃ , — It relates to a method selected from the group consisting of CN and -F.

Another embodiment of this invention is that R ^{8 in} formula 1 is 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, It relates to a process selected from the group consisting of — (CH ₂ ) _q SO ₂ NHR ³¹ and —C (═O) -aryl-halogen.

Another embodiment of the present invention is that the R ⁹ moieties in formula 1 may be the same or different, each independently 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 a method selected from the group consisting of —SO ₂ N (H) R ³⁰ .

Another embodiment of the present invention is that the R ⁹ moieties in Formula 1 may be the same or different, each independently 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) -cyclopropi Le _{-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, It relates to a method selected from the group consisting of = S and = O.

In another embodiment of the present invention, the R ⁹ moieties in formula 1 may be the same or different and each independently represents 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, -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 a method selected from the group consisting of —N (H) S (═O) ₂ -alkyl.

Another embodiment of this invention is directed to a method wherein R ^{10 in} formula 1 is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl.

Another embodiment of this invention is directed to a method wherein R ^{10 in} formula 1 is selected from the group consisting of —CH ₃ , —CH ₂ CH ₃ and —CH ₂ CH ₂ CH ₃ , wherein m is 0-2. .

Another embodiment of this invention is directed to a method wherein R ^{11 in} formula 1 is selected from the group consisting of H, alkyl, hydroxyalkyl, and carbonyl.

Another embodiment of this invention is directed to a method wherein R ^{11 in} formula 1 is H or —CH ₃ .

Another embodiment of this invention is directed to a method wherein R ^{12 in} formula 1 is selected from the group consisting of H, CN, —C (═O) N (R ³⁰ ) ₂ and alkyl.

Another embodiment of the present invention, ^{R 12} in Formula 1, H, to a method selected from the group consisting of _-CH 3, CN and _-CH 2 CH _3.

Another embodiment of this invention is directed to a method wherein the ring atoms of ring D in formula 1 are independently C, N, O and S and are substituted with 0 to 4 R ²⁰ moieties.

Another embodiment of this invention is directed to a method wherein the ring atom of ring D in formula 1 is independently C or N and is substituted with 0 to 4 R ²⁰ moieties.

Another embodiment of this invention is that ring D in formula 1 is a 5-6 membered aryl ring, heteroaryl ring, heterocyclenyl ring or heterocyclyl ring, substituted with 0-4 R ²⁰ moieties. Regarding the method.

Another embodiment of the present invention is that the R ²⁰ moieties in formula 1 may be the same or different, each independently H, alkyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylheteroaryl, alkylsulfinyl. , Alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkoxy, aryl, aryloxy, cyano, cycloalkyl, cycloalkenyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, trifluoromethyl, trifluoromethoxy,

からなる群から選択される方法に関する。

To a method selected from the group consisting of

Another embodiment of the present invention is that the R ²⁰ moieties in formula 1 may be the same or different, each independently H, alkyl, amino, halogen,

からなる群から選択される方法に関する。

To a method selected from the group consisting of

Another embodiment of the present invention is that the two R ²⁰ moieties in formula 1 are joined together to form a 5 or 6 membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring; Wherein said 5 or 6 membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl and heteroaryl rings are fused to ring D, wherein the fused ring is optionally substituted with 0-4 R ²¹ moieties .

In another embodiment of the present invention, the R ²⁰ moieties in formula 1 may be the same or different and each independently represents 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 It relates to a method selected from the group consisting of S (O ₂ ) CH ₃ , —C (═O) NH ₂ and

本発明の別の実施形態は、式１中のＲ^２１部分は同一でも異なっていてもよく、各々が独立に、Ｈ、アルキル、アルケニル、アルキルアリール、アルキニル、アルコキシ、アルキルアミノ、シアノ、シクロアルキル、ホルミル、ハロゲン、ハロアルキル、ヒドロキシアルキル、ニトロおよびトリフルオロメトキシからなる群から選択される方法に関する。

Another embodiment of the present invention is that the R ²¹ moieties in formula 1 may be the same or different, each independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl. , Formyl, halogen, haloalkyl, hydroxyalkyl, nitro and trifluoromethoxy.

In another embodiment of the present invention, Y in Formula 1 is — (CHR ¹³ ) _r —, — (CR ¹³ R ¹³ ) _r —, —C (═O) —, —CHR ¹³ C (═O) It relates to a method selected from the group consisting of — and — (CHR ¹³ ) _r C (═O).

Another embodiment of the present invention is that Y in Formula 1 is — (CHR ¹³ ) _r —, — (CR ¹³ R ¹³ ) _r —, —C (═O) — and —CHR ¹³ C (═O) A method selected from the group consisting of:

Another embodiment of the present invention is that Y in Formula 1 is —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 - is selected from the group consisting of Related to the method.

  Another embodiment of this invention is directed to a method wherein m in formula 1 is 0-2.

  Another embodiment of this invention is directed to a method wherein n in formula 1 is 0-2.

  Another embodiment of this invention is directed to a method wherein q in formula 1 is 1 or 2.

  Another embodiment of this invention is directed to a method wherein r in formula 1 is 1 or 2.

  Another embodiment of this invention is directed to a method wherein ring G in formula 1 is selected from the group consisting of:

は、単結合または二重結合であり；
Ｒ^３は、Ｈ、アルキル、ハロアルキル、ヒドロキシアルキル、ハロゲン、−Ｎ（Ｒ^３０）_２、−ＯＲ^３０および−ＣＦ_３からなる群から選択され；
Ｒ^６は、Ｈ、アルキル、ハロゲン、ヒドロキシアルキル、−ＣＮ、−Ｎ（Ｒ^３０）_２、−ＯＲ^３０、−Ｎ＝ＣＨ−アルキル、−ＮＲ^３０Ｃ（＝Ｏ）アルキルおよび−ＮＲ^３０Ｃ（＝Ｏ）Ｎ（Ｒ^３０）_２からなる群から選択され；
Ｒ^９部分は同一でも異なっていてもよく、各々が独立に、Ｈ、アルキル、シクロアルキル、−Ｃ（＝Ｏ）Ｎ（Ｈ）Ｒ^３０、−Ｃ（＝Ｏ）ＯＲ^３０、−Ｃ（＝Ｏ）アルキル、−（ＣＨ_２）_ｑＯＨ、−（ＣＨ_２）_ｑＯＲ^３１、−（ＣＨ_２）_ｑＮＨ_２、−（ＣＨ_２）_ｑＮＨＲ^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）および−ＳＯ_２Ｎ（Ｈ）Ｒ^３０からなる群から選択され；
Ｒ^１０は、Ｈ、アルキル、アラルキル、ヒドロキシアルキルおよびカルボニルからなる群から選択され；
Ｒ^１１は、Ｈ、アルキル、ヒドロキシアルキルおよびカルボニルからなる群から選択され；
Ｒ^１２は、Ｈ、ＣＮ、−Ｃ（＝Ｏ）Ｎ（Ｒ^３０）_２およびアルキルからなる群から選択され；
環Ｄは、５〜６員のアリール環、ヘテロアリール環、ヘテロシクレニル環またはヘテロシクリル環であり、０〜４個のＲ^２０部分で置換されており；
Ｒ^２０部分は同一でも異なっていてもよく、各々が独立に、Ｈ、アルキル、シクロアルキル、アミノ、ハロゲン、

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 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 selected from the group;
The R ⁹ moieties may be the same or different and each is independently 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) the group consisting of ^{R 30} Selected from;
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 5-6 membered aryl ring, heteroaryl ring, heterocyclenyl ring or heterocyclyl ring, substituted with 0-4 R ²⁰ moieties;
The R ²⁰ moieties may be the same or different and each is independently H, alkyl, cycloalkyl, amino, halogen,

および−ＯＳＯ_２（Ｒ^３１）からなる群から選択され；あるいは、２個のＲ^２０部分は結合して５または６員のアリール環、シクロアルキル環、ヘテロシクレニル環、ヘテロシクリル環またはヘテロアリール環を形成し、前記５または６員のアリール環、シクロアルキル環、ヘテロシクレニル環、ヘテロシクリル環およびヘテロアリール環は環Ｄに縮合し、その縮合環は任意に０〜４個のＲ^２１部分で置換されており；
Ｒ^２１部分は同一でも異なっていてもよく、各々が独立に、Ｈ、アルキル、アルケニル、アルキルアリール、アルキニル、アルコキシ、アルキルアミノ、シアノ、シクロアルキル、ホルミル、ハロゲン、ハロアルキル、ヒドロキシアルキル、ニトロおよびトリフルオロメトキシからなる群から選択され；
Ｙは、−ＣＨ_２−、−ＣＨ_２ＣＨ_２−、−ＣＨ（ＣＨ_３）−、−ＣＨ_２ＣＨ_２Ｏ−、−ＣＨ（ＣＨ_２ＯＨ）−、−ＣＨ（ＣＨ_２ＯＣＨ_２−フェニル）−、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）ＣＨ_２−および−ＣＨ（Ｃ＝Ｏ）Ｏ−アルキル−からなる群から選択され；
ｍは０〜２であり；
ｎは０〜２であり；
ｑは１または２であり；および
ｒは１または２である。

And -OSO ₂ (R ³¹ ); or two R ²⁰ moieties joined to form a 5 or 6 membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring And the 5- or 6-membered aryl ring, cycloalkyl ring, heterocyclenyl ring, heterocyclyl ring and heteroaryl ring are fused to ring D, and the fused ring is optionally substituted with 0 to 4 R ²¹ moieties. ;
The R ²¹ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro and tri Selected from the group consisting of fluoromethoxy;
Y _{is, -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 - is selected from the group consisting of;
m is 0-2;
n is 0-2;
q is 1 or 2; and r is 1 or 2.

  Another embodiment of the invention relates to a method wherein the compound of formula 1 is represented by structural formulas 2-11 below.

式中：
Ｒ^８部分は同一でも異なっていてもよく、各々が独立に、Ｈ、アルキル、アルケニル、アリールアルキル、シクロアルキル、−（ＣＨ_２）_ｑＯＨ、−（ＣＨ_２）_ｑＯＲ^３１、−（ＣＨ_２）_ｑＮＨ_２、−（ＣＨ_２）_ｑＮＨＲ^３１、−（ＣＨ_２）_ｑＣ（＝Ｏ）ＮＨＲ^３１、−（ＣＨ_２）_ｑＳＯ_２Ｒ^３１、−（ＣＨ_２）_ｑＮＳＯ_２Ｒ^３１、−（ＣＨ_２）_ｑＳＯ_２ＮＨＲ^３１および−Ｃ（＝Ｏ）−アリール−ハロゲンからなる群から選択され；
Ｒ^９部分は同一でも異なっていてもよく、各々が独立に、Ｈ、アルキル、シクロアルキル、−Ｃ（＝Ｏ）Ｎ（Ｈ）Ｒ^３０、−Ｃ（＝Ｏ）ＯＲ^３０、−Ｃ（＝Ｏ）アルキル、−（ＣΗ_２）_ｑＯＨ、−（ＣＨ_２）_ｑＯＲ^３１、−（ＣＨ_２）_ｑＮＨ_２、−（ＣＨ_２）_ｑＮＨＲ^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）および−ＳＯ_２Ｎ（Ｈ）Ｒ^３０からなる群から選択され；
ＬはＣまたはＮであり；
式４の

In the formula:
The R ⁸ moieties may be the same or different and each is independently 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, Selected from the group consisting of — (CH ₂ ) _q SO ₂ NHR ³¹ and —C (═O) -aryl-halogen;
The R ⁹ moieties may be the same or different and each is independently 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) the group consisting of ^{R 30} Selected from;
L is C or N;
Equation 4

は、単結合または二重結合であり；
式９のＸは、Ｎ、ＯまたはＳであり；
ｐは０〜４であり；および
ｍ、ｎ、ｑ、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^２０およびＹは、請求項１に定義する通りである。

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 this invention is that R ^{3 in} formulas 2-11 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, —N (R ³⁰ ) ₂ , —OR ^30, and —CF _3. On how to be.

Another embodiment of this invention is that R ^{6 in} formulas 2-11 is H, alkyl, halogen, hydroxyalkyl, —CN, —N (R ³⁰ ) ₂ , —OR ³⁰ , —N═CH-alkyl, It relates to a process selected from the group consisting of —NR ³⁰ C (═O) alkyl and —NR ³⁰ C (═O) N (R ³⁰ ) ₂ .

Another embodiment of this invention is that the R ⁹ moieties in formulas 2-11 are the same or different and each is independently 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) - Shikuropu Propyl _{-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, It relates to a method selected from the group consisting of = S and = O.

Another embodiment of this invention is directed to a method wherein R ^{10 in} formulas 2-11 is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl.

Another embodiment of this invention is directed to a method wherein R ^{11 in} formulas 2-11 is selected from the group consisting of H, alkyl, hydroxyalkyl, and carbonyl.

Another embodiment of the present invention, ^{R 12} in the formula 2-11 is, H, to a method selected from the group consisting of _-CH 3, CN or _-CH 2 CH _3.

Another embodiment of the present invention is that the R ²⁰ moieties in formulas 2-11 may be the same or different, each independently H, alkyl, cycloalkyl, amino, halogen,

および−ＯＳＯ_２（Ｒ^３１）からなる群から選択され；あるいは、２個のＲ^２０部分は結合して５または６員のアリール環、シクロアルキル環、ヘテロシクレニル環、ヘテロシクリル環またはヘテロアリール環を形成し、前記５または６員のアリール環、シクロアルキル環、ヘテロシクレニル環、ヘテロシクリル環およびヘテロアリール環は環Ｄに縮合し、その縮合環は任意に０〜４個のＲ^２１部分で置換されており；および
Ｒ^２１部分は同一でも異なっていてもよく、各々が独立に、Ｈ、アルキル、アルケニル、アルキルアリール、アルキニル、アルコキシ、アルキルアミノ、シアノ、シクロアルキル、ホルミル、ハロゲン、ハロアルキル、ヒドロキシアルキル、ニトロおよびトリフルオロメトキシからなる群から選択される、方法に関する。

And -OSO ₂ (R ³¹ ); or two R ²⁰ moieties joined to form a 5 or 6 membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring And the 5- or 6-membered aryl ring, cycloalkyl ring, heterocyclenyl ring, heterocyclyl ring and heteroaryl ring are fused to ring D, and the fused ring is optionally substituted with 0 to 4 R ²¹ moieties. And R ²¹ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro; And a method selected from the group consisting of trifluoromethoxy About.

Another embodiment of this invention is that the R ²⁰ moieties in formulas 2-11 may be the same or different and each independently represents 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,

からなる群から選択され、あるいは、２個のＲ^２０部分は結合して５または６員のアリール環、シクロアルキル環、ヘテロシクレニル環、ヘテロシクリル環またはヘテロアリール環を形成し、前記５または６員のアリール環、シクロアルキル環、ヘテロシクレニル環、ヘテロシクリル環およびヘテロアリール環は環Ｄに縮合し、その縮合環は任意に０〜４個のＲ^２１部分で置換されており；
Ｒ^２１部分は同一でも異なっていてもよく、各々が独立に、Ｈ、アルキル、アルケニル、アルキルアリール、アルキニル、アルコキシ、アルキルアミノ、シアノ、シクロアルキル、ホルミル、ハロゲン、ハロアルキル、ヒドロキシアルキル、ニトロおよびトリフルオロメトキシからなる群から選択される、方法に関する。

Or the two R ²⁰ moieties are joined to form a 5 or 6 membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring, said 5 or 6 membered The aryl, cycloalkyl, heterocyclenyl, heterocyclyl and heteroaryl rings are fused to Ring D, which is optionally substituted with 0-4 R ²¹ moieties;
The R ²¹ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro and tri It relates to a process selected from the group consisting of fluoromethoxy.

  Another embodiment of this invention is directed to a method wherein L in formulas 2-11 set forth above is carbon.

  Another embodiment of this invention is directed to a method wherein L in formulas 2-11 set forth above is nitrogen.

Another embodiment of the present invention is that Y in the formulas 2 to 11 shown above is —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 - To a method selected from the group consisting of

Another embodiment of this invention is that R ^{3 in} formulas 2-11 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, —N (R ³⁰ ) ₂ , —OR ^30, and —CF _3. Is;
R ⁶ is 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 selected from the group;
The R ⁹ moieties may be the same or different and each is independently 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) the group consisting of ^{R 30} Selected from;
R ¹⁰ is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl and carbonyl;
The R ²⁰ moieties may be the same or different and each is independently H, alkyl, cycloalkyl, amino, halogen,

および−ＯＳＯ_２（Ｒ^３１）からなる群から選択され；あるいは、２個のＲ^２０部分は結合して５または６員のアリール環、シクロアルキル環、ヘテロシクレニル環、ヘテロシクリル環またはヘテロアリール環を形成し、前記５または６員のアリール環、シクロアルキル環、ヘテロシクレニル環、ヘテロシクリル環およびヘテロアリール環は環Ｄに縮合し、その縮合環は任意に０〜４個のＲ^２１部分で置換されており；
Ｒ^２１部分は同一でも異なっていてもよく、各々が独立に、Ｈ、アルキル、アルケニル、アルキルアリール、アルキニル、アルコキシ、アルキルアミノ、シアノ、シクロアルキル、ホルミル、ハロゲン、ハロアルキル、ヒドロキシアルキル、ニトロおよびトリフルオロメトキシからなる群から選択され；
Ｙは、−ＣＨ_２−、−ＣＨ_２ＣＨ_２−、−ＣＨ（ＣＨ_３）−、−ＣＨ_２ＣＨ_２Ｏ−、−ＣＨ（ＣＨ_２ＯＨ）−、−ＣＨ（ＣＨ_２ＯＣＨ_２−フェニル）−、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）ＣＨ_２−および−ＣＨ（Ｃ＝Ｏ）Ｏ−アルキル−からなる群から選択され；
ｍは０〜２であり；
ｎは０〜２であり；
ｑは１または２であり；および
ｒは１または２である、方法に関する。

And -OSO ₂ (R ³¹ ); or two R ²⁰ moieties joined to form a 5 or 6 membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring And the 5- or 6-membered aryl ring, cycloalkyl ring, heterocyclenyl ring, heterocyclyl ring and heteroaryl ring are fused to ring D, and the fused ring is optionally substituted with 0 to 4 R ²¹ moieties. ;
The R ²¹ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro and tri Selected from the group consisting of fluoromethoxy;
Y _{is, -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 - is selected from the group consisting of;
m is 0-2;
n is 0-2;
q is 1 or 2, and r is 1 or 2.

Another embodiment of this invention is directed to a method wherein the compound or pharmaceutically acceptable salt, solvate or ester thereof is selected from the group consisting of: For some compounds, human IC ₅₀ values (in nM) are listed (in parentheses below the structure).

本発明の別の実施形態は、化合物が以下の表１に示す化合物（またはその薬学的に許容される塩、溶媒和物またはエステル）のリストから選択される方法に関する。この表１の化合物に関しては、ＩＣ_５０の評価を一緒に示す。ＩＣ_５０値は、約２５ナノモル濃度（ｎＭ）未満のＩＣ_５０値を「Ａ」、約２５〜約１００ｎＭの範囲のＩＣ_５０値を「Ｂ」、および約１００ｎＭを超えるＩＣ_５０値を「Ｃ」と評価した。たとえば、化合物番号１のＩＣ_５０値は、０．２ｎＭである。

Another embodiment of the invention relates to a method wherein the compound is selected from the list of compounds (or pharmaceutically acceptable salts, solvates or esters thereof) shown in Table 1 below. For this compound in Table 1, the IC ₅₀ rating is shown together. IC ₅₀ values are “A” for IC ₅₀ values less than about 25 nanomolar (nM), “B” for IC ₅₀ values in the range of about 25 to about 100 nM, and “C” for IC ₅₀ values above about 100 nM. It was evaluated. For example, the IC ₅₀ value for Compound No. 1 is 0.2 nM.

本発明の別の実施形態は、式１に記載の化合物が精製された形である方法に関する。

Another embodiment of this invention is directed to a method wherein the compound of formula 1 is in purified form.

  Another embodiment of the invention is a pharmaceutical composition wherein at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or solvate thereof is combined with at least one pharmaceutically acceptable carrier. It relates to a method comprising an ester.

  In another embodiment of the invention, the pharmaceutical composition comprises, in addition to the compound of formula 1, at least one other drug, agent, drug, antibody and / or inhibitor that treats a CXCR3 chemokine receptor mediated disease. Further comprising the method.

  When a combination therapy is administered to a patient in need of administration of the combination therapy, the combined therapeutic agent or the pharmaceutical composition containing the therapeutic agent may be any, for example, sequentially, simultaneously, together, together, etc. In the order. The amounts of the various active ingredients in such combination therapies may be different (different dosages) or the same (same dosage). Thus, by way of non-limiting illustration, the compound of Formula 1 and another therapeutic agent may be present in a fixed amount (dosage) in a single dosage unit (eg, capsule, tablet, etc.). . A commercial example of such a single dosage unit containing a fixed amount of two active compounds is VYTORIN® (commercially available from Merck Schering-Plough Pharmaceuticals, Kenilworth, New Jersey).

  In yet another embodiment, the present invention discloses a method for preparing a pharmaceutical composition comprising a heterocyclic substituted piperazine compound of the invention of formula 1 as an active ingredient. The pharmaceutical compositions and methods of the present invention generally comprise the intended dosage form, ie, an oral tablet, capsule (either solid, semi-solid or liquid), powder for construction, oral gel, elixir. Appropriate carrier materials appropriately selected for the agent, dispersible granules, syrup, suspension, etc., and the active ingredient are mixed and administered according to conventional medical practice. For example, for oral administration in the form of a tablet or capsule, the active ingredient of the drug may be lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid form), etc. It may be combined with any pharmaceutically acceptable oral non-toxic, inert carrier. In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may be added to the mixture. Powders and tablets may constitute from about 5 to about 95 percent of the composition of the invention. Suitable binders include starches, gelatin, natural sugars, corn sweeteners, natural or synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycols and waxes. Lubricants that can be used in the above dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include starch, methylcellulose, guar gum and the like. Moreover, you may include a sweetening agent, a flavoring agent, and a preservative as needed. Some of the above terms are discussed in detail below, namely disintegrants, diluents, lubricants, binders and the like.

  In addition, the compositions of the present invention can be formulated in sustained release form to control the release rate of one or more optional components or active ingredients in order to optimize therapeutic effects, such as anti-inflammatory activity. Also good. Suitable dosage forms for sustained release are layered tablets containing layers with different disintegration rates, or a controlled release polymer matrix impregnated with active elements into tablet form, or a porous polymer matrix so impregnated or encapsulated Capsules containing

  Liquid form preparations include solutions, suspensions and emulsions. For example, water for parenteral injection or water-propylene glycol solution can be mentioned. Alternatively, sweeteners and opacifiers may be added to oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

  Aerosol formulations suitable for inhalation include liquid and pulverulent solids and may be combined with a pharmaceutically acceptable carrier such as an inert compressed gas, eg 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 component is dispersed homogeneously therein, as by stirring or similar mixing. The homogeneous molten mixture is then poured into convenient sized molds and allowed to cool and solidify.

  In addition, some solid form preparations are intended to be converted into liquid form preparations immediately before use in oral administration or parenteral administration. Liquid forms include solutions, suspensions and emulsions.

  Furthermore, the compounds of the present invention may be capable of transdermal delivery. The transdermal composition may be in the form of a cream, lotion, aerosol and / or emulsion, and in such a case may be included in a matrix-type or reservoir-type transdermal patch that is standard in the art.

  Preferably the compounds of the invention are administered orally.

  Preferably, the medicinal product is in unit dosage form. In such form, the medicament is subdivided into suitably sized unit doses containing appropriate quantities of the active component, eg, an effective amount to achieve the desired purpose.

  The amount of the active composition of the present invention in a unit dose formulation will usually be from about 1.0 milligrams to about 1,000 milligrams, preferably from about 1.0 to about 950 milligrams, more preferably about 1 depending on the particular application. It may be varied or adjusted from 0.0 to about 500 milligrams, generally from about 1 to about 250 milligrams. The actual dosage used may vary depending on the patient's age, sex, weight and severity of the condition being treated. Such techniques are well known to those skilled in the art.

  In general, the human oral dosage form containing the active ingredients may be administered once or twice daily. The amount and frequency of administration will be adjusted according to the judgment of the attending clinician. A generally recommended daily dosage regimen for oral administration may range from about 1.0 milligrams to about 1,000 milligrams per day in single or divided doses.

  In the following, some useful terms are explained.

  Capsules refer to special containers or enclosures made of methylcellulose, polyvinyl alcohol or modified gelatin or starch so that a composition containing the active ingredient can be retained or contained. Hard shell capsules are generally made from a blend of bone gelatin and pork skin gelatin with relatively high gel strength. The capsule itself may contain small amounts of pigments, opacifiers, plasticizers and preservatives.

  A tablet refers to a compressed or molded solid dosage form containing the active ingredients and suitable diluents. Tablets can be prepared by compressing a mixture or a granulated product obtained by wet granulation, dry granulation or compaction.

  An oral gel refers to a gel in which an active ingredient is dispersed or solubilized in a hydrophilic semi-solid matrix.

  Powder for composition refers to a powder blend that contains the active ingredient and a suitable diluent and can be suspended in water or juice.

  Diluent refers to substances that primarily make up the majority of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition ranges 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%, even more preferably from about 12 to about It may be in the range of 60%.

  A disintegrant refers to a material added to help the composition break (disintegrate) and release the drug. As preferred disintegrants, starches; “cold water soluble” modified starches such as sodium carboxymethyl starch; natural or synthetic gums such as locust bean, karaya, gour, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystals Cross-linked microcrystalline cellulose such as basic cellulose and croscarmellose sodium; alginates such as alginic acid and sodium alginate; clays such as bentonite; and foamable mixtures. The amount of disintegrant in the composition may range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.

  A binder refers to a substance that acts as an “adhesive” by binding or “adhering” powders in a formulation to form granules and adhere. Adding a binder increases the adhesive strength already present 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; substances obtained from seaweed such as alginic acid, sodium alginate and calcium alginate; methylcellulose And cellulose derivative materials such as sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as aluminum magnesium silicate. The amount of binder in the composition may range from about 2 to about 20%, more preferably from about 3 to about 10%, even more preferably from about 3 to about 6% by weight of the composition.

  Lubricant refers to a substance that enables tablets or granules after compression to be taken out of a mold or die by reducing friction or wear in addition to the dosage form. Suitable lubricants include metal stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting wax; and sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol and d and water-soluble lubricants such as' l-leucine. Since the lubricant must be present on the surface of the granule and between this surface and the part of the tablet press, it is most often added at the final step before compression. The amount of lubricant in the composition ranges 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. It may be.

  A glidant is a material that prevents solidification of the granulated product, improves flow characteristics, and makes the flow smooth and uniform. Suitable glidants include silicon dioxide and talc. The amount of glidant in the composition may range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.

  A colorant is an excipient that imparts color to a composition or dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed on a suitable adsorbent such as clay or aluminum oxide. The amount of colorant may range 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 an active ingredient or therapeutic portion of a drug is absorbed into the systemic circulation from a 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 granules produced by compression, or wet methods or other special procedures. Conventional methods for producing other forms for administration such as capsules, suppositories and the like are also known.

  It will be apparent to those skilled in the art that many modifications, variations and variations can be made in material and method to the present disclosure. Such modifications, variations and changes are intended to be within the spirit and scope of the invention.

  As mentioned above, the present invention also includes tautomers, enantiomers and other stereoisomers of the present compounds. Thus, as one skilled in the art knows, certain imidazole compounds may exist as tautomers. Such variations are intended to be within the scope of the present invention. Certain compounds of the present invention may exist in various crystalline or amorphous forms. Any physical form of the invention is contemplated.

  In the present invention, the compound of the present invention containing atomic isotopes in an unnatural ratio (ie, “radiolabeled compound”), regardless of whether its use is as a therapeutic, diagnostic, or research reagent, Intended.

  Another embodiment of the present invention is the use of a pharmaceutical composition as disclosed above for treating a disease of a CXCR3 chemokine receptor mediated disease in a patient in need of treatment, wherein the therapeutically effective amount of at least one Disclosed is a use comprising administering to a patient a compound of Formula 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

  In another embodiment, the method combines (a) a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate thereof in combination with a pharmaceutically acceptable carrier. Or (b) administering to a patient simultaneously or sequentially with at least one other drug, agent, drug, antibody and / or inhibitor for treating a CXCR3 chemokine receptor mediated disease .

  In another embodiment, at least one compound of Formula 1 binds to the CXCR3 receptor.

  The method comprises (a) at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate or ester thereof in a therapeutically effective amount, (b) a disease modifying anti-rheumatic agent; Steroidal anti-inflammatory drugs; COX-2 selective inhibitors; COX-1 inhibitors; immunosuppressants (such as cyclosporine and methotrexate); steroids (such as corticosteroids such as glucoluticoids); PDE-IV inhibitors 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 A biological response modifier; simultaneous or sequential with at least one drug selected from the group consisting of anti-inflammatory and therapeutic agents Administration may further be included.

  Another embodiment of the invention relates to a method wherein at least one drug of (b) is a chemokine inhibitor.

  Another embodiment of the invention relates to a method wherein at least one drug of (b) is a chemokine inhibitor that is a CXCR2 receptor antagonist or agonist.

  Another embodiment of the invention is that the CXCR3 chemokine receptor mediated disease is chronic obstructive pulmonary disease (COPD), asthma, fibrotic disease, systemic lupus erythematosus (SLE) and graft-versus-host disease (GVHD) To a method selected from the group consisting of

  Another embodiment of the invention relates to a method 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 invention relates to a method wherein the CXCR3 chemokine receptor mediated disease is systemic lupus erythematosus (SLE).

  Another embodiment of the present invention is a method wherein the CXCR3 chemokine receptor mediated disease is selected from the group consisting of chronic obstructive pulmonary disease (COPD) and asthma, the method of treatment comprising a compound of formula 1 And simultaneously or sequentially administering at least one compound selected from the group consisting of β-agonists, muscarinic receptor antagonists, PDE4 inhibitors and corticosteroids.

  Another embodiment of the present invention is that the CXCR3 chemokine receptor mediated disease is systemic lupus erythematosus (SLE), wherein the method of treatment is performed simultaneously or sequentially with a compound of formula 1 and an immunosuppressant and It relates to a method comprising administering at least one compound selected from the group consisting of corticosteroids.

  In another embodiment, the compound of Formula 1 is 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-to-host reaction, allograft rejection, acute respiratory distress syndrome, delayed hypersensitivity reaction, atherosclerosis, cerebral ischemia, osteoarthritis, multiple sclerosis, angiogenesis , Osteoporosis, gingivitis, respiratory virus, herpes virus, hepatitis virus, HIV, Kaposi's sarcoma-related virus, meningitis, cystic fibrosis, early labor, cough, pruritus, multiple organ dysfunction Psoriatic arthritis, herpes zoster, encephalitis, traumatic brain injury, CNS tumor, interstitial pneumonitis, hypersensitivity, crystal-induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis , Eye inflammation, corneal neovascularization, polymyositis, acne, esophagitis, glossitis, airflow obstruction, bronchiectasis, bronchiolitis, obstructive bronchitis, chronic bronchitis, dyspnea, Emphysema, hypercapnia, hyperinflation, hypoxemia, hyperoxia-induced inflammation, hypoxia, pulmonary fibrosis, pulmonary hypertension, peritonitis due to continuous ambulatory peritoneal dialysis, granulocyte ericia Disease, sarcoidosis, peripheral airway disease, ventilation and blood flow mismatch, wheezing, cold, gout, alcoholic liver disease, lupus, periodontitis, cancer, transplantation reperfusion injury, early transplant rejection, airway hyperresponsiveness, allergy Contact dermatitis, allergic nose Alopecia areata, autoimmune deafness, autoimmune hemolytic syndrome, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian dysfunction, autoimmune orchiditis, autoimmune thrombocytopenia, chronic inflammatory Demyelinating polyneuropathy, cirrhosis, dermatomyositis, diabetes, drug-induced autoimmunity, endometriosis, fibrosis, gastritis, Goodpasture syndrome, Graves' disease, Guillain-Barre disease, Hashimoto's thyroiditis, hepatitis-related self Immunity, HIV-related autoimmune syndrome and blood disorders, hypophytis, interstitial cystitis, juvenile arthritis, Langerhans' cell histocytosis, lichen planus, metal-mediated autoimmunity , Myocarditis, myositis, neuropathy, nephritis syndrome, optic neuritis, pancreatitis, post-infection autoimmunity, primary Bile cirrhosis, reactive arthritis, ankylosing spondylitis, Reiter syndrome, reperfusion injury, scleritis, scleroderma, secondary hematological signs of autoimmune disease, silicone implant related autoimmune disease, It can be used to treat a disease selected from the group consisting of Sjogren's syndrome, systemic lupus erythematosus, transverse myelitis, tubulointerstitial nephritis, uveitis, and vitiglio.

  Although the present invention has been described in conjunction with the specific embodiments described above, many alternatives, modifications and variations will be apparent to those skilled in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

  All documents / references (eg, patent gazettes, registered patents or scientific journal articles) mentioned in this application are incorporated by reference in their entirety.

Claims (58)

Chronic obstructive pulmonary disease (COPD), asthma, sarcoidosis, systemic lupus erythematosus (SLE), ankylosing spondylitis, fibrotic disease, pulmonary fibrosis, alopecia areata, scleroderma, lichen planus lupus erythematosus, disc In a patient in need of treatment for a CXCR3 chemokine receptor-mediated disease selected from the group consisting of erythematosus, dermatomyositis, Behcet's disease, Wegener's disease, atopic dermatitis and graft-versus-host disease (GVHD) Comprising administering to the patient a therapeutically effective amount of at least one compound having the general structure shown in Formula 1 below, or a pharmaceutically acceptable salt, solvate or ester thereof: :

In the formula:
G represents a 5-membered heteroaryl ring or heterocyclenyl ring, the heteroaryl ring or heterocyclenyl ring comprising at least one —C═N— moiety as part of the heteroaryl ring or heterocyclenyl ring, wherein the heteroaryl The ring or heterocyclenyl ring optionally further comprises one or more moieties selected from the group consisting of N, N (→ O), O, S, S (O) and S (O ₂ ) on the ring. The moieties may be the same or different and each is independently selected, and the heteroaryl or heterocyclenyl ring may be (i) unsubstituted or (ii) optionally independently 1 Or substituted with one or more R ⁹ substituents on a plurality of ring carbon atoms, or one or more R ^{8 on} one or more ring nitrogen atoms. May be substituted with substituents, and the R ⁸ and R ⁹ substituents may be the same or different;
The R ³ and R ⁶ moieties may be the same or different and each is independently 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 Selected from the group consisting of (R ³⁰ ) ₂ and —N (R ³⁰ ) C (═O) R ³¹ ;
The R ⁸ moieties may be the same or different and each is independently 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 may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, arylalkyl, alkoxy, amidinyl, aryl, cycloalkyl, cyano, heteroaryl, heterocyclyl, hydroxyl,

Selected from the group consisting of:
The R ¹⁰ moieties may be the same or different and each is independently H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, alkylaryl, arylalkyl, —CO ₂ H, hydroxyalkyl, —C (═ Selected from the group consisting of 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 may be the same or different and each is independently H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, alkylaryl, arylalkyl, carboxamide, CO ₂ H, — (CH ₂ ) _q Selected from the group consisting of OH, — (CH ₂ ) _q OR ³¹ , —OR ³⁰ , halogen, ═O and —C (═O) R ³¹ ;
The R ¹² moieties may be the same or different and each is independently H, alkyl, —CN, —C (═O) N (R ³⁰ ) ₂ , — (CH ₂ ) _q OH, — (CH ₂ ) _q Selected from the group consisting of OR ³¹ and —S (O ₂ ) R ³¹ ;
Ring D is a 5- to 9-membered cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, heterocyclenyl ring or heterocyclyl ring, and 0 to 4 heteroatoms independently selected from O, S or N And ring D is unsubstituted or optionally substituted with 1 to 5 independently selected R ²⁰ moieties;
The R ²⁰ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, Aminoalkyl, amidinyl, aralkyl, aralkyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, Heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy,

Or two R ²⁰ moieties joined together to form a 5 or 6 membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl or heteroaryl ring, wherein the 5 or 6 A membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl or heteroaryl ring is fused to ring D, said fused ring optionally substituted with 0-4 R ²¹ moieties;
The R ²¹ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl , Aminoalkyl, amidinyl, aralkyl, aralkyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, carboxamide, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl , Heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy,

Selected from the group consisting of:
Y is a covalent bond, — (CR ¹³ R ¹³ ) _r —, —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 Selected from the group consisting of C (═O) — and — (CHR ¹³ ) _r N (H) C (═O) —; or Y is cycloalkyl, heterocyclenyl or heterocyclyl, wherein the cycloalkyl, heterocyclenyl or heterocyclyl Is fused with ring D;
The R ¹³ moieties may be the same or different and each is independently H, alkyl, alkylaryl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocyclenyl, heterocyclyl, spiroalkyl,

Selected from the group consisting of:
The R ³⁰ moieties may be the same or different and each is independently H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, -cycloalkylalkyl, CN, — (CH ₂ ) _q OH, — (CH ₂ ). _q O-alkyl, - _{(CH 2) q} O alkylaryl, - _{(CH 2) q} O aryl, - _{(CH 2) q} O aralkyl, - _{(CH 2) q} O _{cycloalkyl, - (CH 2) q NH} 2 , - _{(CH 2)} q NH _{alkyl, - (CH 2) q N} ( _{alkyl) 2, - (CH 2)} q NH alkyl aryl, - _{(CH 2)} q NH aryl, - _{(CH 2)} q NH aralkyl, - _{(CH 2)} q NH _{cycloalkyl, - (CH 2) q C} (= O) O- _{alkyl, - (CH 2) q C} (= O) NH -alkyl, - _{(CH 2) q} (= O) N _{(alkyl) 2, - (CH 2)} q C (= O) NH -alkyl _{aryl, - (CH 2) q C} (= O) NH _{aryl, - (CH 2) q C} (= O) NH aralkyl, — (CH ₂ ) _q C (═O) NH cycloalkyl, — (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 NSO} 2 _{aralkyl, - (CH 2) q NSO} 2 _{cycloalkyl, - (CH 2) q SO} 2 NH _{-alkyl, - (CH 2) q SO} 2 NH -alkyl aryl, _{- (CH 2) q SO 2} NH aryl, _{- (CH 2) q SO 2} NH aralkyl, _{- (CH 2) q SO 2} NH cycloalkyl, heterocyclenyl, is selected from the group consisting of heterocyclyl and heteroaryl;
The R ³¹ moieties may be the same or different and each is independently alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, — (CH ₂ ) _q OH, — (CH ₂ ) _q O alkyl, — (CH ₂ ) _q O alkylaryl, - _{(CH 2) q} O aryl, - _{(CH 2) q} O aralkyl, - _{(CH 2) q} O _{cycloalkyl, - (CH 2) q NH} 2, - (CH 2) q NH Alkyl, — (CH ₂ ) _q N (alkyl) ₂ , — (CH ₂ ) _q NH alkylaryl, — (CH ₂ ) _q NH aryl, — (CH ₂ ) _q NH aralkyl, — (CH ₂ ) _q NH cyclo _{alkyl, - (CH 2) q C} (= O) NH _{-alkyl, - (CH 2) q C} (= O) N ( _{alkyl) 2, - (CH 2)} q C (= O) NH alkylarylene _{, - (CH 2) q C} (= O) NH _{aryl, - (CH 2) q C} (= O) NH _{aralkyl, - (CH 2) q C} (= O) NH cycloalkyl, - _{(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 alkyl aryl, — (CH ₂ ) _q NSO ₂ aryl, — (CH ₂ ) _q NSO ₂ aralkyl, — (CH ₂ ) _q NSO ₂ cycloalkyl, — ( CH _{2) q} SO _{2 NH-alkyl, - (CH 2) q SO} 2 NH -alkyl _{aryl, - (CH 2) q SO} 2 NH _{aryl, - (CH 2) q SO} 2 NH aralkyl _{, - (CH 2) q SO} 2 NH cycloalkyl, heterocyclenyl, is selected from the group consisting of heterocyclyl and heteroaryl;
m is 0-4;
n is 0-4;
each q may be the same or different and each is independently selected from 1-5; and r is 1-4.
However, two adjacent double bonds do not exist in any ring, and when nitrogen is substituted with two alkyl groups, the two alkyl groups are arbitrarily bonded to each other to form a ring. Can be the way.   The method according to claim 1, wherein G represents a dihydroimidazole ring, an imidazole ring, a dihydrooxazole ring, an oxazole ring, a dihydrooxadiazole ring, an oxadiazole ring, a triazole ring or a tetrazole ring. Ring G is selected from the group consisting of:

Where

The method according to claim 1, wherein is a single bond or a double bond. The method of claim 1, wherein R ³ is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, —N (R ³⁰ ) ₂ , —OR ³⁰ and —CF ₃ . 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. Item 5. The method according to Item 4. R ⁶ is H, alkyl, halogen, hydroxyalkyl, —CN, —N (R ³⁰ ) ₂ , —OR ³⁰ , —N═CH-alkyl, —NR ³⁰ C (═O) alkyl and —NR ³⁰ C ( The method of claim 1, selected from the group consisting of ═O) N (R ³⁰ ) ₂ . 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. Item 7. The method according to Item 6. R ⁸ is 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 The method of claim 1, selected from the group consisting of (═O) -aryl-halogen. The R ⁹ moieties may be the same or different and each is independently 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) the group consisting of ^{R 30} The method of claim 1, wherein the method is selected from: The R ⁹ moieties may be the same or different and each is independently 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} ( _{H 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. The method of claim 1. The R ⁹ moieties may be the same or different, and each is independently 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, -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 - is selected from the group consisting of alkyl, The method of claim 10. The method of claim 1, wherein R ¹⁰ is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl. R ¹⁰ _is, H, -CH 3, selected from the group consisting of _-CH 2 CH ₃ and _-CH 2 _CH 2 _{CH 3,} m is 0-2, A method according to claim 12. The method of claim 1, wherein R ¹¹ is selected from the group consisting of H, alkyl, hydroxyalkyl, and carbonyl. The method of claim 14, wherein R ¹¹ is H or —CH ₃ . The method of claim 1, wherein R ¹² is selected from the group consisting of H, CN, —C (═O) N (R ³⁰ ) ₂ and alkyl. The method of claim 16, wherein R ¹² is selected from the group consisting of H, —CH ₃ , CN and —CH ₂ CH ₃ . The method of claim 1, wherein the ring atoms of ring D are independently C, N, O and S, and are substituted with 0 to 4 R ²⁰ moieties. Ring D is a 5-6 membered aryl ring, heteroaryl ring, a heterocyclenyl ring or heterocyclyl ring is substituted with 0-4 R ²⁰ moieties A method according to claim 1. The R ²⁰ moieties may be the same or different and each is independently H, alkyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylheteroaryl, alkylsulfinyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkoxy, Aryl, aryloxy, cyano, cycloalkyl, cycloalkenyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, trifluoromethyl, trifluoromethoxy,

The method of claim 1, wherein the method is selected from the group consisting of: The R ²⁰ moieties may be the same or different and each is independently H, alkyl, cycloalkyl, amino, halogen,

The method of claim 1, wherein the method is selected from the group consisting of: Two R ²⁰ moieties are joined together to form a 5 or 6 membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring, said 5 or 6 membered aryl, cycloalkyl ring The method of claim 1, wherein the heterocyclenyl ring, heterocyclyl ring, and heteroaryl ring are fused to Ring D, wherein the fused ring is optionally substituted with 0-4 R ²¹ moieties. The R ²⁰ moieties may be the same or different and each is independently 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 ,

The method of claim 1, wherein the method is selected from the group consisting of: The R ²¹ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro and tri The method of claim 1, wherein the method is selected from the group consisting of fluoromethoxy. Y represents — (CHR ¹³ ) _r —, — (CR ¹³ R ¹³ ) _r —, —C (═O) —, —CHR ¹³ C (═O) — and — (CHR ¹³ ) _r C (═O). The method of claim 1, wherein the method is selected from the group consisting of: Y _{is, -CH 2 -, - CH 2} CH 2 -, - CH (CH 3) -, - CH 2 CH 2 O -, - CH (CH 2 OH) -, - CH (CH 2 OCH 2 - phenyl) The method of claim 1, selected from the group consisting of —, —C (═O) —, —C (═O) CH ₂ —, and —CH (C═O) O-alkyl-.   The method of claim 1, wherein m is 0-2.   The method of claim 1, wherein n is 0-2.   The method of claim 1, wherein q is 1 or 2.   The method of claim 1, wherein r is 1 or 2. 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 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 selected from the group;
The R ⁹ moieties may be the same or different and each is independently 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 Selected;
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 5-6 membered aryl ring, heteroaryl ring, heterocyclenyl ring or heterocyclyl ring, substituted with 0-4 R ²⁰ moieties;
The R ²⁰ moieties may be the same or different and each is independently H, alkyl, cycloalkyl, amino, halogen,

And it is selected from the group consisting of -OSO ₂ ^{(R 31);} or, two of ^{R 20} moieties are joined together, 5 or 6 membered aryl ring, a cycloalkyl ring, heterocyclenyl ring, heterocyclyl or heteroaryl Forming a ring, the 5- or 6-membered aryl ring, cycloalkyl ring, heterocyclenyl ring, heterocyclyl ring and heteroaryl ring fused to ring D, the fused ring optionally substituted with 0-4 R ²¹ moieties Has been;
The R ²¹ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro and Selected from the group consisting of trifluoromethoxy;
Y _{is, -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 - is selected from the group consisting of;
m is 0-2;
n is 0-2;
2. The method of claim 1, wherein q is 1 or 2; and r is 1 or 2. Formula 1 is represented by Structural Formulas 2-11 below:

In the formula:
The R ⁸ moieties may be the same or different and each is independently 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, Selected from the group consisting of — (CH ₂ ) _q SO ₂ NHR ³¹ and —C (═O) -aryl-halogen;
The R ⁹ moieties may be the same or different and each is independently 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 Selected;
L is C or N;
Equation 4

Is a single bond or a double bond;
X in formula 9 is N, O or S;
The method of claim 1, wherein p is 0-4; and m, n, q, R ¹⁰ , R ¹¹ , R ¹² , R ²⁰ and Y are as defined in claim 1. R ³ is, H, alkyl, haloalkyl, hydroxyalkyl, ^halogen, -N _(R 30) ^2, is selected from the group consisting of ^{-OR 30} and -CF _3, The method of claim 32. R ⁶ is 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) is selected from the group consisting of _2, the method of claim 32. The R ⁹ moieties are the same or different and each is independently 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 , selected from the group consisting of —N (CH ₂ CH ₃ ) S (═O) ₂ -phenyl-alkyl, —N (H) S (═O) ₂ -alkyl, ═S and ═O. 33. The method according to 32. R ¹⁰ is, H, alkyl, aralkyl, selected from the group consisting of hydroxyalkyl and carbonyl method of claim 32. R ¹¹ is, H, alkyl, selected from the group consisting of hydroxyalkyl and carbonyl method of claim 32. R ¹² is, H, is selected from the group consisting of _-CH 3, CN or _-CH 2 CH _3, The method of claim 32. The R ²⁰ moieties may be the same or different and each is independently H, alkyl, cycloalkyl, amino, halogen,

And it is selected from the group consisting of -OSO ₂ ^{(R 31);} or, two of ^{R 20} moieties are joined together, 5 or 6 membered aryl ring, a cycloalkyl ring, heterocyclenyl ring, heterocyclyl or heteroaryl Forming a ring, the 5- or 6-membered aryl ring, cycloalkyl ring, heterocyclenyl ring, heterocyclyl ring and heteroaryl ring fused to ring D, the fused ring optionally substituted with 0-4 R ²¹ moieties Has been;
The R ²¹ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro and tri 35. The method of claim 32, selected from the group consisting of fluoromethoxy. The R ²⁰ moieties may be the same or different and each is independently 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 ,

Or two R ²⁰ moieties joined together to form a 5 or 6 membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring, wherein the 5 or 6 A membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl and heteroaryl ring is fused to Ring D, said fused ring optionally substituted with 0-4 R ²¹ moieties;
The R ²¹ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro and tri 40. The method of claim 39, selected from the group consisting of fluoromethoxy.   33. The method of claim 32, wherein L is carbon.   35. The method of claim 32, wherein L is nitrogen. Y _{is, -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 - is selected from the group consisting of the method of claim 32. 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 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 selected from the group;
The R ⁹ moieties may be the same or different and each is independently 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 Selected;
R ¹⁰ is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl and carbonyl;
The R ²⁰ moieties may be the same or different and each is independently H, alkyl, cycloalkyl, amino, halogen,

And it is selected from the group consisting of -OSO 2 _(R ^31); or, two of R ²⁰ moiety is bonded to a 5- or 6-membered aryl ring together, cycloalkyl ring, heterocyclenyl ring, heterocyclyl or heteroaryl ring The 5- or 6-membered aryl ring, cycloalkyl ring, heterocyclenyl ring, heterocyclyl ring and heteroaryl ring are fused to ring D, which is optionally substituted with 0-4 R ²¹ moieties. And;
The R ²¹ moieties may be the same or different and each is independently H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro and tri Selected from the group consisting of fluoromethoxy;
Y _{is, -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 - is selected from the group consisting of;
m is 0-2;
n is 0-2;
35. The method of claim 32, wherein q is 1 or 2; and r is 1 or 2. Said compound of formula I is:

Or the method of claim 1 selected from the group consisting of pharmaceutically acceptable salts, solvates or esters thereof.

46. The method of claim 45, selected from the group consisting of or a pharmaceutically acceptable salt, solvate or ester thereof.   The CXCR3 chemokine receptor mediated disease is selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, fibrotic disease, systemic lupus erythematosus (SLE) and graft-versus-host disease (GVHD); The method of claim 1.   2. The method of claim 1, wherein the CXCR3 chemokine receptor mediated disease is selected from the group consisting of chronic obstructive pulmonary disease (COPD) and asthma.   2. The method of claim 1, wherein the CXCR3 chemokine receptor mediated disease is systemic lupus erythematosus (SLE). Chronic obstructive pulmonary disease (COPD), asthma, sarcoidosis, systemic lupus erythematosus (SLE), ankylosing spondylitis, fibrotic disease, pulmonary fibrosis, alopecia areata, scleroderma, lichen planus lupus erythematosus, disc In a patient in need of treatment for a CXCR3 chemokine receptor-mediated disease selected from the group consisting of erythematosus, dermatomyositis, Behcet's disease, Wegener's disease, atopic dermatitis and graft-versus-host disease (GVHD), A method for treating a disease comprising a therapeutically effective amount of a compound of formula

Or administering a pharmaceutically acceptable salt or solvate thereof to the patient.   52. The method of claim 51, wherein the salt is a mesylate salt.   Administering at least one other drug, agent, drug, antibody and / or inhibitor simultaneously or sequentially in combination with a pharmaceutically acceptable carrier to treat a CXCR3 chemokine receptor-mediated disease. The method of claim 1, further comprising:   2. The method of claim 1, wherein the compound binds to a CXCR3 receptor.   Non-steroidal anti-inflammatory agent; COX-2 selective inhibitor; COX-1 inhibitor; immunosuppressive agent; steroid; PDE-IV inhibitor, anti-TNF-α compound, TNF-α- Group consisting of convertase inhibitor, cytokine inhibitor, MMP inhibitor, glucocorticoid, corticosteroid, chemokine inhibitor, CB2 selective inhibitor, p38 inhibitor, biological response modifier; anti-inflammatory drug and therapeutic agent The method of claim 1, further comprising administering at least one drug selected from: simultaneously or sequentially.   55. The method of claim 54, wherein the at least one drug is a chemokine inhibitor.   56. The method of claim 55, wherein the chemokine inhibitor is a CXCR2 receptor agonist or antagonist.   49. The method of claim 48, further comprising administering simultaneously or sequentially at least one compound selected from the group consisting of a beta-agonist, a muscarinic receptor antagonist, a PDE4 inhibitor and a corticosteroid.   50. The method of claim 49, further comprising administering simultaneously or sequentially at least one compound selected from the group consisting of an immunosuppressant and a corticosteroid.