MXPA00000148A

MXPA00000148A - Compounds and methods

Info

Publication number: MXPA00000148A
Application number: MXPA/A/2000/000148A
Authority: MX
Inventors: William E Bondinell; James A Chan
Original assignee: William E Bondinell; James A Chan; Smithkline Beecham Corporation
Priority date: 1997-07-03
Filing date: 2000-01-03
Publication date: 2001-11-21

Abstract

This invention relates to substituted benzanilides which are ligands, agonists or antagonists, of the CCR5 receptor. In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5, including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, by the use of substituted benzanilides which are CCR5 receptor antagonists. Furthermore, since CD8+T cells have been implicated in COPD, CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therapeutic in the treatment of COPD. Also, since CCR5 is a co-receptor for the entry of HIV into cells, selective receptor ligands may be useful in the treatment of HIV infection.

Description

COMPOUNDS AND METHODS FIELD OF THE INVENTION This invention relates to substituted benzanilides which are ligands, agonists or antagonists of the CC-CKR5 receptor of chemokine CC now designated CCR5. { Nature Medicine 1996, 2, 1174-8). In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5.

BACKGROUND OF THE INVENTION T cells are not only key regulators of the immune response to infectious agents, but they are also thought to be critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases. Increased numbers or the increased activation state of T cells, especially CD4 + T cells have been demonstrated in the synovium of individuals with rheumatoid arthritis (MJ Elliott and RN Maini, Int. Arch. Allerqy Immunol., 104: 112-1125, 1994), in the bronchial mucosa of asthmatics (CJ Corrigan and AB Kay, Immunol., 13: 501-506, 1992), in multiple sclerosis lesions (R. Martin and HF McFarland, Crit. Rev. Clin. Lab. Sci. : 121-182, 1995), in psoriatic lesions (JL Jones, J. Berth-Jone, A. Fletcher and PE Hutchinson, J. Pathol 174: 77-82, 1994) and in fatty streaks of atherosclerosis (R. Ross, Annu, Rev. Physiol. 57: 791-804, 1995). T cells, as well as other inflammatory cells, will migrate to tissues in response to the production of a variety of chemotactic factors. Among these factors are a superfamily of 8-12 kDa proteins known as chemokines. These proteins share structural characteristics such as the presence of 3-4 conserved cysteine residues. RANTES, which means normal T cells regulated after activation expressed and secreted, is an 8 kDa protein member of CC branch of the Isa chemokine family. These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors. The CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues, and the members of this family induce predominantly the migration of mononuclear, eosinophilic and basophilic cells (M. Baggiolini, B. Dewald, and B. Moser, Adv. Immunol., 55: 97-179, 1994, and JJ Oppenheim, COC zachariae, N. Mukaida, and K. Matsushima, Annu, Rev. Immunol 9: 617-648, 1991). RANTES potentially produces chemotaxis of T cells, basophils, eosinophils, monocytes and mast cells. RANTES was originally identified as an induced gene product after activation of the T cell antigen (TJ Schall, J. Jongstra, BJ Dyer, J. Jorgensen, et al., J. Immunol 141: 1018-1025, 1998), however , RANTES has shown to be k? - synthesized and secreted by a diverse group of cells including epithelial and endothelial cells (C. Stellato, LA Gorgone, D. Proud, et al., Gorgone, A. Portier, et al., J. Immunol. 154: 1870- 1878, 1994), synovial fibroblasts (P. Rathanaswami, M. Hachicha, M. Sadick, TJ Schall, and others, J., Biol. Chem. 268: 5834-5839, 1993) and dermal fibroblasts (M. Sticherling, M. Kupper, F. Kotrowitz, E. Bomscheuer et al., J. Invest. Dermatol. 105: 585-591, 1995), mesangial cells (G. Wolf, S. Aberle, F. Thaiss, and others, Kidney lnt.44 : 795-804, 1994) and platelets (Y. Koameyoshi, A. Dorschner, Al Mallet, E christophers, et al., J. Exp. Med. 176: 587-592, 1992). In these cells, the RANTES mRNA is rapidly over-regulated in response to IL-1 or TNFa. Although RANTES mRNA is not normally detected in normal tissues (J: M: Pattison, PJ Nelson, and A: M: Krensky, Clin.Immunother.4: 1-8, 1995), an increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate. For example, RANTES mRNA was visualized using in situ hybridization in renal allografts subjected to rejection (J.M. Pattison, P.J. Nelson, and A.M. Krensky, Clin.Immunother.4: 1-8, 1995) and K.C. Nadeau, H. Azuma and N.l. Tilney, Proc. Nati Acad. USA 92: 8729-8733, 1995) on the skin of patients with atopic dermatitis after exposure to antigen (S. Ying, L. Taborda-Barata, Q. Meng. Humbert et al., J. Exp. Med. 181: 2153-2159, 1995), and in endothelial cells of coronary arteries subjected to accelerated atherosclerosis after cardiac transplantation (J: M: Pattison, PJ Nelson, and AM Krensky, Clin.Immunother.4: 1-8, 1995). In addition, the increased immunoreactive protein for RANTES has been detected in bronchoalveolar lavage fluid (R. Alam, J. York, M Boyers, et al., Am. J. Resp. Crit. Care Med. 149: A951, 1994) and sputum of asthmatic individuals (CM Gelder, PS Thomas, DH Yates, IM Adcock et al., Thorax 50: 1033-1037, 1995). Several receptors that bind to RANTES have been identified.

In particular, CCR5, when expressed either in HEK 293 cells or CHO cells, binds to RANTES. This receptor is expressed in T cells and in monocytes and macrophages, immune / inflammatory cells that are important in maintaining a chronic inflammatory reaction. The pharmacological characterization of CCR5 indicates similarities with the RANTES binding site observed in isolated T cells. Therefore, the antagonism of the action of RANTES on CCR5, as well as the antagonism of other natural ligands of CCR5, should inhibit the recruitment of T cells in inflammatory lesions and provide a novel therapeutic approach for the treatment of atopic and autoimmune disorders. Since T cells express CCR5, selective CCR5 receptor ligands, particularly antagonists, are prone to provide beneficial effects in diseases including, but not limited to, asthma and atopic disorders (e.g., atopic dematitis and allergy), arthritis rheumatoid, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis and inflammatory bowel disease, all in mammals, preferably humans. In addition, since CD8 + T cells have been implicated in COPD, CCR5 may play a role in their recruitment and therefore antagonists for CCR5 could provide a potential therapeutic effect in the treatment of COPD. Similarly, since CCR5 is a co-receptor for the entry of HIV into cells, selective receptor ligands may be useful in the treatment of HIV infection. It has been reported that a subset of compounds included in formula (I) have 5-HT receptor activity (International application publication number WO 95/15954, published June 15, 1995, International application publication number WO 95/17398 , published June 29, 1995, international application publication number WO 95/26328, published October 5, 1995, international application publication number WO 96/06079, published February 29, 1996, GB 2276161 published on 21 September 1994 and GB 2279165, published September 21, 1994, international application publication number WO 95/30675 published November 16, 1995, international application publication number WO 95/17401, published June 29, 1995. International Application Publication No. WO 96/31508, published October 10, 1996, International Application Publication No. WO 97/10824 published March 27, 1997; International application number WO 97/11934 published April 25, 1996; international application publication number WO 96/19477 published June 27, 1996; International Application Publication No. WO 97/17350 published May 15, 1997; international application publication ^ &^ number WO 97/34900 published on September 25, 1997; International Application Publication No. WO 97/34901 published September 25, 1997; International Application Publication No. WO 97/35862 published October 2, 1997; International Application Publication No. WO 97/19070, published May 29, 1997; International Application Publication No. WO 95/32967 published December 7, 1995; International Application Publication No. WO 97/07120 published February 27, 1997; patent of E.U.A. 3,931, 195, issued on January 6, 1976 and patent of E.U.A. 4,000,143, issued December 28, 1996). Surprisingly, it has now been discovered that this class of non-peptide compounds, in particular substituted benzanilides of the formula (I), function as receptor ligands of CCR5, and therefore have utility in the treatment and prevention of disease states mediated by receptor mechanisms of CCR5.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to the novel use of a CCR5 ligand for the treatment of certain disease states, including but limited to, asthma and atopic disorders (eg, atopic dematitis and allergies), rheumatoid arthritis, sarcoidosis and fibrotic diseases, asterosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease and HIV infection, all in mammals, preferably humans. The compounds that are preferred to be used as CCR5 ligands are those compounds of the formula (I) as described herein.

DETAILED DESCRIPTION OF THE INVENTION It has now been discovered that the substituted benzanilides of the formula (I) are receptor ligands of CCR5. It has now also been discovered that the selective inhibition of CCR5 receptor mechanisms by treatment with the receptor ligands of the formula (I), or a pharmaceutically acceptable salt thereof, represents a novel therapeutic and preventive approach for the treatment of a variety of disease states, including, but not limited to, asthma and atopic disorders (e.g., atopic dematitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, asterosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease , all in mammals, preferably humans. In addition, since CD8 + T cells have been implicated in COPD, CCR5 may play a role in their recruitment and therefore antagonists for CCR5 could provide a potential therapeutic effect in the treatment of COPD. Similarly, since CCR5 is a co-receptor of cell entry, selective receptor ligands could be useful in the treatment of HIV infection.

* »G || ^. -. ^ *? ', «- ^ w_. -and j -. _and.

Compounds for use herein include the CCR5 ligands as described in International Application Publication No. WO 95/15954, published June 15, 1995, (USSN 08 / 652,581, filed June 7, 1996); International Application Publication No. WO 95/17398, published June 29, 1995, (USSN 08 / 663,291, filed June 21, 1996); International Application Publication No. WO 95/26328, published October 5, 1995, (USSN 08 / 718,481, filed September 26, 1996); International application publication number WO 95/06079, published February 29, 1996, (USSN 08 / 793,428, filed on February 21, 1997); GB 2276161 published September 21, 1994 and GB 2276165 published September 21, 1994); International Application Publication No. WO 95/30675, published November 16, 1995, (USSN 08 / 737,147); International Application Publication No. WO 95/17401, published June 29, 1995, (USSN 08 / 663,290, filed June 21, 1996); International Application Publication No. WO 95/31508, published October 10, 1996, (USSN 08 / 930,848, filed October 7, 1997); International Application Publication No. WO 97/10824, published March 27, 1997, (USSN 09 / 043,346); International Application Publication No. WO 96/11934, published April 25, 1996, (USSN 08 / 817,619); International Application Publication No. WO 96/19477, published June 27, 1996, (USSN 08 / 849,932); International Application Publication No. WO 97/17350, published May 15, 1997, (USSN 09 / 068,382, filed May 8, 1998); International Application Publication No. WO 97/34900, published September 25, 1997, (Case No. P31419); International Application Publication No. WO 97/34901, published September 25, 1997, (Case No. P31418); International Application Publication No. WO 97/35862, published October 2, 1997, (Case No. P31426); International application publication number WO 97/19070, published May 29, 1997, (USSN 09 / 077,263); International application publication number WO 95/32967, published December 7, 1995, (USSN 08 / 737,660); International Application Publication No. WO 97/07120, published February 27, 1997, (USSN 09/011, 338, filed on February 11, 1998); patent of E.U.A. 3,931, 195, issued on January 6, 1976 and patent of E.U.A. 4,000,143, issued December 28, 1976. The compounds that are preferred to be used as CCR5 ligands are those compounds of formula (I) as mentioned herein. Each of these references is incorporated in the present in its entirety. A group of compounds that are preferred to be used herein are those compounds of formula (I) or a pharmaceutically acceptable salt thereof: Ar- A- E Formula I wherein Ar represents a group selected from (i), (ii) ) or (iii); wherein: R1 and R2 are independently hydrogen, d-β alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- cycloalkyl, C3-6 cycloalkenyl, aryl, (CH2) aNR7R8, (CH2) aNR7COR9 , (CH2) aNR7C02R10, (CH2) aNR7C02R11, (CH2) aCONR12R13, hydroxyC1-6alkyl, C4-4alkoxyalkyl (optionally substituted by an alkoxy or hydroxy group of C-), (CH2) aCOR, alkyl C? -6, (CH2) bOC (O) R14, CR15 = NOR16, CNR15 = NOR16, COR17, CONR12R13, CONR12 (CH2) cO-C4 alkyl; CONR12 (CH2) aCO2R18, CONHNR19R20, CONR12SO2R21, C02R22, cyano, trifluoromethyl, NR7R8, NR7COR9, NR23CO (CH2) aNR23R24, NR23CONR23R24, NR7CO2R10, NR7SO2R11, N = CNR23NR23R24, nitro, hydroxy, C1-6 alkoxy, hydroxyalkoxy of C? -6, C 1-6 alkoxy-C? -6 alkoxy, OC (0) NR25R26, SR27, SOR28, S02R28, S02NR25R26 or halogen; a is 1, 2, 3 or 4; R7 and R8 are independently hydrogen or C? -6 alkyl, or NR7R8 forms a heterocyclic ring having 5 or 6 ring member having 5 to 6 ring members which can be optionally substituted by a ? ii «^ ____________ a_H _ ^ _ Bl_______________i Ettafc -« «---- to J - and £ - oxo group and, when there are 6 ring members, an oxygen or sulfur atom may optionally be contained in the ring; R9 is hydrogen, C-? -6 alkyl or C? -4 alkoxyalkyl; R10 is C? -6 alkyl; R11 is C-? -6 alkyl or phenyl; R12 and R13 are independently hydrogen or C-? -6 alkyl, or NR12R13 forms a saturated heterocyclic ring having 5 or 6 members which, when there are 6 ring members, may optionally contain in the ring an oxygen or sulfur atom; b is 0, 1, 2 or 3; R14 is C- alkyl, optionally substituted by an alkoxy of R15 and R16 are independently hydrogen or C-? -6 alkyl; R17 is hydrogen or C? -6 alkyl; c is 1, 2 or 3; R18 is hydrogen or C? -6 alkyl; R19 and R20 are independently hydrogen or C? -6 alkyl; R21 is hydrogen or C? -6 alkyl; R22 is hydrogen or C-? -6 alkyl optionally substituted with one or two substituents selected from C 1-6 alkyl, C? -6 alkoxy > hydroxy or NR7R8; R 23 and R 24 are independently hydrogen or C 1-6 alkyl; R25 and R26 are independently hydrogen or d-6 alkyl, NR25R26 forms a saturated heterocyclic ring having 5 or 6 members which, when there are 6 ring members, may optionally contain in the ring an oxygen or sulfur atom; R27 is hydrogen or C? -6 alkyl; R28 is d-β alkyl; P is a 5- to 7-membered heterocyclic ring containing 1 to 4 heterogeneous atoms selected from oxygen, nitrogen or sulfur; R3 and R4 are independently hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-6 cycloalkenyl, C1-6 hydroxyalkyl, d-alkyl. e-C1-6alkyl, CONR29R30, CO2R3? cyano, aryl, trifluoromethyl, NR29R30, nitro, hydroxy, C1-6 alkoxy, acyloxy or halogen; R29, R30 and R31 are independently hydrogen or d-β alkyl; R5 is hydrogen, d-6 alkyl, C1-6 alkoxy or halogen; R6 is hydrogen, d-6 alkyl, C3-7 cycloalkyl (optionally substituted by a hydroxy or an oxo group), hydroxyalkyl of d-β, C3-6 hydroxyalkenyl > hydroxyalkynyl of C3-6, (CH2) dOR32, (CH2) dCOR33, (CH2) dCR34 = NOR35, CONR36R37, CO2R38, hydroxy, O (CH2) eR39, NR36R37, SR40, SO2NR41R42 or halogen; d is 0, 1, 2, 3, 4, 5 or 6; R 32 is C 1 -6 alkyl, d-β hydroxyalkyl or C 1 - alkanoyl; R33 is hydrogen or d-β alkyl; R34 is hydrogen or d-β alkyl; R 35 is hydrogen or d-6 alkyl; R36 and R37 are independently hydrogen or d-6 alkyl, or NR36R37 forms a saturated heterocyclic ring having 5 or 6 members, which may be optionally substituted by an oxo group and, when there are 6 ring members, may optionally contain one atom of oxygen or sulfur, or an NH or NR43, wherein R43 is alkyl of d-6, COR44 or C02R45, wherein R44 and R45 are independently hydrogen or alkyl of d-6; R38 is hydrogen or C? -6 alkyl; e is 1, 2, 3, 4, 5 or 6; R39 is C1-6 alkoxy, CO2H, C02C1-6 alkyl or CONR36R37; R40 is d-β alkyl; R41 and R42 are independently hydrogen or C1-6alkyl; alternatively, R5 and R6 form a fused benzo ring optionally substituted with d-6alkyl, C-? -6alkoxy or halogen; when Ar is (i), (ii) or (iii), and A is CONR46, NHCO, -NHCH2 or CH2NH, wherein R46 is hydrogen or d-β alkyl, E represents (a): wherein R > 47"and D R48 are independently hydrogen or C 1-6 alkyl; í- '-rit.i! -ii-tirt _MM¿MaÉ ^., ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ C? -6, C02R53, NHCO2R54, hydroxy, d-6alkoxy or halogen wherein R53 is hydrogen or alkyl of d-6, and R54 is alkyl of d-6; R50 and R51 are independently hydrogen, C1-6 alkyl. C3- cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one or two heterogeneous atoms selected from oxygen, nitrogen or sulfur; B is oxygen, S (0) h wherein h is 0, 1 or 2, CR55 = CR56 or CR55R56 wherein R55 and R56 are independently hydrogen or alkyl of C -? - 6, or B is NR57 wherein R57 is hydrogen, C1-6 alkyl or phenylalkyl Ci-6 R52 is hydrogen, or R52 taken together with R46 forms a group D wherein D is (CR58R59), where i is 2, 3 or 4 and R58 and R59 are independently hydrogen or d-6 alkyl, or D is (CR58R59) rG where j is 0, 1, 2 or 3 and G is oxygen, sulfur or CR58 = CR59; f is 1 to 4; and g is 1 or 2; when Ar is (i), (ii) or (iii) and A is CONR60, NHCO or CH2N, where R60 is hydrogen or C-? 6 alkyl, E represents (b): The R61 is hydrogen or alkyl of d-6 and R61 and R60 together form a -K- group when K is (CR65R66) m when m is 2, 3, or 4 and R65 and R66 are independently hydrogen or d-6 alkyl or K is (CR65R66) nL when n is 0, 1, 2 or 3 and L is oxygen, sulfur or CR65 = CR66; R62 is hydrogen or C? -6 alkyl; R63 and R64 are independently hydrogen or C? -6 alkyl; J is oxygen, CR67R58 or NR69 wherein R67, R68 and R69 are independently hydrogen or alkyl of d-6 or J is a group S (O) m wherein m is 0, 1 or 2; k is 1, 2 6 3; I is 1, 2 or 3; when Ar is (i), (ii) or (iii) and A is CONR70, NHCO, -NHCH2 or CH2NH, wherein R70 is hydrogen or alkyl of d-6, E represents (c): wherein: M is oxygen, S (O) p wherein p is 0, 1 or 2, CR76 = CR77 or CR76R77 wherein R76 and R77 are independently hydrogen or alkyl of d-6, or M is NR78 wherein R78 is hydrogen or alkyl; R71 and R72 are independently hydrogen or d-6 alkyl; __ £ __ £ ___ £ £ i '!) - _ i ?? £ _ _,.-__.- and i_______i R73 is hydrogen, d-6 alkyl, C02R79, NHC02R80, hydroxy, d-6 alkoxy or halogen wherein R79 is hydrogen or alkyl of d-β and R80 is C1-6 alkyl, R74 is hydrogen or together with R70 forms a group Q when Q is CR81 = CR82, CR81 = CR82CR81R82 or (CR81R82) q where q is 2 or 3 and R81 and R82 are independently hydrogen or d-β alkyl; n is 0, 1, 2 or 3; or is 1 or 2; R75 is a group of the formula (d): wherein r, s and t are independently integers having the value 1, 2 or 3; or R75 is a group of the formula (e): wherein u is 0, 1, 2 or 3 and R83 is hydrogen or C? -6 alkyl; when Ar is (i), (ii) or (iii) and A is CONH, NHCO or CH2NH, E represents (f): «ÍM_l__i _______ Í ______ l R84 and R85 are independently hydrogen or d-β alkyl; R86 and R87 are independently hydrogen, d-β alkyl, C3-7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached they form an optionally substituted 5- to 7-membered heterocyclic ring containing one to two heterogeneous atoms Selected oxygen, nitrogen or sulfur; T is - (CR88R89) W- or -0 (CR88R89) x- wherein R88 and R89 are independently hydrogen or C? -6 alkyl, wherein w is 2 or 3 and x is 1, 2 or 3; v is 1 to 4; and W is oxygen, S (O) and wherein y is 0, 1 or 2, or W is NR90 where R90 is hydrogen or d-6 alkyl, or W is CR91 = CR92 or CR91R92 where R91 and R92 they are independently hydrogen or C 1-6 alkyl; when Ar is (i), (ii) or (iii) and A is CONR93, NHCO or CH2NH wherein R93 is hydrogen or alkyl of d-6, E represents a group (g): R94 is hydrogen, halogen, hydroxy, d-β alkyl or C-? 6 alkoxy, or R94 and R93 taken together form a group -X- where X is (CR97R98) aa wherein aa is 2, 3 or 4 and R97 and R98 are independently hydrogen or alkyl of d-6 or X is (CR97R98) ab-Y, where ab is 0, 1, 2 or 3 and Y is oxygen, sulfur or CR97 = CR98; R95 is hydrogen, C1-6 alkyl, C02R99, NHCO2R10 °, hydroxy, d-6 alkoxy or halogen, wherein R95 is hydrogen or d-β alkyl and R100 is d-β alkyl; z is 1 or 2; and R96 is an optionally substituted saturated or partially saturated 5- to 7-membered heterocyclic ring containing 1 to 3 heterogeneous atoms selected from nitrogen, oxygen or sulfur, or R96 is an optionally substituted 6,6 or 6.5 bicyclic ring containing a nitrogen atom and optionally an additional heterogeneous atom selected from oxygen, nitrogen or sulfur; when Ar is (i), (ii) or (iii) and A is CONR101, NHCO or CH2NH, wherein R101 is hydrogen or alkyl of d-6, E represents a group (h): (h); R102 is hydrogen or d-6 alkyl, d-6 alkoxy or halogen, or R102 together with R101 form a group -AA-, where AA is (CR107R108) ad, wherein ad is 1, 2 or 3 and R107 and R108 are independently hydrogen or C? -6 alkyl or AA is (CR107 = CR108) ae-AB, where ae is 0, 1 or 2 and AB is oxygen, sulfur, CR107 = CR108, CR107 = N, CR102NR108 or N = N; R? O3 and R? O4 S0 |? Ncjepenc |mente hydrogen or d-β alkyl ", R 5 and RIOT are nc | epenc |, hydrogen, d-6 alkyl, C 3-7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached, they form a 5- to 7-membered heterocyclic ring optionally substituted containing one or two heterogeneous atoms selected from oxygen, nitrogen or sulfur; ac is 0 to 4; Z is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heterogeneous atoms selected from oxygen, nitrogen or sulfur; when Ar is (i), (ii) or (iii) and A is CONR109, NHCO or CH2NH, wherein R109 is hydrogen or C? -6 alkyl, E represents a group (i): ^ Aßß ^ R110 is hydrogen or C1-6alkyl, or R110 and R109 together form an -AD- group, where AD is (CR115R116) ah, where ah is 2, 3 or 4 and R115 and R116 are independently hydrogen or d-β alkyl. or AD is where ai is 0, 1, 2 or 3 and AE is oxygen, sulfur or CR115 = CR116; R n and R n 2 are nc epencly hydrogen, d-6 alkyl, C 3-7 cycloalkyl, aralkyl, or together with the nitrogen atoms to which they are attached form a 5- to 7-membered heterocyclic ring optionally substituted containing one to two heterogeneous atoms selected from oxygen, nitrogen or sulfur; R? I3 and R114 are independently hydrogen or d-β alkyl; AC is oxygen, CR117R118 or NR119, wherein R117, R118 and R119 are independently hydrogen or C? -6 alkyl, or AC is a group S (O) aj, wherein aj is 0, 1 or 2; af is 1, 2 or 3; ag is 1, 2, 3 or 4; and ah is O, 1, 2, 3 or 4. Suitably, when Ar is (i) or (ii), the terminal phenyl group in (i) and (ii) can be attached to the phenyl group carrying a group A in any position. Preferably, the terminal phenyl ring is attached to the phenyl carrier group A in a meta or para position to group A, most preferably to group A.

Suitably, P is a 5- to 7-membered heterocyclic ring containing 1 to 4 heterogeneous atoms selected from oxygen, nitrogen or sulfur. Examples of suitable heterocyclic rings include thienyl, furyl, triazolyl, diazolyl, imidazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl and dioxanyl. Suitably, the heterocyclic rings can be linked to the rest of the molecule by a carbon atom or, when present, a nitrogen atom. Preferably, P is oxadiazolyl. Suitably, when Ar is (iii), R6 may be attached to the phenyl ring at any position. Preferably, R6 is attached meta or para to group A. Most preferably, R6 is attached in the para position to group A. Suitably, R1 and R2 are independently hydrogen, C6-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- cycloalkyl, C3-6 cycloalkenyl, aryl, (CH2) aNR7R8, (CH2) aNR7COR9, (CH2) aNR7CO2R10, (CH2) aNR7S02R11, (CH2) aCONR12R13, hydroxyalkyl of d. 6, C- alkoxyalkyl, (optionally substituted by a C 1-4 alkoxy or hydroxy group), (CH 2) aCO 2 C 1-6 alkyl, (CH 2) bOC (0) R 14, C 15 = NOR 16, CNR 15 = NOR 16, COR 17, CONR12R13, CONR12 (CH2) C1-4alkyl, CONR12 (CH2) aC? 2R18, CONHR19R20, CONR12SO2R21, CO2R22, cyano, trifluoromethyl, NR7R8, NR7COR9, NR23CO (CH2) aNR23R24, NR23CONR23R24, NR7C02R1 °, NR7SO2R11, N = CNR23NR23R24 , nitro, hydroxy, d-6-alkoxy, C6-hydroxy-alkoxy, d-6-C6-alkoxy alkoxy, OC (0) NR25R26, SR27, SOR28, SO2R28, SO2NR25R26 or halogen. Preferably, at least one of __ ^ t___ j | R1 or R2 is independently hydrogen, d6 alkyl, preferably methyl, d6 alkoxy, preferably methoxy, preferably 3-position., hydroxy, preferably in the 3-position, cyano, preferably in the 4-position and (CH 2) bOC (O) R 14, wherein b is preferably 0, and R 14 is preferably ethyl. Suitably, R3 and R4 are independently hydrogen, C6-6alkyl, C3- cycloalkyl, d-6-cycloalkenyl, Ci-hydroxyalkyl. 6, C6-C6 alkyl, CONR29R30, C02R31, cyano, aryl, trifluoromethyl, NR29R30, nitro, hydroxy, d-6 alkoxy, acyloxy or halogen. Preferably, R3 is hydrogen and d-6 alkyl, most preferably methyl. R4-P is preferably CH3-oxadiazolyl. Suitably, R6 is hydrogen, C6-6 alkyl, C3-7 cycloalkyl (optionally substituted by a hydroxy group or an oxo group), hydroxyC1-6 alkyl, C3-6 hydroxyalkenyl, C3-6 hydroxyalkynyl , (CH2) dOR32, (CH2) dCOR33, (CH2) dCR34 = NOR35, CONR36R37, CO2R38, hydroxy, O (CH2) eR39, NR36R37, SR40, SO2NR41R42 or halogen. Preferably, R6 is C3-7 cycloalkyl, most preferably cyclohexyl, or halogen, most preferably iodine. Preferably, R7 and R8 are independently hydrogen or C? -6 alkyl; Preferably, R9 is hydrogen or C1-6alkyl; Preferably, R 11 is Ci-β alkyl; Preferably, R12 and R13 are independently hydrogen or d-6 alkyl, Preferably, R14 is d6 alkyl; Preferably, R22 is hydrogen or d-6 alkyl; Preferably, R25 and R26 are independently hydrogen or d-6 alkyl. Properly, E represents (a). When E represents (a), the -B (CR47R48) f-NR50R51 and R49 groups can be attached to the phenyl ring at any position. Preferably, the group -B (CR47R48) f-NR50R51 is located meta or para to the amide bond, most preferably meta. Preferably, the R49 group is located for the amide bond. Preferably, the group R49 is alkoxy, most preferably methoxy, or halogen, most preferably iodine. Preferably, B is oxygen or CR55R56. Preferably, f is 2 or 3. Suitably, R50 and R51 are d-6 alkyl, preferably isopropyl or tert-butyl; C3-7 cycloalkyl, preferably cyclohexyl; or together with the nitrogen atom to which they are attached, they form a 5- to 7-membered heterocyclic ring. Preferred compounds of the formula (I) are those in which E represents (a), and in which B is oxygen, CR55R56 is CH2 and f is 2, and wherein B is CH2, CR55R56 is CH2 and f is 2 , and where B is oxygen, R55R56 is | _ | 2 and f is 3 a compound of the formula (I) is particularly preferred wherein B is oxygen, CR55R56 is CH2 and f is 2. R52 is preferably hydrogen.

Other preferred compounds of the formula (I) are those in which E represents (a) and preferably R50 and R51 are isopropyl, R50 is isopropyl and R51 is tert-butyl or cyclohexyl, or NR50R51 is 2. 2,6,6-tetramethylpiperidine. Most preferably, R50 and R51 are isopropyl, R50 is isopropyl and R51 is tert-butyl, or NR50R51 is 2,2,6,6, -tetramethylpiperidine. Preferably, R49 is methoxy. When E represents (b), k is preferably 1, J is preferably oxygen and R62 is preferably d-6 alkyl, most preferably methyl or isopropyl. When E represents (c), n is preferably 1, M is preferably oxygen, R71 and R72 are preferably hydrogen, R73 is preferably para-alkoxy, most preferably para-OCH3, R74 is preferably hydrogen and R75 is preferably a group of the formula (e) wherein u is 2, and R83 is preferably d-6 alkyl, most preferably methyl. The term "d-6 alkyl" is used herein in all cases to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the length of the chain is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and the like. The terms "halo" or "halogen" are used interchangeably herein in all cases to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.

The terms "cycloalkyl" and "cyclic alkyl" are used herein in all cases to mean cyclic radicals, preferably comprising 3 to 7 carbon atoms and which may be mono-fused ring systems. or bicycles which may also include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl, and the like. The term "alkenyl" is used herein in all cases to mean a straight or branched chain radical of 2 to 6 carbon atoms, unless the length is limited thereto, where there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. The term "cycloalkenyl" is used herein to mean cyclic radicals, preferably 5 to 8 carbons, which have at least one double bond between two of the carbon atoms in the ring, including but not limited to cyclopentenyl, cyclohexenyl and similar. The term "alkynyl" is used herein in all cases to indicate a straight or branched chain radical of 2 to 8 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1 -propylene, 2-propylene and the like.

The term "aryl" is used herein in all cases to indicate substituted or unsubstituted aromatic rings of 5-14 members, or ring systems which may include bi- or tri-cyclic systems, including, but not limited to phenyl , naphthyl and simians. The term "aralkyl" is used herein in all cases to indicate an aryl portion as defined above, which is connected to an alkyl portion as defined above, for example, benzyl or phenethyl and the like. The term "alkoxy" is used herein in all cases to indicate a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, attached to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and the like. The terms "hydroxyalkyl of d-6" and "hydroxyalkyl" are used interchangeably herein to indicate a hydroxyl group attached to an alkyl group of C? -6 as defined above, including, but not limited to methanol, ethanol, n -propanol, isopropanol, n-butanol, sec-butanol, isotutanol, tert-butanol and the like. The term "CA alkoxyalkyl" is used herein in all cases to denote a C? Alkoxy group, as defined above, attached to an alkyl group as defined above, such as an ether, eg, CH3- CH2-O-CH2-CH2-CH3.

The term "d-β hydroxyalkoxy" is used herein in all cases to indicate a hydroxyl group attached to an alkoxy group as defined above, for example, HO-CH 2 -CH (OH) CH 3. The term "d-β-alkoxy of d-β" is used herein in all cases to indicate an alkoxy group as defined above, substituted with an alkoxy group as defined above. The term "acyloxy" is used herein in all cases to indicate a portion -OC (0) -R, wherein R is hydrogen or d-β alkyl- The term "C? -4 alkanoyl" is used herein in all cases to indicate a C (0) C 1 - alkyl group wherein the alkyl portion is as defined above. The term "heterogeneous atom" is used herein in all cases to indicate an oxygen atom, a sulfur atom or an atom in nitrogen. It will be recognized that when the heterogeneous atom is nitrogen, it can form a portion NRaRb, where Ra and Rb are, independently, hydrogen or alkyl of da C6, or together with the nitrogen atom to which they are attached, form a ring of 5, 6 or 7 saturated or unsaturated members, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, pyridine and the like. It will be recognized that the saturated or unsaturated 5, 6 or 7 membered ring may optionally have one or more additional heterogeneous atoms in the ring. The term "heterocyclic" is used herein in all cases to indicate a 5- to 10-membered saturated or fully or partially unsaturated ring system (unless the cyclic ring system is otherwise limited) in which one or more rings contain one or more heterogeneous atoms, including but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine and the like. The term "disease status mediated by CCR5" is used herein in all cases to indicate any disease state that is mediated (or modulated) by CCR5. Suitably, the pharmaceutically acceptable salts of the formula (I) include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citratro, acetate, lactate, methanesulfonate. p-toluenesulfonate. palmitate, salicylate and stearate. Among the compounds of the invention that are preferred are the following: N- [3- (2-D-methylamino) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,3 , 4-oxadizol-3-yl) - (1,1'-biphenyl) -4-carboxamide; N- [3- (2-Methylamino) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - (1,1' -biphenyl) ) 4-carboxamide; N- [3- (2-Amino) etpxi-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - (1', 1'- biphenyl) 4-carboxamide; N- [3- (2-Dimethylamino-1-methyl) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - (1, 1'-biphenyl) -4-carboxamide; 3- (2-Dimethylaminoethoxy) -4-methoxy-N- [2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) [1, 1'-biphenyl] oxalate ] -4-benzamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - (1, 1-) oxalate biphenyl) -4-carboxamide; N- [3- (2-Dimethylaminoethoxy) -4-methoxyphenyl] -4 '- (5-ethyl-1, 2,4-oxadiazol-3-yl) -2'-methylbiphenyl-4-carboxamide; N- [3- (2-Pyrrolidin-1-ylethoxy) -4-methoxyphenyl] -4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -2'-methylbiphenyl-4-carboxamide; N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl-2'-ethyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - (1,1-biphenyl) hydrochloride -4-carboxamide; N- (3- (2-dimethylamino) ethoxy-4-methoxyphenyl) -2 ', 3-dimethyl-4' - (5-methyl-1, 2,4-oxadiazol-3-yl) - (1, 1'-biphenyl) -4-carboxamide; N- [3 - ((S) -1-Methylpyrrolidin-2-ylmethoxy) -4-methoxyphenyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -2'-methyl-biphenyl -4-carboxamide; N- [3- (1-methyl-3-piperidinyloxy) -4-methoxyphenyl] -4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -2'-methyl-biphenyl ester oxalate -4-carboxamide; N- [3- (1-methyl-3-azepinyloxy) -4-methoxyphenyl] -4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -2'-methyl-biphenyl- oxalate 4-carboxamide; N- [4-methoxy-3- (quinuclidin-3-yloxy) phenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4-oxalate carboxamide; N- [3 - ((R) -1-Methylpyrrolidin-2-imethoxy) -4-methoxyphenyl] -4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -2'-methyl- biphenyl-4-carboxamide; N- [3- (1-Methylpyrrolidin-3-yl) -4-methoxy-phenyl] -4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -2'-methyl-biphenyl- 4-carboxamide; N- [3 - ((R) -pyrrolidin-2-ylmethoxy) -4-methoxyphenyl] -4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -2'-methylbiphenyl- hydrochloride 4-carboxamide; N- [3- (Azetidin-2-ylmethoxy) -4-methoxy-phenyl] -4 '- (5-methyl-1,2,4-oxadiazol-3-yl) -2'-methylbiphenyl-4-hydrochloride carboxamide; N- [2- (Dimethylaminomethyl) 1,4-benzodioxan-7-yl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4-carboxamide; N- [2- (Dimethylaminomethyl) -1,4-benzodioxan-6-yl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -2'-methyl -biphenyl-4-carboxamide; 2,3-Dihydro-6- (2-dimethylaminoethoxy) -5-methoxy-1- [4- (2-methyl-4- (5-methyl-1, 2,4-oxadiazol-3-yl) phenyl) benzoyl ] indole; 6- (2-Dimethylaminoethoxy) -5-methoxy-1- [4- (2-methyl-4- (5-methyl-1, 2,4-oxadiazol-3-yl) phenyl) benzoyl] indole; 2,3-Dihydro-6- (2-dimethylaminoethoxy) -5-methoxy-2-methyl- [4- (2-methyl-4- (5-methyl-1, 2,4-oxadiazole-3-yl oxalate! l) phenyl) benzoyl] dol; 6- (2-Dimethylaminoethoxy) -5-methoxy-2-methyl-1 - [4- (2-methyl-4- (5-methyl-1, 2,4-oxadiazol-3-yl) phenyl) benzoyl oxalate ] indole; [7- (2-Dimethylaminoethoxy) -6-methoxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl] [2'-methyl-4 '- (5-methyl-1, 2-oxalate. , 4-oxadiazol-3-yl) -biphenyl-4-yl] methanone; Oxalate of [8- (2-dimethylaminoethoxy) -7-methoxy-2,3,4,5-tetrahydro-1 H -benz [b] azepin-1 -yl] - [2'-methyl-4 '- (5 -methyl-1, 2,4-oxadiazol-3-yl) -biphenyl-4-yl-methanone: - [4- (2-Methyl-4- (5-methyl-1, 2,4-oxadiazol-3-yl) phenyl) -benzoylamino] spiro [(2,3-dihyddrobenzofuran) -3,4 'hydrochloride] -piperidine; 2,3,6,7-Tetrahydro-1 '-methyl-5- [2'-methyl-4' - (5-methyl-1, 2,4-oxadiazol-3-yl) bifenyl chloride -4-carbonyl] furo [2,3-f] ndol-3-spiro-4'-piperidine; 5- [4 '- (5-Dimethylamino-1, 2,4-oxadiazol-3-yl) -2'-methylbiphenyl-4-carbonyl] -1'-methyl-2, 3,5,6,7-hydrochloride , 8-hexahydrospiro [furo [2, 3-g] quinolino-3,4'-piperidine]; 5- [4 '- (5-hydroxymethyl-1, 2,4-oxadiazol-3-yl) -2'-methylbiphenyl-4-carbonyl] -1'-methyl-2,3,6,7-tetrahydrospiro hydrochloride [furo [2,3-f] indole-3,4'-piperidine]; 5- [4 '- (5-methoxymethyl-1, 2,4-oxadiazol-3-yl) -2'-methylbiphenyl-4-carbonyl] -1'-methyl-2,3,6,7-tetrahydrospiro hydrochloride [furo [2,3-f] indole] -3,4'-piperidine; 4'-ax- (dimethylamino) -5- [2'-methylene-4 '- [(5-methyl-1, 2,4-oxadiazole-Si biphenyl) -iOcarbonyl ^. S.ey-tetrahydrospyrotrophide hydrochloride ^. S-flindol-Sr-cyclohexane]; N- [3- (2-Dimethylamino) ethoxy-phenyl] - [1,1 '-biphenyl] -4-carboxamide; N- [4- (2-Dimethylamino) ethoxy -phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [2- (3-Dimethylamino) propoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Morpholin-1-yl) ethoxy] -4-methoxyphenyl] - [1, r-biphenyl] -4-carboxamide; N- [3- (2-Dicyclohexylamino) ethoxy-4-methoxyphenyl] - [1, 1] '-biphenyl] -4-carboxamide; N-Ethyl-N- [3- [2- (N-isopropyl-N-methylamino) ethoxy] -4-methoxyphenyl] -1,1 '-biphenyl-4-carboxamide; N-Methyl-N- [3- (2-diisopropylamino) ethoxy] -4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - (1 , 1-biphenyl) -4-carboxamide; N-Methyl-N- [3- (2-diisopropylamino) ethoxy] -4-methoxyphenyl] - [1,1'-biphenyl) -4-carboxamide; N- [3- (2-Diisopropylammon) ethoxy] -4-methoxyphenyl] -4-iodobenzamide; N- [3- (2-Diisopropylamino) ethoxy] -4-methoxyphenyl] -3-bromobenzamide; N- [3- (2-Diisopropylamino) ethoxy] -4-methoxyphenyl] -4- (methoxy) benzamide; N- [4- (2-Diisopropylamino) ethoxy-phenyl] -4-iodobenzamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -3-iodobenzamide; N- [3- (2-Diisopropylamino) ethoxy-phenyl] -3-iodobenzamide; N- [3- (2-Diethylamino) ethoxy-phenyl] -3-iodobenzamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -4-bromobenzamide; N- [4- (2-Diisopropylamino) ethoxy-phenyl] -4-bromobenzamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -3-bromobenzamide; N- [4- (2-Diisopropylamino) ethoxy-phenyl] -4- (isopropyl) benzamide; N - [- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -4- (cyclohexyl) benzamide; N- [4- (2-Diethylamino) ethoxy-phenyl] -4- (cyclohexyl) benzamide; N- [4- (2-Diisopropylamino) ethoxy-phenyl] -4'-ethyl- [1,1'-b? Phenyl] -4-carboxamide; gSScC N- [4- (2-Diethylamino) ethoxy-phenyl] -4'-ethyl- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Dimethylamino) ethoxy-phenyl] -4-methoxyphenyl] -4'-methoxy- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Dimethylamino) ethoxy-phenyl] -4-methoxyphenyl] -4'-hydroxy- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Dimethylamino) ethoxy-4-methoxyphenyl] -3'-hydroxy- [1,1'-biphenyl] -4-carboxamide; N- [2- (Dimethylaminomethyl) -1,4-benzodiaxan-7-yl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4-carboxamide and N- [2- (Dimethylaminomethyl) -1,4-benzodiaxan-6-yl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4- carboxamide. Among the compounds of the invention that are most preferred are the following: N- [3- (3-Dimethylamino) propoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4- oxadiazol-3-yl) - (1,1'-bifeni) l-4-carboxamide; N- [3- (2-Piperidin) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - (1,1'-biphenyl) ) l-4-carboxamide; N- [3- (3-dimethylaminopropyl) -4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4-carboxamide oxalate; N- [3- (1-methyl-4-pperidyl) -4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl ester oxalate -4-carboxamide; N- [3- (1-methyl-3-piperidyl) -4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4-oxalate -carboxamide; N- [7- (2-dimethylamino) ethoxy-2,3-dihydrobenzofuran-5-yl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -1 , 1'-biphenyl-4-carboxamide; Oxalate of [3- (dimethylaminoethyl) -3,6,7,8-tetrahydro-2H-furo [2,3-g] quinolin-5-yl] - [2'-methyl-4 '- (5-methyl- [1, 2,4] -oxadiazol-3-yl) -biphenyl-4-yl] -methanone; 5- [4- (2-Methyl-4- (5-methyl-1, 2,4-oxadiazol-3-yl) phenyl) benzoylamino] spiro [(2,3-dihydrobenzofuran) -3,4'- oxalate] (1-methylhexahydroazepine)]; 2,3,5,6,7,8-hexahydro-1'-methyl-5-oxalate. { 2'-methyl-4 '- [(5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4-yl] carbonyl} furo [2,3-g] quinolino-3-spiro-4'-piperidine; 6,7,8,9-Tetrahydro-1'-methyl-5 - [[2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) [1, 1' - biphenyl] -4-yl] carbonyl] -spiro [2H-furo [2,3-h] [1] benzazepin-3 (5H), 4'-piperidine]; 2,3,5,6,7,8-Hexahydro-5- [4 '- (5-hydroxymethyl-1, 2,4-oxadiazol-3-yl) -2'-methylbiphenyl-4-carbonyl hydrochloride ] -1 '-methylspiro [furo [2,3-g] quinoline-3,4'-piperidine]; 4 '(Dimethylamino) -5- [2'-methyl-4' - [(5-methyl-1, 2,4-oxadiazol-3-yl) -biphenyl-4-yl] carbonyl] -2.3.6.7 hydrochloride -tetrahydrospiro [furo [2,3-f] indol-3-1 '-cyclohexane]; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl] -3-carboxamide; N- [3- (3-Dimethylamino) propoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [4- (3-Dimethylamino) propoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide; £ ^ ft "'* .j. ^ | ^ N- [3- (Diethylamino) ethoxy-4-methoxyphenyl] - [1,1' -biphenyl] -4-carboxamide; N- [3- (2- ( Piperidin-1-yl) ethoxy-4-methoxyphenyl] - [1,1 '-biphenyl] -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-2-methylphenyl] -2'-methyl-4' - (5-methyl-1, 2,4-oxadiazol-3-yl) - [1,1 '-biphenyl] -4-carboxamide; N- [3- (2-Dipropylamino) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-4-methylphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-4-ethylphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-4- (methoxycarbonylamino) phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [1,1-Biphenyl] -4-yl-3- (2-diisopropylamino) ethoxy-4-methoxybenzamide; N- [3- (2-Diisopropylamino) ethoxy-4- (ethoxycarbonyl) phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [4- (2-Diisopropylamino) ethoxy-3-methoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [2- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [2-Fluoro-4- (2-diisopropylamino) ethoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [4- (2-Diisopropylamino) ethoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [2- (2-Diisopropylamino) ethoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4-bromobenzamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4- (isopropyl) -benzamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4- (cyclohexyl) -benzamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -3,4-dichloro-benzamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -3,5-dichlorobenzamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4- (nitro) benzamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -3-iodobenzamide; N- [4- (2-Diisopropylamino) ethoxy-phenyl] -3-iodobenzamide; N- [4- (2-Diisopropylamino) ethoxy-phenyl] -3-bromobenzamide; N- [4- (2-Diisopropylamino) ethoxy-phenyl] -4- (cyclohexyl) benzamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxy-phenyl] -4- (cyclohexyl) benzamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -4'-ethyl- [1,1'-biphenyl] -4-carboxamide; MMtaaÉ _____________? ^^ jgjg ^ gggÉ. ^^ & ^ &3fc ^ N- [3- (2-Diisopropylamino) ethoxy-phenyl] -4'-ethyl-] - 4 '- [1,1' -biphenyl] -4 -carboxamide and N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -3'-methoxy- [1,1'-biphenyl] -4-carboxamide). Among the compounds of the invention which are most preferred are the following compounds: N- [3- (2-Diisopropylamino) ethoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazole-3-) il) - (1,1 '-biphenyl) -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - (1,1' -biphenyl) -4-carboxamide; Oxallate 5- [4- (2-methyl-4- (5-methyl-1, 2,4-oxadiazol-3-yl) phenyl) benzoylamino] spiro [(2,3-dihydrobenzofuran) -3,4'- (1-methylpiperidine)] N- [3- (2-Diisopropylammon) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -2'-methyl) - (1,1'-biphenyl) -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-phenyl] -2'-meth1-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - [1,1' -biphenyl] -4-carboxamide; N- [3- [2- (N-Cycloexy-N-isopropylamino) ethoxy] -4-methoxyphenyl] - [1,1'-biphenyl) -4-carboxamide; N- [3- [2- (cis-2,6-Dimethyl-piperidin-1-yl) ethoxy] -4-methoxyphenyl] - [1,1'-biphenyl) -4-carboxamide; t & m ^ N- [3- [2- (N-Ethyl-N-isopropylamino) ethoxy] -4-methoxyphenyl] - [1,1'-biphenol) -4-carboxamide; N- [3- [2- (2,5-Dimetipyrrolidin-1-yl) ethoxy] -4-methoxyphenyl] - [1,1'-biphenyl) -4-carboxamide; N- [4-Methoxy-3- [2- (2,2,6,6-tetramethylpiperidin-1-yl) ethoxy] phenyl] - [1,1 '-biphenyl) -4-carboxamide; N- [3- [2- (N-t-Butyl-N-isopropyl) aminoethoxy] -4-methoxyphenyl] - [1,1'-biphenyl) -4-carboxamide; N- [3- (3-Diisopropylamino) propyloxy-4-methoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (3- (Diisopropylamino) propyl-4-methoxyphenyl] - [1,1'-biphenyl) -4-carboxamide; N- [3- (2- (Diisopropylaminol) ethoxy] -4-iodophenyl] - [1,1'-biphenyl) -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl) -4-methanamine dihydrochloride; N- [3- (2-Diisopropylamino) ethoxy-4-methoxy-phenyl] -4'-cyano-1,1 '-biphenyl) -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4'cyano-2'-methyl-1,1'-biphenyl-4-carboximide; N- [3- (2- (Diisopropylamino) ethoxy-4-methoxyphenyl] -2-naphthalenecarboxamide; N- (1'-methylstyrene [benzofuran-3 (2H), 4'-piperidin] -5-yl- [1,1-biphenyl] -4-carboxamide; N- [3- [2- (N-lsopropyl- N-methylamino) ethoxy] -4-methoxyphenyl] - [1,1 '-biphenyl] -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4- (iodo) benzamide; N - [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4- (cycloexy) benzamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4'-ethyl- [1, 1 ' -biphenyl] -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -3'-methoxy- [1,1'-biphenyl] -4-carboxamide; N- [3- (2 -Disopropylamino) ethoxy-4-methoxyphenyl] -4'-acetyl- [1, 1 'biphenyl] -4-carboxamide; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -3'-methoxy- [ 1, 1 'biphenyl] -4-carboxamide and N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -3'-hydroxy- [1,1'-biphenyl] -4-carboxamide. Excluded from the scope of this invention are the following: N- [3- (2-Dimethylaminoethoxy) -4-methoxyphenyl] -4 '- (5-dimethylamino-1,4-oxadiazol-3-yl) -2'-methylbiphenyl -4-carboxamide; N- [3- (1-Methylazetidin-2-methoxy) -4-methoxy enyl]] - 4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -2'-methylbiphenyl-4-carboxamide;[7- (2-Dimethylaminoethoxy) -6-methoxy-3,4-dihydro-2H-quinolin-1-yl] [2'-methyl- [1, 2,4] -oxadiazol-3-yl) biphenyl ester oxalate -4-yl] -metanone; 2,3,6,7-Tetrahydro-1 '-methyl-5- [2'-methyl-4' - (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4-carbonyl oxalate ] -furo [2,3-f] indol-3-spiro-3'-piperidine 5- [4 '- (5-Methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4-carbonyl] - 1'-methyl-2,3,6,7-tetrahydrofuro [2,3-f] indol-3-spiro-4'-pipepdine; 1'-Ethyl-5- [2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -biphenyl-4-carbonyl] -2,3,6,7-tetrahydrospiro [2,3-f] indole-3,4'-p-peridine; N- [2- (2-Dimethylamino) ethoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] benzamide; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl] -2-carboxamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -4- (methoxy) benzamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -4- (nitro) benzamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -4- (nitro) benzamide; N- [3- (2-Dimethylamino) ethoxy-4-methoxyphenyl] -4- (nitro) benzamide; N- [3- (Dimethylamino) ethoxy-4-methoxyphenyl] - [1,1-biphenyl] -4-carboxamide; N- [3- (2-Dimethylamino) ethoxy-4-methoxyphenyl] -4'-chloro- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -4'-hydroxy- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -4'-acetyl- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Dimethylamino) ethoxy-4-methoxy-phenol] -4'-acetyl- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Dimethylamino) ethoxy-4-methoxyphenyl] -3'-chloro- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -3'-nitro- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Dimethylamino) ethoxy-4-methoxyphenyl] -3'-nitro- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -4-iodobenzamide; N- [4- (2-Diethylamino) ethoxy-phenyl] -4-iodobenzamide; N- [4- (2-Diisopropylamino) ethoxy-phenyl] -4-iodobenzamide; N- [4- (2-Diethylamino) ethoxy-phenyl] -3-iodobenzamide; N- [2- (2-Diisopropylamino) ethoxy-phenyl] -3-iodobenzamide; N- [2- (2-Diethylamino) ethoxy-phenyl] -3-iodobenzamide; N- [3- (2-Diethylamino) ethoxy-phenyl] -4-bromobenzamide; N- [2- (2-Diisopropylamino) ethoxy-phenyl] -4-bromobenzamide; N- [2- (2-Diethylamino) ethoxy-phenyl] -4-bromobenzamide; N- [4- (2-Diethylamino) ethoxy-phenyl] -3-bromobenzamide; N- [2- (2-Diisopropylamino) ethoxy-phenyl] -3-bromobenzamide; N- [2- (2-Diethylamino) ethoxy-phenyl] -3-bromobenzamide; N- [3- (2-Diethylamino) ethoxy-4-methoxyphenyl] -4- (dimethylamino) benzamide; -Diisopropylamino) ethoxy-phenyl] -4- (dimethylamino) benzamide; -Dietylamino) ethoxy-phenyl] -4- (dimethylamino) benzamide; -Diisopropylamino) ethoxy-phenyl] -4- (dimethylamino) benzamide; -Dietylamino) ethoxy-phenyl] -4- (isopropyl) benzamide; -Diisopropylamino) ethoxy-phenyl] -4- (isopropyl) benzamide; -Dietylamino) ethoxy-phenyl] -4- (isopropyl) benzamide; -Dietylamino) ethoxy-phenyl] -4- (cycloexyl) benzamide; -Diisopropylamino) ethoxy-phenyl] -4- (cycloexyl) benzamide; -Dietylamino) ethoxy-phenyl] -4- (cycloexyl) benzamide; -Diisopropylamino) ethoxy-phenyl] -4'-ethyl- [1,1'-biphenyl] -4-carboxamide and N- [2- (2-diethylamino) ethoxy-phenyl] -4'-ethyl- [1, 1 '-biphenyl] -4-carboxamide.

Formulation of pharmaceutical compositions The pharmaceutically effective compositions of this invention (and the pharmaceutically acceptable salts thereof) are administered in conventional dosage forms prepared by combining a compound of the formula (I) ("active ingredient") in an amount sufficient to treat COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, diseases ^^^ autoimmune such as multiple sclerosis, inflammatory bowel disease and HIV infection, ("CCR5-mediated disease states") with standard pharmaceutical vehicles or diluents according to conventional procedures well known in the art. These methods may include mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired preparation. The pharmaceutical vehicle used can be, for example, be it a solid or liquid. Exemplary solid carriers are lactose, alba earth, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary liquid vehicles are syrup, peanut oil, olive oil, water and the like. Similarly, the vehicle or diluent may include time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax. A wide variety of pharmaceutical forms can be used.

Therefore, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but will preferably be from 25 mg to about 1000 mg. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as a vial or non-aqueous liquid suspension. ^ ij ^^^ tejgg The active ingredient can also be administered topically to a mammal in need of treatment or prophylaxis of disease states mediated by CCR5. The amount of active ingredient required for the therapeutic effect in topical administration, of course, will vary with the compound chosen, the nature and severity of the disease state being treated and the mammal being treated, and is finally doctor's discretion. An appropriate dose of an active ingredient is 1.5 mg to 500 mg for topical administration, with the most preferred dose being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily. By the term "topical administration" is meant non-systemic administration and includes the application of the active ingredient externally to the epidermis, to the oral cavity and the instillation of a compound as such in the ear, eye and nose, and where the compound does not enter significantly to the bloodstream. By the term "systemic administration" is meant oral, intravenous, intraperitoneal and intramuscular administration. Although it is possible to administer an active ingredient only as the pure chemical, it is preferably presented as a pharmaceutical formulation. The active ingredient may constitute, for topical administration, from 0.001% to 10% w / w, for example from 1% to 2% by weight of the formulation although this may constitute as much as 10% w / w but from Preferably no more than 5% w / w and more preferred from 0.1% to 1% w / w of the formulation. The topical formulations of the present invention, both for veterinary and medical use, comprise an active ingredient together with one or more acceptable vehicle or vehicles thereof and optionally any other therapeutic ingredients. The vehicle (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not be harmful to the container thereof. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetrating through the skin to the site of inflammation such as balms, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The drops according to the present invention may comprise sterile oily or aqueous solutions or suspensions and may be prepared by dissolving the active ingredient in an appropriate alcoholic or aqueous solution of a bactericidal and / or fungicidal agent and / or any other suitable preservative, and preferably includes a surfactant. The resulting solution can then be clarified by filtration, transferred to an appropriate container which is then sealed and sterilized by autoclaving or maintaining it at 98-100 ° C for half an hour. Alternatively, the solution can be sterilized by filtration and transferred to the container by aseptic technique. Examples of agents ... a ._ * M__ "^ - '- - • • ^" ^^^.? MHfafc ... .. .., .-, ^ .. "...___.

Suitable bactericides and fungicides to be included in the drops are phenylmercuric nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include dilute glycerol alcohol and propylene glycol. Lotions in accordance with the present invention include those suitable for application to the skin or eye. An ophthalmic lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for preparing the drops. Lotions or balsams for application to the skin may also include an agent to accelerate drying and to refresh the skin, such as an alcohol or acetone and / or a humectant such as glycerol or an oil such as castor oil or arachis oil. The creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. These can be made by mixing the active ingredient in finely divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of appropriate machinery, with an oily or non-oily base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metal soap; a mucilage; an oil of natural origin such as almond oil, corn oil, arachis oil, castor oil or olive oil; wool fat or its derivatives, or a fatty acid such as stearic acid or oleic acid together with such an alcohol i 'fMf-t? fffí ......_ and | ^ ________________ A -______ as propylene glycol. The formulation may incorporate any suitable surfactant such as an anionic, cationic or nonionic surfactant such as esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as siliceous silicas and other ingredients such as lanolin may also be included. The active ingredient can also be administered by inhalation. By the term "inhalation" is meant administration by intranasal route or administration by oral inhalation. Appropriate dosage forms for such administration, such as an aerosol formulation or metered dose inhaler, can be prepared by conventional techniques. The amount of daily dose of active ingredient administered by inhalation ranges from 0.1 mg to approximately 100 mg per day, preferably from 1 mg to approximately 10 mg per day. In one aspect, this invention relates to a method for treating COPD, asthma and atopic disorders (e.g., dermatitis and atopic allergy), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, disease inflammatory bowel and HIV infection, all in mammals, preferably human, which comprises administering to said mammal an effective amount of a CCR5 receptor ligand, in particular, a compound as shown in formula (I). jUJ ^^^ g ^^^^^^^^^! ^ ^^^^^^ With the term "treatment" is meant any prophylactic or therapeutic therapy. Such a compound of formula (I) can be administered to such a mammal in a conventional dosage form prepared by combining the compound of formula (I) with a conventional pharmaceutically acceptable carrier or diluent in accordance with known techniques. The person skilled in the art will recognize that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The compound of formula (I) is administered to a mammal in need of treatment for asthma and atopic disorders (e.g., dermatitis and atopic alles), rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel diseases and HIV infection, in an amount sufficient to diminish the symptoms associated with these disease states. The route of administration can be orally or parenterally. The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, intrarectal, intravaginal or intraperitoneal administration. Generally preferred are subcutaneous and intramuscular parenteral administration forms. The daily parenteral dosage regimen will preferably be from 30 mg to about 300 mg of active ingredient per day. The regime of B * iMtfMihaiMilMitf ____ Mft____ Daily oral dosage will preferably be from 100 mg to approximately 2000 mg of active ingredient per day. The person skilled in the art will recognize that the optimum amount and separation of individual doses of a compound of the formula (I) is determined by the nature and degree of the condition being treated, the form, route and site of administration and the particular mammal that is being treated, and that such optimal conditions can be determined by conventional techniques. The person skilled in the art will also appreciate that the optimum course of treatment, ie the number of doses of the compound of the formula (I) given per day for a defined number of days, can be determined by one skilled in the art using tests. of determination of the course of treatment.

Methods of Preparation The compounds of the formula (I) can be prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials can not be obtained from a commercial source, their synthesis is described herein, or they may be prepared by methods known in the art. Specifically, the compounds of the formula (I) wherein R is represented by a group (a), A is CONH and E is represented by the ^ __ É _______ tt ________ Íi _________? n ^^ m ^ ^ i £ u & group (d), were prepared in accordance with the methods of international application publication number WO 95/15954, published on June 15, 1995. The compounds of the formula (I) in which R is represented by the group ( a), A is CONH and E is represented by group (e), were prepared in accordance with the methods of international application publication number WO 95/17401, published on June 29, 1995. The compounds of the formula ( I) in which R is represented by group (a), A is CONH and E is represented by the group (f), were prepared in accordance with the methods of the international application publication number WO 96/31508 published on October 10, nineteen ninety six. The compounds of the formula (I) in which R is represented by the group (a), A is CONH and E is represented by the groups (g) or (h), were prepared in accordance with the methods of the publication of international application number WO 95/30675, published November 16, 1995. The compounds of the formula (I) in which R is represented by the group (a), A is CONH and E is represented by the group (j), were prepared in accordance with the methods of international application publication number WO 96/11934, published on April 25, 1996. The compounds of the formula (I) in which R is represented by the group (a) ) and AE is represented by group (k), were prepared in accordance with the methods of international application publication number WO 95/17398, published on June 29, 1995. The compounds of the formula (I) in which R is represented by group (a) and AE is represented by group (I), were prepared in accordance with the methods of international application publication number WO 97/07120, published on February 27, 1997. The compounds of the formula (I) in which R is represented by group (a) and AE is represented by group (m), were prepared in accordance with the methods of international application publication number WO 96/19477, published on 27 June 1996. The compounds of e formula (I) in which R is represented by group (a) and AE is represented by group (n), were prepared in accordance with the methods of international application publication number WO 96/19477, published on May 29, 1997. Specifically, the compounds of the formula (I) in which Ar is represented by groups (i), (ii) or (iii), A is CONR46, NHCO or CH2NH and E is represented by group (a), were prepared in accordance with the methods of the publication of international application number WO 95/15954, published June 15, 1995, international application publication number WO 95/17398, published June 29, 1995, international application publication number WO 95/263284, published October 5, 1995 , International Application Publication No. WO 96/06079, published February 29, 1996, GB 2276161 ^^^^^^^^ s ^^^^^ ng ^^^^^^^^^^^^^^^ published on September 21, 1994 and GB 2276165 published on September 21, 1994. The compounds of the formula (I) in which Ar is (i) or (ii), and A is CONR60 or NHCO and E is represented by group (b), were prepared in accordance with the methods of the application publication international number WO 95/11934, published on April 25, 1995 and WO 95/19477, published on June 27, 1995. Four other applications cover the spiro compounds: WO 97/17350, published May 15, 1997; WO 97/34900, published on September 25, 1997; WO 97/34901, published September 25, 1997; WO 97/35862 published October 2, 1997. The compounds of the formula (I) in which Ar is (i), (ii) or (iii), A is CONR70, NHCO or CH2NH and E represents (c), were prepared in accordance with the methods of the international application publication number WO 95/306758 published on November 16, 1995 and GB 2276165 published on September 21, 1994. The compounds of formula (I) in which Ar is (ii), A is CONH or NHCO and E represents (f), were prepared in accordance with the methods of International Application Publication No. WO 95/17401, published June 29, 1995. The compounds of the formula (I) in which Ar is (i) or (ii), A is CONR93 and E represents a group (g), were prepared in accordance with the methods of International Application Publication No. WO 96/31508, published October 10, 1996. ^ | ! ___- The compounds of the formula (I) in which Ar is (i) or (ii), A is CONR101 and E represents the group (h), were prepared in accordance with the methods of the international application number publications WO 95/32767, published December 7, 1995 and WO 97/07120, published February 27, 1997. The compounds of the formula (I) in which Ar is (i) or (ii), A is CONR109 or CH2NH and E represent group (i), were prepared in accordance with the methods of international application publication number WO 97/19070, published May 29, 1997. The compounds of formula (I) are also prepared by the method of scheme 1 using solid phase chemistry. Resin 1-1 (WO 98/17695) is coupled with appropriately substituted carboxyphenyl boronic acid, for example 4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) benzoic acid using Suzuki conditions, for example, an appropriate palladium reagent, such as tetrakis (triphenylphosphine) palladium (0), and an appropriate base, such as sodium carbonate, in an appropriate solvent, such as ethanol and toluene, at a temperature suitable, such as 90 ° C, for an appropriate period, such as 24 hours, to get the biphenylcarboxylic acid 1-2 attached to resin. Adduct 1-2 is condensed with anilines 1-4, suitably substituted, prepared by methods known in the art from commercially available starting materials or as described herein, using methods known in the art. For example, treatment of 1-2 with an appropriate reagent, such as oxalyl chloride, in an appropriate solvent such as toluene, allows to obtain the adduct biphenylcarbonyl chloride 1-3. Treatment of 1-3 with 1-4 in an appropriate solvent such as dichloromethane, in the presence of an appropriate base, such as diisopropylethylamine, yields the biphenylcarboxanilide adduct, 1-5. Treatment of 1-5 with an appropriate acid and solvent, such as trifluoroacetic acid / dichloromethane / water (50: 48: 2) allows to obtain 1-6 which are the compounds of the formula (I).

SCHEME 1 _Afe "-. a) 4-carboxybenzeneboronic acid, (Ph3P) 4Pd, Na2CO3, EtOH, toluene, 90 ° C, 24 h; b) (COCI) 2l toluene; c) 4, diisopropylethylamine, CH2Cl2; d) CF3CO2H, CH2Cl2). The compounds of the formula (I) are also prepared by the method of scheme 2 using solid phase chemistry. Reacted appropriately substituted (alkylamino) ethoxyanilines 2-1, such as 3- (2-diisopropylamino) -ethoxy-4-methoxyaniline, synthesized in accordance with literature methods from commercially available starting materials and by methods described herein, with 4-formyl-3-5-dimethoxyphenol-resin from Merrifield 2-2 (Boojamra, et al., J. Org. Chem. 1995, 60, 5742), are treated with a reducing agent suitable, such as sodium triacetoxyborohydride, in a suitable solvent, such as dimethylformamide containing 1% acetic acid, to achieve 2-3. Resin-bound aniline 2-3 is condensed with an appropriately substituted benzoic acid or biphenylcarboxylic acid, which can be obtained commercially or synthesized by methods known in the art, using an appropriate activating agent, such as N-bromosuccinimide and triphenylphosphine, in a suitable solvent, such as dichloromethane, dimethylformamide and pyridine, to achieve 2-4. Treatment of 2-4 with an appropriate acid and solvent, such as trifluoroacetic acid: dichloromethane: water (50: 48: 2) gives the desired benzanilide or biphenylcarboxanilide 2-5 which are the compounds of the formula (I). :_and__"_. rá $ _-__. ~ SCHEME 2 a) BAL resin, NaBH (OAc) 3, 1% HOAc, DMF; b) X-benzoic acid, N-bromosuccinimide, Ph3P, pyridine; c) TFA, CH2Cl2, H20. The invention will now be described with reference to the following examples which are illustrative only and should not be considered as a limitation of the field of the present invention. In the examples, the mass spectra were performed on a VGZab mass spectrometer using rapid atom bombardment, unless otherwise indicated. s-- "& _ _ -a_.

EXAMPLES PREPARATION 1 Preparation of 4- (2-diisopropylamino) ethoxy-3-methoxyaniline a) 4- (2-dithylamine) ethoxy-3-methoxy-1-nitrobenzene A mixture of 4-nitroguayacol (1.0 g, 5.9 mmol), 2-diisopropylaminoethyl chloride hydrochloride (1.2) was refluxed. g, 5.9 mmoles) and powdered potassium carbonate (1.38 g, 10 mmol) in dry acetone (100 ml), stirred for 16 h, cooled, filtered and the filtrate was concentrated in vacuo. The residue was separated between ethyl acetate (300 ml) and water (40 ml) and the organic phase was washed with water (40 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound: MS ( ES) m / e 297.2 [M + H] +. b) 4- (2-dithylamino) ethoxy-3-methoxyaniline A mixture of the compound of preparation 1 (a) (1.6 g, 5.4 mmoles) and 5% palladium on carbon (0.3 g) ) in absolute ethanol (100 ml) was stirred under a hydrogen atmosphere (3.51 kg / cm2) for 2.5 h, filtered and the filtrate was concentrated in vacuo to give the title compound: MS (ES) m / e 267.3 [M + H] +.

PREPARATIONS 2-8 Preparation of 2- (2-diisopropylamino, ethoxy-4-methoxyaniline, 3- (2-diisopropylamino) ethoxyaniline, 4- (2-diisopropylamino) ethoxy-2-fluoroaniline, 4- (2-diisopropylamino) ethoxyaniline, 2- (2-diisopropylamino) ethoxyaniline, 3- (2-diisopropylamino) ethoxy-2-methylaniline and 3-, 2-diisopropylamino) ethoxy-4-methylaniline Following the procedure of preparation 1, except that 4-nitroguayacol is replaced by 5-methoxy-2-nitrophenol, 3-nitrophenol, 3-fluoro-4-nitrophenol, 4-nitrophenol, 2-nitrophenol, 2-methyl-3- nitrophenol or 2-methyl-5-nitrophenol, the title compounds were obtained: 2- (2-diisopropylamino) ethoxy-4-methoxyaniline: MS (ES) m / e 267.2 [M + H] +; 3- (2-diisopropylamino) ethoxyaniline: MS (ES) m / e 237.2 [M + H] +; 4- (2-diisopropylamino) ethoxy-2-fluoroaniline: MS (ES) m / e 255.0 [M + H] +; 4- (2-diisopropylamino) ethoxyaniline: MS (ES) m / e 237.2 [M + H] +; 2- (2-diisopropylamino) ethoxyaniline: MS (ES) m / e 237.1 [M + H] +; 3- (2-diisopropylamino) ethoxy-2-methylaniline: MS (ES) m / e 251.2 [M + H] +; and 3- (2-diisopropylamino) ethoxy-4-methylaniline: MS (ES) m / e 251.1 [M + H] +.

PREPARATION 9 Preparation of 3- (2-dicyclohexylamino) ethoxy-4-methoxyaniline a) N, N-dicyclohexyl-2-methoxy-5-nitro-phenoxyacetamide A solution of 2-methoxy-5-nitro-phenoxyacetyl chloride (0.22 g, 0.9 mmol) was added, which was prepared from 2-methoxy-5-nitro-phenoxyacetic acid (Brown et al., J. Chem. Soc. 1955, 3681) and thionyl chloride, in dichloromethane (10 ml) to a mixture of dicyclohexylamine (0.16 g, 0.9 mmol) ) and diisopropylethylamine (0.23 g, 1.76 mmol) in dichloromethane (20 ml), was kept at room temperature for 16 hours, washed with water (2 x 20 ml), dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from methanol to obtain the title compound (0.16 g). b) N-hydroxyclohexyl-2-methoxy-5-amino-phenoxyacetamide Following the procedure of preparation 1 (b), except that the compound of preparation 1 (a) is replaced by the compound of preparation (a), the title compound was obtained. c) 3- (2-dicyclohexylamino) ethoxy-4-methoxyaniline A solution of the compound of preparation 9 (b) (0.15 g, 0.04 mmol) in anhydrous tetrahydrofuran (25 ml) was treated with borane 1.0 M in tetrahydrofuran (4.3 ml, 4.3 mmol), refluxed for 3 hours, maintained at room temperature for 16 hours, carefully treated with methanol (5 ml), heated to reflux for 30 minutes, cooled and concentrated to vacuum. The residue was separated between ethyl acetate (75 ml) and water (15 ml) and the organic phase was washed with water (15 ml), dried Na2SO4), concentrated in vacuo and the residue was purified by preparative TLC (Whatman PLK5F, 10% ethanol / dichloromethane-1% triethylamine) to give the title compound.

PREPARATION 10 Preparation of 3- (2-dipropylamino) ethoxy-4-methoxyaniline a) 3- (2-dipropylammon) ethoxy-4-methoxy-1-nitrobenzene A solution of 3- (2-bromoethoxy) -4-methoxy-1-nitrobenzene (Mutai et al., Tetrahedron, 1984, 40 , 1755) (0.5 g, 1.8 mmol) and dipropylamine (1.8 g, 18 mmol) in dimethylformamide (10 ml) with potassium iodide (0.28 g, 1.9 mmol) and potassium carbonate (0.42 g, 3 mmol) was heated to 100 ° C and stirred for 16 hours. The mixture was cooled, diluted with dichloromethane (100 ml), filtered and the filtrate was concentrated in vacuo. The residue was separated between ethyl acetate (150 ml) and water (30 ml) and the organic phase was washed with water (4 x 30 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound: MS (ES) m / e 297.1 [M + H] +. b) 3-, 2-dipropylamino) ethoxy-4-methoxyaniline Following the procedure of preparation 1 (b), except that the compound of preparation 1 (a) is replaced by the compound of preparation 10 (a) , the title compound was obtained: MS (ES) m / e 267.0 [M + H] +.

PREPARATIONS 11-16 Preparation of 3-r2- (N-cyclohexyl-N-isopropylamino, ethoxy, -4-methoxyaniline, 3-r2- (cis-2,6-dimethylpiperidin-1-diDeoxy-4-methoxyaniline , 3- f2- (N-Ethyl-N-isopropylamino) ethoxy-1-4-methoxyaniline, 3-r2- (2,5-dimethypyrrolidin-1-yl-ethyloxy-4-methoxyaniline, 4-methoxy-3-y2- (2, 2,6,6-tetramethylpiperidin-1-yl) -ethoxyaniline and 3-.2- (Nt-butyl-N-isopropyl) aminoethoxy-4-methoxyaniline.

Following the procedure of preparation 10, except that dipropylamine is replaced by N-isopropylcyhoxyhexylamine, cis-2,6-dimethylpiperidine, N-ethyl isopropylamine, 2,5-dimethylpyrrolidine, 2,2,6,6-tetramethylpiperidine or N-terbi- butylisopropylamine, the title compounds were obtained: 3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy] -4-methoxyaniline: MS (ES) m / e 307.2 [M + H] +; 3- [2- (cis-2-6-dimethylpiperidin-1-yl) ethoxy] -4-methoxyaniline: MS (ES) m / e 279.3 [M + H] +; ~. ^^ __ .. ", ..___» _- ^ .., "_a ______ * _ E_______, ..,? ^^^^ i ^ 3- [2- (N-Ethyl-N-isopropylamino) ethoxy] -4-methoxyaniline: MS (ES) m / e 253.1 [M + H] +; 3- [2- (2,5-dimethylpyrrolidin-1-yl) ethoxy] -4-methoxyaniline: MS (ES) m / e 265.1 [M + H] +; 4-methoxy-3- [2- (2,2,6,6-tetramethylpiperidin-1-yl) ethoxy] aniline: MS (ES) m / e 307.0 [M + H] +; and 3- [2- (N-t-butyl-N-isopropyl) aminoethoxy] -4-methoxyaniline: MS (ES) m / e 281 [M + H] +.

PREPARATIONS 17-18 Preparation of 3-r2-fN-isopropyl-N-methylamino) ethoxy1-4-methoxyaniline and N-ethyl-3-r2-fN-isopropyl-N-methylamino) ethoxy1-4-methoxyaniline a) 3-22- (N-ε-propyl-N-methylamino) ethoxy-1-4-methoxy-1-nitrobenzene Following the example of Preparation 10 (a), except that dipropylamine was replaced by N-methylisopropylamine, it was obtained The title compound: MS (ES) m / e 269.4 [M + H] +. b) 3-.2- (N-isopropyl-methalamine) ethoxy-4-methoxyaniline and N-ethyl-3-.2- (N-isopropyl-methylamine) No.etoxi1-4-methoxyaniline Following the procedure of preparation 1 (b), except that the compound of preparation 1 (a) was replaced by the compound of preparation 17 (a), a mixture was obtained of the title compounds: _ «* _ Ga_ÉH _» ^ '? S_l »w_. 3- [2- (N-isopropyl-N-methylamino) ethoxy] -4-methoxyaniline: MS (ES) m / e 239.1 [M + H] +; and N-ethyl-3- [2- (N-isopropyl-N-methylamino) ethoxy] -4-methoxyaniline MS (ES) m / e 267.1 [M + H] +.

PREPARATION 19 Preparation of 3- (3-diisopropylamino) propyloxy-4-methoxyaniline a) 3- (3-bromopropoxy) -4-methoxy-1-nitrobenzene A stirred mixture of 2-methoxy-5-nitrophenol (5.0 g, 29.6 mmole) and powdered potassium carbonate (6.5 g, 47.4 mmole) in dimethylformamide (50 ml) was treated with 1-3-dibromopropane (80.8 g, 0.4 moles), heated at 90 ° C for 2 hours, cooled, diluted with dichloromethane (250 ml) and filtered. The filtrate was concentrated in vacuo and the residue was crystallized from methanol. The resulting solid was triturated with 30% ethyl acetate / hexane and then with 30% boiling ethyl acetate / hexane. The combined organic phases were concentrated in vacuo to obtain the title compound: 1 H NMR (300 MHz, CDCl 3) d 7.92 (dd, 1 H), 7.75 (d, 1 H), 6.92 (dd, 1 H), 4.20 (t, 2H), 3.95 (s, 3H), 3.62 (t, 2H), 2.40 (m, 2H). b) 3- (3-dithylamino) propyloxy-4-methoxyaniline Following the procedure of preparation 1 (b), except that the compound of preparation 1 (a) is replaced by the compound of preparation 19 (a), the title compound was obtained: MS (ES) m / e 281.1 [M + H] +.

PREPARATION 20 Preparation of 3-_3-diisopropylamino, propyl-4-methoxyaniline a) N, N-diisopropyl-3- (2-methoxy-5-nitropheniDpropionamide A solution of 3- (2-methoxy-5-nitrophenyl) propionyl chloride (0.46 g, 1.9 mmol), prepared at from 3- (2-methoxy-5-nitrophenyl) propionic acid (Asano et al., J. Pharm. Soc. Japan, 1950, 70, 480) and thionyl chloride, in dichloromethane (5 ml) was added in one portion to a solution of diisopropylamine (0.67 g, 6.6 mmol) in dichloromethane (20 ml), was stirred for 16 hours, washed with water (2 x 20 ml), dried (Na2SO) and concentrated in vacuo to obtain The title compound: MS (ES) m / e 309.1 [M + H] +. b) N, Nd-isopropyl-3- (2-methoxy-5-nitrophenol) propyllamine A solution of the compound of Preparation 20 (a) (0.6 g, 1.95 mmol) in dry tetrahydrofuran was treated. (50 ml) with 1.0 M borane in tetrahydrofuran (15 ml, 15 mmol), refluxed for 2 hours, allowed to cool, stirred for 16 hours and carefully treated with methanol (10 ml). The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (250 ml) and washed with water (2 x 40 ml). The organic phase Dry (Na SO4) and concentrate in vacuo to obtain the title compound: (0.52 g): MS (ES) m / e 295.1 [M + H] +. c) 3- (3-diisopropylamino) propyl-4-methoxyaniline Following the procedure of preparation 1 (b), except that the compound of preparation 1 (a) is replaced by the Compound of preparation 20 (b), the title compound was obtained: MS (ES) m / e 265.3 [M + H] +.

PREPARATION 21 Preparation of 3-_2-diisopropylamino) ethoxy-4-iodoaniline a) 3- (2-disopropylamino) ethoxy-4-vodo-1-nitrobenzene Following the procedure of Preparation 1 (a), except that 4-nitroguayacol is replaced by 2-iodo-5-nitrophenol (Change et al. al., Australian J. Chem., 1997, 50, 767), the title compound was obtained: MS (ES) m / e 392.5 [M + H] +. b) 3- (2-diisopropylamino) ethoxy-4-vodoanaline A mixture of the compound of preparation 21 (a) (0.5 g, 1.27 mmol) and ferrous sulfate heptahydrate (10.0 g, 36 mmol) in water ( 50 ml) was stirred, heated to 100 ° C and treated with concentrated ammonium hydroxide (6 ml) which was added dropwise over a period of 5 minutes. The mixture was stirred for 5 minutes, cooled, filtered and the filtrate was extracted with ethyl acetate. The organic phase was dried, concentrated in vacuo and the residue was subjected to chromatography (silica gel, 5% methanol / dichloromethane) to obtain the title compound as a yellow solid (0.37 g): MS (ES) m / e 362.8 [M + H] +.

PREPARATION 22 Preparation of 3-, 2-diisopropylamino) ethoxy-4-ethylaniline hydrochloride a) 3- (2-d, 5-propylamino) ethoxy-4-trimethylsilylethyl, -1-nitrobenzene A mixture of the compound of preparation 21 (a) (2.0 g, 5 mmol), trimethylsilylacetylene (0.8 g , 8 mmol), palladium acetate (15 mg) and triphenylphosphine (30 mg) in degassed triethylamine (25 ml) was heated at 90 ° C for 16 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient in steps, 0-1% methanol / dichloromethane-ammonia) to obtain the title compound (1.0 g): MS (ES) m / e 363 [M + h] +. b) 3- (2-diisopropylamino) ethoxy-4-ethynyl-1-nitrobenzene A solution of the compound of preparation 22 (a) (1 g, 2.7 mmol) in methanol (20 ml) was treated with Potassium carbonate (100 mg), i_f_p_ | ff | i iprpff and '? fBt "' __¡__ stirred for 5 hours, the vacuum was concentrated and the residue was dissolved in dichloromethane and washed with 5% aqueous sodium carbonate and with brine. dried (MgSO4) and concentrated in vacuo to obtain the title compound (0.75 g): MS (ES) m / e 291.0 [M + H] +. c) 3- (2-Di-isopropylamino) ethoxy-4-ethylaniline hydrochloride A mixture of the compound of preparation 22 (b) (0.73 g, 2.5 mmol) (0.6 g) and 10% Palladium on carbon (200 mg) in methanol / ethanol 1: 1 (60 ml) was stirred under a hydrogen atmosphere for 4 hours, filtered through Supercel, and filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, treated with hydrogen chloride in ether, stirred and filtered to give the title compound (0.6 g): MS (ES) m / e 265.1 [M + H] +.

PREPARATION 23 Preparation of 3- (2-diisopropylamino, ethoxy-4- (methoxycarbonylamino.aniline a) 3-, 2-diisopropylamino) ethoxy-4-nitroaniline hydrochloride Following the procedure of Preparation 1 (a), except that 4-nitroguayacol was replaced by 2-amino-5-nitrophenol, the composed title: MS (ES) m / e 281.9 [M + H] +. b) 3- (2-disopropylammon) ethoxy-4- (methoxycarbonyllamine) -1-nitrobenzene A solution of the compound of preparation 23 (a) (1.27 g, 4 mmoles) and Diisopropylethylamine (2.1 mt,% 2 mmol) in dichloromethane (25 ml) was treated with methyl chloroformate (0.38 g, 4 mmol), stirred for 7 days, treated with water and the organic phase was washed with brine, dried and concentrated in vacuum. The residue was purified by flash chromatography (silica gel, gradient in steps, 0-1% methanol / dichloromethane-ammonia) to obtain the title compound. MS (ES) m / e 339.9 [M + H] +. c) 3- (2-d) Propylamino) ethoxy-4- (methoxycarbonylamino) aniline Following the procedure of preparation 1 (b), except that the compound of preparation 1 (a) is replaced by the Compound of preparation 23 (b), the title compound was obtained: MS (ES) m / e 310.0 [M + H] +.

PREPARATION 24 Preparation of 3- (2-diisopropylamino) ethoxy-4-methoxy-N-methyl-aniline a) N-formyl-3- (2-d, 5-propylamino) ethoxy-4-methoxyaniline A mixture of formic acid (0.3 g, 6.4 mmol) and acetic anhydride (0.53 g, 5.2 mmol) was heated at 50 ° C. C for 2 hours, cooled, diluted with anhydrous tetrahydrofuran (10 ml) and treated in one portion with a solution of 3- (2-diisopropylamino) ethoxy-4-methoxyaniline (WO 95/15954) (0.5 g, 2 mmoles) in tetrahydrofuran (5 ml). The resulting mixture was stirred for 16 hours, concentrated in vacuo, and the residue was partitioned between ethyl acetate (85 ml) and 5% aqueous sodium carbonate solution (10 ml). The organic phase was washed with 5% sodium carbonate (10 ml) and then with brine (10 ml), dried (Na 2 SO 4) and concentrated in vacuo to obtain the title compound (0.57 g): MS (ES) m / e 295.4 [M + H] +. b) 3- (2-diisopropylamino) ethoxy-4-methoxy-N-methyl-aniline A solution of the compound of preparation 24 (a) (0.57 g, 1.9 mmol) in dry tetrahydrofuran ( 25 ml) with 2.0M borane in tetrahydrofuran (2.4 ml, 4.8 mmol), stirred and refluxed for 3 hours. The mixture was cooled, maintained at room temperature for 18 hours, carefully treated with methanol (10 ml), heated to reflux for 1 hour, cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (25 ml) and water (25 ml) and the organic phase was washed with water (25 ml) and with brine (25 ml), dried (Na 2 SO 4), and concentrated in vacuo to give obtain the title compound (0.5 g): MS (ES) m / e 281.4 [M + H] +. gttájMÍ PREPARACIONES 25-26 Preparation of 2-dimethylaminomethyl-1,4-benzodioxan-6-amine v 2- dimethylaminomethyl-1,4-benzodioxan-7-amine a) 2-chloromethyl-6-nitro-1,4-benzodioxane and 2-chloromethyl-7-nitro-1,4-benzodioxane Following the procedure of Gazz. Chim. Ital., 87, 1038-49, (1958), 2-chloromethyl-1,4-benzodioxane (2 g, 11 mmol) in glacial acetic acid (15 ml) was stirred, cooled and treated with nitric acid (11 ml ) that was added in a period of 5 minutes. The mixture was heated at 95 ° C for 40 minutes, cooled and carefully poured into water. The resulting mixture was extracted with chloroform and the organic layer was washed and dried (Na2SO4). The residue was distilled, p. eb 166-8 ° C / 1 mm Hg, to give a mixture of the title compounds (1.39 g). b) 2-dimethylammonium-6-nitro-1,4-benzodioxane and 2-dimethylmethano-7-nitro-1,4-benzodoxane The compounds of the preparations 25 (a) -26 (a) (1.64 g, 7 mmol) were dissolved in an excess of dimethylamine (15 ml) and heated at 150 ° C in a pressure vessel for 16 hours. The mixture was cooled, triturated with ether and filtered. The filtrate was concentrated in vacuo and the residue distilled, e.g. eb 120-130 ° C / 1 mm Hg, to give the title compounds (788 mg) as an orange oil. The product was further purified ._S84aj * 3i «8¡_a» > by treatment with acid / base to give a mixture of the title compounds (600 mg). c) 2-dimethylaminomethyl-1,4-benzodioxan-6-amine v 2- 5 dimethylaminomethyl-1,4-benzodioxan-7-amino The compounds of the preparations 25 (b) -26 (b) (600 mg, 2.5 mmol) and 10% palladium on carbon (200 mg) in ethanol (30 ml) were stirred under hydrogen (1 atm) for 1 hour. The mixture was filtered, concentrated in vacuo and subjected to chromatography (silica gel, gradient in 10 steps, 0-4% methanol / chloroform) followed by thin layer chromatography (step gradient, 1-2% methanol chloroform) to give the title compounds: 2-dimethylaminomethyl-1,4-benzodioxan-6-amine, TLC Rf0.56 (silica gel, 10% ethanol / chloroform); and 2-dimethylaminomethyl-1,4-benzodioxan-7-amine, TLC Rf 0.51 (silica gel 10% ethanol / chloroform).

EXAMPLE 1 Preparation of N- [3- (2-diisopropylamino, ethoxy-4-methoxypheniH-1, 1-biphenyl-4-carboxamide A solution of 4-biphenylcarbonyl chloride (0.32 g, 1.5 mmol), prepared from 4-biphenylcarboxylic acid and thionyl chloride, was added in one portion to a solution of 3- (2-diisopropylamino) ethoxy-4-methoxyaniline (WO 95/15954) (0.37 g, 1.5 mmol) and diisopropylethylamine (0.19 g, 1.5 mmol) in dichloromethane (20 ml). The resulting mixture was stirred for 16 hours, extracted with 5% aqueous sodium carbonate solution (10 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10% methanol / dichloromethane) to give the title compound (0.22 g): MS (ES) m / e 447.1 [M + H] +.

EXAMPLE 2 Preparation of N-r3- (2-diisopropylamino-ethoxy-4-methoxyphenyl-2'-methyl-f-1,1-biphenyl-4-carboxamide Following the procedure of Example 1, except that 4-biphenylcarboxylic acid was substituted with 2'-methyl-4-biphenylcarboxylic acid (Klein et al., J. Med Chem. 1998, 41, 437), the title compound was obtained: MS (ES) m / e 461.3 [M + H] +.

EXAMPLE 3 Preparation of N-r3-_2-diisopropylamino) ethoxy-4-methoxy-phenyl-1, 1-biphenyl-3-carboxamide Following the procedure of example 1, except that 4-biphenylcarboxylic acid was replaced by 3-biphenylcarboxylic acid, the title compound was obtained: MS (ES) m / e 447.3 [M + H] +.

EXAMPLES 4-11 Preparation of N-r3- (2-dimethylamino) ethoxy-phenan-ri, 1-biphenyl-4-carboxamide; N-r4- (2-d.methylamino) ethoxy-phenol-1,1,1 '-biphenyl-4-carboxamide; N-f2- (3-dimethylamino) propoxy-phenin-p, 1-biphenyl-4-carboxamide: N-r3- (3-dimethylamino) propoxy-phenin-1, 1-biphenyl-4-carboxamide; N-r4- (3-dimethylamino) propoxy-phenyl-ri, 1-biphenyl-4-carboxamide; N-r3-, dietMan.ino) ethoxy-4-methoxyphenyl-1,1-biphenyl-4-carboxamide; N-r3-f2-f piperidin-1-yl) ethoxyl-4-methoxyphenyl-1,1-biphenin-4-carboxamide and N-r3-f2 (4-morpholinyl) ethoxy-1-4-methoxyphenin-1,1-biphenyl -4- carboxamide.

Following the procedure of Example 1, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline is replaced by 3- (2-dimethylamino) ethoxyaniline (WO 95/26328), 4- (2-dimethylamino) ethoxyaniline ( WO 96/23769), 2- (3-dimethylamino) propoxyaniline (WO95 / 15954), 3- (3-dimethylamino) propoxyaniline (W095 / 15954), 4- (3-dimethylamino) propoxyaniline (US Pat. No. 3,994,900), 3 - (2-diethylamino) ethoxy-4-methoxyaniline (WO 95/15954), 3- [2- (piperidin-1-yl) ethoxy] -4-methoxyaniline (WO 95/15954) or 3- [2- (4-morpholinyl) ethoxy] -4-methoxyaniline (WO 95/15954), the title compounds were obtained: N- [3- (2-dimethylamino) ethoxy-phenyl] - [1,1 '-biphenyl] -4 -carboxamide: MS (ES) m / e 361 [M + H] +; N- [4- (2-dimethylamino) ethoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 361 [M + H] +; N- [2- (3-dimethylamino) propoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 375 [M + H] +; N- [3- (3-dimethylamino) propoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 373 [M-H] +; N- [4- (3-dimethylamino) propoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 375 [M + H] +; N- [3- (diethylamino) ethoxy-4-methoxyphenyl] - [1,1'-b-phenyl] -4-carboxamide: MS (ES) m / e 419.5 [M + H] +; N- [3- [2- (piperidin-1-yl) ethoxy] -4-methoxyphenyl] - [1, r-biphenyl] -4-carboxamide: MS (ES) m / e 431.3 [M + H] +; and N- [3- [2- (4-morpholinyl) ethoxy] -4-methoxyphenyl] - [1,1 '-biphenyl] -4-carboxamide: MS (ES) m / e 433.0 [M + H] +.

«Ja¿aan > gS _ »« »_ _ > EXAMPLES 12-13 Preparation of N-β3-, 2-diisopropylamino) ethoxy-2-methylphenyl-2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl, -1 .R-biphenyl-4-carboxamide and N-f3- (2-diisopropylamino) ethoxy-phen.p-2'-methyl-4 '-. 5-methyl-1, 2,4-oxadiazol-3-yl) - f1, 1 '- biphenyl-4-carboxamide Following the procedure of example 1, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline is replaced by the compounds of preparation 7 or preparation 3 and because 4-biphenylcarboxylic acid is substituted by 2, -methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl] -4-carboxylic acid (EP 0533268), the title compounds were obtained: N- [3- (2-diisopropylamino) ethoxy-2 -methylphenyl] -2'-methyl-4, - (5-methyl-1, 2,4-oxadiazol-3-yl) - [1, r-biphenyl] -4-carboxamide: MS (ES) m / e 527.3 [M + H] +; and N- [3- (2-diisopropylamino) ethoxy-phenyl] -2'-methyl-4, - (5-methyl-1, 2,4-oxadiazol-S-ilHI .I'-biphenylM-carboxamide: MS ( ES) m / e 513.2 [M + H] +.

EXAMPLE 14 Preparation of N-r3-, 2-dipropylamino) ethoxy-4-methoxy-phenyl-ri. 1 '-biphenyl-carboxamide Following the procedure of example 1, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline was replaced by the compound of preparation 10 (b), the title compound was obtained: MS (ES) ) m / e 447.1 [M + H] +.

EXAMPLES 15-22 Preparation of N-f3- (2-dicyclohexylamino) ethoxy-4-methoxyphenyl-ri. 1'-biphenin-4-carboxamide; N-r3-r2- (N-cyclohexyl-N-isopropylamino) ethoxy-1-4-methoxyphenin-ri, 1'-biphenylcarboxamide; N-r3-r2- (cis-2,6-dimethylpiperidin-1-yl-ethyl-4-methoxyphenin-p, 1'-biphenyl-4-carboxamide: N-r3-r2-N-ethyl-N-isopropylamino , -ethoxy-1-4-methoxyphen-p-1,1 '-bifenill-4-carboxamide; N-r3-l "2- (2,5-dimethylpyridin-lidin-1-iDetoxy M-methoxyphenyl-M .1'-biphenyl) 4-carboxamide; N-r4-methoxy-3-r2 - (2,2,6,6-tetramethylpiperidn-1-yl) ethoxy-phenin-1,1 '-biphenyl-4-carboxamide; -r3-r2- (N-tert-butyl-N-isopropyl) aminoethoxyl-4-methoxyphenyl-f 1.1 '-biphenin-4-carboxamide and N-r3- (2-diisopropylamino) ethoxy-4-methylphen-p , 1-biphenyl-4-carboxamide Following the procedure of example 1, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline was replaced by the compounds of preparation 9, preparations 11-16 or preparation 8, the title compounds were obtained: N- [3 - (2-dicyclohexylamino) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 527.5 [M + H] +; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy] -4-methoxyphenyl] - [1, r-biphenyl] -carboxamide: MS (ES) m / e 487.2 [M + H] +; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] 4-methoxyphenyl] - [1,1-biphenyl] -4-carboxamide: MS (ES) m / e 459.0 [ M + H] +; N- [3- [2- (N-Ethyl-N-isopropylamino) ethoxy] -4-methoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 433.1 [M + H] +; N- [3- [2- (2,5-Dimethylpyrrolidin-1-yl) ethoxy] -4-methoxyphenyl] - [1,1-biphenyl] -4-carboxamide: MS (ES) m / e 445.0 [M + H] +; N- [4-methoxy-3- [2- (2,2,6,6-tetramethylpiperidin-1-yl) ethoxy] phenyl] -1,1-biphenyl-4-carboxamide: MS (ES) m / e 486.9 [M + H] +; N- [3- [2- (N-tert-Butyl-N-isopropyl) aminoethoxy] -4-methoxyphenyl] - [1,1-biphenyl] -4-carboxamide: MS (ES) m / e 460.9 [M + H] +; and N- [3- (2-diisopropylamino) ethoxy-4-methylphenyl] - [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 431.0 [M + H] +.

EXAMPLE 23 Preparation of N-r3- (3-diisopropylamino) propyloxy-4-methoxyphenylH 1, 1'-biphenyl-4-carboxamide Following the procedure of example 1, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline was replaced by the compound of preparation 19 (b), the title compound was obtained: MS (ES) m / e 461.0 [ M + H] +.

EXAMPLE 24 Preparation of N-r3- (3-di-5-propylamino) propyl-4-methoxyphenn-ri, 1'-biphenyl-4-carboxamide Following the procedure of example 1, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline was replaced by the compound of preparation 20 (c), the title compound was obtained: MS (ES) m / e 445.2 [ M + H] +.

EXAMPLE 25 Preparation of N-r3- (2-diisopropylamino) ethoxy-4-iodophenin-f 1, 1 '-biphenyl-4-carboxamide Following the procedure of example 1, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline was replaced by the compound of preparation 21 (b), the title compound was obtained: MS (ES) m / e 542.9 [ M + H] +.

EXAMPLE 26 Preparation of N-r3-_2-diisopropylamino) ethoxy-4-ethylpheniphenyl-1,1'-bipheni-4-carboxamide Following the procedure of Example 1, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline was replaced by the compound of Preparation 22 (c), the title compound was obtained: MS (ES) m / e 445.1 [M + H] +.

EXAMPLE 27 Preparation of N-r3- (2-diisopropylamino) ethoxy-4- (methoxycarbonyl-amino.pheniH-.1.1 '-biphenyl-4-carboxamide Following the procedure of example 1, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline was replaced by the compound of preparation 23 (c), the title compound was obtained: MS (ES) m / e 490.1 [ M + H] +.

EXAMPLE 28 Preparation of N-M, 1'-b-phenyl-4-yl-3- (2-diiso-propylamino) ethoxy-4-methoxybenzamide a) N-f1, 1'-biphenyl-1,4-yl-3-hydroxy-4-methoxybenzamide A solution of 3-hydroxy-4-methoxybenzoic acid (0.5 g, 3 mmol) in dichloromethane and dimethylformamide was added. cooled to -20 ° C and N-bromosuccinimide (0.57 g, 3.2 mmol) and triphenylphosphine (0.8 g, 3.1 mmol) were added in one portion. The mixture was stirred at -20 ° C for 10 minutes and treated with a solution of 4-aminobiphenyl (0.5 g, 3 mmol) and dry pyridine (0.3 g, 3.8 mmol) in dichloromethane (5 ml). The mixture was allowed to warm to room temperature, stirred for 20 hours, concentrated in vacuo and the residue was stirred in 5% methanol / dichloromethane (40 ml) and filtered. The filtrate was concentrated in vacuo, subjected to chromatography (silica gel, 5% methanol / dichloromethane) and the factions containing the product were mixed, concentrated in vacuo and dissolved in dichloromethane from which the compound precipitated. of the title (0.11 g): MS (ES) m / e 320 [M + H] +. b) N-1, 1'-b-phenyl] -4-yl-3- (2-diisopropylammon) ethoxy-4-methoxybenzamide Following the procedure of Preparation 1 (a), except that 4 is replaced Nitroguayacol by the compound of Example 28 (a) gave the title compound: MS (ES) m / e 446.6 [M + H] +.

EXAMPLE 29 Preparation of N-1,3- (2-diisopropylamino-ethoxy-4-methoxyphenyl-M, 1'-biphenyl-4-methanamine dihydrochloride A solution of the compound of example 1 (70 mg, 0.16 mmol) in anhydrous tetrahydrofuran (25 ml) was treated with 1.0 M borane in tetrahydrofuran (1.56 ml, 1.56 mmol), heated to reflux for 3 hours, cooled, maintained at room temperature for 16 hours, carefully treated with methanol (5 ml), stirred for 1 hour and concentrated in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (10 ml) and the organic phase was dried (Na 2 SO 4), concentrated in vacuo, dissolved in dichloromethane and treated with hydrogen chloride in ether to obtain the compound of the title (51 mg): MS (ES) m / e 433.3 [M + H] +.

EXAMPLE-31 Preparation of N-f3- (2-diisopropyl-ñ-Tno) -ethoxy-4-methoxy-phenyl-1-4'-cyano-1,1 '-biphenyl-4-carboxamide and N-r3- (2-diisopropylamino) ethoxy 4-methoxy-phenyl-2-cyano-4-methyl-4-biphenyl-m-carboxamide Following the procedure of Example 1, except that 4-biphenylcarboxylic acid is replaced with 4'-cyano-4'-methyl-4-acid. biphenylcarboxylic acid (WO 94/12181) or 4'-cyano-4'-methyl-4-biphenylcarboxylic acid (WO 96/19477), the title compounds were obtained: 10 N- [3- (2-diisopropylamino) ethoxy-4 -methoxyphenyl] -4'-cyano-1,1-b-phenyl-4-carboxamide): MS (ES) m / e 472.0 [M + H] +; and N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] 4'-cyano-2'-methyl-1,1-biphenyl-4-carboxamide): MS (ES) m / e 486.0 [ M + H] +.

EXAMPLE 32 Preparation of N-r3- (2-diisopropylamino) ethoxy-4- (ethoxycarbonyl) phen1p-1,1 '- biphenyl-4-carboxamide Following the procedure of example 1, except that 3- (2-diisopropylamino) -ethoxy-4-methoxyaniline is substituted by 3- (2-diisopropylamino) ethoxy-4- (ethoxycarbonyl) aniline (Clinton, et al., J. Am. Chem. Soc. 1957, 79, 2290), the title compound was obtained: MS (ES) m / e 489.1 [M + H] +. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ggg ^ j ^ gj ^^^^^^^^ ^^^^^^^^^^^^^^^^^ EXAMPLE 33 Preparation of N-r3- (2-diisopropylamino) ethoxy-4-methoxyphenyl-2-naphthalenecarboxamide Following the procedure of Example 1, except that 4-biphenylcarboxylic acid was replaced by 2-naphthalenecarboxylic acid, the title compound was obtained: MS (ES) m / e 421.3 [M + H] +.

EXAMPLE 34 Preparation of N- (1 '-methylpyrorbenzofuran-3 (2H), 4'-piperidin-5-yl-.1.1'-biphenyl-4-carboxamide Following the procedure of example 1, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline is replaced by 1-methyl-spiro [benzofuran-3 (2H), 4'-piperidin] -5-amine ( WO 96/11934), the title compound was obtained: MS (ES) m / e 399.2 [M + H] +. . .___ F # EXAMPLES 35-36 Preparation of N-r3-r2- (N-isopropyl-N-methylamino-ethoxyl-4-methoxyphenyl), 1'-biphenip-4-carboxamide and N-ethyl-N- [3-f2- (N-isopropyl-N-methylamino) ethoxy-1-4-methoxyphenin-1,1 '-biphenyl-4-carboxamide Following the procedure of Example 1, except that 3- (2-diisopropylamino) ethoxy-4- is substituted methoxyaniline by the compounds of the preparations 17 (b) and 18 (b), the title compounds were obtained: N- [3- [2- (N-isopropyl-N-methylamino) ethoxy] -4-methoxyphenyl] - [ 1, 1'-10 biphenyl] -4-carboxamide: MS (ES) m / e 419.1 [M + H] +, and N-ethyl-N- -p-N-isopropyl-N-methylamino-jetoxy ^ -methoxyphenyl-1 .l'- biphenyl-4-carboxamide: MS (ES) m / e 446.3 [M + H] +.

EXAMPLE 37 Preparation of N-methyl-N-r3- (2-diisopropylamino) ethoxy-4-methoxyphen-2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) , -. 1, 1 '-bifenill-4-carboxamide Following the procedure of Example 1, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline is replaced by the compound of the Preparation 24 (b) and because 4-biphenylcarboxylic acid is substituted by 2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl] -4-carboxylic acid (EP 0533268 ), the title compound was obtained: MS (ES) m / e 557.3 [M + H] +.

Jsfegfe.JS áü. -_- " »-.« "¿_ Jt_D.it, - a- a. _ .. ^^ .. ^ __ i __. < a _- ^ .._____________ «to _________- ,. - "ffllHIitrr _» "-...,.,, _" &"_, _ EXAMPLE 38 Preparation of N-methyl-N-r3- (diisopropylamino) ethoxy-4-methoxyphenyl-. 1.1 '-biphenyl- 4-carboxamide Following the example procedure, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline was replaced by the compound of preparation 24 (b), the title compound was obtained: MS (ES) m / e 461.3 [ M + H] +.

EXAMPLE 39 Preparation of N-r4- (2-disopropylamino) ethoxy-3-methoxyphenyl-M, 1'-biphenyl-4-carboxamide a) 4 '- (4-biphenylcarboxylic acid) bound to resin. Phenyl bromide bound to resin was expanded (WO 98/17695, 3- scheme 18) (1.0 g, 1.22 mmole) in a mixture of toluene (10 ml) and ethanol (4 ml) for 30 minutes and treated with 4-carboxybenzanboronic acid (0.6 g, 3.6 mmol), tetrakis (triphenylphosphine) palladium (0) (0.2 g) and 2M aqueous sodium carbonate solution (3.6 ml, 7.2 mmoles). The mixture was heated to reflux for 24 hours, cooled and the resin was filtered and washed sequentially with dichloromethane, methanol, methanol / water 1: 1 containing 15 drops of concentrated hydrochloric acid, 1: 1 methanol / water, dichloromethane and methanol. The resulting resin was dried under vacuum. b) 4 '- (biphenyl-4-carbonyl) chloride bound to resin The resin of example 39 (a) (0.06 g) and oxalyl chloride (0.13 g, 1 mmol) in toluene (10 ml) were stirred for 16 hours. hours, it was filtered and washed with toluene and dichloromethane. c) 4'-rN-. { Resin-bound 4- (2-diisopropylammon) ethoxy-3-methoxyphenyl-1, 1'-b-phenyl] -4-carboxamide A mixture of the resin of example 39 (b), the preparation compound 1 (b) (0.13 g, 0.5 mmol) and diisopropylethylamine (0.05 g, 0.4 mmol) in dichloromethane (15 ml) was stirred for 20 hours, the resin was filtered, washed with dichloromethane (3 x 20 ml) and with methanol ( 2 x 20 ml) and dried in vacuo for 16 hours. d) N- [4- (2-diisopropyllamine) ethoxy-3-methoxyphenyl] -f1, 1'-b-phenyl-4-carboxamide A mixture of the resin of example 39 (c) , trifluoroacetic acid (3 ml) and dichloromethane (0.5 ml) was stirred for 20 hours and the resin was filtered and washed with methanol (3 x 10 ml). The filtrate was concentrated in vacuo and the residue was partitioned between dichloromethane (50 ml) and 10% aqueous sodium hydroxide solution (5 ml). The organic phase was washed with water, dried (Na 2 SO) and concentrated in vacuo to give the title compound: MS (ES) m / e 447.4 [M + H] +. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ biphenyl-4-carboxamide; N-r3- (2-diisopropylamino) ethoxy-phenan-ri-1'-biphenyl-4-carboxamide; N-r2-fluoro-4- (2-diisopropylamino) ethoxy-phenyl-f1,1 '-biphenyl-4-carboxamide; N-f4- (2-diisopropylamino) ethoxy-phenin-p. 1 '-biphenip-4-carboxamide and N-f2- (2-diisopropylamino) ethoxy-phenin-ri, 1'-biphenyl-4-carboxamide Following the procedure of Example 39 (c) -39 (d), except that the compound of Preparation 1 was replaced by the compounds of Preparations 2-6, the title compounds were obtained: N- [2- (2- diisopropylamino) ethoxy-4-methoxyphenyl] - [1,1-biphenyl] -4-carboxamide: MS (ES) m / e 447.3 [M + H] +; N- [3- (2-Diisopropylamino) ethoxy-phenyl] - [1,1-biphenyl] -4-carboxamide: MS (ES) m / e 417.5 [M + H] +; N- [2-fluoro-4- (2-diisopropylamino) ethoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 435.4 [M + H] +; N- [4- (2-Diisopropylammon) ethoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 417.4 [M + H] +; and N- [2- (2-diisopropylamino) ethoxy-phenyl] - [1,1 '-biphenyl] -4-carboxamide: MS (ES) m / e 417.4 [M + H] +.

EXAMPLE 45 Preparation of N-f3- (2-diisopropJtomino, ethoxy-4-methoxyphenyl-4- (iodobenzamide a) adduct of 3- (2-di-) soproxylamino) ethoxy-4-methoxyaniline /, 4-formyl-3,5-dimethoxyphenoxy, -resine from Merrifield A mixture of 4-formyl-3 , 5-dimethoxyphenoxy-resin from Merrifield (Boojamra et al., J. Org. Chem. 1995, 60, 5742), 3- (2-diisopropylamino) ethoxy-4-methoxyaniline (WO 9515954) and sodium triacetoxyborohydride in dimethylformamide containing 1% acetic acid was stirred to obtain the title adduct. b) Adduct N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenin-4-vedobenzamide /, 4-formyl-3,5-d, methoxyphenoxy) -resine from Merrifield 15 the resin of example 45 (a) in dimethylformamide with pyridine and with an excess of a mixture of equivalent amounts of 4-iodobenzoic acid, N-bromosuccinimide and triphenylphosphine. The resin was washed to obtain the adduct of the title. c) N-.3-.2-d¡¡-propylamino) ethoxy-4-methoxyphenyl-4-vodobenzamide The resin of Example 45 (b) was stirred in a mixture of trifluoroacetic acid: dichloromethane: water (50: 48: 2), it was filtered and the filtrate was ^^ ^^^^^ gtó ^^^^^^^^^^^ l ^^^^^^.; J * ^^^^^^^ AA ^? £ 4 * ¡& ^ ¡j '> g concentrated in vacuo to obtain the title compound: MS (ES) m / e 497.8 [M + H] +.

EXAMPLES 46-70 5 Following the procedure of Example 45, except that 3- (2-diethylamino) ethoxyaniline (WO 95/15954), 4- (2-diethylamino) ethoxyaniline (Wyatt et al., J. Med. Chem. 1995, 38, 1657), 3- (2-diethylamino) ethoxy-4-methoxyaniline (WO 96/23769), 3- (2-diisopropylamino) ethoxy-4-methoxyaniline (WO 95/15954), and the compounds of preparations 3 and 5, and used 4-isopropylbenzoic acid, 4-cyclohexylbenzoic acid, 4'-ethyl-4-biphenylcarboxylic acid, 4-nitrobenzoic acid, 4-methoxybenzoic acid, 3-bromobenzoic acid, 3-iodobenzoic acid , 4-bromobenzoic acid and 4-iodobenzoic acid the following compounds were obtained: 15 N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4-iodobenzamide: MS (ES) m / e 497.0 [M + H ] +; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4-bromobenzamide: MS (ES) m / e 449.0 [M + H] +; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -3-bromobenzamide: MS (ES) m / e 449.0 [M + H] +; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4- (isopropyl) benzamide: MS (ES) m / e 413.2 [M + H] +; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4'-ethyl- [1,1-biphenyl] -4-carboxamide: MS (ES) m / e 475.2 [M + H] +; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4- (methoxy) benzamide: MS (ES) m / e 401.3 [M + H] +; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4- (nitro) benzamide: MS (ES) m / e 416.5 [M + H] +; N- [4- (2-diisopropylamino) ethoxy-phenyl] -4-iodobenzamide: MS (ES) m / e 467.0 [M + H] +; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -3-iodobenzamide: MS (ES) m / e 497.0 [M + H] +; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -3-iodobenzamide: MS (ES) m / e 460.0 [M + H] +; N- [4- (2-Diisopropylamino) ethoxy-phenyl] -3-iodobenzamide: MS (ES) m / e 467.0 [M + H] +; N- [3- (2-Diisopropylamino) ethoxy-phenyl] -3-iodobenzamide: MS (ES) m / e 476.0 [M + H] +; N- [3- (2-diethylamino) ethoxy-phenyl] -3-iodobenzamide: MS (ES) m / e 439.0 [M + H] +; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4-bromobenzamide: MS (ES) m / e 423.0 [M + H] +; N- [4- (2-disopropylamino) ethoxy-phenyl] -4-bromobenzamide: MS (ES) m / e 418.8 [M + H] +; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -3-bromobenzamide: MS (ES) m / e 423.0 [M + H] +; N- [4- (2-diisopropylamino) ethoxy-phenyl] -3-bromobenzamide: MS (ES) m / e 418.8 [M + H] +; N- [4- (2-Diisopropylamino) ethoxy-phenyl] -4 (isopropyl) benzamide: MS (ES) m / e 383.2 [M + H] +; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4- (cyclohexyl) benzamide: MS (ES) m / e 425.2 [M + H] +; N- [4- (2-Diisopropylamino) ethoxy-phenyl] -4- (cyclohexyl) benzamide: MS (ES) m / e 423.0 [M + H] +; N- [4- (2-diethylamino) ethoxy-phenyl] -4- (cyclohexyl) benzamide: MS (ES) m / e 395.0 [M + H] +; N- [3- (2-dethialamino) ethoxy-4-methoxyphenyl] -4, -ethyl- [1,1] -biphenyl] -4-carboxamide: MS (ES) m / e 447.2 [M + H] +; N- [4- (2-Diisopropylamino) ethoxy-phenyl] -4'-ethyl- [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 445.2 [M + H] +; N- [4- (2-diethylamino) ethoxy-phenyl] -4'-ethyl- [1,1-biphenyl] -4-carboxamide: MS (ES) m / e 417.4 [M + H] +; and N- [3- (2-diisopropylamino) ethoxy-phenyl] -4'-etl1- [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 445.2 [M + H] + .

EXAMPLES 71-73 Preparation of N- [3- (2-diisopropylamino) ethoxy-4-methoxy-phenyl-1,3-dichlorobenzamide. N-r3- (2-diisopropylamino) ethoxy-4-methoxyphenol-3,5-dichlorobenzamide and N-f3- (2-diisopropylamino) ethoxy-4-methoxy-phenin-4- (cyclohexyl) benzamide Following the procedure of Example 1, except that 4-biphenylcarboxylic acid was replaced by 3,4-dichlorobenzoic acid, 3,5-dichlorobenzoic acid or 4-cyclohexylbenzoic acid, the title compounds were obtained: N- [3- (2- diisopropylamino) ethoxy-4-methoxyphenyl] -3,4-dichlorobenzamide: MS (ES) m / e 439.3 [M + H] +; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -3,5-dichlorobenzamide: MS (ES) m / e 439.2 [M + H] +; and N- [3- (2-diisopropylamino) ethoxy-4-methox? -phenyl] -4- (cyclohexyl) -benzamide: MS (ES) m / e 453.0 [M + H] +.

EXAMPLE 74 Preparation of N-r3- (2-diisopropytamino-ethoxy-4-methoxyphenyl-3'-methoxy-1, 1'-biphenyl-4-carboxamide a) Adduct of N-.3- (2-d¡¡sopropyllamine) ethoxy-4-rethoxyphenyl] -4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan -2-l) benzamide / (4-formyl-3,5-dimethoxyphenoxy-Merrifield resin) Following the procedure of example 45 (b), except that 4-iodobenzoic acid is replaced by 4-iodobenzoic acid. (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) benzoic acid (Guiles et al., J. Org. Chem 1996, 61, 5169) the title adduct was obtained. b) Adduct of N-.3-, 2-diisopropylammon) ethoxy-4-methoxyphen-3'-methoxy-p, 1'-biphenin-4-carboxamide / (4-formyl-3, 5-dimethoxyphenoxy) -resin from Merrifield Following the general procedure of Guiles et al., J. Org.

Chem. 1996, 61, 5169, the adduct of example 74 (a) was reacted in dimethylformamide with 3-iodoanisole, tetrakis (triphenylphosphine) palladium (0) and aqueous potassium carbonate solution at 80 ° C for 18 h to obtain the adduct of the title.

~ »Sa3BaiSam« faith ,. . "" Rf v. «Kfetmwfr .Ma > _or.. c) N- [3- (2-disopropylammon) ethoxy-4-methoxyphenyl] -3'-methoxy- [1,1'-biphenyl-4-carboxamide] Following the procedure of the example 45 (c), except that the adduct of example 42 (b) is replaced by the adduct of example 74 (b), the title compound was obtained: MS (ES) m / e 477.2 [M + H] +.

EXAMPLES 75-81 Preparation of N-r3- (2-dimethylamino) ethoxy-4-methoxyphenyl-4'-methoxy-f 1, 1'-biphenyl-4-carboxamide; N-r3- (2-dimethylamino) ethoxy-4-methoxy-phenol, -4'-10-hydroxy-fl, 1'-biphenyl-4-carboxamide; N-r3-.2-diisopropylamino) ethoxy-4-methoxy-phenyl-4'-acetyl-1,1 '.bifenMl-4-carboxamide; N-f3- (2-diethylamino) ethoxy-4-methoxyphen-3'-methoxy-ri. 1 '-biphenip-4-carboxamide; N-f3-f2-dimethylamino) ethoxy-4-methoxyphenyl-3'-methoxy-1, 1-biphenyl-4-carboxamide; N-R3- (2-diisopropylamino) ethoxy-4-methoxyphenyl-3'-hydroxy-1,1,1-biphenyl-4-carboxamide and N-r3- (2-dimethylamino) ethoxy- 4-methoxyphenyl-3'-hydroxy-fl, 1 '-bifenin-4-carboxamide Following the procedure of Example 74, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline (WO95 / 15954), 3- (2- diethylamino) ethoxy-4-methoxyaniline and 3- (2-dimethylamino) are used. ethoxy-4-methoxyaniline, and 3-iodophenol, 3-iodoanisole and 4'-iodoacetophenone were used, the title compounds were obtained: N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -4'-methoxy- [1,1] biphenyl] -4-carboxamide: MS (ES) m / e 421.0 [M + H] +; N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -4'-hydroxy- [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 407.2 [M + H] +; N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4, -acetyl- [1,1'-biphenyl] -4-carboxamide: MS (ES) m / e 489.2 [M + H] +; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -3, -methoxy- [1,1] biphenyl] -4-carboxamide: MS (ES) m / e 449.2 [M + H] +; N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -3'-methoxy- [1,1-biphenyl] -4-carboxamide: MS (ES) m / e 421.0 [M + H] +; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3'-hydroxy- [1,1-biphenyl] -4-carboxamide: MS (ES) m / e 463.2 [M + H] +; and N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -3, -hydroxy- [1,1-biphenyl] -4-carboxamide: MS (ES) m / e 407.2 [M + H] + .

EXAMPLE 82 Preparation of N-22- (d.methylamnomethyl) -1,4-benzodioxan-7-ill-2'-methyl-4'- (5-methyl-1, 2,4-oxadizol-3-yl) ) biphenyl-4-carboxamide The compound of Preparation 26 (c) (188 mg, 0.6 mmol) in tetrahydrofuran (30 mL) was treated with a solution of sodium hydroxide (55 mg) in water (1 mL) and 2'-methyl chloride was added. -4, - (5-methyl-1, 2,4-oxadiazol-3-yl) -biphenyl-4-carbonyl (WO 95/15954) (0.6 mmol). The mixture was stirred for 16 h, concentrated in vacuo and separated between water and chloroform. The organic phase was dried (Na2SO4) and concentrated in vacuo to give a white foam which was subjected to chromatography (basic alumina, ethyl acetate) to obtain the title compound, m.p. 92-94 ° C. EXAMPLE 84 Preparation of N-_2-dimethylaminomethyl) -1,4-benzodioxan-6-p-2'-methyl-4'- (5-methyl-1,2,4-oxadiazol-3-yl) biphenyl- 4- Following the procedure of Example 82, except that the compound of Preparation 26 (c) is replaced by the compound of Preparation 25 (c), the title compound, m.p. 188-190 ° C.

BIOLOGICAL DATA 15 CCR5 receptor binding assay CHO cell membranes (0.25 x 106 cell equivalents) obtained from CHO cells stably transfected with CCR5 with 0.3125I-RANTES were incubated in a 96-well plate for 45 minutes at a time. room temperature (final reaction volume 200 ul). The reaction was terminated by filtration and the filters (GF / C) were washed 12 times with a solution of phosphate-buffered saline containing 0.1% bovine serum albumin and 0.05% NaN3. Radioactivity linked to Filters were measured using liquid. Non-specific binding was determined in the presence of unlabeled RANTES (10 or 30 nM) and averaged 30-50% total binding.

Functional test of CCR5 receptor The cellular functional test used to evaluate the antagonist activity of compounds was the mobilization of Ca2 + induced by RANTES in RBL 2H3 cells stably expressing the hCCR5 receptor (RBL 2H3 hCCR5). The agonist activity is determined by mobilization of Ca2 + in the The same cells can be inhibited by a selective CCR5 antagonist. Cells were grown up to 80-100% confluence in T-150 flasks and washed with phosphate-buffered saline. The cells were elevated from the flasks by treating them with 3 ml of 1 mM EDTA for 3 minutes at room temperature and diluting up to 2 X 106. cells / ml with Krebs Ringer Henseleit buffer (KRH, 118 mM NaCl, 4.6 mM KCl, 25 mM NaHCO3, 1 mM KH2PO4 and 11 mM glucose) containing 5 mM HEPES (pH 7.4), 1 mM CaCl2, 1 mM MgCl2 and 0.1% BSA and centrifuged at 200 g for 3 minutes. The cells were resuspended up to 2 X 106 cells / ml in the same solution regulator with 2 μM of Fura-2AM and incubated for 35 minutes at 37 ° C. The cells were centrifuged at 200 x g for 3 minutes and resuspended in the same buffer without Fura-2AM, then incubated for 15 minutes at 37 ° C to complete the hydrolysis of Fura-2AM.

Intragular, and then centrifuged again as above. Cells (10 6 cells / ml) were resuspended in cold KRH with 5 mM HEPES (pH 7.4), 1 mM CaCl 2, 1 mM MgCl 2 and 0.1% gelatin and kept on ice until evaluated. For the 5 antagonist studies, aliquots of cells (2 ml) were preheated at 37 ° C for 5 min. in 3 ml plastic containers and the fluorescence was measured in a fluorometer (Johnson Foundation Biomedical Group, Philadelphia, PA, USA) with magnetic stirring and the temperature was maintained at 37 ° C. The excitation was adjusted to 340 nm and the emission was adjusted to 510 nm. Various were added concentrations of the antagonist or vehicle and the fluorescence was monitored for approximately 15 seconds to ensure that there was no change in the baseline fluorescence, followed by the addition of 33 nM RANTES. The maximum Ca2 + concentration achieved after stimulation with 33 nM RANTES was calculated as described by Grynkiewicz et al. (1985). He The maximum percentage of Ca2 + induced by RANTES was determined for each antagonist concentration and Cl50, defined as the concentration of the test compound that inhibits 50% of the maximum response to 33 nM RANTES, obtained from the concentration-response curves ( 5-7 concentrations of antagonists). The compounds of this invention showed a ligand-to-CCR5 receptor activity having Cl50 values in the range of 0.0001 to 100 μM. The complete structure / activity relationship for the compounds of this invention is not yet established. However, given the description in ^ * ^^^ j ^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^ j »the present one, one skilled in the art can use the present tests to properly determine which compounds of the formula (I) are ligands of the CCR5 receptor and which are bound thereto with an IC50 value in the range of 0.0001 at 100 μM. All publications, including, but not limited to, patents and patent applications cited in this specification, are incorporated herein by reference as if each individual publication was specifically and individually indicated to be incorporated herein by reference as indicated. completely. The above description fully describes the invention including the preferred embodiments thereof. The modifications and improvements of the modalities specifically described herein are within the scope of the following claims. Without further elaboration it is believed that one skilled in the art can, given the description , use the present invention in its entirety. Therefore, any of the examples should be considered as illustrative only and not as limiting the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are as defined below. -fei-t.-üatte.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof: Ar- A- E Formula I wherein Ar represents a group selected from (i), (ii) or (iii); wherein: R1 and R2 are independently hydrogen, d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- cycloalkyl, C3-6 cycloalkenyl, aryl, (CH2) aNR7R8, (CH2) aNR7COR9 , (CH2) aNR7C02R10, (CH2) aNR7C02R11, (CH2) aCONR12R13, hydroxyalkyl of d-6, alkoxyalkyl of C? -4 (optionally substituted by an alkoxy or hydroxy group of C-), (CH2) aCOR2, alkyl of C ? -6, (CH2) bOC (0) R14, CR15 = NOR16, CNR15 = NOR16, COR17, CONR12R13, CONR12 (CH2) cO-C4 alkyl, CONR12 (CH2) aCO2R18, CONHNR19R20, CONR12SO2R21, CO2R22, cyano, trifluoromethyl, NR7R8, NR7COR9, NR23CO (CH2) aNR23R24, NR23CONR23R24, NR7CO2R10, NR7SO2R11, N = CNR23NR23R24, nitro, hydroxy, d-6-alkoxy, d-6-hydroxyalkoxy, C1-6-alkoxy-C1-6-alkoxy, OC (O) NR25R26, SR27, SOR28, SO2R28, SO2NR25R26 or halogen; a is 1, 2, 3 or 4; R7 and R8 are independently hydrogen or C? -6 alkyl, or NR7R8 forms a heterocyclic ring having 5 or 6 ring member having 5 to 6 ring members that can be optionally substituted by an oxo group and, when there are 6 members of ring, may optionally contain in the ring an oxygen or sulfur atom; R9 is hydrogen, d-β alkyl or C1-4 alkoxyalkyl; R10 is d6 alkyl; R11 is C? -β alkyl or phenyl; R12 and R13 are independently hydrogen or C-? -6 alkyl, or NR12R13 forms a saturated heterocyclic ring having 5 or 6 members which, when there are 6 ring members, may optionally contain in the ring an oxygen or sulfur atom; b is 0, 1, 2 or 3; R 14 is d 4 alkyl, optionally substituted by a d-β alkoxy; R 15 and R 16 are independently hydrogen or C 1-6 alkyl; R17 is hydrogen or C? -6 alkyl; c is 1, 2 or 3; R18 is hydrogen or C1-6alkyl; R19 and R20 are independently hydrogen or d-β alkyl; R21 is hydrogen or C? -6 alkyl; R22 is hydrogen or d-β alkyl optionally substituted with one or two substituents selected from alkyl of d-6, alkoxy of d-β, hydroxy or NR7R8; R23 and R24 are independently hydrogen or d-6 alkyl; R25 and R26 are independently hydrogen or d-6 alkyl, NR25R26 forms a saturated heterocyclic ring having 5 or 6 members which, when there are 6 ring members, may optionally contain in the ring an oxygen or sulfur atom; R27 is hydrogen or Ci-β alkyl; R28 is C? -6? Alkyl? P is a 5- to 7-membered heterocyclic ring containing 1 to 4 heterogeneous atoms selected from oxygen, nitrogen or sulfur; R3 and R4 are independently hydrogen, d-6 alkyl, C3-7 cycloalkyl, C3-6 cycloalkenyl, C6-6 hydroxyalkyl, C6-6 alkyl- d-6 alkyl, CONR29R30, C02R31, cyano , aryl, trifluoromethyl, NR29R30, nitro, hydroxy, d-6 alkoxy, acyloxy or halogen; R29, R30 and R31 are independently hydrogen or C1-6 alkyl; R5 is hydrogen, d-6 alkyl, d-6 alkoxy or halogen; R6 is hydrogen, d-β alkyl, C3-7 cycloalkyl (optionally substituted by a hydroxy or an oxo group), hydroxyalkyl of d-6, hydroxyalkenyl of C3-6, hydroxyalkynyl of C3-6, (CH2) dOR32, (CH2) dCOR33, (CH2) dCR34 = NOR35, CONR36R37, CO2R38, hydroxy, O (CH2) eR39, NR36R37, SR40, S02NR41R42 or halogen; d is 0, 1, 2, 3, 4, 5 or 6; R 32 is C 1 -6 alkyl, d-β hydroxyalkyl or C 1-4 alkanoyl; R33 is hydrogen or Ci-β alkyl; R34 is hydrogen or d-6 alkyl; R 35 is hydrogen or d-6 alkyl; R36 and R37 are independently hydrogen or d-6 alkyl, or NR36R37 forms a saturated heterocyclic ring having 5 or 6 members, which may be optionally substituted by an oxo group and, when there are 6 ring members, may optionally contain one atom of oxygen or sulfur, or an NH or NR43, wherein R43 is C1-6 alkyl, COR44 or CO2R45, wherein R44 and R45 are independently hydrogen or d-6 alkyl; R38 is hydrogen or C? -6 alkyl; e is 1, 2, 3, 4, 5 or 6; R39 is d-6 alkoxy) CO2H, C02alkyl of d-6 or CONR36R37; R40 is C? -6 alkyl; R41 and R42 are independently hydrogen or alkyl of alternatively, R5 and R6 form a fused benzo ring optionally substituted with d-6 alkyl, d-β alkoxy or halogen; when Ar is (i), (ii) or (iii), and A is CONR46, NHCO, -NHCH2 or CH2NH, wherein R46 is hydrogen or C1-6 alkyl, E represents (a): wherein R47 and R48 are independently hydrogen or d-6 alkyl; R49 is hydrogen, d-6 alkyl, C02R53, NHC02R54, hydroxy, d-6 alkoxy or halogen wherein R53 is hydrogen or C1-6 alkyl. and R54 is d6 alkyl; R5o and R5i are independently hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached they form an optionally substituted 5- to 7-membered heterocyclic ring containing one or two heterogeneous atoms selected from oxygen, nitrogen or sulfur; B is oxygen, S (O) h wherein h is 0, 1 or 2, CR55 = CR56 or R55R56 wherein R55 and R56 are independently hydrogen or alkyl of d-6, or B is NR57 wherein R57 is hydrogen, alkyl of C? -6 or phenylalkyl of Ci-β; R52 is hydrogen, or R52 taken together with R46 forms a group D wherein D is (CR58R59), where i is 2, 3 or 4 and R58 and R59 are independently hydrogen or C? -6 alkyl, or D is (? CR58R59) rG where j is 0, 1, 2 or 3 and G is oxygen, sulfur or CR58 = CR59; f is 1 to 4; and g is 1 or 2; when Ar is (i), (ii) or (iii) and A is CONR60, NHCO or CH2N, where R60 is hydrogen or C-? 6 alkyl, E represents (b): R61 is hydrogen or alkyl of d-6 and R61 and R60 together form a group-K- when K is (CR65R66) m when m is 2, 3, or 4 and R65 and R66 are independently hydrogen or alkyl of d-6 or K is (CR65R66) nL when n is 0, 1, 2 or 3 and L is oxygen, sulfur or CR65 = CR66; R62 is hydrogen or C1-6alkyl; R63 and R64 are independently hydrogen or C1-6alkyl; J is oxygen, CR67R58 or NR69 wherein R67, R68 and R69 are independently hydrogen or alkyl of d-6 or J is a group S (O) m wherein m is 0, 1 or 2; k is 1, 2 or 3; I is 1, 2 or 3; when Ar is (i), (ii) or (iii) and A is CONR70, NHCO, -NHCH2 or CH2NH, wherein R70 is hydrogen or alkyl of d-6, E represents (c): wherein: M is oxygen, S (O) p wherein p is 0, 1 or 2, CR76 = CR77 or CR76R77 wherein R76 and R77 are independently hydrogen or alkyl of d-6, or M is NR78 wherein R78 is hydrogen or alkyl; R71 and R72 are independently hydrogen or d-6 alkyl; R73 is hydrogen, C? -6 alkyl, CO2R79, NHCO2R80, hydroxy, C? -6 alkoxy or halogen wherein R79 is hydrogen or C? -6 alkyl and R80 is C? -6 alkyl; R74 is hydrogen or together with R70 forms a group Q when Q is CR81 = CR82, CR81 = CR82CR81R82 or (CR81R82) q where q is 2 or 3 and R81 and R82 are independently hydrogen or C1-6alkyl; n is 0, 1, 2 or 3; or is 1 or 2; R75 is a group of the formula (d): wherein r, s and t are independently integers having the value 1, 2 or 3; or R75 is a group of the formula (e): wherein u is 0, 1, 2 or 3 and R83 is hydrogen or d-6 alkyl; when Ar is (i), (ii) or (iii) and A is CONH, NHCO or CH2NH, E represents (f): R84 and R85 are independently hydrogen or d-6 alkyl; R86 and R87 are independently hydrogen, d-6 alkyl, C3-7 cycloalkyl. aralkyl, or together with the nitrogen atom to which they are attached, form an optionally substituted 5- to 7-membered heterocyclic ring containing one to two heterogeneous atoms selected from oxygen, nitrogen or sulfur; T is - (CR88R89) W- or -0 (CR88R89) x- wherein R88 and R89 are independently hydrogen or d-6 alkyl, wherein w is 2 or 3 and x is 1, 2 or 3; v is 1 to 4; and W is oxygen, S (O) and wherein y is 0, 1 or 2, or W is NR90 wherein R90 is hydrogen or d-6 alkyl) or W is CR91 = CR92 or CR91R92 wherein R91 and R92 are independently hydrogen or d-β alkyl; when Ar is (i), (ii) or (iii) and A is CONR93, NHCO or CH2NH wherein R93 is hydrogen or alkyl of d-6, E represents a group (g): R94 is hydrogen, halogen, hydroxy, d-β alkyl or d-6 alkoxy, or R94 and R93 taken together form a group -X- wherein X is (CR97R98) aa wherein aa is 2, 3 or 4 and R97 and R98 are independently hydrogen or C? -β alkyl or X is (CR97R98) ab-Y, wherein ab is 0, 1, 2 or 3 and Y is oxygen, sulfur or CR97 = CR98; R95 is hydrogen, d-6 alkyl > CO2R99, NHCO2R100, hydroxy, d-6alkoxy or halogen, wherein R95 is hydrogen or alkyl of d-6 and R100 is alkyl of d-β; z is 1 or 2; and R96 is a saturated or partially saturated 5- to 7-membered heterocyclic ring optionally substituted ^^^^^^^^^^^^^^^^^^^^^^ g ^^^^ contains 1 to 3 heterogeneous atoms selected from nitrogen, oxygen or sulfur, or R96 is a bicyclic ring 6, 6 or 6.5 optionally substituted containing a nitrogen atom and optionally an additional heterogeneous atom selected from oxygen, nitrogen or sulfur; when Ar is (i), (ii) or (iii) and A is CONR101, NHCO or CH2NH, wherein R101 is hydrogen or C-? 6 alkyl, E represents a group (h): R102 is hydrogen or d-6 alkyl, d-6 alkoxy or halogen, or R together with R101 form a group -AA-, where AA is (CR107R108) ad, wherein ad is 1, 2 or 3 and R107 and R108 are independently hydrogen or d-6 alkyl or AA is (CR 07 = CR108) ae-AB, where ae is 0, 1 or 2 and AB is oxygen, sulfur, CR 07 = CR108, CR107 = N, CR102NR108 or N = N; R103 and R104 are independently hydrogen or d-6 alkyl; R105 and R106 are independently hydrogen, C1-6 alkyl. C3.7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached, form an optionally substituted 5- to 7-membered heterocyclic ring containing one or two heterogeneous atoms selected from oxygen, nitrogen or sulfur; ac is 0 to 4; Z is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heterogeneous atoms selected from oxygen, nitrogen or sulfur; when Ar is (i), (ii) or (ii) and A is CONR109, NHCO or CH2NH, wherein R109 is hydrogen or alkyl of d-6, E represents a group (!): R110 is hydrogen or C1-6alkyl, or R110 and R109 together form an -AD- group, wherein AD is (CR115R116) ah, wherein ah is 2, 3 or 4 and R115 and R116 are independently hydrogen or alkyl d-ß, or AD is (CR ?? 5R? i6) arAE, in 10 where ai is 0, 1, 2 or 3 and AE is oxygen, sulfur or CR115 = CR116; R111 and R112 are independently hydrogen, d-6 alkyl, C3- cycloalkyl, aralkyl, or together with the nitrogen atoms to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one to two heterogeneous atoms selected of oxygen, nitrogen or sulfur; R113 15 and R114 are independently hydrogen or d-6 alkyl; AC is oxygen, CR117R118 or NR119, wherein R117, R118 and R119 are independently hydrogen or C1-6 alkyl, or AC is a group S (O) aj, wherein aj is 0, 1 or 2; af is 1, 2 or 3; ag is 1, 2, 3 or 4 and ah is 0, 1, 2, 3 or 4, in the manufacture of a medicament for treating a disease state mediated by CCR-5 in 20 mammals

2. The use according to claim 1, wherein the compound of the formula (I) is a compound selected from: N- [3- (3-dimethylamino) propoxy-4-methoxyphenyl] -2'-methyl- 4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - (1, 1 '-bifeni) l-4-carboxamide; N- [3- (2-piperidin) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - (1,1' -bifeni) ) l-4-carboxamide; N- [3- (3-dimethylaminopropyl) -4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4-carboxamide oxalate; N- [3- (1-methyl-4-piperidyl) -4-methoxyphenyl] -2'- 5-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl- oxalate 4-carboxamide; N- [3- (1-methyl-3-piperidyl) -4-methoxy-phenyl] -2'-methyl-4 '- (5-methyl-1,2,4-oxadiazol-3-yl) biphenyl ester oxalate -4- carboxamide; N- [7- (2-dimethylamino) ethoxy-2,3-dihydrobenzofuran-5-yl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -1, 1'-biphenyl-4-carboxamide; [3- (dimethylaminoethyl) -3,6,7,8-tetrahydro-2H-furo [2,3-g] quinolin-5-yl] - [2'-methyl-4 '- (5-10-methyl) oxalate - [1, 2,4] -oxadiazol-3-yl) -biphenyl-4-yl] -methanone; oxalate of 5- [4- (2-methyl-4- (5-methyl-1, 2,4-oxadiazol-3-yl) phenyl) benzoylamino] spiro [(2,3-dihydrobenzofuran) - 3,4'- (1-methylhexahydroazepine)]; 2,3,5,6,7,8-hexahydro-1'-methyl-5-oxalate. { 2'-methyl-4 '- [(5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4-yl] carbonyl} furo [2,3-g] quinolino-3-spiro-4'-piperidine; 6,7,8,9-tetrahydro-1 '-methyl-5 - [[2'-methyl-4' - (5-methyl-1, 2,4-oxadiazol-3-yl) [1, 1 ' -biphenyl] -4-yl] carbonyl] -spiro [2 H -furo [2,3-h] [1] benzazepin-3 (5H), 4'-piperidine]; 2,3,5,6,7,8-hexahydro-5- [4 '- (5-hydroxymethyl-1,4-oxadiazol-3-yl) -2'-methylbiphenyl-4-carbonyl] - hydrochloride 1'-methyl spiro [furo [2,3- g] quinoline-3,4'-piperidine]; 4 '(Dimethylamino) -5- [2'-methyl-4' - [(5-methyl-1, 2,4-oxadiazol-3-yl) -biphenyl-4-yl] carbonyl] hydrochloride] -2.3.6.7 -tetrahydrospiro [furo [2,3- 20 f] indol-3-1 '-ciciohexane]; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl] -3-carboxamide; N- [3- (3-dimethylamino) propoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [4- (3-dimethylamino) propoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (diethylamino) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2- ^^^^^^^ ^^^^^^^^^^^^^^^^^^^^ (piperidin-1-yl) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-2-methylphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - [1, 1' -biphenyl] -4-carboxamide; N- [3- (2-dipropylamino) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-diisopropylammon) ethoxy-4-methylphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4-ethylphenyl] - [1,1'-b-phenyl] -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4- (methoxycarbonylamino) phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [1,1'-biphenyl] -4-yl-3- (2-diisopropylamino) ethoxy-4-methoxybenzamide; N- [3- (2-diisopropylamino) ethoxy-4- (ethoxycarbonyl) phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [4- (2-diisopropylamino) ethoxy-3-methoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [2- (2-diisopropylamino) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy] -phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [2-fluoro-4- (2-diisopropylamino) ethoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [4- (2-diisopropylamino) ethoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [2- (2-diisopropylamino) ethoxy-phenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4-bromobenzamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4- (isopropyl) -benzamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4- (cyclohexyl) -benzamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3,4-dichloro-benzamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3,5-dichlorobenzamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4- (n.) Benzamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3-iodobenzamide; N- [4- (2-diisopropylamino) ethoxy-phenyl] -3-iodobenzamide; N- [4- (2-diisopropylamino) ethoxy-phenyl] -3-bromobenzamide; N- [4- (2-diisopropylamino) ethoxy-phenyl] -4- "> _ _ii_t &amp & amp; amp; _ < .. (cyclohexyl) benzamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxy-phenyl] -4- (cyclohexyl) benzamide; N- [3- (2-diethylamino) ethoxy-4-methoxy-phenol] -4'-ethyl- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-phenyl] -4'-ethyl-] - 4 '- [1,1' -biphenyl] -4-carboxamide and N- [3- (2-dimethylamino) ethoxy- 4-methoxyphenyl] -3'-methoxy- [1,1'-biphenyl] -4-carboxamide). Among the compounds of the invention that are most preferred are the following compounds: N- [3- (2-diisopropylamino) ethoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazole-3-) il) - (1,1 '-biphenyl) -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - (1,1' -biphenyl) -4-carboxamide; 5- [4- (2-methyl-4- (5-methyl-1, 2,4-oxadiazol-3-yl) phenyl) benzoylamino] spiro [(2,3-dihydrobenzofuran) -3,4 oxalate] '- (1-methylpiperidine)]; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -2'-methyl) - (1,1'-biphenyl) -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-phenyl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) - [1,1' -biphenyl) - 4-carboxamide; N- [3- [2- (N-Cycloexyl-N-isopropylamino) ethoxy] -4-methoxyphenyl] - [1,1'-biphenyl) -4-carboxamide; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4-methoxyphenyl] - [1,1'-biphenyl) -4-carboxamide; N- [3- [2- (N-ethyl-N-isopropylamino) ethoxy] -4-methoxyphenyl] - [1,1'-biphenyl) -4-carboxamide; N- [3- [2- (2,5-Dimetipyrrolidin-1-yl) ethoxy] -4-methoxyphenyl] - [1,1'-biphenyl) -4-carboxamide; N- [4-methoxy-3- [2- (2,2,6,6-tetramethylpiperidin-1-yl) ethoxy] phenyl] - [1,1'-biphenyl) -4-carboxamide; N- [3- [2- (N-t-Butyl-N-isopropyl) aminoethoxy] -4-methoxyphenyl] - [1,1'-biphenyl) -4-carboxamide; N- [3- (3-diisopropylamino) propyloxy-4-methoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (3- (diisopropylamino) propyl-4-methoxyphenyl] - [1,1'-biphenyl) -4-carboxamide; N- [3- (2- (diisopropylaminol) ethoxy] -4-iodophenyl] - [1,1 '- .TO_. { _a8s? Ai? Biphenyl) -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl) -4-methanamine dihydrochloride; N- [3- (2-diisopropylamino) ethoxy-4-methoxy-phenyl] -4'-cyano-1,1 '-biphenyl) -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4'cyano-2'-methyl-1,1 '-biphenyl-4-carboximide; N- [3- (2- (diisopropylamino) ethoxy-4-methoxyphenyl] -2-naphthalenecarboxamide; N- (1'-methylspiro [benzofuran-3 (2H), 4'-pperidin] -5-yl- [1, 1'-biphenyl] -4-carboxamide; N- [3- [2- (N -isopropyl-N-methylamino) ethoxy] -4-methoxyphenyl] - [1,1 '-biphenyl] -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4- (iodine) benzamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4- (cycloexy) benzamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4'-ethyl- [1 , 1 '-biphenyl] -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3'-methoxy- [1,1'-biphenyl] -4-carboxamide; N- [3 - (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4'-acetyl- [1, 1 'biphenyl] -4-carboxamide; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -3'- methoxy- [1,1 'biphenyl] -4-carboxamide and N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3'-hydroxy- [1,1'-biphenyl] -4-carboxamide The compounds which are excluded from the scope of this invention are the following: N- [3- (2-dimethylaminoethoxy) -4-methoxyphenyl] -4 '- (5-dimethylamino-1, 2,4-oxadiazol-3-yl. ) -2'-methylbiphenyl-4-carboxamide; N- [3- (1-methylazetidin-1-methylmethoxy-methoxyphenyl) -l-methyl-d-methyl -l ^^ -oxadiazol-S -yl) ^ '-methylbiphenyl-4-carboxamide; [7- (2-dimethylaminoethoxy) -6-methoxy-3,4-dihydro-2H-quinolin-1-yl] [2'-methyl- [1, 2,4] -oxadiazol-3-yl) biphenyl ester oxalate -4-yl] -metanone; 2,3,6,7-tetrahydro-1 '-methyl-5- [2'-methyl-4' - (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4-carbonyl oxalate ] -furo [2,3-f] indol-3-spiro-3'-piperidine; 5- [4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) biphenyl-4-carbonyl] -1' -methyl-2,3,6,7-tetrahydrofuro [2,3-f] ] indole-3-spiro-4'-piperidine; 1'-ethyl-5- [2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) -biphenyl-4-carbonyl] -2,3,6,7-tetrahydrospiro [2,3-f] indole-3,4'-piperidine; N- [2- (2-dimethylamino) ethoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] benzamide; N- [3- (2-diisopropylamino) ethoxy-5-methoxyphenyl] - [1,1'-biphenyl] -2-carboxamide; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4- (methoxy) benzamide; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4- (nitro) benzamide; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4- (nitro) benzamide; N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -4- (nitro) benzamide; N- [3- (dimethylamino) ethoxy-4-methoxyphenyl] - [1,1'-biphenyl] -4-carboxamide; N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -4'-chloro- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4'-hydroxy- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4'-acetyl- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -4'-acetyl- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -3'-chloro- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -3'-nitro- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -3'-nitro- [1,1'-biphenyl] -4-carboxamide; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4-iodobenzamide; N- [4- (2-diethylamino) ethoxy-phenyl] -4-iodobenzamide; N- [4- (2-diisopropylamino) ethoxy-phenyl] -4-iodobenzamide; N- [4- (2-diethylamino) ethoxy-phenyl] -3-iodobenzamide; N- [2- (2-diisopropylamino) ethoxy-phenyl] -3-iodobenzamide; N- [2- (2-diethylamino) ethoxy-phenyl] -3-iodobenzamide; N- [3- (2-diethylamino) ethoxy-phenyl] -4-bromobenzamide; N- [2- (2-diisopropylamino) ethoxy-phenyl] -4-bromobenzamide; N- [2- (2-diethylamino) ethoxy-phenyl] -4-bromobenzamide; N- [4- (2-diethylamino) ethoxy-phenyl] -3-bromobenzamide; ^^ & ^^^^^^^^^^^ ^^^^^^^^ g ^^^^^^^^^^^^ * ^^ _ ^^ _______ ^^^^^ ^^^^^ ^ HBB ^ N- [2- (2-diisopropylamino) ethoxy-phenyl] -3-bromobenzamide; N- [2- (2-diethylamino) ethoxy-phenyl] -3-bromobenzamide; N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4- (dimethylamino) benzamide; N- [4- (2-diisopropylamino) ethoxy-phenyl] -4- (dimethylamino) benzamide; N- [4- (2-diethylamino) ethoxy-phenyl] -4- (dimethylamino) benzamide; N- [2- (2-diisopropylamino) ethoxy-phenyl] -4- (dimethylamino) benzamide; N- [2- (2-diethylamino) ethoxy-phenyl] -4- (isopropyl) benzamide; N- [2- (2-diisopropylamino) ethoxy-phenyl] -4- (isopropyl) benzamide; N- [2- (2-diethylamino) ethoxy-phenyl] -4- (isopropyl) benzamide; N- [3- (2-diethylamino) ethoxy-phenyl] -4- (cyclo-ethyl) -benzamide; N- [2- (2-diisopropylamino) ethoxy-phenyl] -4- (cycloexyl) benzamide; N- [2- (2-diethylamino) ethoxy-phenyl] -4- (cyclo-ethyl) -benzamide; N- [2- (2-diisopropylamino) ethoxy-phenyl] -4'-ethyl- [1,1'-biphenyl] -4-carboxamide and N- [2- (2-diethylamino) ethoxy-phenyl] -4 ' -ethyl- [1,1-biphenyl] -4-carboxamide.

3. The use according to claim 1, wherein the The disease is selected from COPD, asthma and atopic disorders, rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease and HIV infection.

4. A compound selected from the group consisting of: N- [3- 20 (2-diisopropylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -2'-methyl- (1,1'-biphenyl) -4-carboxamide; N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -2-naphthalenecarboxamide; N- [2- (dimethylaminomethyl) 1,4-benzodioxan-7-yl] -2'-methyl-4 '- (5-methyl-1, 2,4-oxadiazole-3-) ^ j ^^^ j ^^ g &8g? = igj ^^^^ Ml ^^ gátog ^^^^^^^^^^^^^^^^ fc ^^^^ gjßß il ) biphenyl-4-carboxamide and N- [2- (dimethylaminomethyl) -1,4-benzodioxan-6-yl] -2'methyl-4 '- (5-methyl-1, 2,4-oxadiazol-3-yl) ) biphenyl-4-carboxamide. ^ g ^^^^^^^^^^ j ^^ * ^^^^^^^