The present invention relates to a sulfonamide derivative which is useful as an active ingredient of pharmaceutical preparations. The sulfonamide derivatives of the pre- sent invention have CCR3 (CC type chemokine receptor 3) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with CCR3 activity, in particular for the treatment of asthma, atopic dermatitis, allergic rhinitis and other inflammatory/immunological disorders.

BACKGROUND ART Chemokines are chemotactic cytokines of which major functions are migration of inflammatory cells that express relevant chemokine receptors on their surfaces to sites of inflammation, and activation of inflammatory cells. There are two classes of chemokines, C--X--C (. alpha. ) and C--C (i), depending on whether the first two cysteines are separated by a single amino acid (C--X--C) or are adjacent (C--C).

One of the C-C family of chemokines, eotaxin, is an 8.4 kDa (74 amino acid) poly- peptide and binds with high affinity solely to the receptor CCR3. In vitro and in vivo eotaxin causes chemotaxis of inflammatory cells expressing CCR3 [Elsner J., Hochstetter R., Kimming D. and Kapp A.: Human eotaxin represents a potent activator of the respiratory burst of human eosinophils. Eur. J. Immunol., 26: 1919- 1925,1996.].

The chemokine receptor CCR3 is a G protein-coupled, seven transmembrane domain receptor (GPCR) which binds to known ligands, in addition to eotaxin, including eotaxin-2 (CCL24), RANTES (CCL5), MCP-3 (CCL7) and MCP-4 (CCL13). CCR3 is expressed on inflammatory cells relevant to the chronic asthma pathology. Such inflammatory cells include Eosinophils [Sabroe I., Conroy D. M., Gerard N. P. , Li Y.,

Collins P. D. , Post T. W. , Jose P. J., Williams T. J., Gerard C. J. , Ponath P. D. J. Immunol. 161: 6139-6147, 1998], basophils [Uguccioni M. , Mackay C. R., Ochensberger B. , Loetscher P. , Rhis S. , LaRosa G. J. , Rao P. , Ponath P. D. , Baggiolini M. , Dahinden C. A. J. Clin. Invest. 100: 1137-1143,1997], Th2 cells [Sallusto F., Mackay C. R., Lanzavecchia A. Science. 277: 2005-2007,1997], alveolar macrophages [Park I. W. , Koziel H. , Hatch W. , Li X. , Du B. , Groopman J. E. Am. J.

Respir. Cell Mol. Biol. 20: 864-71,1999] and mast cells [Oliveira S. H. and Lukacs N. W. Inflamm. Res. 50: 168-174. 2001]. Very recently, it was reported that BEAS- 2B, an epithelial cell line, stimulated with TNF-a and IFN-y, expressed CCR3 [Stellato C. , Brummet M. E. , Plitt J. R., Shahabuddin S. , Baroody F. M. , Liu M., Ponath P. D. , and Beck L. A. J. Immunol., 166: 1457-1461,2001.].

In animal models, eotaxin-knockout mice showed decreased eosinophilia after antigen challenge [Rothenberg M. E. , MacLean J. A., Pearlman E. , Luster A. D. and Leder P. J. Exp. Med. , 185: 785-790, 1997] and in IL5-/eotaxin-double knock-out mice there is no eosinophilia or AHR in response to antigen challenge [Foster P. S., Mould A. W. , Yang M. , Mackenzie J. , Mattes J. , Hogan S. P. , Mahalingam S., Mckenzie A. N. J. , Rothenberg M. E. , Young I. G., Matthaei K. I. and Webb D. C.

Immunol. Rev. , 179,173-181, 2001]. Clinically, expression of eotaxin and CCR3 mRNA and protein is observed in the lung tissues of atopic asthmatics and is associated with AHR, reduced FEVl and lung eosinophilia [Ying S. , Robin D. S., Meng Q. , Rottman J. , Kennedy R., Ringler D. J. , Mackay C. R. , Daugherty B. L., Springer M. S. , Durham S. R. , Williams T. J. and Kay A. B.: Enhanced expression of eotaxin and CCR3 mRNA and protein in atopic asthma. Association with airway hyperresponsiveness and predominant colocalization of eotaxin mRNA to bronchial epithelial and endothelial cells. Eur. J. Immunol., 27,3507-3516, 1997; Lamkhioued Renzi P. M. , AbiYounes S. , GarciaZepada E. A. , Allakhverdi Z. , Ghaffar O., Rothenberg M. D. , Luster A. D. and Hamid Q.: Increased expressions of eotaxin in bronchoalveolar lavage and airways of asthmatic contributes to the chemotaxis of eosinophils to the site of inflammation. J. Immunol., 159: 4593-4601, 1997 ; Jahnz- Royk K., Plusa T. and Mierzejewska J.: Eotaxin in serum of patients with asthma or

chronic obstructive pulmonary disease: relationship with eosinophil cationic protein and lung function. Mediators of Inflammation, 9: 175-179,2000]. In addition, in allergic rhinitis, CCR3-expressing Th2 lymphocytes co-localize with eosinophils in nasal polyps in close proximity to eotaxin-expressing cells [Gerber B. O., Zanni M. P., Uguccioni M. , Loetscher M. , Mackay C. R. , Pichler W. J., Yawalkar N., Baggiolini M. and Moser B.: Functional expression of the eotaxin receptor CCR3 in T lymphocytes co-localizing with eosinophils. CURRENT BIOLOGY 7: 836-843,1997]. Moreover, viral infections (RSV, influenza virus) which are known risk factors in asthma, result in increased eotaxin expression in lung tissue which is correlated with tissue eosinophilia [Matsukura S. , Kokubo F., Kubo H. , Tomita T., Tokunaga H. , Kadokura M. , Yamamoto T. , Kuroiwa Y. , Ohno T. , Suzaki H. and Adachi M.: Expression of RANTES by normal airway epithelial cells after influenza virus A infection. Am. J.

Respir. Cell and Mol. Biol. , 18: 255-264,1998 ; Saito T. , Deskin R. W. , Casola A., Haeberle H. , Olszewska B. , Ernest P. B., Alam R. , Ogra P. L. and Garofalo R.: Selective regulation of chemokine production in human epithelial cells. J. Infec. Dis., 175 : 497-504,1997].

Thus the binding of CCR3 and related chemokine including eotaxin has been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis, and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and athero- sclerosis. It is also implicated that binding of CCR3 and related chemokine is an important factor of virus infections including HIV [ (Marone G, de Paulis A, Florio G, Petraroli A, Rossi F, Triggiani M.: Int Arch Allergy Immunol 2001 Jun; 125 (2)/89- 95), (Li Y et al. , : Blood 2001 Jun 1 ; 97 (11): 3484-90), and (Marone G, Florio G, Petraroli A, Triggiani M, de Paulis A: Trends Immunol 2001 May ; 22 (5): 229-32) ], lung granuloma (Ruth JH, Lukacs NW, Warmington KS, Polak TJ, Burdick M, Kunkel SL, Stricter RM, Chensue SW: J Immunol 1998 Oct 15; 161 (8): 4276-82), and Alzheimer's diseases (Xia MQ, Qin SX, Wu LJ, Mackay CR, and Hyman BT: Am J Pathol 1998 Ju1 ; 153 (1): 31-37).

Therefore, CCR3 is an important target and antagonism of CCR3 is likely to be effective in the treatment of such inflammatory and immunoregulatory disorders and diseases.

WO 00/76514 and WO 00/76513 disclose cyclopentyl modulators of chemokine receptors including CCR3 activity represented by the general formula: wherein X", x, y, Rl', Ruz', R3', R4'R5', R6'R'and R8'are defined in the application.

Other applications also disclose CCR3 modulators.

However, none of the reference and other reference discloses simple sulfonamide derivatives having CCR3 antagonistic activity.

The development of a compound having effective CCR3 antagonistic activity and can be used for the prophylaxis and treatment of diseases associated with CCR3 activity has been desired.

SUMMARY OF THE INVENTION As the result of extensive studies on chemical modification of sulfonamide derivatives, the present inventors have found that the compounds of the structure related to the present invention have unexpectedly excellent CCR3 antagonistic activity. The present invention has been accomplished based on these findings.

This invention is to provide novel sulfonamide derivatives shown by the following formula (I), its tautomeric and stereoisomeric form, and the salts thereof.

X represents phenyl, which is substituted by 0 to 5 substituents independently selected from the group consisting of Rl, R2, R3, R4 and R° or pyridine, which is substituted by 0 to 5 substituents independently selected from the group consisting of Rl, R2, R3 and R4 wherein Rl is hydrogen, halogen, hydroxy, straight-or branched-Cl-6 alkyl optionally substituted by mono, di or tri halogen, straight-or branched-C1_6 alkoxy, straight-or branched-CI-6 alkoxy carbonyl, amino, straight-or branched-Cl-6 alkylamino, di (straight- or branched-C 1 _6 alkyl) amino, straight-or branched-Cl-6 alkanoyl, nitro, or phenyl,

R2 is hydrogen, halogen, straight-or branched-C1_6 alkyl optionally substi-tuted by mono, di or tri halogen, straight-or branched-Ci-6 alkoxy, or cyano, or R'and R2 together form benzene ring or C5-8 cycloalkyl fused to the adjacent phenyl or pyridine, R3 is hydrogen, halogen, or straight-or branched-C1_6 alkyl, R4 is hydrogen, halogen, or straight-or branched- C1-6 alkyl, R° is hydrogen, halogen, or straight-or branched-Cl-6 alkyl, Y represents O, NH, NCH3 S, S (O), or SO2 ; Zl represents CH or N; Z2 represents CH or N with the proviso that both Zl and Z2 cannot be N at the same time; Rs represents hydrogen, halogen, hydroxy, straight-or branched-Cl-6 alkyl optionally substituted by mono, di or tri halogen or hydroxy, straight-or branched-C,-6 alkoxy, straight-or branched-C,-6 alkoxy- carbonyl, amino, straight-or branched-C1_6 alkanoylamino, phenyl- (CH2) q-carbonylamino (wherein q represents an integer selected from 0 to 6), straight-or branched-CI-6 alkylbenzoylamino, naphthyl- carbonylamino, thenoylamino, nitro, cyano, carboxy, straight-or

branched-C1_6 alkyl sulfonyl, oxazolidinonyl, or substituents represented by the formula, -SO2-NR51R52, or -CO-NR51R52, wherein R51 and R52 are independently selected from the group consisting of hydrogen, straight-or branched-C1_6 alkyl optionally substituted by cyano or carbamoyl and tetrazolyl optionally substituted by C1-6 alkylnitrile, or R51 and R52 may form, together with the adjacent N, a saturated 5 to 8 membered ring optionally interrupted by NH, R6 represents hydrogen, halogen, straight or branched C1-6 alkyl option- ally substituted by mono di or tri halogen, or straight or branched Cl-6 alkoxy, or Rs and R6 may form a pyrrol ring fused to adjacent phenyl, or pyridine; and R7 represents

R711 R'4 N- (CH2) p A ring N 1 73 R (CH 2) P-N- N R72 R711 R74 XB B ring (CH2) p N- R or R712 R711 C ring D ringN U wherein n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3, R71 is hydrogen, C3-8 cycloalkyl optionally interrupted by NH, N-CH3 or O, straight-or branched C1-6 alkoxycarbonyl, phenyl optionally substituted by straight-or branched C1-6 alkyl, benzyl, formyl, or straight-or branched Cl-6 alkyl

wherein the alkyl is optionally substituted by hydroxy, straight-or branched- C1-6 alkoxy, hydroxy straight-or branched-C1_6 alkoxy, carboxy, straight-or branched-CI-6 alkoxycarbonyl, straight-or branched-C1_6 alkylthio, di (straight-or branched-Cl-6 alkyl) amino, mono, di or tri halogen, or C3-8 cycloalkyl optionally interrupted by NHorO, R711 and R712 are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, straight-or branched C1-6 alkyl optionally substituted by hydroxy, carboxy, or mono, di or tri halogen, carbamoyl, di (straight-or branched C1-6 alkyl) amino carb- onyl, and -NR711aR711b wherein Ruila and Rlllb are independently selected from the group consisting of hydrogen, straight-or branched-C,-6 alkyl, straight-or branched-C1_6 alkanoyl, and straight-or branched-C1_6 alkyl- sulfonyl, or R71 and R711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring ; R72 is hydrogen, or straight-or branched- C1-6 alkyl ; R73 is hydrogen, or straight-or branched- C1-6 alkyl, R74 is hydrogen, or straight-or branched-C1-6 alkyl optionally substituted by phenyl, or

R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally substituted by C,-6 alkyl and optionally interrupted by NH or O ; R75 is straight-or branched-C1_6 alkylene or a 3 to 8 membered saturated or unsaturated ring; p represents an integer selected from 0 to 4; A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom; B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and C ring and D ring together form a 7 to 12 membered diazabicyclic ring.

A 7 to 12 membered diazabicyclic ring stands for a saturated bicyclic ring system consisting of 5 to 10 carbon atoms and 1 to 2 nitrogen atoms, wherein said bicyclic ring system does not exhibit a spiro ring connection. Preferred are 8 to 10 membered ring systems.

This invention is also to provide a method for treating or preventing a CCR3 related disorder or disease in a human or animal subject, comprising administering to said subject a therapeutically effective amount of the sulfonamide derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof.

Further this invention is to provide a use of the sulfonamide derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt

thereof in the preparation of a medicament for treating or preventing a CCR3 related disorder or disease.

The compounds of the present invention surprisingly show excellent CCR3 antagonistic activity. They are, therefore suitable for the production of medicament or medical composition, which may be useful to treat CCR3 related diseases.

More specifically, since the compounds of the present invention antagonise CCR3, they are useful for treatment and prophylaxis of diseases as follows: asthma, rhinitis, and allergic diseases, and autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis.

Therefore, CCR3 is an important target and antagonism of CCR3 is likely to be effective in the treatment and prophylaxis of such inflammatory and immuno- regulatory disorders and diseases.

The compounds of the present invention are also useful for treatment and prophylaxis of diseases like virus infections including HIV, lung granuloma, and Alzheimer's diseases, since the diseases also relate to CCR3.

In another embodiment, the compounds of formula (I) are those wherein: X, Y, Z, Z', R', R, R', R4, R'and R7 are as defined above, Rs is chloro, iodo, nitro, or cyano, and R6 is hydrogen.

In another embodiment, the compounds of formula (I) are those wherein:

X, Y, Z1 and Z2 are as defined above, Rl is halogen, or straight-or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen; R2 is halogen, or straight-or branched-Cl-6 alkyl optionally substituted by mono, di or tri halogen; R3 is hydrogen; R4 is hydrogen; R° is hydrogen; Rs is halogen, nitro, or cyano ; R6 is hydrogen; and R7 represents

4 N- (CH2) P A ring N 1 73 or R-9 (CH2) p-N- or Or C ring D ring N wherein n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3, R71 is hydrogen, straight-or branched Cl-6 alkyl optionally substituted by hydroxy or hydroxy straight-or branched-CI-6 alkoxy, 3-8 cycloalkyl, straight-or branched C1-6 alkoxycarbonyl, phenyl optionally substituted by straight-or branched C1_6 alkyl, benzyl, or formyl, R711 and R712 are independently selected from the group consisting of hydrogen, halogen, carboxy, or straight-or branched C1-6 alkyl, or R71 and R711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring; R72 is hydrogen, or straight-or branched-Cl 6 alkyl,

R73 is hydrogen, or straight-or branched-CI_6 alkyl, R74 is hydrogen, or straight-or branched-C1_6 alkyl, or R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O ; R7s is straight-or branched- C1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring; p represents an integer selected from 0 to 4; A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom; B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NIB is the only hetero atom; and C ring and D ring together form a 7 to 12 membered diazabicyclic ring.

In another embodiment, the compounds of formula (I) are those wherein: X, Y, Zi and Z2 are as defined above, R1 and R2 are identical or different and represent chloro, or methyl; R3 is hydrogen or fluoro; R4 is hydrogen;

R° is hydrogen; Rs is chloro, iodo, nitro, or cyano; R6 is hydrogen; and R7 represents s N Ra 711 4 R712 R71/ßm R NR75 N 1 73 172 R R72 N- (CH2) p A ring N, rus R R74 ß (CH2) P-N- R72 or R 74 C ring D ring N wherein

n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3, R71 is hydrogen, straight-or branched CI-6 alkyl optionally substituted by hydroxy or hydroxy straight-or branched- C1-6 alkoxy, C3-8 cycloalkyl, straight-or branched CI-6 alkoxycarbonyl, phenyl optionally substi- tuted by straight-or branched Cl 6 alkyl, benzyl, or formyl, R711 and R711 are independently selected from the group consisting of hydro- gen, halogen, carboxy, or straight-or branched C1_6 alkyl, or R71 and R 711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring; R72 is hydrogen, or straight-or branched-C,-6 alkyl ; R73 is hydrogen, or straight-or branched-C1-6 alkyl, R74 is hydrogen, or straight-or branched-Cl-6 alkyl, or R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or 0 ; R7s is straight-or branched-Cl-6 alkylene or a 3 to 8 membered saturated or unsaturated ring; p represents an integer selected from 0 to 4; A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom;

B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and C ring and D ring together form a 7 to 12 membered diazabicyclic ring.

In another embodiment, the compounds of formula (I) are those wherein: X, Y, Zl and Z2 are as defined above, R'is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl, tert-butyl, tri- fluoromethyl, methoxy, amino, dimethylamino, acetyl, or nitro ; R2 is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, or cyano; R3 is hydrogen or fluoro; R4 is hydrogen ; R° is hydrogen; Rs is chloro, iodo, nitro, or cyano; R6 is hydrogen; and R7 represents

R74 NR75 N R73 R72 R"R" N- (CH2) P A ring N R B rin R-9 (CN2) p-N- or or C ring D ring N C ring D ring N wherein n represents an integer 1, m represents an integer selected from 1 or 2, R7l represents hydrogen, methyl, ethyl or isopropyl ; R711 represents hydrogen, methyl, or carboxy R7l2 represents hydrogen or methyl, or

R71 and R711 may form, together with the adjacent N atom, a 5 membered saturated ring; R72 is hydrogen, methyl, or ethyl; R73 is hydrogen, or methyl, R74 is hydrogen, methyl, or ethyl, or R73 and R74 may form, together with adjacent N atom, piperidino, morpholino, or pyrrolidino; k75 is phenyl; p represents an integer selected from 0 to 4; A ring represents piperidino, or pyrrolidino; B ring represents pyrrolidino; and C ring and D ring together form a 7 to 12 membered diazabicyclic ring.

Yet other preferred compounds of formula (I) represent formula (I-2) and are those

wherein Rl is hydrogen, halogen, straight-or branched-C1-6 alkyl optionally substituted by mono, di or tri halogen, straight-or branched-Cl 6 alkoxy, straight-or branched-C1_6 alkoxy carbonyl, amino, straight-or branched-Cl 6 alkylamino, di (straight- or branched-C -6 alkyl) amino, straight-or branched- C1-6 alkanoyl, or nitro, R2 is hydrogen, halogen, straight-or branched-C1 6 alkyl optionally substituted by mono, di or tri halogen, straight-or branched-Cl 6 alkoxy, or cyano, or R1 and R2 may form benzene ring or C5-8 cycloalkyl fused to the adjacent phenyl; R3 is hydrogen or halogen, Y represents O, NH, NCH3, S, S (O), or SOa ; Rs is hydrogen, halogen, hydroxy, straight-or branched-C,-6 alkyl optionally substituted by mono, di, or tri halogen or hydroxy, straight-or branched-C1_6 alkoxy, straight-or branched-CI-6 alkoxycarbonyl, amino, straight-or branched- C1-6 alkanoylamino, phenyl-(CH2) q-carbonylamino (wherein q represents an integer selected from 0 to 6), straight-or branched- C1-6 alkyl- benzoylamino, naphthylcarbonylamino, thenoylamino, nitro, cyano, carboxy, straight-or branched-C1-6 alkyl sulfonyl, oxazolidinonyl, or substituents represented by the formula, -SO2-NR51R52, or -CO-NR51R52, wherein R51 and R52 are identical or different and represent hydrogen, straight-or branched-C,-6 alkyl optionally substituted by cyano or carbamoyl, tetrazolyl optionally substituted by C1-6 alkylnitrile, or R51 and R52

may form, together with the adjacent N, a saturated 5 to 8 membered ring optionally interrupted by NH, R6 is hydrogen, halogen, straight or branched Cl 6 alkyl optionally substituted by mono, di or tri halogen, or straight or branched C1-6 alkoxy, or Rs and R6 may form a pyrrol ring fused to adjacent phenyl; and R7 represents R711 nN R712 m R71/N m 5 R74 NR75 N 173 172 R711 R74 N- (CH2) P A ring N 1 73 R R711 R74 ring (CH2) P-N- v R72

or R74 C ring D ring N R74< f wherein n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3, R71 is hydrogen, straight-or branched C1-6 alkyl optionally substi- tuted by hydroxy or hydroxy straight-or branched-Cl 6 alkoxy, C3-8 cycloalkyl, straight-or branched CI-6 alkoxycarbonyl, phenyl optionally substituted by straight-or branched C1-6 alkyl, benzyl, or formyl, R711 and k"'are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, straight-or branched Cl-6 alkyl optionally substituted by hydroxy, carboxy, or mono, di or tri halogen, carbamoyl, di (straight-or branched Cl-6 alkyl) amino carbonyl, or -NR711aR711b wherein R7lla and R711b are independently selected from the group consisting of hydrogen, straight-or branched- C1-6 alkyl, straight-or branched-C1_6 alkanoyl, or straight- or branched-CI-6 alkylsulfonyl, or

R7l and R711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring; R72 is hydrogen, or straight-or branched-Cl-6 alkyl ; R73 is hydrogen, or straight-or branched-CI-6 alkyl, R74 is hydrogen, or straight-or branched-C1-6 alkyl, or R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O ; R75 is straight-or branched-CI-6 alkylene or a 3 to 8 membered saturated or unsaturated ring; p represents an integer selected from 0 to 4; A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom; B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and C ring and D ring together form a 7 to 12 membered diazabi- cyclic ring.

Yet other preferred compounds of formula (I-2) are those wherein: Rl is hydrogen, halogen, straight-or branched-C1-6 alkyl optionally substituted by mono, di or tri halogen, straight-or branched-Cl 6 alkoxy, straight-or

branched- C1-6 alkoxy carbonyl, amino, straight-or branched-Cl 6 alkyl- amino, di (straight-or branched-Cl 6 alkyl) amino, straight-or branched-C1_6 alkanoyl, or nitro, R2 is hydrogen, halogen, straight-or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen, straight-or branched-C, 6 alkoxy, or cyano, or RI and Ra may form benzene ring or C5-8 cycloalkyl fused to the adjacent phenyl; R3 is hydrogen or halogen, Y represents O, NH, NCH3, S, S (O), or S02 ; R 5 is chloro, iodo, nitro, or cyano; R6 is hydrogen; and R7 represents

R 74 N- (CH2) p A ring N R73 '4 8 B ri n R74= (CH2) PN or Ouf or C ring D ring wherein n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3, R71 is hydrogen, straight-or branched Cl-6 alkyl optionally substituted by hydroxy or hydroxy straight-or branched-C1_6 alkoxy, C3-8 cycloalkyl, straight-or branched C1-6 alkoxycarbonyl, phenyl optionally substituted by straight-or branched Cl-6 alkyl, benzyl, or formyl, R711 and R712 are independently selected from the group consisting of hydrogen, halogen, carboxy, or straight-or branched Cl-6 alkyl, or R71 and R711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring ;

R72 is hydrogen, or straight-or branched-C1-6 alkyl ; R73 is hydrogen, or straight-or branched-C1-6 alkyl, R74 is hydrogen, or straight-or branched-C1-6 alkyl, or R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O ; R7s is straight-or branched-C1_6 alkylene or a 3 to 8 membered saturated or unsaturated ring; p represents an integer selected from 0 to 4; A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom; B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and C ring and D ring together form a 7 to 12 membered diazabicyclic ring.

In another embodiment, the compounds of formula (I-2) are those wherein: Ri is hydrogen, halogen, or straight-or branched-C1-6 alkyl optionally substi- tuted by mono, di or tri halogen; R2 is hydrogen, halogen, or straight-or branched-Cl-6 alkyl optionally substituted by mono, di or tri halogen; R3 is hydrogen or halogen,

m N R, 2 R711 tam R71/N m N-R75 N- R73 R72 R'4 N- (CH2) P A ring N R73 R R74 B ring (CH2) P-N- I 172 or 74 ring D ring N wherein Y is O, NH, NCH3, S, S (O0, or SO2 ; Rs is halogen, nitro, or cyano ; R6 is hydrogen; and R7 represents

n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3, R71 is hydrogen, straight-or branched Cl alkyl optionally substituted by hydroxy or hydroxy straight-or branched-C1_6 alkoxy, C3-8 cycloalkyl, straight-or branched C1-6 alkoxycarbonyl, phenyl optionally substi- tuted by straight-or branched Cl-6 alkyl, benzyl, or formyl, R711 represents hydrogen, methyl, or carboxy, R712 represents hydrogen or methyl, or R71 and R7'1 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring; R72 is hydrogen, or straight-or branched-C,-6 alkyl ; R73 is hydrogen, or straight-or branched-Cl 6 alkyl, R74 is hydrogen, or straight-or branched-C1 6 alkyl, or R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O ; R7s is straight-or branched- C1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring; p represents an integer selected from 0 to 4;

A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom; B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and C ring and D ring together form a 7 to 12 membered diazabicyclic ring.

In another embodiment, the compounds of formula (I-2) are those wherein: Rl, R2 and R3 are identical or different and represent hydrogen, chloro, or methyl; Y is O, NH, NCH3, S, S (O), or S02 ; Rs is chloro, iodo, nitro, or cyano; R6 is hydrogen; and R7 represents R711 nN/ n R71/NAm R NR75 N R73 R72 R74 N- (CH2) p A ring N I R73

g ring (CH2) P-N- or or or R- (. Cring t Dring N- wherein n represents an integer selected from 1 to 3, m represents an integer selected from 1 to 3, * 71 is hydrogen, straight-or branched C1-6 alkyl optionally substituted by hydroxy or hydroxy straight-or branched-C1_6 alkoxy, C3-8 cycloalkyl, straight-or branched C1-6 alkoxycarbonyl, phenyl optionally substi- tuted by straight-or branched C1-6 alkyl, benzyl, or formyl, R711 represents hydrogen, methyl, or carboxy or R71 and R711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring ; R72 is hydrogen, or straight-or branched- C1-6 alkyl ; R73 is hydrogen, or straight-or branched-C1_6 alkyl ;

R74 is hydrogen, or straight-or branched-C1-6 alkyl ; or R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O ; R7s is straight-or branched-Cl-6 alkylene or a 3 to 8 membered saturated or unsaturated ring; p represents an integer selected from 0 to 4; A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom; B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and C ring and D ring together form a 7 to 12 membered diazabicyclic ring.

In another embodiment, the compounds of formula (I-2) are those wherein Rl is halogen, or straight-or branched-Cl-6 alkyl optionally substituted by mono, di or tri halogen; R is halogen, or straight-or branched-Cl-6 alkyl optionally substituted by mono, di or tri halogen; R3 is hydrogen or fluoro; Y is O, NH, NCH3, S, S (O), or SO2 ;

Rs is hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, methoxy, amino, acetylamino, isobutylcarbonylamino, tert-butylcarbonylamino, benzo- ylamino, benzylcarbonylamino, phenethylcarbonylamino, methylbenzoyl- amino, naphthylcarbonylamino, thenoylamino, nitro, cyano, methylsulfonyl, dimethyaminosulfonyl, piperazinosulfonyl, dimethyaminocarbonyl, or piperazinocarbonyl; R6 is hydrogen, methyl, or methoxy; or Rs and R6 may form a pyrrol ring fused to adjacent phenyl; and R7 represents 4 zu i'IDT a Rs N- (CHZ) P A ring N ruz Ra B g ring (CH2) p-N- R72

or C ring D ring J wherein n represents an integer 1, m represents an integer 1 or 2, R71 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, branched pentyl, hydroxyethyl, hydroxyethoxyethyl, cyclopentyl, cyclohexyl, tert- butoxycarbonyl, phenyl, tolyl, benzyl, or formyl, R 711represents hydrogen, methyl, or carboxy, R712 represents hydrogen or methyl, or R71 and R711 may form, together with the adjacent N atom, a 5 membered saturated ring; R72 is hydrogen, methyl, or ethyl; R73 is hydrogen, or methyl, R74 is hydrogen, methyl, or ethyl, or R73 and R74 may form, together with adjacent N atom, piperidino, morpholino, or pyrrolidino;

R75 is phenyl; p represents an integer selected from 0 to 4; A ring represents piperidino, or pyrrolidino; B ring represents pyrrolidino; and C ring and D ring together form a 7 to 12 membered diazabicyclic ring.

In another embodiment, the compounds of formula (1-2) are those wherein; Rl is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl, tert-butyl, tri- fluoromethyl, methoxy, amino, dimethylamino, acetyl, or nitro; R2 is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, or cyano ; R3 is hydrogen or fluoro; Y is O, NH, NCH3, S, S (O), or SO2 ; Rs is hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, methoxy, amino, acetylamino, isobutylcarbonylamino, tert-butylcarbonylamino, benzoyl- amino, benzylcarbonylamino, phenethylcarbonylamino, methylbenzoylamino, naphthylcarbonylamino, thenoylamino, nitro, cyano, methylsulfonyl, dimethyl- aminosulfonyl, piperazinosulfonyl, dimethylaminocarbonyl, or piperazino- carbonyl; R6 is hydrogen, methyl, or methoxy; or

R5 and R6 may form a pyrrol ring fused to adjacent phenyl, and R7 represents / rN R7, 2 m 2 3 R'-N-R-N- R73 R72 R 74 N- (CH2) p A ring N R73 \ t R 74 B B ring (CH 2) P-N- or ; or R C ring D ring wherein n represents an integer 1, m represents an integer 1 or 2,

R71 represents hydrogen, methyl, ethyl, isopropyl, sec-butyl, branched pentyl, hydroxyethyl, hydroxyethoxyethyl, cyclopentyl, cyclohexyl, tert-butoxycarbonyl, phenyl, tolyl, benzyl, or formyl, R711 represents hydrogen, methyl, or carboxy R732 represents hydrogen or methyl, or R71 and R711 may form, together with the adjacent N atom, a 5 membered saturated ring; R72 is hydrogen, methyl, or ethyl, R73 is hydrogen, or methyl, R74 is hydrogen, methyl, or ethyl, or R73 and R74 may form, together with adjacent N atom, piperidino, morpholino, or pyrrolidino; R7s is phenyl; p represents an integer selected from 0 to 4; A ring represents piperidino, or pyrrolidino; B ring represents pyrrolidino; and C ring and D ring together form a 7 to 12 membered diazabicyclic ring.

In another embodiment, the compounds of formula (1-2) are those wherein;

Rl is chloro, bromo, or methyl; R2 is hydrogen, chloro, bromo, or methyl; R3 is hydrogen or fluoro; Y represents O, S, or S (O) ; Rs represents hydrogen, chloro, nitro, or cyano; R6 represents hydrogen; R7 represents 711 R711 NS N N/ R j- c HN R74NR75 N R74 N-R'N-I Han Ra Ra N_Rs N- R73 R72 N- (CH) p A ring N 173 R74_@ (CH) p-N R'

wherein R71 represents hydrogen, methyl, ethyl or isopropyl ; R711 represents hydrogen, methyl, or carboxy; R712 represents hydrogen or methyl; R72 is hydrogen, methyl, or ethyl; R73 is hydrogen, methyl, or ethyl; R74 is hydrogen, methyl, or ethyl; or R73 and R74 may form, together with adjacent N atom, piperidino, or pyrrolidino, R75 is phenyl; p represents integer 0 or 1 ; A ring represents piperidino, or pyrrolidino; and B ring represents pyrrolidino.

The preferable compounds of the present invention are as follows: 1- { [2- (3, 5-dimethylphenoxy)-5-nitrophenyl] sulfonyl}-4-ethylpiperazine, 1- { [2- (3, 5-dichlorophenoxy)-5- nitrophenyl] sulfonyl} piperazine, 1- { [2- (3, 5-dimethylphenoxy) -5-nitrophenyl] sulfonyl}-4-isopropylpiperazine, 4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl) benzonitrile, 1- [5-chloro-2-(3,5-dimethylphenoxy) phenyl] sulfonyl}-4-ethylpiperazine, 1- {[2-(3, 5-dichlorophenoxy)-5-nitrophenyl] sulfonyl}-4-(1-pyrrolidinyl) piperidine, 4-(3,5-dichlorophenoxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl ]sulfonyl} benzonitrile, 4-(3,5-dichlorophenoxy)-3-(1-piperazinylsulfonyl) benzonitrile, <BR> <BR> <BR> <BR> 1- { [2- (3, 5-dichlorophenoxy)-5-nitrophenyl] sulfonyl}-N, N-diethyl-3-pyrrolidinamine, (2S)-1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-2-( 1-pyrrolidinylmethyl)- pyrrolidine, 3- [ (4aR, 7aR) -octahydro-6H-pyrrolo [3,4-b] pyridin-6-ylsulfonyl]-4- (3, 5-dichloro- phenoxy) benzonitrile, 4- [ (3, 5-dichlorophenyl) sulfonyl]-3-(1-piperazinylsulfonyl) benzonitrile, 4- [ (3, 5-dichlorophenyl) sulfinyl]-3- (1-piperazinylsulfonyl) benzonitrile, 1-f [2- (3, 5-dibromophenoxy) -5-nitrophenyl] sulfonyl} piperazine, 1-1 [2- (3, 5-dichloro-2-fluorophenoxy) -5-nitrophenyl] sulfonyl} piperazine, 1-{[5-cyano-2-(3, 5-dichlorophenoxy) phenyl] sulfonyl}-2-piperazinecarboxylic acid, <BR> <BR> <BR> <BR> 1- {[2-(3, 5-dichlorophenoxy)-5-nikophenyl] sulfonyl}-2-piperazinecarboxylic acid,<BR> <BR> <BR> <BR> <BR> <BR> <BR> 1- { [2- (3, 5-dimethylphenoxy)-5-nitrophenyl] sulfonyl}-1, 4-diazepane, 1-{[2-(3, 5-dichlorophenoxy) -5-nitrophenyl] sulfonyl}-1, 4-diazepane, 1- { [2- (3, 5-dichlorophenoxy)-5-nitrophenyl] sulfonyl}-3, 5-dimethylpiperazine, 3- (1, 4-diazepan-1-ylsulfonyl)-4- (3, 5-dichlorophenoxy) benzonitrile, l'- { [2- (3, 5-dichlorophenoxy) -5-nitrophenyl] sulfonyl}-1, 3'-bipyrrolidine, 3-(1,3'-bipyrrolidin-1'-ylsulfonyl)-4-(3, 5-dichlorophenoxy) benzonitrile, 1-({2-[(3,5-dichlorophenyl)sulfanyl]-5-nitrophenyl}sulfonyl) -4-(1-pyrrolidinyl)piperidine, 4- (3, 5-dichlorophenoxy)-3- (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H)-ylsulfonyl) benzo- nitrile, and 3- (1, 4-diazepan-1-ylsulfonyl)-4- [ (3, 5-dichlorophenyl) sulfanyl] benzonitrile,

and their tautomeric and stereoisomeric form, and physiologically acceptable salts thereof.

The compound of the formula (I) of the present invention can be prepared by combining various known methods. In some embodiments, one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the com- pounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in"Protective Groups in Organic Synthesis (3rd Edition) "by Greene and Wuts, John Wiley and Sons, New York 1999.

The compound represented by the general formula (I-a) can be prepared by the Reaction A or A'below. wherein X, Z1, Z2 and R6 are as defined above, Y'is O, NH, or S, R5 is nitro, Ci. 6 alkyl, C1 6 alkylsulfonyl, carboxy and R7 is the same as R7 as defined above or protected R7.

Reaction A x O L p L L wS H_R'R'/l HY, _X Ry O Y 1 1 R Base 0 1-tR , I R6 Base Basa R 1 2 (I-a)

Compound 1 (wherein L and L'are identical or different and represent leaving group, such as halogen atom e. g. , fluorine, chlorine, bromine, or iodine atom; C6-10 aryl- sulfonyloxy group e. g. , benzenesulfonyloxy, or p-toluenesulfonyloxy ; and C14 alkyl- sulfonyloxy group, e. g., trifluoromethanesulfonyloxy, methanesulfonyloxy and the like) and H-R7 can be reacted to obtain compound 2 in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetra- hydrofuran (THF) and 1,2-dimethoxyethane ; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyr- rolidone; sulfoxides such as dimethyl sulfoxide, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about-10°C to 200°C, and preferably about 10°C to 80°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 hr to 24 hrs.

The reaction can be advantageously conducted in the presence of a base. The examples of the base include an alkali metal hydride such as sodium hydride or potassium hydride; alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium

hydrogen carbonate; organic amines such as pyridine, triethylamine and N, N- diisopropylethylamine, and others.

Then compound 2 and HY'-X (wherein X and Y'are the same as defined above) can be reacted in a similar manner as that of the reaction of A-1 and H-R7 to obtain the compound (I-a). Reaction A' L Y' yp Y' W O// za HY'-X W z2/ Rs _.. z R tZV s tZt s R R 3 4 HR 5 y, X Y' Y'' S 2 Rr/, W ZRs I_a) Z1tR5. lR Compound 3 (wherein L is identical or different and represent leaving group, such as halogen atom e. g. , fluorine, chlorine, bromine, or iodine atom; C6-lo arylsulfonyloxy group e. g., benzenesulfonyloxy, or p-toluenesulfonyloxy ; and CI-4 alkylsulfonyloxy group, e. g., trifluoromethanesulfonyloxy, methanesulfonyloxy and the like, W represents nitro, halogen, thiol, C1_6 alkyl sulfinyl, sulfinic acid, sulfonic acid, sulfon- amide and the like) and HY'-X can be reacted to obtain compound 4 in a similar manner as that for the preparation of I-a from compound 2 and HY'-X.

Compound 4 can be converted to compound 5 (wherein L'is as defined above) by known method in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane ; ethers such as diethyl ether,

isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane ; nitriles such as acetonitrile ; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); organic acid such as acetic acid; inorganic acid such as HCl and H2SO4 ; water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to about-10°C to 200°C, and preferably about 10°C to 80°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.

Then compound 5 and H-R7 can be reacted to obtain (I-a) in a similar manner as that for the preparation of compound 2 from compound 1 and H-R7.

The compound (I-a) can be further reacted to modify R7, e. g. to deprotect, or to modify R5 to obtain the compound having amino, halogen, hydroxy, cyano, C1-6 alkoxy or amide group.

Alternatively, the compound represented by the general formula (I-b) can be prepared by the Reaction B below.

(I-b) wherein X, zl and Z2 are as defined above, R5 is halogen, carboxy or nitro and R7 is the same as R7 as defined above or protected R7.

Reaction B oH O O 1) O O LJ [-) 7 C'. J. Z L Z I 1-R5"-e- R5" deprotection 6 7 of methoxy group 8 Ex v I X-L"0 0 x L (1-b) (I-b)

Reaction B is especially advantageous when R5 is Br.

First, compound 6 and sulfonic acid halide (e. g., chlorosulfonic acid) or equivalent thereof can be reacted to obtain compound 7 (wherein L'is as defined above) in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane ; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane ; nitriles such as aceto- nitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.

Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about-10°C to 200°C, and preferably about 10°C to 80°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.

Compound 8 can be prepared from compound 7 in two steps; (step 1) the reaction with H-R7' and (step 2) deprotection of methoxy group. (step 1) The reaction of

compound 7 and H-R7'can be performed in a similar manner as that for the preparation of compound 2 from compound 1 and H-R7 * (Step 2) The successive deprotection of methoxy group to obtain B-3 can be done by the reaction with Lewis acid such as, for example, BBr3, in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to about-10°C to 200°C, and preferably about 10°C to 80°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.

Then compound 8 can be reacted with X-L" (wherein X is defined as above, L" represents leaving group, such as boronic acid, halogen atom e. g. , fluorine, chlorine, bromine, or iodine atom) to obtain the compound (I-b). The reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane ; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane ; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as aceto- nitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and others.

Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to about-10°C to 200°C, and preferably about 10°C to 100°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs. The reaction can be carried out in the presence of a catalyst, including for instance, cooper salts such as cooper (II) acetate, palladium salts such as palladium (acetate, and others. The reaction can be

advantageously conducted in the presence of a base. The examples of the base include an alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; carbonates such as cesium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N, N-diisopropylethylamine, and others.

The compound (I-b) can be further reacted to modify R7', e. g. to deprotect, or to modify Rs to obtain the compound having amino, halogen, hydroxy, cyano, Cl-6 alkoxy or amide group.

The compound (I-c) below can be advantageously prepared by the Reaction C below.

X, ZI, Z2 and W"are as defined above, Y"is NH or S, and R7 is the same as R as defined above or protected R. Reaction C l F3 , H O=S=O zX S vS s R,/\ ZZ w Z2 -, e zz z z z 8 9 (I-C)

First, compound 8, which can be prepared as described in the Reaction B can be reacted with either trifluoromethanesulfonic anhydride or trifluoromethanesulfonic chloride to obtain compound 9. The reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane ; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane ; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N- dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to about-10°C to 200°C, and preferably about 0°C to 100°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs. The reaction can be advantageously conducted in the presence of a base. The examples of the base include organic amines such as pyridine, triethylamine and N, N-diisopropylethylamine, and others.

Then compound 9 and HY-X can be reacted to obtain compound (I-c) in a similar manner as that for I-a from compound 2 and HY-X.

The compound (I-c) can be further reacted to modify R7, e. g. to deprotect, or to modify Rs to obtain the compound having amino, halogen, hydroxy, cyano, Cl-6 alkoxy or amide group.

The compound (I-d) below can be prepared by the Reaction D below.

wherein X, Zl, Z2, Rs and R6 are as defined above, Y"'is SO or SO2 and R7' is the same as R as defined above or protected R7.

Reaction D The sulfoxide compounds of the formula (I-d') can be prepared by oxidation of compound (I-a') using appropriate oxidant including but not limited to, peroxide, such as hydrogen peroxide, t-butyl peroxide; peracids such as meta-chloroperbenzoic acid and the like. The reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloro- ethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethyl- acetamide and N-methylpyrrolidone, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to about-10°C to 200°C, and preferably about 0°C to 100°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.

The sulfone compounds of the formula (I-d") can be prepared by oxidation of compound (I-a') with an oxidant such as, for example, sodium periodate (NaI04) or sodium hypochlorite (NaOCI) in the presence of catalyst such as, for instance, ruthenium (hui) chloride.

The reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2- dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used. The reaction temperature is usually, but not limited to about-10°C to 200°C, and preferably about 0°C to 100°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.

The sulfone compounds of the formula (I-d") can also be prepared by oxidation of compound (I-d') in a similar manner as that for the oxidation of compound (I-a').

The compound (I-d') and (I-d") can be further reacted to modify R7, e. g. , to deprotect, or to modify 1t5 to obtain the compound having amino, halogen, hydroxy, cyano, Cl-6 alkoxy or amide group.

When the compound shown by the formula (I) or a salt thereof has tautomeric isomers and/or stereoisomers (e. g, geometrical isomers and conformational isomers), each of their separated isomer and mixtures are also included in the scope of the present invention.

When the compound shown by the formula (I) or a salt thereof has an asymmetric carbon in the structure, their optically active compounds and racemic mixtures are also included in the scope of the present invention.

Typical salts of the compound shown by the formula (I) include salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively.

Acids to form acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.

Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris (hydroxymethyl) aminomethane, and the like. Examples of inorganic bases include, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

The compound of the present invention or a salts thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and/or hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.

The compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols

and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts. The compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.

The dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.

The compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients.

Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.

Yet another embodiment of the present invention is pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically- acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically-acceptable excipients therefore. In making the compositions of the present invention, the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. The carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions,

solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

For oral administration, the active ingredient may be combined with an oral, and non- toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, acacia, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.

In powder forms, the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient. The active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets. The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention. Suitable solid carriers are magnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.

Sterile liquid formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.

The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in suitable oil.

The formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals. A unit dosage form can be a capsule or tablets, or a number of capsules or tablets. A "unit dose"is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients. The quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.

Typical oral dosages of the present invention, when used for the indicated effects, will range from about O. Olmg/kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day. In the case of parenteral administration, it has generally proven advantageous to administer quantities of about 0.001 to 100mg/kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.

EXAMPLES The present invention will be described in detail below in the form of examples, but they should by no means be construed as defining the metes and bounds of the present invention.

In the examples below, all quantitative data, if not stated otherwise, relate to percentages by weight.

'H NMR spectra were recorded using either Bruker DRX-300 (300MHz for 1H) spectrometer in CDC13. Chemical shifts are reported in parts per million (ppm) with tetramethylsilane (TMS) as an internal standard at zero ppm. Coupling constant (J) are given in hertz and the abbreviations s, d, t, q, m, and br refer to singlet, doublet, triplet, quartet, multiplet, and broad, respectively. Mass spectroscopy data were recorded on a FINNIGAN MAT 95. TLC was performed on a precoated silica gel plate (Merck silica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150um)) was used for all column chromatography separations.

All chemicals were reagent grade and were purchased from Sigma-Aldrich, Wako pure chemical industries, Ltd. , Tokyo kasei kogyo Co. , Ltd. , Nacalai tesque, Inc., Watanabe Chemical Ind. Ltd. , Maybridge plc, Lancaster Synthesis Ltd., Merck KgaA, Kanto Chemical Co. , Ltd.

The effects of the present compounds were examined by the following assays and pharmacological tests.

[Determination of IC50 values of compounds in receptor binding assay] (1) cell Human CCR3-transformed K562 cells were used. The cloned CCR3 cDNA was constructed with pcDNA3 vector and transfected into a K562 cell line.

The human CCR3-transformed K562 cells were maintained in RPMI-1640 (Cat. #22400-089, Life Technologies) supplemented with 10% FCS (Cat. #A- 1115-L, Hyclone), 55 µM 2-mercaptoethanol (Cat. #21985-023, Life Tech- nologies), 1 mM sodium pyruvate (Cat. #11360-070, Life Technologies), 100 units/ml of penicillin G and 100 pLg/ml of streptomycin (Cat. #15140-122, Life Technologies), and 0.4 mg/ml of Geneticin (Cat. #10131-035, Life Tech- nologies) (hereinafter called"culture medium"). Before the receptor binding assay, cells were pretreated with 5 mM sodium butyrate (Cat. &num 193-01522, Wako)-containing the culture medium (2 x 105 cells/ml) for 20-24 hours to increase the expression of CCR3.

(2) Receptor binding assay (RBA) Butyrate-pretreated cells, suspended in binding buffer (25 mM HEPES pH 7.6, 1 mM CaCl2, 5 mM MgCl2, 0.5% BSA, 0. 1% NaN30 at a cell density of 2 x 106 cells/ml, were added into 60 IlVwell in the 96-well round bottom polypropylene plate (Cat. #3365, Costar). Compounds, diluted with the binding buffer (4-times higher concentration of the final concentration), were added into 30 Ill/well in the polypropylene plate. [125I]-labeled human eotaxin (Cat. &num IM290, Amersham Pharmacia Biotech), diluted with the binding buffer at the concentration of 0.4 nM (final concentration ; 0. 1 nM), was added into 30 µl/well in the polypropylene plate. Total 120 Ill/well of binding reaction mixture (60 pl/well of cell suspension, 30 pl/well of compound solution, and 30 pl/well of [125I]-labeled eotaxin) were incubated in the polypropylene plate for 1 hour at room temperature after the incubation,

100 p. l/well of the reaction mixture was transferred to a filtration plate (Cat. #MAFB-NOB, Millipore), and washed with the washing buffer (25 mM HEPES pH 7.6, 1 mM Cads, 5 mM MgCl2, 0.5% BSA, 0.1% NaN3, 0.5 M NaCl) twice. The 96-well filtration plate was pretreated with 100 Ill/well of 0.5% polyethylenimine (Cat. #P-3143, Sigma) for 2-4 hours at room tempera- ture and washed with the washing buffer twice before use. The non-specific binding was determined by parallel incubation in the presence of 500 nM of non-labeled eotaxin (Cat. #23209, Genzyme Techne). The radioactivities remained on the filter were measured by liquid scintillation counter (TopCountTM, Packard) after an addition of 45 Al/well of scintillant (Microscint20, Cat. #6013621, Packard). The inhibition percent at each concentration of compound was calculated, and IC50 values were determined from the inhibition curve.

[Determination of IC50 values of compounds in calcium mobilization assay] (ICso Ca2+) (1) cell Human CCR3-transformed K562 cells were used. The human CCR3- transformed K562 cells were maintained in RPMI-1640 supplemented with 10% FCS, 55 M 2-mercaptoethanol (Cat. #21985-023, Life Technologies), 1 mM sodium pyruvate, 100 units/ml of penicillin G and 100 pg/ml of streptomycin and 0.4 mg/ml of Geneticin. Before the calcium mobilization assay, cells were pretreated with 5 mM sodium butyrate-containing the culture medium (2 x 105 cells/ml) for 20-24 hours to increase the expression of CCR3.

(2) Calcium mobilization assay Butyrate-pretreated cells were loaded with Fluo-3AM (Cat. #F-1242, Molecu- lar Probes) in loading buffer (Hanks'solution Cat. #05906 Nissui, 20 mM HEPES pH 7.6, 0.1% BSA, 1 mM probenecid Cat. #P-8761 Sigma, I 1M Fluo-3AM, 0. 01% pluronic F-127 Cat. #P-6866 Molecular Probes) at a cell density of 1 x 107 cells/ml. Then, cells were washed with calcium assay buffer (Hanks'solution Cat. #05906 Nissui, 20 mM HEPES pH 7.6, 0.1% BSA, 1 mM Probenecid Cat. #P-8761 Sigma). The cell suspension (3.3 x 106 cells/ml) was added into 60 pVwell in the 96-well clear bottom black plate (Cat. &num 3904, Costar). Compounds, diluted (5-times concentration of the final concentration) with the calcium assay buffer, were added into 20 41/well in the plate 10 minutes before assay. Human recombinant eotaxin, diluted with the calcium assay buffer at the concentration of 50 nM (final concen- tration; 10 nM), was added into in a polypropylene plate (Cat. #3365, Costar).

Mobilization of cytoplasmic calcium was measured by FDSS-6000 or FDSS- 3000 (Hamamatsu Photonics) over 60 sec after the stimulation with 10 nM eotaxin. The inhibition percent at the each concentration of compound was calculated, and IC50 values were determined from the inhibition curve.

[Determination of IC50 values of compounds in chemotaxis assay] (1) cell Human CCR3-transformed L1. 2 cells were used. Human CCR3-expressing LI. 2 stable transformant was established by electroporation, referring to the methods described in J. Exp. Med. 183: 2437-2448,1996. The human CCR3- transformed L1. 2 cells were maintained in RPMI-1640 supplemented with 10% FCS, 100 units/ml of penicillin G and 100 pLg/ml of streptomycin, and 0.4 mg/ml of Geneticin. One day before the chemotaxis assay, cells were

pretreated with 5 mM sodium butyrate-containing culture medium (5 x 105 cells/ml) for 20-24 hours to increase the expression of CCR3.

(2) Chemotaxis assay Butyrate-pretreated cells were suspended in chemotaxis buffer (Hanks' solution Cat. #05906 Nissui, 20 mM HEPES pH 7.6, 0.1% human serum albumin Cat. #A-1887 Sigma) at a cell density of 1.1 x 107 cells/ml. A mixture of 90 Ill of cell suspension and 10 p1 of compound solution diluted with chemotaxis buffer (10-times concentration of the final concentration) were preincubated for 10 minutes at 37°C. The mixture of cells and com- pounds was added into the upper chamber of the 24-well chemotaxis chamber (Transwell, Cat. #3421, Costar, pore size; 5 pm). 0. 5 ml of 10 nM of human recombinant eotaxin (Cat. #23209, Genzyme Techne) solution, diluted with chemotaxis buffer, was added into the lower chamber of the chemotaxis plate.

Then, chemotaxis was performed in C02 incubator at 37°C for 4 hours. After 4hrs incubation, migrated cells were counted using FACScan (Becton Dickinson). The inhibition percent at the each concentration of compound was calculated, and IC50 values were determined from the inhibition curve.

[Selectivity test] Selectivity test was done in calcium mobilization assay and in receptor binding assay by using CCR1, CCR2, CCR4, CCR5, CCR7, CCR8, CXCR1 and PAR-1 (peptidase activate receptor) stable transformants. Methods for the test are the same as that of CCR3. Only the difference is that different stable transformants were used for these selectivity tests.

[Determination of IC50 values of compounds in chemotaxis assay with the use of human eosinophilsl Human eosinophils were purified from peripheral blood. Twenty five ml of heparinized blood was layered on 15 ml of Mono-Poly Resolving Medium (&num 16-980- 49DN, ICN Biomedicals Co. Ltd, Japan) in 50 ml tube (&num 2335-050, Iwaki, Japan) gently and then centrifuged at 400G, for 20 min, at room temperature. After centrifu- gation, red blood cells were removed by hypotonic lysis. The polymorphonuclear leukocyte pellet was incubated with anti-human CD16 Microbeads (#130-045-701, Milteynyi Biotec GmbH, Germany) for 30 min at 4°C. After washing the cells, magnetically labeled neutrophils were then depleted by applying the cell suspension to BS columns (#130-041-304, Milteynyi Biotec GmbH, Germany) attached to VarioMACS (#130-090-282, Milteynyi Biotec GmbH, Germany).

Chemotaxis assay with the use of the obtained eosinophils was done by the same protocols as that using CCR3 stable transformants, L1. 2 cells.

[Primate Chronic Asthma Model: Protocol] Materials and Methods : The animals used in this study were wild caught, adult male cynomolgus monkeys (Macaca fascicularis) weighing 4.0 to 9.0 kg (Charles River BRF, Inc.). All animals studied demonstrated a naturally occurring respiratory sensitivity to inhaled Ascaris suuni extract. Animals were housed individually in environmentally controlled rooms in open mesh cages and provided food twice daily and water ad libitum. Each animal was fasted for approximately 12 hours prior to the day of study. For each study the animals were anesthetized with ketamine hydro- chloride (7mg/kg, i. m. ; Ketaset, Fort Dodge, IA) and xylazine (1. 2mg/kg, i. m.; Bayer Corp. , Elkart, IN), incubated with a cuffed endotracheal tube (5.0 mm ID ; Mallinckrodt Critical Care, Glen Falls, NY) and seated in a specially designed support chair. Ketamine (5 mg/kg, i. m. ) was used to supplement anesthesia as needed.

Studv Protocol : Airway responsiveness (AR) to inhaled methachroline followed by bronchoalveolar lavage (BAL) to assess airway cellular composition (ACC) were determined 3 days before (day 0) and 3 days after (day 10) three alternate-day (days 3,5, 7) inhalations of Ascaris suuni extract. Animals were rested 6 to 8 weeks between studies to allow airway responsiveness and inflammation to return to baseline (pre-antigen) levels. Treatment studies were bracketed by vehicle control studies to assure that no changes in sensitivity to antigen occurred over time.

The test compounds dissolved in Ethanol: PEG400: Water (10: 50: 40 v/v) were administered under light anesthetisia. yste7n and Inhalation Challenzes : Aerosol inhalation challenges were administered by intermittent positive pressure breathing with a Bird Mark 7A respirator and micronebulizer (model 8158). Each challenge consisted of 30 breaths (maximum inspiratory pressure=20 cmH20). Ascaris suum extract (Greer Labora- tories, Lenoir, NC) was diluted with PBS to a final threshold concentration previously determined for each animal and administered as an aerosol (particle size <2 llm). Methacholine (Sigma Chemical Co, St. Louis, Missouri) was dissolved in PBS at a concentration of 100 mg/ml and serial dilutions of 30,10, 3,1, 0.3 and 0.1 mg/ml were subsequently prepared for nebulization.

Measurement of Respiratorv Svstem Resistance (Rrs) : The animal was connected to a Harvard Ventilator (Harvard Apparatus, S. Natick, MA) via the endotracheal tube and ventilated at a rate between 30-35 breaths per minute. Airflow was measured by a Fleisch (Hans Rudolph) pneumotachograph and thoracic pressure was measured by a validyne pressure transducer (as the difference between the pressure at the distal end of the endotracheal tube and room pressure). The pneumotachograph and validyne were connected to a pre-amplifier and then into an MI2 respiratory analyzer (Malvern, PA). Using the primary signals of flow and pressure the analyzer

computed airway resistance and compliance (as well as a number of other respiratory parameters).

Methacholine Dose Response Deterfninations : To assess airway responsiveness to inhaled methacholine, cumulative dose response curves were constructed by administering increasing concentrations of methacholine until increases in Rrs of between 100 and 200% were obtained. A vehicle control challenge was performed prior to the first dose of methacholine. Changes in Rrs were measured continuously over a 10 minute period post aerosol challenge. Aerosol challenges were separated by 5 to 10 minutes or until Rrs returned to baseline values.

Determination oPCloo Talues : The resistance obtained with PBS was set as zero.

The percentage increase in resistance above zero at each dose of methacholine was entered into the computer and the program used an algorithm to determine the exact methacholine concentration which caused an increase in resistance of 100% above baseline (PCico). Differences (day 10-day 0) in PCio0 values were calculated as logs (base 10) to normalize the data and account for the large variation in absolute values for the PCIOO between animals.

Bronclaoalveolar Lavage : Following methacholine dose response determinations each monkey was placed in the supine position and a fiberoptic bronchoscope (Olympus Optical, model 3C-10, Lake Success, NY) was guided past the carina and wedged into a fifth to seventh generation bronchus. A total of 15 ml of bicarbonate buffered saline (pH 7.4) was infused and gently aspirated through a channel in the bronchoscope. Collected samples were immediately centrifuged at 2000 rpm for 10 minutes at 4°C. The resulting pellets were resuspended in Ca++ and Mg++ free Hank's balanced salt solution. To avoid possible effects of the BAL procedure on lung cellular composition, BAL was performed on alternating right and left lungs. Total white cells per milliliter of BAL fluid was obtained using a Coulter counter (Coulter Corp. , Miami, FL). BAL cell composition was determined by counting a minimum of 200 cells from a Wright's stained cytospin slide preparation.

Blood Samples : Blood samples were collected prior to and 30minutes, lhr and 2hr after the first dose of the test compounds (morning of day 2), immediately before each subsequent dose, and 30 minutes, lhr and 2hr after the final dose (evening of day 9). Blood was collected from the femoral vein into EDTA, centrifuged at 1500 rpm for 15minutes at 4°C and the plasma stored at-70°C until assayed for the test compounds.

Statistical Analysis : All data were evaluated statistically with the use of students t- test where a p value <0.05 was considered statistically significant.

Results of receptor binding assay (RBA), Ca2+ mobilization assay (Ca2+) are shown in Examples and tables of the Examples below. The data corresponds to the compounds as yielded by solid phase synthesis and thus to levels of purity of about 40 to 90%. For practical reasons, the compounds are grouped in three classes of activity as follows: IC50=A 1pM<B 10 pM<C The compounds of the present invention also show more than 100-fold selectivity against CCR1 CCR5, CCR7, CCR8 and CXCR1 in receptor binding assays.

The compounds of the present invention show dose-dependent inhibitory effect on eotaxin-induced chemotaxis of human eosinophils and strong activity in vivo assays.

Example 1-1 (1) To the solution of 2-chloro-5-nitrobenzenesulfonyl chloride (3.84 g, 15 mmol) in dry THF (30 ml) was added dropwise the mixture of Boc- piperazine (3.07 g, 16.5 mmol) and N, N-diisopropylethylamine (2.33 g, 18 mmol) in dry THF (10 ml) at 0°C with stirring. The mixture was then stirred at room temperature for 3 hrs. The solvent was evaporated and CH2C12 was added to the residue. The mixture was washed with 0.5 N aqueous HC1, brine, saturated aqueous NaHC03, brine, successively, dried over MgS04.

The solvent was evaporated to give tert-butyl 4- [ (2-chloro-5-nitrophenyl)- sulfonyl]-l-piperazinecarboxylate as white powder (5. 80g, 95.3%). (2) To the solution of 3,5-dimethylphenol (1.92 g, 15.72 mmol) in DMF (50 ml) was added NaH (60%, 0.629g, 15.72 mmol) at 0°C with stirring. tert-Butyl 4- [ (2-

chloro-5-nitrophenyl) sulfonyl]-1-piperazinecarboxylate (5.80 g, 14.29 mmol) was added to the mixture after 30 min. The mixture was stirred at room tempera- ture for 2 hrs. 100 ml of ice water was added, the precipitate was collected by filtration, washed with water and dried in vacuo to give tert-butyl 4-{[2- (3, 5-dimethylphenoxy)-5-nitrophenyl] sulfonyl}-1-piperazinecarboxylate as white powder (6.90 g, 98.2%) : mp 232-233°C ; 1H NMR (500 MHz, CDC13). 1.45 (9H, s), 2.35 (6H, s), 3.35 (4H, t, J = 5 Hz), 3.51 (4H, t, J = 5 Hz), 6.72 (2H, s), 6.91-6. 95 (2H, m), 8.26 (1H, t), 8. 86 (1H, s); HPLC-MS (ESI): Calcd for C23H29N307S [M + H] + 492, Found: 492.

Molecular weight: 491.5675 Activity grade RBA: C Activity grade Ca2+ : C Example 1-2 (1) To the suspension of ter-butyl 4- { [2- (3, 5-dimethylphenoxy) -5-nitrophenyl]- sulfonyl}-l-piperazinecarboxylate (620 mg, 1.26 mmol) which was prepared in the Example 1-1 in CH2C12 (3ml) was added trifluoloacetic acid (2 ml) at 0°C, the mixture was stirred at 0°C for 3 hrs. The solvent was evaporated in vacuo and 20 ml of toluene was added, the solvent was evaporated in vacuo again. To the residue was added CH2C12 (15 ml), and the mixture was cooled

to 0°C. 4 N HC1 solution in 1, 4-dioxane (2 ml) was added and the mixture was stirred for 15 min at 0°C. The solvent was evaporated, and diethyl ether (5 ml) was added to the residue. The precipitate was collected by filtration and dried to give 1-f [2- (3, 5-dimethylphenoxy)-5-nitrophenyl] sulfonyl} pi- perazine hydrochloride (480 mg, 88. 9%): mp 264-266°C ; 1H NMR (300 MHz, DMSO-d6) # 2.33 (6H, s), 3.18 (4H, br), 3.56 (4H, br), 6.96 (2H, s), 7. 03-7. 05 (2H, m), 8.45 (1H, q, J = 9.2 Hz), 8.60 (H, d, J = 2.8 Hz), 9.38 (2H, br); HPLC-MS (ESI) : Calcd for C18H21N30sS [M + H] + 392, Found: 392.

Molecular weight : 427.9101 Activity grade RBA: A Activity grade Ca2+ : A In the similar manner as described in Example 1-1 or 1-2 above, compounds in Example 1-3 to 1-100 as shown in Table 1 were synthesized.

Table 1 EX. No molstructure MW M+1 mp RBA Ca2+ F F F zou HA zip 1-3 HN N-s 505. 47344 392 120-125 A A 0// zu ouzo F CIN p p F I I 1-4 s 435. 83682 400 273-274 A A 0 HAN 00 0 cl3 CIH \ I CH3 1-5 11 459. 90894 424 211-213 C C s HAN CIH F - nez F r-F CIH 1-6 s 535. 85272 500 188-191 A A N'// (D 0 HAN oxo H3C CH3 CH3 / zu i S1 a3S/; CH, 51 475 141-143 C a Tj cl' han CH, 00 CH, Cil 11 $ ciH 455. 96432 420 182-185 A A c T-0" H, ouzo C [H 00 CH, 11 s CH, 1-9 o Nso 441. 93723 406 168-170 A A ouzo CIH R O 1-10 |-10 | o Po | 424. 86584 389 265-267 B HO B . Ouzo 11 CIH 0 1-11 HNC t 449. 9165 414 196-198 B A rTf han 0 0 aH HC go I O O 1-12 s 413. 88305 378 167-169 B B HN/ Ouzo 0 0 CIH NF CIH 0 ola 1-13 °"N% s 487. 79257 379 246-248 C C HNJ N// - nez 0 p O HN N-S 1-14 nix 381. 38542 382 118-120 B zu _. N+ 0 F CIH 0 \ 1-15 HN/--\ N-417. 84639 382 227-229 B zu i cl, O 0 'cl3 CIH O HNN-S 1-16 0 413. 88305 378 188-192 C o~9o CIH 0, 6 0 1-17 N-sf 413. 88305 378 242-244 A ouzo i o No o i F \F\ 1 Vs 0 477. 41926 363 B B HN,,) _ N+ 0 Fuzz F O pX OH CH s O O' 1-19 n N o I w 507. 44575 394 C C HN/ 0 0 ouzo Fi, F F oh F \ p 1-20 HNC ° t 495. 40969 382 C C o 0 HO 0 0 F Clip NCH F O O 1-21 pi 533. 52762 420 c c HNJ C C HN'\ ouzo Ho _oh O O' 1-22 II 511. 86429 398 C C HN/ 0 O_. 0 0 OU/ FI 0 1-23 502. 42914 Ho HN/ 0 0j X OH Fi0, 6 1-24 s 491. 44635 378 A A N'// HN/ HAN 0 0 Ol 0t X OH F O O 1-25 s 495. 40969 382 A A o HN/ HAN 0 0 p CH3 's s JL. 1-26 CIH O 9 567. 55814 495 214-220 HN CIH 0son On CIH O OH 0 1-27 N 429 88245 394 142 A A HN/ Ci 0 O O O 1 Z8 C jN V | 434. 30099 398 166-169 B A HN/ CIH + 0 O /I 00 t. O O 1-29 C N, S 9 ll 424. 86584 389 133 B B HNJ CIL 0 0 0 Hic Ou ou u 0 -30 Cll XN 441. 8936 406 194-200 C C N HAN, / 00 (' 0 HNJ HN/ CIH NOZ / O \ I NiCHa O O I 1-32 s L ; rl3 442. 92481 407 182 C B HN/ NO, ce cl 1-33 ^ Ng% \ 468. 74602 432 260-264 A A HAN CIH Nos / 0 ; t oF rNl 1-34 N 467. 85434 432 128 A A HNJ/ CIL CH, Chug O s0 00 P 1-35 N 461. 0025 425 267-268 B A HNJ/ CIH CH. 0 cl, O \ I CHa H C 1-36 0t5 t CH 455. 95432 420 155 B A HN CIH NO, A.. 1-37 0 443. 90954 408 113 A A N. s HN J CIH N02 NO, 'NO O Z O i0 i X NO 444. 85349 409 150 B A HNJ CIH Y CIH Nos O-Br °i t CIH9O 478. 75199 442 119 A A HNJ/ CIL NOS CH, f 455. 95432 420 140-150 A A fun 00 CL, a H 00 CH, O O \ CHa 1-42 - Rjtj 531. 50589 459 288-290 C C i cru H C'HN N-S 0 \ CH3 1-42 -- o 531. 50589 459 288-290 C C non- 0 nez cl 1 CHEZ 0 OCH, 1-43 Cl 9/sQ 450. 91099 415 238-239 A A c nus H HNJ I/ F F F CN \ C ! H 0 I C O i O 1-44 °ss'9 441. 93723 406 159 B B CIH oJ\cl HAN NO, a aH 1-45 01-S , 0 482. 77311 446 168 A A ni H I/ Nô ;, CH, CH, 1-46 O O \ CH3 450. 91099 415 250-251 C C cl N// In 0 F F F O CH3 rN 1-47 HNJ 457. 93663 422 188 B C NOZ CH3 CIH a A 1-48"C ' o o a X < t 508 8 135 471 170 A A CH3 ouzo ouzo CH3 CH3 1-49 CH, 412 9391 377 125 A NEZ HN OH AU CIH CH3 G O \ CI 1-50 V I 49877251 452 181 X f"h HN, 0 a au ah 1-51 C °4S'X 44 92 _ 145 A ru J F a OH H F OH f 1-52 01-396. 9397 361 136A Nazi CL 3 °Y° o'" i N 1-53 aH 495. 34155 423 amorphous B ru dz HNJ I/ NO 0 aH OH OSO H. C °°JL 1-54 3 vNo ; ¢ 455. 96432 420 159 A A HN Cl CIH OH 1-55 C NS 471. 74954 n. d. 231 A HN ci nez HAN aH NO, cl X °+ t 458. 19352 421 255-257A A HN/ r3 CI HAN aH ci ci 1-57 502. 64452 467 269-271A A w HN/ aH B' CH3 /I 1-58 ff '400. 90304 365 204 A W CIH HNJ F) 6 ci I 0 0 1-59 441. 73892 405 306 A Han J zozo CIH OH CHEZ HN N,, il 1-60 os 448. 32808 412 204 B B ouzo 0 o''N o HN HN 0 0 CH3 N,, Il 1-61 cil 441. 93723 406 220 B B oxo aH HAN 00 CF6 N O O \ CI-I os con 1-62 o I 427. 91014 392 142 A A ouzo o o au HN . O O-v'C Nus 1-63 o I 427. 91014 392 142 B A i ouzo cl go N, 11 HN N\O O 1-64 C H 427. 91014 392 141 A A ouzo ouzo cl AH HN N,, Il 1-65 LD s CH, 441. 93723 406 187 A A o coo 00 CH3 CL H HO 00 CH, N, ll 1-66 os 455. 96432 420 193 B B o ouzo ouzo aH han C S O O-v N NII 1-67 ol 414. 87063 379 248 A ouzo o-o aH HO 0 0 Asz 1-68 0 475. 95474 440 99 A ouzo ouzo au HN -9 O OXCH _ _ 1-69 441. 93723 406 248 A o ouzo o o HAN N 11 0, s 1-70 11 X XCH, 414. 87063 379 237 A ouzo aH N, lu HN O O OH 1-71 LD s 429. 88245 394 182 A 11 ouzo 0 0 aH HN O HAN 1-72 0 453. 94838 418 168 A ouzo F CIH F/F HN 0 F 1-73 s F 489. 80811 454 297 A 0 0 _. N 0"-0 0 0 F HN 'O O F 1-74 O4F 471. 81768 436 104 A A o ouzo ouzo o- Ah HN--,) 0 0 CH, 1-75 s 458. 88058 423 215 A o ouzo ber Br CIL HN Null 1-76 s 557. 64802 521 205 A A o cl _ N+ Cl Cl CIL HN -O O CI 1 =7 ot 488. 73845 450 263 A A coo 0 0 o o a aH HN O \ I G 1-78 Xi 482. 77311 445 >300 A H I N O O Ci-riz Go 9 O O XCH 1-79 s 462. 35517 427 178-179 A A i CF OH HAN 0 0 HN O O 1-80 O-N>o 448. 32808 413 166-167 A A 0 0 cl3 C3 au N, ll HN OJ v'CH3 1-81 s 490. 40935 455 c c ouzo ah HAN 0 0 a N 1-82 os I G 468. 74602 433 173-174 B ouzo o o CIL HN N-10 0 a oit 468. 74602 433 167-168 C I I N a GEH HO zozo 1-84 CN>S) a 468. 74602 433 179-180 A A zu ouzo HAN HN to o a oil 1-85 o-' 452. 29142 417 172-173 0 0 ci ce CIH 11 HN N O O G 1-86 os ci 503. 19105 468 188-189 A A -''k ouzo aH HAN I HN N, pu N¢O 512 75597 475 240-241 A A Ho O 1 0 0 0-0 O CI-1 O O 0 CF 435. 50275 436 163-164 A A A N ? H, o o 0 CF 1-89 479. 55633 480 A A oyo CH, au aw o-"cH, -90 H C Sz 9 3 441. 93723 406 A A Hz o 0"0 GH p G _ _. Nos 1-91 s'9 482. 77311 446 261-263 A A HN I I o_. N cru CH, O o oJSCH3 O O 1-92 H3C\ N IS 455. 96432 420 A A HN\ J/ CA HHN CH, 0 a via 0% O 1-93 N S 496. 8002 460 A A Han\ J CIH CH3 p'O CH3 CH OCH, X _ Ns 455. 96432 420 >300 A HO CH3 aH oAa a /I cl H O \ G N OSiO 1-95 P4 11 442. 70778 446 220-221 A H a cl osa O \ G O O 1-96 r'H'S 496. 8002 A HAN J CIH' OH. TU CIL ci ob cl 1-97 siJ. 460. 33923 460 148-151 A H, nec oxo zu I o o ° ci s 504. 34918 504 200-201 A _. nez 0 Choral cil/ Chiral 468. 74602 432 247-250 HAN ouzo oxo Choral CIH 1-100 488. 74802p432 255-258 p 0 0 0-0 Example 2-1

(1) To the solution of 3,5-dimethylthiophenol (82.94 mg, 0.60 mmol) in dry THF (5ml) was added NaH (60%, 24 mg, 0.60 mmol). tert-Butyl 4- [ (2-chloro-5- nitrophenyl) sulfonyl]-l-piperazinecarboxylate (162mg, 0.4 mmol), which was prepared in the step (l) of Example 1-1, was added to the solution after lOmin.

The resulting mixture was stirred at room temperature overnight. 60 mg of K2CO3 was added and the mixture was stirred at room temperature for 6hrs.

EtoAc was added and the mixture was washed by 10% aqueous Na2C03, brine, successively. The organic layer was dried over MgS04. The solvent was evaporated to 3 ml, the produced white crystal was collected by filtration and dried to give ter-butyl 4- ( {2- [ (3, 5-dimethylphenyl) sulfanyl]-5-nitrophenyl}- sulfonyl)-l-piperazinecarboxylate (148 mg, 72. 9%).

(2) To the solution of tert-butyl 4-({2-[(3, 5-dimethylphenyl) sulfanyl]-5-nitro- phenyl} sulfonyl)-l-piperazinecarboxylate (100 mg, 0.20 mmol) in dry CH2C12 (3 ml) was added 4 N HCl (0.5 ml) solution in 1,4-dioxane, the mixture was stirred overnight at room temperature. The solvent was evaporated, and 5ml of diethyl ether was added to the residue. The precipitate was collected by filtration and dried to give 1- ( {2- [ (3, 5-dimethylphenyl) - sulfanyl]-5-nitrophenyl} sulfonyl) piperazine hydrochloride (82 mg, 93.8%) : mp 225-227°C ; 1H NMR (300 MHz, DMSO-d6) 8 2.34 (6H, s), 3.18 (4H, br), 3.63 (4H, br), 7.09 (1H, d, J = 9Hz), 7.25 (1H, s), 7.31 (2H, s), 8. 30 (1H, q, J = 9 Hz), 8.54 (1H, d, J = 2), 9.57 (2H, br); HPLC-MS (ESI) : Calcd for C18H2lN304S2 [M + H] + 408, Found: 408.

Molecular weight: 443.9747 Activity grade RBA: A Activity grade Ca2+ : A In the similar manner as described in Example 2-1 above, compounds in Example 2- 2 to 2-24 as shown in Table 2 were synthesized.

Table 2 t OtMJ . EX. No. molstructure MW M+1 mp RBA Ca2+ o cri N 2-2 os 532. 46856 533 147-148 A A ci N _ N+ N'lu CI \ IN\o s ci 2-3 s 530. 49625 531 191-192 A A °'lu cl ci s i H CH, CH3 - nu ci cil-T Cl HAN H N 2-5 CIH H 458. 77238 421 189 A ouzo _ N+ cl cl O 0 S CI 2-6 548. 46796 548 156-158 A H3C0 ^'N J I/ lu v 0-0 o'o ci Sb"Cl Ns 476. 40383 476 147-149 A 2-7 zu ci cl S \ CI | HzN A 2_g 512. 8648 476 205-207 A MON CIH CIL cl S \"CI Ct sLa 520. 45741 520 131-133 A Hz ouzo ce / g CI 2-10 NoSD 520. 41378 520 209-211 A 0 0--o + 0"-0 _ A Chiral __ CIH CI 050 2-11 H2N-C"s 484. 81062 448 270 A A L oNo L o No CIH Choral Raz 0. 0 f vs 484. 81062 449 263 A A 0 0 ouzo a i 2-13 sj : : ci 518. 4851 518 A A I ouzo , ci OUZO H HN \ I S NS O 2-14 0//415. 92056 380 B -. zu OXO H3C/CH3 CI H HN \ I S ICH 2-15 o 458. 00183 422 274 B -. , ci OXO ICI I, so S CH3 NS O 2-16 ° 0 429. 94765 394 229-231 A -. _. N+ O O CI ! b L-t S \ CI NSO 2-17 g/St 450 36559 414 235-237 A 0 0 ci Ouzo Cl H HN \ 2-18 N O S CI 2-18 eNoS-484. 81062 448 262-264 A Hz ouzo N Zur S \ F NSO 2-19 °"SX 433. 91099 398 236-238 A Ouzo F F OUZO , cul Ha F CI \ I F S 2-20 XNsS'9 F F 551. 91732 516 230-231 A cl zu H ho s N 0 S NS O 2-21 O'I 465. 9811 430 273 g 2-21 0 0 0 ci CAF s j t s-a kN. 0 ! 2-22 s. 516. 46916 516 213 A A zu O_. nô cl cri CH, Cl 2-23 N, o 464. 39268 464 102 A A C3 / zu a cl cri 2-24 N S \ 490. 43092 490 A A o -. ouzo O Q Example 3-1

(1) To the solution of 3,5-dimethylaniline (96.9 mg, 0. 80 mmol) in dry THF (15 ml) was added NaH (60%, 24 mg, 0.6 mmol) followed by tert-butyl 4- [ (2- chloro-5-nitrophenyl) sulfonyl]-1-piperazinecarboxylate (162.3 mg, 0.40 mmol), which was prepared in the step (1) of Example 1-1 and the mixture was stirred at 80°C for 2 hrs. The solvent was evaporated and 15 ml of ice water was added to the residue. The mixture was extracted with CH2C12. The combined extract was washed with saturated aqueous NaHC03, brine, successively, dried over MgS 04. The solvent was evaporated and 10 ml of diethyl ether was added to the residue, the produced precipitate was collected by filtration and dried to give tert-butyl 4- ( {2- [ (3, 5-dimethylphenyl) amino]-5-nitrophenyl}- sulfonyl)-l-piperazinecarboxylate (110 mg, 56. 1%).

(2) To the suspension of tert-butyl 4- ( {2- [ (3, 5-dimcthylphenyl) amino]-5-nitro- phenyl} sulfonyl)-l-piperazinecarboxylate (150 mg, 0.31 mmol) in CHUCK (2 ml) was added 4N HC1 solution in 1,4-dioxane (lml), the mixture was stirred for 2 hrs at room temperature. The mixture was filtered. The filtrate was evaporated, and 5ml of diethyl ether was added to the residue. The precipitate was collected by filtration and dried to give N- (3, 5-dimethyl- phenyl)-4-nitro-2- (l-piperazinylsulfonyl) aniline dihydrochloride (115 mg, 81.2%) : mp 175-179°C ; 1H NMR (300 MHz, DMSO-d6) 6 2.30 (6H, s), 3.18 (4H, t, J = 5. 3 Hz), 3.44 (4H, q, J = 5. 3 Hz), 6.97 (3H, s), 7.10 (1H, d, J = 9.4 Hz), 8.25 (1H, q, J = 9.4 Hz), 8.34 (1H, d, J = 2.64 Hz), 8.47 (1H, s), 9.23 (2H, br); HPLC-MS (ESI) : Calcd for CisH22N404S [M + H] + 391, Found: 391.

Molecular weight: 463. 3864 Activity grade RBA: A In the similar manner as described in Example 3-1 above, compounds in Example 3- 2 to 3-12 as shown in Table 3 were synthesized.

Table 3 EX. No. molstructure MW M+1 mp RBA Ca2+ CIH cl I 3-2 °ts'467. 76129 431 160 A A HN _ N Zu HN O O vs N 3-3 HNW t 412. 89832 377 155 B B ouzo CIH CH, O p HN \ VS 3-4 H J 412. 89832 377 158 B B han CIH ah CL3 0 han fTI 3-5 HN 412. 89832 377 239-240 C B ouzo CIH OH zu HN Q i r"f Yi 3-6 HN 433. 31626 397 a C ! B oxo CIL CIH CI 0 0 H HAN O\ O r'NS \ 3-7 HNJ 9 433. 31626 397 150 A coo CIH cri \ 0.. 0" ? N T 3-8 CIH 433. 31626 397 267 A ouzo CIH F----- 0 0 HI f), HJ fJ 3_g 3-9 HN 416. 86166 381 275 A ouzo CIH F 0 0 HN O p HN \ S 3-10 N 416. 86166 381 A han oxo CIH ;--, IF O p HN o., or N f3, I HN 3 11 | o N A o nô CIH OH O p HN \ N I r3 3-12 HN 1 428. 89772 393 241-242 A - oxo OH Example 4-1

(1) To the solution of 2-chloro-5-nitrobenzenesulfonyl chloride (2. 05g, 8 mmol) in THF (60 ml) was added the solution of 4-(1-pyrrolidinyl) piperidine (1.23 g, 8 mmol) and NEt3 (0.89g, 8.8 mmol) in THF (15 ml) dropwise. The mixture was stirred at room temperature for 2hrs. 3,5-Dichlorophenol (1.96 g, 12 mmol) was added to the above mixture followed by NaH (60%, 0.96 g, 12 mmol). The resulting mixture was stirred at 65°C for 8 hrs, and cooled to room temperature. The precipitate was collected by filtration and washed with THF, Et20, and water, successively, dried in vacuo to give 1- { [2- (3, 5- dichlorophenoxy)-5-nitrophenyl] sulfonyl}-4- (l-pyrrolidinyl) piperidine as white powder (3.2 g, 79. 9%) : mp 217-218°C ; 1H NMR (500 MHz, CDC13) 8 1.26 (2H, s), 1.63 (4H, d, J = 10 Hz), 1.77 (4H, s), 1.92 (2H, d, J = 6. 1Hz), 2.15 (1H, m), 2.34 (6H, s), 2.97 (2H, p, J = 10 Hz), 3.86 (2H, q, J = 9.3 Hz), 6.74 (2H, s), 6.90 (1H, d, J = 9.1 Hz), 6.94 (1H, s), 8. 24 (1H, q, J = 9.1 Hz), 8.86 (1H, d, J = 2.85 Hz); HPLC-MS (ESI) : Calcd for C21H23Cs2N305S [M + H] + 501, Found : 500 and 502

Molecular weight: 500.4046 IC50 (CCR3): 8 uM ICso (Ca2+) : 7 µM ICso (Chemotaxis): 5 µM In the similar manner as described in Example 4-1 above, compounds in Example 4- 2 to 4-41 as shown in Table 4 were synthesized.

Table 4 EX. No. molstructure MW M+1 mp RBA Ca2+ CH, O O CH3 4-2 433. 53044 434 A A N Hz N H// 0 0 0'0 CHEZ 0 0 CH, 4-3 N-S 435, 50275 436 B A N zu ouzo cru O O CH3 4-4 SN ól t 405. 47626 406 131-132 A A Hic H CN I/ zu '3 0 0 CH3 4-5 C, 419. 50335 420 111-112 A A o I FC"-- CH3 1-0 CHU 0-CH, 4-6 N I 473. 59577 474 190-192 A A /nu/ 1 o-o CL I q 4-7-0//s 467. 54795 468 168-169 C C o-* 0 CL, oxo O O \ CH3 4-8 481. 57504 482 168-170 C C 0 1 N + H, C- 0-0 CH, 0 OCH, 4-9 481. 57504 482 123-124 C i 0 0 . F- CH, 0 OCH, 4-10 s 419. 45972 437 210-212 C r ! 0 0 zu su I 4-11 CNN-I 459. 56868 460 156-158 A 0 1 o No CH, --N 0 4-12 HC p N-0 CH, 447. 55753 448 86-88 A A 0 ouzo CH, 0 I"CN-0, &CH, t _Ns 419. 50335 420 115-116 A A T) 01 CH, cl, H, C N"CH, 0-1 : : 'CH, 0 4-14 N-407. 4922 408 75-77 A A in zu 0 0 /I \ H C 3 | 4-15 o Nso | 433 53044 434 129-131 A A 0 1 oxo CHEZ /i 4-16 N N-S 447. 55753 448 134-135 A A H'c -- o zu 0 0 H3 , c I 0 cl3 -2-, Sl 461. 58462 462 93-95 A A ouzo chug Nc 0 CN 4-18)-N, -s'L 461. 58462 462 131-132 A B 0 0 0 CH3 I 0 0 CH3 4-19 o No 459. 56868 460 169-171 A A zu a o- nô a O O \ G 4-20 H3c\ | 448. 32808 448 105-107 A A han H, C'N 03C ci Cl Foc + o_. N 4-21 o 9 466. 39341 488 120-121 A A -. ouzo ce ci LEZ o CI I I 4-22 N s 500. 40456 500 200-202 A A ouzo 0-" Cl H3C\ AMA 4-23 460. 33923460 SA 'in Fi C-ND 0 Ouzo H3 c3 O 0 NS \ 4-24 CIH 469. 99141 434 262-264 A A i CIL cl a B o H3CN) °41 482. 34559 483 226 B 0 0 zu O CH3 0 N'' iN O O CH3 0,,, S 475. 56808 476 178-179 A A li erz o cl N CI No 151640396517 182-183pA j 0 10 oxo 0 N 0 s-&CF 4 N, ll 4-28 os 491. 63268 492 143-144 A o i w i cl ci 0 c 0. 4-29 COS+} 514. 43165 515 173-174 A A i o_. NN ci ci 0 cri 4-30 534 s 9 531. 46226 531 98-99 A 1 ! 1 ; H, C y Cl cl 4-31 0-Sl-0 503. 40808 503 138-140 A H3CoN~Nx) C, I zu ci O \ CI O 0 4-32 NS 529. 44632 529 167-169 A NJ I/ o"o CH,, I 0 0 CF6 4-33 NS I 487. 50173 488 A A / 0'o F c I-- ci zu 4-34 N 528. 33761 528 166-167 A A 4-34 ouzo zoo 0 O. N O ce \ 476. 38226 476 134 A CH3 CH3 H I/ ci cl a O O CI 4-36 r---NIs 504. 39281 504 145 A A 0 0 cri oc 0 4-37 N 532. 40336 532 160-162 A HsC\/0 II NJ I/ 0-. 0 zu ce ci O \ CI 4-38 C/'50>$ 466. 37747 486 A A lu ouzo Ci cl CH3 O CI X Cl | 462. 35517 462 A ouzo oxo t CH3 CI 4-40 01, S. -0 502. 4205 502 A ce ci o ci 0 X ~"sD 474. 36632 474 A y 0 0 Example 5-1

(1) The mixture of tert-butyl 4-f [2- (3, 5-dimethylphenoxy) -5-nitrophenyl]- sulfonyl}-l-piperazinecarboxylate (6. 80g, 13.83 mmol), which was prepared in the step (2) of Example 1-1 and 10% Pd-C (1) in methanol (600 ml) was stirred at room temperature under 1 ATM of H2 for 5 hrs. The Pa-C was filtered off. The filtrate was evaporated to 30 ml. The produced crystals was collected by filtration to give tert-butyl 4-{[5-amino-2-(3, 5-dimethyl- phenoxy) phenyl] sulfonyl}-l-piperazinecarboxylate (6.0 g, 94.0%). : HPLC- MS (ESI): Calcd for C23H3lN305S [M + H] + 462, Found: 462.

Molecular weight: 461.5846 Activity grade RBA: C Activity grade Ca2+ : C Example 5-2

(1) To the mixture of copper (I) chloride (39.6 mg, 0.4 mmol) and tert-butyl nitrite (41.2 mg, 0.4 mmol) in CH3CN (10 ml) was added tert-butyl 4-{[5- amino-2- (3, 5-dimethylphenoxy) phenyl] sulfonyl}-1-piperazinecarboxylate (92.3 mg, 0.2 mmol) which was prepared in the Example 5-1 at 60°C. The mixture was stirred at 65-70°C for 2hrs, and cooled to room temperature. The solvent was evaporated. CH2Cl2 was added to the residue and the mixture was washed with 15 ml of 4N NaOH, 30 ml of brine, successively, dried over MgS04. The solvent was evaporated, and the residue was purified by preparative TLC on silica gel (CH2C12/CH30H =35/1) to give tert-butyl-4- {[5-chloro-2-(3, 5-dimethylphenoxy) phenyl] sulfonyl}-1-piperazinecarboxylate (56.0 mg, 58.2%).

(2) To the suspension of ter-butyl 4-{[5-chloro-2-(3, 5-dimethylphenoxy) phen- yl] sulfonyl}-l-piperazinecarboxylate (40.0 mg, 0.08 mmol) in dry CH2C12 (1.5 ml) was added 0.3 ml of 4N hydrogen chloride solution in 1,4-dioxane, the mixture was stirred for 5 hrs at room temperature. The solvent was evaporated, and diethyl ether (5 ml) was added to the residue. The produced precipitate was collected by filtration and dried to give I-f [5-chloro-2- (3, 5- dimethylphenoxy) phenyl] sulfonyl} piperazine hydrochloride (24.0 mg, 69.2%) : mp 202-204 °C ; 1H NMR (300 MHz, DMSO-d6) 8 2.30 (6H, s), 3.14 (4H, be), 3.50 (4H, br), 6.82 (2H, s), 6.91 (1H, s), 6.97 (1H, d, J = 8.7 Hz), 7.70 (1H, t, J = 8.7 Hz), 7.82 (1H, d, J = 2.3 Hz), 9.57 (2H, br); HPLC- MS (ESI) : Calcd for C18H21CIN203S [M + H] + 381, Found: 381.

Molecular weight: 417.3576 Activity grade RBA: A Activity grade Ca2+ : A In the similar manner as described in Example 5-1 or 5-2 above, compounds in Example 5-3 to 5-8 as shown in Table 5 were synthesized.

Table 5 EX. No. molstructure MW M+1 mp RBA Ca2+ F F F xi O O CH 5-3 Ho 475. 49058 362 133-135 C C HN N-S Nez NF H C O \ CH 5-4 3 N N-S 3 408. 95085 409 120-122 A A a ce ci \ 5-5 H, C 0-&CH, 500. 40225 501 133-134 A A o 0 i 0 OCH, 5-6 508. 80904 473 241-243AA ci j 0 1 HAN I CH3 o' OO)' X s NzSt92 448. 41534 376 183 C C F3 HAN CIH aH CH3 CH, CL 5_8 OSO 431. 38473 395 148 Pizza Han 11 f3 CIL Example 6-1

(1) To the solution of tert-butyl 4-{[5-amino-2-(3, 5-dimethylphenoxy) phenyl]- sulfonyl}-l-piperazinecarboxylate (138. 5mg, 0.30 mmol) prepared in the step (1) of Example 5-1 in CH2C12 (5 ml) was added nitrosonium tetrafluoroborate (38. 5 mg, 0.33 mmol) at 0 °C and the solution was stirred at 0°C for 30 min.

The solvent was evaporated. The residue was dissolved in methanol (5 ml) and the solution of Cu2O (64.4 mg, 0.45 mmol) and CuSO4. 3H20 (724.8 mg, 3 mmol) in 10ml of water was added to the above solution at 0°C. The mixture was stirred at 0°C for 30 min. The solvent was evaporated and ethyl acetate was added. The mixture was washed with 1 N aqueous NaOH, brine, successively and dried over MgS04. The solvent was evaporated and the residue was purified by preparative TLC on silica gel (CH2C12/CH3OH = 20/1) to give tert-butyl 4-{[2-(3, 5-dimethylphenoxy) -5-hydroxyphenyl]- sulfonyl}-l-piperazinecarboxylate (39.0 mg, 28. 1%).

(2) To the suspension of tert-butyl 4- { [2- (3, 5-dimethylphenoxy) -5-hydroxy- phenyl] sulfonyl}-l-piperazinecarboxylate (12.0 mg, 0.03 mmol) in dry CH2C12 (lml) was added 4 N HC1 solution in 1, 4-dioxane (0. 18 ml), the mixture was stirred 5hrs at room temperature. The solvent was evaporated, and 3ml of diethyl ether was added to the residue. The precipitate was collected by filtration and dried to give 4- (3, 5-dimethylphenoxy)-3- (1- piperazinylsulfonyl) phenol hydrochloride (9.0 mg, 87.0%) : mp >286 1H NMR (300 MHz, DMSO-d6) 8 2.24 (6H, s), 3.12 (4H, br), 3.36 (4H, br), 6.56 (2H, s), 6.76 (1H, s), 6.96 (1H, d, J = 9 Hz), 7.08 (1H, q, J = 9 Hz), 7.25 (1H, d, J = 2.6 Hz), 9.03 (2H, br), 10.06 (1H, s); HPLC-MS (ESI) : Calcd for Ci8H22N204S [M + H] + 363, Found: 363.

Molecular weight: 398. 9120 Activity grade RBA: C Activity grade Ca2+ : C

Example 6-2 (1) To the solution of tert-butyl 4-{[2-(3, 5-dimethylphenoxy) -5-hydroxyphenyl]- sulfonyl}-l-piperazinecarboxylate (20.0 mg, 0.04 mmol), which was prepared in the step (1) of Example 6-1 in dry DMF (lml) was added methyl iodide (30.7 mg, 0.22 mmol) and K2CO3 (12.0 mg, 0.09 mmol). The mixture was stirred at room temperature for 3 hrs. The solvent was evaporated in vacuo and 3ml of ice water was added. The white precipitate was collected by filtration and washed with 1 N aqueous NaOH, water and dried to give tert- butyl 4-f [2- (3, 5-dimethylphenoxy) -5-methoxyphenyl] sulfonyl}-1-piperazine- carboxylate as white powder (20.0 mg, 97. 1%).

(2) To the solution of tert-butyl 4- { [2- (3, 5-dimethylphenoxy)-5-methoxyphenyl]- sulfonyl}-l-piperazinecarboxylate (18. 0 mg, 0.04 mmol) in dry CH2Cl2 (1 ml) was added 4 N HCl (0.2 ml) solution in 1,4-dioxane, the mixture was stirred 5 hrs at room temperature. The solvent was evaporated, and 3 ml of diethyl ether was added to the residue. The precipitate was collected by filtration and dried to give 4- (3, 5-dimethylphenoxy)-3- (1-piperazinylsulfonyl) phenol hydro- chloride (12.0 mg, 76.9%) : mp 175-177°C ; 1H NMR (300 MHz, DMSO-d6) 8 2.25 (6H, s), 3.12 (4H, t, J = 4.5 Hz), 3.40 (4H, d, J = 4.5 Hz), 3. 82 (3H, s), 6.62 (2H, s), 6.80 (1H, s), 7.04 (1H, d, J = 9.1 Hz), 7.27 (1H, q, J = 9.1 Hz), 7.33 (1H, d, J = 3.0 Hz), 9.24 (2H, br); HPLC-MS (ESI): Calcd for CisH24Nz04S [M + H] + 377, Found: 377.

Molecular weight: 412.9391 Activity grade RBA: A Activity grade Ca2+ : B In the similar manner as described in Example 6-1 or 6-2 above, compounds in Example 6-3,6-4 and 6-5 as shown in Table 6 were synthesized.

Table 6 EX. No. molstructure MW M+1 mp RBA Ca2+ CH3 0 0 \ cl 6-3 ici 3 364. 4421 365 116-118 A A s HN3N' 0 CL ci 0 0 ci 11 6-4"I's 412. 2974 412 179-181 9 7 0 HN 0 N cri cl 0 0 GI I I 6-5 ZCN/\ ? 480. 4169 480 186-18 20 17 j ! ! N N Example 7-1

(1) To the mixture of tert-butyl 4-{[5-amino-2-(3, 5-dimethylphenoxy) phenyl]- sulfonyl}-l-piperazinecarboxylate (369 mg, 0. 80 mmol), which was prepared in the step (1) of Example 5-1, and triethylamine (97 mg, 0.96 mmol) in dry CH2C12 (20 ml) was added dropwise the solution of phenylacetyl chloride (130 mg, 0.84 mmol) in THF (5 ml) at 0°C with stirring. The mixture was then stirred at RT for 3 hrs, and CH2C12 was added. The mixture was washed with 0.5 N aqueous HC1, brine, saturated aqueous NaHC03, brine, succes- sively, dried over MgS04. The solvent was evaporated. Dry CH2C12 (15 ml) was added to the residue. 4 N HC1 solution in 2,4-dioxane (lml) was added to the solution at 0°C with stirring. The mixture was then stirred at room temperature for 3 hrs. The obtained precipitate was collected to give product as HC1 salt. The HC1 salt was suspended in 10 ml of ice water and the PH of the mixture was adjusted to 8 by addition of saturated aqueous NaHC03, extracted by CH2C12. The combined extract was washed with saturated aqueous NaHC03, brine, successively, dried over MgS04. The solvent was evaporated. 5 ml of methanol was added to the residue and the white precipitate was collected by filtration and washed with ether and dried to give

N- [4- (3, 5-dimethylphenoxy)-3- (1-piperazinylsulfonyl) phenyl] -2-phenylacet- amide (330 mg, 86.0%) : mp 228-230°C ; 1H NMR (300 MHz, CDC13). 2.28 (6H, s), 2.87 (4H, br), 3.24 (4H, br), 3.74 (2H, s), 6.62 (2H, s), 6.79 (1H, s), 6.87 (1H, d, J = 8. 8 Hz), 7.34-7. 62 (6H, m), 7.62 (1H, s), 7.95 (1H, q, J = 8. 8 Hz); HPLC-MS (ESI) : Calcd for C26H29N304S [M + H] + 480, Found: 480.

Molecular weight: 479.6027 Activity grade RBA : C Activity grade Ca2+ : C In the similar manner as described in Example 7-1 above, compounds in Example 7- 2 to 7-9 as shown in Table 7 were synthesized.

Table 7 EX. No. molstructure MW M+1 mp RBA Ca2+ CH3 N 7-2 HNJ CH3 403. 504 404 C C HN dz H3C CH3 0 0 zon N 0 445. 5852 446 C C C C han OHH3 CH3 CH 0 s HN J 7-4/-445. 5852 446 C C HN 0 CH3 H3C CH, CIL /-\ ? HAN NUS 7-5 502. 0366 466 C C OH CL CIL , 0 C. HN N-S 7-6 516. 0637 484 C C 0NH I CF OH) t) CIH Y HN N S 7-7 552. 0972 516 C B 0 NH NU CH, 0 \\ 5-0 7-8 HN 493. 6298 494 C C 0 cl3 0 po ru 7-9) =" 471. 6014 472 C C HN ) e=0 0 Example 8-1

(1) To a solution of 4-bromoanisole (2.00 g, 10.7 mmol) in CHC13 (20 ml) was added chlorosulfonic acid (1.49 ml, 22.5 mmol) at 0°C. This mixture was stirred at room temperature for 2 hrs, and then poured into ice water (50 ml).

This mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over anhydrous MgS04, filtered, and concen- trated to give crude 5-bromo-2-methoxybenzenesulfonyl chloride (0.760 g, 24.9%).

(2) To a solution of 5-bromo-2-methoxybenzenesulfonyl chloride (760 mg, 2.66 mmol) and Et3N (445 ul, 3.19 mmol) in CH2C12 (20 ml) was added 1- (t- butoxycarbonyl) piperazine (521 mg, 2.80 mmol) at 0°C. This mixture was stirred at room temperature for 6 hrs, and then diluted with Et20, washed with 10% citric acid solution, aqueous NaHC03, and brine. The organic layer was dried over anhydrous Na2S04, filtered, and concentrated to give crude sulfonamide (716 mg).

To a solution of the sulfonamide (716 mg, 1.65 mmol) in CHUCK (5 ml) was added 1M BBr3 solution in CH2Cl2 (3.30 ml, 3.30 mmol) at 0°C. This mixture was stirred at 0°C for 1 hr. After basifing with 3M aqueous NaOH (20 ml), THF (15 ml) and Di-t-butyl dicabonate (718 mg, 3.29 mmol) were added to the mixture at 0°C. The mixture was stirred at room temperature overnight. This mixture was extracted with Et20. The organic extract was dried over anhydrous Na2S04, filtered, and concentrated to give di (Boc)- compound. To hydrolize t-butyl carbonate, the residue was treated with K2CO3 (455 mg, 3.29 mmol) in MeOH (10 ml) at room temperature for 5 hrs.

After removing MeOH by evaporation, the residue was acidified with 10% citric acid solution. This aqueous mixture was extracted with EtoAc. The organic extract was dried over anhydrous Na2S04, filtered, and concentrated to give tert-butyl 4- [ (5-bromo-2-hydroxyphenyl) sulfonyl]-l-piperazinecarb- oxylate (526 mg, 47.0%).

(3) To a mixture of ter-butyl 4- [ (5-bromo-2-hydroxyphenyl) sulfonyl]-1-pip- erazinecarboxylate (410 mg, 0.973 mmol), 3,5-dimethylphenylbronic acid (219 mg, 1.46 mmol), Cu (OAc) 2 (177 mg, 0.973 mmol), and powdered 4A molecular sieves (820 mg) in CHsClz (10 ml) was added Et3N (0.678 ml, 4.87 mmol) at room temperature. This mixture was stirred at room tempera- ture under ambient atmosphere overnight. The resulting slurry was filtered through Celite. The filtrate was diluted with EtoAc, and washed with aqueous NH4Cl, NaHC03, and brine. The organic layer was dried over anhy- drous Na2S04, filtered, and concentrated. Et20 was added to the residue.

The resulting precipitate was collected by filtration, and washed with Et20.

This solid was purified by column chromatography on silica gel (CHCl3/MeOH=99/l) to give tert-butyl 4- { [5-bromo-2- (3, 5-dimethyl- phenoxy) phenyl] sulfonyl}-l-piperazinecarboxylate (320 mg, 62.6%).

(4) To a solution of tert-butyl 4-{[5-bromo-2-(3, 5-dimethylphenoxy) phenyl]- sulfonyl}-l-piperazinecarboxylate (25.0 mg, 48. 0) J. mol) in CH2C12 (1. 0 ml) was added 4M HCl solution in 1,4-dioxane (100 µl, 400 mol) at 0°C. This mixture was stirred at room temperature overnight. Solvents were removed by evaporation. The resulting residue was suspended in Et2O, and collected by filtration to give a white amorphous, 1-{[5-bromo-2-(3, 5-dimethyl- phenoxy) phenyl] sulfonyl} piperazine hydrochloride (20.0 mg, 90.2%) : 1H NMR (300 MHz, CDC13) 6 2.31 (6 H, s), 3.12-3. 38 (4H, br), 3.60-3. 84 (4H, br), 6.72 (2H, s), 6.75 (1H, d, J= 8.7 Hz), 6. 87 (1H, s), 7.54 (1H, dd, J= 2.3, 8. 7 Hz), 8. 05 (1H, d, J = 2.3 Hz), 9.79-10. 40 (2H, br); HPLC-MS (ESI) : Calcd for C18H2iBrN203S [M + H] + 425 and 427, Found: 425 and 427.

Molecular weight: 461.8086 Activity grade RBA: A Activity grade Ca2+ : A Example 9-1

(1) A mixture of tert-butyl 4-{[5-bromo-2-(3, 5-dimethylphenoxy) phenyl] sulfon- yl}-l-piperazinecarboxylate (95.0 mg, 181 mol), which was prepared in the step (3) of Example 8-1, CuCN (32.4 mg, 362 mol), and Pd (PPh3) 4 (20.9 mg, 18.1 µmol) in DMF (2 ml) was heated at 150°C overnight. After cooling to room temperature, this mixture was diluted with CH2C12, and washed with ammonia solution and brine. The organic layer was dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by column chromatography on silica gel (Hexane/EtoAc=3/1~2/1) to give tert- butyl 4- [5-cyano-2- (3, 5-dimethylphenoxy) phenyl] sulfonyl}-1-piperazine- carboxylate (14.0 mg, 16.4%). (2) To a solution of tert-butyl 4-{[5-cyano-2-(3,5-dimethylphenoxy) phenyl] - sulfonyl}-l-piperazinecarboxylate (14.0 mg, 29.7 pmol) in CH2Cl2 (1. 0 ml)

was added 4M HC1 solution in dioxane (0.2 ml) at room temperature. This mixture was stirred at room temperature overnight. Dioxane was removed by evaporation. The residue was suspended in Et2O. The resulting precipitate was collected by filtration to give 4- (3, 5-dimethylphenoxy)-3- (1-piperazinyl- sulfonyl) benzonitrile hydrochloride (6.0 mg, 49.6 %) : 1H NMR (300 MHz, CDC13) 6 2.34 (6 H, s), 3.28-3. 47 (4H, br), 3.67-3. 83 (4H, br), 6.78 (2H, s), 6. 89 (1H, d, J= 8. 6 Hz), 6.95 (1H, s), 7.69 (1H, dd, J= 1.9, 8.6 Hz), 8. 24 (1H, d, J = 1.9 Hz), 9.97-10. 32 (2H, br); HPLC-MS (ESI) : Calcd for ClgH21N303S [M + H] + 372, Found: 372.

Molecular weight: 407.9225 Activity grade RBA: A Activity grade Ca2+ : A Example 10-1 (1) To 4-chlorobenzoic acid (1.00 g, 6.39 mmol) was added chlorosulfonic acid (2. 55 ml, 38.3 mmol) at room temperature dropwise. This mixture was heated at 150°C for 6 hrs. After cooling to room temperature, the mixture was diluted with CH2C12. This solution was added to ice water. Two phases were separated. The organic phase was washed with brine, and then dried over anhydrous MgS04, filtered, and concentrated to give crude 4-chloro-3- (chlorosulfonyl) benzoic acid (0.720 g, 43.9%).

(2) To a solution of 4-chloro-3- (chlorosulfonyl) benzoic acid (200 mg, 0. 784 mmol) and Et3N (130 µl, 0.938 mmol) in CH2C12 (5 ml) was added 1- (t-butoxycarbonyl) piperazine (161 mg, 0. 864 mmol) at 0°C. This mixture was stirred at room temperature overnight, and then diluted with CH2C12, washed with 10% citric acid solution. The organic layer was dried over anhy- drous Na2S04, filtered, and concentrated. The residue was suspended in Et20, and the precipitate was collected by filtration to give crude 3-{[4-(tert- butoxycarbonyl)-l-piperazinyl] sulfonyl}-4-chlorobenzoic acid (200 mg, 63.0%).

(3) To a mixture of 3- {[4-(tert-butoxycarbonyl)-1-piperazinyl] sulfonyl}-4- chlorobenzoic acid (340 mg, 0.840 mmol), dimethylammonium chloride (137 mg, 1.68 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydro- chloride (193 mg, 1.01 mmol), and HOBT (136 mg, 1.01 mmol) in CH2C12 was added Et3N (410 J. l, 2.96 mmol) at 0°C. This mixture was stirred at room temperature for two days. The mixture was diluted with EtoAc, and washed with 10% citric acid solution, aqueous NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated.

The residue was purified by column chromatography on silica gel (EtoAc) to give tert-butyl 4- (f 2-chloro-5- [ (dimethylamino) carbonyl] phenyl} sulfonyl)-1- piperazinecarboxylate (258 mg, 71.1%).

(4) To a mixture of tert-butyl 4-({2-chloro-5-[(dimethylamino) carbonyl] phen- yl} sulfonyl)-l-piperazinecarboxylate (248 mg, 0.574 mmol) and 3,5-dimeth- ylphenol (140 mg, 0. 859 mmol) in DMF (2 ml) was added t-BuOK (129 mg, 1.15 mmol) at room temperature. This mixture was heated at 150°C for two days. After cooling to room temperature, ice water (10 ml) was added to the mixture. Two phases were separated. The aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with aqueous NaHC03 and brine, dried over anhydrous Na2S04, filtered, and concentrated. This residue was purified by column chromatography on silica gel (Hexane/- EtoAc=1/2) to give tert-butyl 4- (f 2- (3, 5-dichlorophenoxy)-5- [ (dimethyl- amino)-carbonyl] phenyl} sulfonyl)-l-piperazinecarboxylate (182 mg, 56.8%).

(5) To a solution of tert-butyl 4- ( {2- (3, 5-dichlorophenoxy)-5- [ (dimethylamino)- carbonyl] phenyl} sulfonyl)-1-piperazinecarboxylate (150 mg, 0.269 mmol) in CH2C12 was added 4M HC1 solution in dioxane (0.300 ml, 1.20 mmol) at 0°C.

This mixture was stirred at room temperature overnight. Solvents were removed by evaporation. The resulting residue was suspended in Et20 and collected by filtration to give 4- (3, 5-dichlorophenoxy) -N, N-dimethyl-3- (1- piperazinylsulfonyl) benzamide hydrochloride (50.0 mg, 37.6%) : mp 197- 199°C ; HPLC-MS (ESI): Calcd for Cl9H2lCl2N304S [M + H] + 458, Found: 458.

Molecular weight: 494. 8279 Activity grade RBA: B Activity grade Ca2+ : B In the similar manner as described in Example 10-1 above, compound in Example 10-2 as shown in Table 10 was synthesized.

Table 10 EX. No. molstructure MW M+1 mp RBA Ca2+ CHs CH3 0 \ cl3 JL 10-2 HN 490. 0443 454 242-247 B A HN J _ gSN'CH3 CIH CIH 0 1 CH3 Example 11-1

(1) To a mixture of 5-fluoro-2-nitrotoluene (1.00 g, 6.45 mmol) in CHC13 (10 ml) was added chlorosulfonic acid (0. 86 ml, 12.9 mmol) dropwise. The mixture was refluxed overnight. After the mixture was cooled to room temperature, the mixture was diluted with CHC13, then ice water was added to the mixture.

The organic layer was extracted with CHC13 and was washed with brine. The extracted organic layer was dried over anhydrous MgS04, filtered, and concentrated in vacuo to give a pale yellow oil.

The oil was dissolved in THF (50 ml). To the solution was added tert-butyl 1-piperazinecarboxylate (1.20 g, 6.45 mmol), and N, N-diisopropylethylamine (1.12 ml, 6.45 mmol) successively. The mixture was stirred at room tempera- ture for 4 hrs. The mixture was concentrated in vacuo. The residue was diluted with ethylacetate and was washed with brine. The organic layer was dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtoAc/Hexane) to give tert-butyl 4-[(2-fluoro-4-methyl-5-nitrophenyl) sulfonyl]-1-piperazine- carboxylate (1.00 g, 38.4 %) as a pale brown solid.

(2) To a solution of 3,5-dimethylphenol (33.3mg, 0.27 mmol) in 1,4-dioxane (1 ml) was added sodium hydride (60 % oil suspension, 11.9 mg, 0.30 mmol) portionwise. The mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of tert-butyl 4- [ (2-fluoro-4-methyl-5- nitrophenyl) sulfonyl]-l-piperazinecarboxylate (100 mg, 0.25 mmol) in 1,4- dioxane (1 ml) slowly. The mixture was stirred at 70°C overnight. After the mixture was cooled to room temperature, the mixture was concentrated in vacuo. The residue was washed with ice water, then was dried in vacuo to give tert-butyl 4- { [2- (3, 5-dimethylphenoxy) -4-methyl-5-nitrophenyl] sulfon- yl}-l-piperazinecarboxylate (92.8 mg, 74.1 %) as a white solid.

(3) tert-butyl 4-f [2- (3, 5-dimethylphenoxy) -4-methyl-5-nitrophenyl] sulfonyl}-1- piperazinecarboxylate (186 mg, 0.368 mmol) was placed in a frame-dried two-necked flask. It was dried in vacuo, then was purged with argon. To the flask was added dry DMF, dimethylformamide dimethyl acetal (0. 0585 ml,

0.441 mmol), and pyrrolidine 0.0369 ml, 0.441 mmol). The mixture was stirred at 110°C for 3 hrs. Additional pyrrolidine (0. 0185 ml, 0.22 mmol) was added to the mixture. The mixture was stirred at 110°C for additional 1 hr.

After the mixture was cooled to room temperature, the mixture was trans- ferred to a solution of 4 M aqueous ammonium acetate in DMF, using additional DMF to rinse the mixture into the reaction flask. To the solution was added 20 % w/v aqueous titanium (E) chloride (1.50 ml, 1.98 mmol) dropwise. The suspension was stirred at room temperature for 15 minutes.

The mixture was made basic with IN aqueous NaOH solution. The mixture was diluted with diethylether. The mixture was filtered, then the organic layer was extracted with diethylether, was washed with brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtoAc/Hexane) to give test- butyl 4-{[5-(3, 5-dimethylphenoxy)-lH-indol-6-yl] sulfonyl}-1-piperazinecarb- oxylate (42.2 mg, 23.6 %) as a pale brown solid. (4) To a solution of tert-butyl 4- { [5- (3, 5-dimethylphenoxy)-lH-indol-6-yl]- sulfonyl}-l-piperazinecarboxylate (15.4 mg, 0.0317 mmol) in CHUCK (1 ml) was added trifluoroacetic acid (0.10 ml) at 0°C. The mixture was stirred at 0°C for 2 hrs. Toluene was added to the mixture, then was concentrated in vacuo. The residue was triturated with diethylether to give 5- (3, 5-dimethyl-

phenoxy)-6- (1-piperazinylsulfonyl)-lH-indole trifluoroacetate (12.7 mg, 80.2%).

HPLC-MS (ESI) : Calcd for C2oH23N303S [M+H] + 368, Found: 368.

Molecular weight : 499.5129 Activity grade RBA: C Activity grade Ca2+ : C Example 12-1 (1) 4-Fluorobenzoic acid (5.0 g, 35.7 mmol) was added to chlorosulfonic acid (31.5 g, 0.27 mol), and the mixture was stirred at 150°C for 2hrs. After cooling to room temperature, the mixture was poured into ice-water dropwise with cooling. The resulting white precipitate was collected by filtration. The solid was washed with water, and dried in vacuo to give 3- (chlorosulfonyl)-4- fluorobenzoic acid (6.33 g, 74.3%).

(2) To a solution of 3- (chlorosulfonyl)-4-fluorobenzoic acid (1.0 g, 4.19 mmol) in THF (10 ml) was added N-tert-butyl 1-homopiperazinecarboxylate (0.92 g, 4.61 mmol) in THF (5 ml) dropwise at 0°C, followed by Et3N (1.08 ml, 6.28 mmol). The mixture was stirred at room temperature for 6hrs. After quenched by water, the solvent was removed by evaporation. The resulting residue was dissolved in 1N NaOH (24 ml), and washed with Et20 two times.

Then the aqueous layer was acidified to pH 3-4 by 1N HC1, then extracted with EtOAc 3 times. The organic layer was dried over anhydrous Na2S04, the solvent was evaporated in vacuo to give 3- { [4- (tert-butoxycarbonyl)-1, 4- diazepan-l-yl] sulfonyl}-4-fluorobenzoic acid as a colorless form (1.12 g, 66.4%) : (3) To a solution of 3-{[4-(tert-butoxyvarbonyl)-1, 4-diazepan-1-yl] sulfonyl}-4- fluorobenzoic acid (250 g, 0.62 mol) in THF (2000 ml) was added CDI (125 g, 0.77 mol) at 0°C under Ar. The mixture was stirred at 0°C for lhr.

Then NH3 gas was bubbled into the mixture for 2 hrs. White precipitate was filtered off, and the filtrate was extracted with EtOAc, washed with 1N HC1, and sat. NaHC03 solution, and brine. The organic extracts were dried over anhydrous Na2S04, the solvent was evaporated in vacuo to give tert-butyl 4- { [5-(aminocarbonyl)-2-fluorophenyl] sulfonyl}-1, 4-diazepane-1-carboxylate as a white solid (240 g, 96.2%)

(4) To a solution of tert-butyl 4-{[5-(aminocarbonyl)-2-fluorophenyl]sulfonyl}- 1, 4-diazepane-1-carboxylate (5.0 g, 12.5 mmol) in dry CH2C12 (150 ml) was added Et3N (6.94 ml, 49.8 mmol) under Ar. Then the solution was cooled to- 5°C (dry ice/i-PrOH). (CF3SO2)2O (3.14 ml, 18.7 mmol) was added to the mixture dropwise, cooling under 5°C. After 1. 5hrs, the reaction was quenched by water, then extracted with CH2Cl2, and washed with water and brine. The organic extract was dried over anhydrous Na2S04. The solvent was evaporated in vacuo. The resulting residue was purified by column chroma- tography on silica-gel (Hexane/EtoAc=1/1) to give tert-butyl 4- [ (5-cyano-2- fluorophenyl) sulfonyl]-1, 4-diazepane-1-carboxylate as a brown oil (4.12 g, 86. 3%) (5) To a solution of ter-butyl 4- [ (5-cyano-2-fluorophenyl) sulfonyl]-1, 4-diaze- pane-1-carboxylate (4. 12 g, 10.75 mmol) and 3,5-dichlorophenol (5.25 g, 32.2 mmol) in dioxane (100 ml) was added NaH (1.54 g, 37.6 mmol). The mixture was stirred under reflux for lhr. After cooled to room temperature, the mixture was quenched by water, and extracted with CH2C12 and washed with IN NaOH, and brine. The organic extract was dried over anhydrous Na2S04, the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica-gel (Hexane/EtoAc=1/1) to give tert-butyl 4-{L5-cyano-2-(3, 5-dichlorophenoxy) phenyl] sulfonyl}-1, 4-diaze- pane-1-carboxylate as a white solid (3. 08 g, 54.5%)

(6) To a solution of tert-butyl 4-{[5-cyano-2-(3, 5-dichlorophenoxy) phenyl]- sulfonyl}-1, 4-diazepane-1-carboxylate (3.1 g, 5.89 mmol) in CH2C12 (60 ml) was added 4N HCl in dioxane (60 ml). The mixture was stirred at room temperature for 2hrs. After the solvent was removed by evaporation, the resulting white solid was washed with CH3CN to give 3- (1, 4-diazepan-1- ylsulfonyl)-4- (3, 5-dichlorophenoxy) benzonitrile hydrochloride as a white solid (2.13 g, 78.2%) : mp 278-280°C ; lH NMR (500 MHz, DMSO-d6) 5 1.99- 2.02 (2H, m), 3.19-3. 24 (4H, m), 3.41-3. 43 (2H, m), 3.64-3. 66 (2H, m), 7.29 (1H, d, J= 8. 5 Hz), 7.41 (2H, m), 7. 59 (1H, m), 8. 12 (1H, dd, J= 2.2, 8.8 Hz), 8. 30 (1H, d, J = 1.9 Hz), 8.99 (1H, br); HPLC-MS (ESI): Calcd for ClsHlgCl3N303S [M+H] + 426 and 428, found : 426 and 428.

Molecular weight: 462. 785 ICso (CCR3): 35 uM ICso (Ca2+) : 20 uM ICso (Chemotaxis): 8 uM In the similar manner as described in Example 12-1 above, compounds in Example 12-2 and 12-3 as shown in Table 12 were synthesized.

Table 12 EX. No. molstructure MW M+1 mp RBA Ca2+ CH3 0 0 CH3 12-2 442. 36752 447 253 B N'11 HN 'cl CIH II N Ci 0 ci 12-3 NS/483. 2034 486 261 B N HN 'CL CIH IN Example 13-1

(1) To a mixture of 4-fluoro-3-nitrobenzoic acid (10.00 g, 54.02 mmol) and 3,5- dichlorophenol (13.21 g, 81.03 mmol) in THF (300 ml) was added NaH (5. 40 g, 135.05 mmol) at room temperature. The reasulting mixture was heated to 70°C. After 2 hrs, the reaction mixture was poured into water and 6N HC1 (15ml) was added. The resulting mixture was extracted with EtOAc.

The extract was washed with brine, and dried over MgS04, the solvent was evaporated in vacuo. The residue was collected by filtration and washed with hexane to give 4- (3, 5-dichlorophenoxy)-3-nitrobenzoic acid as a slight yellow powder (15.29 g 86. 3%).

(2) To a cooled solution of 4- (3, 5-dichlorophenoxy) -3-nitrobenzoic acid (15.29 g, 46. 60 mmol) in THF (300 ml), was added CDI (11.33 g, 69.90 mmol) and

resulting mixture was allowed to warm to room temperature. After 2 hrs, the mixture was cooled with ice-bath and then NH3 gas was introduced directly into the reaction mixture. After 2 hrs, the reaction mixture was condensed under reduce pressure. The residue was dissolved in water and the resulting mixture was extracted with EtOAc. The extract was washed with 1N NaOH, 1N HC1, and brine, dried over MgS04. The solvent was evaporated in vacuo.

The crude product was collected by filtration and washed with MeCN to give 4- (3, 5-dichlorophenoxy)-3-nitrobenzamide as a white powder (15.72 g, quantitative).

(3) The solution of 4- (3, 5-dichlorophenoxy)-3-nitrobenzamide (15.50 g, 47.38 mmol) and i-Pr2EtN (49.52 ml, 284.30 mmol) in CH2C12 (500 ml) was cooled to-5°C with dry-ice/i-PrOH bath. Tf20 (16. 04 ml, 94.77 mmol) was added dropwise to the mixture below 0°C and then additional i-Pr2EtN (24.76 ml, 142.15 mmol) and Tf2O (12.03 ml, 71.08 mmol) was added. The mixture was stirred at 0°C for 30 min. Water was added into the reaction mixture and the resulting mixture was condensed under reduced pressure.

The obtained residue was partitioned between water and EtOAc and the resulting mixture was extracted with EtOAc. The extract was washed with 1N HC1 and brine, dried over MgS04. The solvent was evaporated in vacuo. The residue was purified by column chromatography on silica-gel (CHCl3/EtoAc

= 100/0 to 95/5) to give 5-cyano-2- (3, 5-dichlorophenoxy) nitrobenzene as a white powder (4. 08 g, 27.9 %).

(4) The mixture of 5-cyano-2- (3, 5-dichlorophenoxy) nitrobenzene (4.08 g, 13.20 mmol) and Tin (II) chloride dihydrate (17.87 g, 79.20 mmol) in EtOAc (200 ml) was heated to reflux for 3hrs. After cooled to room temperature, the reaction mixture was poured into sat. NaHC03. The mixture was extracted with EtOAc. The extract was washed with brine, and dried over MgS04. The solvent was evaporated in vacuo to give 5-cyano-2- (3, 5-dichlorophenoxy) - aniline (3.53 g, 95.8 %).

(5) 5-Cyano-2- (3, 5-dichlorophenoxy) aniline (3.53 g, 12.65 mmol) was dissolved in the mixture of cone. HC1 (6.33 ml) and AcOH 2.53 ml). The solution was cooled to 0°C and sodium nitrite (0.96 g, 13.91 mmol) in water (1.27 ml) was added dropwise with stirring. After 30 min, the reaction mixture was added dropwise to the suspended mixture of CuCl (0.63 g, 6.32 mmol) in saturated solution of S02 in AcOH (25.32 ml) at 5°C. The reaction mixture was stirred at 10°C for 30 min, poured into water and the resulting mixture was extracted with EtOAc. The extract was washed with sat. NaHC03, brine, and dried over MgS04. The solvent was evaporated in vacuo to give 5-cyano-2- (3, 5- dichlorophenoxy) phenylsulfonylchloride as a brown powder (4.45 g, 97 %). ci cri /choral L 1 I CH3 IChiral 11-1 , s Z-IP H3c 0 8 Clzilt I N u, \ N O /H / N N N (6) To a solution of 5-cyano-2- (3, 5-dichlorophenoxy) phenylsulfonylchloride (0. 03 g 0. 08 mmol) in THF (1 ml), (3S)- (tert-butoxycarbonylamino) pyr- rolidine (0.05 g, 0.25 mmol) was added. The reaction mixture was stirred at room temperature overnight, then poured into water and the resulting mixture was extracted with EtOAc. The extract was washed with brine, and dried over MgS04. The solvent was evaporated in vacuo. The residue was purified by preparative TLC on silica gel (CH2Cl2/CH30H = 25/1) to give 1-{5-cyano- 2- (3,5-dichlorophenoxy) phenylsulfonyl}- (3S)- (tert-butoxycarbonylamino)- pyrrolidine as an oil (0.02 g, 47%). ci ci Chiral Chiral c3 I 1 O O O CI O O CI H i O R o Cl R o Cl H C HO) N N N N N N

(7) To the solution of 1- {5-cyano-2- (3, 5-dichlorophenoxy) phenylsulfonyl}- (3S)- (tert-butoxycarbonylamino) pyrrolidine (0.03 g, 0.04 mmol) in 1,4-dioxane (1 ml) was added 4N HCl (1 ml) in 1, 4-dioxane. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo.

The obtained residue was dissolved in THF followed by addition of ether. The produced precipitate was collected by filtration, washed with ether and dried in vacuo to give 1-{5-cyano-2-(3, 5-dichlorophenoxy) phenylsulfonyl}- (3S)- aminopyrrolidine hydrocloride as a white powder (13.4 mg, 77%): mp 276°C ; IH NMR (500 MHz, DMSO-d6) 8 1.92-1. 97 (1H, m), 2.15-2. 22 (1H, m), 3.34-3. 41 (2H, m), 3.51-3. 56 (1H, m), 3.63-3. 67 (1H, m), 3.79-3. 83 (1H, m), 7.34 (1H, d, J= 8. 8 Hz), 7.39 (2H, dd, J= 1.6, 1.9 Hz), 8.13 (1H, dd, J= 8.5, 2.2 Hz), 8.21 (3H, br), 8. 29 (1H, d, J= 1.9) ; HPLC-MS (ESI) : calcd for C17Hl5Cl2N303S [M+H] + 411 and 413, Found: 411 and 413.

Molecular weight: 448. 758 Activity grade Ca2+ : A In the similar manner as described in Example 13-1 above, compounds in Example 13-2 to 13-12 as shown in Table 13 were synthesized.

Table 13 EX. No. molstructure MW M+1 mp RBA Ca2+ i w I ci 13-2 0 o ci 542. 4886 542 90-93 B B 11 N I choral N N C 1°l OACI 13-3 nit 480. 41691 480 144-145 A ! N Cl choral I HN 13-4 HNdN-/t 424. 30855 424 311-312 A A N C ! Chirat H H N O O CI Nip 13-5 H 452. 36273 452 163-165 B A N N Choral /I H O O CI \ II 13-6 N-S 452. 36273 452 164-165 30 40+G9 How H N N cul o ci 13-7 7 520 66613 483 240 A A CIH IN 11 H 1°l O Cì 13-8 422. 72013 426 214 A H 0 CIL NUI Cl Cl HO O O CI 13-9 492. 76832 457 262 7 12+G12 CIL HNJ N N cl CIL 13-10 N OSO N N) 2 470. 76473 434 104 A N N cri cl 13-11 CN 466. 38982 467 13 8 u N Cl 13-12 N s 452. 36273 452 161 A N N Example 14-1

(1) To a cold (10°C) solution of 3-{[4-(tert-butoxycarbonyl)-l-piperazinyl]- sulfonyl}-4-fluorobenzoic acid (0.200 g, 0.515 mmol) and 3,5-dimethyl- phenol (0.063 g, 0.515 mmol) in 1,4-dioxane (1.0 ml) was added NaH (0.041 g, 1.030 mmol), and the stirring was continued for 15 min. The mixture was heated at 120°C for 3 hrs. N-Methyl-2-pyrollidone (1.0 ml) was added to the mixture, which was then heated at 120°C overnight. After cooled to room temperature, the mixture was quenched with water and then extracted with a 1: 1 mixture of EtOAc and hexane. The aqueous phase was separated, and the organic phase was extracted with water. The combined aqueous phase was acidified to pH 3-4 with IN HCI, and then extracted with EtOAc. The separated organic phase was washed with water and brine, dried over Na2S04.

The solvent was evaporated in vacuo. The residue was suspended in boiled MeOH for 1 h. After cooling to room temperature, the precipitate was collected by filtration, washed with MeOH and dried in vacuo to give 3-{[4- (tert-butoxycarbonyl)-1-piperazinyl] sulfonyl}-4-(3, 5-dimethylphenoxy) - benzoic acid (0.101 g, 40.0%) : HPLC-MS (ESI): Calcd for C24H3oN207S [M + H] + 491, Found: 391 (-Boc)

(2) To a solution of 3-{[4-(tert-butoxycarbonyl)-1-piperazinyl] sulfonyl}-4-(3, 5- dimethylphenoxy) benzoic acid (0.030 g, 0.061 mmol) in 1,4-dioxane (0.5 ml) was added 4N HCl in 1,4-dioxane (1.5 ml). The mixture was further stirred at room temperature for 3 hrs, and then concentrated in vacuo. The residue was washed twice with CH3CN and dried in vacuo to give 4- (3, 5-dimethylphen- oxy)-3- (1-piperazinylsulfonyl) benzoic acid hydrochloride (0.027 g, quanti- tative) :'H NMR (500 MHz, DMSO-d6) 5 2.31 (6H, s), 3.17 (4H, br), 3.47 (4H, br), 6.87 (1H, s), 6.96 (1H, s), 6.98 (1H, br), 8. 15 (1H, dd, J= 2.2, 8. 8 Hz), 8. 39 (1H, d, J= 2.2 Hz), 9.19 (1H, br), 13.36 (1H, br); HPLC-MS (ESI): Calcd for Cl9H22N205S [M + H] + 391, Found: 391.

Molecular weight: 426.922 Activity grade Ca2+ : A In the similar manner as described in Example 14-1 above, compounds in Example 14-2 to 14-4 as shown in Table 14 were synthesized.

Table 14 EX. No. molstructure MW M+1 mp RBA Ca2+ CH30 C3 O N N H3CON O \ I CH3 14-2 ; S 490. 5799 391 222 A 0"oh 0 O OU Cl cri CIL zozo 14-3 467. 75844 431 >260 A 0 OH cl ce 0 0 14-4 s 487. 72433 466 307 B Null HN 0CI O O Na+ Example 15-1

(1) To a solution of 3- { [4- (tert-butoxycarbonyl)-l-piperazinyl] sulfonyl}-4- (3, 5- dimethylphenoxy) benzoic acid (0.100 g, 0.204 mmol) in THF (1.0 ml) was added 1, 1'-carbonylimidazole (0.041 g, 0.255 mmol), and the mixture was stirred at room temperature. After 3 hrs, 0. 5M NH3 in 1,4-dioxane was added, and the stirring was continued overnight. The resultant mixture was concen- trated in vacuo, and the residue was partitioned between EtOAc and saturated NaHCO3. The separated organic phase was washed with water and brine, dried over Na2SO4. The solvent was evaporated in vacuo. The solid obtained was washed with EtOH and dried in vacuo to give ter-butyl 4-{[5-(amino- carbonyl)-2- (3, 5-dimethylphenoxy) phenyl] sulfonyl}-1-piperazinecarboxylate (0.071 g, . 71. 1%).

(2) To a suspension of tert-butyl 4- { [5- (aminocarbonyl)-2- (3, 5-dimethylphenoxy) - phenyl] sulfonyl}-1-piperazinecarboxylate (0.057 g, 0.116 mmol) in 1,4-dioxane

(1.0 ml) was added 4N HC1 in 1,4-dioxane (3.0 ml), and the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo, washed twice with CH3CN and dried in vacuo to give 4- (3, 5-dimethylphenoxy)-3- (l- piperazinylsulfonyl) benzamide hydrochloride (0.047 g, 94.8%) : 1H NMR (500 MHz, DMSO-d6) 8 2.30 (6H, s), 3.16 (4H, br), 3.45 (4H, br), 6.83 (1H, s), 6.94 (1H, s), 6.95 (1H, d, J= 8.8 Hz), 7.51 (1H, s), 8.11 (1H, dd, J = 2.2, 8.5 Hz), 8.18 (1H, s), 8.37 (1H, d, J= 2.2 Hz), 9.22 (2H, s); HPLC-MS (ESI) : Calcd for ClsH23N304S [M + H] + 390, Found: 390.

Molecular weight : 425. 937 Activity grade RBA: Activity grade Ca2+ : A Example 15-2 (1) To a mixture of 3-{[4-(tert-butoxycarbonyl)-1-piperazinyl] sulfonyl}-4-(3, 5- dimethylphenoxy) benzoic acid (0.300 g, 0.612 mmol), K2C03 (0. 169 g, 1.223 mmol) and DMF (3.0 ml) was added MeI (0.174 g, 1.223 mmol), and the stirring was continued at room temperature overnight. The mixture was quenched with water, and extracted with EtOAc. The separated organic phase was washed with water and brine, dried over Na2S04. The solvent was evaporated in vacuo. The residue was recrystallized from MeOH to give tert- butyl 4-{r2-(3, 5-dimethylphenoxy)-5-(methoxycarbonyl) phenyl] sulfonyl3-1- piperazinecarboxylate (0.276 g, 89%).

(2) To a suspension of tert-butyl 4-{[2-(3, 5-dimethylphenoxy)-5-(methoxy- carbonyl) phenyl] sulfonyl}-l-piperazinecarboxylate (0.030 g, 0.059 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in 1,4-dioxane (3.0 ml). The resulting clear solution was stirred at room temperature for 3 hrs. The mixture was concentrated in vacuo, washed twice with Et20 and dried in vacuo to give methyl 4- (3, 5-dimethylphenoxy)-3- (1-piperazinylsulfonyl) benzoate hy- drochloride (0.027 g, quantative): mp 120°C ; lH NMR (500 MHz, DMSO-d6) 8 2.31 (6H, s), 3.16 (4H, br), 3. 48 (4H, br), 3.88 (3H, s), 6. 89 (2H, s), 6.97 (1H, d, J= 2.3 Hz), 6. 98 (1H, s), 8.17 (2H, dd, J= 2.3, 9.0 Hz), 8.40 (1H, d, J = 2.3 Hz), 9.22 (2H, br); HPLC-MS (ESI) : Calcd for C2oH24N205S [M + H] + 405, Found: 405.

Molecular weight: 440.949 Activity grade Ca2+ : A In the similar manner as described in Example 15-1 or 15-2 above, compounds in Example 15-3 and 15-4 as shown in Table 15 were synthesized.

Table 15 EX. No. molstructure MW M+1 mp RBA Ca2+ CH3 I 0 0 CH, 15-3 Is 460. 38286 424 161 B O HN ICI HAN ce 0 0 15-4 s F 484. 76414 488 >300 B HN \ CIH ° NH2

Example 16-1 (1) To a cold (0°C) solution of 4-f [2- (3, 5-dimethylphenoxy)-5- (methoxycarb- onyl) phenyl] sulfonyl}-l-piperazinecarboxylate (0.227 g, 0.450 mmol) in THF (3.0 ml) was added LiBH4 (0.012 g, 0.540 mmol). The mixture was stirred at room temperature for 3 hrs, and at 60°C for 4 hrs. After cooled to room temperature, the mixture was quenched with saturated NH4Cl, and extracted with EtOAc. The separated organic phase was washed with water and brine, dried over Na2S04. The solvent was evaporated in vacuo. The residue was purified by recrystallization from CH3CN to give tert-butyl 4-{[2-(3, 5- dimethylphenoxy)-5- (hydroxymethyl) phenyl] sulfonyl}-1-piperazinecarb- oxylate (0. 156 g, 72.8%).

(2) To a solution of tert-butyl 4- { [2- (3, 5-dimethylphenoxy)-5- (hydroxymethyl)- phenyl] sulfonyl}-l-piperazinecarboxylate (0.027 g, 0.057 mmol) in 1,4- dioxane (1.0 ml) was added 4N HC1 in 1,4-dioxane (3.0 ml). The mixture was stirred at room temperature for 3 hrs. The mixture was concentrated in vacuo,

washed twice with Et20 and dried in vacuo to give [4- (3, 5-dimethylphenoxy) - 3- (1-piperazinylsulfonyl) phenyl] methanol hydrochloride (0.020 g, 85.5%) : mp 160'C'H NMR (500 MHz, DMSO-d6) 8 2.27 (6H, s), 3.14 (4H, br), 3.39 (4H, br), 4. 53 (2H, d, J= 5.7 Hz), 5.42 (1H, t, J= 5.7 Hz), 6.71 (2H, s), 6.86 (1H, s), 6.96 (1H, d, J= 8.5 Hz), 7.57 (1H, dd, J= 2.2, 8. 5 Hz), 7.83 (1H, d, J = 1.9 Hz), 9.12 (2H, br); HPLC-MS (ESI) : Calcd for Cl9H24N204S [M + H] + 377, Found: 377.

Molecular weight: 412.939 Activity grade Ca2+ : A Example 17-1 (1) To a stirred suspension of NaH (60%, 0.015 g, 0.375 mmol) in 1,4-dioxane (2. 0ml) was added 3,5-dichlorothiophenol (0.067 g, 0.374 mmol). After 15 min, tert-butyl 4- [ (5-cyano-2-fluorophenyl) sulfonyl]-1-piperazinecarb- oxylate (0.100 g, 0.271 mmol) was added, and the suspension was stirred at room temperature for 10 min. THF (0.5 ml) was added, and the stirring was continued for 2 hrs. The mixture was quenched with water, and extracted with EtOAc and saturated aqueous NaHC03 solution. The separated organic phase was washed with water and brine, dried over Na2S04. The solvent was evaporated in vacuo. The residue was recrystallized from CH3CN to give tert- butyl 4- {5-cyano-2-[(3, 5-dichlorophenyl) sulfanyl] phenyl} sulfonyl)-1-pip- erazinecarboxylate (0.088 g, 61.5%).

(2) To a solution of tert-butyl 4- (f5-cyano-2- [ (3, 5-dichlorophenyl) sulfanyl] - phenyl} sulfonyl)-l-piperazinecarboxylate (0.020 g, 0. 038 mmol) in 1,4- dioxane (1.0 ml) was added 4N HCl in 1,4-dioxane (3.0 ml), and the stirring was continued for 3 hrs. The mixture was concentrated in vacuo. The residue was recrystallized from diisopropylether. The solid obtained was washed with diisopropylether, dried in vacuo to give 4- [ (3, 5-dichlorophenyl) sulfanyl]-3- (l- piperazinylsulfonyl) benzonitrile hydrochloride (0.017 g, 96.6%) : mp 82°C 1H NMR (500 MHz, DMSO-d6) 8 3.19 (4H, br), 3.53 (4H, br), 7. 18 (1H, d, J= 8.5 Hz), 7.73 (1H, d, J= 1.9 Hz), 7. 87 (1H, t, J= 1.9 Hz), 7.97 (1H, dd, J= 1.3, 8. 5 Hz), 8.3 (1H, d, J = 1.6 Hz), 8.99 (2H, br) ; HPLC-MS (ESI) : Calcd for C17Hl5Cl2N302S2 [M + H] + 428, Found: 428.

Molecular weight: 464.823 ICso (CCR3): 3 uM IC50 (Ca2+) : 2, uM ICso (Chemotaxis): 2 I1M In the similar manner as described in Example 17-1 above, compounds in Example 17-2 and 17-3 as shown in Table 17 were synthesized.

Table 17 EX. No. molstructure MW M+1 mp RBA Ca2+ cul s-a oo ! 17-2 N 516. 53436 516 124 A H3C'oNJ 9 N N CI ci S) CI 17-3 478. 85006 442 277-2783 1 "\ J LJ CIH N N Example 18-1

(1) To a stirred mixture of tert-butyl 4- ( {5-cyano-2- [ (3, 5-dichlorophenyl) - sulfanyl] phenyl} sulfonyl)-l-piperazinecarboxylate (0.011 g, 0. 020 mmol), CCl4 (0.4 ml), CH3CN (0.4 ml) and water (0. 8 ml) was added NaI04 (0.030 g, 0. 142 mmol) followed by RuCl3 (0.003 g, 0. 014 mmol). The mixture was stirred at room temperature for 4 hrs. The mixture was partitioned between EtOAc and water. The separated organic phase was washed with saturated aqueous NaHC03 solution and brine, dried over Na2S04. The solvent was evaporated in vacuo. The residue was dissolved in hot CH3CN, and allowed to cool to room temperature. The precipitate was collected by filtration, washed with CH3CN, and dried in vacuo to give tert-butyl 4- ( {5-cyano-2- [ (3, 5-dichlorophenyl) sulfonyl] phenyl} sulfonyl)-1-piperazinecarboxylate (0.016 g, 60.3%).

(2) To a suspension of tert-butyl 4-({5-cyano-2-[(3, 5-dichlorophenyl) sulfonyl]- phenyl} sulfonyl)-l-piperazinecarboxylate (0.011 g) in 1,4-dioxane (0. 5 ml) was added 4N HCl in 1,4-dioxane (1.5 ml), and the stirring was continued for 3 hrs. The mixture was concentrated in vacuo, and recrystallized with diiso- propylether. The obtained solid was washed with diisopropylether, and dried in vacuo to give 4- [ (3, 5-dichlorophenyl) sulfonyl]-3-(1-piperazinylsulfonyl)- benzonitrile hydrochloride (0.008 g, 82%): mp 258°C'H NMR (500 MHz, DMSO-d6) 8 3.15 (4H, br), 3.57 (4H, br), 7.94 (2H, d, J= 1.9 Hz), 8.05 (1H, t, J= 1.9 Hz), 8. 52-8. 55 (2H, m), 8.72 (1H, d, J= 8.5 Hz), 8. 96 (2H, br); FAB-MS: Calcd for C17Hl5Cl2N304S2 [M + H] + 460, Found: 460.

Molecular weight: 496. 821 IC5o (CCR3): 1, 2uM ICso (Ca2+) : 7 uM Example 19-1

(1) To a cold (0°C) solution of tert-butyl 4- ( {5-cyano-2- [ (3, 5-dichlorophenyl) - sulfanyl] phenyl} sulfonyl)-l-piperazinecarboxylate (0.022 g, 0. 042 mmol) in CH2C12 (0.6 ml) was added m-chloroperbenzoic acid (0.022 g, 0.062 mmol), and the stirring was continued for 1 h. The mixture was allowed to warm to room temperature, and stirred for 30 min. The mixture was quenched with 10% Na2SO3 solution, and extracted with EtOAc. The extract was washed with saturated NaHC03, water and brine, dried over Na2S04. The solvent was evaporated in vacuo. The solid obtained was washed twice with MeOH and dried in vacuo to give tert-butyl 4- ( {5-cyano-2- [ (3, 5-dichlorophenyl) sulfinyl]- phenyl} sulfonyl)-l-piperazinecarboxylate (0.022 g, 97.1%).

(2) To a suspension of tert-butyl 4- ( {5-cyano-2- [ (3, 5-dichlorophenyl) sulfinyl]- phenyl} sulfonyl)-l-piperazinecarboxylate (0.017 g, 0.031 mmol) in 1,4- dioxane (1.0 ml) was added 4N HC1 in 1,4-dioxane (3.0 ml). The mixture was stirred at room temperature for 3 hrs, and then concentrated in vacuo. The residue was washed twice with CH3CN, and dried in vacuo to give 4- [ (3, 5- dichlorophenyl) sulfinyl]-3- (l-piperazinylsulfonyl) benzonitrile hydrochloride (0.008 g, 53.3%) : mp 219°C'H NMR (500 MHz, DMSO-d6) 8 3.20-3. 24 (4H, m), 3.43-3. 46 (4H, m), 7.74 (1H, d, J= 1.9 Hz), 7. 85 (1H, t, J= 1.9 Hz), 8.42 (1H, d, J= 1.6 Hz), 8.47 (1H, dd, J= 1.6, 8. 2 Hz), 8.52 (1H, d, J= 8. 2 Hz), 8.87 (2H, br); FAB-MS: Calcd for Cl7Ho5Cl2N303S2 [M + H] + 444, Found: 444.

Molecular weight: 480.822 Activity grade Ca2+ : B Example 20-1 (1) A solution of tert-butyl 4- [ (5-cyano-2-fluorophenyl) sulfonyl]-l-piperazine- carboxylate (0.100 g, 0.271 mmol) in THF (2.0 ml) was cooled with a water bath, and KOtBu (0.033 g, 0. 298 mmol) was added with stirring. The mixture was heated at reflux for 7 hrs. After cooled to room temperature, KOtBu (0.030 g, 0.267 mmol) was added, and the mixture was heated at reflux overnight. After cooled to room temperature, the mixture was quenched with

saturated NH4Cl, and extracted with EtOAc. The separated organic phase was washed with water and brine, dried over Na2S04. The solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (Hexane/EtOAc=4/1). The product obtained was suspended in hexane including a small amount of EtOAc, collected by filtration, washed with hexane including a small amount of EtOAc, and dried in vacuo to give tert- butyl 4- ( {5-cyano-2- [ (3, 5-dichlorophenyl) amino] phenyl} sulfonyl)-l-pip- erazinecarboxylate (0.087 g, 62.8%).

(2) To a solution of tert-butyl 4- ( {5-cyano-2- [ (3, 5-dichlorophenyl) amino]- phenyl} sulfonyl)-l-piperazinecarboxylate (0.035 g, 0. 068 mmol) in 1,4- dioxane (0.5 ml) was added 4N HC1 in 1,4-dioxane (1.5 ml), and the stirring was continued for 3 hrs. The mixture was concentrated in vacuo. The residue was crystallized from CH3CN, washed with CH3CN, and dried in vacuo to give 4- [ (3, 5-dichlorophenyl) amino]-3- (1-piperazinylsulfonyl) benzonitrile hy- drochloride (0.030 g, 97.9%) : lH NMR (500 MHz, DMSO-d6) 8 3.13-3. 16 (4H, m), 3. 34-3. 37 (4H, m), 7. 37 (1H, d, J= 8. 8 Hz), 7. 39-7. 41 (1H, m), 7.41 (2H, s), 7.93 (1H, dd, J= 2.2, 8. 8 Hz), 8. 13 (1H, d, J = 2.2 Hz), 8.41 (1H, s), 8. 87 (2H, br); FAB-MS: Calcd for Cl7Hl6Cl2N402S [M + H] + 411, Found: 411.

Molecular weight: 447.773 Activity grade RBA: A Activity grade Ca2+ : A Example 21-1 (1) To a cold (0°C) solution of tert-butyl 4-({5-cyano-2-[(3, 5-dichlorophenyl)- aminogphenyl} sulfonyl)-l-piperazinecarboxylate (0.049 g, 0.096 mmol) in DMF (1.5 ml) including MeI (0.041 g, 0.287 mmol) was added NaH (0.005 g, 0.115 mmol), and the stirring was continued for 1 h. The mixture was allowed to warm to room temperature, and the stirred was continued for 2 hrs. The mixture was cooled with ice-water bath, quenched with saturated NH4C1 solution, and extracted with EtOAc and water. The separated organic phase was washed with brine, dried over Na2S04. The solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (Hexane/EtOAc=4/1) to give tert-butyl 4-({5-cyano-2-[(3, 5-dichlorophenyl) - (methyl) amino] phenyl} sulfonyl)-l-piperazinecarboxylate (0.048 g, 95. 3%).

(2) To a suspension of tert-butyl 4-({5-cyano-2-[(3, 5-dichlorophenyl) (methyl)- amino] phenyl} sulfonyl)-l-piperazinecarboxylate (0.043 g, 0.082 mmol) in 1,4-dioxane (1.0 ml) was added 4N HC1 in 1,4-dioxane (3.0 ml). The mixture was stirred at room temperature for 2 hrs, and then concentrated in vacuo. The residue was washed twice with Et20, and dried in vacuo to give 4- [ (3, 5- dichlorophenyl) (methyl) amino]-3- (1-piperazinylsulfonyl) benzonitrile hydro- chloride (0.037 g, 97.9%) : mp 163°CIH NMR (500 MHz, DMSO-d6) 5 2.98 (4H, br), 3.18 (3H, s), 3.29 (4H, br), 6. 53 (2H, d, J = 1.6 Hz), 6.97 (1H, t, J= 1.6 Hz), 7.71 (1H, d, J= 8.2 Hz), 8. 31 (1H, dd, J= 2.2, 8. 2 Hz), 8. 39 (1H, d, J= 1.9 Hz), 8.92 (2H, br); FAB-MS: Calcd for Cl8HI8C12N402S [M + H] + 425, Found: Molecular weight: 461.800 Activity grade Ca2+ : B In the similar manner as described in Example 21-1 above, compounds in Example 21-2 as shown in Table 21 were synthesized.

Table 21 EX. No. molstructure MW M+1 mp RBA Ca2+ CH, N rn H, o S J 21-2 HNxJ W 440. 9525 405 243 A HN/ -. CIH I I Example 22-1

(1) To a cold (0°C) mixture of 3-{[4-(tert-butoxycarbonyl)-1-piperazinyl] sulfon- yl}-4- (3, 5-dimethylphenoxy) benzoic acid (0. 450 g, 0. 917 mmol), 3-amino- propionitrile (0.072 g, 1.009 mmol), HOBt (0.186 g, 1.376 mmol) and DMF (5.0 ml) was added 1-ethyl-3- (3-dimethylaminopropyl)-carbodiimide hydro- chloride (0.211 g, 1.101 mmol). After 15 min, the mixture was allowed to warm to room temperature, and the stirring was continued overnight. The mixture was partitioned between EtOAc and water. The separated organic phase was washed with saturated NaHC03 solution, water and brine, dried over Na2S04. The solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (Hexane/EtOAc=1/2) to give tert- butyl 4-{[5-{[(2-cyanoethyl) amino] carbonyl}-2- (3, 5-dimethylphenoxy) phen- yl] sulfonyl3-1-piperazinecarboxylate (0.490 g, 98.4%).

(2) To a solution of tert-butyl 4-{[5-{[(2-cyanoethyl)amino]carbonyl}-2-(3, 5-di- methylphenoxy) phenyl] sulfonyl}-1-piperazinecarboxylate (0. 030 g, 0. 055 mmol) in 1,4-dioxane (1.0 ml) was added 4N HC1 in 1,4-dioxane (3.0 ml). The mixture was stirred at room temperature for 1.5 hrs, and then concentrated in vacuo. The residue was crystallized from Et20, washed with Et20 and dried in vacuo to give N- (2-cyanoethyl)-4- (3, 5-dimethylphenoxy)-3- (l-piperazinylsulfonyl) benzamide hydrochloride (0.025 g, 94.4%) : mp 101°C'H NMR (500 MHz, DMSO-d6) 8 2.30 (6H, s), 2.79 (2H, t, J = 6.4 Hz), 3.14-3. 18 (4H, m), 3.42-3. 45 (4H, m), 3.47-3. 54 (2H, m), 6.82 (2H, s), 6.95 (1H, s), 7.02 (1H, d, J= 8.7 Hz), 8.10 (1H, dd, J= 2.3, 8.7 Hz), 8. 38 (1H, d, J= 2.3 Hz), 9.02 (2H, br), 9.84 (1H, t, J= 6.0 Hz); HPLC-MS (ESI) : Calcd for C22H26N404S [M + H] + 443, Found: 443.

Molecular weight : 479.001 Activity grade Ca2+ : A Example 22-2 (1) A mixture of tert-butyl 4-{[5-{[(2-cyanoethyl) amino] carbonyl}-2- (3, 5-dimeth- ylphenoxy) phenyl] sulfonyl}-l-piperazinecarboxylate (0.040 g, 0.074 mmol) and 4 N HCl in 1,4-dioxane (3.0 ml) was stirred for 1.5 hrs. 5N HCl was added, and the stirring was continued for 3 days. The mixture was concentrated in vacuo, and the residue was recrystallized from CH3CN. The solid obtained was

washed twice with CH3CN and dried in vacuo to give N- [4- (3, 5-dimeth- ylphenoxy)-3- (l-piperazinylsulfonyl) benzoyl]-beta-alanineamide hydrochloride (0.036 g, 98. 3%) : mp 121°C 1H NMR (500 MHz, DMSO-d6) 5 2. 30 (6H, s), 2. 36 (2H, t, J= 7.3 Hz), 3.16 (4H, br), 3.42-3. 46 (6H, m), 6.81 (2H, s), 6.83 (1H, s), 6.94 (1H, s), 6.98 (1H, d, J= 8. 5 Hz), 7.36 (1H, s), 8. 08 (1H, dd, J= 2.2, 8. 8 Hz), 8. 35 (1H, d, J = 2.2 Hz), 8.76 (1H, t, J= 5.7 Hz), 9.13 (2H, br): HPLC-MS (ESI) : Calcd for C22H28N4O5S [M + Ho+ 461, Found: 461.

Molecular weight: 497.017 Activity grade Ca2+ : A Example 22-3 (1) To a solution of tert-butyl 4- { [5- { [ (2-eyanoethyl) amino] carbonyl}-2- (3, 5-di- methylphenoxy) phenyl] sulfonyl}-l-piperazinecarboxylate (0. 396 g, 0. 730 mmol) in CH3CN (3.0 ml) was added triphenylphosphine (0.230 g, 0.876 g). The mixture was gently heated with a heat gun until a clear solution resulted. The mixture was cooled with an ice-water bath, and diethyl azodicarboxylate (0. 138 ml, 0. 876mmol) and azidotrimethylsilane (0.116 ml, 0.876 mmol) were added successively. The mixture was allowed to warm to room temperature, and the stirring was continued overnight. A solution of triphenylphosphine (0.115 g, 0.438 mmol), diethyl azodicarboxylate (0.069 ml, 0.438 mmol) and azido- trimethylsilane (0.058 ml, 0. 437 mmol) were added successively, and the

mixture was stirred for 3 days. The mixture was diluted with EtOAc, and washed with water. The separated organic phase was washed with saturated NaHC03 solution, water and brine, dried over Na2S04. The solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (Hexane/EtOAc=l/l) to give tert-butyl 4-{[5-[1-(2-cyanoethyl)-1H- tetraazol-5-yl]-2- (3, 5-dimethylphenoxy) phenyl] sulfonyl}-l-piperazinecarb- oxylate (0.338 g, 81.6%).

(2) To a solution of tert-butyl 4-{[5-[1-(2-cyanoethyl)-1H-tetraazol-5-yl]-2-(3, 5-di- methylphenoxy) phenyl]sulfonyl}-1-piperazinecarboxylate (0.030 g, 0.053 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in 1,4-dioxane (3.0 ml). The mixture was stirred at room temperature for 2 hrs, then concentrated in vacuo. The residue was recrystallized from Et2O, washed with Et20 and dried in vacuo to give 3-{5-r4-(3, 5-dimethylphenoxy)-3-(l-piperazinylSulfonyl) phenyl]-lH- tetraazol-l-yl} propanenitrile hydrochloride (0.021 g, 78.8%) : mp 125'C'H NMR (500 MHz, DMSO-d6) 8 2.32 (6H, s), 3.18 (4H, br), 3.23 (2H, t, J = 6.3 Hz), 3.50 (4H, br), 4.76 (2H, t, J = 6.3 Hz), 6.89 (2H, s), 6.99 (1H, s), 7.10 (1H, d, J= 8.5 Hz), 8.04 (1H, dd, J= 1.9, 8.5 Hz), 8.26 (1H, d, J= 1. 9 Hz), 9.05 (2H, br); HPLC-MS (ESI) : Calcd for C22H25N703S [M + H] + 468, Found : 468.

Molecular weight: 504.014 Activity grade Ca2+ : A Example 22-4

(1) To a solution of tert-butyl 4-{[5-[1-(2-cyanoethyl)-1H-tetraazol-5-yl]-2-(3, 5-di- methylphenoxy) phenyl] sulfonyl}-l-piperazinecarboxylate (0. 150 g, 0. 264 mmol) in CH2C12 (2.0 ml) was added DBU (0.119 ml, 0.793 mmol), and the mixture was stirred at room temperature for 2.5 hrs. The mixture was diluted with EtOAc, and washed with 1N HCI. The separated organic phase was washed with water and brine, dried over Na2S04. The solvent was evaporated in vacuo. The residue was recrystallized from Et2O. The solid was collected by filtration, washed with Et20 and dried in vacuo to give tert-butyl 4- { [2- (3, 5-dimethylphenoxy)-5- (lH-tetra- azol-5-yl) phenyl] sulfonyl}-l-piperazinecarboxylate (0.096 g, 70. 6%).

(2) To a solution of tert-butyl 4- { [2- (3, 5-dimethylphenoxy)-5- (lH-tetraazol-5- yl) phenyl] sulfonyl}-l-piperazinecarboxylate (0.050 g, 0.097 mmol) in 1,4- dioxane (1.0 ml) was added 4N HCI in 1,4-dioxane (3.0 ml). The mixture was stirred at room temperature for 2 hrs. The precipitate was collected by filtration, washed with 1,4-dioxane and Et20, dried in vacuo to give 1-{[2- (3, 5-dimethylphenoxy)-5-(lH-tetraazol-5-yl) phenyl] sulfonyl} piperazine hydrochloride (0. 037 g, 84.4%) : mp 213°C lH NMR (500 MHz, DMSO-) § 2.31 (6H, s), 3. 18 (4H, br), 3.48 (4H, br), 6.86 (2H, s), 6.96 (1H, s), 7.14 (1H, d, J= 8. 8 Hz), 8.29 (1H, dd, J= 2.2, 8.8 Hz), 8.56 (1H, d, J= 2.2 Hz), 9.07 (2H, br); HPLC-MS (ESI) : Calcd for Cl9H22N603S [M + H] + 415, Found: 415.

Molecular weight: 450.950 Activity grade Ca2+ : A Example 23-1 (1) 2- (3, 5-dimethylphenoxy)-4-nitrobenzic acid was prepared by the same procedure of 4- (3, 5-dichlorophenoxy)-3-nitrobenzoic acid (Example 13- (1)).

(2) The mixture of 2- (3, 5-dimethylphenoxy) -4-nitrobenzic acid (1.72 g, 6.00 mmol), diphenyl phosphoroazidate (1. 98 g, 7.20 mmol) and triethyl- amine (1.00 ml, 7.20 mmol) in tert-butanol was heated to 80°C overnight.

After cooled to room temperature, the reaction mixture was poured into water and the resulting mixture was extracted with EtOAc. The extract was washed with brine, and dried over MgS04. The solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (CHCl3/Hexane = 65/35) to give a colorless oil. The obtained oil was dissolve into 4N HCl in 1,4-dioxane and the resulting mixture was stirred overnight. Then the reaction mixture was condensed under reduced pressure. The obtained material was dissolved in THF followed addition of ether. The precipitate was collected by filtration, washed with ether and dried in vacuo to give 2- (3, 5- dimethylphenoxy)-4-nitroaniline hydrochloride as yellow powder. (0.18 g, 10%) (3) 2- (3, 5-dimethylphenoxy)-4-nitrobenzensulfonylchloride was prepared by the same procedure of 5-cyano-2- (3, 5-dichlorophenoxy) phenylsulfonylchloride (Example 13- (5)).

(4) tert-Butyl 4- 2-(3,5-dimethylphenoxy)-4-nitrophenylsulfonyl}-1-piperazine- carboxylate was prepared by the same procedure of 1-{5-cyano-2-(3, 5- dichlorophenoxy) phenylsulfonyl- (3S)- (tert-butoxycarbonylamino) pyrrolidine (Example 13-1 (6)).

(5) 1- {2- (3, 5-dimethylphenoxy)-4-nitrophenylsulfonyl} piperazine hydrochloride was prepared by the same procedure of 1-{5-cyano-2-(3, 5-dichlorophenoxy) - phenylsulfonyl}- (3S)-aminopyrrolidine hydrochloride (Example 13- (7)) : mp 284°C 'H NMR (500 MHz, DMSO-d6) 0 ; 2.32 (6H, s), 3. 18-3. 19 (4H, m), 3.51-3. 53 (4H, m), 6.92 (2H, s), 7.01 (1H, s), 7.52 (1H, d, J= 1.9 Hz), 8. 08 8 (1H, dd, J=

8.5, 2.2 Hz), 8.15 (1H, d, J= 8.5 Hz), 9.28 (2H, br); HPLC-MS (ESI): calcd for Ci8H22ClFN203S [M+H] + 392, Found: 392.

Molecular weight: 427. 910 Activity grade Ca2+ : A Example 24-1 (1) To a vigorously stirred mixture of m-nitrobenzenesulfonyl chloride (3.00 g, 13.5 mmol), trifluoroacetic acid (6.5 ml, 84.4 mmol) and conc. sulfuric acid (2.6 ml, 47.8 mmol) was added N-bromosuccinimide (3.61 g, 20.3 mmol) in portions over an hour period. This mixture was stirred at 45°C for 88 hrs. The mixture was poured into 25 ml of ice-water, the organic layer was separated, and the aqueous layer was extracted with CH2C12 to remove very small amount of 3-bromo-5-nitrobenzenesulfonyl chloride. The aqueous layer was concentrated to give a mixture of 3-bromo-5-nitrobenzenesulfonic acid, 3- nitrobenzenesulfonic acid and sulfuric acid. To the mixture was added 8N NaOH and the resulting precipitate was collected by filtration and washed with water to give sodium 3-bromo-5-nitrobenzenesulfonate (256 mg, 6.2%).

(2) A suspension of sodium 3-bromo-5-nitrobenzenesulfonate (140 mg, 0.46 mmol) in phosphorus oxychloride (1.0 ml, 10.7 mmol) was refluxed for 1 hr. Phosphorus pentachloride (192 mg, 0.92 mmol) was added and the mixture was stirred at 150°C for additional 1 hr. After cooling to room temperature, the mixture was evaporated. The resulting residue was neu- tralized with 4N NaOH and the product was extracted with EtOAc. The organic layer was dried over anhydrous MgS04. The solvent was evaporated in vacuo to give 3-bromo-5-nitrobenzenesulfonyl chloride (103 mg, 74%).

(3) To a mixture of 3-bromo-5-nitrobenzenesulfonyl chloride (100 mg, 0.33 mmol) and N, N-diisopropylethylamine (0.069 ml, 0.40 mmol) in THF (3 ml) was added dropwise the solution of tert-butyl 1-piperazinecarboxylate (68 mg, 0.37 mmol) in THF (2 ml) at 0°C. The mixture was stirred at room temperature for 1 hr. Solvent was removed by evaporation. The resulting residue was diluted with CH2C12 and washed with 0.5 N HC1, brine, aqueous NaHCO3, and brine, then dried over anhydrous MgS04. The solvent was removed by evaporation and the residue was purified by preparative TLC on silica gel (Hexane/EtOAc=2/1) to give tert-butyl 4- [ (3-bromo-5-nitrophenyl)- sulfonyl]-l-piperazinecarboxylate (116 mg, 77%); MS (FAB) : Calcd for C15H20BrN3O6S [M+H]+ 450 and 452, Found: 350 and 352 (-Boc).

(4) To a suspension of sodium hydride (6.7 mg, 0.17 mmol) in DMF (2 ml) was added 3,5-dimethylphenol (20 mg, 0.17 mmol) at 0°C. This mixture was stirred for 10 min. tert-butyl 4- [ (3-bromo-5-nitrophenyl) sulfonyl]-1-piper- azinecarboxylate (50 mg, 0.11 mmol) was added to and the mixture was stirred at 90°C for 2.5 hrs. The reaction mixture was diluted with EtOAc and washed with aqueous NaHC03 and brine. The organic layer was dried over anhydrous MgS04. The solvent was evaporated in vacuo. The residue was purified by preparative TLC on silica gel (Hexane/EtoAc=2/1). The resulting solid was suspended in ether/hexane/CHC13 and collected by filtration to give ter-butyl 4- { [3-bromo-5- (3, 5-dimethylphenoxy) phenyl] sulfonyl}-1-piper- azinecarboxylate (19.5 mg, 33%): mp 155 °C ; HPLC-MS (ESI): Calcd for C23H29BrN2OsS [M+H] + 525 and 527, Found: 425 and 427 (-Boc).

(5) A solution of tert-butyl 4- { [3-bromo-5- (3, 5-dimethylphenoxy) phenyl]- sulfonyl}-l-piperazinecarboxylate (17 mg, 0.032 mmol) in 4N HC1 solution in 1,4-dioxane (2 ml, 8 mmol) was stirred at room temperature overnight.

Solvent was removed by evaporation to give 1- { [3-bromo-5- (3, 5-dimethyl-

phenoxy) phenyl] sulfonyl} piperazine hydrochloride (14.9 mg, 99%): mp >84°C (decomposed) ; 1H NMR (500 MHz, DMSO-d6) 8 2.30 (6H, s), 3.20 (8H, br), 6.79 (2H, s), 6.93 (1H, S), 7.25 (1H, s), 7.60 (1H, d, J=2.0 Hz), 7. 66 (1H, s), 8.99 (1H, br); HPLC-MS (ESI) : Calcd for CigH2lBrN203S [M+H] + 425 and 427, Found: 425 and 427.

Molecular weight: 461. 808 Activity grade Ca2+ : A Example 25-1 (1) To a mixture of 4-hydroxypyridine-3-sulfonic acid (1.00 g, 5.71 mmol) and phosphorus pentachloride (2.38 g, 11.4 mmol) was added phosphorus oxy- chloride (1.06 ml, 11.4 mmol) dropwise at 0°C. The mixture was refluxed for 5 hrs. After the mixture was cooled to room temperature, cooled aqueous NaHC03 was added to the mixture carefully. The mixture was extracted with CHC13. The organic layer was dried over anhydrous MgS04. The solvent was evaporated in vacuo to give 4-chloro-3-pyridinesulfonyl chloride as colorless oil (0.97 g, 80. 1 %).

(2) A mixture of 4-chloro-3-pyridinesulfonyl chloride (0.97 g, 4.57 mmol), tert- butyl 1-piperazinecarboxylate (0.94 g, 5.03 mmol), and N, N-diisopropyl- ethylamine (0. 88 ml, 5.03 mmol) in THF (50 ml) was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was washed with ice water, then was dried in vacuo to give tert-butyl 4-[(4- chloro-3-pyridinyl) sulfonyl]-1-piperazinecarboxylate as a pale yellow solid (1.51 g, 91. 3 %).

(3) To a solution of 3,5-dimethylphenol (37.1 mg, 0.30 mmol) in 1,4-dioxane (lml) was added sodium hydride (60 % oil suspension, 13.3 mg, 0.33 mmol) portionwise. The mixture was stirred at room temperature for 30 min. To the mixture was added a solution of ter-t-butyl 4- [ (4-chloro-3-pyridinyl) sulfonyl]- 1-piperazinecarboxylate (100 mg, 0. 28mmol) in 1,4-dioxane (lml) slowly.

The mixture was stirred at 70°C overnight. After the mixture was cooled to room temperature, the mixture was concentrated in vacuo. The residue was washed with ice water, dried in vacuo to give tert-butyl 4-{[4-(3, 5-dimethyl- phenoxy) -3-pyridinyl] sulfonyl}-1-piperazinecarboxylate (110 mg, 88.9 %) as a white solid.

(4) To a solution of tert-butyl 4-{[4-(3,5-dimethylphenoxy)-3-pyridinyl] sulfon- yl}-l-piperazinecarboxylate (23.4 mg, 0.0523 mmol) in CH2CI2 (lml) was added 4N HCl in 1,4-dioxane (0.25 ml). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was triturated with diethylether, dried in vacuo to give 1-{[4-(3, 5-dimethyl- phenoxy) -3-pyridinyl] sulfonyl} piperazine hydrochloride (17 mg, 76 %) as a white solid: mp 220°C ; 1H NMR (300 MHz, DMSO-d6) 8 2.33 (6H, s), 3.19 (4H, m), 3. 52 (4H, m), 6.84 (1H, d, J = 6 Hz), 7.00 (2H, s), 7.03 (1H"s), 8. 65 (1H, d, J = 6 Hz), 8.88 (1H, s), 9.35 (2H, br); HPLC-MS (ESI): Calcd for Cl, H21N303S [M+H] + 348, Found: 348.

Molecular weight: 420. 361 Activity grade RBA: B Activity grade Ca2+ : A In the similar manner as described in Example 25-1 above, compounds in Example 25-2 as shown in Table 25 were synthesized.

Table 25 EX. No. molstructure MW M+1 mp RBA Ca2+ ci cl o ci oSo 25-2 CNo t 461. 19704 388 213-215 A A HN N CIH CIH Example 26-1

(1) To a suspension of sodium hydride (4.5 mg, 0.11 mmol) in THF (2 ml) was added 2- [ (3, 5-dichlorophenyl) sulfanyl]-5-nitro-N-[2-(1-piperidinyl) ethyl] benzenesulfon- amide (50 mg, 0.10 mmol) at 0°C. The mixture was stirred at 0°C for 10 min.

Methyl iodide (0. 01 ml, 0.15 mmol) was added and the mixture was stirred at 0°C for 30 min then room temperature overnight. The reaction mixture was diluted with EtOAc and washed with aqueous NaHC03 and brine. The organic layer was dried over anhydrous MgS04. The solvent was evaporated in vacuo.

The residue was purified by preparative TLC on silica gel (CHCl3/MeOH=9/l) to give 2- [ (3, 5-dichlorophenyl) sulfanyl]-N-methyl-5-nitro-N [2- (1-piperidinyl)- ethyl] benzenesulfonamide (18 mg, 35.0%) : mp 113-114 °C ; lH NMR (300 MHz, CDC13) 5 1.42 (2H, m), 1.52 (4H, m), 2.41 (4H, m), 2.57 (2H, t, J=7. 0 Hz), 3.03 (3H, s), 3.47 (2H, t, J=7. 0 Hz), 7.07 (1H, d, J=8. 7 Hz), 7.45 (2H, m), 7.51 (1H, t, J=1. 9 Hz), 8.14 (1H, dd, J=2. 3,8. 7 Hz), 8. 79 (1H, d, J=2. 3 Hz); HPLC-MS (ESI): Calcd for C20H23Cl2N3O4S2 [M+H]+ 504 and 506, Found: 504 and 506.

Molecular weight : 504. 458 Activity grade RBA: A Activity grade Ca2+ : A In the similar manner as described in Example 26-1 above, compounds in Example 26-2 and 26-3 as shown in Table 26 were synthesized.

Table 26 EX. No. molstructure MW M+1 mp RBA Ca2+ cl ob"ci H c o o 26-2 H3Cs ONkS't 490 40935 490 108-110 A N N CH3 CH3 CH3 Y ouzo Ci CI S CI 26-3 H3CuN/yoNeSa 506. 47395 506 144-145 A CH3 CH3 CH3 v _. N 0-0

Operative examples relating to pharmaceutical compositions The compounds according to the invention can be converted into pharmaceutical preparations as follows : Tablet Composition 100 mg of the compound of Example 1-1, 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, curvature radius 12 mm.

Preparation The mixture of active component, lactose and starch is granulated with a 5% solution (m/m) of the PVP in water. After drying, the granules are mixed with magnesium stearate for 5 min. This mixture is moulded using a customary tablet press (tablet format, see above). The moulding force applied is typically 15 kN.

Orally administrable suspension Composition 1000 mg of the compound of Example 1-1,1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compound according to the invention is provided by 10 ml of oral suspension.

Preparation The Rhodigel is suspended in ethanol and the active component is added to the suspension. The water is added with stirring. Stirring is continued for about 6h until the swelling of the Rhodigel is complete.