WO2002034760A2 - Compounds and methods - Google Patents

Abstract

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

Description

COMPOUNDS AND METHODS

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

BACKGROUND OF THE INVENTION

T cells are not only key regulators of the immune response to infectious agents but are believed critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases. Increased numbers or enhanced activation state of T cells, especially CD4+ T cells, have been demonstrated in the synovium of individuals with rheumatoid arthritis (M.J. Elliott and R. N. Maini, Int. Arch. Allergy Immunol. 104: 112-1125, 1994), in the bronchial mucosa of asthmatics (C.J. Corrigan and A.B. Kay, Immunol. Today 13:501-506, 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarland, Crit. Rev. Clin. Lab. Sci. 32: 121-182, 1995), in psoriatic lesions (J.L. Jones, J. Berth- Jone, A. Fletcher and P.E. Hutchinson, J. Pathol. 174: 77-82, 1994) and in the fatty streaks of atherosclerosis (R. Ross, Annu. Rev. Physiol. 57: 791- 804, 1995).

T cells, as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors. Among these factors are a superfamily of 8-12 kDa proteins known as the chemokines. These proteins share structural features such as the presence of 3-4 conserved cysteine residues. RANTES, which stands for Regulated upon Activation Normal T cell Expressed and Secreted, is an 8 kDa protein member of CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors. The CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues and members of this family predominately elicit the migration of mononuclear cells, eosinophils and basophils (M. Baggiolini, B. Dewald, and B. Moser, Adv. Immunol. 55: 97-179, 1994; and J.J. Oppenheim, C.O.C. Zachariae, N. Mukaida, and K. Matsushima, Annu. Rev. Immunol. 9: 617-648, 1991).

RANTES potently produces chemotaxis of T cells, basophils, eosinophils, monocytes and mast cells. RANTES was originally identified as gene product induced late after antigen activation of T-cells (TJ. Schall, J. Jongstra, B.J. Dyer, J. Jorgensen, et al., J. Immunol. 141:1018-1025, 1988), however, RANTES has been shown to be synthesized and secreted by a diverse group of cells that include 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, O. Devergne, G. Gorgone, A. Portier, et al., J. Immunol. 154: 1870-1878, 1994), synovial fibroblasts (P. Rathanaswami, M. Hachicha, M. Sadick, TJ. Schall, et al., J. Biol. Chem. 268: 5834-5839, 1993) and dermal 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. 44: 795-804,

1994) and platelets (Y. Koameyoshi, A. Dorschner, A.I. Mallet, E. Christophers, et al., J. Exp. Med. 176: 587-592, 1992). In these cells, RANTES mRNA is rapidly upregulated in response to IL-1 or TNFα. Although RANTES mRNA is not usually detected in normal tissues (J.M. Pattison, PJ. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995), increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate. For example, RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J.M. Pattison, PJ. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995; and K.C. Nadeau, H. Azu a and N.I. Tilney, Proc. Natl. Acad. USA 92: 8729- 8733, 1995) in the skin of atopic dermatitis patients after exposure to antigen (S. Ying, L. Taborda-Barata, Q. Meng, M. Humbert, et al., J. Exp. Med. 181: 2153- 2159, 1995), and in endothelial cells of coronary arteries undergoing accelerated atherosclerosis after cardiac transplant (J.M. Pattison, P J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995). Further, increased immunoreactive protein for RANTES has been detected in bronchoalveolar lavage fluid (R. Alam, J. York, M. Boyers, et al., Am. J. Resp. Crit. Care Med. 149: A951, 1994) and sputum from asthmatic individuals (CM. Gelder, P.S. Thomas, D.H. Yates, I.M. Adcock, et al., Thorax 50: 1033-1037, 1995).

Several receptors have been identified that bind RANTES. In particular, CCR5, when expressed in either HEK 293 cells or CHO cells, binds RANTES. This receptor is expressed in T-cells and in monocytes and macrophages, immune/inflammatory cells which are important in the maintenance of a chronic inflammatory reaction. Pharmacological characterization of CCR5 indicates similarities to the RANTES binding site observed on isolated T cells. Therefore, antagonism of RANTES' action on CCR5, as well as antagonism of other natural modulators of CCR5, should inhibit the recruitment and activation of T cells and macrophages into inflammatory lesions and provide a novel therapeutic approach for the treatment of atopic and autoimmune disorders.

Since T cells express CCR5, selective receptor modulators of CCR5, particularly antagonists, are likely to provide beneficial effects in diseases including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, and inflammatory bowel disease, all in mammals, preferably humans. Furthermore, since CD8+ T cells have been implicated in chronic obstructive pulmonary disease (COPD), CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therapeutic activity in the treatment of COPD. Also, since CCR5 is a co-receptor for the entry of HTN into cells, selective receptor modulators may be useful in the treatment of HIV infection. A subset of compounds included in formula (I) have been reported to have

5-HT A/lB/lD ^receptor antagonist activity (WO 98/47885, published 29 October 1998), or 5-HT^c receptor antagonist activity (WO 96/23769, published 8 August 1996), or CCK and/or gastrin receptor binding affinity (WO 93/20099).

Surprisingly, it has now been discovered that a class of non-peptide compounds, in particular substituted urea compounds of formula (I), function as CCR5 receptor modulators, and therefore, have utility in the treatment and prevention of disease states mediated by CCR5 receptor mechanisms.

SUMMARY OF THE INVENTION The present invention is to novel compounds of formula (I) and their novel use as CCR5 modulators for the treatment of certain disease states, including, but not limited to, COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, all in mammals, preferably humans. The preferred compounds for use as CCR5 modulators are those compounds of Formula (I) as noted herein.

Further, the present invention is directed to methods for making and using the compounds of formula (I), as well as pharmaceutical compositions of formula (I) or a pharmaceutically acceptable salts or solvates thereof.

Yet further, the present invention is directed to a compound of formula (I) for use in treating CCR5-mediated diseases.

Still further, the present invention is directed to a compound of formula (I) as an anti-inflammatory agent.

DETAILED DESCRIPTION OF THE INVENTION

It has now been discovered that substituted ureas of formula (I) are CCR5 receptor modulators. It has also now been discovered that selective inhibition of CCR5 receptor mechanisms by treatment with the receptor modulators of formula (I), or a pharmaceutically acceptable salt thereof, represents a novel therapeutic and preventative approach to the treatment of a variety of disease states, including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, and inflammatory bowel disease, all in mammals, preferably humans. Furthermore, since CD8+ T cells have been implicated in COPD, CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therapeutic in the treatment of COPD. Also, since CCR5 is a co-receptor for entry into cells, selective receptor modulators may be useful in the treatment of HIV infection. Preferred compounds for use as CCR5 modulators are those compounds of formula (I) as noted herein.

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

Formula I

wherein: a basic nitrogen in moiety E may be optionally quaternized with C^galkyl or is optionally present as the N-oxide;

R" is hydrogen, C^galkyl, or R" together with the nitrogen to which it is attached may form a heterocyclic ring with an aryl ring of E; Q' is a group selected from (i)-(vii):

wherein:

R1 is independently selected from hydrogen, or one or more of C^.galkyl, C2_6 lkenyl, C2-6^a'kynyl, C3_7Cycloalkyl, C3_6cycloalkenyl, CH2CF3, aryl, aralkyl, (CH₂)a'NR²R^3', (CH₂)a'NR²'COR4', (CH₂)_a'NR³ CO₂R⁵', (CH₂)a'NR^2'SO₂R⁶', (CH2)_a€ONR⁷R^8',

(optionally substituted by a Cι_4alkoxy or hydroxy group),

(CH₂)bOC(O)R⁹', C lO^NOR¹ i', CNRIO^ ORH', COR¹²', CONR⁷R^8', CONR⁷'(CH2)_cOCι_4alkyl, CONR⁷'(CH2)_aCO₂R¹³', CO HNR¹⁴'R1⁵', CONR⁷ SO₂R^16', CO₂R¹⁷', cyano, trifluoromethyl, NR²R³', NR² COR⁴', NRl8'CO(CH₂)_a'NRⁱ⁸ R^19', NR1⁸'CONR¹⁸'R19', NR^2'CO₂R⁵', NR²'S0₂R⁶', N=CNRi⁸'NR¹⁸R¹⁹', nitro, hydroxy, C galkoxy, OCF3, hydroxyC^galkoxy, C^alkoxyCμgalkoxy, OC(O)NR²⁰R²¹', SR²²', SOR²³', SO₂R²³', SO2NR²0 R21 _} QPh, SPh or halogen, or R^' is a 5- to 7-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, optionally substituted with hydrogen, Cj.galkyl, C3_7cycloalkyl, C3_gcycloalkenyl, hydroxyC[^alkyl, (Cι__6 lk l)Cι_6 lkyl, CONR⁷R^8', C0₂R^17', cyano, aryl, trifluoromethyl, nitro, hydroxy, Cj.galkoxy, acyloxy, or halogen; a' is 1,2, 3 or 4; b'isO, l,2or3; c'is l,2or3; R ^'andR³ are independently hydrogen or Ci.galkyl, or R² and R³ together with the nitrogen to which they are attached, form a 5- to 6-membered heterocyclic ring which ring may be optionally substituted by an oxo group, or, when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;

R^4' is hydrogen, C_j.galkyl or

RS^' is C^alkyl;

R^' is C^.galkyl or phenyl;

R^7' and R⁸' are independently hydrogen or Cj^galkyl, or R⁷ and R⁸ together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring, wherein when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;

R⁹' is C_j^alkyl, optionally substituted by a Cj.galkoxy;

R^O' nd R-^^' re independently hydrogen or Cj.galkyl;

R^^2' is hydrogen or Ci _galkyl;

R! ' is hydrogen or C .galkyl; R1⁴ and R^' are independently hydrogen or Cj__galkyl;

R1" is hydrogen or C^.^alkyl;

R!⁷' is hydrogen or Cj .galkyl optionally substituted with one or more substituents selected from C_|_ alkyl, C .galkoxy, hydroxy, or NR² R³';

R^⁸' and ^⁹ are independently hydrogen or Ci .galkyl; R ^' and R²^' are independently hydrogen or C _j.galkyl, or R²^' and R^{2 i}' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when the ring is 6-membered, may optionally contain in the ring one oxygen or one sulfur atom.

R²~ is hydrogen or C _galkyl; R²³' is Ci_6alkyl;

R² is independently selected from hydrogen, or one or more of Cj_^galkyl, aryl, oxo or OR^a, wherein R^a is H or C^alkyl;

E represents a group (a):

in which

B is oxygen, CsC, S(O)_c, CR⁷=CR⁸, or CR⁷R⁸, or B is NR⁹; R! and R² are independently hydrogen or C^galkyl; alternatively

R³ and R⁴ are independently hydrogen, C_{j .}^alkyl, C_β^cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C i ^alkyl, aryl, CONR WR ^{1 1}, NR ¹⁰R^, hydroxy, OCOR¹², NHCOCF3, NHSO₂R¹³, NHCO₂R¹⁴, or NHCOCQ-6alkyl wherein the alkyl of NHCOCQ. galkyl is optionally substituted by OH;

R⁵ is hydrogen, C^alkyl, aryl, CN, CONR¹⁵R*⁶, CO₂R¹⁷, trifluoromethyl, NHCO2R^ , hydroxy, C_j.galkoxy, benzyloxy, OCH2CO2Cj_ ₆alkyl, OCF3, S(O)_dR¹⁹, SO₂NR²⁰R²¹- or halogen; R6 is hydrogen, C_|_galkyl, aryl, trifluoromethyl, hydroxy, C _galkoxy or halogen, or R^ taken together with R" forms a group D where D is (CR² R² )_e or D is (CR²²R²³)_f-G where G is oxygen, sulfur or CR²²=CR²³, CR²²=N, =CR²²O, =CR²²S, or =CR²²-NR²³;

R⁷, R⁸, RlO, RU, Rl², Rl5, _R16, _R17, _R20, _R21, _R22, _{and R}23 _are independently hydrogen or Cι_6alkyl;

R⁹ is hydrogen, Cj_6alkyl, ^or phenylC^galkyl;

R¹³, Rⁱ⁴, R¹⁸, and R ⁹ are independently C^galkyl; a is 1, 2, 3, or 4; b is 1 or 2; c and d are independently 0, 1 or 2; e is 2, 3 or 4; f is O, 1, 2 or 3; alternatively, E represents a group (b):

R²⁴, R 5, _R26_{; R}27_{) R}28_{; R}29_{? R}31_{> an}d R³² are independently hydrogen or Cι_galkyl;

R³0 is hydrogen, C galkyl, or C3_7cyclo lkyl;

R³³ is hydrogen, Cj^alkyl, trifluoromethyl, hydroxy or halogen, or R³³ and R" together form a group -K- where K is (CR³ R³5)_{j or} pς j_s (CR ⁴R³5)j __M and M is oxygen, sulfur, CR³⁴=CR³⁵, CR ⁴=N, or N=N;

J is oxygen, CR³⁶R³⁷, or NR³⁸, or J is a group S(O)k;

R³⁴, R³⁵, R³⁶, R37₅ and R³⁸ are independently hydrogen or C galkyl; g is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3, or 4; j is 0, 1, 2, or 3; k is 0, 1 or 2; alternatively, E represents a group (c):

in which:

Q is oxygen, S(O)_n, CR⁴⁴=CR⁴⁵, CR R⁴⁵, or Q is NR⁴⁶; R³⁹ and R⁴^ are independently hydrogen or C galkyl; R -l is a group of formula (d):

(

or R⁴* is a group of formula (e):

R⁴² is hydrogen, Ci^al yl, aryl, CN, CONR⁴⁸R⁴⁹, CO₂R⁵⁰, trifluoromethyl, NHCO9R⁵¹, hydroxy, C .galkoxy, benzyloxy, OCH2CO2C1. galkyl, OCF3, S(O)_sR⁵², SO₂NR⁵³R⁵⁴, or halogen;

R⁴³ is hydrogen or R⁴³ together with R" forms a group R where R is CR⁵⁵=CR56, CR55=CR56CR55R56_{5 or} (CR55R56)_t;

R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁸, R⁴⁹, R⁵⁰, R⁵³, R⁵⁴, R⁵⁵, and R⁵⁶ are independently hydrogen or C_j.galkyl;

R⁴⁷ is hydrogen, C^alkyl, or C3_7 cycloalkyl;

R^l and R^² are independently Ct_^galkyl;

1 is 0, 1, 2, or 3; m is 1 or 2; n is 0, 1, or 2 o, p, and q are independently integers having the value 1, 2, or 3; r is 0,1 , 2, or 3; s is 0, 1, or 2; t is 2 or 3; alternatively, E represents a group (f):

R^ and R^⁸ are independently hydrogen or Chalky 1;

R^⁹ and R^0 are independently hydrogen, C_j galkyl, C3_7cycIoaIkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C^galkyl, aryl, CONR⁶¹R⁶², NR⁶lR⁶², hydroxy, OCOR⁶³,

NHCOCF3, NHSO₂R⁶⁴, NHCO₂R⁶⁵, or NHCOC₀-6alkyl wherein the alkyl of

NHCOCQ-6alkyl is optionally substituted by OH;

T is -(CR⁶6R⁶⁷)_V- or -O(CR66R67)_W__;

W is oxygen, S(O)_x, NR⁶⁸, or W is C≡C, CR⁶⁹=CR⁷0 or CR⁶⁹R⁷⁰; R⁶¹, R⁶², R⁶³, R⁶⁶, R⁶⁷ R^⁸, R69, _and R70 _are independently hydrogen or C^.galkyl;

R^⁴ and R^5 are independently C^galkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; alternatively, E represents a group (g):

R⁷^ is a 5- to 7-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and optionally a further 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur or R⁷ is an optionally substituted 6,6 or 6,5 bicyclic ring containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulfur, which ring systems may be optionally substituted with one or more of C^.galkyl and optionally substituted on nitrogen with hydrogen, C_j^alkyl or C3_7cycloalkyl;

R⁷² is hydrogen, C^alkyl, aryl, CN, CONR⁷⁴R⁷⁵, CO₂R⁷⁶, trifluoromethyl, NHCO2R⁷⁷, hydroxy, Cj.galkoxy, benzyloxy, OCH2CO2C1. galkyl, OCF3, S(O)_zR⁷⁸, SO2NR⁷⁹R⁸⁰, or halogen;

R⁷³ is hydrogen, C_j^alkyl, hydroxy, Ci .galkoxy or halogen, or R⁷³ and R" taken together from a group -X- where X is (CR^{8 i}R⁸ )_aa or X is (CR^{8 1}R⁸²)_ab-Y and Y is oxygen, sulfur or CR⁸¹=CR⁸²; R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁹, R⁸⁰, R^{8 1}, and R⁸² are independently hydrogen or

C ι__6alkyl;

R⁷⁷ and R⁷⁸ are independently C galkyl; y is 1 or 2; z is 0, 1, or 2; aa is 2, 3 or 4; ab is 0, 1, 2 or 3; alternatively, E represents a group (h):

^R87 (h);

R⁸³ and R⁸⁴ are independently hydrogen or Ct_^galkyl; R⁸^ and R ^ are independently hydrogen, C galkyl, C3_7cyclo lkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C^alkyl, aryl, CONR⁸⁸R⁸⁹, NR⁹⁰R⁹¹, hydroxy, OCOR⁹², NHCOCF3, NHSOoR⁹³, NHCO₂R⁹⁴, or NHCOCo-ealkyl wherein the alkyl of NHCθCø-6alkyl is optionally substituted by OH;

R⁸⁷ is hydrogen or C^.galkyl, Cj_^galkoxy, or halogen, or R⁸⁷ together with R" forms a group -AA- where AA is (CR⁹⁵R⁹⁶)_ad or AA is (CR⁹5=CR⁹⁶)_ae-AB and AB is oxygen, sulfur, CR ⁵=CR⁹⁶, CR⁹⁵=N, CR⁹⁵NR⁹⁶ or N=N;

Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;

R⁸⁸, R⁸⁹, R⁹⁰, R⁹*, R⁹², R⁹5, and R⁹⁶ are independently hydrogen or C ^alkyl; R⁹³ and R⁹⁴ are independently C .galkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; alternatively, E represents a group (i):

R⁹⁷ and R⁹⁸ are independently hydrogen, Cj^alkyl, C3_7cycIoaIkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C^alkyl, aryl, CONR¹⁰²R¹⁰³, NR104R¹⁰⁵, hydroxy, OCOR*⁰⁶, NHCOCF3, NHSO₂ R¹⁰⁷, NHCO₂R¹⁰⁸, or NHCOC₀_6alkyl wherein the alkyl of HCOCo-6alkyl is optionally substituted by OH;

R⁹⁹ and RlOO _are independently hydrogen or Cl-6alkyl; RIOI is hydrogen or C j.gal yl or R*01 and R" together form a group -AD- where AD is (CR¹⁰⁹R^{1 1()})ai or AD is (CRi°⁹R^{l i0})_aj-AE and AE is oxygen, sulfur or CRl°⁹=CRl¹⁰;

AC is oxygen, CRlHR¹-¹² or NR^{l i3} or AC is a group S(O)_a ;

_R102 R103, _R104 _R105_; R106, R109, RI IO, _Rll l, RI.12, _and RU3 _are independently hydrogen or Chalky 1;

Rⁱ⁰⁷ and R¹⁰⁸ are independently Cl-6alkyl; af is O, 1, 2, 3, or 4; ag is 1, 2, or 3; ah is 1, 2, 3 or 4; ai is 2, 3 or 4; aj is 0, 1, 2, or 3; and ak is 0, 1 or 2, provided that when R"is H; Q' is (vi); R²" is H; E is (a); R³*, R³² and R³6 are H; R³³ is OCH3; d is 2; e is 1; R³⁴ and R³^ are isopropyl; and B is O, then R^' is not 7-nitro, 7-bromo-8-hydroxy, 7,8~dimethoxy-6-(4-methoxyphenyI), 7,8-dimethoxy- 6-phenyl, 6-chloro-7,8-dimethoxy-9-ρhenyl, 6-bromo-7,8-dimethoxy, 6-chloro-7,8- dimethoxy, 7,8-dimethoxy, H, 7-hydroxy, 6-hydroxy 7-bromo-8-methoxy, or 7- amino, and further, provided that when R"is H; Q' is (vi); R²" is H; E is (g); R⁷^ is H; R⁷ό is 4-OCH3; z is 1 and R⁷⁷ is N-isopropylpiperidin-4-yl, then R^{1 '} is not 7,8-dimethoxy-6-phenyl, or 6-chloro-7,8-dimethoxy-9-phenyl, and further provided that when Q' is (ii); R" R³¹ , R³², R³³ and R 6 _are hydrogen; R²" is hydrogen; E is (a); d is 2; R³⁴ and R ^ are methyl; B is oxygen, R*' is not 5- methylthio-6-trifluoromethyl or 5-methoxy-6-trifluoromethyI, and further provided that when Q' is (ii); R" R^{3 i}, R³², R³³ and R³⁶ are hydrogen; R²" is hydrogen; E is (a); d is 2; R³⁴ and R³⁵ are methyl; B is R³⁹R⁴⁰ wherein R³⁹ and R⁴⁰ are hydrogen, R¹' is not 5-methoxy-6-trifluoromethyl.

For compounds of formula (I) various embodiments are as follows. It will be understood that the basic nitrogen in moiety E may be optionally quatemized with C ^.galkyl or is optionally present as the N-oxide.

Suitably, R" is hydrogen, C^alkyl, or R" together with the nitrogen to which it is attached may form a heterocyclic ring with an aryl ring of E. Preferably, R" is hydrogen. Suitably, Q' is selected from the groups (i)-(vii), listed above. Preferably,

Q' is selected from the groups (i), (v) and (vi).

Suitably, R^' is independently selected from hydrogen, or one or more (it will be understood that up to four R^^' substituents may substitute Q) C^.galkyl, C2-6alkenyl, C2-6al ynyl, C3_7cycloalkyl, C3_gcycloalkenyl, CH2CF3, aryl, aralkyl, (CH )a'NR²R³', (CH₂)_a'NR²'COR^4', (CH2)a R² CO₂R^5',

(CH2)_a'NR^2'S02R^6', (CH2)_a'CONR⁷R⁸', hydroxyCι_₆alkyl, C^alkoxyalkyl (optionally substituted by a C^alkoxy or hydroxy group), (CH2)aCO2C|_galkyl, (CH₂)bOC(O)R^9', CR¹⁰'=NORll^', CNR^NOR¹¹', COR*²', CONR⁷ R⁸', CONR⁷'(CH2)_cOC₁.₄alkyl, CONR^7'(CH2)aCO₂R^{13 '}, CONHNR¹ R¹⁵', CONR⁷ SO R¹⁶', CO₂R^17', cyano, trifluoromethyl, NR² R³', NR² COR⁴',

NRl^8'CO(CH₂)_a'NR¹⁸ R^19', NRⁱ⁸CONRl⁸Rl^9', NR² C02R^5', NR²'SO₂R⁶', N=CNR¹⁸NRⁱ⁸Rⁱ⁹', nitro, hydroxy, Cj^alkoxy, OCF3, hydroxyC^galkoxy, C^alkoxyC^galkoxy, OC(O)NR²⁰R²1', SR^22', SOR²³', SO₂R²³', SO2NR²^ R-l , OPh, SPh or halogen, or Rl is a 5- to 7-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, optionally substituted with hydrogen, C galkyl, C3 7cycloalkyl, C3„gcycloalkenyl, hydroxyCj.galkyl, (C galky C^galkyl, CONR⁷ R^8', CO2R¹⁷', cyano, aryl, trifluoromethyl, nitro, hydroxy, Cj.βalkoxy, acyloxy, or halogen. Preferably, R^' is halogen, Cμgalkyl, or aryl. Suitably, R- is independently selected from hydrogen, or one or more of

Cj_^galkyl, aryl, oxo or OR^a, wherein R^a is H or C^.galkyl; with the privoso that when R~ is OR^a, it may not be on the position adjacent to N. Preferably, R²" is hydrogen.

Suitably, R^2' and R³ are independently hydrogen or C_j^galkyl, or suitably, R- and R³ together with the nitrogen to which they are attached, form a 5- to 6- membered heterocyclic ring. Suitably, the ring may be optionally substituted by an oxo group, or, when R² and R³ form a 6-membered ring, the ring may optionally contain one oxygen or one sulfur atom. When the ring is a 6-membered ring substituted by an oxygen or sulfur atom, the oxygen or sulfur atom are preferably in the 4-position.

Suitably, R^{7 '} and R⁸ are independently hydrogen or C j_^galkyl, or suitably, R⁷' and R^{8 '} together with the nitrogen to which they are attached form a 5- to 6- membered saturated heterocyclic ring. Suitably, when the ring is 6-membered, the ring may optionally contain one oxygen or one sulfur atom.

Suitably, R^^7' is hydrogen or C^.galkyl, wherein the C_j.galkyl is optionally substituted with one or more substituents selected from Cj^alkyl, CJ galkoxy, hydroxy, or NR² R³ .

Suitably, substituent E is selected from the following groups:

Preferably, E is selected from group (a), (b) and (g).

E suitably represents a group (a):

wherein:

B is suitably oxygen, C≡C, S(0)_c, CR⁷=CR⁸> or CR⁷R⁸, or B is NR⁹. B is preferably CR⁷R⁸, or oxygen. More preferably, B is CH2 or oxygen.

R ! and R² are suitably independently hydrogen

Preferably, R *• and R² are hydrogen.

R³ and R⁴ are suitably independently hydrogen, C^.galkyl, C3_ ycycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include Cχ_6alkyl, aryl, CON 1°R11, NR^R¹*, hydroxy, OCOR*², NHCOCF3, NHSO₂ R¹³, NHCO₂R¹⁴ or NHCOC₀_6aIkyl wherein the alkyl of NHCOCθ-6^alkyl is optionally substituted by OH. Preferably R³ and R⁴ are both C|_6alkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur. More preferably, R³ and R⁴ are C3_gal yl, or together with the nitrogen to which they are attached form a 6-membered ring, optionally substituted with one or more of Cχ_5alkyl. Most preferably, R³ and R⁴ are both isopropyl, or together with the nitrogen to which they are attached are l-(2,2,6,6-tetramethylpiperidinyl). Preferably, B-(CRlR²)_a-NR³R⁴ is ortho to R⁵, eta to Q'CON(R") and para to R⁶, and R⁵ is para to Q'CON(R").

R⁵ is suitably hydrogen, Ci .βalkyl, aryl, CN, CONR¹⁵R¹⁶, CO2R¹⁷, trifluoromethyl, NHCO₂R¹⁸, hydroxy, Cjμgalkoxy, benzyloxy, OCH2CO2C1. galkyl, OCF3, S(O)_dR¹⁹, SO₂NR²⁰R²¹, or halogen. R5 is preferably C_j__ galkoxy; more preferably methoxy. When R^ is methoxy, it is preferably para to Q'CON(R").

R^ is suitably hydrogen, Cj.βalkyl, aryl, trifluoromethyl, hydroxy, Cι__ galkoxy, or halogen, or R° taken together with R" forms a group D where D is (CR ²R ³)_e or D is (CR²²R ³)_f-G where G is oxygen, sulfur, or CR²²=CR²³, CR²²=N, =CR²²O, =CR²²S, or =CR ²-NR²³. Preferably, R⁶ is hydrogen. R⁷, R⁸, RlO, Rll, _R12_, R15, R W R!7, R20, _R21, R22, _{and R}23 _are suitably independently hydrogen or Chalk 1.

R⁹ is suitably hydrogen, C_j.galkyl, or phenylC_[_6alkyl.

R¹³, R¹⁴, R¹⁸, and R^⁹ are suitably independently Cj galkyl. a is suitably 1, 2, 3, or 4. Preferably, a is 2 or 3, more preferably, a is 2 or 3 when B is oxygen and a is 2 when B is CH2, most preferably, a is 2 when B is oxygen or CH2. b is suitably I or 2. Preferably, b is 1. c and d are suitably independently 0, 1, or 2. e is suitably 2, 3, or 4. f is suitably 0, 1, 2, or 3. Alternatively, E suitably represents a group (b):

wherein: R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³¹, and R³² are suitably independently hydrogen or

R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³*, and R³² are preferably hydrogen.

R ^ is suitably hydrogen, C_j galkyl, or C3_7cycloalkyl. Preferably, R³^ is C galkyl, more preferably, ^ is C3_galkyl, most preferably, R ^ is isopropyl. R³³ is suitably hydrogen, Cj.galkyl, trifluoromethyl, hydroxy or halogen, or R³³ and R" together form a group -K- where K is (CR³⁴R³5)j or K is (CR³⁴R³⁵)j -M and M is oxygen, sulfur, CR³⁴=CR35, CR³⁴=N, or N=N. Preferably, R³ is hydrogen.

J is suitably oxygen, CR3 R 7_{5 or} N 38_{^ or} j_s a group S(O)^. Preferably, J is oxygen. Preferably, J is para to Q'CON(R"). g is suitably 1, 2, or 3. Preferably, g is 2 or 3, more preferably 2. h is suitably 1, 2, or 3. Preferably, h is 1. i is suitably 2, 3, or 4. j is suitably 0, 1, 2, or 3. k is suitably 0, 1 or 2.

Alternatively, E suitably represents a group (g):

Wherein:

R⁷³ is suitably hydrogen, C[_galkyl, hydroxy, Cj-galkoxy or halogen, or R⁷³ and R" taken together from a group -X- where X is (CR^{8 i}R⁸²)_aa, wherein aa is 2, 3 or 4, and R⁸^ and R⁸² are independently hydrogen or Cj.galkyl, or X is (CR⁸ ^R ²)_ab"Y₅ wherein ab is 0, 1, 2 or 3, and Y is oxygen, sulfur or CR⁸ ι=CR⁸² wherein R⁸^ and R⁸² are independently hydrogen or C galkyl. Preferably R⁷3 is hydrogen. R⁷² is suitably hydrogen, C i .galkyl, aryl, CN, CONR⁷⁴R⁷⁵, CO₂R⁷⁶, trifluoromethyl, NHCO R⁷⁷, hydroxy, Cjμgalkoxy, benzyloxy, OCH2CO2C1. galkyl, OCF3, S(O)_zR⁷⁸, SO₂NR⁷⁹R⁸⁰, or halogen wherein R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁹ and R ^ are independently hydrogen or Cj.galkyl, R⁷⁷ and R⁷⁸ are C_j galkyl, and z is 0, 1, or 2. R⁷² is preferably Cj^galkoxy; more preferably R⁷² is methoxy. When R⁷² is methoxy, it is preferably para to Q'CON(R"). Suitably, y is an integer from 1-2. Preferably y is 1. Suitably, R⁷^ is an optionally substituted 5- to 7-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and optionally a further one or two heteroatoms selected from nitrogen, oxygen or sulfur, which ring system may be optionally substituted with one or more of C_|_galkyl and substituted on nitrogen with hydrogen, Cχ_galkyl, or C3_7cycloalkyl. Preferably the substituent on nitrogen is C3_6alkyl, or C3_7cycloalkyl. More preferably, the substituent on nitrogen is isopropyl.

Alternatively R⁷^ is suitably an optionally substituted 6,6 or 6,5-bicyclic ring system containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulfur, which ring systems may be optionally substituted with one or more of C_j galkyl and substituted on nitrogen with hydrogen, C _galkyl, or C3_7cycloalkyl. Preferably the substituent on nitrogen is Cj_^galkyl, or C3_7cycloal yI. More preferably, the substituent on nitrogen is isopropyl.

Preferably R⁷¹ is meta to Q'CON(R").

Examples of such ring systems include, but are not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, 1,2,3,6- tetrahydropyridine, hexahydroazepine, tropane, isoquinuclidine and granatane rings. Preferably R⁷^ is 4-piperidinyl, substituted on carbon with hydrogen.

The term "C .galkyl" is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. The terms "halo" or "halogen" are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine. The terms "cycloalkyl" and "cyclic alkyl" are used herein at all occurrences to mean cyclic radicals, preferably comprising 3 to 7 carbon atoms which may be mono- or bicyclo- fused ring systems which may additionally include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydronaphthalenyl, and the like.

The term "alkenyl" is used herein at all occurrences to mean a straight or branched chain radical of 2 to 6 carbon atoms, unless the length is limited thereto, wherein there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, 1-propenyl, 2-propenyI, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl, and the like.

The term "cycloalkenyl" is used herein to mean cyclic radicals, preferably of 5 to 8 carbons, which have at least one double bond between two of the carbon atoms in the ring, including but not limited to cyclopentenyl, cyclohexenyl, and the like. The term "alkynyl" is used herein at all occurrences to mean a straight or branched chain radical of 2 to 8 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1- propylene, 2-propylene, and the like. The term "aryl" is used herein at all occurrences to mean 6-14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, including, but not limited to phenyl, naphthalenyl, biphenyl, phenanthryl, anthracenyl, and the like.

The term "heteroaryl" is used herein at all occurrences to mean a 5-14- membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, which ring or ring systems contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, including, but not limited to, indolyl, benzofuranyl, thianaphthenyl, quinolyl, isoquinolyl, pyrrolyl, furanyl, thienyl, pyridyl, and the like. The term "aralkyl" is used herein at all occurrences to mean an aryl moiety as defined above, which is connected to an alkyl moiety as defined above, for example, benzyl or phenethyl, and the like.

The term "alkoxy" is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.

The term "oxo" is used herein at all occurrences to mean a double bonded oxygen atom attached to a chemical moiety as a substituent.

The terms "hydroxyC galkyl" and "hydroxyalkyl" are used herein interchangeably to mean an hydroxyl group bonded to a C[_galkyl group 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 "C_|_4alkoxyalkyl" is used herein at all occurrences to mean a Cj_ 4alkoxy group as defined above bonded to an alkyl group as defined above, such as an ether, e.g., CH3-CH2-O-CH2-CH2-CH3.

The term "hydroxyC^galkoxy" is used herein at all occurrences to mean an hydroxyl group bonded to an alkoxy group as defined above, e.g., HO-CH₂-CH(OH)CH₃.

The term "Ci.galkoxyCj.galkoxy" is used herein at all occurrences to mean an alkoxy group as defined above, substituted with an alkoxy group as defined above. The term "acyloxy" is used herein at all occurrences to mean a moiety

-O-C(O)-R, wherein R is hydrogen or Cj^galkyl.

The term " C^alkanoyl " is used herein at all occurrences to mean a C(O)Ci-4alkyl group wherein the alkyl portion is as defined above.

The term "heteroatom" is used herein at all occurrences to mean an oxygen atom, a sulfur atom or a nitrogen atom. It will be recognized that when the heteroatom is nitrogen, it may form an NR_aRb moiety, wherein R_a and R5 are, independently, hydrogen or C_j to Cg alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6- or 7-membered ring, including, but not limited to, pyrrolidine, piperidine, piperazine, orpholine, pyridine, and the like. It will be recognized that the saturated or unsaturated 5-, 6- or 7-membered ring may optionally have one or more additional heteroatoms in the ring.

The term "heterocyclic" is used herein at all occurrences to mean a saturated or wholly or partially unsaturated 5-10-membered ring system (unless the cyclic ring system is otherwise limited) in which one or more rings contain one or more heteroatoms, including, but not limited to, pyπolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, 1,2,3,6-tetrahydropyridine, hexahydroazepine, and the like.

The term "optionally substituted" is used herein at all occurrences to mean, unless otherwise defined, an optionally substituted 5- to 7-membered heterocyclic ring wherein the optional substituents are one or more of C^galkyl.

The term "CCR5 mediated disease state" is used herein at all occurrences to mean any disease state which is mediated (or modulated) by CCR5.

Suitably, pharmaceutically acceptable salts of formula (I) include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate, and stearate.

The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention.

The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. The stereocenters may be of any combination of R and S configuration, for example, (R,R), (R,S), (S,S) or (S,R). All of these compounds are within the scope of the present invention.

Among the preferred compounds of this invention are the following compounds:

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-3,4-dihydro-lH- isoquinoline-2-carboxamide; N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-3,4-dihydro-2H- quinoline-1-carboxamide;

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-2,3-dihydro-indole- 1-carboxamide;

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-7-methoxy-8-nitro- 2,3,4, 5-tetrahydro-lH-3-benzazepine-3-carboxamide;

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-7-hydroxy-8-nitro- 2,3,4, 5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-7-methoxy-2,3,4,5- tetrahydro-lH-benzazepine-3-carboxamide; N-[3-(l-Isopropyl-piperidin~4-yl)-4-methoxy-phenyl]- 7-hydroxy-8- methanesulfinyl-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-7-(5-methyl- [l,2,4]oxadiazol-3-yl)-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-2,3,4,5-tetrahydro- lH-indano[4,5-d]azapine-3-carboxamide;

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-6-fluoro-7,8- dimethoxy-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide; N-[3-(2-Diisopropylamino-ethoxy)- 4-methoxy-phenyl]-7- methanesulfonyl-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-7-sulfamoyl- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide; N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy~phenyl]-6-phenoxy-2,3,4,5- tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(2 -Diisopropylamino-ethoxy)-4-methoxy-phenyl]-6-methyl-2, 3,4,5- tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-7-hydroxy-8-nitro- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-7-methoxy-2, 3,4,5- tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]- 7-bromo-8-hydroxy- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide; N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-7-hydroxy-8- methanesulfinyl-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-7-(5-methyl- [l,2,4]oxadiazol-3-yl)-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-7,8-dimethoxy-6-(4- methoxy-phenyl)-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-6-bromo-7,8- dimethoxy-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-6-chloro-7,8- dimethoxy-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide; N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-6-fluoro-7,8- dimethoxy-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-8-methoxy-7- sulfonic acid-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-7-methanesulfonyl- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-6-hydroxy-9- methanesulfonyl-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(LIsopropyl-piperidin-4-yl)-4methoxy-phenyl]-7,8-dimethoxy- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide; N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-2,3,4,5-tetrahydro- lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-7-hydroxy-2, 3,4,5- tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-6-hydroxy-2,3,4,5- tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-7-bromo-8-methoxy- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-7-nitro-2, 3,4,5- tetrahydro- lH-benzazepine-3-carboxamide; and

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-7-methoxy-8-nitro- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide.

Among the more preferred compounds of the invention are the following compounds:

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-2,3-dihydro-lH- isoindole-2-carboxamide; N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-4,5-dichloro-2,3- dihydro-lH-isoindole-2-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-4,5-dichloro-2,3- dihydro-lH-isoindole-2-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-2,3,4,5-tetrahydro- lH-indano[4,5-d]azapine-3-carboxamide;

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-6-phenoxy-2, 3,4,5- tetrahydro- lH-benzazepine-3-carboxamide; and

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-6-methyl-2,3,4,5- tetrahydro-lH-benzazepine-3-carboxamide.

Among the most preferred compounds of this invention are the following compounds:

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-2,3-dihydro-lH- benzo[f]isoindole-2-carboxamide; N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-5,6-dichloro-2,3- dihydro-lH-isoindole-2-carboxamide;

N-[3-[3-[Bis-l-methylethylamino]propoxy]-4-methoxyphenyl]-5,6- dichloro-2,3-dihydro-lH-isoindole-2-carboxamide;

N-[3-[2-[2,2,6,6-Tetramethylpiperidin-l-yl]ethoxy]-4-methoxyphenyl]-5,6- dichloro-2,3-dihydro-lH-isoindole-2-carboxamide.

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-5-chloro-2,3- dihydro-lH-isoindole-2-carboxamide; N-[2,3-Dihydro-l -isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-5,6- dichloro-2,3-dihydro-lH-isoindole-2-carboxamide;

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-5-chloro-2,3- dihydro-lH-isoindole-2-carboxamide; N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-5,6-dichloro-2,3- dihydro-lH-isoindole-2-carboxamide; and

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-2,3-dihydro-lH- benzo[f]isoindole-2-carboxamide.

Formulation of Pharmaceutical Compositions

The pharmaceutically effective compounds of this invention (and the pharmaceutically acceptable salts thereof) are administered in conventional dosage forms prepared by combining a compound of formula (I) ("active ingredient") in an amount sufficient to treat COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, ("CCR5-mediated disease states") with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will 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, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.

The active ingredient may also be administered topically to a mammal in need of treatment or prophylaxis of CCR5 mediated disease states. The amount of active

90 ingredient required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the disease state being treated and the mammal undergoing treatment, and is ultimately at the discretion of the physician. A suitable dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most prefeπed dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily.

By topical administration is meant non-systemic administration and includes the application of the active ingredient externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.

While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.

The topical formulations of the present invention, both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s). The carrier(s) 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 semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.

Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcoholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98- 100°C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.

Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.

Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis. The basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, 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. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques. The daily dosage amount of the active ingredient administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day.

In one aspect, this invention relates to a method of treating COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, all in mammals, preferably humans, which comprises administering to such mammal an effective amount of a CCR5 receptor modulator, in particular, a compound as depicted in formula (I). By the term "treating" is meant either prophylactic or therapeutic therapy.

Such formula (I) compound can be administered to such mammal in a conventional dosage form prepared by combining the formula (I) compound with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The formula (I) compound is administered to a mammal in need of treatment for asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HJV infection, in an amount sufficient to decrease symptoms associated with these disease states. The route of administration may be oral or parenteral.

In another aspect, the invention relates to a method for modulating factors which exacerbate the symptoms of the CCR5-mediated diseases described herein. The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. The daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day of active ingredient. The daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day of active ingredient.

It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a formula (I) compound will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the formula (I) compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

Methods of Preparation

The compounds of formula (I) were prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials were unavailable from a commercial source, their synthesis is described herein, or they were prepared by procedures known in the art. For example, compounds of formula (I) were prepared by treating a suitably substituted aniline with triphosgene followed by treatment with a suitably substituted isoindoine, 3- benzazapine, etc.

Suitably substituted isondolines used to prepare compounds of formula (I) where Q' is (i) or (v) were prepared according to the methods of J. Med. Chem.

1990, 33, 596.

Suitably substituted tetrahydro-3-benzazapines used to prepare compounds of formula (I) where Q' is (vi) were prepared according to the methods of J Med.

Chem. 1986, 29, 1904 and international application publication number WO 93/00094.

Suitably substituted anilines used to prepare compounds of formula (I) where E is a group of formula (a) were prepared according to the methods of international application publication number WO 95/15954, published 15 June

1995, international application publication number WO 95/17398, published 29 June 1995, international application publication number WO 95/26328, published

5 October 1995, and international application publication number WO 96/06079, published 29 February 1996.

Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (b) were prepared according to the methods of international application publication number WO 95/11934, published 25 April

1995, and WO 95/19477, published 27 June 1995. Four other applications relate to the spiro compounds WO 97/17350 published 15 May 1997; WO 97/34900 published 25 September 1997; WO 97/34901 published 25 September 1997; WO

97/35862 published 2 October 1997. Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (g) were prepared according to the methods of

Attorney Docket No. P51156P.

The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. In the Examples, mass spectra were performed upon a Sciex mass spectrometer using electrospray ionization, unless otherwise indicated. EXAMPLES

Example 1 N-[2,3-Dihydro-r-isopropyl-spiiO[benzofuran-5-yl-3,4'-piperidine11-5,6-dichloro- 2,3-dihydro-lH-isoindole-2-carboxamide

Triphosgene (67 mg, 0.23 mmol)was added to a solution of 3-(2- diisopropylamino)ethoxy-4-methoxyaniline (WO 95/15954)(200 mg, 0.75 mmol), and dichloromethane (4 mL). After 30 min triethyamine (0.42 mL, 0.30 g, 3.0 mmol) was added. The mixture was maintained for lh and then 5,6-Dichloro-2,3- dihydro-lH isoindole (130 mg, 0.75 mmol) was added and the mixture stirred at rt for 16h. The mixture was diluted with dichloromethane, extracted with 10% Na₂CO₃; dried (MgSO^ and concetrated in vacuo. The residue was chromatographed (silica gel, 3% methanol/dichloromethane with 0.2% triethylamine) to give the title compound. MS(ES) m/e 480.2 [M+Η]⁺.

Examples 2-6 Following the procedure for Example 1, except substituting 2,3-dihydro- lH-isoindole, 2,3-dihydro-lH-benzo[/ isoindole, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline and 2,3-dihydro-lH-indole for 5,6-Dichloro-2,3- dihydro-lH isoindole, gave the following compounds:

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-2,3-dihydro-lΗ- isoindole-2-carboxamide: MS(ES) m/e 412.1 [M+HJ+;

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-2,3-dihydro-lH- benzo[f]isoindole-2-carboxamide: MS(ES) m/e 462.0 [M+H]⁺; N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-3,4-dihydro-lH- isoquinoline-2-carboxamide: MS(ES) m/e 426.0 [M+H]⁺;

N-[3-(2-DiisopropyIamino-ethoxy)-4-methoxy-phenyl]-3,4-dihydro-2H- quinoline-1-carboxamide: MS(ES) m/e 426.0 [M+H] ";

N-[3-(2-DiisopropyIamino-ethoxy)-4-methoxy-phenyl]-2,3-dihydro-indole- 1-carbox amide: MS(ES) m/e 412.0 [M+H]+.

Examples 7 Following the procedure for Example 1, except substituting l'-(l- methy^]ethyl)spiro[benzofuran-3(2H)-4'-piperidin]-5-amine for 3-(2- diisopropylamino)ethoxy-4-methoxyaniline gave the following compound:

N-[2,3-Dihydro-l'-isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-5,6- dichIoro-2,3-dihydro-lΗ-isoindole-2-carboxamide) : MS(ES) m/e 460.0 [M+H]⁺. Examples 8 N-r3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl1-4,5-dichloro-2,3-dihydro- 1 H-isoindole-2-carboxamide Triphosgene (9.2 mg, 0.033 mmol) was added to a solution of 3-(2- diisopropylamino)ethoxy-4-methoxyaniline (WO 95/15954) (27 mg, 0.10 mmol) in dichloromethane (1 mL). The mixture was stirred for 30 min and then triethylamine ( 0.056 mL, 40 mg, 0.4 mmol) was added. The mixture was stirred an additional 1 h, treated with 4,5-dichloro-2,3-dihydro-lH-isoindole (19 mg, 0.10 mmol), and the mixture stirred at RT overnight. The resultant mixture was concentrated in vacuo and the residue was purified by preparative ΗPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A:0.1% trifluoroacetic acid in acetonitrile B:0.1% aqueous trifluoroacetic acid, A:10 to 90% during 10 min, UV detection at 254 nm) to give the title compound. MS(ES) m e 480.2 [M+Η] +.

Examples 9-19 Following the procedure for Example 8, except substituting 5-chloro-2,3-dihydro-lH-isoindole, 7-methoxy-8-nitro-2,3,4,5-tetrahydro-lH- benzo[< ]azepine, 7-hydroxy-8-nitro-2,3,4,5-tetrahydro-lH-benzo[<i]azepine, 7- methoxy-2,3,4,5-tetrahydro-lH-benzo[< ]azepine, 7-hydroxy-8-methanesulfinyl- 2,3,4,5-tetrahydro-lH-benzo[iJazepine, 7-(5-methyl-[l,2,4]oxadiazol-3-yl)- 2,3,4,5-tetrahydro-lH-benzo[ύT|azepine, l,2,3,6J,8,9,10-Octahydro-8-aza- cyclohepta[e]indene, 6-Fluoro-7,8-dimethoxy-2,3,4,5-tetrahydro-lH- benzo[ύT]azepine, 7-Methanesulfonyl-2,3,4,5-tetrahydro-lH-benzo[<f)azepine, 7- Sulfamoyl-2,3,4,5-tetrahydro-lH-benzo[ ]azepine, 6-Phenoxy-2,3,4,5-tetrahydro- lH-benzo[<f]^azepine and 6-Methyl-2,3,4,5~tetrahydro-lH-benzo[ ]azepine for 4,5- dichloro-2,3-dihydro-lH-isoindole gave the following compounds:

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-5-chloro-2,3- dihydro-lΗ-isoindole-2-carboxamide: MS(ES) m/e 446.2 [M+H]+; N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-7-methoxy-8-nitro-

2,3,4,5-tetrahydro-lH-3-benzazepine-3-carboxamide: MS(ES) m/e 515.4 [M+H]+; N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-7-hydroxy-8-nitro- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 501.4 [M+H]+; N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-7-methoxy-2,3,4,5- tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m e 470.4 [M+H]+; N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]- 7-hydroxy-8- methanesulfinyl-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MSfES) m/e 518.4 [M+H]+;

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-7-(5-methyl- [l,2,4]oxadiazoI-3-yI)-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 522.2 [M+H]+; N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-2,3,4,5-tetrahydro- lH-indano[4,5-d]azapine-3-carboxamide: MS(ES) m/e 480.4 [M+H]+;

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-6-fluoro-7,8- dimethoxy-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 518.4 [M+H]+; N-[3-(2-Diisopropylamino-ethoxy)- 4-methoxy-phenyl]-7~ methanesulfonyl-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 518.4 [M+FQ+;

N-[3-(2JDiisopropylamino-ethoxy)-4-methoxy-phenyl]-7-sulfamoyl- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 518.4 [M+H]+; N-[3-(2~Diisopropylamino-ethoxy)-4-methoxy-phenyl]-6-phenoxy-2,3,4,5- tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 532.4 [M+H] ^";

N-[3-(2-Diisopropylamino-ethoxy)-4-methoxy-phenyl]-6-methyl-2, 3,4,5- tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 454.4 [M+H]⁺;

Examples 20-46

Following the procedure for Example 8, except substituting 5-chloro-2,3- dihydro-lH-isoindole, 4,5-chloro-2,3-dihydro-lH-isoindole, 7-hydroxy-8-nitro- 2,3,4, 5-tetrahydro-lH-benzo[< lazepine, 7-methoxy~2,3,4,5-tetrahydro-lH- benzo[<i]azepine, 7-bromo-8-hydroxy-2,3,4,5-tetrahydro-lH-benzo[<f)azepine, 7- hydroxy-8-methanesulfinyI~2,3,4,5-tetrahydro-lH-benzo[ ]azepine, 7-(5-methyl- [l,2,4]oxadiazol-3-yl)- 2,3,4,5-tetrahydro-lH-benzo[< ]azepine, 7,8-dimethoxy-6- (4-methoxy-phenyl)- 2,3,4,5-tetrahydro-lH-benzo[<i]azepine, 1,2,3,6,7,8,9, 10- octahydro-8-aza-cyclohepta[e]indene, 6-bromo-7,8-dimethoxy-2,3,4,5-tetrahydro- lH-benzo[<JJazepine, 6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-lH- benzo[<J|azepine, 6-fluoro-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[d]azepine, 8-methoxy-2,3,4,5-tetrahydro-lH-benzo[rf]azepine-7-sulfonic acid, 7- methanesulfonyl-2,3,4,5-tetrahydro-lH-benzo[ύT]azepine, 6-hydroxy-9- methanesulfonyl-2,3,4,5-tetrahydro-lH-benzo[f/]azepine, 7,8-dimethoxy-2,3,4,5- tetrahydro-lH-benzo[<r/]azepine, 2,3,4,5-tetrahydro-benzo[όf]azepine, 6-phenoxy- 2,3,4,5-tetrahydro-lH-benzo[ ]azepine, 6-methyl-2,3,4,5-tetrahydro-lH- benzo[< ]azepine, 7-hydroxy-2,3,4,5-tetrahydro- 1 H-benzo[ ]azepine, 6-hydroxy- 2,3,4,5-tetrahydro-lH-benzo[c/]azepine, 7-bromo-8-methoxy-2,3,4,5-tetrahydro- lH-benzol lazepine, 7-nitro-2,3,4,5-tetrahydro-l H-benzohV]azepine, 7-methoxy- 8-nitro-2,3,4,5-tetrahydro-lH-benzo[ ]azepine, l,2-dihydro-lH-benzo[f]isoindole and 5,6-dichloro-2,3-dihydro-lH-isoindole for 4,5-dichloro-2,3-dihydro-lH- isoindole and 3-(l-isopropyl-piperidin-4-yl)-4-rnethoxy-phenylamine (P51156)for 3-(2-diisopropylamino)ethoxy-4-methoxyaniline gave the following compounds: N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-5-chloro-2,3- dihydro-lΗ-isoindole-2-carboxamide: MS(ES) m/e 428.2 [M+HJ+;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-4,5-dichloro-2,3- dihydro-lH-isoindole-2-carboxamide: MS(ES) m/e 462.2 [M+HJ+; N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-7-hydroxy-8-nitro-

2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 483.4 [M+HJ+; N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-7-methoxy-2, 3,4,5- tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 452.2 [M+H]+;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]- 7-bromo-8-hydroxy- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 516.4

[M+H]⁺;N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-7-hydroxy-8- methanesulfinyl-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 500.4 [M+H]+;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-7-(5-methyl- [l,2,4]oxadiazol-3-yl)-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 504.4 [M+HJ+;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-7,8-dimethoxy-6-(4- methoxy-phenyl)-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 588.4 [M+HJ+; N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-2,3,4,5-tetrahydro- lH-indano[4,5-d]azapine-3-carboxamide: MS(ES) m e 462.4 [M+H]⁺;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-6-bromo-7,8- dimethoxy-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 560.2 [M+H]+; N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-6-chloro-7,8- dimethoxy-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 516.4 [M+H]+;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-6-fluoro-7,8- dimethoxy-2,3,4,5-tetrahydro-lH-benzazepine-3-carbox: MS(ES) m/e 500.4 [M+H]+;N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-8-methoxy-7- sulfonic acid-2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 532.2 [M+H]+; N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-7-methanesulfonyl- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 500.4 [M+H]⁺;N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-6-hydroxy-9- methanesulfonyl-2,3,4,5-tetrahydro- lH-benzazepine-3-carboxamide: MS(ES) m/e 516.4 [M+H]+;

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-7,8-dimethoxy- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 482.4 [M+HJ+;

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-2,3,4,5-tetrahydro- lH-benzazepine-3-carboxamide: MS(ES) m/e 422.2 [M+H]+; N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-6-phenoxy-2, 3,4,5- tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 514.4 [M+H]+;

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-6-methyl-2,3,4,5- tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 436.4 [M+H]⁺;

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-7-hydroxy-2, 3,4,5- tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 438.2 [M+H]⁺;

N-[3-(l-Isoproρyl-piperidin-4-yl)-4methoxy-phenyl]-6-hydroxy-2,3,4,5- tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 438.2 [M+H]⁺;

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-7-bromo-8-methoxy- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 530.2 [M+H]⁺; N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-7-nitro-2, 3,4,5- tetrahydro-iH-benzazepine-3-carboxamide: MS(ES) m/e 467.4 [M+H]⁺;

N-[3-(l-Isopropyl-piperidin-4-yl)-4methoxy-phenyl]-7-methoxy-8-nitro- 2,3,4,5-tetrahydro-lH-benzazepine-3-carboxamide: MS(ES) m/e 497.4 [M+H]+; N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-2,3-dihydro-lH- benzo[f]isoindole-2-carboxamide;: MS(ES) m/e 444.3 [M+H]+;

N-[3-(l-Isopropyl-piperidin-4-yl)-4-methoxy-phenyl]-5,6-dichloro-2,3- dihydro-lH-isoindole-2-carboxamide: MS(ES) m/e 462.2 [M+H]+.

Example 47 Following the procedure for Example 8, except substituting 5,6-dichloro-

2,3-dihydro-lH-isoindole for 4,5-dichloro-2,3-dihydro-lH-isoindole and 3-(3- Diisopropylamino-propoxy)-4-methoxy-phenylamine (WO 00/06153) for 3-(2- diisopropylamino)ethoxy-4-methoxyaniline gave the following compound: N-[3-[3-[Bis-l-methylethylamino]propoxy]-4-methoxyphenyl]-5,6- dichloro-2,3-dihydro-lΗ-isoindole-2-carboxamide: MS(ES) m/e 494.4 [M+H]+.

Example 48 Following the procedure for Example 8, except substituting 5,6-dichloro- 2,3-dihydro-lH-isoindole for 4,5-dichloro-2,3-dihydro-lH-isoindole and 4- Methoxy-3-[2-(2,2,6,6-tetramethyl-piperidin-l-yl)-ethoxy]-phenylamine (WO 00/06153) for 3-(2-diisopropylamino)ethoxy-4-methoxyaniline gave the following compound:

N-[3-[2-[2,2,6,6-Tetramethylpiperidin-l-yl]ethoxy]-4-methoxyphenyl]-5,6- dichloro-2,3-dihydro-lΗ-isoindole-2-carboxamide: MS(ES) m/e 520.2 [M+H]+.

Biological Data:

CCR5 Receptor Binding Assay

CHO cell membranes (0.25 xlO⁶ cell equivalents) derived from CHO cells stably transfected with CCR5 were incubated with 0.3 ¹²⁵I-RANTES in a 96 well plate for 45 min. at room temperature (final reaction volume 200 ul). The reaction was terminated by filtration and the filters (GF/C) were washed twelve times with a solution of phosphate buffered saline containing 0.1 % bovine serum albumin and 0.05 % Na 3. The radioactivity bound to filters was measured by liquid scintillation spectrometry. Non-specific binding was determined in the presence of unlabelled RANTES (10 or 30 nM) and averages 30-50% of total binding.

CCR5 Receptor Functional Assay

The cellular functional assay used to assess antagonist activity of compounds was

RANTES-induced Ca ⁺ mobilization in RBL 2H3 cells stably expressing the hCCR5 receptor (RBL 2H3 hCCR5). Agonist activity is determined by Ca²+ mobilization in the same cells which is inhibitable by a selective CCR5 antagonist. Cells were grown to 80-100% confluency in T-150 flasks and washed with phosphate-buffered saline. Cells were lifted from the flasks by treating with 3 mL of 1 mM EDTA for 3 min. at room temperature and diluting to 2 X 10^ cells/mL with Krebs Ringer Henseleit buffer (KRH; 118 mM NaCl, 4.6 mM KCl, 25 mM NaHCO₃, 1 mM KH2PO4 and 11 mM glucose) containing 5 mM HEPES (pH 7.4), 1 mM CaCl₂, 1 mM MgCl₂ and 0.1% BSA and centrifuged at 200g for 3 min. Cells were resuspended at 2 X 10^ cells/mL in the same buffer with 2 μM Fura-2AM, and incubated for 35 min. at 37° C. Cells were centrifuged at 200 x g for 3 min. and resuspended in the same buffer without Fura-2AM, then incubated for 15 min. at 37° C to complete the hydrolysis of intracellular Fura-2AM, and then centrifuged as before. Cells (10^ cells/mL) were resuspended in cold KRH with 5 mM HEPES (pH 7.4), 1 mM CaCl₂, 1 mM MgCl₂ and 0.1% gelatin and maintained on ice until assayed. For antagonist studies, aliquots (2 mL) of cells were prewarmed at 37° C for 5 min. in 3 mL plastic cuvettes and fluorescence measured in a fluorometer (Johnson Foundation Biomedical Group, Philadelphia, PA, USA) with magnetic stirring and temperature maintained at 37° C. Excitation was set at 340 nm and emission set at 510 nm. Various concentrations of antagonists or vehicle were added and fluorescence monitored for -15 sec to ensure that there was no change in baseline fluorescence, followed by the addition of 33 nM RANTES. Maximal Ca²+ attained after 33 nM RANTES stimulation was calculated as described by Grynkiewicz et al., (1985). The percent of maximal RANTES-induced Ca²⁺ was determined for each concentration of antagonist and the IC50 defined as the concentration of test compound that inhibits 50% of the maximal 33 nM RANTES response, obtained from the concentration-response curves (5-7 concentrations of antagonists). The compounds of this invention show CCR5 receptor modulator activity having IC50 values in the range of 0.0001 to 100 μM. The full structure/activity relationship has not yet been established for the compounds of this invention. However, given the disclosure herein, one of ordinary skill in the art can utilize the present assays in order to determine which compounds of formula (I) are modulators of the CCR5 receptor and which bind thereto with an IC50 value in the range of 0.0001 to 100 μM.

All publications, including, but not limited to, patents and patent applications cited in this specification, are herein incoφorated by reference as if each individual publication were specifically and individually indicated to be incoφorated by reference herein as though fully set forth.

The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration it is believed that one skilled in the art can, given the preceding description, utilize the present invention to its fullest extent. Therefore any examples are to be construed as merely illustrative and not a limitation on the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is claimed is:

1. A method of treating a CCR5-mediated disease state in mammals which comprises administering to a mammal in need of such treatment, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

Foπnula I

wherein: a basic nitrogen in moiety E may be optionally quatemized with Cj.galkyl or is optionally present as the N-oxide;

R" is hydrogen, C^alkyl, or R" together with the nitrogen to which it is attached may form a heterocyclic ring with an aryl ring of E;

Q' is a group selected from (i)-(vii):

wherein: Rl is independently selected from hydrogen, or one or more of C __βalkyl,

C2-6^aI!<enyl, C2_6alkynyl, C3_7cycloalkyI, C3_βcycloalkenyl, CH2CF3, aryl, aralkyl, (CH )a'NR^{2 ,}R^{3 '}, (CH₂)a'NR^2'COR^4', (CH2)_a'NR^{3 '}CO₂R^{5 '}, (CH2)_a'NR²'SO₂R^6', (CH₂)_aCONR⁷ R^8', hydroxyC..₆alkyl, C^alkoxyalkyl (optionally substituted by a C_j^alkoxy or hydroxy group), (CH2)_a'CO2Ci_(5alkyl, (CH₂)bOC(O)R⁹', CRiO^'-NOR^11', CNRW=NOR ^', COR^12', CONR⁷R^8', CONR^7,(CH₂)c C₁.₄alkyl, CONR^7,(CH2)aCO₂R^13', CONHNR¹⁴^^15', CONR⁷SO₂R^16', CO₂R^17', cyano, trifluoromethyl, NR²R^3', NR²COR^4', NR^18'CO(CH2)a'NR^18'R^19', NR^i8'CONRl⁸Rⁱ⁹', NR²'CO₂R^5', NR²'SO₂R^6', N=CNR¹⁸'NR^18'R^19', nitro, hydroxy, Cj_₆alkoxy, OCF3, hydroxyC^alkoxy, C galkoxyC_j.βalkoxy, OC(O)NR²⁰'R^21', SR²²', SOR^23', SO₂R^23',

OPh, SPh or halogen, or R¹' is a 5- to 7-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, optionally substituted with hydrogen, C1 _galkyl, C3_7cycloalkyl, C3_6cycloalkenyl, hydroxyC^galkyl, (C|_6alkyl)C _6alkyl, CONR⁷ R⁸', CO2R¹⁷', cyano, aryl, trifluoromethyl, nitro, hydroxy, C^.galkoxy, acyloxy, or halogen; a' is 1,2, 3 or 4; b'isO, 1, 2 or 3; c'is 1,2 or 3;

R²' and R³' are independently hydrogen or Cj galkyl, or R² and R³' together with the nitrogen to which they are attached, form a 5- to 6-membered heterocyclic ring which ring may be optionally substituted by an oxo group, or, when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;

R⁴ is hydrogen, Cj.galkyl or Cj^alkoxyalkyl; R⁵'isC₁_6alkyl; R is

orphenyl; R⁷ and R⁸ are independently hydrogen or Cj.galkyl, or R⁷ andR⁸' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring, wherein when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;

R⁹ is C _4alkyl, optionally substituted by a Cj.galkoxy; RIO and R¹¹' are independently hydrogen or Cj^galkyl;

R¹² is hydrogen or C_j.galkyl; R¹³ is hydrogen or C_j.galkyl;

R¹⁴ and R^ are independently hydrogen or C_j.galkyl;

R¹" is hydrogen or Cy.galkyl; R¹⁷ is hydrogen or Cj^alkyl optionally substituted with one or more substituents selected from C^alkyl, C^galkoxy, hydroxy, or NR²R^3';

R¹⁸ andR¹⁹ are independently hydrogen or C_j^galkyl; R²^^' and R² ' are independently hydrogen or C βalkyl, or R²^^' and R²¹ together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when the ring is 6-membered, may optionally contain in the ring one oxygen or one sulfur atom. R²² is hydrogen or Cj^galkyl;

R²³' is C_j_₍5alkyl;

R² ' is independently selected from hydrogen, or one or more of Cj__galkyl, aryl, oxo or OR^a, wherein R^a is H or C .galkyl;

E represents a group (a):

^H° (a); in which

B is oxygen, G≡C, S(O)_c, CR⁷=CR⁸, or CR⁷R⁸, or B is NR⁹;

R and R² are independently hydrogen or Cj.galkyl; alternatively B(CRiR )_a is OCRiR CRl(OH)CR!R² or

R³ and R⁴ are independently hydrogen, C _6alkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include Cμealkyl, aryl, CONRiOR^{1 1}, NR^R¹*, hydroxy, OCOR¹², NHCOCF3, NHSO₂R¹³, NHCO₂R¹⁴, or NHCOC₀-6^alkyl wherein the alkyl of NHCOC₀. galkyl is optionally substituted by OH;

R⁵ is hydrogen, C^galkyl, aryl, CN, CONR¹⁵R¹⁶, CO₂R¹⁷, trifluoromethyl, NHCO2R¹⁸, hydroxy, C^alkoxy, benzyloxy, OOFpX^Ci. ₆alkyl, OCF3, S(O)_dR¹⁹, SO₂NR ⁰R²¹ or halogen; R^ is hydrogen, C .galkyl, aryl, trifluoromethyl, hydroxy, Cj.galkoxy or halogen, or R^0" taken together with R" forms a group D where D is (CR²²R ³)_e or D is (CR²²R²³)f-G where G is oxygen, sulfur or CR ²=CR²³, CR²²=N, =CR²²O, =CR²²S, or =CR²²-NR²³;

R⁷ _, R⁸, iO, Rll, R l2_: R15, _R16, _R17, R20, R21, _R22, _{and R}23 _are independently hydrogen or C_|.galkyl;

R⁹ is hydrogen, Cj.galkyl, or phenylC _galkyl; R¹³, R¹⁴, R¹⁸, and R¹⁹ are independently C galkyl; a is 1, 2, 3, or 4; b is 1 or 2; c and d are independently 0, 1 or 2; e is 2, 3 or 4; f is O, l , 2 or 3; alternatively, E represents a group (b):

R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³¹, and R³² are independently hydrogen or C^galkyl;

R30 is hydrogen, C^galkyl, or C3_7cycloalkyl;

R³³ is hydrogen, C^.galkyl, trifluoromethyl, hydroxy or halogen, or R³³ and R" together form a group -K- where K is (CR³⁴R³⁵)i or K is (CR³⁴R ⁵)j -M and M is oxygen, sulfur, CR³⁴=CR35, CR³⁴=N, or N=N;

J is oxygen, CR 6R37_{5 or} NR³⁸, or J is a group 8(0)^;

R³⁴, R35_; R36_; R37_{; an} R38 _are independently hydrogen or Ci _.galkyl; g is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3, or 4; j is 0, 1, 2, or 3; k is O, l or 2; alternatively, E represents a group (c):

in which:

Q is oxygen, S(O)_n, CR⁴⁴=CR⁴⁵, CR⁴⁴R⁴5, or Q is NR⁴⁶; R3 _and R ^ are independently hydrogen or C_j^galkyl; R⁴¹ is a group of formula (d):

or R⁴¹ is a group of formula (e):

R⁴² is hydrogen, C^alkyl, aryl, CN, CONR⁴⁸R⁴⁹, CO₂R⁵⁰, trifluoromethyl, NHCO2R^ , hydroxy, C^.galkoxy, benzyloxy, OCH2CO2C1.. 6alkyl, OCF3, S(O)_sR⁵², SO₂NR⁵³R⁵⁴, or halogen;

R⁴³ is hydrogen or R⁴³ together with R" forms a group R where R is CR55=CR⁵⁶,

_or (CR55 56_)t;

R⁴⁴, R⁴5, R⁴6, R48_; R49_; R50_{5 R}53_{? R}54_; R55_{; and R}56 _are independently hydrogen or Cj.galkyl; R⁴⁷ is hydrogen, C^.galkyl, or C3_7 cycloalkyl;

R^ and R^² are independently C_ji.galkyl; l is O, 1, 2, or 3; m is 1 or 2; n is 0, 1, or 2 o, p, and q are independently integers having the value 1, 2, or 3; r is 0,1, 2, or 3; s is 0, 1, or 2; t is 2 or 3; alternatively, E represents a group (f):

R5⁷ and * are independently hydrogen or C^.galkyl; R5 and R60 _are independently hydrogen, C_j.galkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C_j^alkyl, aryl, CONR⁶¹R⁶², NR61R 2_; hydroxy, OCOR⁶³, NHCOCF3, NHSO₂R⁶⁴, NHCO₂R⁶⁵, or NHCOC₀_6alkyl wherein the alkyl of NHCOCo-6^alkyl is optionally substituted by OH; T is ~(CR⁶⁶R⁶⁷)v- or -O(CR66R67_)W__; W is oxygen, S(O)_x, NR⁶⁸, or W is C≡C, CR6 =CR⁷⁰ or CR⁶⁹R⁷⁰;

R61 , R62, R63, R66, R67 R68_> R69, _{and R}70 _are independently hydrogen or C^.galkyl; R⁶⁴ and R⁶⁵ are independently C^galkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; ) x is O, 1 or 2; alternatively, E represents a group (g):

R⁷ is a 5- to 7-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and optionally a further 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur or R⁷¹ is an optionally substituted 6,6 or 6,5 bicyclic ring containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulfur, which ring systems may be optionally substituted with one or more of Ci ..galkyl and optionally substituted on nitrogen with hydrogen, C _galkyl or C3_7cycloalkyl; R⁷² is hydrogen, C^alkyl, aryl, CN, CONR⁷⁴R⁷⁵, CO₂R⁷⁶, trifluoromethyl, NHCO2R⁷⁷, hydroxy, C^.^alkoxy, benzyloxy, OCH2CO2C1. ₆alkyl, OCF3, S(O)_zR⁷⁸, SO₂NR⁷⁹R⁸⁰, or halogen;

R⁷³ is hydrogen, C galkyl, hydroxy, C^.galkoxy or halogen, or R⁷³ and R" taken together from a group -X- where X is (CR⁸¹R ²)_aa or X is (CR⁸lR⁸ )_ab-Y and Y is oxygen, sulfur or CR⁸¹=CR⁸²;

R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁹, R⁸⁰, R⁸¹, and R⁸² are independently hydrogen or Ci .galkyl;

R⁷⁷ and R⁷⁸ are independently C_j^.galkyl; y is 1 or 2; z is O, 1, or 2; aa is 2, 3 or 4; ab is O, 1, 2 or 3; alternatively, E represents a group (h):

^R87 (h); R⁸³ and R⁸⁴ are independently hydrogen or C ^ lkyl;

R⁸^ and R⁸⁶ are independently hydrogen, C_j.galkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include Cι _6alkyl, aryl, CONR⁸⁸R⁸⁹, NR ⁰R⁹¹, hydroxy, OCOR⁹², NHCOCF3, NHSO₂R⁹³, NHCO2R⁹⁴, or HCOC₀„6alkyl wherein the alkyl of NHCOCo-όalkyl is optionally substituted by OH; R⁸⁷ is hydrogen or C 1.galkyl, C^.^alkoxy, or halogen, or R⁸⁷ together with R" forms a group -AA- where AA is (CR⁹⁵R ⁶)_ad or AA is (CR⁹⁵=CR 6)_ae-AB and AB is oxygen, sulfur, CR⁹5=CR⁹⁶, CR ⁵=N, CR⁹⁵NR⁹⁶ or N=N;

Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;

R88_> R89_; R90₎ R91₅ R92_; R95_{? and R}96 _are independently hydrogen or

Cχ_6alkyl;

R⁹³ and R⁹⁴ are independently C .galkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; alternatively, E represents a group (i):

R⁹⁷ and R⁹⁸ are independently hydrogen, Cj.galkyl, C3_7cycIoalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C galkyl, aryl, CONR^RiO³, NR¹⁰⁴R¹⁰⁵, hydroxy, OCORiO⁶, NHCOCF3, NHSO₂ R¹⁰⁷, NHCO₂R¹⁰⁸, or NHCOC₀_6 lkyl wherein the alkyl of NHCOCθ-6^alkyl is optionally substituted by OH;

R⁹⁹ and R- ^ _are independently hydrogen or Cl-6alkyl; R^ΪO-¹ is hydrogen or C|_galkyl or R^l and R" together form a group -AD- where AD is (CR^^R^{1 10})ai or AD is (CR¹⁰ R¹¹⁰)_aj-AE and AE is oxygen, sulfur or CR¹⁰ =CR^{1 10}; AC is oxygen, CR ^ιR ^{1 12} or NR¹^ or AC is a group S(O)_ak;

R102, R103_, Rl04, R 105, _R106_{; R}109 I IO, RI U _R 112, _and Rl 13 are independently hydrogen or C ^galkyl;

R ¹⁰⁷ and R ^⁸ are independently Cl-6alkyl; af is O, 1, 2, 3, or 4; ag is 1, 2, or 3; ah is 1 , 2, 3 or 4; ai is 2, 3 or 4; aj is 0, 1, 2, or 3; and ak is 0, 1 or 2.

2. The method as claimed in claim 1, wherein the disease is selected from COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection.

3. A compound of formula (I):

Formula I

wherein: a basic nitrogen in moiety E may be optionally quatemized with C j.βalkyl or is optionally present as the N-oxide;

R" is hydrogen, Cj.galkyl, or R" together with the nitrogen to which it is attached may form a heterocyclic ring with an aryl ring of E;

Q' is a group selected from (i)-(vii):

wherein:

R¹' is independently selected from hydrogen, or one or more of Cj.galkyl, C2_6^alkenyl, C2-6^alkynyl, C3_7cycloalkyl, C3_gcycloalkenyl, CH2CF3, aryl, aralkyl, (CH2)_a'NR²R^3', (CH2)_a'NR²'COR⁴', (CH₂)_a'NR³ CO₂R⁵', (CH₂)_a'NR^2'SO₂R^6', (CH )_aCONR⁷R⁸', hydroxyCj.galkyl, Cι_₄alkoxyaIkyl (optionally substituted by a C_j_4alkoxy or hydroxy group), (CH2)_a ^: 02C _6alkyl, (CH₂)b C(O)R⁹', CRl '=NOR^ιr, CNR^NORl¹', COR¹²', CONR⁷R⁸', CONR⁷'(CH2)c C₁. alkyl, CONR^C^a^R^13', C0NHNR1⁴'R¹⁵', CONR⁷'SO₂R^16', CO₂R¹⁷', cyano, trifluoromethyl, NR²R^3', NR²COR⁴', NRl⁸'CO(CH2)_a'NR¹⁸ R¹⁹', NR^18'CONR¹⁸ R¹⁹', NR²CO₂R⁵', NR² SO₂R^6', N=CNR¹⁸ NR¹⁸ R¹⁹', nitro, hydroxy, Cj^alkoxy, OCF3, hydroxyCi^alkoxy, Cι_₆alkoxyCi_6alkoxy, OC(O)NR ⁰R²¹', SR^22', SOR^23', SO₂R^23', SO2NR²0'R² ', OPh, SPh or halogen, or R ' is a 5- to 7-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, optionally substituted with hydrogen, Cj_^.galkyl, C3_7cycloalkyl, C3_gcycloalkenyl, hydroxyCj.galkyl,

CONR⁷R⁸', CO2R¹⁷', cyano, aryl, trifluoromethyl, nitro, hydroxy, C_j_6alkoxy, acyloxy, or halogen; a' is 1,2, 3 or 4; b'isO, l,2or3; c'is 1, 2 or3;

R^2' and R^3' are independently hydrogen or C^_βalkyl, or R² and R³ together with the nitrogen to which they are attached, form a 5- to 6-membered heterocyclic ring which ring may be optionally substituted by an oxo group, or, when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;

R⁴' is hydrogen, C_j_6^alkyl or Cj^alkoxyalkyl; RS' is Cj.galkyl; R6^' is Cι_galkyl or phenyl; R^{7 '} and R^8' are independently hydrogen or C_j.galkyl, or R⁷' and R⁸' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring, wherein when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;

R⁹' is C_j_4alkyl, optionally substituted by a Cj^galkoxy; R^^' and Ril' are independently hydrogen or Chal y!;

R ² is hydrogen or C _6alkyl; R¹³ is hydrogen or Cj_6alkyl;

R^⁴ and R¹^' are independently hydrogen or Ci .galkyl; R¹⁶ is hydrogen or Cj.galkyl; R¹⁷ is hydrogen or Cj.galkyl optionally substituted with one or more substituents selected from Cj.βalkyl, C^.galkoxy, hydroxy, or NR R³'; R^⁸ and R ⁹' are independently hydrogen or C _galkyl; R²0' and R^{2 '} are independently hydrogen or C galkyl, or R²^' and R²1^' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when the ring is 6-membered, may optionally contain in the ring one oxygen or one sulfur atom. R²²' is hydrogen or Cι_galkyl; R^{23 '} is Cι_6alkyl;

R- 9 " is independently selected from hydrogen, or one or more of Ci _5alkyl, aryl, oxo or OR^a, wherein R^a is H or C_j.galkyl;

E represents a group (a):

^R6 (a); in which

B is oxygen, C≡C, S(0)_c, CR⁷=CR⁸, or CR⁷R⁸, or B is NR⁹; R¹ and R² are independently hydrogen or C_j._βalkyl; alternatively

B(CRlR2)_a is OCRlR2cRl(OH)CRlR² or

R³ and R⁴ are independently hydrogen, C^galkyl, C3 ₇cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C_j^alkyl, aryl, CONR^R¹¹, NR^R^{1 1}, hydroxy, OCOR¹², NHCOCF3, NHSO R¹³, NHCO₂R¹⁴, or NHCOC₀-6alkyl wherein the alkyl of NHCOCQ. galkyl is optionally substituted by OH; R⁵ is hydrogen, Ci.galkyl, aryl, CN, CONR¹⁵R¹⁶, CO2R¹⁷, trifluoromethyl, NHCO2R¹⁸, hydroxy, C .galkoxy, benzyloxy, OCH2CO2Cj. ₆alkyl, OCF3, S(0)_dR¹⁹, SO₂NR²⁰R²¹ or halogen;

R6 is hydrogen, Cj.galkyl, aryl, trifluoromethyl, hydroxy, C_j.galkoxy or halogen, or R⁶ taken together with R" forms a group D where D is (CR ²R² )_e or D is (CR²²R²³)_f-G where G is oxygen, sulfur or CR²²=CR²³, CR²²=N, =CR²²O, =CR²²S, or =CR ²-NR²³;

R⁷, R⁸, lO, Rll, _R12_: R15₅ R 16_: R! 7, _R20, R21, _R22, _and R²³ are independently hydrogen or C_j_5alkyl;

R⁹ is hydrogen, Cj.galkyl, or phenylCj.galkyl; R¹³, R¹⁴, R¹⁸, and R*⁹ are independently C galkyl; a is 1, 2, 3, or 4; b is 1 or 2; c and d are independently 0, 1 or 2; e is 2, 3 or 4; f is 0, 1, 2 or 3; alternatively, E represents a group (b):

R²⁴ R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R31, and R³² are independently hydrogen or Cj.galkyl; 30 is hydrogen, Cj.ζalkyl, or C3_7cycloalkyl;

R³³ is hydrogen, C|_galkyl, trifluoromethyl, hydroxy or halogen, or R33 and R" together form a group -K- where K is (CR³⁴R35)J _or K is (CR³⁴R35)J _jyτ and M is oxygen, sulfur, CR³⁴=:CR35, CR3⁴=N, or N=N;

J is oxygen, CR³⁶R³⁷, orNR³⁸, or J is a group S(O)_k; R³⁴, R³⁵, R36_; R37_{5 an} R38 _are independently hydrogen or C_j_6alkyl; g is 1 , 2 or 3; h is 1 , 2 or 3; i is 2, 3, or 4; j is O, l , 2, or 3; k is 0, 1 or 2; alternatively, E represents a group (c):

in which:

Q is oxygen, S(O)_n, CR⁴ =CR⁴⁵, CR⁴⁴R⁴⁵, or Q is NR⁴⁶; R3 and R⁴^ are independently hydrogen or Cj^alkyl; R⁴¹ is a group of formula (d):

(

or R⁴ is a group of formula (e):

R⁴² is hydrogen, Cj_₆alkyl, aryl, CN, CONR⁴⁸R⁴⁹, CO₂R⁵⁰, trifluoromethyl, Nffl R^¹, hydroxy, C_j^alkoxy, benzyloxy, OCH2CO2C_j_ galkyl, OCF₃, S(O)_sR⁵², SO₂NR⁵³R⁵⁴, or halogen; R⁴³ is hydrogen or R⁴³ together with R" forms a group R where R is

CR⁵⁵=CR56, CR⁵⁵=CR⁵⁶CR55R56_{; or} (CR55R56)_t;

R⁴⁴ _, R⁴5, R⁴6, R⁴8_{; R}49_; R50, R53, _R54₅ R55, _{and R}56 _are independently hydrogen or C_j^alkyl;

R⁴⁷ is hydrogen, C galkyl, or C3.7 cycloalkyl; R^¹ and R^² are independently Cχ_6al yl; l is O, 1, 2, or 3; m is 1 or 2; n is 0, 1, or 2 o, p, and q are independently integers having the value 1, 2, or 3; r is 0,1, 2, or 3; s is O, 1, or 2; t is 2 or 3; alternatively, E represents a group (f):

R^⁷ and R^ are independently hydrogen or Cj_galkyl; R⁵⁹ and R⁶⁰ are independently hydrogen, Cj.galkyl, C3_7cycloalkyI, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C_j.galkyl, aryl, CONR⁶¹R⁶², NR⁶ⁱR⁶², hydroxy, OCOR⁶³, NHCOCF3, NHSO₂R⁶⁴ NHCO₂R⁶⁵, or NHCOCθ-6^alkyl wherein the alkyl of NHCOCo-6^alkyl is optionally substituted by OH; T is -(CR⁶⁶R67_)V_ _or -0(CR66R67)_W._;

W is oxygen, S(O)_x, NR⁶⁸, or W is C≡C, CR⁶⁹=CR⁷⁰ or CR⁶⁹R⁷⁰; R⁶¹, R⁶², R6 , R66_; R67 R68_; R69_{; and R}70 _are independently hydrogen or Cj.galkyl; R⁶⁴ and R^5 are independently C_j^galkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; alternatively, E represents a group (g):

g); R⁷ is a 5- to 7-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and optionally a further 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur or R⁷¹ is an optionally substituted 6,6 or 6,5 bicyclic ring containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulfur, which ring systems may be optionally substituted with one or more of Cj^galkyl and optionally substituted on nitrogen with hydrogen, Cj.galkyl or C3_ cycIoalkyI;

R⁷² is hydrogen, Cι_6^al yl, aryl, CN, CONR⁷⁴R⁷⁵, CO2R⁷⁶, trifluoromethyl, NHCO2R⁷⁷, hydroxy, C^.galkoxy, benzyloxy, 009^02^. ₆alkyl, OCF3, S(0)₂R⁷⁸, SO₂NR⁷⁹R⁸0, or halogen;

R⁷³ is hydrogen, C j.galkyl, hydroxy, C galkoxy or halogen, or R⁷³ and R" taken together from a group -X- where X is (CR^{8 L}R⁸²)_aa ^or X is (CR⁸¹R⁸²)_ab-Y and Y is oxygen, sulfur or CR^{8 !}=CR⁸²;

R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁹, R⁸⁰, R⁸¹, and R⁸² are independently hydrogen or C^alkyl; R⁷⁷ and R⁷⁸ are independently C_j.galkyl; y is 1 or 2; z is 0, 1, or 2; aa is 2, 3 or 4; ab is 0, 1, 2 or 3; alternatively, E represents a group (h):

^R87 (h);

R and R⁸⁴ are independently hydrogen or C_j.galkyl; R⁸5 and R ⁶ are independently hydrogen, C_j_όalkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include Cj^alkyl, aryl, CONR⁸⁸R⁸⁹, NR⁹⁰R⁹¹, hydroxy, OCOR⁹², NHCOCF3, NHSO₂R⁹³, NHCO₂R⁹⁴ or NHCOC₀-6alkyl wherein the alkyl of NHCOCo-6alkyl is optionally substituted by OH; R⁸⁷ is hydrogen or Cj.galkyl, C^.galkoxy, or halogen, or R⁸⁷ together with R" forms a group -AA- where AA is (CR ⁵R⁹⁶)_a or AA is (CR⁹⁵=CR⁹⁶)_ae-AB and AB is oxygen, sulfur, CR⁹5=CR⁹6, CR⁹⁵=N, CR⁹⁵NR⁹6 ₀r N=N;

Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;

R⁸⁸, R⁸⁹, R⁹⁰, R⁹¹, R⁹², R⁹⁵, and R⁹⁶ are independently hydrogen or C galkyl;

R⁹ and R⁹⁴ are independently C_j_galkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; alternatively, E represents a group (i):

R⁹⁷ and R⁹⁸ are independently hydrogen, Cj^galkyl, C3_7cyclo Ikyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C_j.₆alkyl, aryl, CONR¹⁰²R¹⁰³, NR¹⁰⁴R¹⁰⁵, hydroxy, OCORiO⁶, NHCOCF3, NHSO₂ R¹⁰⁷, NHCO₂R¹⁰⁸, or NHCOC₀-6alkyl wherein the alkyl of NHCOC()-6alkyl is optionally substituted by OH;

R⁹⁹ and R ^ are independently hydrogen or Cl-6alkyl; RlOl is hydrogen or C_j.galkyl or R¹^ and R" together form a group -AD- where AD is (CR¹⁰9RH0)ai or AD is (CR¹⁰⁹R¹¹⁰)_aj-AE and AE is oxygen, sulfur or CRl°⁹=CR¹¹⁰;

AC is oxygen, CR ^{1 J}-R^{1 12} or NR^{1 13} or AC is a group S(O)_ak;

R102, _R103_{5 R}104 R105, _R106, _R109, RIIO, RIII, R112, _{and R}113 _are independently hydrogen or C_|_galkyl;

R¹⁰⁷ and R¹⁰⁸ are independently Cl-6alkyl; af is O, 1, 2, 3, or 4; ag is 1, 2, or 3; ah is 1, 2, 3 or 4; ai is 2, 3 or 4; aj is 0, 1, 2, or 3; and ak is 0, 1 or 2, provided that when R"is H; Q' is (vi); R²" is H; E is (a); R³1, R32 _an R36 _{are H;} R33 is OCH3; d is 2; e is 1; R3⁴ _and R3 are isopropyl; and B is O, then R^^' is not 7-nitro, 7-bromo-8-hydroxy, 7,8-dimethoxy-6-(4-methoxyphenyl), 7,8-dimethoxy- 6-phenyl, 6-chloro-7,8-dimethoxy-9-phenyl, 6-bromo-7,8-dimethoxy, 6-chloro-7,8- dimethoxy, 7,8-dimethoxy, H, 7-hydroxy, 6-hydroxy 7-bromo-8-methoxy, or 7- amino, and further, provided that when R"is H; Q' is (vi); R²' is H; E is (g); R⁷^ is H; R⁷⁶ is 4-OCH3; z is 1 and R⁷⁷ is N-isopropylpiperidin-4-yl, then R^{1 '} is not 7,8-dimethoxy-6-phenyl, or 6-chloro-7,8-dimethoxy-9-phenyl, and further provided that when Q' is (ii); R" R³¹, R32, R33 _and R 6 are hydrogen; R²" is hydrogen; E is (a); d is 2; R³⁴ and R³^ are methyl; B is oxygen, R¹ ' is not 5- methylthio-6-trifluoromethyl or 5-methoxy-6-trifluoromethyl, and further provided that when Q' is (ii); R" R³¹, R³², R³³ and R³⁶ are hydrogen; R²" is hydrogen; E is (a); d is 2; R³⁴ and R³⁵ are methyl; B is R³⁹R⁴0 wherein R³⁹ and R⁴⁰ are hydrogen, R^1' is not 5-methoxy-6-trifluoromethyl.

4. A pharmaceutical composition comprising a compound as claimed in claim 3 and a pharmaceutically acceptable caπier.