CZ474999A3 - Pharmaceutical preparation for treating pathological states mediated by CCR5 - Google Patents

Abstract

This solution provides a pharmaceutical composition for treatment CCR5 mediated disease states substituted benzanilides of the general formula I which they have the meanings of the substituents given in the description are ligands, CCR5 receptor agonists or antagonists.

Description

The present invention provides a pharmaceutical composition for the treatment of CCR5 mediated disease states with substituted benzanilides of formula I having the meanings of the substituents disclosed herein and being CCR5 receptor ligands, agonists or antagonists.

BACKGROUND OF THE INVENTION

T cells are not only key regulators of the immune response to infectious agents, but are believed to be critical for initiating and maintaining an inflammatory response in many chronic diseases. An increased number or elevated state of T cell activity, particularly CD4 + T cells, has been shown in the articular intracellular membranes of individuals with rheumatoid arthritis [M.J. Elliot and R.N. Maini,

Int. Sheet. Allergy Immunol. 104, 112-1125 (1994)], in the bronchial mucosa of asthmatics [C.J. Korrigan and A.B. Kay Immunol. Today, 13, 501-506 (1992)], in lesions of multiple sclerosis [R. Martin and H.F. McFarland, Crit. Roar. Clin. Sci. 32, 121-182 (1995)], in psoriatic lesions [J.L. Jones, J. Berth-Jone, A. Fletcher, and Ρ. E. Hutchinson, J. Pathol. 174, 77-82 (1994)] and in the furrows of atherosclerosis [R. Ross, Anna. Roar. Physiol. 57, 791-804 (1995)].

T cells, like other inflammatory cells, can travel to tissues in response to the production of a variety of chemotactic agents. Among these factors, superfamily of 8- to 12-kDa proteins are known as chemokines. These proteins share structural features such as the presence of 3 to 4 conserved cysteine residues. RANTES meaning 4 4 4444444 44 4 _ O - 4444 44 4 4 * 44

4444 44 4 4444 Regulated upon Activation Normal T cell expressed and secreted, the 8-kDa protein is a member of the CC department of the chemokine family. These proteins restore and revive immune and inflammatory cells through interaction with G-protein coupled receptors. The separation of CC is defined by the absence of an amino acid residue between the first two cysteine residues, and members of this family predominantly induce the movement of mononuclear cells, eosinophilic leukocytes, and basophilic granulocytes [M. Baggiolini, B. Dewald and B. Moser, Adv. Immunol. 55, 97-179 (1994)] and [J.

J. Oppenheim, C.O. Zachariae, N. Mukaida, and K. Matsushima, Annu. Roar. Immunol., 9, 617-648 (1991)].

RANTES effectively induces chemotaxis of T cells, basophilic granulocytes, eosinophilic leukocytes, monocytes and mast cells. RANTES was originally identified as a gene product induced after antigen activation of T cells [T. J. Schall, J. Jongstra, B.J. Dyer, J. Jorgensen et al., J. Immunol. 141, 1018-1025 (1988)], however, it has been shown that RANTES is synthesized and secreted by a diverse group of cells including epithelial and endothelial cells [C. Stellato, L.A. Beck, G.A. Gorgone, D, Proud et al.,

J. Immunol. 155, 410-418 (1995)] and [A. Marfaing-Koka, 0. Devergne, G. Gorgone, A. Portier et al., J. Immunol. 154, 1870-1878 (1994)], synovial fibroblasts, [P.

Rathanaswami, M. Hachich, M. Sadick, T. J. Schall et al., J. Biol. Chem. 268, 5834-5839 (1993)] and skin fibroblasts [M. Sticherling, M. Kupper, F. Koltrowitz, E. Bornscheuer et al., J. Invest. Dermatol. 105,585-591 (1995)], mesangial cells [G. Wolf, S. Aberle. F. Thaiss et al., Kidney Int. 4, 795-804 (1995)] and platelets [Y. Koameyoshi, A. Dorschner, A.I Mallet, E. Christophers et al., J. Exp.

9 9 ♦ - J - · · · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

Copper. 17, 6, 587-592 (1992)]. In these cells RANTES mRNA is rapidly increased in response to IL-1 or _TNF. Although RANTES mRNA is not commonly detected in normal tissues [JM Pattison, PJ Nelson and AM Krensky, Clin. Immunother.

8, 1-8 (1995)], an elevated mRNA or protein was found in diseases characterized by mononuclear infiltration. For example, RANTES mRNA was imaged using in situ hybridization in renal allografts in a past healing [J. Pattison, M., Nelson, P., and Krensky, A. M., Clin. Immunother. 4_, 1-8 (1995)] and [K. C. Nadeau, H. Azuma and Ν. I. Tilney, Why. Nati. Acad. USA 92, 87298733 (1995)], in the skin of patients with atopic dermatitis after antigen challenge [S. Ying, L. Taborda-Barat, Q. Meng. M. Hubert et al., J. Exp. Copper. 181, 2153-2159 (1995)] and in coronary artery endothelial cells after intense atherosclerosis following cardiac transplantation [J. Pattison, M., Nelson, P., and Krensky, A. M., Clin. Immunother.

4, 1-8 (1995)]. In addition, a protein with increased immunoreactivity to RANTES was detected in bronchoalveolar lavage fluid [R. Alarm, J. York, M. Boyers et al., Am. J. Resp. Crit. Care Med. 149, A951 (1994)] and in the respiratory tract of asthmatic individuals [C. Gelder, M.P. Thomas, D.H. Yates, I.M. Adcock et al., Thorax 50, 1033-1037 (1995)].

Several receptors that bind RANTES have been identified. In particular, RANTES binds CCR5 when expressed by either HEK 293 cells or CHO cells. This receptor is expressed in T cells and in monocytes and macrophages, immune / inflammatory cells, which are important in maintaining a chronic inflammatory response. Pharmacological characterization of CCR5 shows similarities to the RANTES binding sites found on isolated T cells. Therefore, it should

The opposite effect of RANTES on CCR5, as well as the opposite effect of other natural ligands of CCR5 treatment, inhibit inhibition of T cell treatments and inhibit the delivery of T cell treatments and and autoimmune diseases.

Because T cells express CCR5, selective CCR5 receptor ligands, particularly antagonists, are likely to be able to provide useful effects in diseases, including but not limited to, mammals, including but not limited to asthmatic and atopic disorders (e.g., atopic dermatitis and allergies) , rheumatoid arthritis, benign lymphogranuloma and other fibrotic disorders, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis and inflammatory bowel disease.

Furthermore, since CD8 + T cells have been implicated in COPD, CCR5 may play a role in their recruitment and thus CCR5 antagonists can provide a potential drug in the treatment of COPD. Also, since CCR5 is a co-receptor for HIV entry into cells, selective receptor ligands may be useful in the treatment of HIV infection.

5-HT receptor activity has been reported for a subset of compounds included in Formula (I) [International Application Publication No. WO 95/15954, published June 15, 1995], [International Application Publication No. WO 95/17398, published 29. June 1995], [International Application Publication No. WO 95/26328, published October 5, 1995], [International Application Publication No. WO 96/06079, Published February 29, 1996], [GB 2276161, Published September 21, 1994] and [GB 2276165, published September 21, 1994], [International Application Publication No. WO 95/30675, Published November 16, 1995], [International Application Publication No. WO 95/17401, Published 29.

0 β

0 0 0 0 0 0

00 · 0 00 0

0000000 00 0; June 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 Publication Number WO 96/11934, published April 25, 1996], [International Application Publication No. WO 96/19477, published June 27, 1996], [International Application Publication No. WO 97/17350, Published May 15, 1997], [International International Application Publication No. WO 97/34900, published 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 7. December 1995], [International Application Publication No. WO 97/07120, published February 27, 1997], [US Pat.

931,195, issued Jan. 6, 1976], [U.S. Patent No. 4,000,143, issued Dec. 28, 1976].

Surprisingly, it has now been found that this group of non-peptidic compounds of especially substituted benzanilides of formula (I) act as CCR5 receptor ligands and thus have utility in the treatment and prevention of disease states mediated by the CCR5 receptor mechanism.

SUMMARY OF THE INVENTION

The present invention relates to a new use of CCR5 ligand for the treatment of certain disease states in mammals, preferably humans, including, but not limited to, asthmatic and atopic disorders (e.g., atopic dermatitis and atopic dermatitis). ··· ♦ · · · · · · · β ·

• ·

Allergies), rheumatoid arthritis, benign lymphogranuloma and other fibrotic disorders, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis and inflammatory bowel disease and HIV infection. Preferred compounds for use as CCR5 ligands are those having the general formula (I) as above.

Detailed description of the invention

It has now been found that substituted compounds of formula (I) are CCR5 receptor ligands. It has now also been found that selective inhibition of the CCR5 receptor mechanism by treatment with the receptor ligands of formula (I), or pharmaceutically acceptable salts thereof, represents a novel therapeutic and preventive approach to treating a variety of disease states, in mammals, preferably humans, including but not including. limited thereto, asthmatic and atopic disorders (e.g., atopic dermatitis and allergies), rheumatoid arthritis, benign lymphogranuloma and other fibrotic disorders, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis and inflammatory bowel disease. Furthermore, since CD8 + T cells have been implicated in COPD, CCR5 may play a role in their recruitment and thus CCR5 antagonists can provide a potential drug in the treatment of COPD. Also, since CCR5 is a co-receptor for cell entry, selective receptor ligands may be useful in the treatment of HIV infection.

Compounds for this use include 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 Number WO 95/17398, published June 29, 1995

(USSN 08/663 291, filed May 21, 1999); [International Application Publication No. WO 95/26328, published October 5, 1995 (USSN 08/718 481, filed September 26, 1996)], [International Application Publication No. WO 96/06079, published May 29, 1996)]. U.S. Patent No. 08 / 793,428, filed Feb. 21, 1996), [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 96/31508, published October 10, 1996 (USSN 08/930 848, filed October 7, 1997)], [International Application Publication No. WO 97/108 24, 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 No. WO 97/34900, published September 25, 1997 (Judgment No. P31419)], [International Application Publication No. WO 97/34901, published September 25, 1997 (Judgment No. P31418)], [International Application No. WO 97/35862, published October 2, 1997 (Judgment No. P31426)], [International Application Publication No. WO 97/19070, published May 29, 1997 (USSN 09/077 263)], [International Application with the publication number WO 95/32967, game filed December 7, 1995 (USSN 08/737 660)], [International Application Publication No. WO 97/07120, published February 27, 1997 (USSN 09/011 338,

44

4 4 4 4 4

4 4 4 4 4 • 4444 44 44 4

4 4 4 4 4

4 4444

4 (filed February 11, 1998)], [U.S. Patent No. 3,931,195, issued January 6, 1976] and [U.S. Patent No. 4,000,143, issued December 28, 1976].

Preferred compounds for use as CCR5 ligands are those compounds of formula (I) as described above.

Each of these references is incorporated herein in their entirety.

A preferred group of compounds for use herein are compounds of formula (I), or a pharmaceutically acceptable salt thereof:

Ar-A-E

Wherein Ar is (ii) or (iii), a group selected from groups (i),

in which

R ¹ and R ² are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkenyl containing 3-6 carbon atoms, aryl, (CH ₂₎ m NR ⁷ R ^8, (CH 2) a NR ⁷ COR ^9, (CH ₂₎ m NR ⁷ CO 2 R ^10, (CH ₂₎ m NR ⁷ SO ₂ R ^n, (CH ₂ ) _and NR ⁷ CONR ¹² R ¹³ , C 1 -C 6 alkyl substituted with hydroxy, C 1 -C 4 alkyl substituted with 4 to 4 carbon atoms. · · · · · · · · · · <<

Carbon atoms (optionally substituted with 1 to 4 carbon atoms or hydroxy),> 15.

, 16 (CH ₂ ) _and CO ₂ C _1-6 alkyl, (CH ₂ ) _b OC (O) R ¹⁴ , CR ¹⁵ = NOR ¹⁶ , COR ¹⁷ , CONR ¹² R ¹³ ,, 12, 18

-CONR ¹² (CH 2) cOCi_4alkyl, CONR ¹² (CH 2) _a CO ₂ R ^18, CONHNR ¹⁹ R ^20, CONR ¹² SO 2 R ^21, CO 2 R ^22, cyano, a trifluoromethyl, NR ⁷ R ^8, NR ⁷ COR ^9, NR ²³ CO (CH 2) a NR ²³ R ²⁴ , NR ²³ CONR ²³ R ²⁴ , NR ⁷ CO ² R ¹⁰ , NR ⁷ SO ² R ¹¹ , N = CNR ²³ NR ²³ R ²⁴ , nitro, C 1 -C 6 alkoxy substituted with hydroxy, C 1 -C 6 alkoxy (C 1 -C 6) -substituted alkoxy, OC (O) NR ²⁵ R ²⁶ , SR ²⁷ , SO ₂ R ²⁸ , SO ₂ NR ²⁵ R ²⁶ or halogen, and is 1, 2, 3 or 4,

R ⁷ and R ⁸ independently of one another are hydrogen or alkyl having 1 to 6 carbon atoms or NR ⁷ R ⁸ form a 5 or 6 membered heterocyclic ring which may be optionally substituted by oxo and if the ring is 6-membered, the ring may optionally contain one oxygen or sulfur atom,

R is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyalkyl group having 1 to 4 carbon atoms,

R ¹⁰ is an alkyl group having 1 to 6 carbon atoms,

R ¹¹ is C 1 -C 6 alkyl or phenyl,

R ¹² and R ¹³ are each independently hydrogen or C 1 -C 6 alkyl, or NR ¹² R ¹³ forms a saturated heterocyclic ring having 5 or 6 members; if the ring is 6-membered, the ring may optionally contain one atom oxygen or sulfur,

«9 9999

9 * 9

9 9 · 9 9 »··

9 ♦ 9 ·

9 9 9

9 9 ♦

9 ♦ · ·

9 · 9

99b is 0, 1, 2 or 3

R ¹⁴ is C 1 -C 4 alkyl optionally substituted with C 1 -C 6 alkoxy,

R ( ¹⁵⁾ and R ( ¹⁶⁾ independently of one another are hydrogen or alkyl having 1 to 6 carbon atoms,

R ( ¹⁷⁾ is hydrogen or (C1-C6) -alkyl, c is 1, 2 or 3,

R ¹⁸ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ¹⁹ and R ²⁰ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms,

R ²¹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ²² is hydrogen or C 1 -C 6 alkyl optionally substituted by one or two substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy or NR ⁷ R ⁸ ,

R ( ²³⁾ and R ( ²⁴⁾ independently of one another are hydrogen or alkyl having 1 to 6 carbon atoms,

R ²⁵ and R ²⁶ independently of one another are hydrogen or C 1 -C 6 alkyl, or NR ²⁵ R ²⁶ forms a saturated heterocyclic ring having 5 or 6 members which, if the members are 6, may optionally contain one atom in the ring oxygen or sulfur atom,

R ²⁷ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

- 11 is an alkyl group having 1 to 6 carbon atoms, fr 0 0 0 * 0

R '

P is a 5 to 7 membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur,

R ³ and R ⁴ are each independently hydrogen, (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl, (C 3 -C 6) cycloalkenyl, (C 1 -C 6) alkyl substituted with hydroxy ,

C _1-6 alkylOC _1-6 alkyl, CONR ²⁹ R ³⁰ , CO ₂ R ³¹ , cyano, aryl, trifluoromethyl, NR ²⁹ R ³⁰ , nitro, acyloxy or halogen,

R ( ³⁰⁾ and R ( ³¹⁾ independently of one another are hydrogen or alkyl having 1 to 6 carbon atoms,

R c is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen,

R c is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl (optionally substituted with hydroxy or oxo), C 1 -C 6 alkyl substituted with hydroxy, C 3 -C 6 alkenyl atoms unsubstitued hydroxy, alkynyl of 3-6 carbon atoms unsubstitued hydroxy, (CH ₂₎ DOR ^32, (CH2) dcor ³³ (CH 2) _d CR ³⁴ = NOR ^35, CONR ³⁶ R ^37, CO ₂ R ^38, hydroxy, O (CH ₂ ) _e R ³⁹ , NR ³⁶ R ³⁷ , SR ⁴ is halogen, d is 0, 1, 2, 3, 4, 5 or 6,

SO ₂ NR ⁴¹ R ⁴² or · «φ φ φ φ φ φ φ φ φ φ φ φ

Φ Φ 6

Φ Φ

Φ Φ

R ³² is C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with hydroxy or C 1 -C 4 alkanoyl,

R ³³ is a hydrogen atom or an alkyl group containing 1 to β carbon atoms,

R ³⁴ is hydrogen or C 1 -C 6 alkyl

R ³⁵ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms

R ( ³⁶⁾ and R ( ³⁷⁾ independently of one another are hydrogen or alkyl having 1 to 6 carbon atoms, or NR ( ^{36) R37} forms a saturated heterocyclic ring having 5 or 6 members which may be optionally substituted by oxo and in the case of 6 optionally contain one oxygen atom, a sulfur atom, or an NH or NR ⁴³ group wherein R ⁴³ is an alkyl group having 1 to 6 carbon atoms, COR ⁴⁴ or CO ₂ R ⁴⁵ wherein R ⁴⁴ and R ⁴⁵ are independently hydrogen or (C 1 -C 6) -alkyl;

R ³⁸ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, e having a value of 1, 2, 3, 4, 5 or 6,

R ³⁹ is C 1 -C 6 alkoxy, CO ₂ H,

COsCx-alkyl or CONR ³⁶ R ³⁷ ,

R ( ⁴⁰⁾ is hydrogen or (C1-C6) -alkyl,

R ⁴¹ and R ⁴² are, independently of one another, a hydrogen atom or an alkyl group containing from 1 to 6 carbon atoms, which is a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms. Or R ⁵ and R ⁵ form a fused benzene ring optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen when Ar is (i), (ii) or (iii) and A is CONR ⁴⁶ , NHCO, -NHCH 2 or CH 2 NH, wherein R ⁴⁶ is hydrogen or C 1 -C 6 alkyl is E (a):

where

R ( ⁴⁷⁾ and R ( ⁴⁸⁾ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms,

R ⁴⁹ is hydrogen, C 1 -C 6 alkyl, CO ₂ R ⁵³ , NHCO ₂ R ⁵⁴ , hydroxy, C 1 -C 6 alkoxy, or halogen wherein R ⁵³ is hydrogen or C 1 -C 6 alkyl carbon,

R ⁵⁰ and R ⁵¹ are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 6- a membered heterocyclic ring containing one to two heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,

B is O, S (O) h wherein h is 0, 1 or 2, CR ⁵⁵ R ⁵⁶ wherein R ⁵⁵ and R ⁵⁶ are independently hydrogen or C 1 -C 6 alkyl, or B is NR ⁵⁷ wherein R ⁵⁷ is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl with a substituted phenyl group,

R ⁵² is hydrogen or R ⁵² together with R ⁴⁶ form a group D, wherein D is (CR ⁵⁸ R ⁵⁹ ) 1, wherein i is 2, 3 or 4 and

R ⁵⁸ and R ⁵⁹ independently of one another are hydrogen or C 1 -C 6 alkyl, or is D (CR ⁵⁸ R ⁵⁹ ) j where j is 0, 1, 2 or 3 and G is oxygen, sulfur or CR ⁵⁸ = CR ⁵⁹ , f has a value of 1 to 4 and g has a value of 1 or 2 if Ar is (i), (ii) or (iii) and A is CONR ⁶⁰ , NHCO or CH ₂ NH in which R ⁶⁰ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, represented by E (b):

R ⁶¹ is hydrogen, C 1 -C 6 alkyl or R ⁶¹ and R ⁶⁰ together form a -K- group, where K is (CR ⁶⁵ R ⁶⁶ ) m in which m is 2, 3 or 4 and R ⁵⁵ and R ⁶⁶ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms, or K (CR ⁶⁵ R ⁶⁶ ) is nL, where n is 0, 1, 2 or 3 and L is an oxygen atom, a sulfur atom or CR ⁶⁵ = CR ⁶⁶

R ⁶² is hydrogen or C 1 -C 6 alkyl, _R 63 _{and R} 64 _are independently H or C 1 -C 6 alkyl,

- 15 J is oxygen, CR ⁶⁷ R ⁶⁸ or NR ⁶⁹ , wherein R ⁶⁷ , R ⁶⁸ and R ⁵⁹ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms or J is S (O) _m where m has a value of 0, 1 or 2, k has a value of 1, 2 or 3, has a value of 1, 2 or 3 when Ar is (i), (ii) or (iii) and A is CONR ⁷⁰ , NHCO, -NHCH ₂ or CH ₂ NH where R is hydrogen or C 1 -C 6 alkyl represents E (c):

R ⁷⁴ in which:

M is an oxygen atom, S (O) _P in which p has a value of 0, 1 or 2, CR ⁷⁶ = CR ⁷⁷ or CR ⁷⁶ R ⁷⁷ where R ⁷⁶ and R ⁷⁷ are independently hydrogen or an alkyl group containing 1 to β or M is NR ⁷⁸ wherein R ⁷⁸ is hydrogen or alkyl,

R ( ⁷¹⁾ and R ( ⁷²⁾ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms,

R ⁷³ is hydrogen, C 1 -C 6 alkyl, CO 2 R ⁷⁹ , NHCO 2 R ⁸⁰ , hydroxy, C 1 -C 6 alkoxy or halogen wherein R ⁷⁹ is hydrogen or C 1 -C 6 alkyl and R ⁸⁰ is an alkyl group containing 1 to β carbon atoms,

R ⁷⁴ is hydrogen or together with R ⁷⁰ forms a group Q, wherein Q is CR ⁸¹ = CR ⁸² , CR ⁸¹ = CR ⁸² CR ⁸¹ R ⁸² or (CR ⁸¹ R ⁸² ) _q wherein q has a value of 2 or 3 and R ⁸¹ and R ⁸² are, independently of one another, hydrogen or C 1 -C 6 alkyl, n

O

R ⁷⁵ is 0, 1, 2 or 3, is 1 or 2, is a group of formula (d):

(CH ₂ ) _f (CH ₂ ) _s (CH ₂ ), (d) where r, sat are independent integers having values of 1, 2 or 3, or is

R ⁷⁵ group of formula (e):

wherein u is an alkyl group

containing 1 to 6 carbon atoms when Ar is (i), (ii) or (iii; or CH ₂ NH) represents E (f):

and A is CONH, NHCO, W - (CR ^ RW ^ -NR ^8s R 37 w // - o • T-

(F)

R ( ⁸⁴⁾ and R ( ⁸⁵⁾ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms, r86 _and 87 _are independently of one another hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, an aralkyl group, or form together with the nitrogen atom to which they are

An optionally substituted 5- to 7-membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur;

T is (CR ⁸⁸ R ⁸⁹ ) W- or -O (CR a ⁸ R ⁸⁹ ) x - wherein R ⁸⁸ and R ⁸⁹ are independently hydrogen or C 1 -C 6 alkyl, w is 2 or 3 and x is 1, 2 or 3, v is 1 to 4 and

W is O, S (O) _y wherein y is 0, 1 or 2, or W is NR ⁹⁰ wherein R ⁹⁰ is hydrogen or C 1 -C 6 alkyl, or W is CR ⁹¹ = CR ⁹² or CR ⁹¹ R ⁹² wherein R ⁹¹ and R ⁹² are independently hydrogen or C 1 -C 6 alkyl when Ar is (i), (ii) or (iii) and A is CONR ⁹³ , NHCO or CH ₂ NH in which R ⁹³ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms represents an E group (g):

(G)

R ⁹⁴ is hydrogen, halogen, hydroxy, (C 1 -C 6) alkyl or (C 1 -C 6) alkoxy, or R ⁹⁴ and R ⁹³ together form -X-, where X is (CR ⁹⁷ R ⁹⁸ ) aa wherein aa is 2, 3 or 4 and R ⁹⁷ and R ⁹⁸ are independently hydrogen or C 1 -C 6 alkyl or X is (CR ⁹⁷ R ⁹⁸ ) a) 3-Y, wherein ab is 0 , 1, 2 or 3 and Y is O, S or CR = CR,

R ⁹⁵ is hydrogen, C 1 -C 6 alkyl, CO ₂ R ⁹⁹ , NHCO ₂ R ¹⁰⁰ , hydroxy;

• · ♦ 0 0 0

0 0 0 0 0

000000 · 0 · 0 0 0 0

An alkoxy group having 1 to 6 carbon atoms or a halogen group, wherein R ⁹⁵ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms and R ¹⁰⁰ is an alkyl group having 1 to 6 carbon atoms, z is 1 or 2;

R ⁹⁶ is an optionally substituted, 5- to 7-membered saturated or partially saturated heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, or R ⁹⁶ is an optionally substituted 6,6 or 6,5 bicyclic ring containing a nitrogen atom and optionally another heteroatom selected from the group consisting of nitrogen, oxygen or sulfur when Ar is (i), (ii) or (iii) and A is CONR ¹⁰¹ , NHCO or CH 2 NH in which R ¹⁰¹ is an atom hydrogen or an alkyl group having 1 to 6 carbon atoms, represents an E group (h):

(CR103R104) - _NR 105R106

R1Q2 (h)

R ¹⁰² is hydrogen or C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen, or R ¹⁰² together with R ¹⁰¹ forms a -AA- group where AA is (CR ¹⁰⁷ R ¹⁰⁸ ) ad and wherein and d is 1, 2 or 3 and R ¹⁰⁷ and R ¹⁰⁸ are independently hydrogen or C 1 -C 6 alkyl or AA is (CR ¹⁰⁷ = CR ¹⁰⁸ ) ae-AB where ae is 0, 1 or 2 and AB is oxygen, sulfur, CR ¹⁰⁷ = CR ^108, CR ¹⁰⁷ = N, CR, NR ¹⁰² or N = ¹⁰⁸ N

• »β

R ( ¹⁰⁾ and R ( ¹⁰⁴⁾ independently of one another are hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms,

R ¹⁰⁵ and R ¹⁰⁶ are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aralkyl, or form, together with the nitrogen atom to which they are attached an optionally substituted 5- to 7-membered member a heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulfur, and c is 0 to 4,

Z is an optionally substituted, 5- to 7-membered heterocyclic ring containing one to three heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur when Ar is (i), (ii) or (iii) and A is CONR ¹⁰⁹ , NHCO or CH ₂ NH, in which R ¹⁰⁹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, represents an E group (i):

^Uo R is hydrogen or alkyl having 1 to 6 carbon atoms or R ¹¹⁰ and R ¹⁰⁹ together form a group AD- where AD is (CR ¹¹⁵ R _{^116), and} h, where h is 2, 3 or 4 and R ¹¹⁵ and R ¹¹⁵ are each independently hydrogen or C 1 -C 6 alkyl or AD is (CR ¹¹⁵ R ¹¹⁶ ) ai-AE where ai is 0, 1, 2 or 3 and AE is oxygen, atom sulfur or CR ¹¹⁵ = CR ^116, • • · · · · · · · · · · · _e · 9 9 9 9 ·· ♦ ♦ · · · ·· he ······· * · · ·

J (J ·· ·· ···········

R ¹¹¹ and R ¹¹² independently of one another are hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aralkyl or, together with the nitrogen atom to which they are attached an optionally substituted 5- to 7-membered a heterocyclic ring containing one or two heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,

R ( ¹¹³⁾ and R ( ¹¹⁴⁾ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms,

AC is O, CR ¹¹⁷ R ¹¹⁸ or NR ¹¹⁹ , wherein R ¹¹⁷ , R ¹¹⁸ and R ¹¹⁹ are independently hydrogen or C 1 -C 6 alkyl, or AC is S (O) in which i 0, 1, or 2

af has a value 1, 2 or 3 ag has a value 1, 2, 3 or 4 a ah has a value 0, 1, 2, 3 or 4. Suitably, when Ar is (i) or (ii), it may be terminal

the phenyl group at (i) and (ii) attached to the phenyl group bearing group A at any position. Preferably, the terminal phenyl ring is attached to the phenyl bearing group A at the meta or para position to the group A, more preferably at the para position to the group A.

Suitably, P is a 5- to 7- membered heterocyclic ring containing 1 to 4 heteroatoms 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, heterocyclic rings may be attached

9 9 9

9 · 9

9 9 9

9 9 9

99

9 9999

9

9 9 · ·

9 9

9 <

to the rest of the molecule via a carbon atom or, if present, via a nitrogen atom. P is preferably oxadiazolyl.

Suitably, when Ar is (iii), R ⁶ may be attached to the phenyl ring at any position. Preferably, R ^{6 is} attached at the meta or para position relative to group A.

Suitably, R ¹ and R ^{2 are each} independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, aryl alkyl, (CH ₂₎ m NR ⁷ R ^8, (CH 2) a NR ⁷ COR ^9, (CH ₂₎ m NR ⁷ CO 2 R ^10, (CH ₂₎ m NR ⁷ SO ₂ R ^u, (CH _{2) a} CONR ¹² R ^13, (C 1 -C 6) alkyl substituted by hydroxy, (C 1 -C 4) alkyl substituted by alkoxy (optionally substituted by C 1 -C 4 alkoxy or hydroxy), (CH ₂ ) CO ₂ C ₁ . ₆ alkyl, (CH ₂ ) _b OC (O) R ¹⁴ , CR ¹⁵ = NOR ¹⁶ , CNR ¹⁵ = NOR ¹⁶ ,

COR ^17, CONR ¹² R ^13, CONR ¹² (CH 2) COCl-4alkyl, CONR ¹² (CH ₂₎ C0 ₂ R ^18, CONHNR ¹⁹ R ^20, CONR ¹² SO 2 R ^21, CO 2 R ^22, cyano, trifluoromethyl, NR ⁷ R ⁸ NR ⁷ R ⁸ NR ⁷ COR ⁹

NR ²³ CO (CH 2) a NR ²³ R ²⁴ , NR ²³ CO ²³ R ²⁴ , NR ⁷ CO ₂ R ¹⁰ , NR ⁷ SO ₂ R ⁿ ,

N = CNR ²³ NR ²³ R ²⁴ , nitro, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy (0) NR ²⁵ R ^26, SR ^27, SOR ^28, SO 2 R ^28, SO 2 NR ²⁵ R ²⁶ or halogen group. Preferably at least one of R ¹ or R ^{2 is} independently hydrogen, C 1 -C 6 alkyl, preferably methyl, C 1 -C 6 alkoxy, preferably methoxy, preferably in the third position, hydroxy , ·· * · · · ·· ·· ·· _"w" ··· 9 · 9 ·

9 9 9 · 9 ·· · «« * * * * *

OO, preferably in the third position, cyano, preferably in the fourth position and (CH ₂ ) t> OC (0) R ¹⁴ , wherein b is preferably 0, and R ¹⁴ is preferably ethyl.

Suitably, R ³ and R ^{4 are each} independently hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 8 cycloalkenyl, C 1 -C 6 alkyl hydroxy, C 1-6 alkylOC 1-6 alkyl, CONR ²⁹ R ³⁰ , CO ² R ³¹ , cyano, aryl, trifluoromethyl, NR ²⁹ R ³⁰ , nitro, hydroxy, C 1 -C 6 alkoxy, acyloxy or halogen. R ³ is preferably a hydrogen atom and an alkyl group having 1 to 6 carbon atoms, more preferably a methyl group. R ⁴ -P is preferably CH ₃ oxadiazolyl.

Suitably, R ⁶ is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl (optionally substituted with hydroxy or oxo), C 1 -C 6 alkyl substituted with hydroxy, C 3 -C 6 alkenyl carbon atoms unsubstitued hydroxy, alkynyl of 3-6 carbon atoms unsubstitued hydroxy, (CH ₂₎ DOR ^32, (CH2) dcor ³³ (CH 2) _d CR ³⁴ = NOR ^35, CONR ³⁶ R ^37, CO ₂ R ³⁸ , hydroxy, O (CH ₂ ) _e R ³⁹ , NR ³⁶ R ³⁷ , SR ⁴⁰ , SO ₂ NR ⁴¹ R ⁴² or a halogen group. R ⁶ is preferably a cycloalkyl group having 3 to 7 carbon atoms, more preferably cyclohexyl or a halogen group, even more preferably iodine.

R ⁷ and R ⁸ are preferably, independently of one another, a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

4444 • 4444 4 • · 4 • 4 4 • · 4 o O 4 4 4 4 “Zj” 44 44

R ⁹ is preferably a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ^u is preferably an alkyl group having 1 to 6 carbon atoms,

R ¹² and R ¹³ are preferably, independently of one another, a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ¹⁴ is preferably an alkyl group having 1 to 6 carbon atoms,

R ²² is preferably a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ²⁵ and R ²⁶ are preferably, independently of one another, a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

E is suitably described by (a). When E is described by (a), the -B (CR ⁴⁷ R ⁴⁸ ) f-NR ⁵⁰ R ⁵¹ and R ⁴⁹ groups can be attached to the phenyl ring at any position. The group -B (CR ⁴⁷ R ⁴⁸ ) _f -NR ⁵⁰ R ⁵¹ is preferably located at the meta or para position relative to the amide bond site, more preferably at the meta position. Preferably, the R ⁴⁹ group is located in the para position relative to the amide bond site. The group R ⁴⁹ is preferably an alkoxy group, more preferably a methoxy group or a halogen group, even more preferably an iodine atom. B is preferably an oxygen atom or CR ⁵⁵ R ⁵⁶ . Preferably f is 2 or 3. R ⁵⁰ and R ⁵¹ are suitably C 1 -C 6 alkyl, preferably isopropyl or tert-butyl, C 3 -C 7 cycloalkyl, preferably cyclohexyl, or taken together with a nitrogen atom to which a 5- to 7-membered heterocyclic ring is attached.

Preferred compounds of formula (I) are those wherein E is (a) and wherein B is oxygen, CR ⁵⁵ R ⁵⁶ is

CH ₂ and f is 2 and where B is O, CR ⁵⁵ R ⁵⁶ is CH ₂

99 9 9

9

9

99 ·· · 9 9 9

9 9 9 9 • · «·· and · 9 9 9

9 9 19

9

9

Particularly preferred is a compound of formula (I) wherein B is oxygen, CR ⁵⁵ R ⁵⁵ is CH ₂ and f is 2. R ⁵² is preferably hydrogen.

Other preferred compounds of formula (I) are those wherein e is (a) and preferably R ⁵⁰ and R ⁵¹ are isopropyl, R ⁵⁰ is isopropyl and R ⁵¹ is tert-butyl or cyclohexyl, or NR ⁵⁰ R ⁵¹ is 2, 2,6,6, -tetramethylpiperidine. More preferably, R ⁵⁰ and R ^{51 are} isopropyl, R ⁵⁰ is isopropyl and R ⁵¹ is tert-butyl, or NR ⁵⁰ R ⁵¹ is 2,2,6,6-tetramethylpiperidine. Preferably R ^{49 is} methoxy.

When E represents (b), k is preferably 1, J is preferably oxygen and R ⁶² is preferably C 1 -C 6 alkyl, more preferably methyl or isopropyl.

When E is (c), n is preferably 1, M is preferably oxygen, R ⁷¹ and R ⁷² are preferably hydrogen, R ⁷³ is preferably alkoxy substituted in the para position, more preferably para-OCH ₃ , R ⁷⁴ is preferably hydrogen and R ⁷⁵ is preferably a group of formula (e) wherein u is 2 and R ⁸³ is preferably an alkyl group having 1 to 6 carbon atoms, more preferably a methyl group.

The term "C _1-6 alkyl" or "C _1-6 alkyl" as used herein in all instances refers to a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is specifically limited, but includes, but is not limited to without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and the like.

The term "halogen" or "halogen group" is used interchangeably herein to refer to radicals derived from elements including chlorine, fluorine, iodine and bromine in all occurrences.

The terms &quot; cycloalkyl &quot; or &quot; cycloalkyl &quot; and &quot; cyclic alkyl &quot; are used herein to refer to cyclic radicals, preferably of 3 to 7 carbon atoms, which may be mono- or bicyclic fused systems which may additionally include, but are not limited to, unsaturated moieties, cyclopropyl, cyclopentyl, cyclohexyl,

1,2,3,4, -tetrahydro-naphthyl and the like.

The term &quot; alkenyl &quot; or &quot; alkenyl &quot; is used herein to refer to a straight or branched radical containing from 2 to 6 carbon atoms in all occurrences, unless the chain length is particularly limited and contains at least one double bond between carbon atoms in the chain, including but not limited to, ethenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

The term "cycloalkenyl" or "cycloalkenyl" is used herein to refer to cyclic radicals, preferably containing from 5 to 8 carbons, containing at least one double bond between two carbon atoms in the ring, including but not limited to cyclic radicals. cyclopentenyl, cyclohexenyl and the like,

The term &quot; alkynyl &quot; or &quot; alkynyl &quot; is used herein to refer to a straight or branched radical containing from 2 to 8 carbon atoms in all occurrences unless the chain length is particularly limited and contains at least one triple bond between two carbon atoms in the chain, including, but not limited to, acetylene, 1propine, 2-propyne, and the like.

Í 99 99 · 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 · 9 9 9 9

The term "aryl" or as used herein to refer to all 5 to 14 membered substituted or unsubstituted aromatic ring system (s), which may include bi- or tricyclic systems , including, but not limited to, phenyl, naphthyl, and the like.

The term "aralkyl" is used herein to refer to an aryl radical as defined above which is attached to an alkyl radical as defined above, for example benzyl or phenethyl, and the like, at all occurrences.

The term "alkoxy" or "alkoxy" is used herein to refer to a straight or branched radical containing from 1 to 6 carbon atoms in all occurrences, unless the length of the chain separately attached to the oxygen atom, including but not limited to, methoxy, is not limited. , ethoxy, n-propoxy, isopropoxy and the like.

The terms "C 1 -C 6 alkyl substituted with hydroxy" or "hydroxyalkyl" are used interchangeably herein to refer to a hydroxyl group attached to an alkyl group having 1 to 6 carbon atoms as defined above, including but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, and the like.

The term &quot; alkoxyalkyl &quot; or &quot; C1-C4-substituted alkyl &quot; is used interchangeably herein to refer to C1-C4alkoxy as defined above attached to an &quot; alkyl group &quot; · ·

- 27 as defined above, such as an ether, for example CH ₃ -CH ₂ -OCH ₂ -CH ₂ -CH ₃ .

The term "C 1 -C 6 alkoxy substituted with hydroxy" is used herein to refer to an hydroxyl group attached to an alkoxy group as defined above, for example, in all instances, e.g.

HO-CH ₂ -CH (OH) CH _third

The term "C 1 -C 6 alkoxy with a substituted C 1 -C 6 alkoxy" is used herein to refer to an alkoxy group, as defined above, substituted to an alkoxy group, as defined above, at all occurrences.

The term "acyloxy" is used herein to refer to the radical -O-C (O) -R where R is hydrogen or C 1 -C 6 alkyl.

The term "C 1 -C 4 alkanoyl" is used herein to refer to the C (O) C 1-4 alkyl group wherein the alkyl moiety is as defined above.

The term "heteroatom" is used herein to refer to an oxygen atom, a sulfur atom or a nitrogen atom in all instances. It will be recognized that when the heteroatom is nitrogen, it may form a radical -NR _a R _b wherein R _a and R _b are independently hydrogen or alkyl of 1 to 6 carbon atoms or may, together with the nitrogen atom to which they are attached form a saturated or unsaturated 5-, 6- or

7-membered ring including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, pyridine and the like. It will be recognized that saturated or unsaturated 5-, three-dimensional or unsaturated.

The 6- or 7-membered ring may optionally have one or more additional heteroatoms in the ring.

The term "heterocyclic" is used herein to refer to a saturated or fully optionally unsaturated 5 to 10 membered ring system (unless the ring system is otherwise limited) in which one or more rings contain one or more heteroatoms, including but not limited to only to them, pyrrolidine, piperidine, piperazine, morpholine, imidazoline, pyrazolidine and the like.

The term "CCR5 mediated disease state" is used herein to refer to any disease state that is mediated (or modulated) by CCR5 in all instances.

Pharmaceutically acceptable salts of formula (I) suitably include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate, or salts with organic acids such as malat, maleat, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, ptoluenesulfonate, palmitate, salicylate and stearate.

Preferred compounds of the invention are the following:

N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -2'-methyl-4'- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4-carboxamide

N- [3- (2-methylamino) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4-carboxamide • 0 0 0 0 β 0 0 0

0 0 ·

0 0 0 0 0

Ν- [3- (2-Amino) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4- carboxamide

N- [3- (2-dimethylamino-1-methyl) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-) biphenyl) 4-carboxamide

3- (2-Dimethylaminoethoxy) -4-methoxy-N- [2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl)] - 4-benzamide oxalate

N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -2 'methyl-4' - (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) - oxalate - 4carboxamide

N- [3- (2-dimethylaminoethoxy) -4-methoxyphenyl] -4'- (5-ethyl-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4-carboxamide

N- [3- (2-1-pyrrolidinylethoxy) -4-methoxyphenyl] -4 '- (5-methyl-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4-carboxamide

N-3- (2-dimethylamino) ethoxy-4-methoxyphenyl-2'-ethyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) (1,1'-biphenyl) -4-carboxamide hydrochloride

N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -2 ', 3-dimethyl-4' - (5-methyl-1,2,4-3-oxadiazolyl) -1,1'-biphenyl-4-carboxamide hydrochloride

N- {3 - [(S) -1-methylpyrrolidin-2-ylmethoxy] -4-methoxyphenyl] -4 '- (5-methyl-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4- carboxamide

N- [3- (1-methyl-3-piperidinyloxy) -4-methoxyphenyl] -4 '- (5-methyl-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4-carboxamide oxalate · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

4- [3- (1-Methyl-3-azepinyloxy) -4-methoxyphenyl] 4 '- (5-methyl-1,2,4-3-oxadiazolyl) -2'-methyl-biphenyl-4-carboxamide oxalate

N- [4-methoxy-3- (quinuclidinyloxy) phenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) biphenyl-4-carboxamide oxalate

N- {3 - [(R) -1-methylpyrrolidin-2-ylmethoxy] -4-methoxyphenyl} -4 '- (5-methyl-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4-carboxamide

N- [3- (1-methyl-3-pyrrolidinyl) -4-methoxyphenyl] -4 '- (5-methyl-1,2,4-3-oxadiazolyl) -2'-methyl-biphenyl-4-carboxamide

N- {3 - [(R) -pyrrolidin-2-ylmethoxy] -4-methoxyphenyl} -4 '- (5-methyl-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4-carboxamide

N- [3- (azetidin-2-ylmethoxy) -4-methoxyphenyl] -4 '- (5-methyl-1,2,4-3-oxadiazolyl) -2' methylbiphenyl-4-carboxamide hydrochloride

N- [2- (dimethylaminomethyl) 1,4-benzo-7-dioxanyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) -biphenyl-4-carboxamide

N- [2- (dimethylaminomethyl) 1,4-benzo-6-dioxanyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) -biphenyl-4-carboxamide

2,3-Dihydro-6- (dimethylaminoethoxy) -5-methoxy-1- {4- [2-methyl-4- (5-methyl-1,2,4-3-oxadiazolyl) phenyl] benzoyl} indole

6- (2-Dimethylaminoethoxy) -5-methoxy-1- {4- [2-methyl-4- (5-methyl-1,2,4-3-oxadiazolyl) phenyl] benzoyl} indole

00000 0 0

2,3-Dihydro-6- (2-dimethylaminoethoxy) -5-methoxy-2-methyl-1- {4- [2-methyl-4- (5-methyl-1,2,4-3-oxadiazolyl) phenyl] benzoyl} oxalate indole

6- (2-Dimethylaminoethoxy) -5-methoxy-2-methyl-1- {4- [2-methyl-4- (5-methyl-1,2,4-3-oxadiazolyl) phenyl] benzoyl} indole oxalate

[7- (2-Dimethylaminoethoxy) -6-methoxy-2-methyl-3,4-dihydro-2H-1-quinolinyl] [2'-methyl-4 '- (5-methyl-1,2,43-oxadiazolyl) oxalate -4-biphenylyl] methanone

[8- (2-Dimethylaminoethoxy) -7-methoxy-2,3,4,5-tetrahydro-1H-benz [b] -1-azepinyl] - [2'-methyl-4 '- (5-methyl-1,2), 4-3-Oxadiazolyl) -4-biphenylyl] methanone

5- (4- [2-Methyl-4- (5-methyl-1,2,4-oxadiazolyl) phenyl] benzoylamino} spiro [(2,3-dihydrobenzofuran) 3,4-piperidine hydrochloride]

2,3,6,7-tetrahydro-1'-methyl-5- [2'methyl-4- (5-methyl-1,2,4-3-oxadiazolyl) biphenyl-4-carbonyl] furo [2,3- f] indole-3-spiro-4'-piperidine]

5- [4 '- (5-dimethylamino-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4-carbonyl] -1'-methyl-2,3,5,6,7,8-hexahydrospiro hydrochloride 2,3-g] quinoline-3,4 'piperidine)

5- [4 '- (5-hydroxymethyl-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4-carbonyl] -1'-methyl-2,3,6,7-tetrahydrospiro hydrochloride [2,3- f] indole-3,4'-piperidine)

5- [4 '- (5-methoxymethyl-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4-carbonyl] -1'-methyl-2,3,6,7-tetrahydrospiro hydrochloride [2,3- f] indole-3,4'-piperidine)

0 1

0 <

0 00

4'-ax- (dimethylamino-5- {2'-methyl-4 '- [(5-methyl-1,2,4-3-oxadiazolyl) -4-biphenylyl] carbonyl} -2,3,6,7-tetrahydroospiro hydrochloride furo [2,3-f] indole-3,1'-cyclohexane)

N- [3- (2-dimethylamino) ethoxyphenyl] - [1,1'-biphenyl] -4-carboxamide

N- [4- (2-dimethylamino) ethoxyphenyl] - [1,1'-biphenyl] -4-carboxamide

N- [2- (3-dimethylamino) propoxyphenyl] - [1,1'-biphenyl] -4-carboxamide

N- [3- (2-1-morpholinyl) ethoxy-4-methoxyphenyl] - [1,1'-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-1,2,4,3-oxadiazolyl) (1,1'-biphenyl) ) -4-carboxamide

N-methyl-N- [3- (diisopropylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4-benzamide

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3-bromobenzamide

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4 (methoxy) benzamide

N- [4- (2-diisopropylamino) ethoxyphenyl] -4-iodobenzamide

N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -3j-benzamide

. 4 9 4 9

994 4,444

4 4 9

44

4 9

4 9

4 4

4 4 4

94

N- [3- (2-diisopropylamino) ethoxyphenyl] -3-iodobenzamide

N- [3- (2-diethylamino) ethoxyphenyl] -3-iodobenzamide

N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4-bromobenzamide

N- [4- (2-diisopropylamino) ethoxyphenyl] -4-bromobenzamide

N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -3-bromobenzamide

N- [4- (2-diisopropylamino) ethoxyphenyl] -4- (isopropyl) benzamide

N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4 (cyclohexyl) benzamide

N- [4- (2-diethylamino) ethoxyphenyl] -4 (cyclohexyl) benzamide

N- [4- (2-diisopropylamino) ethoxyphenyl] -4'-ethyl- (1,1'biphenyl) -4-carboxamide

N- [4- (2-diethylamino) ethoxyphenyl] -4'-ethyl- (1,1'-biphenyl) -4-carboxamide

N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -4 'methoxy- (1,1'-biphenyl) -4-carboxamide

N- [3- (2-dimethylamino) ethoxy-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-benzo-7-dioxanyl] -2'-methyl-4 '- (5-methyl-1,2,4,3-oxadiazolyl) biphenyl-4-carboxamide;

9 9 9 9 9 9 9 9 · · · 9 9 9 9 9 ·

9,999 9999999 99 9

9 9 9 9 9 9 9 9 9

9 9 9 99

Ν- [2- (dimethylaminomethyl) -1,4-benzo-6-dioxanyl] -2 'methyl-4' - (5-methyl-1,2,4,3-oxadiazolyl) biphenyl-4-carboxamide

More preferred compounds of the invention are the following:

N- [3- (3-dimethylamino) propoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4-carboxamide

N- [3- (2-piperidin) ethoxy-4-methoxyphenyl] -2'-methyl-4 '(5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4 -carboxamide

N- [3- (3-dimethylaminopropyl) -4-methoxyphenyl] 2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) -biphenyl-4-carboxamide oxalate

N- [3- (1-methyl-4-piperidyl) -4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) -biphenyl-4-carboxamide oxalate

N- [3- (1-methyl-3-piperidyl) methoxyphenyl] -2'-methyl-4'- (5-methyl-1,2,4-3-oxadiazolyl) biphenyl-4-carboxamide oxalate

N- [7- (2-dimethylamino) ethoxy-2,3-dihydro-5-benzofuranyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) biphenyl-4-carboxamide

[3- (dimethylaminomethyl) -3,6,7,8-tetrahydro-2H-furo (2,3-g) -5-quinolinyl] - {2'-methyl-4 '- [5-methyl- (1,2) -oxalate oxalate 4) 3-oxadiazolyl] -4-biphenylyl} -methanone

5- {4- [2-Methyl-4- (5-methyl-1,2,4-3-oxadiazolyl) phenyl] benzoylamino} -spiro [2,3-dihydro-benzofuran] -3,4 '(1) oxalate -methylhexahydroazepine)] φ φ φ φ φ φφ φφφ

Φ Φ • · • • • • φ φ φ φ φ φ

2,3,5,6,7,8-Hexahydro-1'-methyl-5- {2'-methyl-4 '- [(5-methyl-1,2,4,3-oxadiazolyl) -4-biphenylyl oxalate Carbonyl} furo (2,3-g) quinoline-3-spiro-4'-piperidine

6,7,8,9-tetrahydro-1'-methyl-5 - {[2'-methyl-4'-5 (methyl-1,2,4,3-oxadiazolyl) (1,1'-4-biphenylyl)] carbonyl} spiro [2H-furo (2,3-h) (1) benzazepine-3- (5H), 4'-piperidine]

2,3,5,6,7,8-Hexahydro-5- [4'- (5-hydroxymethyl-1,2,4,3-oxadiazolyl) -2'-methylbiphenyl-4-carbonyl] -1'-methylspiro [furo] hydrochloride (2,3-g) quinoline-3,4'-piperidine]

4 '- (Dimethylamino) -5- {2'-methyl-4' - [(5-methyl-1,2,4,3-oxadiazolyl) -4-biphenylyl] carbonyl} 2,3,6,7-tetrahydro-spiro [furo] hydrochloride (2,3-f) Indole-3,1'-cyclohexane]

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -3-carboxamide

N- [3- (3-dimethylamino) propoxyphenyl] - (1,1'-biphenyl) -4-carboxamide

N- [4- (3-dimethylamino) propoxyphenyl] - (1,1'-biphenyl) -4-carboxamide

N- [3- (diethylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide

N- {3- [2- (1-piperidinyl) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide

N- [3- (2-diisopropylamino) ethoxy-2-methylphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4-carboxamide

N- [3- (2-dipropylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide • 0 0

0

0 • 0

00

0000

0

0 0 0 0 0 0 0

0 0 0 0000 0 0

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) ethoxyphenyl] - (1,1'-biphenyl) 4-carboxamide

N- [2-fluoro-4- (2-diisopropylamino) ethoxyphenyl] - (1,1'-biphenyl) -4-carboxamide

N- [4- (2-diisopropylamino) ethoxyphenyl] - (1,1'-biphenyl) 4-carboxamide

N- [2- (2-diisopropylamino) ethoxyphenyl] - (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 ·

• 9 · 9

9 9 9 9999

9 9 9 ·

9 • 9 ······

Ν- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -3,4-dichlorobenzamide

Ν- [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) ethoxyphenyl] -3-iodobenzamide

N- [4- (2-diisopropylamino) ethoxyphenyl] -3-bromobenzamide

N- [4- (2-diisopropylamino) ethoxyphenyl] -4 (cyclohexyl) benzamide

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4- (cyclohexyl) benzamide

N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4-ethyl (1,1'-biphenyl) -4-carboxamide

N- [3- (2-diisopropylamino) ethoxyphenyl] -4'-ethyl- (1,1'-biphenyl) -4-carboxamide

N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -3'-methoxy- (1,1'-biphenyl) -4-carboxamide.

The most preferred compounds of the invention are the following:

N- [3- (2-diisopropylamino) ethoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4-carboxamide

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -2 'methyl-4' - (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4-carboxamide · ♦ · · • · • · · · · · · · · · · · · ·

5- {4- [2-Methyl-4- (5-methyl-1,2,4-oxadiazolyl) phenyl] benzoylamino} spiro oxalate [(2,3-dihydrobenzofuran) 3,4'- (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) ethoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4-carboxamide

N- {3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide

N- {3- [2- (cis-2,6-dimethyl-1-piperidinyl) 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-dimethyl-1-pyrrolidinyl) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide

N- {4-methoxy-3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide

N- {3- [2- (N-tert-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-diisopropylamino) ethoxy-4-iodophenyl] - (1,1'-biphenyl) -4-carboxamide

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -4-methanamine dihydrochloride · e · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4'-cyano-1,1'-biphenyl-4-carboxamide

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4'-cyano-2'-methyl-1,1'-biphenyl-4-carboxamide

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -2-naphthalenecarboxamide

N- {1'-methylspiro-5- [benzofuran-3 (2H), 4'-piperidin] 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 (iodo) benzamide

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4- (cyclohexyl) 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 excluded from the scope of the invention are as follows:

N- [3- (2-dimethylaminoethoxy) -4-methoxyphenyl] -4 '- (5-dimethylamino-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4-carboxamide 9 9 9 9

9 9 9 9 9

9999 99 99 · · · · · · · · · ·

Ν- [3- (1-methyl-2-azetidinylmethoxy) -4-methoxyphenyl] 4 '- (5-methyl-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4-carboxamide

[7- (2-Dimethylaminoethoxy) -6-methoxy-3,4-dihydro-2H-1-quinolinyl] - {[2'-methyl- (1,2,4) -3-oxadiazolyl] -4-biphenylyl} oxalate - methanone

2,3,6,7-Tetrahydro-1'-methyl-5- [2'-methyl-4 '(5-methyl-1,2,4-3-oxadiazolyl) biphenyl-4-carbonyl] -furo (oxalate) ( 2,3f) indole-3-spiro-3'-piperidine

5- [4 '- (5-Methyl-1,2,4-3-oxadiazolyl) 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-1,2,4-3-oxadiazolyl) -biphenyl-4-carbonyl] -2,3,6,7-tetrahydrospirofuro 3f) 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-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] - (1,1'-biphenyl) -4-carboxamide

4 4 4

4 V 4 4

4444 4 4 45

4 4 4

4 4 4 4

Ν- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4'-chloro (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-benzamide

N- [4- (2-diethylamino) ethoxyphenyl] -4-iodobenzamide N- [2- (2-diethylamino) ethoxyphenyl] -4-iodobenzamide N- [4- (2-diethylamino) ethoxyphenyl] -3-iodobenzamide N- [2- (2-Diisopropylamino) ethoxyphenyl] -3-iodobenzamide N- [2- (2-diethylamino) ethoxyphenyl] -3-iodobenzamide N- [3- (2-diethylamino) ethoxyphenyl] -4-bromobenzamide

N- [2- (2-diisopropylamino) ethoxyphenyl] -4-bromobenzamide

N- [2- (2-diethylamino) ethoxyphenyl] -4-bromobenzamide

N- [4- (2-diethylamino) ethoxyphenyl] -3-bromobenzamide

N- [2- (2-diisopropylamino) ethoxyphenyl] -3-bromobenzamide

N- [2- (2-diethylamino) ethoxyphenyl] -3-bromobenzamide

N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4 (dimethylamino) benzamide

9 9 9 · 9 9 * 9 9. 9

9 9 9 9 9 4 4 9 9 $ 999 9,999 4 9,999

9 9 9 9 · · 9 · 9 9

Ν- [4- (2-diisopropylamino) ethoxyphenyl] -4- (dimethylamino) benzamide

N- [4- (2-diethylamino) ethoxyphenyl] -4- (dimethylamino) benzamide

N- [2- (2-diisopropylamino) ethoxyphenyl] -4- (dimethylamino) benzamide

N- [2- (2-diethylamino) ethoxyphenyl] -4- (dimethylamino) benzamide

N- [4- (2-diethylamino) ethoxyphenyl] -4- (isopropyl) benzamide

N- [2- (2-diisopropylamino) ethoxyphenyl] -4- (isopropyl) benzamide

N- [2- (2-diethylamino) ethoxyphenyl] -4- (isopropyl) benzamide

N- [3- (2-diethylamino) ethoxyphenyl] -4- (cyclohexyl) benzamide

N- [2- (2-diisopropylamino) ethoxyphenyl] -4- (cyclohexyl) benzamide

N- [2- (2-diethylamino) ethoxyphenyl] -4- (cyclohexyl) benzamide

N- [2- (2-diisopropylamino) ethoxyphenyl] -4'-ethyl- (1,1'biphenyl) -4-carboxamide; and

N- [2- (2-diethylamino) ethoxyphenyl] -4'-ethyl- (1,1'-biphenyl) -4-carboxamide.

Formulation of pharmaceutical compositions

The pharmaceutically active compounds of the invention (and pharmaceutically acceptable salts thereof) in conventional dosage forms prepared by combining a compound of formula (I) ("active ingredient") in an amount

• 4 * 4 * 9 * 4 4 9 9 sufficient for treatment COPD, asthma and atopic diseases (such as atopic dermatitis and allergies), rheumatoid arthritis, benign lymphogranuloma and other fibrotic disorders, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease and HIV infection ("CC-mediated disease states") 5) with conventional pharmaceutical carriers or diluents according to conventional procedures well known in the art. Such procedures may include mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired formulation.

For example, the pharmaceutical carrier employed may be both solid and liquid. Examples of solid carriers are lactose, white clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, olive oil, water and the like. Similarly, the carrier or diluent may contain a release retardant 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. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule, in the form of powder or pellets, in the form of powders or lozenges. The amount of solid carrier will vary widely, but will preferably be from about 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, a sterile injectable solution such as an ampoule or a non-aqueous liquid suspension.

For the treatment or prevention of CCR5 mediated disease states, the active ingredient may also be administered topically to a mammal. The amount of active ingredient required for • · ·

The therapeutic effect of topical administration will, of course, depend upon the compound selected, the nature and severity of the condition being treated and the prior treatment of the mammal, and in particular the judgment of the physician. A suitable dose of the active ingredient is from about 1.5 mg to about 500 mg for topical administration, most preferably the dosage will be from about 1 mg to about 100 mg, for example about 5 to about 25 mg, administered twice daily or three times daily.

Topical administration is referred to as non-systemic administration and includes the use of the active ingredient externally on the skin, in the oral cavity, and instillation of such compound into the ear, eye or nose and where the compound does not significantly enter the blood stream. By systemic administration is meant oral, intravenous, intraperitoneal and intra-muscular administration.

Although it is possible to administer the active ingredient as a raw chemical, it is preferable to administer it as a pharmaceutical composition. For topical administration, the active ingredient may comprise from about 0.001% to about 10% by weight, for example from about 1% to about 2% by weight of the composition, although it may comprise more than 10% by weight but preferably no more than 5% by weight and even more preferably from about 0.1% to about 1% by weight of the composition.

The topical formulations of the present invention, both for veterinary use and for human use, include the active ingredient together with one or more acceptable carrier (s) and optionally other therapeutic (s). (e) component (s). The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Formulations suitable for topical administration include liquid or partially liquid formulations suitable for penetration through

4 4 4

4 4 4 4 4 ·

444 4444444 44 4 skin to the site of inflammation such as liquid ointments, lotions, creams, ointments or pastes and drops suitable for administration to the eye, ear or nose.

The drops of the invention may comprise sterile aqueous or oily suspensions and may be prepared by dissolving the active ingredient in a suitable alcoholic or aqueous solution of a bactericidal and / or fungicidal agent and / or any other suitable preservative and preferably containing a surfactant. The resulting solution can then be purified by filtration, transferred to a suitable container, which is then hermetically sealed and sterilized by autoclaving or holding at 98 to 100 ° C for half to one hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in 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 glycerol, dilute alcohol and propylene glycol.

Lotions of the invention include those suitable for application to the skin or eye. The eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for droplet preparation. Lotions or liquid ointments for application to the skin may also include an agent to accelerate drying and to cool the skin, such as alcohol or acetone, and / or a moisturizing agent such as glycerol or an oil such as castor oil or peanut oil.

The creams, ointments or pastes of the invention are semi-solid formulations of the active ingredient for external application. They can

999 99 99

9 9 9 9999

9 9 9

999 9999999 99 «

99 9 9999 • 99 · 99 ·· · 9 ·

Be prepared by mixing the active ingredient in finely divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous liquid, with the aid of a suitable device, with a greasy or non-greasy base. The base may include hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, metal soap, acacia, natural origin oil such as almond oil, corn oil, peanut oil, castor oil or olive oil, sheep wool fat or derivatives thereof or fatty acids such as stearic acid or oleic acid together with an alcohol such as propylene glycol. The formulation may include any suitable surfactant such as an anionic, cationic or nonionic surfactant such as esters or compounds thereof with polyoxyethylene. Suspending agents such as natural rubbers, cellulose derivatives or inorganic materials such as silica dinases, and other ingredients such as lanolin may also be included.

The active ingredient may also be administered by inhalation. By "inhalation" is meant intranasal and oral inhalation administration. Suitable dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional methods. The daily dosage amount of active ingredient administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably from about 1 mg to about 10 mg per day.

In one aspect, the invention relates to a method of treating COPD, asthma and atopic disorders (e.g., atopic dermatitis and allergies), rheumatoid arthritis, benign lymphogranuloma and other fibrotic disorders, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis and inflammatory bowel disease and HIV infection all in mammals, 9 9 ·

9 9 9 • 9

Preferably in humans, which comprises administering an effective amount of a CCR5 receptor ligand, particularly a compound as depicted by formula (I).

By "treatment" is meant prophylactic or therapeutic treatment. Such a compound having formula (I) may be administered to such mammal in a conventional dosage form prepared by combining a compound of formula (I) with a conventional pharmaceutically acceptable carrier or diluent by known methods. It will be appreciated by those skilled in the art that the nature and nature of the pharmaceutically acceptable carrier or diluent is determined by the amount of active ingredient with which it is combined, the route of administration and other well-known variables. The compound of formula (I) is administered to mammals in need of treatment for asthma and atopic disorders (e.g., atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis and inflammatory bowel disease and HIV infection in an amount sufficient to reduce symptoms. associated with these disease states. The route of administration may be oral or parenteral.

The term "parenteral" as used herein includes intravenous administration, intramuscular administration, subcutaneous administration, intrarectal administration, intravaginal administration, and intramuscular administration. Subcutaneous and intramuscular administration are generally more preferred. The daily dosage regimen for parenteral administration will preferably be from about 30 mg to about 300 mg of active ingredient per day. The daily dosage regimen for oral administration will preferably be from about 100 mg to about 2000 mg of active ingredient per day.

It will be appreciated by those skilled in the art that the optimum amount and distribution of individual dosages of the compound of formula (I) will be appreciated

9 9 9 9 9 9 4 9 4

4 9 9 9 9 9 9 4 9 · • · 9 9 9 9999999 · 9 9 _ Λ Q - 9 9 9 · 9 9 · 9 9 9 9 ⁴⁰ 99 9 «99« 9 · 9 · (I) to be determined by nature and spreading the condition to be treated, the species, the route and the site of administration, and in particular in the treatment of mammals, and that this optimum can be determined by conventional means. It will also be understood by one of ordinary skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of formula (I) administered per day for a specified number of days, can be ascertained by one skilled in the art using routine tests.

Methods of preparation

Compounds of formula (I) may be prepared by methods recognized in the art from commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein or can be prepared by methods known in the art.

In particular, compounds of formula (I) wherein R is represented by group (a), A is CONH and E is represented by group (d) were prepared according to the methods disclosed in WO 95/15954, published June 15, 1995.

Compounds of formula (I) wherein R is represented by group (a), A is CONH and E is represented by group (e) were prepared according to the methods disclosed in WO 95/17401, published June 29, 1995.

Compounds of formula (I), wherein R is represented by group (a), A is CONH and E is represented by group (f), were prepared according to the methods disclosed in WO 96/31508, published October 10, 1996.

Compounds of formula (I) wherein R is represented by group (a), A is CONH and E is represented by group (g) or (h) were prepared according to the methods disclosed in WO 95/30675, published November 16, 1995.

- 48 • · 0

0 ·

0 0

0 0 0 · 0 00 00 ♦ 0 00 00 0 0 0 0 0 0 0 0 0000 00 00 0 0 0 00 00 • 0 * 0 0 00

Compounds of formula (I) wherein R is represented by group (a), A is CONH and E is represented by group (j) were prepared according to the methods disclosed in WO 96/11934, published April 25, 1996.

Compounds of formula (I) wherein R is represented by group (a) and AE is represented by group (k) were prepared according to the methods disclosed in WO 95/17398, published June 29, 1995.

Compounds of formula (I) wherein R is represented by group (a) and AE is represented by group (1) were prepared according to the methods disclosed in WO 97/07120, published February 27, 1997.

Compounds of formula (I) wherein R is represented by group (a) and AE is represented by group (m) were prepared according to the methods disclosed in WO 96/19477, published June 27, 1996.

Compounds of formula (I) wherein R is represented by group (a) and AE is represented by group (η) were prepared according to the methods disclosed in WO 97/19070, published May 29, 1997.

In particular, compounds of formula (I) wherein Ar is represented by group (i), (ii) or (iii), A is CONR ⁴⁶ , NHCO or CH ₂ NH and E is represented by group (a) were prepared according to the methods set forth in WO 95/15954, published June 29, 1995, WO 95/17398, published June 29, 1995, WO 95/263284, published October 5, 1995,

WO 96/06079, published February 29, 1996, GB 2276161, published September 21, 1994 and GB 2276165, published September 21, 1994.

Compounds of formula (I) wherein Ar is

O is represented by group (i), (ii) or (iii), A is CONR,

9

9 9 · · · · · · · ·

NHCO and E are represented by group (b), were prepared according to the methods disclosed in WO 95/11934, published April 25, 1995 and WO 95/19477, published June 27, 1995. The four following applications cover spiro compounds:

WO 97/17350, published May 15, 1997, WO 97/34900, published September 25, 1997, WO 97/34901, published September 25, 1997, WO 97/35862, published October 2, 1997.

Compounds of formula (I) wherein Ar is represented by group (i), (ii) or (iii), A is CONR ⁷⁰ , NHCO or CH ₂ NH and E is represented by group (c) were prepared according to the methods described in WO 95/306758, published November 16, 1995; and GB 2276165, published September 21, 1994.

Compounds of formula (I) wherein Ar is (ii), A is CONH or NHCO and E is represented by group (f) were prepared according to the methods disclosed in WO 95/17401, published June 29, 1995.

Compounds of formula (I) wherein Ar is represented by group (i) or (ii), A is CONR ⁹³ and E is represented by group (g) were prepared according to the methods disclosed in WO 96/31508, published October 10, 1996.

Compounds of formula (I) wherein Ar is represented by group (i) or (ii), A is CONR and E is represented by group (h) were prepared according to the methods disclosed in WO 95/32767, published December 7, 1995 and WO 97/07120, published Feb. 27, 1997.

Compounds of formula (I) wherein Ar is represented by group (i) or (ii), and A is CONR ¹⁰⁹ or CH ₂ NH and E is represented by group (i) were prepared according to the methods disclosed in WO 97/19070, published May 29, 1997.

♦ · · * * * * * * * * * * * * * *

9 9 9 9 9 9999 9 9 · · · - with 1 - · · · · · · · · ♦ ·

4 «99 99 99 99

Compounds of formula (I) are also prepared by the method of Scheme 1, utilizing solid phase chemistry. Resin 1-1 (WO 98/17695) is coupled with a suitably substituted carboxyphenylboronic acid, for example 4- (4,4,5,5-tetramethyl-1,3,2-2-dioxaborolanyl) benzoic acid, using Suzuki conditions, e.g. a palladium reagent such as tetrakis (triphenylphosphine) palladium (0), and a suitable base such as sodium carbonate in a suitable solvent such as ethanol and toluene at a suitable temperature such as 90 ° C for a suitable time such as 24 hours to give resin-bound biphenylcarboxylic acid 1-2. Addition compound 1-2 is condensed with suitably substituted anilines 1-4 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 a suitable reagent such as oxalyl chloride in a suitable solvent such as toluene affords the biphenylcarbonyl chloride addition product 1-3. Treatment of 1-3 with 1-4 in a suitable solvent such as dichloromethane in the presence of a suitable base such as diisopropylethylamine affords the biphenylcarboxanilide addition product 1-5. Treatment of 1-5 with a suitable acid and solvent such as a 50: 48: 2 mixture of trifluoroacetic acid, dichloromethane and water gives 1-6 which are compounds of formula (I).

0000 0

0000 0 0 0

0 0 0 0 ·

0 «0

0 0 0

Scheme 1

a) 4-carboxybenzeneboronic acid, tetrakis (triphenylphosphine) palladium, sodium carbonate, ethanol, toluene, 90 ° C;

0 0 0 0 0 0

0 0 0

00

0 0

0 0

0 0 0 0 0 0000 0 0 0

0

00 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

00 hours, b) (COCl) ₂ , toluene, c) 4, diisopropylethylamine, dichloromethane, d) trifluoroacetic acid, dichloromethane.

Compounds of formula (I) are also prepared by the method of Scheme 2, using solid-state chemistry. Appropriate substituted (alkylamino) ethoxyanilines 2-1 such as 3- (2-diisopropylamino) -ethoxy-4-methoxyaniline, synthesized according to literature methods from commercially available starting materials and methods described herein, are reacted with 4-formyl-3. 5-dimethoxyphenol-Merrifield resin 2-2 [Boojamra et al., J. Org. Chem. 60, 5742, (1995)] and treated with a suitable reducing agent such as sodium triacetoxyborohydride in a suitable solvent such as dimethylformamide containing 1% acetic acid to give 2-3. Resin-bound aniline 2-3 is condensed with an appropriately substituted benzoic acid or biphenylcarboxylic acid, which is commercially available or synthesized by methods known in the art, using a suitable activating agent such as N-bromosuccinimide and triphenylphosphine in a suitable solvent such as dichloromethane, dimethylformamide and pyridine to give 2-4. Treatment of 2-4 with a suitable acid and solvent such as a 50: 48: 2 mixture of trifluoroacetic acid, dichloromethane and water affords the desired benzanilide or biphenylcarboxanilide 2-5 which is a compound of formula (X).

• 4 · »

44 44

4 «4,444 444 4

4,444 · 4444

4444 4444 44 44

4444 44 4 4444

44

a) BAL resin, sodium triacetoxyborohydride, dimethylformamide with 1% acetic acid, b) halobenzoic acid, N-bromosuccinimide, triphenylphosphine, pyridine, dichloromethane, water.

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated by the following examples, which are given for illustrative purposes only and are not to be construed as limiting the scope of the invention. If not specified

999 • 999

9 99 99

9 9 9 9 9

9 9 9 9 9 9

9,999 99 99 9

9 9 9 9 9

Otherwise, the mass spectra in the examples are obtained on a VG Zab mass spectrometer using fast atom irradiation.

Preparation 1

Preparation of 4- (2-diisopropylamino) ethoxy-3-methoxyaniline

a) 4- (2-diisopropylamino) ethoxy-3-methoxy-nitrobenzene

A mixture of 4-nitroguaiacol (1.0 g, 5.9 mmol), hydrochloride

2-diisopropylaminoethyl chloride (1.2 g, 5.9 mmol) and powdered potassium carbonate (1.38 g, 10 mmol) in anhydrous acetone (100 mL) was heated to reflux, stirred, cooled, filtered and the filtrate was evaporated in vacuo. The residue was partitioned between ethyl acetate (300 mL) and water (40 mL), and the organic phase was washed with 40 mL of water, dried over sodium sulfate and evaporated in vacuo to give the title compound: MS (ES) m / e 297.2 [M + H] &lt; + ^&gt; .

b) 4- (2-diisopropylamino) ethoxy-3-methoxyaniline

A mixture of the compound of Preparation 1a (1.6 g, 5.4 mmol) and 5% palladium on carbon (0.3 g) in absolute ethanol (100 mL) was shaken under a hydrogen atmosphere of 2.5 psi for 2.5 hours. (50 psi), filtered and the filtrate was evaporated in vacuo to give the title compound of this example: MS (ES) m / e 267.3 [M + H] ⁺ .

Preparations 2 to 8

Preparation of 2- (2-diisopropylamino) ethoxy-4-methoxyaniline, 3- (2-diisopropylamino) ethoxyaniline, 4- (2-diisopropylamino) 56

0 000 0000 00 0 0000 0 0 0 0 0 0 000 0000000 00 0 0000 00 0 0000 00 00 00 0 0 · · 0-ethoxy-2-fluoroaniline, 4- (2-diisopropylamino) ethoxyaniline

2- (2-diisopropylamino) ethoxyaniline, 3- (2-diisopropylamino) ethoxy-2-methylaniline and 3- (2-diisopropylamino) ethoxy-4-methylaniline

Using the procedure of Preparation 1, except that 4-nitroguaiacol 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 gave the compounds named in the title of this example:

2- (2-diisopropylamino) ethoxy-4-methoxyaniline: MS (ES) m / e 267.2 [M + H] &lt; + ^&gt;

3- (2-diisopropylamino) ethoxyaniline: MS (ES) m / e 237.2 [M + H] &lt; + ^&gt;

4- (2-diisopropylamino) -ethoxy-2-fluoroaniline: MS (ES) m / e 255.0 [M + H] &lt; + ^&gt;

4- (2-diisopropylamino) ethoxyaniline: MS (ES) m / e 237.2 [M + H] &lt; + ^&gt;

2- (2-diisopropylamino) ethoxyaniline: MS (ES) m / e 237.1 [M + H] &lt; + ^&gt;

3- (2-Diisopropylamino) ethoxy-2-methylaniline: MS (ES) m / e 251.2 [M + H] ⁺ a

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-nitrophenoxyacetyl chloride (0.22 g, 0.9 mmol) (prepared from 2-methoxy-5-nitrophenoxyacetic acid [Brown et al., J. Chem. Soc., 3681, (1955)) and

9

9

999 9,999 9 9

9 9 • 9 9 ·

9 · 9

9 9 9

99 thionyl chloride) in 10 mL of dichloromethane was added to a mixture of dicyclohexylamine (0.16 g, 0.9 mmol) and diisopropylethylamine (0.23 g, 1.76 mmol) in dichloromethane (20 mL), left at room temperature for 16 min. hours, washed with 2 x 20 mL water, dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from methanol to give the title compound (0.16 g).

N, N-dicyclohexyl-2-methoxy-5-aminophenoxyacetamide

The process of Preparation 1 (b), except that the compound of Preparation 9 (a) was replaced with the compound of Preparation 1 (a), gave the title compound of this Example.

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 a 1.0 M solution of borane in tetrahydrofuran (4.3 mL, 4.3 mmol), refluxed. with a condenser for 3 hours, left at room temperature for 16 hours, carefully treated with methanol (5 ml), heated to reflux for 30 minutes, cooled and evaporated in vacuo. The residue was partitioned between 75 mL of ethyl acetate and 15 mL of water and the organic phase was washed with water (15 mL), dried over sodium sulfate, evaporated in vacuo and the residue purified by preparative TLC (Whatman PLK5F, 10% ethanol in dichloromethane and 1% triethylamine). to give the title compound of this example.

Preparation 10

Preparation of 3- (2-dipropylamino) ethoxy-4-methoxyaniline

a) 3- (2-Dipropylamino) ethoxy-4-methoxy-1-nitrobenzene

0

0 0 0 0 0

0 0 0

0 0 0

A solution of 3- (2-bromoethoxy) ethoxy-4-methoxy-1-nitrobenzene [Mutai et al., Tetrahedron, 40, 1755, (1948)] (0.5 g, 1.8 mmol) and dipropylamine (1.8 g, 18 mmol) in 10 mL of dimethylformamide containing 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 h. The mixture was cooled, diluted with dichloromethane (100 mL), filtered and the filtrate evaporated in vacuo. The residue was partitioned between 150 mL of ethyl acetate and 30 mL of water, and the organic phase was washed with 4 x 30 mL of water, dried over sodium sulfate and evaporated in vacuo to give the title compound: MS (ES) m / e 297.1 [M + H] ⁺ .

b) 3- (2-dipropylamino) ethoxy-4-methoxyaniline

The process of Preparation 1 (b), except that the compound of Preparation 10 (a) was substituted for the compound of Preparation 1 (a), gave the title compound of the following example: MS (ES) m / e 267.0 [M + H] ⁺ .

Preparations 11 to 16

Preparation of 3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy] -4-methoxyaniline, 3- [2- (cis-2,6-dimethyl-1-piperidinyl) ethoxy] -4-methoxyaniline, 3- [2- (N-ethyl-N-isopropylamino) ethoxy] -4-methoxyaniline, 3- [2- (2,5-dimethyl-1-pyrrolidinyl) ethoxy] -4-methoxyaniline, 3- [2- (2,2, 6,6-Tetra-methyl-1-piperidinyl) -ethoxy] aniline; and 3- [2- (N-tert-butyl-Nisopropyl) aminoethoxy] -4-methoxyaniline.

Preparation of Preparation 10, except that with Nisopropylcyclohexylamine, cis-2,6-dimethylpiperidine, Nethylisopropylamine, 2,5-dimethylpyrrolidine, 2,2,6,6-tetramethylpiperidine or N-tert-butylisopropylamine

4 4 4 4444 4444

4444 4444 44 44 ·

4444 44 4 4444

44 44 4 44 44 replaced dipropylamine to give the title compounds of this example:

3- [2- (N-cyclohexyl-N-isopropylamino) -ethoxy] -4-methoxyaniline: MS (ES) m / e 307.2 [M + H] ⁺ ,

3- [2- (cis-2,6-dimethyl-1-piperidinyl) -ethoxy] -4-methoxyaniline: MS (ES) m / e 279.3 [M + H] ⁺ ,

3- [2- (N-ethyl-N-isopropylamino) -ethoxy] -4-methoxyaniline: MS (ES) m / e 253.1 [M + H] ⁺ ,

3- [2- (2,5-Dimethyl-1-pyrrolidinyl) -ethoxy] -4-methoxyaniline: MS (ES) m / e 265.1 [M + H] ⁺ ,

3- [2- (2,2,6,6-Tetramethyl-1-piperidinyl) -ethoxy] aniline: MS (ES) m / e 307.0 [M + H] ⁺ a

3- [2- (N-tert-Butyl-N-isopropyl) aminoethoxy] -4-methoxyaniline: MS (ES) m / e 281 [M + H] ⁺ .

Preparations 17 and 18

Preparation of 3- [2- (N-isopropyl-N-methylamino) ethoxy] -4-methoxy aniline and N-ethyl-3- [2- (N-isopropyl-N-methylamino) ethoxy] 4-methoxy-aniline

a) 3- [2- (N-Isopropyl-N-methylamino) ethoxy] -4-methoxy-1-nitrobenzene

The procedure of Preparation 10 (a), except that N-methylisopropylamine was replaced by dipropylamine, afforded the title compound of this example: MS (ES) m / e 269.4 [M + H] ⁺ .

b) 3- [2- (N-isopropyl-N-methylamino) ethoxy] -4-methoxyaniline and N-ethyl-3- [2- (N-isopropyl-N-methylamino) ethoxy] -4-methoxyaniline

9,999,999

9,999,999

9999 9999 99 99 9 - 50 - 9999 999 9999

99 99 99 99

The process of Preparation 1 (b), except that the compound of Preparation 17 (a) was replaced by the compound of Preparation 1 (a), gave a mixture of the compounds named in the title of this example:

3- [2- (N-Isopropyl-N-methylamino) ethoxy] -4-methoxyaniline: MS (ES) m / e 239.1 [M + H] ^&lt; ⁺ &^gt;

N-ethyl-3- [2- (N-isopropyl-N-methylamino) ethoxy] -4-methoxyaniline: MS (ES) m / e 267.1 [M + H] ⁺ .

9 99 9

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 mmol) and powdered potassium carbonate (6.5 g, 47.4 mmol) in dimethylformamide (50 mL) was treated with 1,3-dibromopropane (80, 8 g (0.4 mol), heated at 90 ° C for 2 h, cooled, diluted with 250 mL of dichloromethane and filtered. The filtrate was evaporated in vacuo and the residue was crystallized from methanol. The resulting solid was triturated with a mixture of 30% ethyl acetate in hexane and then with a boiling mixture of 30% ethyl acetate in hexane. The combined organics were concentrated in vacuo to afford the title compound of this example: ^{Χ Η} NMR (300 MHz, CDC1 ₃₎ δ 7.92 (dd, 1H), 7.75 (d, 1H), 6.92 (dd 1 H, 4.20 (t, 2H), 3.95 (s, 3H), 3.62 (t, 2H), 2.40 (m, 2H).

b) 3- (3-diisopropylamino) propyloxy-4-methoxyaniline

Preparation Method 1 (b), except that the compound of Preparation 19 (a) was replaced by the compound of Preparation 1 (a),

4 · ···· «« 44 44 94

4 4 4 4 9 9 9 9 4

9994 4994 44 44

4 4 9 9 4

44,444,444 gave the title compound of this example: 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-nitrophenyl) propionamide

A solution of 3- (2-methoxy-5-nitrophenyl) propionyl chloride (0.46 g, 1.9 mmol) prepared from 3- (2-methoxy-5-nitrophenyl) propionic acid [Asano et al., J. Pharm. Soc. Japan, 70, 480, (1950)] and thionyl chloride, in 5 mL of dichloromethane was added simultaneously to a solution of diisopropylamine (0.67 g, 6.6 mmol) in 20 mL of dichloromethane, stirred for 16 hours, washed with 2 x 20 mL water, dried over sodium sulfate and concentrated in vacuo to give the title compound of this example: MS (ES) m / z 309.1 [M + H] ⁺ .

b) N, N-diisopropyl-3- (2-methoxy-5-nitrophenyl) propylamine

A solution of the compound of Preparation 20 (a) (0.6 g, 1.95 mmol) in anhydrous tetrahydrofuran (50 mL) was treated with a 1.0 M solution of borane in tetrahydrofuran (15 mL, 15 mmol), heated to reflux for 2 hours. hours, allowed to cool, stirred for 16 hours and then carefully treated with 10 ml of methanol. The mixture was evaporated in vacuo and the residue was dissolved in 250 mL of dichloromethane and washed with 2 x 40 mL of water. The organic phase was dried over sodium sulfate and concentrated in vacuo to give the title compound (0.52 g): MS (ES) m / z 295.1 [M + H] ⁺ .

c) 3- (3-diisopropylamino) propyl-4-methoxyaniline

44 · «

4 4 4 4 4

9 4

4495 4 9 99 9

4 4 4 4 4 · · 49 49 49 49 49 49

4 9 4 999

4 4 4

The procedure of Preparation 1 (b), except that the compound of Preparation 20 (b) was replaced by the compound of Preparation 1 (a), gave the title compound of the following example: MS (ES) m / e 265.3 [M + H] ⁺ .

Preparation 21

Preparation of 3- (2-diisopropylamino) ethoxy-4-iodoaniline

a) 3- (2-diisopropylamino) ethoxy-4-iodo-1-nitrobenzene

The process of Preparation 1 (a), except that it was replaced

2-iodo-5-nitrophenol [Cambie et al., Australian J. Chem.,

50, 767, (1997)] 4-nitroguaiacol gave the title compound of this example: MS (ES) m / e 392.5 [M + H] ⁺ .

b) 3- (2-diisopropylamino) ethoxy-4-iodoaniline

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) was added dropwise over 5 minutes. The mixture was stirred, cooled, filtered for 5 minutes and the filtrate was extracted with ethyl acetate.

The organic phase was dried, evaporated in vacuo and the residue chromatographed (silica gel, 5% methanol in dichloromethane) to give 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

4 9 4

4444999 45 4

4 · · · ·

9 44 94

A mixture of the compound of Preparation 21 (a) (2.0 g, 5 mmol), trimethylsilylethine (0.8 g, 8 mmol), palladium acetate (15 mg) and triphenylphosphine (30 mg) in degassed triethylamine (25 mL) was added for Heat at 90 ° C for 16 hours. The mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, step gradient, 0 to 1% methanol mixed with dichloromethane and ammonia) to give the title compound (1.0 g): MS (ES) m / e 363 [M + H] ] ⁺ .

b) 3- (2-diisopropylamino) ethoxy-4-ethynyl-nitrobenzene

A solution of the compound of Preparation 22 (a) (1 g, 2.7 mmol) in mL of methanol was treated with potassium carbonate (100 mg), stirred for 5 hours, evaporated in vacuo and the residue dissolved in dichloromethane and washed with 5% aq. potassium carbonate solution and aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated in vacuo to give the title compound (0.75 g): MS (ES) m / e 291.1 [M + H] ⁺ .

c) 3- (2-diisopropylamino) 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 60 mL of 1: 1 methanol / ethanol was shaken 4 hours under a hydrogen atmosphere, filtered through a bed of Supercel and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, treated with a solution of hydrogen chloride in ether, stirred and filtered to give the title compound (0.6 g): MS (ES) m / e 265.1 [M + H] ⁺ .

• · · · · · · · · · · · · · · · ·

0 · ·· • · ·

«. · · · · · · · ·

Preparation 23

Preparation of 3- (2-diisopropylamino) ethoxy-4- (methoxycarbonylamino) aniline.

(a) 3- (2-diisopropylamino) ethoxy-4-nitroaniline hydrochloride

The procedure of Preparation 1 (a), except that it was replaced with 2-amino-5-nitrophenol to 4-nitroguaiacol, gave the title compound of this example: MS (ES) m / e 281.9 [M + H] ⁺ .

b) 3- (2-diisopropylamino) ethoxy-4- (methoxycarbonylamino) -1-nitrobenzene

A solution of the compound of Preparation 23 (a) (1.27 g, 4 mmol) and diisopropylethylamine (2.1 mL, 12 mmol) in 25 mL of dichloromethane was treated with methyl chloroformate (0.38 g, 4 mmol), stirred for 7 hours, mixed with water and the organic phase was washed with brine, dried and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, step gradient, 0 to 1% methanol in dichloromethane / ammonia) to afford the title compound: MS (ES) m / e 339.9 [M + H] ⁺ .

c) 3- (2-diisopropylamino) ethoxy-4- (methoxycarbonylamino) aniline

The process of Preparation 1 (b), except that the compound of Preparation 23 (b) was replaced by the compound of Preparation 1 (a), gave the title compound of the following example: MS (ES) m / e 310.0 [M + H] ⁺ .

»· · · ·

0 «· 0» 0

0 ·

0 0 0 0

Preparation 24

Preparation of 3- (2-diisopropylamino) ethoxy-4-methoxy-N-methylaniline

(a) N-formyl-3- (2-diisopropylamino) 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 for 2 h, cooled, diluted with anhydrous tetrahydrofuran (10 mL) and processed in one batch with solution

3- (2-diisopropylamino) ethoxy-4-methoxyaniline [WO 95/15954] (0.5 g, 2 mmol) in 5 mL of tetrahydrofuran. The resulting mixture was stirred for 16 h, evaporated in vacuo and the residue partitioned between ethyl acetate (85 mL) and 5% aqueous sodium carbonate solution (10 mL). The organic phase was washed with 5% sodium carbonate solution (10 ml) and then with brine (10 ml), dried over sodium sulfate and evaporated in vacuo to give the title compound (0.57 g): MS (ES) m / e 295.4 [M + H] &lt; + ^&gt; .

b) 3- (2-diisopropylamino) ethoxy-4-methoxy-N-methylaniline

A solution of the compound of Preparation 24 (a) (0.57 g, 1.9 mmol) in anhydrous tetrahydrofuran (25 mL) was treated with a 2.0 M solution of borane in tetrahydrofuran (2.4 mL, 4.8 mmol), stirred and boiled under reflux for 3 hours. The mixture was cooled, left at room temperature for 18 hours, carefully treated with 10 ml of methanol, refluxed for 1 hour, cooled and evaporated in vacuo. The residue was partitioned between ethyl acetate (25 ml) and water (25 ml), the organic phase was washed with 25 ml of water and 25 ml of aqueous sodium chloride solution, dried over sodium sulfate and concentrated. • · · · · · · · · · · · · · · · · · · · · · · · · · · ·

9 9 9 9 evaporated in vacuo to give the title compound (0.5 g): MS (ES) m / e 281.4 [M] + H] ⁺ .

Preparations 25 and 26

Preparation of 2-dimethylaminomethyl-1,4-benzodioxan-6-amine and 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 from [Gazz. Ital., 87, 1038-49 (1958)], a mixture of 2-chloromethyl-1,4-benzodioxane (2 g, 11 mmol) in 15 ml of glacial acetic acid was stirred, cooled and treated with nitric acid (11 ml), which was added over 5 minutes. The mixture was heated at 95 ° C for 40 minutes, cooled and poured carefully into water. The resulting mixture was extracted with chloroform and the organic layer was washed and dried (sodium sulfate). The residue was distilled, b.p. 166-168 ° C / 1 mm Hg, to give a mixture of the title compounds (1.39 g).

b) 2-dimethylaminomethyl-6-nitro-1,4-benzodioxane and 2-dimethylaminomethyl-7-nitro-1,4-benzodioxane

Compounds of Preparations 25 (a) to 26 (a) (1.64 g, 7 mmol) were dissolved in excess dimethylamine (15 mL) and heated in a pressure vessel at 150 ° C for 16 h.

The mixture was cooled triturated with ether and filtered. The filtrate was evaporated in vacuo and the residue distilled at a boiling point of 120-130 ° C / 1 mm Hg to give the title compound (788 mg) as an orange colored oil. The product was further purified by acid / base treatment to give a mixture of the title compounds of this example (600 mg).

·························· 9 9 · · * · · ······· · · · · 9 · ··· ♦

Ό / ···· · * ♦ · 8 * ·

c) 2-dimethylaminomethyl-1,4-benzodioxan-6-amine and 2-dimethylaminomethyl-1,4-benzodioxan-7-amine

Compounds of Preparations 25 (b) to 26 (b) (600 mg, 2.5 mmol) and 10% palladium on carbon (200 mg) in ethanol (30 mL) were stirred under an atmosphere of hydrogen (101.325 kPa) for 1 hour. . The mixture was filtered, evaporated in vacuo and subjected to chromatography (silica gel, step gradient, 0 to 4% methanol in chloroform) followed by thick layer chromatography (step gradient, 1 to 2% methanol in chloroform) to give the title compounds of this example:

2-dimethylaminomethyl-1,4-benzodioxan-6-amine, TLC retention factor (Rf) 0.56 (silica gel, 10% ethanol in chloroform).

2-dimethylaminomethyl-1,4-benzodioxan-7-amine, TLC retention factor (Rf) 0.51 (silica gel, 10% ethanol in chloroform).

Example 1

Preparation of N- [3- (2-diisopropylamino) ethoxy-4-ethoxyphenyl] (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 over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10%, three to three to three to three to three to three to three methanol to dichloromethane) to give the title compound. Example (0.22 g): MS (ES) m / e 447.1 [M + H] ⁺ .

Example 2

Preparation of N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] 2'-methyl- (1,1'-biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by 2'-methyl-4-biphenylcarboxylic acid [Klein et al., J Med. Chem., 41, 437 (1998)] 4-biphenylcarboxylic acid, gave the title compound of this example: MS (ES) m / e 461.3 [M + H] ⁺ .

Example 3

Preparation of N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] (1,1'-biphenyl) -3-carboxamide

The procedure of Example 1, except that it is replaced by 3-biphenylcarboxylic acid, 4-biphenylcarboxylic acid, gave the title compound of this example: MS (ES) m / e 447.3 [M + H] ⁺ .

Examples 4 to 11

Preparation of N- [3- (2-dimethylamino) ethoxyphenyl] - (1,1'-biphenyl) 4-carboxamide, N- [4- (2-dimethylamino) ethoxyphenyl] - (1,1'-biphenyl) -4-carboxamide N- [2- (3-dimethylamino) propoxyphenyl] - (1,1'-biphenyl) -4-carboxamide, N- [3- (3-dimethylamino) propoxyphenyl] - (1,1'-biphenyl) 4-carboxamide, N- [4- (3-dimethylamino) propoxyphenyl] - (1,1'-biphenyl) -4-carboxamide,

N- [3- (diethylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -4- 69 • • • • • • • • • • • • • • • • • • • φφφφφφφ φφ

carboxamide, N- {3- [2- (1-piperidinyl) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide, and N- {3- [2- (4-morpholinyl) ethoxy] - 4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by 3- (2-dimethylamino) ethoxyaniline [WO 95/15954], 3- (3-dimethylamino) propoxyaniline [US 3 994 900], 3- (2-diethylamino) ethoxy- 4-methoxyaniline [WO 95/15954], 3- [2 (1-piperidin-yl) ethoxy] -4-methoxyaniline [WO 95/15954] or 3- [2- (4-morpholinyl) ethoxy] -4-methoxyaniline [WO 95/15954] to 3- (2-diisopropylamino) ethoxy-4-methoxyaniline, gave the title compounds of this example:

N- [3- (2-dimethylamino) ethoxyphenyl] - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 361 [M + H] ⁺ ,

N- [4- (2-dimethylamino) ethoxyphenyl] - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 361 [M + H] &lt; + &^gt;,

N- [2- (3-dimethylamino) propoxyphenyl] - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 375 [M + H] ⁺ ,

N- [3- (3-dimethylamino) propoxyphenyl] - (1,1'-biphenyl) 4-carboxamide: MS (ES) m / e 373 [M + H] ^4- ,

N- [4- (3-dimethylamino) propoxyphenyl] - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 375 [M + H] ⁺ ,

N- [3- (diethylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 419.5 [M + H] ⁺ ,

N- {3- [2- (1-piperidinyl) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 431.3 [M + H] ⁺ ,

N- {3- [2- (4-morpholinyl) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 433.0 [M + H] ⁺ .

9999 9999 9999 9 9 9 9 9 9 99 99 99

Examples 12 and 13

Preparation of N- [3- (2-diisopropylamino) ethoxy-2-methylphenyl] -2'methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) - 4-carboxamide and N- [3- (2-diisopropylamino) ethoxyphenyl] -2'methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4carboxamide

The procedure of Example 1, except that it is replaced by the compound of Preparation 7 or Preparation 3 of 3- (2-diisopropylamino) ethoxy-4-methoxyaniline and replaced by 2'methyl- [4 '- (5-methyl-1,2) [3-oxadiazolyl] biphenyl] -4-carboxylic acid [EP 0 533 268] 4-biphenylcarboxylic acid, gave the title compounds of this example:

N- [3- (2-diisopropylamino) ethoxy-2-methylphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4-carboxamide MS: (ES) m / e 527.3 [M + H] ^&lt; ⁺ &^gt;

N- [3- (2-diisopropylamino) ethoxyphenyl] -2'-methyl-4'- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4-carboxamide:

MS (ES) m / e 513.2 [M + H] &lt; + ^&gt; .

Example 14

Preparation of N- [3- (2-dipropylamino) ethoxy-4-methoxyphenyl] (1,1'-biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by the compound of Preparation 10 (b) 3- (2-diisopropylamino) ethoxy-4-methoxyaniline, gave the title compound of this example: MS (ES) m / e 447.1 [M + H] ⁺ .

Examples 15 to 22 • φ · · · · · · · · · · φ · φ · φ · φ «φ« φ φ φ φ φ φ φ φ · · · · φ φφ φφ · ♦ · ··

Preparation of Ν- [3- (2-Dicyclohexylamino) ethoxy-4-methoxyphenyl] (1,1'-biphenyl) -4-carboxamide, N- {3- [2- (N-cyclohexyl-Nisopropylamino) ethoxy] -4- methoxyphenyl} - (1,1'-biphenyl) carboxamide, N- {3- [2- (cis-2,6-1-dimethylpiperidinyl) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4 N- {3- [2- (N-ethyl-N-isopropylamino) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -carboxamide, N- {3- [2- (2,5- dimethyl-1-pyrrolidinyl) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide, N- {4-methoxy-3- [2- (2,2,6,6-tetramethyl) -1-piperidinyl) ethoxy] phenyl} - (1,1'-biphenyl) -4-carboxamide, N- {3- [2- (N-tert-butyl-N-isopropyl) aminoethoxy] -4-methoxyphenyl}} - (1,1'-biphenyl) -4-carboxamide and N- {3- [2- (2-diisopropylamino) ethoxy] -4-methylphenyl} - (1,1'-biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by the compound of Preparation 9, Preparations 11 to 16, or Preparation 8

3- (2-diisopropylamino) ethoxy-4-methoxyaniline, gave the title compounds of this example:

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} - (1,1'-biphenyl) -carboxamide: MS (ES) m / e 487.2 [M + H] ⁺ ,

N- {3- [2- (cis-2,6-1-dimethyl-piperidinyl) -ethoxy] -4-methoxy-phenyl} - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 459.0 [ M + H] ⁺ ,

N- {3- [2- (N-ethyl-N-isopropylamino) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -carboxamide: MS (ES) m / e 433.1 [M + H] ⁺ ,

N- {3- [2- (2,5-dimethyl-1-pyrrolidinyl) -ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 445.0 [ M + H] ⁺ , · · · · · · · · · · · ·

0000000 00 0

N- {4-methoxy-3- [2- (2,6,6-tetramethyl-1-piperidinyl) ethoxy] phenyl} - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 486.9 [M + H] &lt; + &^gt;,

N- {3- [2- (N-tert-butyl-N-isopropyl) aminoethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 460.9 [M + H] ⁺ a

N- {3- [2- (2-diisopropylamino) -ethoxy] -4-methyl-phenyl} (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 431.0 [M + H] ⁺ .

Example 23

Preparation of N- [3- (3-diisopropylamino) propyloxy-4-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by the compound of Preparation 19 (b) 3- (2-diisopropylamino) ethoxy-4-methoxyaniline, gave the title compound of this example: MS (ES) m / e 461.0 [M + H] ⁺ .

Example 24

Preparation of N- [3- (3-diisopropylamino) propyl-4-methoxyphenyl] (1,1'-biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by the compound of Preparation 20 (c) to give 3- (2-diisopropylamino) ethoxy-4-methoxyaniline, gave the title compound of this example: MS (ES) m / e 445, 2 [M + H] &lt; + ^&gt; .

Example 25

Preparation of N- [3- (2-diisopropylamino) ethoxy-4-iodophenyl] - (1,1'-biphenyl) -4-carboxamide

4

4444

The procedure of Example 1, except that it is replaced by the compound of Preparation 21 (b) 3- (2-diisopropylamino) ethoxy-4-methoxyaniline, gave the title compound of this example: MS (ES) m / e 442.9 [M + H] ⁺ .

Example 26

Preparation of N- [3- (3-diisopropylamino) ethoxy-4-ethylphenyl] (1,1'-biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by the compound of Preparation 22 (c) 3- (2-diisopropylamino) ethoxy-4-methoxyaniline, gave the title compound of this example: MS (ES) m / e 445.1 [M + H] ⁺ .

Example 27

Preparation of N- [3- (3-diisopropylamino) ethoxy-4- (methoxycarbonylamino) phenyl] - (1,1'-biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by the compound of Preparation 23 (c) 3- (2-diisopropylamino) ethoxy-4-methoxyaniline, gave the title compound of this example: MS (ES) m / e 490.1 [M + H] ⁺ .

Example 28

Preparation of N- (1,1'-biphenyl) -4-yl-3- (2-diisopropylamino) ethoxy-4-methoxybenzamide

a) N- (1,1'-biphenyl) -4-yl-3-hydroxy-4-methoxybenzamide

A solution of 3-hydroxy-4-methoxybenzoic acid (0.5 g, 3 mmol) in dichloromethane and dimethylformamide was cooled to -20 ° C after which N was added in one portion at a time. ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Bromosuccinimide (0.57 g, 3.2 mmol) and triphenylphosphine (0.8 g, 3.1 mmol). The mixture was stirred at -20 ° C for 10 minutes and then treated with a solution of 4-aminobiphenyl (0.5 g, mmol) and anhydrous pyridine (0.3 g, 3.8 mmol) in 5 mL of dichloromethane. The mixture was allowed to warm to room temperature, stirred for 20 hours, evaporated in vacuo and the residue stirred in 5% methanol in dichloromethane (40 mL) and filtered, the filtrate evaporated in vacuo, chromatographed (silica gel, 5% methanol) in dichloromethane) and fractions containing the product were collected, evaporated in vacuo and dissolved in dichloromethane from which the title compound (0.11 g) precipitated: MS (ES) m / e 320 [M + H] ⁺ .

b) N- (1,1'-biphenyl) -4-yl-3- (2-diisopropylamino) ethoxy-4-methoxybenzamide

The procedure of Preparation 1 (a), except that it is replaced by the compound of Example 28 (a), nitroguaiacol, gave the title compound of this example: MS (ES) m / e 446.6 [M + H] ⁺ .

Example 29

Preparation of N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] - (1,1'-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 a 1.0 M solution of borane in tetrahydrofuran (1.56 mL, 1.56 mmol), heated to reflux for 3 hours. , cooled, left at room temperature for 16 hours, carefully treated with 5 ml of methanol, stirred for 1 hour, and stirred for 1 hour and stirred for 1 hour. · · · ♦ »

Φ · ·· • · φ φ · · φ φ φ φφ · Φ evaporated in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (10 mL) and the organic phase was dried over sodium sulfate, concentrated in vacuo, dissolved in dichloromethane and treated with a solution of hydrogen chloride in ether to give the title compound: MS (ES) m / e 433.3 [M + H] <^+> .

Examples 30 and 31

Preparation of N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] 4'-cyano-1,1'-biphenyl-4-carboxamide and N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4 ' -cyano-2'-methyl-1,1'-biphenyl-4-carboxamide

Of Example 1, except that it is replaced by 4'-cyano-4-biphenylcarboxylic acid [WO 94/12181] or 4'-cyano-4-methyl-4-biphenylcarboxylic acid [WO 96/19477] 4- biphenylcarboxylic acid, gave the title compounds of this example:

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4'-cyano-1,1'-biphenyl-4-carboxamide: MS (ES) m / e 472.0 [M + H] ⁺ a

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- [3- (2-diisopropylamino) ethoxy-4- (ethoxycarbonyl) phenyl] - (1,1'-biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by 3- (2-diisopropylamino) ethoxy-4- (ethoxycarbonyl) aniline [Clinton et al., J. Am. Chem. Soc., 79, 2290, (1957)], 39 9 9 99 9 99 99

9,999,999,999 ·· * - 76— · 9,9 9 9 9 9 9 9 9 In 99 99 99 9 99 99 (2-diisopropylamino) ethoxy-4-methoxyaniline provided the title compound of the following example: MS (ES) m / e 489.1 [M + H] &lt; + ^&gt; .

Example 33

Preparation of N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -2-naphthalenecarboxamide

The procedure of Example 1, except that it is replaced by 2-naphthalenecarboxylic acid 4-biphenylcarboxylic acid, afforded the title compound of this example: MS (ES) m / e 421.3 [M + H] ⁺ .

Example 34

Preparation of N- {1'-methylspiro [benzofuran-3 (2H), 4'-piperidin] 5-yl} - (1,1'-biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by 1'-methyl-spiro [benzofuran-3 (2H), 4'-piperidin] -5-amine [WO 96/11934] 3- (2-diisopropylamino) ethoxy- 4-methoxyaniline gave the title compound of this example: MS (ES) m / e 399.2 [M + H] ⁺ .

Examples 35 and 36

Preparation of N- {3- [2- (N-isopropyl-N-methylamino) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide and N-ethyl-N- {3 [2- (N -isopropyl-N-methylamino) ethoxy] -4-methoxyphenyl} (1,1'-biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by the compound of Preparations 17 (b) and 18 (b) 3- (2-diisopropylamino) -77.

9 «9999

9 9 9 9 9 9 9 9 9

9 9 «

9 · * »

9 9 9 € 9 9 «ethoxy-4-methoxyaniline, gave the compounds named in the title of this example:

N- {3- [2- (N-Isopropyl-N-methylamino) -ethoxy] -4-methoxy-phenyl} - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 419.1 [M + H] ] ⁺ a

N-ethyl-N- {3- [2- (N-isopropyl-N-methylamino) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 446.3 [M + H] &lt; + ^&gt; .

Example 37

Preparation of N-methyl-N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) (1,1'-) biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by the compound of Preparation 24 (b) 3- (2-diisopropylamino) ethoxy-4-methoxyaniline and replaced by [2'-methyl-4 '- (5-methyl-1,2,4- 3-Oxadiazolyl) biphenyl] -4-carboxylic acid [EP 0 533 268] 4-biphenylcarboxylic acid gave the title compound of the example: MS (ES) m / e 557.3 [M + H] ⁺ .

Example 38

Preparation of N-methyl-N- [3- (diisopropylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide

The procedure of Example 1, except that it is replaced by the compound of Preparation 24 (b) 3- (2-diisopropylamino) ethoxy-4-methoxyaniline, gave the title compound of this example: MS (ES) m / e 461.3 [M + H] ⁺ .

• · • ·

Example 39

Preparation of Ν- [4- (2-diisopropylamino) ethoxy-3-methoxyphenyl] (1,1'-biphenyl) -4-carboxamide

a) Resin-bound 4 '- (4-biphenylcarboxylic acid)

Resin-bound phenyl bromide [WO 98/17695, Scheme 18] (1.0 g, 1.22 mmol) was swelled in a mixture of 10 mL of toluene and 4 mL of ethanol for 30 minutes and treated with 4-carboxybenzeneboronic 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 mmol). The mixture was refluxed for 24 hours, cooled and the resin was filtered and washed successively with dichloromethane, methanol, 1: 1 methanol / water containing 15 drops of concentrated hydrochloric acid, 1: 1 methanol / water, dichloromethane and water. methanol. The resulting resin was dried under vacuum.

b) resin-bound 4 '- (biphenyl-4-carbonyl chloride)

The resin of Example 39 (a) (0.06 g) and oxalyl chloride (0.13 g, 1 mmol) in toluene (10 mL) were shaken for 16 hours, filtered and washed with toluene and dichloromethane.

c) resin-bound 4 '- {N- [4- (2-diisopropylamino) ethoxy-3-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide}

A mixture of the resin of Example 39 (b), the compound of Preparation 1 (b) (0.13 g, 0.5 mmol) and diisopropylethylamine (0.05 g, 0.4 mmol) in 15 mL of dichloromethane was shaken for 20 hours. The resin was filtered, washed with 3 x 20 mL dichloromethane and 2 x 20 mL methanol and dried in vacuo for 16 hours.

0 · • 0 0 0 0 0 0 <0 · «0 ·· · β 0 · 0000 0 00 00» • 0 0 0 0 0 0

d) N- [4- (2-diisopropylamino) ethoxy-3-methoxyphenyl] (1,1'-biphenyl) -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, then the resin was filtered and washed with 3 x 10 mL of methanol. The filtrate was evaporated in vacuo and the residue was partitioned between 50 mL of dichloromethane and 5 mL of 10% aqueous sodium hydroxide. The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo to give the title compound of this example: MS (ES) m / e 447.4 [M + H] ⁺ .

Examples 40 to 44

Preparation of N- [2- (2-diisopropylamino) ethoxy-3-methoxyphenyl] (1,1'-biphenyl) -4-carboxamide, N- [3- (2-diisopropylamino) ethoxyphenyl] - (1,1'-biphenyl) ) -4-carboxamide, N- [2-fluoro-4- (2-diisopropylamino) ethoxyphenyl] - (1,1'-biphenyl) -4-carboxamide, N- [4- (2-diisopropylamino) ethoxyphenyl] - (1, 1'-biphenyl) -4-carboxamide; and N- [2- (2-diisopropylamino) ethoxyphenyl] - (1,1'-biphenyl) -4-carboxamide.

The procedure of Examples 39 (c) to 39 (d), except that the compound of Preparation 2 to 6 is replaced by the compound of Preparation 1, provided the title compounds of this Example:

N- [2- (2-diisopropylamino) ethoxy-3-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 447.3 [M + H] ⁺ ,

N- [3- (2-diisopropylamino) -ethoxyphenyl] - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 417.5 [M + H] ⁺ ,

N- (2-fluoro-4- (2-diisopropylamino) ethoxyphenyl) - (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 435.4 [M + H] ⁺ , ⁺ J • J

0 · «» ······························································ 9 9 9 9 9 9 9

99 ·· · ·· ·

N- [4- (2-diisopropylamino) ethoxyphenyl] - (1,1'-biphenyl) 4-carboxamide: 417.4 [M + H] ⁺ a

N- [2- (2-diisopropylamino) ethoxyphenyl] - (1,1'-biphenyl) 4-carboxamide: MS (ES) m / e 417.4 [M + H] ⁺ .

Example 45

Preparation of N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4 (iodo) benzamide

a) [3- (Diisopropylaminoethoxy-4-methoxyaniline) / (4-formyl-3,5-dimethoxyphenoxy) -Merrifield resin addition compound

A mixture of 4-formyl-3,5-dimethoxyphenoxy-Merrifield resin [Boojamra et al., J. Org. Chem. 60, 5742 (1995)]

3- (2-diisopropylamino) ethoxy-4-methoxyaniline [WO 95/15954] and sodium triacetoxyborohydride in dimethylformamide containing 1% acetic acid were shaken to give the title compound of this example.

b) N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4-iodobenzamide / (4-formyl-3,5-dimethoxyphenoxy) -Merifield resin addition compound

The resin of Example 45 (a) in dimethylformamide was treated with pyridine and an excess of a mixture of equivalent amounts of 4-iodobenzoic acid, N-bromosuccinimide and triphenylphosphine. The resin was washed to give the title compound of this example.

c) N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4 (iodo) benzamide

The resin of Example 45 (b) was stirred in a mixture of trifluoroacetic acid, dichloromethane and water in a ratio of:

I · 4 · · ··

About · · · · · · · · · · · · · · · · · · · · · · · · · ·

50: 48: 2, filtered and the filtrate evaporated in vacuo to give the title compound of this example: MS (ES) m / e 497.8 [M + H] ⁺ .

Examples 46 to 70

The procedure of Example 45 except that 3- (2-diethylamino) ethoxyaniline [WO 95/15954], 4- (2-diethylamino) ethoxyaniline [Wyatt et al., J. Med. Chem.,

38, 1657, (1995)], 3- (2-diethylamino) ethoxy-4-methoxyaniline [WO 96/23769], 3- (2-diisopropylamino) ethoxy-4-methoxyaniline [WO 95/15954] and compounds of Preparation 3 and Preparation 5 and using 4-isopropylbenzoic acid, 4-cyclohexylbenzoic acid, 4'-ethyl-4biphenylcarboxylic acid, 4-nitrobenzoic acid, 4-methoxybenzoic acid, 3-bromobenzoic acid, 3-iodobenzoic acid, 4-bromobenzoic acid and 4-iodobenzoic acid gave the following compounds:

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] -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] &lt; + &^gt;,

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4- (nitro) benzamide: MS (ES) m / e 416.5 [M + H] &lt; + &^gt;

4 4 »

4 4 4

4 4 4

44

4 ·

4 4 • 4 4 «4 4 4

N- [4- (2-diisopropylamino) ethoxyphenyl] -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-diethylamino) ethoxy-4-methoxyphenyl] -3-iodobenzamide: MS (ES) m / e 460.0 [M + H] ⁺ ,

N- [4- (2-diisopropylamino) ethoxyphenyl] -3-iodobenzamide: MS (ES) m / e 467.0 [M + H] ⁺ ,

N- [3- (2-diisopropylamino) ethoxyphenyl] -3-iodobenzamide: MS (ES) m / e 476.0 [M + H] ⁺ ,

N- [3- (2-diethylamino) ethoxyphenyl] -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-diisopropylamino) ethoxyphenyl] -4-bromobenzamide: MS (ES) m / e 418.8 [M + H] ⁺ ,

N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -3-bromobenzamide: MS (ES) m / e 423.0 [M + H] ⁺ ,

N- [4- (2-diisopropylamino) ethoxyphenyl] -3-bromobenzamide: MS (ES) m / e 418.8 [M + H] &lt; + &^gt;,

N- [4- (2-diisopropylamino) ethoxyphenyl] -4- (isopropyl) benzamide: MS (ES) m / e 382.2 [M + H] &lt; + &^gt;,

N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4- (cyclohexyl) benzamide: MS (ES) m / e 425.2 [M + H] ⁺ ,

N- (4- (2-diisopropylamino) ethoxyphenyl) -4- (cyclohexyl) benzamide: MS (ES) m / e 423.0 [M + H] ⁺ ,

N- [4- (2-diethylamino) ethoxyphenyl] -4- (cyclohexyl) benzamide: MS (ES) m / e 395.0 [M + H] &lt; + &^gt;

Ν- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4'-ethyl (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 447.2 [M + H] ⁺ ,

N- [4- (2-diisopropylamino) ethoxyphenyl] -4'-ethyl- (1,1'biphenyl) -4-carboxamide: MS (ES) m / e 445.2 [M + H] ⁺ ,

N- [4- (2-diethylamino) ethoxyphenyl] -4'-ethyl- (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 417.4 [M + H] ⁺ ,

N- [3- (2-diisopropylamino) ethoxyphenyl] -4'-ethyl- (1,1'-biphenyl) -4-carboxamide: MS (ES) m / e 445.2 [M + H] ⁺ .

Examples 71 to 73

Preparation of N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] 3,4-dichlorobenzamide, N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3,5-dichlorobenzamide and N- [3 - ( 2-diisopropylamino) ethoxy-4-methoxyphenyl] -4 (cyclohexyl) benzamide,

The procedure of Example 1, except that it is replaced with 3,4-dichlorobenzoic acid, 3,5-dichlorobenzoic acid or 4-cyclohexylbenzoic acid 4-biphenylcarboxylic acid, gave the title compounds of this example:

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3,4-dichlorobenzamide: MS (ES) m / e 439.3 [M + H] &lt; + &^gt;,

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3,5-dichlorobenzamide: MS (ES) m / e 439.2 [M + H] ^&lt; ⁺ &^gt;

N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4- (cyclohexyl) benzamide: MS (ES) m / e 453.0 [M + H] ⁺ .

Example 74 «» • · 9 9 »9

Preparation of Ν- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3'-methoxy- (1,1'-biphenyl) -4-carboxamide,

a) N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -4- (4,4,5,5-tetramethyl-1,3,2-2-dioxaborolanyl) benzamide / (4-formyl-3) addition compound 5-dimethoxyphenoxy) -Merrifield resins

The procedure of Example 45 (b), except that it is replaced by 4- (4,4,5,5-tetramethyl-1,3,2-2-dioxaborolanyl) -benzoic acid [Guiles et al., J. Org. Chem.,

61, 5169, (1996)] 4-iodobenzoic acid gave the addition compound named in the title of this example.

b) N- [3- (2-Diisopropylamino) ethoxy-4-methoxyphenyl] -3'-methoxy- (1,1'-biphenyl) -4-carboxamide / (4-formyl-3,5-dimethoxyphenoxy) -Merrifield resin addition compound

Following the general procedure of Guiles et al., J. Org. Chem.

61, 5169, (1996), reacting the addition compound of Example 74 (a) in dimethylformamide with 3-iodoanisole, tetrakis (triphenylphosphine) palladium (0) and an aqueous potassium carbonate solution at 80 ° C for 18 hours to obtain an addition the title compound of this example.

c) N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3'-methoxy- (1,1'-biphenyl) -4-carboxamide

The procedure of Example 45 (c), except that it was replaced by the addition compound of Example 74 (b), the addition compound of Example 42 (b), provided the title compound of this example: MS (ES) m / e 477.2 [M + H] &lt; + ^&gt; .

Examples 75 to 81

Preparation of Ν- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -4'-methoxy- (1,1'-biphenyl) -4-carboxamide, N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4'-acetyl- (1,1'-biphenyl) -4-carboxamide] -4'-hydroxy- (1,1'-biphenyl) -4-carboxamide N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -3'-methoxy- (1,1'-biphenyl) -4-carboxamide, N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] - 3'-methoxy- (1,1'-biphenyl) -4-carboxamide, N [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3'-hydroxy (1,1'-biphenyl) -4-carboxamide and N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -3'-hydroxy- (1,1'-biphenyl) -4-carboxamide

The procedure of Example 74, except that 3- (2-diisopropylamino) ethoxy-4-methoxyaniline [WO 95/15954], 3- (2-diethylamino) ethoxy-4-methoxyaniline and 3- (2-dimethylamino) is used. ethoxy-4-methoxyaniline and using 3-iodophenol, 3-iodoanisole and 4'-iodoacetophenone gave the title compounds of this example:

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] &lt; + ^&gt; ,

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] &lt; + ^&gt; ,

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- [2- (dimethylaminomethyl) -1,4-benzo-7-dioxanyl] 2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) 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-4 '- (5 mL) was added. methyl-1,2,4-3-oxadiazolyl) biphenyl-4-carbonyl chloride [WO 95/15954] (0.6 mmol). The mixture was stirred for 16 hours, evaporated in vacuo and partitioned between water and chloroform. The organic phase was dried over sodium sulfate and evaporated in vacuo to give a white foam which was chromatographed (basic alumina, ethyl acetate) to give the title compound of this example. Melting point 92-94 ° C.

Example 84

Preparation of N- [2- (dimethylaminomethyl) -1,4-benzo-6-dioxanyl] 2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) biphenyl) -4-carboxamide

0 «(·

0 ·

0

0

The procedure of Example 82, except that it is replaced by the compound of Preparation 25 (c), the compound of Preparation 26 (c), gave the title compound of this Example. Mp 188-190 ° C.

Biological data

Analysis of CCR5 receptor binding

CHO cell membranes (0.25 x 10 ⁶ cell equivalents) derived from cells permanently transfected with CCR5 were incubated with 0.3 ¹²⁵ I-RANTES in a 96-well plate for 45 minutes at room temperature (final reaction volume 200 µΐ). The reaction was terminated by filtration and the filters (GF / C) were washed 12 times with phosphate buffered saline containing 0.1% bovine serum albumin and 0.05% NaN 3. Radioactivity trapped on the filters was measured by liquid scintillation spectrometry. Non-specific binding was determined by the presence of unlabeled RANTES (10 or 30 nM) with an average of 30 to 50% of total binding.

Analysis of CCR5 receptor functionality

The cell functionality analysis used to test the antagonist activity of the compounds was RANTES-induced Ca ⁺ mobilization in RBL 2H3 cells stably expressing the hCCR5 receptor (RBL 2H3 hCCR5). Antagonist activity is determined by mobilizing Ca ⁺ in the same cells that are inhibited by a selective CCR5 antagonist. Cells were grown to 80-100% confluency in T-150 flasks and washed with phosphate buffered saline. Cells were transferred from the flasks by treatment with 3 ml of 1 mM EDTA for 3

- 88 • 4 9 99 · 4 · 4 · 4 · 4 · 4 · 4 ·

9,999 9 9,999 9

4 minutes at room temperature and diluted to 2 x 10 ⁵ cells / ml with Krebs Ringer Henseleit buffer (KRH, 118 mM sodium chloride, 4.6 mM potassium chloride, 25 mM bicarbonate) sodium phosphate, 1 mM potassium dihydrogen phosphate and 11 mM glucose) containing 5 mM HEPES (pH 7.4), mM calcium chloride, 1 mM magnesium chloride, and 0.1% BSA, and centrifuged at 200 g for 3 minutes. The cells were resuspended at 2 x 10 ⁶ cells / ml in the same buffer with 2 µΜ Eura-2AM and then cultured at 37 ° C for 15 minutes to complete hydrolysis of the intracellular Fura-2AM and then centrifuged as described above. Cells (10 6 cells / ml) were resuspended in cold KRH with 5 ml HEPES (pH 7.4), 1 mM calcium chloride and 0.1% gelatin and left on an ice bath until analysis. For antagonist studies, aliquots (2 ml) of cells were pre-heated to 37 ° C for 5 minutes in 3 ml plastic cuvettes and magnetic stirring while maintaining the temperature at 37 ° C on a fluorometer (Johnson Foundation Biomedical Group, Philadelphia, PA). (USA) measured fluorescence. The excitation wavelength was set to 340 nm and the emission wavelength to 510 nm. Various concentrations of antagonists or vehicle were added and fluorescence was monitored for about 15 seconds to provide baseline fluorescence, followed by the addition of 33 nM RANTES. The maximum Ca ²⁺ achieved after stimulation with 33 nM RANTES was calculated as described by Gynkiewitz et al., (1985). Percent of the highest Ca ²⁺ induced by RANTES for each of the antagonist concentrations was determined, and IC ₅₀ , defined as the concentration of test compound that inhibits 50% of the maximal response elicited by 33 mM RANTES, was determined from the concentration-response curves (5-7 antagonist concentrations).

- 89 0 «

0 0 0 0 0 0 0 0 0 0 0 0 0 · 0

0 0 0 »0

0 0 0 0 · «0 00 0 0 * 00 0 0 0 0 0 ·

000000 00 *

0 0 0 0 • 0 0 0

The compounds of the invention exhibit CCR5 receptor ligand activity with IC ₅₀ values ranging from 0.0001 to 100 µΜ. The structure-activity relationships have not yet been established for the compounds of the present invention. However, in view of this disclosure, one skilled in the art can utilize said analysis to determine which compounds of formula (I) are CCR5 receptor ligands and which bind to it with an IC 50 in the range of 0.0001 to 100 µΜ.

All publications, including but not limited to the patents and patent applications cited in this specification, are incorporated herein by reference, as well as each individual publication being specifically and individually designated for inclusion in the references in its entirety.

The above description fully discloses the invention, including preferred embodiments thereof. Changes and improvements to the embodiments specifically described herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art using the foregoing description will utilize the present invention to its fullest extent. Therefore, the examples are to be construed as merely illustrative and not limiting the scope of the invention in any way. Embodiments of the invention whose particular features or advantages are protected are as defined below.

Claims (4)

PATENT CLAIMS 1'-ethyl-5- [2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazol-yl) biphenyl-4-carbonyl] -2,3,6,7-tetrahydrospirofuro ( 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-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] - (1,1'-biphenyl) -4-carboxamide, N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4'-chloro (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, 108. · Ν- [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) ethoxyphenyl] -4-iodobenzamide, N- [2- (2-diethylamino) ethoxyphenyl] -4-iodobenzamide, N- [4- (2-diethylamino) ethoxyphenyl] -3-iodobenzamide, N- [2- (2-diisopropylamino) ethoxyphenyl] -3-iodobenzamide, N- [2- (2-diethylamino) ethoxyphenyl] -3-iodobenzamide, N- [3- (2-diethylamino) ethoxyphenyl] -4-bromobenzamide, N- [2- (2-diisopropylamino) ethoxyphenyl] -4-bromobenzamide, N- [2- (2-diethylamino) ethoxyphenyl] -4-bromobenzamide, N- [4- (2-diethylamino) ethoxyphenyl] -3-bromobenzamide, N- [2- (2-diisopropylamino) ethoxyphenyl] -3-bromobenzamide, N- [2- (2-diethylamino) ethoxyphenyl] -3-bromobenzamide, N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4- (dimethylamino) benzamide, N- [4- (2-diisopropylamino) ethoxyphenyl] -4- (dimethylamino) benzamide, N- [4- (2-diethylamino) ethoxyphenyl] -4- (dimethylamino) benzamide, N- [2- (2-diisopropylamino) ethoxyphenyl] -4- (dimethylamino) benzamide, N- [2- (2-diethylamino) ethoxyphenyl] -4- (dimethylamino) benzamide, N- [4- (2-diethylamino) ethoxyphenyl] -4- (isopropyl) -benzamide, N- [2- (2-diisopropylamino) ethoxyphenyl] -4- (isopropyl) benzamide, 10 £ * N- [2- (2-diethylamino) ethoxyphenyl] -4- (isopropyl) -benzamide, N- [3- (2-diethylamino) ethoxyphenyl] -4- (cyclohexyl) -benzamide N- [2- (2-diisopropylamino) ethoxyphenyl] -4- (cyclohexyl) benzamide, N- [2- (2-diethylamino) ethoxyphenyl] -4- (cyclohexyl) -benzamide N- [2- (2-diisopropylamino) ethoxyphenyl] -4'-ethyl- (1,1'biphenyl) -4-carboxamide; and N- [2- (2-diethylamino) ethoxyphenyl] -4'-ethyl- (1,1'-biphenyl) 4-carboxamide, for the manufacture of a medicament for the treatment of a CCR5 mediated condition in a mammal. 1,2,4,3-Oxadiazolyl) -2'-methylbiphenyl-4-carbonyl] -1'-methylspiro [furo (2,3-g) quinoline-3,4'-piperidine], 4 '- (dimethylamino) - 5- {2'-Methyl-4 '- [(5-methyl-1,2,4,3-oxadiazolyl) -4-biphenylyl] carbonyl} 2,3,6,7tetrahydrospiro [furo (2,3-f) indole] -3,1'-cyclohexane], N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -3-carboxamide, N- [3- (3-dimethylamino) propoxyphenyl] - (1,1'-biphenyl) -4-carboxamide, N- [4- (3-dimethylamino) propoxyphenyl] - (1,1'-biphenyl) -4-carboxamide, N- [3- (diethylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) 4-carboxamide, N- {3- [2- (1-piperidinyl) ethoxy] -4-methoxyphenyl} - (l _r 1 '-biphenyl) -4-carboxamide, N- [3- (2-diisopropylamino) ethoxy-2-methylphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4- carboxamide, N- [3- (2-dipropylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide, 103 * a · a · a a 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) ethoxyphenyl] - (1,1'-biphenyl) -4-carboxamide, N- [2-fluoro-4- (2-diisopropylamino) ethoxyphenyl] - (1,1'-biphenyl) -4-carboxamide, N- [4- (2-diisopropylamino) ethoxyphenyl] - (1,1'-biphenyl) -4-carboxamide, N- [2- (2-diisopropylamino) ethoxyphenyl] - (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-dichlorobenzamide, 104 · * · · · ··· · · « [- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3,5-dichlorobenzamide, Ν- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4 (nitro) benzamide, N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -3-benzamide, N- [4- (2-diisopropylamino) ethoxyphenyl] -3-iodobenzamide, N- [4- (2-diisopropylamino) ethoxyphenyl] -3-bromobenzamide, N- [4- (2-diisopropylamino) ethoxyphenyl] -4 (cyclohexyl) benzamide, N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4- (cyclohexyl) benzamide, N- [3- (2-diethylamino) ethoxy-4-methoxyphenyl] -4-ethyl- (1,1'-biphenyl) -4-carboxamide, N- [3- (2-diisopropylamino) ethoxyphenyl] -4'-ethyl- (1,1'-biphenyl) -4-carboxamide; and N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl] -3'-methoxy (1,1'-biphenyl) -4-carboxamide, more preferred compounds include: N- [3- (2-diisopropylamino) ethoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4-carboxamide, N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4 5- {4- [2-methyl-4- (5-methyl-1,2,4-3-oxadiazolyl) phenyl] benzoylamino) spiro [(2,3-dihydrobenzofuran) 3,4 '- (1-methylpiperidine) -carboxamide oxalate ], N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] - (1,1'-biphenyl) -4-carboxamide; ························ 4 4 4 4 4 4 4 4 4 4 4 · · 4 4 • • · 4 4 Ν- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -2'-methyl (1,1'-biphenyl) -4-carboxamide, Ν- [3- (2-diisopropylamino) ethoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4-carboxamide, N- {3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide, N- {3- [2- (cis-2,6-dimethyl-1-piperidinyl) 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-dimethyl-1-pyrrolidinyl) ethoxy] -4-methoxyphenyl} - (1,1'-biphenyl) -4-carboxamide, N- {4-methoxy-3- [2- (2,2,6,6-tetrahydro-1-piperidinyl) -ethoxy] -4-methoxy-phenyl} - (1,1'-biphenyl) -4-carboxamide, N- {3- [2- (N-tert-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-diisopropylamino) ethoxy-4-iodophenyl] - (1,1'-biphenyl) -4-carboxamide, dihydrochloride N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] - (1,1 ') -biphenyl) -4-methanamine, N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4'-cyano-1,1'-biphenyl-4-carboxamide, N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4'-cyano-2'-methyl-1,1'-biphenyl-4-carboxamide, N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -2-naphthalenecarboxamide, 106 4,444 4 4 «•• 44 44 ·· •» 4 4 4 4 · 4 4 4 4 · 4 · 4 · 44 44 N- {1'-methylspiro-5- [benzofuran-3 (2H), 4'-piperidin] -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 (iodo) benzamide, N- [3- (2-diisopropylamino) ethoxy-4-methoxyphenyl] -4- (cyclohexyl) 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, provided that the following compounds are excluded: N- [3- (2-dimethylaminoethoxy) -4-methoxyphenyl] -4 '- (5-dimethylamino-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4-carboxamide, N- [3- (1-methyl-2-azetidinylmethoxy) -4-methoxyphenyl] -4 '- (5-methyl-1,2,4-3-oxadiazolyl) -2'-methylbiphenyl-4-carboxamide oxalate [7] - (2-dimethylaminoethoxy) -6-methoxy-3,4-dihydro-2H-1-quinolinyl] - {[2'-methyl- (1,2,4) -3-oxadiazol-yl] -4-biphenylyl} methanone, oxalate 2 3,6,7-tetrahydro-1'-methyl-5- [2'-methyl-4'- (5-methyl-1,2,4-3-oxadiazolyl) biphenyl-4-carbonyl] -furo (2,3f) Indole-3-spiro-3'-piperidine; 5- [4 '- (5-methyl-1,2,4-3-oxadiazolyl) biphenyl-4-carbonyl] -1'-methyl-2,3,6,7-tetrahydrofuro (2,3-f) indole- 3-spiro-4'-piperidine, 1 is 1, 2 or 3 when Ar is (i), (ii) or (iii) and A is CONR ⁷⁰ , NHCO, NHCH 2 or CH ₂ NH, wherein R ⁷⁰ is hydrogen or alkyl of 1 to 6 carbon atoms, represents E (c): in which: M is an oxygen atom, S (O) _P , wherein p is 0, 1 or 2, CR ⁷⁶ = CR ⁷⁷ or CR ⁷⁶ R ⁷⁷ , wherein R ⁷⁶ and R ⁷⁷ are independently hydrogen or an alkyl group containing 1 to 2 6 carbon atoms, or M is NR ⁷⁸ wherein R ⁷⁸ is hydrogen or alkyl, R ( ⁷¹⁾ and R ( ⁷²⁾ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms, R ⁷³ is hydrogen, alkyl of 1 to 6 atoms; 97 · · ^{- 7} ' 4 4 « 4 4 4 4 4 4444 «44 · 43 4 4 9 4 4 · 4 4 4 4 4 4 4 80 alkyl, CO ₂ R ^79, NHCO ₂ R ^ou, hydroxy, alkoxy containing 1 to 6 carbon atoms or a halo group, wherein R ⁷⁹ is hydrogen or alkyl having 1 to 6 carbon atoms and R ⁸⁰ is an alkyl group having 1 to 6 carbon atoms, R ⁷⁴ is a hydrogen atom or together with R ⁷⁰ forms a group Q wherein Q is CR ⁸¹ = CR ⁸² , CR ⁸¹ = CR ⁸² 'CR ⁸¹ R ⁸² or (CR ⁸¹ R ⁸² ) _q wherein q is 2 or 3 and R ( ⁸¹⁾ and R ( ⁸²⁾ independently of one another are hydrogen or alkyl having 1 to 6 carbon atoms, having a value of 0, 1, 2 or 3, having a value of 1 or 2, is a group of formula (d): (CH ₂ ), (CH ₂ ) _s (CH ₂ ), (d) wherein r, sat are independent integers having values of 1, 2 or 3, or is a group of formula (e): -í> pu '—N \ R83: e) wherein u is 0, 1, 2 or 3 and R ⁸³ is hydrogen or C 1-6 alkyl when Ar is (i), (ii) or (iii) and A is CONH, NHCO, or CH ₂ NH, E represents (f): W - (CR84 _{R8S) - NR6R87} T * 9 9 • 9 9§ 9 9 » 9 9 · » 9 · ♦ · 9 · · “ 9 9 »9 · 9 · · R ( ⁸⁴⁾ and R ( ⁸⁵⁾ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms, r86 _and 87 _are independently of one another hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, an aralkyl group, or together with the nitrogen atom to which they are attached an optionally substituted 5- to 7-membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, T is (CR ⁸⁸ R ⁸⁹ ) w - or -O (CR ⁸⁸ R ⁸⁹ ) x -, wherein R ⁸⁸ and R ⁸⁹ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms, w is 2 or 3 axes has a value of 1, 2 or 3, v is 1 to 4, and W is O, S (O) _y where y is 0, 1 or 2, or W is NR ⁹⁰ wherein R ⁹⁰ is hydrogen or C 1 -C 6 alkyl, or W is CR ⁹¹ = CR ⁹² or CR ³¹ R ⁹² , wherein R ⁹¹ and R ⁹² are independently hydrogen or C 1 -C 6 alkyl when Ar is (i), (ii) or (iii) and A is CONR ⁹³ , NHCO or CH ₂ NH, wherein R ⁹³ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, represents an E group (g): R ⁹⁴ is hydrogen, halogen, hydroxy, (C 1 -C 6) alkyl or (C 1 -C 6) alkoxy, or R ⁹⁴ and R ⁹³ together form -X-, where X is (CR ⁹⁷ R ⁹⁸ ) _aa wherein aa is 2, 3 or 4 and R ⁹⁷ and R ⁹⁸ are independently hydrogen or C 1 -C 6 alkyl or X is 99. 0 · (CR ⁹⁷ R ⁹⁸ ) ab-Y, where ab is 0, 1, 2 or 3 and Y is oxygen, sulfur or CR ⁹⁷ = CR ⁹⁸ , R ⁹⁵ is hydrogen, C 1 -C 6 alkyl, CO 2 R ⁹⁹ , NHCO 2 R ¹⁰⁰ , hydroxy, alkoxy C 1 -C 6 or halogen wherein R ⁹⁵ is hydrogen or C 1 -C 6 alkyl and R ¹⁰⁰ is C 1 -C 6 alkyl, z is 1 or 2 and R ⁹⁶ is an optionally substituted, 5- to 7-membered saturated or partially saturated heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, or R ⁹⁶ is an optionally substituted 6,6 or 6,5 bicyclic ring containing a nitrogen atom and optionally another heteroatom selected from the group consisting of nitrogen, oxygen or sulfur when Ar is (i), (ii) or (iii) and A is CONR ¹⁰¹ , NHCO or CH ₂ NH, wherein R ¹⁰¹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, represents an E group (h): Z - + - (CR 1 ^O 3 R 1 ^W ) - NR ¹⁰⁵ R ¹⁰⁶ R102 (h) R ¹⁰² is hydrogen or C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halo, or R ¹⁰² together with R ¹⁰¹ forms a -AA- group where AA is (CR ¹⁰⁷ R ¹⁰⁸ ) and / or and d is 1, 2 or 3 and R ¹⁰⁷ and R ¹⁰⁸ are independently hydrogen or C 1 -C 6 alkyl or AA is (CR ¹⁰⁷ = CR ¹⁰⁸ ) _ae -AB wherein ae is 0, 1 or 2 and AB is oxygen, sulfur, CR ¹⁰⁷ = CR ^108, CR ¹⁰⁷ = N, CR, NR ¹⁰² or N = ¹⁰⁸ N R ¹⁰³ and R ¹⁰⁴ are, independently of one another, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, • φ • ΦΦΦ 100 ALIGN! φ ¹ R ¹⁰⁵ and R ¹⁰⁶ are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aralkyl or together with the nitrogen atom to which they are attached an optionally substituted 5- to 7- a membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulfur, and c is 0 to 4, Z is an optionally substituted, 5- to 7-membered heterocyclic ring containing one to three heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur when Ar is (i), (ii) or (iii) and A is CONR ¹⁰⁹ , NHCO or CH 2 NH, wherein R ¹⁰⁹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, represents an E group (i): (CH _{2) h} -NR ^{112 in} the R "(CH _{2) aI} OR ⁿ³ R ” ⁴ ) and _g (i) R110 R ( ¹¹⁰⁾ is hydrogen or alkyl having 1 to 6 carbon atoms or R ( ¹¹⁰⁾ and R ( ¹⁰⁹⁾ together are AD-, where AD is (CR ¹¹⁵ R ¹¹⁶ ) and where ah is 2, 3 or 4 and R ¹¹⁵ and R 11 ¹¹⁶ are independently hydrogen or C 1 -C 6 alkyl or AD is (CR ¹¹⁵ R ¹¹⁶ ) _and i-AE, wherein ai is 0, 1, 2 or 3 and AE is O, S or ^R111 and ^R121 independently of one another are hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aralkyl or, together with the nitrogen atom to which they are attached optionally substituted 5- to 7- a membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulfur; 100 * «··· R ( ¹¹³⁾ and R ( ¹¹⁴⁾ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms, AC is O, CR ^U7 R ¹¹⁸ or NR ¹¹⁹ , wherein R ¹¹⁷ , R ¹¹⁸ and R ¹¹⁹ are independently hydrogen or C 1 -C 6 alkyl, or AC is S (O) _and j in which: aj is 0, 1, or 2, af Is 1, 2, or 3 ag is 1, 2, 3 or 4; and ah 0, 1, 2, 3, or 4 for the manufacture of a pharmaceutical composition for the treatment of a CCR5 mediated disease condition in a mammal. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: Ar-A-E (I) wherein Ar is a group selected from (i), (ii) or (iii) in which R ¹ and R ² are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkenyl containing 3-6 carbon atoms, aryl, (CH 2) a NR ⁷ R ^8, (CH ₂₎ m NR ⁷ COR ^9, (CH 2) a NR ⁷ CO 2 R ^10, (CH ₂₎ m NR ⁷ SO 2 ^N (CH 2) _a NR ⁷ CONR ¹² R ¹³ , (C 1 -C 6) alkyl substituted with hydroxy, C (C 1 -C 4) alkyl (optionally substituted C 1 -C 4 alkoxy or hydroxy), (CH ₂ ) _and CO ₂ C _1-6 alkyl, (CH ₂ ) _b OC (O) R ¹⁴ , CR ¹⁵ = NOR ¹⁶ , COR ¹⁷ , CONR ¹² R ¹³ , CONR ¹² (CH 2) cOC 1-4 alkyl, CONR ¹² (CH 2) _and CO ₂ R ^18, CONHNR ¹⁹ R ^20, CONR ¹² SO 2 R ^21, CO 2 R ^22, cyano, a trifluoromethyl, NR ⁷ R ^8, NR ⁷ COR ⁹ , NR ²³ CO (CH 2) and NR ²³ R ²⁴ , NR ²³ CONR ²³ R ²⁴ , NR ⁷ CO ₂ R ¹⁰ , NR ⁷ SO ₂ R ⁿ , 9 9 < ? ι :: 9 9 9 9 9 9 9 9 9 9 9 99 ·> · • 9 9 9 9 β 9 9 9 I 9 9 9 O 9 9 9 n N = CNR NR R, nitro, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, OC (0) NR ²⁵ R ²⁶ SR ²⁷ , SO ² R ²⁸ , SO ² NR ²⁵ R ²⁶ or a halogen group, and is 1, 2, 3 or 4, R ⁷ and R ⁸ independently of one another are hydrogen or alkyl having 1 to 6 carbon atoms or NR ⁷ R ⁸ form a 5 or 6 membered heterocyclic ring which may be optionally substituted by oxo and if the ring is 6-membered, the ring may optionally contain one oxygen or sulfur atom, R ⁹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyalkyl group having 1 to 4 carbon atoms, R ¹⁰ is an alkyl group having 1 to 6 carbon atoms, R ¹¹ is C 1 -C 6 alkyl or phenyl, R ¹² and R ¹³ are each independently hydrogen or C 1 -C 6 alkyl, or NR ¹² R ¹³ forms a saturated heterocyclic ring having 5 or 6 members; if the ring is 6-membered, the ring may optionally contain one atom oxygen or sulfur, b is 0, 1, 2 or 3, R ¹⁴ is C 1 -C 4 alkyl optionally substituted with C 1 -C 6 alkoxy, R ( ¹⁵⁾ and R ( ¹⁶⁾ independently of one another are hydrogen or alkyl having 1 to 6 carbon atoms, R ¹⁷ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; 0 0 • 0 0 0 · 0 · 0 (0 * · c is 1, 2, or 3) R ¹⁸ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R and R are each independently hydrogen or (C 1 -C 6) alkyl, R ²¹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ²² is hydrogen or C 1 -C 6 alkyl optionally substituted with one or two substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy and NR ⁷ R 11 ⁸ , ppo λ R and R are, independently of one another, a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ²⁵ and R ²⁶ are independently hydrogen or C 1 -C 6 alkyl, or NR ²⁵ R ²⁶ forms a saturated heterocyclic ring having 5 or β members, which, if the members are 6, may optionally contain one in the ring an oxygen atom or a sulfur atom, R ²⁷ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ²⁸ is an alkyl group having 1 to 6 carbon atoms, P is a 5-7 membered heterocyclic ring containing 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, R ³ and R ⁴ are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 cycloalkenyl, C 1 -C 6 alkyl substituted with hydroxy , C 1-6 alkylC 1-6 alkyl, CONR ²⁹ R ³⁰ , CO ² R ³¹ , cyano, aryl & trifluoromethyl, NR ²⁹ R ³⁰ , nitro, hydroxy, C 1 -C 6 alkoxy, acyloxy or halogen, R, R and R are each independently hydrogen or (C 1 -C 6) alkyl, R ⁵ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a halogen group, R ⁶ is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl (optionally substituted with hydroxy or oxo), C 1 -C 6 alkyl substituted with hydroxy, C 3 -C 7 alkenyl 6 carbon atoms unsubstitued hydroxy, alkynyl of 3-6 carbon atoms unsubstitued hydroxy, (CH _{2) d} OR ³² (CH2) dcor ³³ (CH2) DCR ³⁴ = NOR ^35, CONR ³⁶ R ^37, CO 2 R ^38, hydroxy, O (CH 2) _e R ³⁹ , NR ³⁶ R ³⁷ , SR ⁴⁰ , SO ₂ NR ⁴¹ R ⁴² or a halogen group, d is 0, 1, 2, 3, 4, 5 or 6, R ³² is C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with hydroxy or C 1 -C 4 alkanoyl, R ( ³³⁾ is hydrogen or (C1-C6) -alkyl, R ³⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ³⁵ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ( ³⁶⁾ and R ( ³⁷⁾ independently of one another are hydrogen or alkyl having 1 to 6 carbon atoms, or NR ( ³⁶⁾ R ( ³⁷⁾ forms a saturated heterocyclic ring having 5 or 6 carbon atoms; the members which may be optionally substituted by an oxo group and, if the members are 6, may optionally contain one oxygen atom, a sulfur atom or an NH group in the ring, or NR ⁴³ where R ⁴³ is an alkyl group having 1 to 6 carbon atoms, COR ⁴⁴ or CO ₂ R ⁴⁵ , wherein R ⁴⁴ and R ⁴⁵ are independently hydrogen or C 1 -C 6 alkyl, R ³⁸ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, e having a value of 1, 2, 3, 4, 5 or 6, R ³⁹ is C 1 -C 6 alkoxy, CO ₂ H, CO ₂ C 1-6 alkyl or CONR ³⁶ R ³⁷ , R ( ⁴⁰⁾ is hydrogen or (C1-C6) -alkyl, R ⁴¹ and R ⁴² are independently hydrogen or alkyl of 1 to 6 carbon atoms, or else R ⁵ and R ⁶ form a fused benzene ring optionally substituted by alkyl containing 1-6 carbon atoms, alkoxy of 1 to 6 carbon carbon or halogen when Ar is (i), (ii) or (iii) and A is CONR ⁴⁶ , NHCO, NHCH ₂ or CH ₂ NH, wherein R ⁴⁶ is hydrogen or C 1 -C 6 alkyl represents E (a): where R ( ⁴⁷⁾ and R ( ⁴⁸⁾ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms, R ⁴⁹ is hydrogen, alkyl of 1 to 6 carbon atoms, CO ² R ⁵³ , NHCO ² R ⁵⁴ , hydroxy, alkoxy of 1 to 6 carbon atoms or a halogen group wherein R ⁵³ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms and R ⁵⁴ is an alkyl group having 1 to 6 carbon atoms, R ⁵⁰ and R ⁵¹ independently of one another are hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aralkyl or, together with the nitrogen atom to which they are attached, form an optionally substituted 5- to β a membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, B is an oxygen atom, S (O) h, where h is 0, 1 or 2, CR ⁵⁵ = CR ⁵⁶ or CR ⁵⁵ R ⁵⁶ , wherein R ⁵⁵ and R ⁵⁶ are each independently hydrogen or C 1 -C 6 alkyl, or B is NR ⁵⁷ wherein R ⁵⁷ is hydrogen, C 1 -C 6 alkyl up to 6 carbon atoms or an alkyl group containing 1 to 6 carbon atoms with a substituted phenyl group, R ⁵² is hydrogen or R ⁵² together with R ⁴⁶ form a group D, wherein D is (CR ⁵⁸ R ⁵⁹ ) 1, where i is 2, 3 or 4 and R ⁵⁸ and R ⁵⁹ independently of one another are hydrogen or C 1 -C 6 alkyl, or is D (CR ⁵⁸ R ⁵⁹ ) j where j is 0, 1, 2 or 3 and G is oxygen, atom sulfur or CR ⁵⁸ = CR ⁵⁹ , f is 1 to 4 and g is 1 or 2 when Ar is (i), (ii) or (iii) and A is CONR ⁶⁰ , NHCO or CH ₂ NH, wherein R ⁶⁰ is hydrogen or C 1 -C 6 alkyl, E is (b): f NRS2 R61 • * «·· 0 R ⁶¹ is hydrogen, alkyl of 1 to 6 carbon atoms, or R ⁶¹ and R ⁶⁰ together form a group -K-, where K is (CR ⁶⁵ R ⁶⁶ ) m, wherein m is 2, 3 or 4 and R ⁶⁵ and R ⁶⁶ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms, or K (CR ⁶⁵ R ⁶⁶ ) is nL, where n is 0, 1, 2 or 3 and L is an oxygen atom, a sulfur atom or CR ⁶⁵ = CR ^6S R ⁶² is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ⁶³ and R ⁶⁴ independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms, J is O, CR ⁶⁷ R ⁶⁸ or NR ⁶⁹ , wherein R ⁶⁷ , R ⁶⁸ and R ⁶⁹ are independently hydrogen or C 1-6 alkyl or J is S (O) _m where m has 0, 1, or 2, k is 1, 2, or 3 Use of a compound of formula (I) according to claim 1 wherein the compound is selected from the group consisting of: N- [3- (3-dimethylamino) propoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4- carboxamide, N- [3- (2-piperidin) ethoxy-4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) - (1,1'-biphenyl) -4- carboxamide, N- [3- (3-dimethylaminopropyl) -4-methoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) -biphenyl-4-carboxamide oxalate, oxalate N - [3- (1-methyl-4-piperidyl) -4-methoxyphenyl] -2'methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) -biphenyl-4-carboxamide, oxalat N - [3- (1-methyl-3-piperidyl) methoxyphenyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) biphenyl-4-carboxamide, N- [7- (2-dimethylamino) ethoxy-2,3-dihydro-5-benzofuranyl] 2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) biphenyl-4-carboxamide, [3- (dimethylaminomethyl) -3,6,7,8-tetrahydro-2H-furo (2,3-g) -5-quinolinyl] - {2'-methyl-4 '- [5-methyl- (1,2) -oxalate oxalate (4) -3-Oxadiazolyl] -4-biphenylyl} -methanone; 102 * {5- {4- [2-methyl-4- (5-methyl-1,2,4-3-oxadiazolyl) phenyl] benzoylamino} -spiro [2,3-dihydro-benzofuran] oxalate - 3,4 '- (1-methylhexahydroazepine)], 2,3,5,6,7,8-hexahydro-1'-methyl-5- {2'-methyl-4' [(5-methyl-1,2 ', 4- (3-oxadiazolyl) -4-biphenylyl] carbonyl} furo (2,3-g) quinoline-3-spiro-4'-piperidine, 6,7,8,9-tetrahydro-1'-methyl-5 - {[2'-methyl-4'-5- (methyl-1,2,4,3-oxadiazolyl) (1,1'-4-biphenylyl] carbonyl} - spiro [2H-furo (2,3-h) (1) benzazepine-3- (5H), 4'-piperidine], 2,3,5,6,7,8-hexahydro-5- [4 '- (5) - hydrochloride -hydroxymethyl Use according to claim 1, for the manufacture of a medicament having an effect against a disease selected from the group comprising COPD, asthma and atopic disorders, rheumatoid arthritis, benign lymphogranuloma and other fibrotic disorders, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis and inflammatory diseases intestines and infections HIV. The use of claim 1, wherein the compound is selected from the group consisting of: 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-4-methoxyphenyl] -2-naphthalenecarboxamide, N- [3- (2-dimethylaminomethyl) -1,4-7-benzodioxanyl] -2'-methyl-4 '- (5-methyl-1,2,4-3-oxadiazolyl) biphenyl-4-carboxamide · · No. · *: ···· ·· · «·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Ν- [2- (dimethylaminomethyl) 1,4-6-benzodioxanyl] -2'-methyl 4 '- (5-methyl-1,2,4-3-oxadiazolyl) biphenyl-4-carboxamide, for the manufacture of a pharmaceutical composition for treatment of CCR5 mediated disease states in mammals.