WO2002059081A2

WO2002059081A2 - Urea derivatives as inhibitors of ccr-3 receptor

Info

Publication number: WO2002059081A2
Application number: PCT/US2002/002280
Authority: WO
Inventors: Michael Hocker; Tsuyoshi Nishitoba; Hirohi Ohashi; Eiji Sawa
Original assignee: Kirin Beer Kabushiki Kaisha
Priority date: 2001-01-26
Filing date: 2002-01-28
Publication date: 2002-08-01
Also published as: WO2002059081A3

Abstract

Urea and amide derivatives inhibit cell function of the chemokine receptor CCR-3. These compounds offer an effective means for treating a range of diseases thought to be mediated by the CCR-3 receptor. A variety of useful area and amide derivatives can be synthesized using liquid and solid-phase synthesis protocols.

Description

UREA DERIVATIVES AS INHIBITORS OF CCR-3 RECEPTOR

BACKGROUND OF THE INVENTION

The present invention relates to certain urea derivatives that are inhibitors of CCR-3 receptor activity, methods for preparing these compounds, pharmaceutical compositions containing such compounds and methods for their use. Chemokines are chemotactic cytokines that are produced by a variety of cells to attract leukocytes to sites of inflammation or lymphoid tissue. CCR-3 is a chemokine receptor that is expressed in a variety of cells, including, but not limited to, eosinophils, basophils, T cells and dendritic cells. See Ponath, P.D. et al , J. Exp. Med. (1996) 183, 2437-2448; Yamada, H. et al, Biochem. Biophys. Res. Comm. (1997) 231, 365-368; Sallusto, F. et al, Science (1997) 277, 2005- 2007; Sato, K. et al, Blood (1999) 93, 34-42. CCR-3 is also known as a co- receptor to HIV virus infection. See He, J. et al, Nature (1997) 385, 645-649. Several chemokines including eotaxm, eotaxin-2, RANTES, MCP-2, MCP-3, MCP- 4 bind to CCR-3 and activate cell functions such as intracellular Ca²⁺ mobilization, chemotactic response, superoxide anion generation and cell aggregation. See Forssmann, U. et al, J. Exp. Med. (1997) 185, 2171-2176; Heath, H. et al, J. Clin. Invest. (1997) 99, 178-184; Uguccioni, M. et al, J. Exp. Med. (1996) 183, 2379-2384; Tenscher, K. et al, Blood (1996) 88, 3195-3199; Sato, K. et al, Blood (1999) 93, 34-42. In particular, eotaxin exhibits a potent and specific chemotactic activity for eosinophils via binding to CCR-3, in vitro and in vivo. See Ponath, P. D. et al, J. Clin. Invest. (1996) 97, 604-612. Tissue eosinophilia is observed in a number of pathological conditions such as asthma, rhinitis, eczema, inflammatory bowel diseases and parasitic infections. See Bousquest, J. et al, N. Eng. J. Med. 323, 1033-1039; Middleton, Jr., E. et al , Chapter 42, ALLERGY PRINCIPLES AND PRACTICE (4^th ed.), volume 2 (Mosby-Year Book, Inc. 1993). In asthma, the airways of patients are infiltrated by a large numbers of eosinophils, and eotaxin production in bronchial mucosa and bronchoalveolar lavage (BALF) is increased. Several studies have suggested a strong correlation between the number of eosinophils in BALF, the eotaxin level in BALF and the clinical parameters of disease severity. See Walker, C. et al, J. Allergy Clin. Immunol. (1991) 88, 935-942; Ying, S. et al, Eur. J.

Immunol (1997) 27, 3507-3516. Furthermore, pretreatment with a CCR-3-antibody has been shown to block chemotaxis and Ca²⁺ influx induced by eotaxin, RANTES, MCP-3 or MCP-4, suggesting that most of the eosinophilic response to these chemokines in allergic and eosinophilic patients is mediated through CCR-3. See Heath, H. et al, J. Clin. Invest. (1997) 99, 178-184. Similarly, it has recently been disclosed that certain cyclic amine derivatives are antagonistic to CCR-3 and may be useful for treating eosinophil-mediated allergic diseases. See EP 0903349A2. Also, CCR-3 expression on human Th2 type T-cells and human cultured dendritic cells mediates cell functions such as chemotactic response. See Sallusto, F. et al. , Science (1997) 277, 2005-2007; Sato, K. et al, Blood (1999) 93, 34-42. In addition, anti-CCR-3 antibody has been shown to inhibit aggregation of T-cells and dendritic cells, suggesting CCR-3 may regulate the interaction of these cells during the process of antigen presentation. See Sato, K. et al. , Blood (1999) 93, 34-42. Therefore, CCR-3 inhibitors may also be useful for regulating immune responses. These examples suggest that CCR-3 -mediated diseases may be treated using compounds that inhibit CCR-3 activity. Because CCR-3 is present on many cell types, however, and is responsible for a variety of disease states, an arsenal of compounds that inhibit CCR-3 activity is required to treat CCR-3-mediated diseases effectively. SUMMARY OF THE INVENTION

To the ends of making available (i) compounds that inhibit CCR-3 receptor activity and (ii) an approach for treating CCR-3-mediated diseases, there is' provided, in accordance with one aspect of the present invention, a compound having the following formula, Formula (I).

Forr nula (I)

or a salt, hydrate, stereoisomer or complex thereof, wherein: n is 0 or 1 ;

m is 2, 3, 4, or 5;

Rll and R12 are independently selected from the group consisting of hydrogen, halogen, alkyl, aryl and heteroaryl wherein the alkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxy amino, amidino, guanidino, and cyanoguanidino; Ar is aryl or heteroaryl

optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, trihalomethoxy, alkyl, alkoxy, cyano, nitro, amino, carboxy, alkyloxycarbonyl, arylmethyloxycarbonyl, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylammo, hydroxy amino, amidmo, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

or

or p is 0, 1 or 2; q is 0, 1 or 2;

R and R4' are independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; and COR9; wherein R9 is hydroxy, alkyl, alkoxy, amino, alkylamino or arylamino;

R5 is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; Rό is selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidmo, guanidino, and cyanoguanidino, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; R7 and Rs are independently selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

Q, T, U, W and L are independently selected from the group of atoms consisting of C, N, O and S; wherein adjacent atoms U-T, T-Q, U-W, W-L may form one or more double bonds, and no pair of said adjacent atoms forms O-O or S- S; R2 is selected from the group consisting of alkyl, alkenyl and alkynyl optionally substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, halogen, acyloxy, hydroxy, nitro, amino, acylamino, alkylamino, cyano, aryl optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy, wherein the alkyl or alkoxy may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, aryloxy, arylmethyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, heteroaryl optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, alkoxy optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, arylmethyloxy optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which is optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which is optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, and heterocycle; provided that no bond is formed between Ri and R2.

There is also provided, in accordance with a second aspect of the present invention, a compound having Formula (F):

(D or a salt, hydrate, or stereoisomer thereof, wherein: m is 2, 3, 4 or 5;

Rn and R12 are independently selected from the group consisting of hydrogen, halogen, C1-5 alkyl, aryl and heteroaryl wherein the C1-5 alkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, Ci-salkyl, Ci-salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

Ar' is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, trihalomethoxy, Ci-salkyl, Ci-salkoxy, cyano, nitro, amino, carboxy, alkyloxycarbonyl, arylmethyloxycarbonyl, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl, aryloxy, heteroaryl, benzyloxy, benzoyl and naphthoyl wherein the aryl, aryloxy, heteroaryl, benzyloxy, benzoyl or naphthoyl is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, Ci-salkyl, C1-5 alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

or

or

p is 0, 1 or 2; q is 0, 1 or 2; R4 and R₄' are independently selected from the group consisting of hydrogen, halogen, C1-5 alkyl, aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, C1-5 alkyl, Ci-salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino and COR9, wherein R9 is hydroxy, G-salkyl, Cι-5alkoxy, amino, alkylamino or arylamino;

R5 is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, C1-5 alkyl, C1-5 alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl, and aryloxy wherein the aryl or aryloxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, C1-5 alkyl, C1-5 alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

Rό is selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, C1-5 alkyl, C1-5 alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl and aryloxy wherein the aryl or aryloxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, C1-5 alkyl, C1-5 alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; R7 and R₈ are independently selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, C1-5 alkyl, C1-5 alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

Q, T, U, W and L are independently selected from the group of atoms consisting of C, N, O and S; wherein adjacent atoms U-T, T-Q, U-W, W-L may form one or more double bonds, and no pair of such adjacent atoms forms O-O or S-S;

R2 is selected from the group consisting of Ci-s alkyl, Ci-s alkenyl and Ci-s alkynyl optionally substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, halogen, acyloxy, hydroxy, nitro, amino, acylamino, alkylamino, cyano, aryl optionally substituted with one or more groups independently selected from the group consisting of C1-5 alkyl or C1-5 alkoxy, wherein the alkyl or alkoxy may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, aryloxy, arylmethyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, heteroaryl optionally substituted with one or more groups independently selected from the group consisting of C1-5 alkyl or C1-5 alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, C1-5 alkoxy optionally substituted with one or more groups independently selected from the group consisting of C1-5 alkyl or C1-5 alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, arylmethyloxy optionally substituted with one or more groups independently selected from the group consisting of C1-5 alkyl or C1-5 alkoxy which is optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, C₃-7 cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of C1-5 alkyl or C1-5 alkoxy which is optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, and heterocycle; provided that no bond is formed between Ri and R2.

Other embodiments of the present invention relate to a pharmaceutical composition that comprises one or more the above-described compounds, and to treating CCR-3 -mediated disease by administering to a patient an effective amount of such a pharmaceutical composition.

In another embodiment, a kit is provided for treating CCR-3 mediated diseases in a patient, comprising (A) a pharmaceutical composition as described above, (B) reagents to effect administration of the pharmaceutical composition to a patient, and (C) instruments to effect administration of the pharmaceutical composition to the patient.

Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood that examples are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the suppression of eosinophil infiltration in bronchoalveolarl lavage fluid (BALF) by Compound No. 12.

Figure 2 shows the suppression of eosinophil infiltration in bronchoalveolarl lavage fluid (BALF) by Compound No. 87.

Scheme 1 is a representation of the synthesis of N-benzylcarbamoyl-N'-[2- (4-chlorophenyl)ethyl]-N'-ethyl-l,3-diaminopropane (Compound No. 1).

Scheme 2 is a representation of the synthesis of 4-[[3-(2- methylbenzylureido)propyl][l-(4-chlorophenyl)ethyl]amino]butanoic acid (Compound No. 13).

Scheme 3 is a representation of the synthesis of methyl 4-[[3-(2- methylbenzylureido)propyl][l-(4-chlorophenyl)ethyl]amino]butylate (Compound No. 27).

Scheme 4 presents the synthesis of 5-[[3-(2,4- dichlorobenzylureido)propyl] [l-(4-chlorophenyl)ethyl]amino]pentanoic acid (Compound No. 47).

Scheme 5 is a representation of the synthesis of [N-(3,4- dichlorophenylcarbamoyl)-N'-[2-(4-chlorophenyl)ethyl]-N'-[2-(2- methoxyethoxy)ethyl]-l,3-diaminopropane (Compound No. 53). Scheme 6 presents the synthesis of 4-[[3-[(4-

Chloroanilino)carbonylamino]propyl](6-methoxy -l-indanyl)amino]butanoic acid (Compound 63).

Scheme 7 presents the synthesis of 4-[[3-[2-[4-(Benzyloxy)-3- methoxyphenyl]acetylamino]propyl][l-(4-chlorophenyl)ethyl]amino]butanoic acid (Compound 87).

Scheme 8 represents the formation of the acyl halide of (4-Benzyloxy-3- methoxyphenyl)acetic acid. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides a new class of compounds which inhibit CCR-3 receptor activity. Because the CCR-3 receptor is understood to mediate a variety of diseases, the disclosed compounds, which are derived from urea, are useful for treating CCR-3 -mediated diseases. Examples of such diseases include, without limitation, eosinophil-mediated diseases such as asthma, rhinitis, eczema, inflammatory bowl diseases, parasitic infections, and diseases that are mediated by T-cells, mast cells (Ochi H. et al., J. Exp. Med. (1999) 190:267-280, Romagnani P. et al., Am. J. Pathol. (1999) 155:1195-1204) and/or dendritic cells, such as autoimmune and inflammatory diseases and HIV infection.

In one embodiment of the present invention, there is provided a variety of compounds that inhibit cell function mediated by the chemokine receptor CCR-3. These compounds are urea derivatives with the formula depicted below as Formula I:

(I)

In another embodiment of the present invention, there is provided another variety of compounds that also inhibit cell function mediated by the chemokine receptor CCR-3. These compounds are amide derivatives of Formula (F) as depicted below:

(D The compounds of Formula (I) and (F), as defined above, include variable groups such as an aryl group, a heteroaryl group and a heterocyclic group.

An aryl group is defined as a 6-15 membered aromatic carbocyclic moiety. This includes but is not limited to phenyl, naphthyl, anthryl, indenyl, phenanthrenyl and others.

A heteroaryl group is defined as a 5-15 membered aromatic ring system containing at least one hetero atom selected from the group consisting of N, O, and S. These include but are not limited to 2- or 3-thienyl, 2- or 3-furyl, 2- or 3- pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5- pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5- isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5-(l,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5-(l,2,4-thiadiazolyl), 1,3,4- thiadiazolyl, 4- or 5-(l,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, 1H- or 2H-tetrazolyl, N-oxido- 2-, 3- or 4- pyridyl, 2-, 4- or 5- pyrimidinyl, N-oxido- 2-, 4- or 5-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, N- oxido-3- or 4-pyridazinyl, benzofuryl, indolyl, benzothiazolyl, benzoxazolyl, triazinyl, oxotriazinyl, tetrazolo[l,5-b]pyridazinyl, triazolo[4,5-b]pyridazinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4- thiazinyl, 1,3-thiazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8- naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanfhridinyl, phenazinyl, phenothiazinyl and phenoxazinyl.

A heterocyclic group is defined as a 5-15 membered non-aromatic ring system containing at least one hetero atom selected from the group consisting of N, O, and S. These include but are not limited to hydrogenated derivatives of 2- or 3- thienyl, 2- or 3-furyl, 2- or 3- pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5- isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5-(l,2,3-thiadiazolyl), 1,2,5- thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, N-oxido- 2-, 3- or 4- pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido- 2-, 4- or 5- pyrimidinyl, 3- or 4- pyridazinyl, pyrazinyl, N-oxido-3- or 4-pyridazinyl, benzofuryl, indolyl, benzothiazolyl, benzoxazolyl, triazinyl, oxotriazinyl, tetrazolo [l,5-b]pyridazinyl, triazolo[4,5-b]pyridazinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, benzimidazolyl, qumolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. The heterocyclic moiety may also include dioxolanyl, morpholinyl, piperidinyl, and piperazinyl.

In another embodiment of the present invention, there is provided a family of compounds which inhibit cell function mediated by the chemokine receptor CCR-3. In general, these compounds have the Formula (II) depicted below:

(II) or a salt, hydrate, stereoisomer or complex thereof, wherein: m is 2, 3, 4 or 5;

Rll and R12 are independently selected from the group consisting of hydrogen, halogen, alkyl, aryl and heteroaryl wherein the alkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; Ar is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, trihalomethoxy, alkyl, alkoxy, cyano, nitro, amino, carboxy, alkyloxycarbonyl, arylmethyloxycarbonyl, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylammo, hydroxyamino, amidino, guanidino, and cyanoguanidino, aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

or

or

or

p is 0, 1 or 2; q is 0, 1 or 2; R₄ and R ' are independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; and COR9; wherein R9 is hydroxy, alkyl, alkoxy, amino, alkylamino or arylamino;

R5 is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

Re is selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

R∑ is selected from the group consisting of alkyl, alkenyl and alkynyl optionally substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, halogen, acyloxy, hydroxy, nitro, amino, acylamino, alkylamino, cyano, aryl optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy, wherein the alkyl or alkoxy may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, aryloxy, arylmethyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, heteroaryl optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, alkoxy optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, arylmethyloxy optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which is optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which is optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, and heterocycle; provided that no bond is formed between Ri and R2. In another example of the present invention, the family of compounds described above has cycloalkyloxy groups that are C -7 cycloalkyloxy groups, cycloalkyl groups that are C3-7 cycloalkyl groups, alkoxy groups that are C1-5 alkoxy groups, alkyl groups that are Ci-β alkyl groups, alkenyl groups that are Cι-8 alkenyl groups and alkynyl groups that are C1-8 alkynyl groups.

In another embodiment of the present invention, there is provided another family of compounds which inhibit cell function mediated by the chemokine receptor CCR-3. In general these compounds have the Formula (III) depicted below.

(III) or a salt, hydrate, stereoisomer, or complex thereof, wherein:

Ar is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, trihalomethoxy, alkyl, alkoxy, cyano, nitro, amino, carboxy, alkyloxycarbonyl, arylmethyloxycarbonyl, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

p is 0, 1 or 2; q is 0, 1 or 2; R₄ and R ' are independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; and COR9; wherein R9 is hydroxy, alkyl, alkoxy, amino, alkylamino or arylamino; R5 is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidmo, guanidino, and cyanoguanidino. In another example of the present invention, the family of compounds described above has cycloalkyloxy groups that are C3-7 cycloalkyloxy groups, cycloalkyl groups that are C3-7 cycloalkyl groups, alkoxy groups that are C1-5 alkoxy groups, alkyl groups that are Ci-β alkyl groups, alkenyl groups that are Ci-s alkenyl groups and alkynyl groups that are Ci-s alkynyl groups.

In yet another embodiment of the present invention, there is provided a compound having Formula (IF) as depicted below:

01') wherein: m is 3 or 4;

Ar' is aryl, optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, Ci-salkyl, G-salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl, aryloxy, benzyloxy, benzoyl, and naphthoyl, wherein the aryl, aryloxy, benzyloxy, benzoyl, or naphthoyl is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, Ci-salkyl, Ci-salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino and cyanoguanidino;

or

R

^■ or

p is 0 or 1; q is 0 or 1;

R nd R₄' is hydrogen,halogen,or Ci salkyl; R5 is aryl, optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, Ci-salkyl, Cι-5alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino;

Re is hydrogen, hydroxy, halogen, trihalomethyl, O-salkyl, O-salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

R7 and R₈ is independently selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, Cι-5alkyl, Ci-salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino and cyanoguanidino;

Q, T, U , W and L is independently selected from the group of atoms consisting of C, N, O and S. Two adjacent atoms of Q, T, U, W and L may make double bond(s), and no pair of such adjacent atoms forms O-O or S-S;

R2 is selected from the group consisting of Ci-salkyl, Ci-salkenyl and Ci- salkynyl, wherein the Ci-salkyl, Ci-salkenyl or Ci-salkynyl is optionally substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, halogen, hydroxy, nitro, amino, acylamino, alkylamino, cyano; provided that Ri and R2 do not form bond(s) with each other in Formula (IF).

R11 and Rι₂ are independently selected from the group consisting of hydrogen, halogen, and Ci salkyl.

In still another embodiment of the present invention, there is provided a compound having Formula (IIP) as depicted below:

(IIF) wherein R2 is selected from the group consisting of

Ci-salkyl, Ci-salkenyl and Ci-salkynyl, optionally substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, alkylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonamide, alkylthio, halogen, hydroxy, nitro, amino, acylamino, alkylamino, cyano,;

Ri and R2 do not form bond(s) with one another in Formula (IIF). R4,R5,R6,R7,R₈,Rιι, R12, U,T,Q,p,and q have the same values as for Formula (IF).

In another embodiment of this invention, U, T and Q are carbon atoms; p and q are 0; Rn and Rι₂ are hydrogen or Cι-₃alkyl.

Finally, an additional embodiment of the present invention provides for Ar' being aryl, optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, trihalomethyl, Ci-salkyl, Ci-salkoxy, cyano, nitro, amino, carboxy, benzyloxy, benzoyl, naphthoyl, aryl, wherein benzyloxy, benzoyl, or naphthoyl is optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, trihalomethyl, Ci-salkyl, and Ci-salkoxy. The compounds of the present invention can be synthesized by various methods including, but not limited to, liquid phase or a solvent based synthesis and solid phase synthesis involving a polymeric resin. The liquid phase synthesis generally involves addition of a substituted or unsubstimted alkyl amine containing compound to a protected amine containing starting material bearing a leaving group (e.g., Cl, Br, I, OTs, OMs, etc.). The resulting product bearing a protonated amine is reacted with an alkyl halide to yield a substituted amine. Then, the protected amine moiety is deprotected by addition of base or, for example, hydrazine. The resultant free amine is reacted with a compound containing an isocyanate to yield the urea derivative.

A second synthesis involves the reaction of aromatic isocyanate with a haloalkylamine. The resultant product is then further reacted with an optionally substituted amine containing compound, the amine of the optionally substituted amine containing compound is substituted by reaction with an alkyl halide to yield the aromatic urea derivative.

An additional method that can be used to prepare the present compounds involves reaction of a protected amine containing starting compound with an alkylamine. The resultant diamine is reacted with an ester containing a leaving group, after deprotection, the aromatic urea derivative is formed by reaction with a compound containing an aromatic isocyanate.

The aromatic urea derivatives can be further derivatized by conventional organic synthesis techniques, for example, an ester can be converted to an acid by addition of a metal hydroxide. Additionally, salts of the compounds can be formed by conventional synthetic techniques, such as addition to an amine moiety to form an ammonium salt.

Solid phase synthesis involves the use of polymeric resins. Reductive amination of the linker to the resin occurs by reacting a haloalkylamine with the polymeric resin. The protonated amine is then protected by reaction with a substituted or unsubstituted acid chloride. The halogen of the original haloalkylamine is displaced by reaction with an alkyl amine compound and reductive amination follows by reaction with an aldehyde. The protected amine is deprotected by reaction with, for example, tin chloride, an acid or an amine. The deprotected amine is subsequently reacted with an isocyanate to yield the urea moiety, the product is isolated by working up the reaction mixture, for example, in HC1 gas.

A method that can be employed for the synthesis of compounds of formula (F), as set forth in Scheme 7, involves the reaction of a protected amine-containing compound with an alkylamine. The resultant diamme is reacted with an aldehyde- carboxyl compound. Following deprotection of the protected amine moiety, the resultant compound is reacted with an aromatic acyl halide to give the aromatic amide derivative.

In one embodiment of the present invention, an effective amount of a pharmaceutical composition comprising one or more of the disclosed compounds is administered to a patient suffering from CCR-3 mediated disease. The active compound of the pharmaceutical composition can be administered in a variety of forms, including, but not limited to a salt, a hydrate or a prodrug. In addition, the pharmaceutical composition can optionally contain suitable carriers or excipients. A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts, hydrates or prodrugs thereof, with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. A "prodrug" refers to an agent that is converted into the parent drug in vivo.

Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may be bioavailable by oral administration, for instance, whereas the parent drug may not be. The prodrug also may have improved solubility in pharmaceutical compositions over the parent drug. As used herein, a "physiologically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. An "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, vegetable oils and polyethylene gly col.

The form of the administered compound depends, in part, upon the use or the route of entry. Such forms should allow the agent to reach a target cell whether the target cell is present in a multicellular host or in culture. For example, pharmacological agents or compositions injected into the blood stream should be soluble in the concentrations used. Other factors are known in the art, and include considerations such as toxicity and forms which prevent the compound or composition from exerting its effect.

A compound of the present invention also can be formulated as a pharmaceutically acceptable salt, e.g. , acid addition salt, and complexes thereof. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of the agent without preventing its physiological effect. Examples of useful alterations in physical properties include, but are not limited to, lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.

A compound of the present invention can be administered to a mammal, including a human patient, using a variety of techniques. For example, for systemic administration, oral administration or injection can be used. For oral administration, a compound of the present invention is formulated into conventional oral administration dosage forms such as capsules, tablets, and tonics. For injection, a compound is formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, a compound can be formulated in a solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced. Examples of systemic administrations by injection include intramuscularly, intravenously, intraperitoneally and subcutaneously. Administration also can be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration also can be achieved, for example, by using nasal sprays or suppositories.

Administration of a compound of the present invention can be achieved by any means which transports the compound to the airways and/or lungs of a mammal, including a human patient. In a preferred embodiment, a compound is administered by generating an aerosol comprised of respirable particles, comprising said compound. Delivery is achieved by animal or patient inhalation of the respirable particles. The respirable particles can be liquid or solid and, optionally, can contain other therapeutic ingredients. For topical administration, the molecules of the invention are formulated into ointments, salves, gels, or creams, as is generally known in the art.

Generally, a therapeutically effective amount for a human patient is between about 10 nmole and 3 mmole of the compound, preferably 1 μmole to 1 mmole. A therapeutically effective amount for a non-human mammal is between about 0.01 and 50 mg/kg, preferably 0.01 and 20 mg/kg. Optimization of the timing and dosage of a disclosed compound is by convention adapted to, among other things, the particular characteristics of the patient or the non-human mammal and the nature and extent of the disease state, and the EC50 or IC50 of the compound. Such adaptations are routine and do not require extraordinary experimentation or skill. In accordance with yet another aspect of the present invention, there is provided a kit suitable for treating CCR-3 mediated diseases in a patient, comprising a pharmaceutical composition comprising one or more compounds of the present invention, reagents to effect administration of the pharmaceutical composition to the patient and instruments to effect adπiinistration of the pharmaceutical composition to the patient. Examples of such instruments mclude, but are not limited to application devices, such as syringes or inhalers.

In yet another example, the claimed compounds are useful for treatment and/or prevention of rheumatoid arthritis. The treatment includes, but not limited to, administration of the claimed compounds through subcutaneous, intradermal, intramuscular, intraperitoneal, intravascular, and intracranial injections to human or other mammalian animal bodies.

EXAMPLES SYNTHESIS OF ACTIVE COMPOUNDS

Example 1. Synthesis of N-Benzylcarbamoyl-N'-[2-(4- chlorophenyl)ethyn-N'-ethyl- 3-diaminopropane (Compound 1)

The following synthesis is depicted in Scheme 1.

Step 1: To a mixture of 2-(4-chlorophenyl)ethylamine (1.56 g, 10 mmol) and potassium carbonate (2.8 g, 20 mmol) in CH₃CN (50 ml) was added N-(3- bromopropyl)phthalimide (3.0 g, 11 mmol). The mixture was refluxed under stirring for 16 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 2.5% methanol/chloroform) to afford N-[3-[2-(4- chloroρhenyl)ethylamino]propyl]phthalimide (2.28 g, 67%): MS(FD) m/e 343

[M+H]⁺; Η NMR (400 MHz, CDCla) δl .84 (m, 2H), 7.71 (m, 2H), 7.24 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 3.74 (d, J = 6.8 Hz, 2H), 2.82 (t, J = 6.8 Hz, 2H), 2.73 (t, J = 6.8 Hz, 2H), 2.66 (t, J = 6.8 Hz, 2H), 1.84 (m, 2H).

Step 2: To a mixture of N-[3-[2-(4- chlorophenyl)ethylamino]propyl]phthalimide (2.28 g, 6.65 mmol) and potassium carbonate (1.8 g, 13 mmol) in CH₃CN (50 ml) was added ethyl iodide (1.6 ml, 20 mmol). The mixture was stirred at 70 °C for 16 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 2% methanol/chloroform) to afford N-[3-[[2-(4- chloroρhenyl)ethyl](ethyl)amino]propyl]phthalimide (1.41 g, 57%): MS(ES⁺) m/e 371 [M+H]⁺; Η NMR (400 MHz, CDCb) £7.84 (m, 2H), 7.71 (m, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 3.71 (t, J = 7.3 Hz, 2H), 2.66 (m, 4H), 2.57 (m, 4H), 1.83 (m, 2H), 1.00 (t, J = 1.1 Hz, 3H). Step 3: To a solution of N-[3-[[2-(4- chlorophenyl)ethyl](ethyl)amino]propyl]phthalimide (1.41 g, 3.8 mmol) in EtOH (20 ml) was added a solution of hydrazine monohydrate (1.5 g, 30 mmol) in EtOH (5 ml). The solution was stirred at RT for 4h, and then filtered. The filtrate was concentrated under vacuum to dryness. After adding water, the mixture was extracted with chloroform, washed with brine, dried over sodium sulfate, and filtered. Concentrating under vacuum gave N-[2-(4-chlorophenyl)ethyl]-N-ethyl-l,3- diaminopropane (903 mg, 99%) which was used in the next step without further purification.

Step 4: To a solution of N-[2-(4-chlorophenyl)ethyl]-N-ethyl-l,3- diaminopropane (30 mg, 0.125 mmol) in CH2CI2 (1 ml) was added benzyl isocyanate (20 mg, 0.15 mmol). After stirring at RT for lh, the reaction mixture was adsorbed on a plate of silica gel and the plate was developed with 17% methanol/chloroform to afford N-benzylcarbamoyl-N'-[2-(4-chlorophenyl)ethyl]-N'- ethyl-l,3-diaminopropane (31.4 mg, 67%): MS(ES ) m/e 408 [M-H]^"; Η NMR (400 MHz, CDCb) δ 7.27 (m, 4H), 7.23 (m, 3H), 7.08 (d, J = 8.5 Hz, 2H), 5.64 (br, 1H), 5.15 (br, 1H), 4.33 (d, J = 5.9 Hz, 2H), 3.24 (m, 2H), 2.72 (m, 4H), 2.62 (m, 4H), 1.68 (m, 2H), 1.04 (m, 3H).

Compound 2, N-Benzylcarbamoyl-N'-[2-(4-chlorophenyl)ethyι]-N'-ethyl- 1,2-diaminoethane, can be obtained in an analogous manner to that described for compound 1 and contains the following characteristics: MS(ES^") m/e 394 [M-H]^"; H NMR (400 MHz, CDCb) δ 7.30 (m, 4H), 7.22 (m, 3H), 7.06 (d, J = 8.5 Hz, 2H), 5.08 (br, 1H), 4.67 (br, 1H), 4.31 (d, J = 5.9 Hz, 2H), 3.18 (m, 2H), 2.63 (m, 4H), 2.55(m, 4H), 0.97 (m, 3H). Compound 44, Methyl 5-[[3-(2,4-dichlorobenzylureido)propyl][l-(4- chlorophenyl)ethyl] amino jpentanoate, can be obtained in an analogous manner to that described for compound 1 and contains the following characteristics: MS(ES⁺) m/e 550 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.36 (m, 2H), 7.26 (bs, 4H), 7.20 (m, IH), 5.03 (br, IH), 4.40 (d, J = 6.1 Hz, 2H), 3.88 (m, IH), 3.61 (s, 3H), 3.21 (m, 2H), 2.44 (m, 3H), 2.29 (m, 3H), 1.62 (m, 3H), 1.45 (m, 3H), 1.29 (d, J = 6.8 Hz, 3H).

Compound 45, Ethyl 6-[[3-(2,4-dichlorobenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]hexanoate, can be obtained in an analogous manner to that described for compound 1 and contains the following characteristics: MS(ES⁺) m/e 578 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.35 (m, 2H), 7.26 (bs, 4H), 7.21 (dd, J = 8.3, 2.2 Hz, IH), 4.72 (br, IH), 4.38 (d, J = 6.1 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.85 (m, IH), 3.15 (m, 2H), 2.43 (m, 4H), 2.27 (t, J = 7.3 Hz, 2H), 1.58 (m, 4H), 1.43 (m, 2H), 1.26 (m, 5H). Compound 46, N-(2,4-Dichlorobenzylcarbamoyl)-N'-[l-(4- chlorophenyl)ethyl]-N'-ethyl-l,3-diaminopropane, can be obtained in an analogous manner to that described for compound 1 and contains the following characteristics: MS(ES⁺) m/e 442 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.35 (m, 2H), 7.29 (bs, 4H), 7.20 (m, IH), 5.19 (m, IH), 4.91 (br, IH), 4.37 (d, J = 6.1 Hz, 2H), 3.89 (m, IH), 3.15 (m, 2H), 2.63 (m, IH), 2.51 (m, 3H), 1.62 (m, 2H), 1.35 (d, J = 6.6 Hz, 3H), 1.05 (m, 3H).

Example 2. Synthesis of 4-rr3-(2-Methylbenzyιureido propyIiri-(4- cMorophenvDemyllaminolbutanoic acid (Compound 13) The following synthesis is depicted in Scheme 2. Step 1: N-(3-bromopropyl)phthalimide (3.5 g, 13 mmol) was added to a mixture of l-(4-chlorophenyl)ethylamine (1.56 g, 10 mmol) and potassium carbonate (1.8 g, 13 mmol) in CHsCN (50 ml). The mixture was stirred at 70 °C for 16 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 1.5% methanol/chloroform) to afford N-[3-[l-(4- chlorophenyl)ethylamino]propyl]phthalimide (2.1 g, 47%): MS(ES⁺) m/e 343 [M+H]⁺; Η NMR (400 MHz, CDCb) δl. 3 (m, 2H), 7.72 (m, 2H), 7.23 (d, J = 1.5 Hz, 4H), 3.73 (m, 3H), 2.50 (m, IH), 2.44 (m, IH), 1.83 (m, 2H), 1.32 (d, J = 6.6 Hz, 3H).

Step 2: To a solution of N-[3-[l-(4- chlorophenyl)ethylamino]propyl]phthalimide (1.4 g, 4.1 mmol) in 20% EtOH/DMF (50 ml) were added succinic semialdehyde (15 wt. % solution in water, 5.0 ml, 8.2 mmol) and BAP (0.80 ml, 8.2 mmol), and the mixture was stirred at RT for 16 h. After adding water, the mixture was extracted with chloroform, washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 5% methanol/chloroform) to afford 4-[[(3-phthalimido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid (1.32 g, 75%): MS(ES⁺) m/e 429 [M+H]⁺ ; Η NMR (400 MHz, CDCb) £7.84 (m, 2H), 7.75 (m, 2H), 7.26 (m, 4H), 4.05 (q, J = 6.8 Hz, IH), 3.68 (m, 2H), 2.81 (m, 2H), 2.69 (m, IH), 2.58 (m, IH), 2.44 (t, J = 5.9 Hz, 2H), 2.01 (m, 2H), 1.82 (m, 2H), 1.51 (d, J = 6.8 Hz, 3H).

Step 3: To a solution of 4-[[(3-phthalimido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid (50 mg, 0.12 mmol) in EtOH (2 ml) was added hydrazine monohydrate (17 μl, 0.35 mmol), and the mixture was stirred at RT for 4 h. After adding chloroform (2 ml) and MeOH (1 ml), the reaction mixture was filtered, and the filtrate was concentrated under vacuum to dryness. After adding chloroform (1.5 ml) and DMF (0.7 ml) to the residue, 2-mefhylbenzyl isocyanate (28 μl, 0.20 mmol) was added, and the mixture was stirred at RT for 16 h. After adding water, the mixture was extracted with 10% methanol/chloroform, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness. The residue was adsorbed on a plate of silica gel and then developed with 17% methanol/chloroform to afford 4-[[3-(2-methylbenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid (24 mg, 45%): MS(ES⁺) m/e 468 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.33 (m, 2H), 7.28 (m, 2H), 7.09 (m, 4H), 6.30 (br, IH), 4.33 (d, J = 3.4 Hz, 2H), 4.14 (q, J = 6.8 Hz, IH), 3.19 (m, 2H), 2.92 (m, IH), 2.82-2.65 (m, 3H), 2.31 (s, 3H), 2.30 (m, 2H), 1.84-1.67 (m, 4H), 1.50 (d, J = 6.8 Hz, 3H).

Compound 4 , 4- [[3 -[ 1 -(4-Bromophenyl)ethylur eidojpropyl] (1,2,3,4- tetrahydro-l-naphthyl)amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES-) m/e 514 [M+H]⁺; Η NMR (400 MHz, DMSO-d6) δ 9.52 (br, IH), 7.67 (br, IH), 7.49 (m, 3H), 7.24 (m, 5H), 6.35 (br, IH), 4.90 (m, IH), 4.69 (m, IH), 3.14 (m, IH), 2.88 (m, IH), 2.71 (m, 8H), 2.08 (m, 2H), 1.92 (m, 3H), 1.63 (m, 3H), 1.29 (m, 3H).

Compound 5 , 4- [[3-(2 , 5-Dichlorobenzylureido)propyl] (1,2,3, 4-tetrahydro- 1 - naphthyl)amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 492 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.59 (d, J = 7.3 Hz, IH), 7.33 (d, J = 8.3 Hz, IH), 7.26 (d, J = 2.2 Hz, IH), 7.18 (m, 2H), 7.12 (m, 2H), 6.83 (br, 2H), 4.54 (m, IH), 4.36 (d, J = 3.9 Hz, 2H), 3.24 (m, 2H), 3.09 (m, IH), 2.74 (m, 5H), 2.43 (m, IH), 2.12 (m, 2H), 2.01-1.83 (m, 4H), 1.77 (m, IH), 1.65 (m, 2H).

Compound 6: MS(ES⁺) m/e 404 [M+H]⁺

Compound 7: MS(ES⁺) m/e 420 [M +H]⁺

Compound 8: MS(ES⁺) m/e 386 [M+H]⁺

Compound 9 , N-(2-Chlorobenzylcarbamoyι)-N ' - [ 1 -(4-chlorophenyl)ethy 1] - N'-butyl-l,3-diaminopropane, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 436 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.41 (m, IH), 7.35 (m, IH), 7.22 (m, 8H), 4.42 (d, J = 6.1 Hz, 2H), 3.88 ( , IH), 3.16 (m, 2H), 2.45 (m, 4H), 1.42 (m, 2H), 1.25 (m, 7H), 0.87 (t, J = 7.3 Hz, 3H). Compound 10, 4-[[3-(2-Chlorobenzylureido)propyl][l-(4- fluorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 450 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.42 (m, IH), 7.35 (m, 2H), 7.29 (m, IH), 7.16 (m, 3H), 7.07 (t, J = 8.5 Hz, 2H), 6.52 (m, IH), 4.44 (d, J = 5.4 Hz, 2H), 4.24 (q, J = 6.8 Hz, IH), 3.22 (m, 2H), 2.98 (m, IH), 2.82-2.74 (m, 3H), 2.35 (m, 2H), 1.84 (m, 4H), 1.55 (d, J = 6.8 Hz, 3H).

Compound 11, 4-[[3-(2-Chlorobenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 488 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.41 (m, IH), 7.35 (d, J = 8.5 Hz, 2H), 7.30 (m, 3H), 7.16 (m, 3H), 6.43 (br, IH), 4.44 (d, J = 4.6 Hz, 2H), 4.19 (q, J = 6.8 Hz, IH), 3.21 (m, 2H), 2.95 (m, IH), 2.82-2.72 (m, 3H), 2.34 (m, 2H), 1.83 (m, 4H), 1.53 (d, J = 6.8 Hz, 3H). Compound 12, 4-[[3-(2,4-Dichlorobenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 522 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.37 (m, 3H), 7.31 (m, 3H), 7.16 (m, IH), 6.69 (br, IH), 4.39 (d, J = 4.6 Hz, 2H), 4.22 (q, J = 6.8 Hz, IH), 3.21 (m, 2H), 2.96 (m, IH), 2.87-2.75 (m, 3H), 2.36 (m, 2H), 1.84 (m, 4H), 1.56 (d, J = 6.8 Hz, 3H).

Compound 14, 4-[[3-(3-Methylbenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 468 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.34 (m, 2H), 7.28 (m, 2H), 7.11 (m, 3H), 7.00 (d, J = 7.1 Hz, IH), 6.31 (br, IH), 4.31 (bs, 2H), 4.15 (q, J= 6.8 Hz, IH), 3.20 (m, IH), 2.91 (m, IH), 2.82-2.67 (m, 3H), 2.33 (m, 2H), 2.29 (s, 3H), 1.84-1.68 (m, 4H), 1.51 (d, J = 6.8 Hz, 3H). Compound 15, 4-[[3-(4-Methylbenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 468 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.34 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 6.30 (br, IH), 4.30 (bs, 2H), 4.15 (q, J = 6.8 Hz, IH), 3.19 (m, 2H), 2.91 (m, IH), 2.82-2.66 (m, 3H), 2.32 (m, 2H), 2.28 (s, 3H), 1.84-1.68 (m, 4H), 1.51 (d, J = 6.8 Hz, 3H).

Compound 16, 4-[[3-(3,4-Dichlorobenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 522 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.41 (d, J = 2.0 Hz, IH), 7.36 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.3 Hz, IH), 7.30 (d, J = 8.5 Hz, 2H), 7.15 (dd, J = 8.3, 2.0 Hz, IH), 6.89 (br, IH), 4.30 (bs, 2H), 4.23 (q, J = 6.8 Hz, IH), 3.21 (m, 2H), 2.96 (m, IH), 2.88-2.76 (m, 3H), 2.36 (m, 2H), 1.82 (m, 4H), 1.56 (d, J = 6.8 Hz, 3H).

Compound 17, 4-[[3-(4-Methoxybenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 484 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.34 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 6.26 (br, IH), 4.27 (bs, 2H), 4.16 (q, J = 6.8 Hz, IH), 3.75 (s, 3H), 3.19 (m, 2H), 2.91 (m, IH), 2.83-2.67 (m, 3H), 2.32 (m, 2H), 1.84-1.68 (m, 4H), 1.52 (d, J = 6.8 Hz, 3H). Compound 18, 4-[[3-(4-Bromobenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 532 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.37 (m, 4H), 7.30 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 6.60 (br, IH), 4.29 (bs, 2H), 4.21 (q, J = 6.8 Hz, IH), 3.20 (m, 2H), 2.94 (m, IH), 2.85-2.70 (m, 3H), 2.33 (m, 2H), 1.84-1.67 (m, 4H), 1.54 (d, J = 6.8 Hz, 3H).

Compound 28, 4-[[3-(Benzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 454 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.34 (d, J = 8.5 Hz, 2H), 7.30 (m, 6H), 7.18 (m, IH), 6.46 (br, IH), 4.35 (bs, 2H), 4.16 (q, J = 6.8 Hz, IH), 3.20 (m, 2H), 2.92 (m, IH), 2.74 ( , 3H), 2.32 (m, 2H), 1.84-1.68 (m, 4H), 1.51 (d, J = 6.8 Hz, 3H). Compound 30, 4-[[3-(2,4-Dichlorobenzylureido)propyl](5-chloro-l- indanyl)amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 512 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.47 (d, J = 8.1 Hz, IH), 7.37 (d, J = 8.3 Hz, IH), 7.30 (m, IH), 7.26 (m, 2H), 7.17 (m, 2H), 6.60 (br, IH), 6.55 (br, IH), 4.78 (m, IH), 4.40 (d, J = 5.9 Hz, 2H), 3.24 (m, 2H), 2.97 (m, 3H), 2.74 (m, 3H), 2.54 (m, IH), 2.32 (m, IH), 2.24 (m, IH), 2.12 (m, IH), 1.92 (m, 2H), 1.85 (m, IH), 1.70 (m, IH).

Compound 31, 4-[[3-(2,4-Dichlorobenzylureido)propyl][l-(3- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 500 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.40 (br, IH), 7.32 (m, 4H), 7.28 (d, J = 2.0 Hz, IH), 7.13 (m, IH), 6.69 (br, IH), 4.35 (m, 2H), 4.24 (q, J = 6.8 Hz, IH), 3.20 (m, 2H), 3.03 (m, IH), 2.86 (m, 3H), 2.34 (m, 2H), 1.86 (m, 4H), 1.58 (d, J = 6.8 Hz, 3H). Compound 32, 4-[[3-(2,4-Dichlorobenzylureido)propyl][l-(2- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m e 522 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.62 (br, IH), 7.43 (m, IH), 7.37 (d, J = 8.3 Hz, IH), 7.31 (m, 3H), 7.16 (m, IH), 6.70 (br, IH), 4.77 (q, J = 6.8 Hz, IH), 4.40 (d, J = 4.1 Hz, 2H), 3.25 (m, 2H), 3.11 (m, IH), 2.88 (m, 3H), 2.45 (m, IH), 2.32 ( , IH), 1.88 (m, 3H), 1.75 (m, IH), 1.58 (d, J = 6.8 Hz, 3H).

Compound 33 , 4-[[3-(2,4-Dichlorobenzylureido)propyl](l ,2,3 ,4-tetrahydro- l-naphthyl)amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 492 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.62 (d, J = 7.3 Hz, IH), 7.36 (d, J = 8.3 Hz, IH), 7.20 (m, 3H), 7.13 (m, 2H), 6.89 (br, IH), 4.57 (m, IH), 4.38 (d, J = 3.4 Hz, 2H), 3.26 (m, 2H), 3.13 (m, IH), 2.87 (m, IH), 2.76 (m, 4H), 2.43 (dd, J = 16.6, 5.6 Hz, IH), 2.13 (m, 2H), 1.94 (m, 4H), 1.75 (m, IH), 1.66 (m, 2H).

Compound 34, 4-[[3-(2,4-Dichlorobenzylureido)propyl][(lR)-l-(4- chloroρhenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 500 [M+H]⁺; ^XH NMR (400 MHz, CDCb) δ 7.35 (m, 3H), 7.30 (m, 3H), 7.16 (dd, J = 8.3, 2.0 Hz, IH), 6.83 (br, IH), 4.39 (d, J = 5.1 Hz, 2H), 4.20 (q, J = 6.8 Hz, IH), 3.19 (m, 2H), 2.95 (m, IH), 2.78 (m, 3H), 2.35 (m, 2H), 1.80 (m, 4H), 1.54 (d, J = 6.8 Hz, 3H).

Compound 35, 4-[[3-(2,4-Dichlorobenzylureido)propyl][(lS)-l-(4- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 500 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.35 (m, 3H), 7.30 (m, 3H), 7.16 (dd, J = 8.3, 2.2 Hz, IH), 6.84 (br, IH), 4.39 (d, J = 5.1 Hz, 2H), 4.19 (q, J = 6.8 Hz, IH), 3.19 (m, 2H), 2.95 (m, IH), 2.78 (m, 3H), 2.36 (m, 2H), 1.80 (m, 4H), 1.53 (d, J = 6.8 Hz, 3H).

Compound 36, 4-[[3-(2,4-Dichlorobenzylureido)propyl](7-methoxy-l ,2,3,4- tetrahydro-l-naphthyl)amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 522 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.35 (d, J = 8.3 Hz, IH), 7.28 (d, J = 2.0 Hz, IH), 7.20 (d, J = 2.4 Hz, IH), 7.14 (dd, J = 8.3, 2.2 Hz, IH), 7.04 (d, J = 8.5 Hz, IH), 6.82 (br, 2H), 6.79 (dd, J = 8.5, 2.4 Hz, IH), 4.52 (t, J = 7.3 Hz, IH), 4.37(d, J = 5.1 Hz, 2H), 3.71 (s, 3H), 3.26 (m, 2H), 3.15 (m, IH), 2.85 (m, IH), 2.75 (m, 2H), 2.68 (m, 2H), 2.46 (m, IH), 2.12 (m, 2H) , 1.95 (m, 4H) , 1.68 (m, 3H) .

Compound 37, 4-[[3-(2,4-Dichlorobenzylureido)propyl][(lS)-l-(4- methylphenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 502 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.38 (d, J = 8.3 Hz, IH), 7.30 (d, J = 2.2 Hz, IH), 7.24 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 7.15 (dd, J = 8.3, 2.0 Hz, IH), 7.06 (br, IH), 4.40 (d, J = 5.4 Hz, 2H), 4.25 (q, J = 6.8 Hz, IH), 3.24 (m, 2H), 3.07 (m, IH), 2.88 (m, 2H), 2.80 (m, IH), 2.37 (m, 2H), 2.35 (s, 3H), 1.88 (m, 3H), 1.75 (m, IH), 1.60 (d, J = 6.8 Hz, 3H). Compound 38, 4-[[3-(2,4-Dichlorobenzylureido)propyl][(lS)-l-(4- methoxylphenyl)ethyl]aminolbutanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 518 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.38 (d, J = 8.3 Hz, IH), 7.28 (m, 3H), 7.16 (dd, J = 8.3, 2.2 Hz, IH), 7.02 (br, IH), 6.90 (d, J = 8.8 Hz, 2H), 4.40 (d, J = 5.4 Hz, 2H), 4.27 (m, IH), 3.80 (s, 3H), 3.24 (m, 2H), 3.05 (m, IH), 2.87 (m, 2H), 2.82 (m, IH), 2.35 (m, 2H), 1.89 (m, 3H),1.77 (m, IH), 1.60 (d, J = 6.8 Hz, 3H).

Compound 39, 4-[[3-(2,4-Dichlorobenzylureido)propyl](l- indanyl)amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 478 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.38 (d, J = 8.3 Hz, IH), 7.30 (m, 3H), 7.22 (m, IH), 7.15 (dd, J = 8.3, 2.0 Hz, IH), 7.01 (br, IH), 6.93 (m, IH), 4.88 (m, IH), 4.40 (d, J = 5.6 Hz, 2H), 3.26 (m, 2H), 3.02 (m, 3H), 2.77 (m, 3H), 2.53 (dd, J = 16.8, 6.8 Hz, IH), 2.35 (m, IH), 2.21 (m, IH), 2.13 (m, IH), 1.93 (m, 3H), 1.71 (m, IH). Compound 40, 4-[[3-(2,4-Dichlorobenzylureido)propyl][l-(4- fluorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 484 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.36 (m, 3H), 7.31 (d, J = 2.0 Hz, IH), 7.16 (dd, J = 8.3, 2.0 Hz, IH), 7.08 (t, J = 8.5 Hz, 2H), 6.80 (br, IH), 4.39 (d, J = 5.4 Hz, 2H), 4.26 (q, J = 6.8 Hz, IH), 3.22 (m, 2H), 2.99 (m, IH), 2.81 (m, 3H), 2.35 (m, 2H), 1.83 (m, 4H), 1.57 (d, J = 6.8 Hz, 3H).

Compound 41, N-(2,4-Dichlorobenzylcarbamoyl)-N'-[l-(4- chlorophenyl)ethyl]-N'-butyl-l,3-diaminopropane, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 470 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.33 (m, 2H), 7.27 (bs, 4H), 7.19 (m, IH), 4.85 (br, IH), 4.36 (d, J = 6.1 Hz, 2H), 3.88 (q, J = 6.8 Hz, IH), 3.13 (m, 2H), 2.45 (m, 4H), 1.58 (m, 2H), 1.43 ( , 2H), 1.32 (d, J = 6.6 Hz, 3H), 1.26 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). Compound 42, 4-[[4-(2,4-Dichlorobenzylureido)butyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 536 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.36 (m, 3H), 7.30 (m, 3H), 7.15 (dd, J = 8.3, 2.0 Hz, IH), 6.72 (m, IH), 6.45 (br, IH), 4.38 (d, J = 5.1 Hz, 2H), 4.23 (q, J = 6.8 Hz, IH), 3.17 (m, 2H), 2.84 (m, 2H), 2.73 (m, IH), 2.60 (m, IH), 2.39 (m, 2H), 1.80 (m, 2H), 1.67 (m, 2H), 1.54 (d, J = 7.1 Hz, 3H), 1.45 (m, 2H).

Compound 43, 4-[[5-(2,4-Dichlorobenzylureido)pentyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 13 and contains the following characteristics: MS(ES⁺) m/e 550 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.38 (m, 3H), 7.33 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 2.2 Hz, IH), 7.16 (m, IH), 6.67 (br, IH), 6.35 (br, IH), 4.39 (d, J = 5.4 Hz, 2H), 4.29 (q, J = 6.8 Hz, IH), 3.19 (m, 2H), 2.83 (m, 2H), 2.68 (m, 2H), 2.42 (m, IH), 2.35 (m, IH), 1.81 (m, 2H), 1.67 (m, 2H), 1.58 (d, J = 7.1 Hz, 3H), 1.46 (m, 4H).

Compounds 6-8 can be obtained in an analogous manner to that of Compound 13. Example 3. Synthesis of Methyl 4-fr3-(2-methylbenzylureido)propyl¹iri-(4- chlorophenvDethyllaminolbutylate (Compound 27)

The following synthesis is depicted in Scheme 3.

To a mixture of 50% KOH (6 ml) and ether (6 ml) was added l-methyl-3- nitro-1-nitrosoguamidine (0.5 g, 3.4 mmol) at 0 °C. After standing at 0 °C for 5 min, the organic layer was transferred to another Erlenmeyer flask at 0 °C, and KOH pellets (0.5 g) was added. After standing at 0 °C for 5 min, the supernatant (1 ml) was added to a solution of 4-[[3-(2-methylbenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid (Compound 13, 16 mg, 0.04 mmol) in CH2CI2 (2 ml) at 0 °C. After stirring at 0 °C for 30 min, the reaction mixture was concentrated under vacuum to dryness, and the residue was adsorbed on a plate of silica gel and then developed with 10% methanol/chloroform to afford Methyl 4-[[3- (2-methylbenzylureido)propyl] [l-(4-chlorophenyl)ethyl]amino]butylate (16 mg , 90%): MS(ES⁺) m/e 482 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.24 (m, 5H), 7.16 (m, 3H), 4.81 (br, IH), 4.59 (br, IH), 4.33 (d, J = 5.4 Hz, 2H), 3.86 (q, J = 6.8 Hz, IH), 3.59 (s, 3H), 3.18 (m, 2H), 2.48 (m, 3H), 2.32 (s, 3H), 2.29 (m, IH), 2.25 (m, 2H), 1.73 (m, 2H), 1.62 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H).

Compound 3, Methyl 4-[[3-[l-(4-Bromophenyl)ethylureido]propyl](l , 2,3,4- tetrahydro-l-naphthyl)amino]butylate, can be obtained in an analogous manner to that described for compound 27 and contains the following characteristics: MS(ES⁺) m/e 530 [M+H]⁺; Η NMR (400 MHz, DMSO-tf6) δ 7.56 (d, J = 7.3 Hz, IH), 7.48 (dd, J = 8.3, 1.2 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.06 (m, 3H), 6.26 ( , IH), 5.71 (m, IH), 4.67 (m, IH), 3.85 (m, IH), 3.54 (s, 3H), 3.00 (m, IH), 2.91 (m, IH), 2.67 (m, 2H), 2.34 ( , 6H), 1.92 (m, 2H), 1.64 (m, 3H), 1.49 ( , 3H), 1.27 (d, J = 7.1 Hz, 3H). Compound 19, Methyl 4-[[3-(2-chlorobenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butylate, can be obtained in an analogous manner to that described for compound 27 and contains the following characteristics: MS(ES⁺) m/e 480 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.41 (dd, J = 7.3, 2.0 Hz, IH), 7.34 (dd, J = 7.3, 2.0 Hz, IH), 7.26 (m, 3H), 7.21 (m, 3H), 4.95 (br, IH), 4.43 (d, J = 6.1 Hz, 2H), 3.87 (m, IH), 3.63 (s, 3H), 3.18 (m, 2H), 2.48 (m, 3H), 2.35 (m, IH), 2.25 (m, 2H), 1.74 (m, 2H), 1.62 (m, 2H), 1.30 (d, J = 6.6 Hz, 3H).

Compound 20, Methyl 4-[[3-(3-methylbenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butylate, can be obtained in an analogous manner to that described for compound 27 and contains the following characteristics: MS(ES⁺) m/e 460 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.26 (s, IH), 7.20 (m, 3H), 7.07 (m, 4H), 4.75 (br, IH), 4.30 (d, J = 5.6 Hz, 2H), 3.85 (m, IH), 3.61 (s, 3H), 3.17 (m, 2H), 2.47 (m, 3H), 2.33 (s, 3H), 2.31 (m, IH), 2.25 (m, 2H), 1.73 (m, 2H), 1.61 (m, 2H), 1.29 (d, J = 6.6 Hz, 3H). Compound 21, Methyl 4-[[3-(4-methylbenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butylate, can be obtained in an analogous manner to that described for compound 27 and contains the following characteristics: MS(ES⁺) m/e 460 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.25 (m, 4H), 7.17 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 4.73 (br, IH), 4.28 (d, J = 5.6 Hz, 2H), 3.85 (q, J = 6.8 Hz, IH), 3.61 (s, 3H), 3.17 (m, 2H), 2.46 (m, 3H), 2.34 (m, IH), 2.32 (s, 3H), 2.25 (m, 2H), 1.72 (m, 2H), 1.60 (m, 2H), 1.29 (d, J = 6.8 Hz, 3H). Compound 22, Methyl 4-[[3-(3,4-dichlorobenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butylate, can be obtained in an analogous manner to that described for compound 27 and contains the following characteristics: MS(ES⁺) m/e 513 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.37 (m, 2H), 7.26 (m, 4H), 7.12 (m, IH), 5.03 (br, IH), 4.29 (d, J = 6.1 Hz, 2H), 3.89 (m, IH), 3.63 (s, 3H), 3.18 (m, 2H), 2.49 (m, 3H), 2.35 (m, IH), 2.27 (m, 2H), 1.75 (m, 2H), 1.62 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H). Compound 23, Methyl 4-[[3-(4-methoxybenzylureido)proρyl][l-(4- chlorophenyl)ethyl]amino]butylate, can be obtained in an analogous maimer to that described for compound 27 and contains the following characteristics: MS(ES⁺) m/e 476 [M+H|⁺; Η NMR (400 MHz, CDCb) δ 1.25 (m, 4H), 7.21 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.75 (br, IH), 4.26 (d, J = 5.6 Hz, 2H), 3.86 (m, IH), 3.79 (s, 3H), 3.61 (s, 3H), 3.16 (m, 2H), 2.47 (m, 3H), 2.35 (m, IH), 2.25 (m, 2H), 1.73 (m, 2H), 1.60 (m, 2H), 1.29 (d, J = 6.8 Hz, 3H).

Compound 24, Methyl 4-[[3-(4-bromobenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butylate, can be obtained in an analogous manner to that described for compound 27 and contains the following characteristics: MS(ES⁺) m/e 525 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.43 (d, J = 8.3 Hz, 2H), 7.26 (m, 4H), 7.17 (d, J = 8.3 Hz, 2H), 4.85 (br, IH), 4.29 (d, J = 5.9 Hz, 2H), 3.89 (m, IH), 3.62 (s, 3H), 3.19 (m, 2H), 2.50 (m, 3H), 2.36 (m, IH), 2.26 (m, 2H), 1.75 (m, 2H), 1.63 (m, 2H), 1.31 (d, J = 6.6 Hz, 3H). Compound 25, Methyl 4-[[3-(benzylureido)propyl] [l-(4- chlorophenyl)ethyl]amino]butylate, can be obtained in an analogous manner to that described for compound 27 and contains the following characteristics: MS(ES⁺) m/e 446 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.30 (m, 3H), 7.25 (m, 6H), 4.82 (br, IH), 4.34 (d, J = 5.9 Hz, 2H), 3.86 (m, IH), 3.61 (s, 3H), 3.18 (m, 2H), 2.48 (m, 3H), 2.35 (m, IH), 2.25 (m, 2H), 1.73 (m, 2H), 1.61 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H).

Compound 26, Methyl 4-[[3-(2,4-dichlorobenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]butylate, can be obtained in an analogous manner to that described for compound 27 and contains the following characteristics: MS(ES⁺) m/e 536 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.36 (m, 2H), 7.26 (m, 4H), 7.20 (m, IH), 4.95 (br, IH), 4.39 (d, J = 6.1 Hz, 2H), 3.88 (m, IH), 3.64 (s, 3H), 3.17 (m, 2H), 2.48 (m, 3H), 2.35 (m, IH), 2.26 (m, 2H), 1.75 (m, 2H), 1.61 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H). Compound 29, Methyl 4-[[3-(2-chlorobenzylureido)propyl][l-(4- fluorophenyl)ethyl]amino]butylate, can be obtained in an analogous manner to that described for compound 27 and contains the following characteristics: MS(ES⁺) m/e 486 [M+Na]⁺; Η NMR (400 MHz, CDCb) δ 7.40 (m, IH), 7.33 (m, IH), 7.26 (m, 2H), 7.20 (m, 2H), 6.97 (m, 2H), 5.04 (br, IH), 4.42 (d, J = 6.1 Hz, 2H), 3.85 (q, J = 6.8 Hz, IH), 3.62 (s, 3H), 3.16 (m, 2H), 2.45 (m, 3H), 2.32 (m, IH), 2.24 (m, 2H), 1.72 (m, 2H), 1.59 ( , 2H), 1.28 (d, J = 6.8 Hz, 3H).

Example 4. Synthesis of 5-Ff3-(2,4-Dichlorobenzylureido)propyflFl-(4- chlorophenyDethynaminolpentanoic acid (Compound 47) The following synthesis is depicted in Scheme 4.

To a solution of Methyl 5-[[3-(2,4-dichlorobenzylureido)propyl][l-(4- chlorophenyl)ethyl]amino]pentanoate (Compound 44, 50 mg, 0.095 mmol) in 10% water/methanol (2 ml) was added lithium hydroxide monohydrate (30 mg, 0.71 mmol). After stirring at RT for 16 h, the reaction mixture was concentrated under vacuum to dryness. After adding 1N-HC1, the mixture was extracted with chloroform, washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness. The residue was adsorbed on a plate of silica gel and the plate was developed with 17% methanol/chloroform to afford 5- [[3-(2,4-dichlorobenzylureido)propyl][l-(4-chlorophenyl)ethyl]amino]pentanoic acid (17 mg, 35%): MS(ES⁺) m/e 514 [M+H]⁺; Η NMR (400 MHz, CDCb) δ 7.32 (bs, 4H), 7.29 (m, 2H), 7.15 (m, IH), 6.32 (br, IH), 4.34 (bs, 2H), 4.06 (q, J = 6.8 Hz, IH), 3.14 (m, 2H), 2.71 (m, IH), 2.64 (m, 2H), 2.52 (m, IH), 2.22 (m, 2H), 1.73 (m, 2H), 1.52 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H).

Example 5. Synthesis of N-(3.4-Dichlorophenylcarbamoyl)-N'-r2-(4- chlorophenyl)ethyn-N'-r2-(2-methoxyethoxy)ethyl1-1.3-diaminopropane (Compound 53)

The following synthesis is depicted in Scheme 5.

Step 1: To a mixture of 2-(4-chlorophenyl)ethylamine (1.56 g, 10 mmol) and potassium carbonate (2.8 g, 20 mmol) in CH3CN (50 ml) was added N-(3- bromopropyl)phthalimide (3.0 g, 11 mmol). The mixture was refluxed under stirring for 16 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 2.5% methanol/chloroform) to afford N-[3-[2-(4- chlorophenyl)ethylamino]propyl]phthalimide (2.28 g, 67%): MS(FD) m/e 343

[M+H]⁺; Η NMR (400 MHz, CDCb) £7.84 (m, 2H), 7.71 (m, 2H), 7.24 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 3.74 (d, J = 6.8 Hz, 2H), 2.82 (t, J = 6.8 Hz, 2H), 2.73 (t, J = 6.8 Hz, 2H), 2.66 (t, J = 6.8 Hz, 2H), 1.84 (m, 2H). Step 2: To a mixture of N-[3-[2-(4- chlorophenyl)ethylamino]propyl]phthalimide (244 mg, 0.712 mmol) and potassium carbonate (148 mg, 1.07 mmol) in CH₃CN (4 ml) was added l-bromo-2-(2- methoxyethoxy)ethane (195 mg, 1.07 mmol). The mixture was refluxed under stirring for 13 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was adsorbed on a plate of silica gel and the plate was developed with 3 % methanol/chloroform to afford N-[3-[[2-(4-chlorophenyl)ethyl] [2-(2-methoxyethoxy)ethyl]amino]propyl]phthalimide (158 mg, 50%): MS(ES⁺) m/e 445 [M+H]⁺; Η NMR (400 MHz, CDCb) £7.84 (m, 2H), 7.71 (m, 2H), 7.22 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 3.70 (m, 2H), 3.58 (m, 2H), 3.53 (m, 4H), 3.37 (s, 3H), 2.71 (m, 6H), 2.62 (m, 2H), 1.83 (m, 2H). Step 3 : To a solution of N-[3-[[2-(4-chlorophenyl)ethyl] [2-(2- methoxyethoxy)ethyl]amino]propyl]phfhalimide (70 mg, 0.16 mmol) in ethanol (3 ml) was added hydrazine monohydrate (53 μl, 1.1 mmol). The solution was stirred at RT for 21 h, and then filtered. The filtrate was concentrated under vacuum to dryness. After adding water, the mixture was extracted with chloroform, washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness. After adding chloroform (2 ml) to the residue, 3,4- dichlorophenyl isocyanate (44 mg, 0.24 mmol) was added, and the mixture was stirred at RT for 1.5 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to dryness. The residue was adsorbed on a plate of silica gel and then developed with 5% methanol/chloroform to afford N-(3,4- dichlorophenylcarbamoyl)-N'-[2-(4-chlorophenyl)ethyl]-N'-[2-(2- methoxyethoxy)ethyl]-l,3-diaminopropane (50 mg, 63 %): MS(ES⁺) m/e 502 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.64 (d, J = 2.4 Hz, IH), 7.61 (br, IH), 7.30 (dd, J = 8.8, 2.4 Hz, IH), 7.25 (m, 3H), 7.11 (d, J = 8.3 Hz, 2H), 6.35 (br, IH), 3.63 (m, 6H), 3.36 (s, 3H), 3.27 (m, 2H), 2.75 (m, 6H), 2.70 (m, 2H), 1.71 (m, 2H).

Compound 48, N-(4-Cyanophenylcarbamoyl)-N'-[2-(2,4- dichlorophenyl)ethyl]-N'-[2-(2-methoxyethoxy)ethyl]-l ,3-diaminopropane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics: MS(ES⁺) m/e 493 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 8.19 (br, IH), 7.53 (m, 5H), 7.34 (d, J = 6.3 Hz, IH), 7.15 (s, IH), 6.42 (br, IH), 3.65 (m, 6H), 3.36 (s, 3H), 3.28 (m, 2H), 2.86 (m, 2H), 2.76 (m, 4H), 2.67 (m, 2H), 1.71 (m, 2H). Compound 49, N-(4-Methoxyphenylcarbamoyl)-N'-[2-(3- chlorophenyl)ethyl]-N'-[2-(2-methoxyethoxy)ethyl]-l ,3-diaminopropane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics: MS(ES⁺) m/e 464 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.28 (d, J = 9.0 Hz, 2H), 7.18 (m, 3H), 7.05 (m, IH), 6.95 (br, IH), 6.81 (d, J = 9.0 Hz, 2H), 5.94 (br, IH), 3.76 (s, 3H), 3.63 (m, 2H), 3.59 (m, 4H), 3.35 (s, 3H), 3.26 (m, 2H), 2.69 (m, 6H), 2.61 (m, 2H), 1.66 (m, 2H).

Compound 50, N-(4-Cyanophenylcarbamoyl)-N'-[2-(3-chlorophenyl)ethyl]- N'-[2-(2-methoxyethoxy)ethyl]-l,3-diaminopropane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics: MS(ES⁺) m/e 459 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.85 (br, IH), 7.55 (m, 2H), 7.50 (m, 2H), 7.17 (m, 3H), 7.05 (m, IH), 6.42 (br, IH), 3.65 (m, 6H), 3.36 (s, 3H), 3.24 (m, 2H), 2.71 (m, 6H), 2.62 (t, J = 5.9 Hz, 2H), 1.69 (m, 2H). Compound 51, N-(3,4-Dichlorophenylcarbamoyl)-N'-[2-(3- chlorophenyl)ethyl]-N'-[2-(2-methoxyethoxy)ethyl]-l ,3-diaminopropane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics: MS(ES⁺) m/e 502 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.64 (d, J = 2.4 Hz, IH), 7.56 (br, IH), 7.31 (dd, J = 8.8, 2.4 Hz, IH), 7.25 (d, J = 8.8 Hz, IH), 7.18 (m, 3H), 7.06 (m, IH), 6.35 (br, IH), 3.65 (m, 6H), 3.36 (s, 3H), 3.24 (m, 2H), 2.71 ( , 6H), 2.63 (t, J = 5.9 Hz, 2H), 1.68 ( , 2H).

Compound 52, N-(3,4-Dichlorophenylcarbamoyl)-N'-[2-(2,4- dichlorophenyl)ethyl]-N'-[2-(2-methoxyethoxy)ethyl]-l ,3-diaminopropane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics: MS(ES⁺) m/e 536 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.65 (d, J = 2.4 Hz, IH), 7.36 (s, IH), 7.31 (dd, J = 8.8, 2.4 Hz, IH), 7.25 (m, IH), 7.15 (m, 2H), 6.35 (br, IH), 3.66 (m, 6H), 3.36 (s, 3H), 3.30 (m, 2H), 2.86 (m, 2H), 2.71 (m, 6H), 1.72 (m, 2H). Compound 54, N-(4-Cyanophenylcarbamoyl)-N'-[2-(3,4- dichlorophenyl)ethyl]-N'-[2-(2-methoxyethoxy)ethyl]-l ,3-diaminopropane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics: MS(ES⁺) m/e 493 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.94 (br, IH), 7.55 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, IH), 7.27 (m, IH), 7.01 (dd, J = 8.3, 2.0 Hz, IH), 6.40 (br, IH), 3.65 (m, 6H), 3.36 (s, 3H), 3.26 (m, 2H), 2.73 (m, 6H), 2.64 (t, J = 5.9 Hz, 2H), 1.71 (m, 2H).

Compound 55, N-(Phenylcarbamoyl)-N'-[2-(3-chlorophenyl)ethyl]-N'-[2-(2- methoxyethoxy)ethyl]-l,3-diaminoproρane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics:

MS(ES⁺) m/e 434 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.40 (dd, J = 8.5, 1.0 Hz, 2H), 7.28 (br, IH), 7.23 (m, 2H), 7.17 ( , 3H), 7.05 (m, IH), 6.95 (m, IH), 6.10 (br, IH), 3.63 (m, 6H), 3.36 (s, 3H), 3.26 (m, 2H), 2.71 (m, 6H) 2.61 (t, J = 6.1 Hz, 2H), 1.66 (m, 2H). Compound 56, N-(3 ,4-Dichlorophenylcarbamoyl)-N'-(2-phenylethyl)-N'-[2- (2-methoxyethoxy)ethyl]-l,3-diaminoproρane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics: MS(ES⁺) m/e 468 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.63 (d, J = 2.4 Hz, IH), 7.49 (br, IH), 7.30 (m, IH), 7.25 (m, 3H), 7.18 (m, 3H), 6.38 (br, IH), 3.63 (m, 6H), 3.35 (s, 3H), 3.26 (m, 2H), 2.74 (m, 4H), 2.70 (m, 2H), 2.63 (m, 2H), 1.68 (m, 2H).

Compound 57, N-(Phenylcarbamoyl)-N'-[2-(3-methoxyphenyl)ethyl]-N'-[2- (2-methoxyethoxy)ethyl]-l,3-diaminopropane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics: MS(ES⁺) m/e 430 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.40 (dd, J = 8.5, 1.0 Hz, 2H), 7.21 (m, 4H), 6.95 (t, J = 7.3 Hz, IH), 6.77 (d, J = 7.6 Hz, IH), 6.73 (m, 2H), 6.18 (br, IH), 3.77 (s, 3H), 3.62 (m, 6H), 3.35 (s, 3H), 3.29 (t, J = 5.6 Hz, 2H), 2.73 (bs, 4H), 2.70 (m, 2H), 2.63 (m, 2H), 1.68 (m, 2H).

Compound 58, N-(Phenylcarbamoyl)-N'-[l-(4-chlorophenyl)ethyl]-N'-[2-(2- methoxyethoxy)ethyl]-l,3-diaminopropane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics: MS(ES ) m/e 432 [M-H]^"; Η NMR (400 MHz, CDCb) £ 7.53 (m, IH), 7.41 (m, 2H), 7.33 (m, 2H), 7.26 (m, 4H), 6.95 (t, J = 6.3 Hz, IH), 6.17 (br, IH), 4.00 (q, J = 6.8 Hz, IH), 3.69-3.45 (m, 7H), 3.19 (m, IH), 2.60 (m, 3H), 2.55 (m, IH), 1.67 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H).

Compound 59, N-(4-Bromophenylcarbamoyl)-N'-[l-(4-chlorophenyl)ethyl]- N'-[2-(2-methoxyethoxy)ethyl]-l,3-diaminopropane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics: MS(ES ) m/e 510 [M-H]^"; Η NMR (400 MHz, CDCb) £ 7.53 (br, IH), 7.33 (m, 4H), 7.27 (m, 4H), 6.33 (br, IH), 4.03 (m, IH), 3.75-3.48 (m, 7H), 3.37 (s, 3H), 3.16 (m, IH), 2.62 (m, 3H), 2.55 (m, IH), 1.68 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H). Compound 60, N-(Phenylcarbamoyl)~N'-[2-(2-chlorophenyl)ethyl]-N'-[2-(2- methoxyethoxy)ethyl]-l,3-diaminopropane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics: MS(ES⁺) m/e 456 [M+Na]⁺; Η NMR (400 MHz, CDCb) £ 7.41 (d, J = 7.6 Hz, 2H), 7.33 (m, IH), 7.29 (br, IH), 7.22 (m, 3H), 7.15 (m, 2H), 6.94 (m, IH), 6.25 (br, IH), 3.66 (m, 6H), 3.36 (s, 3H), 3.30 (m, 2H), 2.88 (m, 2H), 2.75 (m, 4H), 2.67 (m, 2H), 1.70 (m, 2H).

Compound 61 , N-(Phenylcarbamoyl)-N'-[2-(4-bromophenyl)ethyl]-N'-[2-(2- methoxyethoxy)ethyl]-l,3-diaminopropane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics:

MS(ES⁺) m/e 500 [M+Na]⁺; Η NMR (400 MHz, CDCb) £ 7.39 (m, 4H), 7.29 (br, IH), 7.23 (m, 2H), 7.05 (d, J = 8.3 Hz, 2H), 6.95 (m, IH), 3.61 (m, 6H), 3.36 (s, 3H), 3.27 (t, J = 5.6 Hz, 2H), 2.69 (m, 6H), 2.62 (m, 2H), 1.68 (m, 2H). Compound 62, N-(Phenylcarbamoyl)-N'-[2-(4-fluorophenyl)ethyl]-N'-[2-(2- methoxyethoxy)ethyl]-l,3-diaminopropane, can be obtained in an analogous manner to that described for compound 53 and contains the following characteristics: MS(ES⁺) m/e 440 [M+Na]⁺; Η NMR (400 MHz, CDCb) £ 7.40 (dd, J = 8.5, 1.0 Hz, 2H), 7.28 (br, IH), 7.23 (m, 2H), 7.13 (m, 2H), 6.95 (m, 3H), 3.63 (m, 6H), 3.37 (s, 3H), 3.27 (m, 2H), 2.70 (m, 6H), 2.63 (m, 2H), 1.68 (m, 2H). Example 6. Synthesis of 4-[[3-[(4-Chloroanilino)carbonylamino1propyll(6- methoxy -l-indanyl)amino1butanoic acid (Compound 63):

The following synthesis is depicted in Scheme 6.

Step 1: To a solution of 6-methoxy-l-indanone (5.0 g, 30 mmol) in EtOH (20 ml) was added sodium borohydride (3.5g, 93 mmol) at 0 °C, and the mixture was stirred at 0 °C for 3 h. The solution was concentrated under vacuum to dryness. After adding water, the mixture was extracted with chloroform, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 30% ethyl acetate/hexane) to afford 6-methoxy-l-indanol (5.0 g, 99%): Η NMR (400 MHz, CDCb) £7.03 (d, J = 8.0 Hz, IH), 6.84 (s, IH), 6.71 (d, J = 8.0 Hz, IH), 5.07 (t, J = 6.0 Hz IH), 2.86 (m, IH), 2.64 (m, IH), 2.39 (m, IH), 1.82 (m, IH).

Step 2: To a solution of 6-methoxy-l-indanol (4.6 g, 28 mmol) in toluen(50 ml) were added iminodicarboxylic acid di-tert-butyl ester (9.2 g, 42 mmol) and tri- n-butylphosphine (8.6 g, 42 mmol), and the mixture was cooled to 0 °C. After adding l,l'-(azodicarbonyl)dipiperidine, the solution was stirred at RT for 3 h, and then filtered. The filtrate was concentrated under vaccum to dryness, and the residue was chromatographed on silica gel (eluting with 4% ethyl acetate/hexane) to afford tert-butyl [(tert-butoxycarbonyl)(6-methoxy-l-indanyl)amino]methanoate (8.5 g, 83%): MS(ES⁺) m/e 386 [M+Na]⁺ ; Η NMR (400 MHz, CDCb) £7.00 (d, J = 8.0 Hz, IH), 6.68 (d, J = 8.0 Hz, IH), 6.64 (s, 3H), 5.70 (t, J = 8.4 Hz, IH), 3.68 (s, 3H), 2.90 (m, IH), 2.72 (m, IH), 2.40 (m, IH), 2.25 (m, IH), 1.29 (m, 18H).

Step 3: tert-Butyl[(tert-butoxycarbonyl)(6-methoxy -1- indanyl)amino]methanoate (8.5g, 23 mmol) in 40% TFA/CH2CI2 was stirred at RT for 2h. After neutralized with 50% NaOHα . the mixture was extracted with chloroform, dried over sodium sulfate, and filtered. Concentrating under vacuum gave l-amino-6-methoxyindan (1.9g, 50%) which was used in the next step without further purification,

Step 4: To a mixture of l-amino-6-mefhoxyindan (1.9 g, 12 mmol) and potassium carbonate (5.0 g, 36 mmol) in CH₃CN (50 ml) was added N-(3- Bromopropyl)phthalimide (3.9 g, 14 mmol). The mixture was refluxed under stirring for 18 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 2.5% methanol/chloroform) to afford 2-[3-[(6-methoxy -l-indanyl)amino]propyl]-l,3- isoindolinedione (2.5 g, 60%): MS(ES⁺) m/e 351 [M+H]⁺; Η NMR (400 MHz, CDCb) £7.75 (m, 2H), 7.63 (m, 2H), 7.05 (d, J = 4.0 Hz, IH), 6.81 (s, IH), 6.65 (d, J = 4.0 Hz, 2H), 4.09 (t, J = 6.8 Hz, IH), 3.72 (m, 5H), 2.72-2.52 (m, 4H), 2.29 (m, IH) ), 1.84-1.71 (m, 3H).

Step 5: To a solution of 2-[3-[(6-methoxy -l-indanyl)amino]propyl]-l,3- isoindolinedione (2.4 g, 7.0 mmol) in 20% EtOH/DMF (30 ml) were added succinic semialdehyde (15 wt. % solution in water, 12 ml, 17 mmol) and BAP (3.6 ml, 35 mmol), and the mixture was stirred at RT for 18 h. After adding water, the mixture was extracted with chloroform, washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 5 % methanol/chloroform) to afford 4-[[3-(l,3-dioxo-2-isoindolyl)propyl](6-methoxy -l-indanyl)amino]butanoic acid (1.3 g, 43 %): MS(ES⁺) m/e 437 [M+H]⁺ ; Η NMR (400 MHz, CDCb) £ 7.81 (m, 2H), 7.71 (m, 2H), 7.05 (m, 2H), 6.75 (d, J = 8.4 Hz, IH), 4.68 (t, J = 6.8 Hz IH), 3.73-3.63 (m, 5H), 2.91-2.74 (m, 3H), 2.62-2.50 (m, 4H), 2.29-2.15 (m, 2H), 2.14-2.01 (m, 3H), 1.96-1.87 (m, IH).

Step 6: To a solution of 4-[[3-(l,3-dioxo-2-isoindolyl)propyl](6-methoxy -1- indanyl)amino]butanoic acid (1.3 g, 3.3 mmol) in EtOH (50 ml) was added hydrazine monohydrate (0.35 ml, 8.5 mmol), and the mixture was stirred at RT for 6 h. After adding chloroform (50 ml) and MeOH (25 ml), the reaction mixture was filtered, and the filtrate was concentrated under vacuum to dryness. After adding DMF (30 ml) to the residue, 4-chlorophenyl isocyanate (1.5 g, 9.7 mmol) was added, and the mixture was stirred at RT for 18 h. After adding water, the mixture was extracted with chloroform, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness. The residue was chromatographed on silica gel (eluting with 17% methanol/chloroform) to afford 4-[[3-[(4- chloroanilino)carbonylamino]propyl] (6-methoxy- 1 -indanyl)amino]butanoic acid (520 mg, 34%): MS(ES^") m/e 458 [M-H]^"; Η NMR (400 MHz, CDCb) £ 9.20(bs, IH), 7.43-7.12 (m, 6H), 7.87 (m, IH), 4.90 (t, J = 6.8 Hz, IH), 4.69 (s, 3H), 3.38- 2.84 (m, 8H), 2.55-2.01(m, 7H), 1.80 (m, IH). Abbreviations:

EtOH ethanol

MeOH methanol

DMF N , N-dimethylformamide

BAP borane and pyridine

TFA trifluoroacetic acid

Tables la, lb, and lc list a variety of compounds that can be synthesized by using one of the methods described above.

Table 1A

Table IB

Table 1C

Example 7. Synthesis of 4-[[3-[2-[4-(Benzyloxy)-3- methoxyphenyl]acetylamino]propyl][l-(4-chlorophenyl)ethyl]amino]butanoic acid (Compound 87)

The following synthesis is depicted in Scheme 7. Step 1: N-(3-Bromopropyl)phthalimide (4.1 g, 15 mmol) was added to a mixture of l-(4-chlorophenyl)ethylamine (2.0 g, 13 mmol) and potassium carbonate (5.3 g, 39 mmol) in CH₃CN (50 ml). The mixture was refluxed under stirring for 18 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 1.5% methanol/chloroform) to afford N-[3-[l-(4-chlorophenyl)ethylamino]propyl]phthalimide (3.0 g, 68%):

MS(ES⁺) m/e 343 [M+H]⁺; Η NMR (400 MHz, CDCb) £7.83 (m, 2H), 7.72 (m, 2H), 7.23 (d, J = 8.0 Hz, 4H), 3.73 (m, 3H), 2.50 (m, IH), 2.44 (m, IH), 1.83 (m, 2H), 1.32 (d, J = 6.6 Hz, 3H).

Step 2: To a solution of N-[3-[l-(4- chlorophenyl)ethylamino]propyl]phthalimide (1.4 g, 4.1 mmol) in 20% EtOH/DMF (50 ml) were added succinic semialdehyde (15 wt. % solution in water, 5.0 ml, 8.2 mmol) and BAP (0.80 ml, 8.2 mmol), and the mixture was stirred at RT for 18 h. After adding water, the mixture was extracted with chloroform, washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel

(eluting with 5% methanol/chloroform) to afford 4-[[(3-phthalimido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid (1.32 g, 75%): MS(ES⁺) m/e 429 [M+H]⁺ ; Η NMR (400 MHz, CDCb) £7.84 (m, 2H), 7.75 (m, 2H), 7.26 (m, 4H), 4.05 (q, J = 6.8 Hz, IH), 3.68 (m, 2H), 2.81 (m, 2H), 2.69 (m, IH), 2.58 (m, IH), 2.44 (t, J = 5.9 Hz, 2H), 2.01 (m, 2H), 1.82 (m, 2H), 1.51 (d, J = 6.8 Hz, 3H). Step 3: To a solution of 4~[[(3-phthalimido)propyl][l-(4- chlorophenyl)ethyl]amino]butanoic acid (2.6 g, 5.3 mmol) in EtOH (10 ml) was added hydrazine monohydrate (0.7 ml, 13.3 mmol), and the mixture was stirred at RT for 6 h, and then filtered. The filtrate was concentrated under vacuum to dryness. After adding water, the mixture was extracted with chloroform, washed with brine, dried over sodium sulfate, and filtered. Concentrating under vacuum gave 4-[(3-aminopropyl)[l-(4-chlorophenyl)ethyl]amino]butanoic acid (1.5 g, 85%) which was used in the next step without further purification. Step 4: (4-Benzyloxy-3-methoxyphenyl)acetic acid (1.8g, 6.7 mmol) in 20%

SOCl₂/CH₂Cbwas refluxed under stirring for 18h(see. Scheme 8). The reaction mixture was concentrated under vaccum to dryness. After adding 1,3-dioxane (10 ml) to the residue, 4-[(3-aminopropyl)[l-(4-chlorophenyl)ethyl]amino]butanoic acid (1.5 g, 4.5 mmol) in DMF (30 ml) was added, and the mixture was stirred at RT for 10 h. After adding water, the mixture was extracted with chloroform, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness. The residue was chromatographed on silica gel (eluting with 17 % methanol/chloroform) to afford 4-[[3-[2-[4-(benzyloxy)-3- methoxyphenyl]acetylamino]propyl][l-(4-chlorophenyl)efhyl]amino]butanoic acid (900mg, 36%) : MS(ES⁺) m e 553 [M+H]⁺ ; Η NMR (400 MHz, CDCb) £ 7.34- 7.15 (m, 9H), 6.76 (m, 2H), 6.69 (m, IH), 5.03 (s, 2H), 3.97 (q, J = 6.8 Hz, IH), 3.79 (s, 3H), 3.36 (s, 2H), 3.13 (m, 2H), 2.56 (m, 2H), 2.44 (m, 2H), 2.24 (m, 2H), 1.71-1.51 (m, 4H), 1.33 (d, J = 6.8 Hz, 3H).

Compound 90, 4-[[3-(4-Biphenylacetylamino)propyl] [l-(4- chlorophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 87 and contains the following characteristics: MS(ES⁺) m/e 493 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.47-7.15 (m, 13H), 6.89 (br, IH), 3.96 (q, J = 6.8 Hz, 3H), 3.46 (s, 2H), 3.15 (m, 2H), 2.57 (m, 2H), 2.44 (m, 2H), 2.24 (m, 2H), 1.69 (m, 2H), 1.58 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H). Compound 109, 4-[[3-[2-[4-(Benzyloxy)phenyl]acetylamino]propyl][(lS)-l-

(4-chlorophenyl)emyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 87 and contains the following characteristics: MS(ES⁺) m/e 524 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.42-7.16 ( , 11H), 6.93 (m, 2H), 5.03 (s, 2H), 4.06 (q, J=6.8Hz IH), 3.46 (s, 2H), 3.21 (m, 2H), 2.70-2.47 (m, 4H), 2.39-2.23 (m, 2H), 1.81-1.62 (m, 4H), 1.44 (d, J=6.8Hz, 3H). Compound 114, 4-[[3-[2-[4-(Benzyloxy)phenyl]acetylamino]propyl][(lS)-l- (4-bromophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 87 and contains the following characteristics:

MS(ES⁺) m/e 569 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.42-7.15 (m, 11H), 6.92 (m, 2H), 5.03 (s, 2H), 4.08 (q, J=6.8Hz IH), 3.44 (s, 2H), 3.21 (m, 2H), 2.74-2.52 (m, 4H), 2.40-2.25 (m, 2H), 1.85-1.60 (m, 4H), 1.47 (d, J=6.8Hz, 3H). Compound 125, 4-[[3-[2-[4-(Benzyloxy)-3- methoxyphenyl] acetylamino]propyl] [( 1 S)- 1 -(4-chlorophenyl)ethyl] amino]butanoic acid, can be obtained in an analogous manner to that described for compound 87 and contains the following characteristics: MS(ES⁺) m/e 554 [M+H]⁺; Η NMR (400 MHz, CDCb) £ 7.42-7.22 (m, 9H), 6.84 (m, 2H), 6.72 (m, IH), 6.61 (br, IH), 5.10 (s, 2H), 4.02 (q, J=6.8Hz IH), 3.86 (s, 3H), 3.43 (s, 2H), 3.20 (m, 2H), 2.67-2.28 (m, 6H), 1.78-1.64 (m, 4H), 1.40 (d, J=6.8Hz, 3H). Compound 126, 4-[[3-[2-[4-(Benzyloxy)-3- methoxyphenyl]acetylamino]propyl][(lS)-l-(4-bromophenyl)ethyl]amino]butanoic acid, can be obtained in an analogous manner to that described for compound 87 and contains the following characteristics: MS(ES⁺) m/e 599 [M+H]⁺; H NMR (400 MHz, CDCb) £ 7.48-7.16 (m, 9H), 6.84 (m, 2H), 6.72 (m, IH), 6.51 (br, IH), 5.10 (s, 2H), 4.00 (q, J=6.8Hz IH), 3.86 (s, 3H), 3.43 (s, 2H), 3.19 (m, 2H), 2.66-2.28 (m, 6H), 1.76-1.63 (m, 4H), 1.40 (d, J=6.8Hz, 3H).

The following compounds, listed in Table ID, were obtained in an analogous manner to those of compounds described above. Table ID

Example 8. Chemotaxis Assay

The inhibitory activity of the compounds against eotaxin-induced chemotaxis was determined by chemotaxis assay using eotaxin and human CCR-3 transfectant cells (CCR3/U937), as described by Ohashi, H. et al, Int Arch Allergy Immunol. (1999) 118, 44-50 with minor modification. CCR-3 transfectant cells were grown in RPMI1640 medium containing 10% fetal calf serum (FCS) and Genetecin 418 (0.8 mg/ml). For the assay, CCR-3 transfectant cells were isolated and resuspended at 1 x 10⁷ cells/ml in assay medium (RPMI 1640 medium containing 0.1 % bovine serum albumin (BSA)). The chemotaxis assay was performed in a 24- well culture plate. Human eotaxin suspended in assay medium was added to the wells at 1 x 10^"9 M along with test compounds at various concentrations. For a positive control, eotaxin was added to the wells without a test compound, and for a negative control, neither eotaxin nor a test compound was added to the wells. Chemotaxicell (Kurabo Co., Ltd.) having 5 micrometers pore size were inserted into each well and 100 micro liters of CCR-3 transfectant cells suspension were added to the top chamber. The plates were incubated at 37 °C for 1 hour. After incubation, migrated cells in lower wells were diluted and counted by particle size distribution analyzer (CDP-500, Sysmex Co., Ltd.).

The results shown in Table 2 indicate that the disclosed compounds inhibit eotaxin-induced chemotaxis.

Table 2

Example 9. Suppression of Eosinophil Infiltration in Bronchoalveolar Lavage Fluid (BALF) by Compound No. 12

Male BALB/c mice were immunized by an intraperitoneal injection of 10 μg OVA adsorbed to 1 mg aluminum hydroxide gel (alum). A booster injection of the same dose of alum-adsorbed OVA was given 5 days later. Unimmunized control mice received saline.

Twelve days after primary immunization, both the immunized and unimmunized mice were exposed to aerosolized antigen. Aerosolization of OVA was performed using a nose-only aerosol chamber adapted for mice. Animals were exposed for 10 minutes to 5 mg/ml OVA aerosolized by an ultrasonic nebulizer (NE-U12, Omron, Tokyo, Japan) driven by a Vacuum pump. The antigen bronchoprovocation was repeated on day 16 and day 20 under the same conditions. Compound No. 12 (CPD No. 12) was dissolved in saline containing 2 % DMSO and 2 % Cremophore and administered intraperitoneally for 9 days, starting on the first day of antigen inhalation.

Twenty-four hours after the final aerosol exposure, bronchoalveolar lavage fluid (BALF) was collected by lavaging whole-lung three times with 0.7-ml aliquots of physiological saline containing 0.1 % BSA via the tracheal cannula while gently massaging the thorax. The BALF recovered from one mouse was pooled, centrifuged, and the cells were resuspended in 100 μl saline containing 0.1 % BSA. Cell numbers were determined using a hemocytometer and 2 x 10⁴ cells were cytecetrifuged onto a glass slide. Cells were stained with Diff-Quik (International reagent, Kobe, Japan), and cell types were identified by morphological criteria. Two hundred cells were examined per slide for differential count. As shown in Figure 1, Compound No. 12 (CPD No. 12) significantly suppressed eosinophil infiltration to bronchoalveolar lavage fluid (BALF).

Example 10. Suppression of Eosinophil Infiltration to Bronchoalveolar

Lavage Fluid (BALF) by Compound 87

Male BALB/c mice were immunized by an intraperitoneal injection of 10 μg

OVA adsorbed to 1 mg aluminium hydroxide gel (alum). A booster injection of the same dose of alum-adsorbed OVA was given 5 days later. Twelve days after primary immunization, eotaxin was given to the immunized mice intratracheally.

Compound 87 was dissolved in water containing 0.5% NaHCO₃ and administered per oral 30 minutes before eotaxin administration. Twenty-four hours after eotaxin administration, bronchoalveolar lavage fluid (BALF) was collected by lavaging whole-lung three times with 0.7-ml aliquots of physiological saline containing 0.1 % BSA via the tracheal cannula while gently massaging the thorax. The BALF recovered from one mouse was pooled, centrifuged, and the cells were resuspended in 100 μl saline containing 0.1 %BSA. Cell numbers were determined using a hemocytometer and 2 x 10⁴ cells were cytecentrifuged onto a glass slide. Cells were stained with Diff-Qick (International Reagent, Kobe, Japan), and cell types were identified by morphological criteria. Two hundred cells were examined per slide for differential count. As shown in Figure 2., Compound 87 significantly suppressed eosinophil infiltration to BALF.

Claims

WE CLAIM

A compound of the Formula (I)

(I)

or a salt, hydrate, or stereoisomer thereof, wherein:

n is 0 or 1 ;

m is 2, 3, 4, or 5;

RI 1 and R12 are independently selected from the group consisting of hydrogen, halogen, alkyl, aryl and heteroaryl wherein the alkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

Ar is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, trihalomethoxy, alkyl, alkoxy, cyano, nitro, amino, carboxy, alkyloxycarbonyl, arylmethyloxycarbonyl, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

or

or

p is 0, 1 or 2; q is 0, 1 or 2; R₄ and Rt' are independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; and COR9; wherein R9 is hydroxy, alkyl, alkoxy, amino, alkylamino or arylamino; R5 is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; Re is selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

R7 and R₈ are independently selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

Q, T, U, W and L are independently selected from the group of atoms consisting of C, N, O and S; wherein adjacent atoms U-T, T-Q, U-W, W-L may form one or more double bonds, and wherein no pair of said adjacent atoms forms O-O or S-S;

R₂ is selected from the group consisting of alkyl, alkenyl and alkynyl optionally substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, halogen, acyloxy, hydroxy, nitro, amino, acylamino, alkylamino, cyano, aryl optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy, wherein the alkyl or alkoxy may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, aryloxy, arylmethyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, heteroaryl optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl. tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, alkoxy optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, arylmethyloxy optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which is optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which is optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, and heterocycle; provided that no bond is formed between Ri and R₂.

2. The compound according to claim 1, wherein m is 3, 4, or 5.

3. The compound according to claim 2, wherein m is 3 or 4.

4. The compound according to claim 3, wherein Ar is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, trihalomethoxy, alkyl, alkoxy, cyano, nitro, amino, carboxy, alkyloxycarbonyl, arylmethyloxycarbonyl, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy; R5 is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy, and aryloxy optionally substituted with one or more groups independently selected from the group consistmg of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy; Re is selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy; R7 and R₈ are independently selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy.

5. The compound of claim 4, wherein R₂ is independently selected from the group consisting of alkyl, alkenyl and alkynyl, substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, acyloxy, acylamino, aryl substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which are substituted with carboxy or alkyloxycarbonyl, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alklylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, aryloxy, arylmethyloxy, acylamino, hydroxy, and halogen, heteroaryl substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which are substituted with carboxy or alkyloxycarbonyl, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alklylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, acylamino, hydroxy, and halogen, alkoxy optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, arylmethyloxy substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which are substituted with carboxy or alkyloxycarbonyl, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alklylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, acylamino, hydroxy, and halogen, and cycloalkyl substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which is substituted with carboxy or alkyloxycarbonyl, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alklylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, and acylamino.

6. The compound of claim 5, wherein R₂ is independently selected from the group consisting of alkyl, alkenyl and alkynyl, substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, and acylamino.

7. The compound of claim 6, wherein R₂ is independently selected from the group consisting of alkyl, alkenyl and alkynyl, substituted with one or more groups independently selected from the group consisting of carboxy and alkyloxycarbonyl .

8. A compound of the Formula (II)

(II) or a salt, hydrate, or stereoisomer thereof, wherein: m is 2, 3, 4 or 5;

Rll and R12 are independently selected from the group consisting of hydrogen, halogen, C1-5 alkyl, aryl and heteroaryl wherein the alkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; yl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, trihalomethoxy, alkyl, alkoxy, cyano, nitro, amino, carboxy, alkyloxycarbonyl, arylmethyloxycarbonyl, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

or

or

or

p is 0, 1 or 2; q is 0, 1 or 2; R₄ and R₄' are independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; and COR9; wherein R9 is hydroxy, alkyl, alkoxy, amino, alkylamino or arylamino; R5 is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; Re is selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

R7 and Rs are independently selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

R2 is selected from the group consisting of alkyl, alkenyl and alkynyl optionally substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, halogen, acyloxy, hydroxy, nitro, amino, acylamino, alkylamino, cyano, aryl optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy, wherein the alkyl or alkoxy may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, aryloxy, arylmethyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, heteroaryl optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, alkoxy optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, arylmethyloxy optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which is optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which is optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, and heterocycle; provided that no bond is formed between Ri and R .

9. The compound according to claim 8, wherein m is 3, 4, or 5.

10. The compound according to claim 9, wherein m is 3 or 4.

11. The compound according to claim 10, wherein Ar is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, trihalomethoxy, alkyl, alkoxy, cyano, nitro, amino, carboxy, alkyloxycarbonyl, arylmethyloxycarbonyl, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy; Rs is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy; Re is selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy;

R7 and Rs are independently selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy.

12. The compound of claim 11, wherein R2 is independently selected from the group consisting of alkyl, alkenyl and alkynyl, substituted with one or mbre groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, acyloxy, acylamino, aryl substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which are substituted with carboxy or alkyloxycarbonyl, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alklylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, aryloxy, arylmethyloxy, acylamino, hydroxy, and halogen, heteroaryl substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which are substituted with carboxy or alkyloxycarbonyl, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alklylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, acylamino, hydroxy, and halogen, alkoxy optionally substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, arylmethyloxy substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which are substituted with carboxy or alkyloxycarbonyl, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alklylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, acylamino, hydroxy, and halogen, and cycloalkyl substituted with one or more groups independently selected from the group consisting of alkyl or alkoxy which is substituted with carboxy or alkyloxycarbonyl, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alklylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, and acylamino.

13. The compound of claim 12, wherein R is independently selected from the group consisting of alkyl, alkenyl and alkynyl, substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, and acylamino.

14. The compound of claim 13, wherein R is independently selected from the group consisting of alkyl, alkenyl and alkynyl, substituted with one or more groups independently selected from the group consisting of carboxy and alkyloxycarbonyl .

15. The compound according to claim 8, wherein the compound is defined in Table 1A.

16. A compound of the Formula (III)

(III) or a salt, hydrate, or stereoisomer thereof, wherein: Ar is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, trihalomethoxy, alkyl, alkoxy, cyano, nitro, amino, carboxy, alkyloxycarbonyl, arylmethyloxycarbonyl, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

p is 0, 1 or 2; q is 0, 1 or 2; R₄ and R ' are independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; and COR₉; wherein R9 is hydroxy, alkyl, alkoxy, amino, alkylamino or arylamino; R5 is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino.

17. The compound according to claim 16, wherein Ar is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, trihalomethoxy, alkyl, alkoxy, cyano, nitro, amino, carboxy, alkyloxycarbonyl, arylmethyloxycarbonyl, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy;

Rs is aryl or heteroaryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy, and aryloxy optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, alkyl, alkoxy, cyano, nitro, amino, and carboxy.

18. The compound according to claim 16, wherein the compound is defined in Table IB:

19. A pharmaceutical composition comprising a compound according to claim 1.

20. A method of treating CCR-3 mediated diseases in a patient, comprising administering to said patient an effective amount of the pharmaceutical composition of claim 19.

21. The method of claim 20, wherein said CCR-3 mediated disease is an eosinophil mediated allergic disease.

22. The method of claim 21, wherein said eosinophil mediated allergic disease is selected from the group consisting of asthma, rhinitis, eczema, inflammatory bowl diseases and parasitic infections.

23. The method of claim 20, wherein said CCR-3 mediated disease is a T-cell or a dendritic cell mediated disease.

24. The method of claim 23, wherein said T-cell or dendritic cell mediated disease is selected from the group consisting of autoimmune diseases and HIV.

25. The method of claim 20, wherein said pharmaceutical composition comprises a prodrug.

26. A kit for treating CCR-3 mediated diseases in a patient, comprising:

(A) the pharmaceutical composition of claim 19;

(B) reagents to effect administration of said pharmaceutical composition to said patient; and

(C) instruments to effect administration of said pharmaceutical composition to said patient.

27. A method of inhibiting a CCR-3 mediated cellular response in a cell which expresses CCR-3, comprising contacting said cell with a compound according to claim 1, such that said cellular response is inhibited.

28. A method according to claim 27, wherein the CCR-3 mediated cellular response is an intracellular calcium mobilization.

29. A method according to claim 28, wherein the CCR-3 mediated cellular response is a chemotaxis.

30. A method of treating a CCR-3 mediated diseases in a mammal, comprising administering to said mammal an effective amount of the pharmaceutical composition according to claim 20.

31. A compound of Formula (F)

(D or a salt, hydrate, or stereoisomer thereof, wherein: m is 2, 3, 4 or 5;

Rπ and Rι₂ are independently selected from the group consisting of hydrogen, halogen, C1-5 alkyl, aryl and heteroaryl wherein the Cι-5 alkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, Ci-salkyl, Ci-salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

or

or

or

p is 0, 1 or 2; q is 0, 1 or 2; R₄ and R ' are independently selected from the group consisting of hydrogen, halogen, Ci-s alkyl, aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group of consisting of hydrogen, hydroxy, halogen, trihalomethyl, Ci-s alkyl, Ci-salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino and COR9, wherein R₉ is hydroxy, Ci-salkyl, Ci-salkoxy, amino, alkylamino or arylamino;

Re is selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, C1-5 alkyl, C1-5 alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl and aryloxy wherein the aryl or aryloxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, C1-5 alkyl, C1-5 alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino; R7 and Rs are independently selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, C1-5 alkyl, C1-5 alkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino;

R2 is selected from the group consisting of Ci-β alkyl, Ci-s alkenyl and C1-8 alkynyl optionally substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, halogen, acyloxy, hydroxy, nitro, amino, acylamino, alkylamino, cyano, aryl optionally substituted with one or more groups independently selected from the group consisting of C1-5 alkyl or C1-5 alkoxy, wherein the alkyl or alkoxy may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, aryloxy, arylmethyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, heteroaryl optionally substituted with one or more groups independently selected from the group consisting of Ci-s alkyl or C1-5 alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen,

C1-5 alkoxy optionally substituted with one or more groups independently selected from the group consisting of C1-5 alkyl or C1-5 alkoxy which may be optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, arylmethyloxy optionally substituted with one or more groups independently selected from the group consisting of C1-5 alkyl or C1-5 alkoxy which is optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidmo, guanidino, cyanoguanidino, hydroxy, and halogen, C₃-7 cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of C1-5 alkyl or C1-5 alkoxy which is optionally substituted with carboxy or alkyloxycarbonyl, cyano, nitro, amino, acylamino, alkylamino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, acyl, acyloxy, hydrazino, hydroxyamino, amidino, guanidino, cyanoguanidino, hydroxy, and halogen, and heterocycle; provided that no bond is formed between Ri and R2.

32. The compound according to claim 31, wherein: m is 3 or 4; Ar' is aryl, optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, Ci-salkyl, Ci-salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, cyanoguanidino, aryl, aryloxy, benzyloxy, benzoyl, and naphthoyl, wherein the aryl, aryloxy, benzyloxy, benzoyl, or naphthoyl is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, Ci-salkyl, Ci-salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino and cyanoguanidino;

or

p is O or 1; q is 0 or 1;

hydrogen,

halogen,

or Cwalkyl;

Rs is aryl, optionally substituted with one or more groups independently selected from the group consisting of

hydroxy, halogen, trihalomethyl, Ci-salkyl, Ci-salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, and cyanoguanidino; Re is hydrogen, hydroxy, halogen, trihalomethyl, Ci-salkyl, Ci- salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino, or cyanoguanidino; R7 and Rs is independently selected from the group consisting of hydrogen, hydroxy, halogen, trihalomethyl, Ci-salkyl, Ci- salkoxy, cyano, nitro, amino, carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, acyl, acyloxy, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylthio, alkylsulfonamide, arylsulfonamide, hydrazino, acylamino, alkylamino, hydroxyamino, amidino, guanidino and cyanoguanidino; Q, T, U , W and L is independently selected from the group of atoms consisting of C, N, O and S. Two adjacent atoms of Q, T, U, W and L may make double bond(s), and no pair of such adjacent atoms forms O-O or S-S;

R₂ is selected from the group consisting of Ci-salkyl, Ci-salkenyl and Ci- ₈alkynyl, wherein the Ci-salkyl, Ci-salkenyl or Ci-salkynyl is optionally substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, alkylsulfonamide, arylsulfonamide, alkylthio, halogen, hydroxy, nitro, amino, acylamino, alkylamino, and cyano; R11 and Rι₂ are independently selected from the group consisting of hydrogen, halogen, and Cι-₃alkyl.

33. The compound according to claim 32, wherein R₂ is selected from the group consisting of:

Ci-salkyl, Ci-salkenyl and Ci-salkynyl, optionally substituted with one or more groups independently selected from the group consisting of carboxy, carbamoyl, alkylcarbamoyl, alkylsulfonylcarbamoyl, alkyloxycarbonyl, tetrazolyl, isoxazolyl, isothiazolyl, alkylsulfonamido, arylsulfonamido, sulfonyl, alkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonamide, alkylthio, halogen, hydroxy, nitro, amino, acylamino, alkylamino, cyano,; wherein R₄,R>,R6,R7,R8,Rn, Rι₂, U,T,Q,p,and q are defined as in claim 32.

34. The compound according to claim 33, wherein U, T and Q are carbon atoms; p and q are 0; and Rn and Rι₂ are hydrogen or Cι-3alkyl.

35. The compound according to claim 34, wherein Ar' is aryl, optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, trihalomethyl, Ci-salkyl, Ci-salkoxy, cyano, nitro, amino, carboxy, benzyloxy, benzoyl, naphthoyl, aryl, wherein benzyloxy, benzoyl, or naphthoyl is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, trihalomethyl, Ci-salkyl, and Ci-salkoxy.

36. A compound according to claim 31, wherein the compound is defined in Table ID.

37. A pharmaceutical composition comprising a compound according to claim 31.

38. A method of treating a CCR-3 mediated disease in a patient, comprising administering to said patient an effective amount of the pharmaceutical composition of claim 37.

39. The method of claim 38, wherein said CCR-3 mediated disease is an eosinophil mediated allergic disease.

40. The method of claim 39, wherein said eosinophil mediated allergic disease is selected from the group consisting of asthma, rhinitis, eczema, inflammatory bowl diseases and parasitic infections.

41. The method of claim 38, wherein said CCR-3 mediated disease is a T-cell or a dendritic cell mediated disease.

42. The method of claim 41, wherein said T-cell or dendritic cell mediated disease is selected from the group consisting of autoimmune diseases and HIN.

43. The method of claim 38, wherein said pharmaceutical composition comprises a prodrug.

44. A kit for treating CCR-3 mediated diseases in a patient, comprising:

(A) the pharmaceutical composition of claim 37;

45. A method of inhibiting a CCR-3 mediated cellular response in a cell which expresses CCR-3, comprising contacting said cell with a compound according to claim 31, such that said cellular response is inhibited.

46. A method according to claim 45, wherein the CCR-3 mediated cellular response is an intracellular calcium mobilization.

47. A method according to claim 46, whereinin the CCR-3 mediated cellular response is a chemotaxis.

48. A method of treating a CCR-3 mediated disease in a mammal, comprising administering to said mammal an effective amount of the pharmaceutical composition according to claim 38.