JP2002521436A - Substituted anilide compounds and methods - Google Patents

Abstract

  (57) [Summary] The present invention relates to substituted anilide compounds that are modulators, agonists or antagonists of the CCR5 receptor. In addition, the present invention relates to the treatment and prevention of conditions mediated by CCR5.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD [0001] The present invention relates to CCR5 (Nature Medicine 1996, 2, 1174-8) today.
Substituted anilide compounds which are modulators, agonists or antagonists of the CC chemokine receptor CC-CKR5, referred to as CC-CKR5. In addition, the present invention relates to treatment and prevention of conditions mediated by CCR5.

BACKGROUND ART [0002] T cells are not only important substances that regulate the immune response to infectious substances, but also play a very important role in initiating and maintaining the inflammatory response in various chronic diseases. . An increase in the number or activation of T cells, especially CD4 + T cells,
In the synovium of rheumatoid arthritis individuals (MJElliott and RNMaini, Int. Arch.A.
llergy Immunol. 104: 112-1125, 1994), on the bronchial mucosa of asthmatic patients (CJ Corrigan and ABKay, Immunol. Today 13: 501-506, 19).
92), in multiple sclerosis lesions (R. Martin and HFMcFarl, Crit. Rev. Clin.
Lab. Sci. 32: 121-182, 1995), in psoriatic lesions (JL Jones, J. Bert
h-Jone, A. Fletcher and PEHutchinson, J. Pathol. 174: 77-82, 1,
994) and in the fatty streak of atherosclerosis (R. Ross, Annu. Rev. Physi
ol. 57: 791-804, 1995). T cells as well as other inflammatory cells will migrate into tissues in response to production of various chemotactic factors. Of these factors, one superfamily, 8-12
The kDa protein is known as a chemokine. These proteins share structural features such as the presence of 3-4 conserved cysteine residues. Regulated upon
RAN is an abbreviation for Activation Normal T cell Expressed and Secreted
TES is an 8 kDa protein in the CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through interaction with G-protein coupled receptors. The CC branch is defined by the absence of intervening amino acid residues between the first two cysteine residues and members of this family are mononuclear cells,
Induces predominantly the migration of eosinophils and basophils (M. Baggiolini, B. Dewald and B. Moser, Adv. Immunol. 55: 97-179, 1994; and JJOppenhei)
m, COC Zachariae, N. Mukaida and K. Matsushima, Annu. Rev. Immunol. 9: 6
17-648, 1991).

[0003] RANTES effectively chemotaxis T cells, basophils, monocytes and mast cells. RANTES was originally identified as a gene product that is induced late after antigen activation of T-cells (TJ Schall, J. Jongstra, BJDyer, J. Jorgen
sen et al., J. Immunol. 141: 1018-1025, 1988)
Are epithelial and endothelial cells (C. Stellato, LABeck, GAGorgone, D. Proud et al., J.
Immunol. 155: 410-418, 1995; and A. Marfaing-Koka, O. Devever.
ne, G. Gorgon, A. Portier et al., J. Immunol. 154: 1870-1878, 199.
4), synovial fibroblasts (P. Rathanaswami, M. Hachicha, M. Sadick, TJ Schall et al., J. Biol. Chem. 268: 5834-5839, 1993) and dermal fibroblasts (M. Stickerling, M. Kupper, F. Koltrowitz, E. Bornscheuer et al., J. Invest. Derma
105: 585-591, 1995), glomerular stromal cells (G. Wolf, S. Aberle
F. Thaiss et al., Kidney Int. 44: 795-804, 1994) and platelets (Y.
Koameyoshi, A. Dorschner, AIMallet, E. Christophers, et al., J. Exp. Med. 176.
: 587-592, 1992) have been shown to be synthesized and secreted by various groups of cells. In these cells, RANTES mRNA is rapidly upregulated in response to IL-1 or TNFα. R
ANTES mRNA is not normally detected in normal cells (JMPattison,
PJ Nelson and AM Krensky, Clin. Immunoother. 4: 1-8, 1995) show increased mRNA or protein in diseases characterized by mononuclear infiltrates. For example, RANTES mRNA can be expressed in rejecting renal allografts (JMPattison, PJ Nelson and AMKrensky, Clin. Immunoother. 4: 1-
8, 1995; and KCNadeau, H. Azuma and NITiney, Proc. Natl. Aca
d. USA 92: 8729-8733, 1995), skin of patients with atopic dermatitis after exposure to antigen (S. Ying, L. Taborda-Barata, Q. Meng, M. Humbert et al., J. Exp.
Med. 181: 2153-2159, 1995) and coronary artery endothelial cells with accelerated progression of atherosclerosis after heart transplantation (JMPattison, PJ Nelson
And AMKrensky, Clin. Immunoother. 4: 1-8, 1995) using the in situ hybridization method. Furthermore, RANTES
Increased immunoreactive proteins related to bronchoalveolar lavage fluid (R. Alam, J. York, M.
Boyers et al., Am. J. Resp. Crit. Care Med. 149: A951, 1994) and sputum from asthmatics (CMGelder, PSThomas, DHYates, IMAdcock et al., Thorax 5).
0: 1033-1037, 1995).

[0004] Several receptors that bind to RANTES have been identified. In particular, CCR5 is
When expressed in either 293 cells or CHO cells, it binds to RANTES. This receptor is expressed on T-cells and on monocytes and macrophages, immune / inflammatory cells that play an important role in maintaining a chronic inflammatory response. CCR
5 can be characterized pharmacologically, and the RANTES observed on isolated T cells
It is similar to the binding site. Thus, the antagonism of RANTES against CCR5 and the antagonism of other natural modulators of CCR5 inhibits the recruitment and activation of T cells and macrophages to inflammatory lesions and is novel for treating atopic and autoimmune diseases To provide appropriate therapy. Because T cells and macrophages express CCR5, selective receptor modulators, particularly antagonists, of CCR5 are useful in all mammals, preferably humans, for asthma and atopic disorders (eg, atopic dermatitis and allergy), chronic Rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases, such as
It is believed to provide effective effects in diseases including, but not limited to, multiple sclerosis and inflammatory bowel disease. Furthermore, since CD8 + T cells and macrophages are involved in COPD, CCR5 plays a role in its recruitment, and thus antagonists of CCR5 may provide an effective therapy in treating CORD. In addition, since CCR5 is a co-receptor for HIV entry into cells, selective receptor modulators may be useful in treating HIV infection. Surprisingly, this time, non-peptidic compounds of this type, particularly the substituted anilide compounds of the present invention, function as CCR5 receptor modulators and therefore have utility in the treatment and prevention of conditions mediated by the CCR5 receptor mechanism. It was found to be.

[0005] In one aspect, the present invention provides a compound of formula (I):

Embedded image

Wherein the basic nitrogen present in the group E is C_1-6May be quaternized with alkyl
Or as an N-oxide; P¹And P²Is independently phenyl, fused bicyclic aryl, oxygen, nitrogen or
And a 5- to 7-membered unit containing 1 to 3 heteroatoms selected from
A cyclic heterocycle, or one to three hetero atoms selected from oxygen, nitrogen and sulfur
A is an 8- to 11-membered fused bicyclic heterocycle containing atoms; A is C (R^{4 '})₂, CR^{4 '}(OR^{5 '}), CO, C = NOR^{6 '}, NR^{7 '}
, Oxygen or S (O)_{c '}L is of the formula: -C (= V) -DR^{8 '}-, -DR^{9 '}-C (= V)-, -CH₂NH
-Or -NHCH₂V is oxygen or sulfur; D is a nitrogen, carbon or CH group; R^{1 '}And R^{2 '}Is independently hydrogen, C_1-6Alkyl, C_2-6Arche
Nil, C_2-6Alkynyl, C_3-7Cycloalkyl, C_3-7Cycloalkenyl
, Aryl, (CH₂)_{d '}NR^{10 '}R^{11 '}, (CH₂)_{d '}NR^{10 '}CO
R^{12 '}, (CH₂)_{d '}NR^{10 '}CO₂R^{13 '}, (CH₂)_{d '}NR^{10 '}S
O₂R^{14 '}, (CH₂)_{d '}CONR^{15 '}R^{16 '}, Hydroxy C_1-6Al
Kill, C_1-4Alkoxyalkyl (one C_1-4Alkoxy or hydroxy
May be substituted with a thio group), (CH₂)_{d '}CO₂C_1-6Alkyl, (CH
₂)_{e '}OC (O) R^{17 '}, CR^{18 '}= NOR^{19 '}, CNR^{20 '}= NOR
^{19 '}, COR^{21 '}, CONR^{15 '}R^{16 '}, CONR^{15 '}(CH₂)_{f '} OC_1-4Alkyl, CONR^{15 '}(CH₂)_{d '}CO₂R^{22 '}, CONNHN
R^{23 '}R^{24 '}, CONR^{15 '}SO₂R^{25 '}, CO₂R^{26 '}, Cyano,
Trifluoromethyl, NR^{10 '}R^{11 '}, NR^{10 '}COR^{12 '}, NR^{27 '} CO (CH₂)_{d '}NR^{27 '}R^{28 '}, NR^{27 '}CONR^{27 '}R^{28 '},
NR^{10 '}CO₂R^{13 '}, NR^{10 '}SO₂R^{14 '}, N = CNR^{27 '}NR ^{27 '} R^{28 '}, Nitro, hydroxy, C_1-6Alkoxy, hydroxy C_{1- 6} Alkoxy, C_1-6Alkoxy C_1-6Alkoxy, OC (O) NR^{29 '}R ^{30 '} , SR^{31 '}, SOR^{32 '}, SO₂R^{32 '}, SO₂NR^{33 '}R^{34 '} , Halogen, C_1-6Alkanoyl, CO₂(CH₂)_{d '}OR^{35 '}Is
Or R^{1 '}Is 1 to 4 hetero atoms selected from oxygen, nitrogen or sulfur
An optionally substituted 5- to 7-membered heterocycle containing atoms;

[0007] R^{3 '}Is hydrogen, C_1-6Alkyl, C_3-6Cycloalkyl, C_3-6Cyclo
Alkenyl, hydroxy C_1-6Alkyl, C_1-6Alkyl OC_1-6Archi
LE, CONR^{36 '}R^{37 '}, CO₂R^{38 '}, Cyano, aryl, trifluoro
Lomethyl, NR^{39 '}R^{40 '}, Nitro, hydroxy, C_1-6Alkoxy, C _1-6 R is alkanoyl, acyloxy or halogen; R^{4 '}, R^{5 '}, R^{6 '}, R^{7 '}, R^{18 '}, R^{19 '}, R^{20 '}, R^{21 '} , R^{22 '}, R^{23 '}, R^{24 '}, R^{27 '}, R^{28 '}, R^{31 '}, R^{35 '},
R^{36 '}, R^{37 '}, R^{38 '}, R^{39 '}And R^{40 '}Is independently hydrogen
Or C_1-6Alkyl; R is R when D is a nitrogen or CH group;^{8 '}Is hydrogen or C_1-6Alkyl
When D is a nitrogen or CH group, R^{9 '}Is hydrogen or C_1-6Alkyl
R; R^{10 '}And R^{11 '}Is independently hydrogen or C_1-6Is alkyl
Or R^{10 '}And R^{11 '}Together with the nitrogen to which they bind
Forming a 5- to 6-membered heterocyclic ring which may be substituted by a xo group,
When there is one ring atom, the ring contains one oxygen or one sulfur atom.
May be R^{12 '}Is hydrogen, C_1-6Alkyl or C_1-4An alkoxyalkyl
R^{13 '}, R^{25 '}And R^{32 '}Is independently C_1-6R is alkyl;^{14 '}Is C_1-6Alkyl or phenyl;

R ^{15 ′} and R ^{16 ′} are independently hydrogen or C _1-6 alkyl, or R ^{15 ′} and R ^{16 ′} together with the nitrogen to which they are attached
Forming a-to 6-membered saturated heterocyclic ring and, when there are 6 ring atoms, 1
R ^{17 ′} is C _1-4 alkyl optionally substituted with C _1-6 alkoxy; R ^{26 ′} is hydrogen or C _{1- 6 alkyl, C 1-6} alkoxy, hydroxy or ^{NR 10 'R 11'} be substituted with 1 or 2 substituents selected from be also _{C 1-6} alkyl; ^{R 29 'and R 30'} Is independently hydrogen or C _1-6 alkyl, or R ^{29 ′} and R ^{30 ′} together with the nitrogen to which they are attached form 5
When forming a-to 6-membered heterocyclic ring and having six ring atoms, the ring may contain one oxygen or one sulfur atom; ^{R33 '} and ^R34' Is independently hydrogen or C _1-6 alkyl, or R ^{33 ′} and R ^{34 ′} together with the nitrogen to which they are attached form 5
When forming a-to 6-membered heterocyclic ring and having 6 ring atoms, the ring may contain one oxygen or one sulfur atom; a 'and b' are Independently, 1, 2 or 3; c 'is 0, 1 or 2; d' is 1, 2, 3 or 4; e 'is 0, 1, 2 or 3; 'Is 1, 2 or 3;

[0009] E is represented by the formula (a):

Embedded image(Where B is oxygen, S (O)_c, CR⁷= CR⁸Or CR⁷R⁸Or B is
NR⁹R¹And R²Is independently hydrogen or C_1-6Alkyl;
To B (CR¹R²)_aIs OCR¹R²CR¹(OH) CR¹R²Or OCR¹R² CR¹(OCOCH₃) CR¹R²R³And R⁴Is independently hydrogen, C_1-6Alkyl, C_3-7Cycloal
Kill, aralkyl, or together with the nitrogen atom to which they are attached,
May contain additional heteroatoms selected from oxygen, nitrogen or sulfur
To form an optionally substituted 5- to 7-membered heterocycle, wherein
The group is C_1-6Alkyl, aryl, CONR¹⁰R¹¹, NR¹⁰R¹¹, Hid
Roxy, OCOR¹², NHCOC_0-6Encompasses alkyl, where alkyl is
Is OH, NHCOCF₃, NHSO₂R¹³And NHCO₂R¹⁴Is replaced by
May be R⁵Is hydrogen, C_1-6Alkyl, aryl, CN, CONR^FifteenR¹⁶, CO ₂ R¹⁷, Trifluoromethyl, NHCO₂R¹⁸, Hydroxy, C_1-6Al
Coxy, benzyloxy, OCH₂CO₂C_1-6Alkyl, OCF₃, S (O) _d R¹⁹, SO₂NR²⁰R²¹Or halogen; R⁶Is hydrogen, C_1-6Alkyl, aryl, trifluoromethyl, hydroxy
, C_1-6Alkoxy or halogen, or R⁶Is R^{8 '}Together with
To form a group D, wherein D is (CR²²R²³)_eOr D is (C
R²²R²³)_f-G, where G is oxygen, sulfur, CR²²= CR²³, CR²²
= N, = CR²²O, = CR²²S or = CR²²-NR²³R⁷, R⁸, R¹⁰, R¹¹, R¹², R^Fifteen, R¹⁶, R¹⁷, R²⁰, R ²¹ , R²²And R²³Is independently hydrogen or C_1-6R is alkyl;⁹Is hydrogen, C_1-6Alkyl or phenyl C_1-6R is alkyl;¹³, R¹⁴, R¹⁸And R¹⁹Is independently C_1-6Alkyl
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; 0, 1, 2 or 3);

Alternatively, E is represented by the formula (b):

Embedded image (Wherein, R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³¹ and R ³² are
Independently, is hydrogen or C _1-6 alkyl; R ³⁰ is hydrogen, C _1-6 alkyl or C _3-7 cycloalkyl; R ³³ is hydrogen, C _1-6 alkyl, trifluoromethyl, hydroxy Or is halogen, or R ³³ and R ^{8 ′} together form a group: —K—, where K is (CR ³⁴ R ³⁵ ) _i or K is (CR ³⁴ R ³⁵ ) _j −
M, wherein M is oxygen, sulfur, CR ³⁴ = CR ³⁵ , CR ³⁴ = N or N = N; J is oxygen, CR ³⁶ R ³⁷ or NR ³⁸ , or J is a group: S (O ) be _{^{k; R 34, R 35,}} R 36, R 37 and ^{R 38} are, independently, hydrogen or _{C 1 -6} alkyl; g is 1, 2 or 3; h is 1 I is 2, 3 or 4; j is 0, 1, 2 or 3; k is 0, 1 or 2);

[0011] Alternatively, E is represented by the formula (c):

Embedded image Wherein Q is oxygen, S (O) _n , CR ⁴⁴ = CR ⁴⁵ , CR ⁴⁴ R ⁴⁵ or Q is NR ⁴⁶ ; R ³⁹ and R ⁴⁰ are independently hydrogen or C It is _1-6 alkyl; ^{R 41} is formula (d):

Embedded image Or R ⁴¹ is a group represented by the formula (e):

Embedded image Wherein R ⁴² is hydrogen, C _1-6 alkyl, aryl, CN, CONR ⁴⁸ R ⁴⁹ , C
O ₂ R ⁵⁰ , trifluoromethyl, NHCO ₂ R ⁵¹ , hydroxy, C _1-6 alkoxy, benzyloxy, OCH ₂ CO ₂ C _1-6 alkyl, OCF ₃ , S (
O) _s R ⁵² , SO ₂ NR ⁵³ R ⁵⁴ or halogen; R ⁴³ is hydrogen, or R ⁴³ together with R ^{8 ′} forms a group R,
Where R is CR ⁵⁵ = CR ⁵⁶ , CR ⁵⁵ = CR ⁵⁶ CR ⁵⁵ R ⁵⁶ or (C
R ⁵⁵ R ⁵⁶ ) _t ; R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁸ , R ⁴⁹ , R ⁵⁰ , R ⁵³ , R ⁵⁴ , R ⁵⁵ and R ⁵⁶ are independently hydrogen or C _1-6 R ⁴⁷ is hydrogen, C _1-6 alkyl or C _3-7 cycloalkyl; R ⁵¹ and R ⁵² are independently C _1-6 alkyl; l is 0, 1, 2 M is 1 or 2; n is 0, 1 or 2; o, p and q are independently integers of 1, 2 or 3; r is 0, 1, 2 Or 3; s is 0, 1 or 2; t is 2 or 3);

Alternatively, E is represented by the formula (f):

Embedded image Wherein R ⁵⁷ and R ⁵⁸ are independently hydrogen or C _1-6 alkyl; R ⁵⁹ and R ⁶⁰ are independently hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl , Aralkyl, or together with the nitrogen atom to which they are attached, optionally substituted 5- to 7-, which may contain further heteroatoms selected from oxygen, nitrogen or sulfur. Wherein the optional substituents are C _1-6 alkyl, aryl, CONR ⁶¹ R ⁶² , NR ⁶¹ R ⁶² ,
Hydroxy, OCOR ⁶³ , NHCOC _0-6 alkyl, which may be substituted with OH, NHCOCF ₃ , NHSO ₂ R ⁶⁴ and NHCO ₂ R ⁶⁵ ; T is — (CR ⁶⁶ R ⁶⁷ ) _v − or _{^{-O (CR 66 R 67) w}} - a is; W is oxygen, S (O) _x, or a ^{NR 68,} or W is ^CR 69 = ^{CR 70} or ^{CR 69 R 70; R 61,} R ⁶² , R ⁶³ , R ⁶⁶ , R ⁶⁷ , R ⁶⁸ , R ⁶⁹ and R ⁷⁰ are
Independently, is hydrogen or C _1-6 alkyl; R ⁶⁴ and R ⁶⁵ are independently C _1-6 alkyl; u is 1-4; v is 2 or 3; w Is 1, 2 or 3; x is 0, 1 or 2);

Alternatively, E is represented by the formula (g):

Embedded image Wherein R ⁷¹ is an optionally substituted 5- to 7-membered saturated or partially saturated heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur; Or R ⁷¹ is an optionally substituted 6,6 or 6,5 bicyclic ring containing one nitrogen atom and one further heteroatom selected from oxygen, nitrogen or sulfur. R ⁷² is hydrogen, C _1-6 alkyl, aryl, CN, CONR ⁷⁴ R ⁷⁵ , C;
O ₂ R ^76, trifluoromethyl, NHCO ₂ R ^77, _{hydroxy, C 1-6} alkoxy, _benzyloxy, OCH ₂ CO _{2 C 1-6} alkyl, _OCF 3, S (
O) zR ⁷⁸ , SO ₂ NR ⁷⁹ R ⁸⁰ or halogen; R ⁷³ is hydrogen, C _1-6 alkyl, hydroxy, C _1-6 alkoxy or halogen, or R ⁷³ and R ^{8 ′} together is to group: -X- is formed, wherein X is ^(CR 81 ^{R 82)} or is _aa, or X is _{^{(CR 81 R 82) a b}} -Y, Y is oxygen, sulfur or ^{CR 81} = CR ⁸² ; R ⁷⁴ , R ⁷⁵ , R ⁷⁶ , R ⁷⁹ , R ⁸⁰ , R ⁸¹ and R ⁸² are independently hydrogen or C _1-6 alkyl; R ⁷⁷ and R ⁷⁸ are independently _and, be a _{C 1-6} alkyl; y is 1 or 2; z is 0, 1 or 2; aa is 2, 3 or 4; ab is 0, 1, 2 or 3 Is a group represented by:

Alternatively, E is represented by the formula (h):

Embedded image(Where: R⁸³And R⁸⁴Is independently hydrogen or C_1-6R is alkyl;⁸⁵And R⁸⁶Is independently hydrogen, C_1-6Alkyl, C_3-7Cyclo
Alkyl, aralkyl or together with the nitrogen atom to which they are attached
Containing one further heteroatom selected from oxygen, nitrogen or sulfur
To form an optionally substituted 5- to 7-membered heterocycle, wherein
Optional substituent is C_1-6Alkyl, aryl, CONR⁸⁸R⁸⁹, NR⁹⁰R ⁹¹ , Hydroxy, OCOR⁹², NHCOC_0-6Including alkyl, where
Alkyl is OH, NHCOCF₃, NHSO₂R⁹³And NHCO₂R⁹⁴ R may be substituted with⁸⁷Is hydrogen, C_1-6Alkyl, C_1-6Is alkoxy or halogen
Or R⁸⁷Is R^{8 '}And forms a group: -AA-, where AA is
(CR⁹⁵R⁹⁶)_adOr AA is (CR⁹⁵= CR⁹⁶)_ae-AB
And AB is oxygen, sulfur, CR⁹⁵= CR⁹⁶, CR⁹⁵= N, CR⁹⁵NR ⁹⁶ Or N = N; Z contains 1-3 heteroatoms selected from oxygen, nitrogen or sulfur
R to form an optionally substituted 5- to 7-membered heterocycle;⁸⁸, R⁸⁹, R⁹⁰, R⁹¹, R⁹², R⁹⁵And R⁹⁶Independently
, Hydrogen or C_1-6R is alkyl;⁹³And R⁹⁴Is independently C_1-6Ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2) or a group represented by the formula:

Alternatively, E is represented by the formula (i):

Embedded image(Where: R⁹⁷And R⁹⁸Is independently hydrogen, C_1-6Alkyl, C_3-7Cyclo
Alkyl, aralkyl or together with the nitrogen atom to which they are attached
Containing one further heteroatom selected from oxygen, nitrogen or sulfur
To form an optionally substituted 5- to 7-membered heterocycle, wherein
Optional substituent is C_1-6Alkyl, aryl, CONR¹⁰²R¹⁰³, NR^{1 04} R¹⁰⁵, Hydroxy, OCOR¹⁰⁶, NHCOC_0-6Includes alkyl
And the alkyl here is OH, NHCOCF₃, NHSO₂R¹⁰⁷And NH
CO₂R¹⁰⁸R may be substituted with⁹⁹And R¹⁰⁰Is independently hydrogen or C_1-6R is alkyl;¹⁰¹Is hydrogen or C_1-6Alkyl or R¹⁰¹And R^{8 '} Together form a group: -AD-, where AD is (CR¹⁰⁹R¹¹⁰)
_aiOr AD is (CR¹⁰⁹R¹¹⁰)_aj-AE, where AE is
Oxygen, sulfur or CR¹⁰⁹= CR¹¹⁰AC is oxygen, CR¹¹¹R¹¹²Or NR¹¹³Or AC is a group
: S (O)_akR¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁹, R¹¹⁰,
R¹¹¹, R¹¹²And R¹¹³Is independently hydrogen or C_1-6Alkyl
R¹⁰⁷And R¹⁰⁸Is independently C_1-6Af is 0, 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; ak is 0, 1 or 2) or a pharmaceutically active salt thereof, and the above-mentioned CCR5 disease.
And its novel use in the treatment of conditions.

[0016] In another aspect, the invention relates to COPD, asthma and atopic disorders (eg, atopic dermatitis and allergies), rheumatoid arthritis, atherogenic in all mammals, preferably humans CC, including, but not limited to, arteriosclerosis, sarcoidosis and other fibrosis-type diseases, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease and HIV infection.
A method of treating a condition mediated by R5, wherein the mammal in need of such treatment is given the formula (
A method comprising administering anilide of I) or a pharmaceutically active salt thereof. In yet another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier for the compound. In particular, the pharmaceutical compositions of the present invention are useful in all mammals, preferably humans, for asthma and atopic disorders (eg, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other Fibrotic disease, psoriasis,
It is used in the treatment of autoimmune diseases, such as multiple sclerosis, inflammatory bowel disease, CCR5 mediated conditions including, but not limited to, CORD and HIV.

BEST MODE FOR CARRYING OUT THE INVENTION It has now been found that substituted anilides of formula (I) are CCR5 receptor modulators. Furthermore, the selective inhibition of the CCR5 receptor mechanism by treatment with a receptor modulator of formula (I) or a pharmaceutically acceptable salt thereof, is associated with CORD, Asthma and atopic disorders (eg, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrosis-type diseases, psoriasis, autoimmune diseases, eg, multiple sclerosis and inflammatory Various pathologies, including bowel disease ("C
It has been found to provide new therapeutic and prophylactic methods for the treatment of CR5-mediated conditions "). Also, since CCR5 is a co-receptor for HIV entry into cells, selective receptor modulators are useful for treating HIV infection.

The term “alkyl”, as used herein, whenever used herein, unless the chain length is limited, refers to straight or branched chain groups having 1 to 6 carbon atoms, methyl, ethyl, n -Propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t
tert-butyl and the like, but are not limited thereto. Whenever the terms "cycloalkyl" and "cyclic alkyl" are used herein, the term monocyclo or bicyclo-, preferably having 3 to 7 carbon atoms, is used.
Refers to a cyclic group of a fused ring system, which may be additionally unsaturated, and includes, but is not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like. The terms "halo" or "halogen" are used interchangeably herein and whenever used, mean a group derived from the elements chlorine, fluorine, iodine and bromine.

The term “heterocycle” as used herein, whenever used herein (unless the ring system is specifically limited) contains one to three heteroatoms selected from oxygen, sulfur or nitrogen. A saturated or partially saturated 5-, 6- or 7-membered ring system,
The ring system may be substituted with C _1-6 alkyl or C _3-7 cycloalkyl. Examples of such rings include, but are not limited to, piperidine, tetrahydropyridine, and piperazine. When a heterocycle is fused to a phenyl group, the "heterocycle" together with the condensed phenyl ring form dihydro-1
Form a ring, including, but not limited to, 1,4-benzoxazine and 1,2,3,4-tetrahydroquinoline, which may be substituted with C _1-6 alkyl or oxo. The term "6,6 or 6,5 bicyclic" contains one nitrogen atom and additionally contains nitrogen,
Means oxygen or one heteroatom may 6,6 or 6,5 bicyclic also contain selected from sulfur, the ring system may be substituted by C _1-6 alkyl. Examples of such ring systems include, but are not limited to, tropane, isoquinuclidine and grananatan rings.

The term “CCR5-mediated condition”, whenever used herein, refers to CC
It refers to any condition mediated (or modulated) by R5. The term "monocyclic heterocycle", whenever used herein, refers to thienyl,
Furyl encompasses pyrrolyl and pyridyl, represented by P ¹ and / or P ^2, oxygen, a single aromatic 5- to 7-membered containing 1 to 3 heteroatoms selected from nitrogen and sulfur Means a ring. The term "fused bicyclic heterocycle," as used herein, whenever used herein, refers to one to three members selected from oxygen, nitrogen and sulfur, including indole, benzofuran, benzothiophene, quinoline and isoquinoline rings. 8 containing heteroatoms
And from 11 to 11 membered fused bicyclic aromatic ring systems. Suitably, pharmaceutically acceptable salts of formula (I) include, but are not limited to, inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate. Salt with, or malate, maleate, fumarate, tartrate, succinate,
Includes salts with organic acids such as citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate and stearate.

The compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the form of solvation with a pharmaceutically acceptable solvent such as water, ethanol and the like is equivalent to the unsolvated form for the purposes of the present invention. The compounds of the present invention may contain one or more asymmetric carbon atoms,
It may exist in racemic and optically active forms. The stereocenter may be in any combination of R and S configurations, for example, (R, R), (R, S), (S,
S) or (S, R). All of these compounds are within the scope of the present invention.

Various specific examples of the compounds of formula (I) are as follows. The basic nitrogen in the E group may be quaternized with C _1-6 alkyl or may be present as an N-oxide. P ¹ and P ² are suitably independently a 5-7 membered monocyclic ring containing 1-3 heteroatoms selected from phenyl, fused bicyclic aryl, oxygen, nitrogen and sulfur. 1 to 3 selected from a heterocycle, or oxygen, nitrogen or sulfur
Is an 8- to 11-membered fused bicyclic heterocycle containing two heteroatoms. Preferably, P ¹ is phenyl and P ² is phenyl or quinoxalinyl. More preferably, P ¹ and P ² are phenyl. When R ^{1 ′} is a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, suitable heterocycles are thienyl, furyl, pyrrolyl, triazolyl, Includes aromatic groups such as diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl and dioxanyl. Saturated and partially saturated rings are also within the scope of the invention, especially rings containing oxo or thioxo groups such as lactams and thiolactams. Suitably, the heterocycle may be linked to the rest of the molecule via a carbon atom or, if present, a nitrogen atom. Suitable substituents for these rings 1 to include two R ^{3 '.}

A is C (R ^{4 ′} ) ₂ , CR ^{4 ′} (OR ^{5 ′} ), CO, C = NOR ^{6 ′} , NR ^{7 ′}
, Oxygen or S (O) _{c '} . Preferably, A is C (R ^{4 ′} ) ₂ , CO, C = N
OR ^{6 ′} , NR ^{7 ′} , oxygen or sulfur. More preferably, A is CH ₂ , C
O, C = NOH, oxygen or sulfur. Most preferably, A is CH ₂ , CO,
Oxygen or sulfur. A is preferably bonded to P ¹ in the meta or para to L, A is more preferably bonded to P ¹ in the para-position relative to L. L is suitably ^{formula: -C (= V) -DR 8} '-, - DR 9' -C (= V) -, -
It is a group represented by CH ₂ NH— or —NHCH ₂ —. L is preferably-
^{C (= V) -DR 8 '} - is. V is suitably oxygen or sulfur. V is preferably oxygen. D is suitably a nitrogen, carbon or CH group. D is preferably nitrogen.

R^{1 '}And R^{2 '}Is suitably, independently, hydrogen, C_1-6Alkyl, C_{2 -6} Alkenyl, C_2-6Alkynyl, C_3-7Cycloalkyl, C_3-7Shiku
Loalkenyl, aryl, (CH₂)_{d '}NR^{10 '}R^{11 '}, (CH₂)_{d '}NR ^{10 '} COR^{12 '}, (CH₂)_{d '}NR^{10 '}CO₂R^{13 '}, (CH₂)_{d '}N
R^{10 '}SO₂R^{14 '}, (CH₂)_{d '}CONR^{15 '}R^{16 '}, Hydroxy C _1-6 Alkyl, C_1-4Alkoxyalkyl (one C_1-4Alkoxy or
May be substituted with a hydroxy group), (CH₂)_{d '}CO₂C_1-6Archi
, (CH₂)_{e '}OC (O) R^{17 '}, CR^{18 '}= NOR^{19 '}, CNR^{20 '} = NOR^{19 '}, COR^{21 '}, CONR^{15 '}R^{16 '}, CONR^{15 '}(C
H₂)_{f '}OC_1-4Alkyl, CONR^{15 '}(CH₂)_{d '}CO₂R^{22 '},
CONHNR^{23 '}R^{24 '}, CONR^{15 '}SO₂R^{25 '}, CO₂R^{26 '} , Cyano, trifluoromethyl, NR^{10 '}R^{11 '}, NR^{10 '}COR^{12 '} , NR^{27 '}CO (CH₂)_{d '}NR^{27 '}R^{28 '}, NR^{27 '}CONR^{27 '} R^{28 '}, NR^{10 '}CO₂R^{13 '}, NR^{10 '}SO₂R^{14 '}, N = CNR ^{27 '} NR^{27 '}R^{28 '}, Nitro, hydroxy, C_1-6Alkoxy, hydro
Kishi C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkoxy, OC (O) N
R^{29 '}R^{30 '}, SR^{31 '}, SOR^{32 '}, SO₂R^{32 '}, SO₂NR^{3 3 '} R^{34 '}, Halogen, C_1-6Alkanoyl, CO₂(CH₂)_{d '}OR^{35 '} Or R^{1 '}Is 1 to 4 selected from oxygen, nitrogen or sulfur
Substituted or unsubstituted 5- to 7-membered heterocycle containing two heteroatoms
. R^{1 '}And R^{2 '}Is preferably hydrogen, C_1-6Alkyl and hydroxy
Or halogen.

R^{3 '}Is suitably hydrogen, C_1-6Alkyl, C_3-6Cycloalkyl, C _3-6 Cycloalkenyl, hydroxy C_1-6Alkyl, C_1-6Alkyl OC _1-6 Alkyl, CONR^{36 '}R^{37 '}, CO₂R^{38 '}, Cyano, aryl
, Trifluoromethyl, NR^{39 '}R^{40 '}, Nitro, hydroxy, C_1-6A
Lucoxy, C_1-6Alkanoyl, acyloxy or halogen. R^{3 '} Is preferably hydrogen, nitro, sulfamoyl or C_1-6Alkylamino
It is. R^{4 '}, R^{5 '}, R^{6 '}, R^{7 '}, R^{18 '}, R^{19 '}, R^{20 '}, R^{21 '} , R^{22 '}, R^{23 '}, R^{24 '}, R^{27 '}, R^{28 '}, R^{31 '}, R^{35 '},
R^{36 '}, R^{37 '}, R^{38 '}, R^{39 '}And R^{40 '}Is suitably independent
And hydrogen or C_1-6Alkyl. When D is a nitrogen or CH group, R^{8 '}Is suitably hydrogen or C_1-6 Alkyl. R^{8 '}Is preferably hydrogen. When D is a nitrogen or CH group, R^{9 '}Is suitably hydrogen or C_1-6 Alkyl. R^{10 '}And R^{11 '}Is suitably, independently, hydrogen or C_1-6Archi
Or R^{10 '}And R^{11 '}Together with the nitrogen to which they bind
To form a 5- to 6-membered heterocyclic ring which may be substituted by an oxo group.
Form, if there are six ring atoms, one oxygen or one sulfur atom in the ring
May be contained. R^{12 '}Is suitably hydrogen, C_1-6Alkyl or C_1-4Alkoxya
It is Luquil. R^{13 '}, R^{25 '}And R^{32 '}Is, independently and independently, C_1-6Archi
It is. R^{14 '}Is, appropriately, C_1-6Alkyl or phenyl.

R ^{15 ′} and R ^{16 ′} are suitably independently hydrogen or C _1-6 alkyl, or R ^{15 ′} and R ^{16 ′} together with the nitrogen to which they are attached. Thus, when a 5- or 6-membered saturated heterocyclic ring is formed and there are six ring atoms, one oxygen or one sulfur atom may be contained in the ring. R ^{17 ′} is suitably C _1-4 alkyl optionally substituted with C _1-6 alkoxy. R ^{26 ′} is suitably hydrogen or C _1-6 optionally substituted by one or two substituents selected from C _1-6 alkyl, C _1-6 alkoxy, hydroxy or NR ^{10 ′} R ^{11 ′} _1-6 alkyl. R ^{29 ′} and R ^{30 ′} are suitably independently hydrogen or C _1-6 alkyl, or R ^{29 ′} and R ^{30 ′} together with the nitrogen to which they are attached form 5 When forming a-to 6-membered heterocyclic ring and having 6 ring atoms, one oxygen or one sulfur atom may be contained in the ring. R ^{33 ′} and R ^{34 ′} are suitably independently hydrogen or C _1-6 alkyl, or R ^{33 ′} and R ^{34 ′} together with the nitrogen to which they are attached form 5 When forming a-to 6-membered heterocyclic ring and having 6 ring atoms, one oxygen or one sulfur atom may be contained in the ring. a ′ and b ′ are independently 1, 2 or 3. c 'is suitably 0, 1 or 2. d 'is suitably 1, 2, 3 or 4. e 'is suitably 0, 1, 2 or 3. f ′ is suitably 1, 2 or 3.

E is suitably represented by the formula (a):

Embedded imageIndicated by B is suitably oxygen, S (O)_c, CR⁷= CR⁸Or CR⁷R⁸Is
, Or B is NR⁹It is. B is preferably CR⁷R⁸Or oxygen.
B is more preferably CH₂Or oxygen. R¹And R²Is suitably, independently, hydrogen or C_1-6Alkyl
, Separately, B (CR¹R²)_aIs OCR¹R²CR¹(OH) CR¹R²Or OCR ¹ R²CR¹(OCOCH₃) CR¹R²It is. Preferably, R¹And R²Is
Hydrogen.

R ³ and R ⁴ are suitably, independently, hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached. Forms an optionally substituted 5- to 7-membered heterocycle, which may contain additional heteroatoms selected from oxygen, nitrogen or sulfur, wherein the optional substituents are C _1-6 alkyl, ^{aryl, CONR 10 R 11, NR 10} R 11, ^hydroxy, encompasses OCOR 12, _{NHCOC 0-6} alkyl, here is substituted _OH, in NHCOCF 3, NHSO ₂ R ¹³ and NHCO ₂ R ^{1 4} It may be. R ³ and R ⁴ are preferably both C _1-6 alkyl or, together with the nitrogen atom to which they are attached, contain a further heteroatom selected from oxygen, nitrogen or sulfur. Forming an optionally substituted 5- to 7-membered heterocycle. More preferably, R ³ and R ⁴ are C _3-6 alkyl, or together with the nitrogen to which they are attached, are substituted by one or more C _1-6 alkyl, N-acetamido or hydroxy. To form an optionally 6-membered ring. Most preferably, ^{R 3} and ^{R 4} is isopropyl or ^{R 3,} is isopropyl, ^{R 4} is tert-
Butyl or, together with the nitrogen to which they are attached, form 1- (2,2,
6,6-tetramethylpiperidinyl), 1- (4-acetamido-2,2,6,6-
1- (4-hydroxy-2,2,6,6-tetramethylpiperidinyl) or 1- (4-hydroxy-2,2,4,6,6-pentamethylpiperidinyl) Nil).

Preferably, B- (CR ¹ R ² ) _a -NR ³ R ⁴ is ortho to R ⁵ ;
It is meta to L and para to R ⁶ , and R ⁵ is para to L. R ⁵ is suitably hydrogen, C _1-6 alkyl, aryl, CN, CONR ¹⁵ R ¹⁶ , CO ₂ R ¹⁷ , trifluoromethyl, NHCO ₂ R ¹⁸ , hydroxy,
C _1-6 alkoxy, benzyloxy, OCH ₂ CO ₂ C _1-6 alkyl, OC
F ₃ , S (O) _d R ¹⁹ , SO ₂ NR ²⁰ R ²¹ or halogen. R ⁵ is
Preferably, it is C _1-6 alkoxy, SC _1-6 alkyl or halogen;
More preferably it is methoxy or methylthio or iodo; most preferably it is methoxy. When R ⁵ is methoxy, it is preferably para to L. R ⁶ is suitably hydrogen, C _1-6 alkyl, aryl, trifluoromethyl, hydroxy, C _1-6 alkoxy or halogen, or R ⁶ together with R ^{5 ′} forms a group D formed, wherein D is ^(CR 22 ^{R 23)} or is _e, or D is _{^{(CR 22 R 23) f -G}} , where G is oxygen, sulfur or CR ^{2
2 = CR 23, CR 22 =} N, = CR 22 O, a = ^{CR 22} S or ⁼ CR 22 ^{-NR 23.} Preferably, R ⁶ is hydrogen.

R⁷, R⁸, R¹⁰, R¹¹, R¹², R^Fifteen, R¹⁶, R¹⁷, R²⁰, R ²¹ , R²²And R²³Is independently hydrogen or C_1-6Alkyl. R⁹Is hydrogen, C_1-6Alkyl or phenyl C_1-6Alkyl. R¹², R¹³, R¹⁴, R¹⁸And R¹⁹Is independently C_1-6Archi
It is. a is suitably 1, 2, 3 or 4. a is preferably 2 or 3
More preferably, when B is oxygen, a is 2 or 3;
H₂A is 2; most preferably, when B is oxygen, a is 2
It is. b is suitably 1 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 is suitably represented by formula (b):

Embedded imageIndicated by R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³¹And R³²Is
Suitably, independently, hydrogen or C_1-6Alkyl. R²⁴, R²⁵, R ²⁶ , R²⁷, R²⁸, R²⁹, R³¹And R³²Is preferably hydrogen
You. R³⁰Is suitably hydrogen, C_1-6Alkyl or C_3-7Cycloalkyl
It is. Preferably, R³⁰Is C_1-6Alkyl; more preferably, R^{3 0} Is C_3-6Alkyl; most preferably, R³⁰Is isopropyl. R³³Is suitably hydrogen, C_1-6Alkyl, trifluoromethyl, hydro
Xy or halogen, or R³³And R^{5 '}Together form a group: -K-
Where K is (CR³⁴R³⁵)_iOr K is (CR³⁴R³⁵)_j−
M, where M is oxygen, sulfur, CR³⁴= CR³⁵, CR³⁴= N or N = N
is there. Preferably, R³³Is hydrogen.

J is suitably oxygen, CR ³⁶ R ³⁷ or NR ³⁸ , or J is a group: S (O) _k . Preferably, J is oxygen. Preferably, J is para to L. R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ and R ³⁸ are suitably, independently, hydrogen or C _1-6 alkyl. g is suitably 1, 2 or 3. Preferably, g is 2 or 3; more preferably, it is 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.

Known compounds that overlap with compounds within the scope of the present invention are as follows. The basic nitrogen in the E group is C_1-6May be quaternized with alkyl,
Or E may be present as N-oxide; E is (b); J is CH₂Is
G is 1, 2 or 3; h is 1, 2 or 3;²⁴, R²⁵, R ²⁶ , R²⁷, R²⁸, R²⁹, R³¹And R³²Is hydrogen; R³⁰But water
Elementary or C_1-6Alkyl; R³³Is hydrogen, C_1-6Alkyl, triflu
O is methyl or halogen; L is CONR^{8 '}Or NR^{9 '}CO
R^{8 '}And R^{9 '}Is independently hydrogen or C_1-6Alkyl; P¹ And P²Is phenyl; A is CO, O or S (O) 0-2;^{1 '} Is hydrogen; R^{2 '}Is hydrogen or one, two or three hydroxy, C1-3
Alkyl, cyano, halogen or trifluoromethyl;^{3 '}Is hydrogen
Is one or two hydroxy, cyano, halogen, trifluoromethyl, CON
R³⁶* R³⁷*, COC1-5 alkyl, CO₂R³⁸*, C_1-6Alkoxy
Or phenyl; R³⁶*, R³⁷* And R³⁸* Independently hydrogen
Or C_1-6Compounds of the sub-group of formula (I), which are alkyl,
WO98 / 25604 published on the 18th as a chemokine receptor modulator
It is listed.

Further, the basic nitrogen in the E group is replaced by C_1-6Even if quaternized with alkyl
Or may be present as an N-oxide; E is (b); J is C
H₂G is 1, 2 or 3; h is 1, 2 or 3; R²⁴,
R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³¹And R³²Is hydrogen;
R³⁰Is hydrogen or C_1-6Alkyl; R³³Is hydrogen, C_1-6Alkyl
, Trifluoromethyl or halogen; L is CH₂NH; P¹But
Nsimidazolyl, benzofuranyl, benzoxazolyl, furanyl, imidazo
Ryl, indolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxo
Sazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinoli
, Thiadiazolyl, thiazolyl, thienyl or triazolyl
A is CO, O or S (O) 0-2; ² Is phenyl; R¹* Is hydrogen or one hydroxy, cyano, halogen
, Trifluoromethyl, NR¹⁰* COR¹²*, NR¹⁰* CO₂R¹³*, NR ²⁷ * CONHR²⁸*, NHS (O) 0-2R¹⁴*, CONR^Fifteen* R¹⁶*, C
OC1-5 alkyl, CO₂R²⁶*, C_1-6Alkoxy, SR³¹*, SOR ³² *, SO₂R³²* Or phenyl or R¹* Is replaced
May be furanyl, imidazolyl, isoxazolyl, isothiazolyl, oki
Sadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl
Selected from, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl
Selected heterocycle; R²* Is hydrogen or one or two hydroxy, cyano
, Halogen, trifluoromethyl, NR¹⁰* COR¹²*, NR¹⁰* CO₂R
¹³*, NR²⁷* CONHR²⁸*, NHS (O) 0-2R¹⁴*, CONR^Fifteen*
R¹⁶*, COC1-5 alkyl, CO₂R²⁶*, C_1-6Alkoxy, SR^{3 1} *, SOR³²*, SO₂R³²* Or phenyl; R^{3 '}Is hydrogen or
One or two hydroxy, cyano, halogen, trifluoromethyl, CONR ³⁶ * R³⁷*, COC1-5 alkyl, CO₂R³⁸*, C_1-6Alkoxy
Or phenyl; R¹⁰*, R¹²*, R^Fifteen*, R¹⁶*, R²⁷*, R²⁸*
, R³¹*, R³⁶*, R³⁷* And R³⁸* Is independently hydrogen or C_1-6 Alkyl; R¹³* And R³²* Is independently C_1-6Alkyl
R¹⁴* Is C_1-6Alkyl or phenyl; R²⁶* Is hydrogen or 1
Or C which may be substituted by two hydroxy_1-6A formula which is alkyl
Compounds of the subgroup of (I) are described in WO 98/25604 published June 18, 1998.
Described as chemokine receptor modulators.

A preferred sub-group of compounds of formula (I) are compounds of formula (Ia):

Embedded image [Wherein R ^{1 ′} , R ^{2 ′} , R ^{3 ′} , P ¹ , P ² , A, a ′, b ′, L, R ²⁴ ,
R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ ,
J, g and h are as defined above.]

Among them, preferred compounds of the present invention are the following compounds: N- [4- [2- (dimethylamino) ethyl] -3,4-dihydro-2H-1,4-
Benzoxazin-6-yl) -4-phenoxybenzamide; N- [3- [2- (diethylamino) ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide; N- [4- [2- [bis (1 -Methylethyl) amino] ethoxy] phenyl]]-4-
Phenoxybenzamide; N- [4- [2- (diethylamino) ethoxy] phenyl] -4-phenoxybenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] phenyl] -4-phenoxy N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-phenoxybenzamide; N- [3- [2- (diethylamino) ethoxy] -4- Methoxyphenyl] -3-phenoxybenzamide; N- [4- [2- [bis (1-methylethyl) amino] ethoxy] phenyl] -3-phenoxybenzamide; N- [4- [2- [bis (1- Methylethyl) amino] ethoxy] phenyl] -4- (
Phenylmethyl) benzamide; N- [2- [2- (diethylamino) ethoxy] phenyl] -4- (phenylmethyl)
N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide; N- [3- [2- [bis (1-methylethyl) Amino] ethoxy] -4-methoxyphenyl] -4- (phenylmethyl) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -2- (phenyl Methyl) thiazole-4-carboxamide hydrochloride; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide methiodide; N- [1 -[2- [bis (1-methylethyl) amino] ethyl] -1,2,3,4-tetrahydroquinol-7-yl] -4-phenoxybenzamide; N- [3- [2- [bis (1 -Methylethyl) amino] ethoxy] -4-methoxy Phenyl] -4- (3-hydroxyphenoxy) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(4-chlorophenyl) sulfinyl] -3-nitrobenzamide;

N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(2,4-dichlorophenyl) sulfinyl] -3-nitrobenzamide; N- N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3-phenoxybenzamide; N- [3- [2- (2,2,6,6-tetramethyl- 1-piperidinyl) ethoxy]-
4-methoxyphenyl] -3-phenoxybenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-phenoxybenzamide; N- [3- [2 -(2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-phenoxybenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-benzoylbenzamide; N- [3- [3 -[Bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-benzoylbenzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy] ]-
4-methoxyphenyl] -4-benzoylbenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (phenylmethyl) benzamide; N- [3 -[2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (phenylmethyl) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(4-chlorophenyl) sulfonyl N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-[(4-chlorophenyl) sulfonyl] benzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-[(4-chlorophenyl) sulfonyl] benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -5-butylamino- 4-phenoxy-3- (sulfamoyl) benzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -5-butylamino-4-phenoxy-3- ( Sulfamoyl) benzamide;

N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -5-butylamino-4-phenoxy-3- (sulfamoyl) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4 -(4-chlorophenoxy) -3-nitrobenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (4-chlorophenoxy) -3 -Nitrobenzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (4-chlorophenoxy) -3-nitrobenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- ( 2-quinoxalinylamino) benzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (2-quinoxalinylamino) benzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (2-quinoxalinylamino) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[( 4-methylphenyl) sulfonyl] -3-nitrobenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-[(4-methylphenyl) sulfonyl ] -3-nitrobenzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-[(4-methylphenyl) sulfonyl] -3-nitrobenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl]- 3-benzoylbenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (methylphenylamino) benzamide; N- [3- [2- [ Bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylamino) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxy Phenyl] -4- (phenylthio) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylsulfonyl) benzamide;

N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylsulfinyl) benzamide; N- [3- [2- [bis (1 -Methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(hydroxyimino) phenylmethyl] benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4- Methoxyphenyl] -4- (hydroxyphenylmethyl) benzamide; N- [1 ′-(1-methylethyl) spiro [benzofuran-3 (2H), 4′5-piperidin] -5-yl] -4-benzoylbenzamide N- [1 ′-(1-methylethyl) spiro [benzofuran-3 (2H), 4′5-piperidin] -5-yl] -4-phenoxybenzamide; and N- [1′- (1-methylethyl) spiro [benzo Run -3 (2H), 4'5- piperidine] -5-yl] -4- (phenylthio) benzamide.

Among them, more preferred compounds of the present invention are the following compounds: N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-phenoxybenzamide N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylmethyl) benzamide; N- [3- [2- [bis (1-methyl) Ethyl) amino] ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide methiodide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- Phenoxybenzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -3-phenoxybenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-phenoxybenzamide; N- [3- [2 -(2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-phenoxybenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-benzoylbenzamide; N- [3- [3 -[Bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-benzoylbenzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy] ]-
4-methoxyphenyl] -4-benzoylbenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (phenylmethyl) benzamide;

N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (phenylmethyl) benzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -5-butylamino-4-phenoxy-3- (sulfamoyl) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4 -[(4-chlorophenyl) oxy] -3-nitrobenzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-[(4-chlorophenyl) oxy] -3-nitrobenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4 -(Phenylthio) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(hydroxyimino) phenylmethyl] benzamide; N- [1 ' -(1-methylethyl) spiro [benzofuran-3 (2H), 4'5-piperidin] -5-yl] -4-benzoylbenzamide trifluoroacetate; N- [1 '-(1-methylethyl) spiro [Benzofuran-3 (2H), 4'5-piperidin] -5-yl] -4-phenoxybenzamide; and N- [1 '-(1-methylethyl) spiro [benzofuran-3 (2H), 4'5 -Piperidin] -5-yl] -4- (phenylthio ) Benzamide.

Among them, the most preferred compounds of the present invention are the following compounds: N- [1 ′-(1-methylethyl) spiro [benzofuran-3 (2H), 4′5-piperidin] -5-yl ] -4-benzoylbenzamide trifluoroacetate; N- [1 '-(1-methylethyl) spiro [benzofuran-3 (2H), 4'5-piperidin] -5-yl] -4-phenoxybenzamide; N- [1 '-(1-Methylethyl) spiro [benzofuran-3 (2H), 4'5-piperidin] -5-yl] -4- (phenylthio) benzamide.

Among these, the compounds excluded from the compounds of the present invention are the following compounds: N- [2- [2- [bis (1-methylethyl) amino] ethoxy] phenyl] -4-phenoxybenzamide N- [2- [2- (diethylamino) ethoxy] phenyl] -4-phenoxybenzamide; N- [4- [2- (diethylamino) ethoxy] phenyl] -3-phenoxybenzamide; N- [2- [2 -[Bis (1-methylethyl) amino] ethoxy] phenyl] -3-phenoxybenzamide; N- [2- [2- (diethylamino) ethoxy] phenyl] -3-phenoxybenzamide; N- [4- [2- (Diethylamino) ethoxy] phenyl] -4- (phenylmethyl)
Benzamide; and N- [2- [2- [bis (1-methylethyl) amino] ethoxy] phenyl] -4- (
Phenylmethyl) benzamide.

Formulation of Pharmaceutical Compositions The pharmaceutically active compounds of the present invention (and pharmaceutically acceptable salts thereof) are useful for converting compounds of the present invention (“active ingredients”) into COPD, asthma and atopic diseases (eg, Atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases, such as
A standard pharmaceutical carrier or diluent in an amount sufficient to treat multiple sclerosis, inflammatory bowel disease and HIV infection ("CCR5-mediated condition"), and conventional procedures well known in the art. In a general dosage form prepared by combining according to the following. These operations include mixing, granulating, compressing or dissolving the ingredients as appropriate to provide the desired formulation. The pharmaceutical carrier employed can be, for example, either a solid or liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin,
Gum arabic, magnesium stearate, stearic acid and the like. Examples 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 in the art, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

A wide variety of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in 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. If a liquid carrier is used, the preparation will be in the form of a sterile injectable solution or non-aqueous liquid suspension such as a syrup, emulsion, soft gelatin capsule, ampoule and the like. The active ingredient can also be administered locally to a mammal in need of treatment or prevention of a CCR5-mediated condition. The amount of active ingredient required for therapeutic action with topical administration will, of course, vary with the compound selected, the nature and severity of the condition being treated, the mammal being treated, and ultimately at the discretion of the consulting physician. It is determined. A suitable dosage for the active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage is 1 mg to 100 mg, for example 5 to 25 mg administered twice or three times a day. Topical administration means non-systemic administration, epidermal application of the active ingredient, topical application to the oral cavity,
And the injection of such compounds into the ear, eye and nose, where the compounds do not significantly enter the bloodstream. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.

If the active ingredient can be administered alone as the raw chemical, it is preferably administered as a pharmaceutical formulation. For topical administration, the active ingredient may be incorporated at 0.001% to 10% w / w, for example 1% to 2% by weight of the formulation.
% W / w may be contained in a large amount, but preferably does not exceed 5% w / w of the preparation, more preferably 0.1% to 1% w / w. The topical formulations of the present invention comprise, for both veterinary and human pharmaceutical uses, one or more acceptable carriers together with the active ingredients, optionally containing other therapeutic ingredients. Is also good. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and must not be harmful to its recipients. Formulations suitable for topical administration are liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as liniment, lotion, cream, ointment or paste, and suitable for administration to the eye, ear or nose Drops are included. Drops of the invention may include sterile aqueous or oily solutions or suspensions, the active ingredient containing a bactericide and / or fungicide and / or other suitable preservative, preferably a surfactant. It is prepared by dissolving in a suitable aqueous or alcoholic solution. The resulting solution is then clarified by filtration, transferred to a suitable container, sealed, autoclaved, or sterilized by maintaining at 98-100 ° C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by aseptic technique. Fungicides or fungicides suitable for incorporation into drops, for example, phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%) Is mentioned. Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.

The lotions of the present invention include those suitable for application to the skin or eyes. Ophthalmic lotions contain a sterile aqueous solution optionally containing a bactericide and are prepared in a manner similar to the preparation of drops. Lotions or liniments for application to the skin may further comprise agents that promote drying and cooling of the skin, such as alcohol or acetone, and / or humectants such as glycerol or oils such as castor oil or peanut oil. The creams, ointments or pastes according to the invention are semisolid formulations of the active ingredient which are suitable for topical application. These are prepared 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 a greasy or non-greasy base using a suitable machine. It is prepared by Bases are hydrocarbons, for example, solid, soft or liquid paraffin, glycerol, beeswax, metal soaps; slurries; oils of natural sources such as almonds, corn, peanuts, castor or olive oil; wool fat or derivatives thereof, or Fatty acids, such as stearic acid or oleic acid, may be included with the alcohol, for example, propylene glycol. The formulation may include a suitable surfactant such as an anionic, cationic or non-ionic surfactant such as an ester or a polyoxyethylene derivative thereof.
It may contain suspending agents such as natural gums, cellulose derivatives or inorganic substances such as siliceous silica and other ingredients such as lanolin.

[0048] The active ingredients can also be administered by inhalation. "Inhalation" means intranasal and oral inhalation administration. Dosage forms suitable for such administration, such as an aerosol formulation or a metered dose inhaler, can be prepared by conventional techniques. The daily dose of the active ingredient administered by inhalation is about 0.1 mg to 100 mg per day,
Preferably about 1 mg to about 10 mg per day. In one aspect, the present invention relates to a method comprising:
COPD, asthma and atopic disorders (eg, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammation The present invention relates to a method for treating sexual bowel disease and HIV infection, which comprises administering to such a mammal an effective amount of a CCR5 receptor modulator, in particular a compound of the present invention.

The term “treatment” refers to prophylactic or therapeutic treatment. Such compounds can be administered to such mammals in conventional dosage forms prepared by combining the compounds of the present invention with conventional pharmaceutically acceptable carriers or diluents according to known techniques. Those of skill in the art will understand that the form and properties of a pharmaceutically acceptable carrier or diluent are determined by the dosage of the active ingredients to be combined, the route of administration and other well-known variables. The compounds are useful in treating COPD, asthma and atopic disorders (eg, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic diseases, psoriasis, autoimmune diseases, eg, multiple sclerosis A mammal in need of treatment for a disease, inflammatory bowel disease and HIV infection is administered in an amount sufficient to reduce the symptoms associated with these conditions. The route of administration can be oral or parenteral. The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, rectal, vaginal or intraperitoneal administration. In general, parenteral administration in subcutaneous and intramuscular forms is preferred. The daily parenteral dosage is preferably from about 30 mg to about 300 m / day.
g of active ingredient. The daily oral dose is preferably about 1 day.
It will consist of from 00 mg to about 2000 mg of active ingredient.

The optimal amount of the compound of the invention and the interval between individual administrations will be determined by the nature and extent of the condition to be treated, the mode of administration, the route and site of administration, and the particular mammal to be treated. One skilled in the art will understand that the optimal amount can be determined by conventional methods. Furthermore, it is clear that the optimal treatment method, ie, the dose of the compound to be administered daily during a given period, can be ascertained by those skilled in the art using routine treatment decision tests.

Preparation Methods Compounds of formula (I) are prepared by condensing an appropriately substituted aryl or heteroaryl carboxylic acid with an appropriately substituted aniline using methods known in the art. The compounds are commercially available or are synthesized from commercially available starting materials by methods known in the art. For example, reacting an appropriately substituted aryl or heteroaryl carboxylic acid with a suitable reagent, such as thionyl chloride, at a suitable temperature, for example, at reflux, to give an aryl or heteroaryl carbonyl chloride, wherein the aryl or heteroaryl carbonyl chloride is Condensation of the optionally substituted aniline with a suitable base, for example diisopropylethylamine, in a suitable solvent, for example dichloromethane, gives the compound of formula (I). Many additional methods for converting carboxylic acids to amides are known and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", I-VI.
Volume (published by Wiley-Interscience).

Compounds of formula (I) may also be prepared using solid-phase chemistry as shown in Scheme I and the general methods described in International Patent Application WO 99/01127 (published January 14, 1999). did. For example, in Scheme I, optionally substituted 3- (2-aminoethoxy) -4-methoxyaniline I-2, such as commercially available 2-methoxy-5-nitrophenol according to the procedure described in WO 99/01127 I-
3- [2- (diisopropylamino) ethoxy] -methoxyaniline synthesized from 1 was subjected to reductive amination using a reducing agent such as sodium triacetoxyborohydride in dimethylformamide containing 1% acetic acid. Attaching to a polymer support, such as Merrifield resin-bound aldehyde I-3, synthesized according to the general protocol of Boojamra et al. (J. Org. Chem. 1995, 60, 5742-3). I-4 is obtained. The resulting resin-bound aniline 1-4 is commercially available, for example, using N-bromosuccinimide and triphenylphosphine in dichloromethane or dichloromethane combined with dimethylformamide in the presence of an organic base such as pyridine. An optionally substituted aryl- or heteroarylcarboxylic acid I- which is available or can be synthesized
Acylation with 5, for example, 4-phenoxybenzoic acid gives I-6. For example, I
-4 is reacted with a 10-fold excess of an equimolar mixture of 3-aryl- or heteroarylcarboxylic acid, triphenylphosphine and N-bromosuccinimide in a suitable solvent, for example dichloromethane, followed by 10-fold An excess of a suitable base, for example, pyridine, is added and the mixture is left for a suitable time, for example, 48 hours.
Stir gently to obtain resin-bound amide I-6. If desired, dimethylformamide can be added to the resulting mixture to increase the solubility of the 3-aryl- or heteroarylcarboxylic acid. I-6 is treated with a mixture of a strong organic acid and an organic solvent in a suitable solvent, for example, trifluoroacetic acid: dichloromethane: water (50: 48: 2), and the desired compound is cleaved from the polymer support, The compound of formula (I), carboxyanilide I-7, is obtained.

Scheme I:

Embedded image(a) Cl (CH₂)₂NR³R⁴, K₂CO₃, CH₃COCH₃(B) H₂,
5% Pd / C, MeOH; (c) Maryfield resin-bound aldehyde (3), N
aBH (OAc)₃1% HOAc, DMF; (d) aryl- or heteroaryl
Carboxylic acid, NBS, Ph₃P, pyridine; (e) TFA, CH₂Cl₂, H
₂O

The present invention will be described with reference to the following examples. It is only an example and does not limit the scope of the invention. In the examples, mass spectrometry was performed on a VG Zab mass spectrometer using fast atom bombardment, unless otherwise specified.

Examples Preparation Example 1 Preparation of 4- (methylphenylamino) benzoic acid Ethyl 4- (methylphenylamino) benzoate (2.65 g, 10 mmol) (T
A solution of etrahedron Lett. 1997, 38, 6359-6362) in tetrahydrofuran (50 mL), ethanol (25 mL) and water (5 mL) was reacted with 1N sodium hydroxide (84 mL) and heated to 50 ° C. for 20 hours. The volume of the mixture was reduced under reduced pressure, diluted with water and extracted three times with ethyl acetate. The aqueous phase was acidified with acetic acid to a pH of about 6, and the precipitated white solid was isolated by filtration, washed with water,
Drying afforded the title compound (1.95 g). MS (ES) m / e 227.8 (
M + H) +.

Preparation Example 2 1 ′-(1-methylethyl) spiro [benzofuran-3 (2H), 4′-piperidine]
Preparation of -5-amine a) 5- and 7-Nitrospiro [benzofuran-3 (2H), 4'-piperidine] 1'-methyl-5- and 7-nitrospiro [benzofuran-3 (2H), 4'-
Piperidine] (WO 96/11934) (3 g, 12 mmol) and diisopropylethylamine (2.5 g, 19 mmol) in 1,2-dichloroethane (80
solution at room temperature in 1-chloroethyl chloroformate (2.3 g, 16 mmol)
And stirred for 1 hour and heated at reflux for 20 minutes. The mixture is cooled, concentrated under reduced pressure, the residue is dissolved in methanol, heated at reflux for 2 hours, concentrated under reduced pressure, and the residue is diluted between dichloromethane (250 mL) and 5% sodium bicarbonate (50 mL). Distributed. The organic phase was washed with 5% sodium bicarbonate (50 mL) and the combined aqueous phases were extracted with dichloromethane (2 × 50 mL). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated to give the title compound (2.65 g).

B) 1 ′-(tert-butoxycarbonyl) -5-nitrospiro [benzofuran-3 (
2H), 4'-piperidine] A solution of the compound of Preparation 2 (a) (2.65 g, 1.13 mmol) in tetrahydrofuran (300 mL) was prepared by adding di-tert-butyl dicarbonate (2.6 g, 12 mmol).
And stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was crystallized from methanol to give the title compound (2.1 g). c) 5-Nitrospiro [benzofuran-3 (2H), 4'-piperidine] The compound of Preparation 2 (b) (2.1 g, 6.3 mmol) in dichloromethane (50)
) and a solution in trifluoroacetic acid (10 mL) were kept at room temperature for 5 hours, concentrated under reduced pressure, and the residue was partitioned between dichloromethane (300 mL) and 5% sodium bicarbonate. The organic phase was washed with 5% sodium bicarbonate and the combined aqueous washes were extracted with dichloromethane. The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound (1.45g). MS (ES) m / e 235.1 [
M + H] ⁺ .

D) 1 ′-(1-methylethyl) -5-nitrospiro [benzofuran-3 (2H), 4
'-Piperidine] The compound of Preparation Example 2 (c) (1.45 g, 6.2 mmol), potassium carbonate powder (
A mixture of 0.86 g (6.2 mmol) and dimethylformamide (50 mL) containing 2-iodopropane (1.1 g, 6.4 mmol) was stirred, heated at 50 ° C. for 4 hours, and treated with 2-iodopropane ( (0.17 g, 1 mmol) at 50 DEG C. for 90 minutes, followed by 2-iodopropane (0.1 g, 1 mmol) at 50 DEG C. for 2 hours. The mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate (200 mL)
And water (20 mL). The organic phase is washed, dried (MgSO ₄ )
After concentration under reduced pressure, the residue was subjected to chromatography (silica gel, 5% methanol / dichloromethane) to obtain the title compound (0.85 g). e) [1 '-(1-Methylethyl) spiro [benzofuran-3 (2H), 4'-piperidin] -5-amine Preparation Example 2 (d) (0.78 g, 2.8 mmol) on carbon 10% palladium (
0.375 g) in methanol (250 mL).
sha) for 40 minutes, filtered and concentrated under reduced pressure to give the title compound (0.6 g).

Preparation Example 3 Preparation of 7-amino-3,4-dihydro-N, N-bis (1-methylethyl) -1 (2H) -quinolinethanamine a) 3,4-dihydro-N, N- Bis (1-methylethyl) -7-nitro-1 (2H)
-Quinolineethaneamine Sodium carbonate (2.9 g, 27 mmol) was converted to 7-nitro-1,2,3,4-tetrahydroquinoline (1.2 g, 6.7 mmol) (US Pat. No. 5,696,133), chloride 2 -(Diisopropylamino) ethyl hydrochloride (4.0 g, 20 mmol)
And a mixture of ethanol (25 mL). The mixture was heated at reflux for 3 hours, filtered and concentrated under reduced pressure. The crude product is chromatographed (silica gel,
Purified by dichloromethane, followed by 5% methanol: dichloromethane)
The title compound was obtained as a yellow oil (1.4 g, 68%). MS (ES) m / e 306.
1 [M + H] ⁺ . b) 7-amino-3,4-dihydro-N, N-bis (1-methylethyl) -1 (2H)
-Quinolineethaneamine A mixture of the compound of Preparation 3 (a) and 5% palladium on carbon in ethanol was hydrogenated at 50 psi. The mixture was filtered and concentrated under reduced pressure to give the title compound.

Preparation 4 Preparation of 2- (phenylmethyl) -4-thiazolecarboxylic acid Benzenethanthioamide (1.0 g, 6.6 mmol) in dioxane (25 m
L) reacting the solution in bromopyrivic acid (1.1 g, 6.6 mmol) with 90
Heated at 0 ° C for 4 hours. The mixture was diluted with water and the tan crystals formed were collected by filtration to give the title compound.

Example 1 Preparation of N- [3- [2- (diethylamino) ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide a) 3- [2 (diethylamino) ethoxy] -4-methoxyaniline / [ 4-Formyl-3,5- (dimethoxy) phenoxy] -Merryfield resin adduct [4-Formyl-3,5- (dimethoxy) phenoxy] -Merryfield resin (B
Oojamra et al., J. Org. Chem. 1995, 60, 5742-3), 3- [2- (diethylamino) ethoxy] -4-methoxyaniline (WO 95/15954) and sodium triacetoxyborohydride in 1% acetic acid. The mixture in dimethylformamide contained was shaken to give the title adduct. b) N- [3- [2 (diethylamino) ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide / [4-formyl-3,5- (dimethoxy) phenoxy] -merryfield resin adduct Example 1 (a) ) Was placed in Irori Micro Kan and reacted with a 10-fold molar excess of a mixture of 4-chlorocinnamic acid, N-bromosuccinimide and triphenylphosphine in equimolar dichloromethane, followed by a 10-fold excess of pyridine. Was added. The mixture was gently stirred for 48 hours, after which the resin was washed three times with dimethylformamide, dichloromethane and methanol to give the title adduct. c) N- [3- [2 (Diethylamino) ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide The resin of Example 1 (b) was treated with trifluoroacetic acid: dichloromethane: water (50:48).
: 2), stirred and filtered, and the filtrate was concentrated under reduced pressure to give the title compound. MS (ES) m / e 435.0 (M + H) +.

Example 2-30 In addition to 3- [2- (diethylamino) ethoxy] -4-methoxyaniline, 4-[(
2-diisopropylamino) ethoxy] aniline (WO99 / 01127), 4-
[2- (Diethylamino) ethoxy] aniline (J. Med. Chem. 1995, 38, 16)
57-65), 3-[(2-diisopropylamino) ethoxy] aniline (WO99
/ 01127), 3-[(2-diisopropylamino) ethoxy] -4-methoxyaniline (WO95 / 15954), 3- [2- (2,2,6,6-tetramethyl-1)
-Piperidinyl) ethoxy] -4-methoxyaniline (WO 99/01127) and 3-[(3-diisopropylamino) propyl] -4-methoxyaniline (WO
99/01127), in addition to 4-phenoxybenzoic acid, 3-phenoxybenzoic acid, 4- (phenylmethyl) benzoic acid, 4-benzoylbenzoic acid, 4-[(4-
Chlorophenyl) sulfonyl] benzoic acid, 5-butylamino-4-phenoxy-3
-(Sulfamoyl) benzoic acid, 4-[(4-chlorophenyl) oxy] -3-nitrobenzoic acid, 2-[(4-carboxyphenyl) amino] quinoxaline and 4-[(4
Following the procedure of Example 1 (a)-(c) except using -methylphenyl) sulfonyl] -3-nitrobenzoic acid, the title compound was obtained:

N- [4- [2- [bis (1-methylethyl) amino] ethoxy] phenyl]]-4-
Phenoxybenzamide: MS (ES) m / e 433.2 (M + H) +; N- [4- [2- (diethylamino) ethoxy] phenyl] -4-phenoxybenzamide: MS (ES) m / e 405.2 ( N- [3- [2- [bis (1-methylethyl) amino] ethoxy] phenyl] -4-phenoxybenzamide: MS (ES) m / e 433.2 (M + H) +; N- [ 3- [2- (diethylamino) ethoxy] -4-methoxyphenyl] -3-phenoxybenzamide: MS (ES) m / e 435.0 (M + H) +; N- [4- [2- [bis (1- Methylethyl) amino] ethoxy] phenyl] -3-phenoxybenzamide: MS (ES) m / e 433.2 (M + H) +; N- [4- [2- [bis (1-methylethyl) amino] ethoxy]. Phenyl] -4- (
Phenylmethyl) benzamide: MS (ES) m / e 431.2 (M + H) +; N- [2- [2- (diethylamino) ethoxy] phenyl] -4- (phenylmethyl)
Benzamide: MS (ES) m / e 403.0 (M + H) +; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3-phenoxybenzamide: MS (ES) m / e 460.9 (M +
H) +; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-Methoxyphenyl] -3-phenoxybenzamide: MS (ES) m / e 5
02.9 (M + H) +; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-phenoxybenzamide: MS (ES) m / e 5
03.3 (M + H) +; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-benzoylbenzamide: MS (ES) m / e 473.3. (M +
H) +; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-benzoylbenzamide: MS (ES) m / e 5
15.3 (M + H) +; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (phenylmethyl) benzamide: MS (ES) m / e 459.3
(M + H) +; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (phenylmethyl) benzamide: MS (ES) m
/ E 501.3 (M + H) +; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(4-chlorophenyl) sulfonyl] benzamide: MS (ES)
m / e 545.2 (M + H) +; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-[(4-chlorophenyl) sulfonyl] benzamide: MS (ES)
m / e 543.2 (M + H) +; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-[(4-chlorophenyl) sulfonyl] benzamide: MS (ES) m / e 585.2 (M + H) +; N- [3- [2- [bis (1-methylethyl) amino] ] Ethoxy] -4-methoxyphenyl] -5-butylamino-4-phenoxy-3- (sulfamoyl) benzamide: MS (ES) m / e 613.3 (M + H) +; N- [3- [3- [ Bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -5-butylamino-4-phenoxy-3- (sulfamoyl) benzamide: MS (ES) m / e 611.3 (M + H) +; N -[3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -5-butylamino-4-phenoxy-3- (sulfamoyl) benzamide: MS (ES) m / e 653.3 (M + H) +; N- [3- [2- [bis (1- Methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (4-chlorophenoxy) -3-nitrobenzamide: MS (ES
) M / e 542.2 (M + H) +; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (4-chlorophenoxy) -3- Nitrobenzamide: MS (ES
) M / e 540.2 (M + H) +; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (4-chlorophenoxy) -3-nitrobenzamide: MS (ES) m / e 582.2 (M + H) +; N- [3- [2- [bis (1-methylethyl) ) Amino] ethoxy] -4-methoxyphenyl] -4- (2-quinoxalinylamino) benzamide: MS (ES) m / e
514.4 (M + H) +; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (2-quinoxalinylamino) benzamide: MS ( ES) m / e
512.4 (M + H) +; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (2-quinoxalinylamino) benzamide: MS
(ES) m / e 554.2 (M + H) +; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(4-methylphenyl). Sulfonyl] -3-nitrobenzamide:
MS (ES) m / e 570.2 (M + H) +; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-[(4-methylphenyl ) Sulfonyl] -3-nitrobenzamide:
MS (ES) m / e 568.3 (M + H) +; and N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-Methoxyphenyl] -4-[(4-methylphenyl) sulfonyl] -3-nitrobenzamide: MS (ES) m / e 610.3 (M + H) +.

Example 31 Preparation of N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-phenoxybenzamide 3-phenoxybenzoic acid (0.11 g, 0.1 3.5 mmol) and thionyl chloride (5 mL) were heated at reflux for 30 minutes and concentrated under reduced pressure to give 3-phenoxybenzoyl chloride, dissolved in dichloromethane (5 mL) and treated with 3-[(2-diisopropylamino) ethoxy. ] -4-methoxyaniline (0.14 g, 0.5 mmol) and diisopropylethylamine (0.07 g, 0.5 mmol).
The mixture was stirred at room temperature for 16 hours, washed twice with 5% sodium carbonate and with water. The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure to give a residue, which was chromatographed (silica gel, 1: 1 ethyl acetate: hexane) to give the title compound (0.12 g). MS (ES) m / e 463.2 (M + H) +.

Examples 32-35 Instead of 3-phenoxybenzoic acid, 4-phenoxybenzoic acid, 4- (phenylmethyl) benzoic acid, 4- (phenylthio) benzoic acid and 4- (phenylsulfonyl)
) Following the procedure of Example 31 except that benzoic acid (Chim. Ther. 1973, 8, 340-1) was used, the title compound was obtained. : N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide: MS (ES) m / e 463.0 (M +
H) +; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylmethyl) benzamide: MS (ES) m / e 460.9.
(M + H) +; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylthio) benzamide: MS (ES) m / e 478.9 (
M + H) +; and N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylsulfonyl) benzamide: MS (ES) m / e 510
0.7 (M + H) +.

Example 36 Preparation of N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (3-hydroxyphenoxy) benzamide 4- (3-hydroxy Phenoxy) benzoic acid (0.23 g, 1 mmol), 3- [
(2-Diisopropylamino) ethoxy] -4-methoxyaniline (0.27 g, 1
Mmol) and BOP reagent (0.44 g, 1 mmol) in acetonitrile (2
(0 mL) was reacted with triethylamine (0.2 g, 2 mmol) and allowed to stir at room temperature for 16 hours. The mixture was diluted with dichloromethane and filtered. The filtrate was washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure to give a residue which was extracted with H
PLC (ODS-A, 20 × 50 mm, A: acetonitrile, B: water-0.1%
Purification by trifluoroacetic acid (10-90% for 10 minutes, UV detection at 254 nm) afforded the title compound. MS (ES) m / e 478.8 (M + H) +.

Example 37-43 4-[(4-Chlorophenyl) sulfinyl] -3-nitrobenzoic acid instead of 4- (3-hydroxyphenoxy) benzoic acid, 4-[(2,4-dichlorophenyl) sulfinyl] -3-Nitrobenzoic acid, 4-benzoylbenzoic acid, 3-benzoylbenzoic acid, the compound of Preparation Example 1, 4- (phenylamino) benzoic acid and 4- (phenylsulfinyl) benzoic acid (Synthesis 1990, 847-9) Following the procedure of Example 36 except using, the title compound was obtained:

N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(4-chlorophenyl) sulfinyl] -3-nitrobenzamide: MS (ES) m / e 573.7 (M + H) +; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(2,4-dichlorophenyl) sulfinyl] -3-Nitrobenzamide: MS (ES) m / e 607.7 (M + H) +; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-. Benzoylbenzamide: MS (ES) m / e 475.3 (M +
H) +; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-benzoylbenzamide: MS (ES) m / e 474.9 (M +
H) +; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (methylphenylamino) benzamide: MS (ES) m / e 47
5.9 (M + H) +; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylamino) benzamide: MS (ES) m / e 462.0
(M + H) +; and N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylsulfinyl) benzamide: MS (ES) m / e 49
4.7 (M + H) +.

Example 44 Preparation of N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-phenoxybenzamide of 4- (3-hydroxyphenoxy) benzoic acid Instead of using 4-phenoxybenzoic acid and using 3-[(3-diisopropylamino) propyl] -4-methoxyaniline instead of 3-[(2-diisopropylamino) ethoxy] -4-methoxyaniline. The title compound was obtained according to the procedure of Example 36. MS (ES
) M / e 461.3 (M + H) +.

Example 45 Preparation of N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(hydroxyimino) phenylmethyl] benzamide Compound (0.24 g, 0.5 mmol), hydroxylamine hydrochloride (0.17 g) and triethylamine (0.24 mL) in ethanol (10 m
The solution in L) was heated to reflux for 20 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water to give the title compound. MS (ES) m / e 490.0 (
M + H) +.

Example 46 Preparation of N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (hydroxyphenylmethyl) benzamide The compound of Example 39 (0 .24 g, 0.5 mmol), ethanol (21 mL)
, A mixture of water (7 mL), methanol (5 mL) and dichloromethane (5 mL) with sodium borohydride (0.13 g, 3.5 mmol) at room temperature
Stirred for hours. The mixture was diluted with water, reduced in volume under reduced pressure, and extracted three times with dichloromethane. The combined organic phases were washed with brine, dried (MgSO ₄ )
Concentration under reduced pressure gave the title compound (40 mg). MS (ES) m / e 477.
2 (M + H) +.

Example 47 Preparation of N- [1 ′-(1-methylethyl) spiro [benzofuran-3 (2H), 4′5-piperidin] -5-yl] -4-benzoylbenzamide trifluoroacetate 4 -Benzoylbenzoic acid (55 mg, 0.254 mmol), Preparation Example 2 (e)
(60 mg, 0.24 mmol) and BOP reagent (108 mg, 0.2
4 mmol) in acetonitrile (5 mL) was added to triethylamine (50 mg).
, 0.5 mmol) and stirred at room temperature for 16 hours. The mixture was quenched with brine and extracted with ethyl acetate. The organic extract was washed with 5% sodium carbonate and brine, dried (MgSO ₄ ) and concentrated under reduced pressure. HPLC of the residue
(ODS-A, 20 × 50 mm, A: acetonitrile, B: water-0.1% trifluoroacetic acid, 10-90% for 10 minutes, UV detection at 254 nm), and purified.
The title compound was obtained. MS (ES) m / e 455.1 (M + H) +.

Examples 48-49 N- [1 ′-(1-methylethyl) spiro [benzofuran-3 (2H), 4′5-piperidin] -5-yl] -4-phenoxybenzamide and N- [1 '-(1-Methylethyl) spiro [benzofuran-3 (2H), 4'5-piperidin] -5-yl]-
Preparation of 4- (phenylthio) benzamide Following the procedure of Example 47 except that 4-phenoxybenzoic acid and 4- (phenylthio) benzoic acid were used instead of 4-benzoylbenzoic acid, the title compound was obtained: N- [1 ′-(1-Methylethyl) spiro [benzofuran-3 (2H), 4′5-piperidin] -5-yl] -4-phenoxybenzamide: MS (ES) m / e 4
43.1 (M + H) +; and N- [1 '-(1-methylethyl) spiro [benzofuran-3 (2H), 4'5-piperidin] -5-yl] -4- (phenylthio) benzamide: MS (ES) m / e
459.1 (M + H) +.

Example 50 Preparation of N- [1- [2- [bis (1-methylethyl) amino] ethyl] -1,2,3,4-tetrahydroquinol-7-yl] -4-phenoxybenzamide 3 -Using 4-phenoxybenzoic acid instead of phenoxybenzoic acid, 3-[(2
Preparation Example 3 in place of -diisopropylamino) ethoxy] -4-methoxyaniline
The title compound was obtained according to the procedure of Example 31 except for using the compound of (b). MS (ES) m / e 472.2 (M + H) +.

Example 51 Preparation of N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide methiodide Example 32 in methanol (3 mL) Compound (93 mg, 0.2 mmol)
Is reacted with iodomethane (8 mL), kept at room temperature for 4 days, concentrated under reduced pressure,
The residue was triturated with ethyl acetate and then with 1: 1 ethyl acetate: ether. The residue was stirred with 1: 1 ethyl acetate: ether for several hours and filtered to give the title compound. MS (ES) m / e 477 (M + H) +.

Example 52 Preparation of N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -2- (phenylmethyl) thiazole-4-carboxamide hydrochloride 3 -Following the procedure of Example 31 except for using the compound of Preparation 4 in place of the phenoxybenzoic acid, the title compound was obtained. MS (ES) m / e 468.0 (
M + H) +.

Biological Data CCR5 Receptor Binding Assay CHO cell membranes (equivalent to 0.25 × 10 ⁴ cells) from CHO cells stably transfected with CCR5 were combined with 0.3 ¹²⁵ I-RANTES for 96 hours. The well plate was incubated for 45 minutes at room temperature (final reaction volume 200 μl). The reaction was stopped by filtration, and 0.1% bovine serum albumin and 0.0% were added.
The filter (GF / C) was washed twice with a phosphate buffered saline solution containing 5% NaN ₃ . Radioactive filters were measured by liquid scintillation spectroscopy. Non-specific binding was measured in the presence of unlabeled RANTES (10 or 30 nM) and averaged 30-50% of total binding.

CCR5 Receptor Function Assay The cell function assay used to assess the antagonist activity of the compound was hCCR
RBL 2H ₃ cells stably expressing 5 receptors (RBL 2H ₃ hCCR5)
Kinetics of Ca ²⁺ induced by RANTES in the cell. Agonist activity can be inhibited by a CCR5 selective antagonist, Ca ^{2 in the} same cell
⁺ Measure mobilization. Cells were grown to 80-100% confluence in T-150 flasks and washed with phosphate buffered saline. Treatment with 3 ml of 1 mM EDTA at room temperature for 3 minutes, 5 mM HEPES (pH 7.4), 1 mM CaCl ₂
Krebs Ringer Henseleit buffer (KRH; 118 mM Na) containing 1 mM MgCl ₂ and 0.1% BSA.
Cl, 4.6 mM KCl, 25 mM NaHCO ₃ , 1 mM KH ₂ PO ₄ and 11
The cells were removed from the flask by diluting to 2 × 10 ⁶ cells / ml (mM glucose) and centrifuged at 200 × g for 3 minutes. 2 μM Fura-2A
The cells were resuspended at 2 × 10 ⁶ cells / ml in the same buffer containing M.
Incubated for 5 minutes. The cells are centrifuged at 200 xg for 3 minutes and F
The cells were resuspended in the same buffer without ura-2AM and incubated at 37 ° C. for 15 minutes to terminate the hydrolysis of Fura-2AM in the cells and then centrifuged as described above. Cells (10 ⁶ cells / ml) were converted to 5 mM HEPES (p
H7.4) resuspended in cold KRH containing 1 mM CaCl ₂ , 1 mM MgCl ₂ and 0.1% gelatin and kept on ice until the assay was performed. When experimenting with antagonists, an aliquot of cells (2 ml) was pre-warmed to 37 ° C. for 5 minutes in a 3 ml plastic cuvette, stirred with a magnetic stirrer, and maintained at 37 ° C. while maintaining a fluorometer (Pennsylvania, USA). ,Philadelphia,
The fluorescence was measured by Johnson, Foundation, Biomedical, Group). 340n excitation
m and emission was measured at 510 nm. Various concentrations of antagonist or vehicle were added and the fluorescence was monitored for １５15 seconds to ensure no change in the fluorescence baseline, followed by the addition of 33 nM RANTES. 33nM RANT
The maximum of Ca ²⁺ obtained after stimulation with ES was calculated as described in Grynkiewicz et al. (1985). The maximum% RANTES-induced Ca ²⁺ was determined for each concentration of antagonist and the IC ₅₀ was defined as the concentration of the test compound that inhibited 50% of the maximum response of RANTES at 33 nM by a concentration response curve (5-7 concentrations). Antagonist).

Compounds of the present invention exhibit CCR5 receptor modulator activity with IC ₅₀ values ranging from 0.0001 to 100 μM. Structure for compound of the invention /
The activity relationship has not yet been fully established. However, the disclosure herein will allow one of skill in the art to determine which compounds of the invention are modulators of the CCR5 receptor and bind with IC ₅₀ values ranging from 0.0001 to 100 μM. The assay can be used. All publications, including, but not limited to, patent publications and patent application publications cited herein, including each individual publication are specifically and individually referred to herein by reference. It is indicated to be a part, and even if fully disclosed, is hereby incorporated by reference. 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, one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. Therefore, it should be construed that each embodiment is merely an example and does not limit the scope of the present invention. Specific examples of the present invention for claiming exclusive rights and privileges are described below.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/47 A61K 31/47 4C063 31/498 31/498 4C086 31/538 31/538 4C206 A61P 1/00 A61P 1/00 4H006 11/06 11/06 17/06 17/06 19/02 19/02 29/00 29/00 101 101 37/00 37/00 37/06 37/06 37/08 37/08 C07C 235/56 C07C 235/56 C07D 211/14 C07D 211/14 215/38 215/38 241/54 241/54 265/36 265/36 277/46 277/46 401/12 401/12 491/107 491 / 107 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, S , TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), AE, AL, AU, BA, BB, BG, BR, CA, CN, CZ, EE, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KP, KR, LC , LK, LR, LT, LV, MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK, SL, TR, TT, UA, US, UZ, VN, YU, ZA (72 Inventor William E. Bondinel United States 19087 Franklin Lane 1512, Wayne, Pennsylvania United States 19406 United States 19406 Bill Smith Boulevard, King of Prussia, Pennsylvania 19414 F Term (reference) 4C031 JA02 4C033 AD13 4C050 AA04 BB07 CC16 EE01 FF02 GG01 HH01 4C054 AA02 BB03 CC03 DD04 EE01 FF01 4C056 AA02 AB01 AC03 AD01 AE01 EB02 EC05 4C063 AA01 BB09 CC03A02 BC ZA45 ZA66 ZA89 ZB01 ZB11 ZB13 ZB15 4C206 AA01 AA02 AA03 GA09 MA01 MA04 NA14 ZA45 ZA66 ZA89 ZA96 ZB01 ZB11 ZB13 ZB15 4H006 AA01 AA03 AB20 AB22 AB26 AB29 BJ50 BP30 BU32

Claims (5)

[Claims] 1. A method of treating a CCR5-mediated condition in a mammal, comprising:
In mammals in need of such treatment, an effective amount of Formula (I):Wherein the basic nitrogen present in the group E is C_1-6May be quaternized with alkyl
Or as an N-oxide; P¹And P²Is independently phenyl, fused bicyclic aryl, oxygen, nitrogen or
And a 5- to 7-membered unit containing 1 to 3 heteroatoms selected from
A cyclic heterocycle, or one to three hetero atoms selected from oxygen, nitrogen and sulfur
A is an 8- to 11-membered fused bicyclic heterocycle containing atoms; A is C (R^{4 '})₂, CR^{4 '}(OR^{5 '}), CO, C = NOR^{6 '}, NR^{7 '}
, Oxygen or S (O)_{c '}L is of the formula: -C (= V) -DR^{8 '}-, -DR^{9 '}-C (= V)-, -CH₂NH
-Or -NHCH₂V is oxygen or sulfur; D is a nitrogen, carbon or CH group; R^{1 '}And R^{2 '}Is independently hydrogen, C_1-6Alkyl, C_2-6Arche
Nil, C_2-6Alkynyl, C_3-7Cycloalkyl, C_3-7Cycloalkenyl
, Aryl, (CH₂)_{d '}NR^{10 '}R^{11 '}, (CH₂)_{d '}NR^{10 '}CO
R^{12 '}, (CH₂)_{d '}NR^{10 '}CO₂R^{13 '}, (CH₂)_{d '}NR^{10 '}S
O₂R^{14 '}, (CH₂)_{d '}CONR^{15 '}R^{16 '}, Hydroxy C_1-6Al
Kill, C_1-4Alkoxyalkyl (one C_1-4Alkoxy or hydroxy
May be substituted with a thio group), (CH₂)_{d '}CO₂C_1-6Alkyl, (CH
₂)_{e '}OC (O) R^{17 '}, CR^{18 '}= NOR^{19 '}, CNR^{20 '}= NOR
^{19 '}, COR^{21 '}, CONR^{15 '}R^{16 '}, CONR^{15 '}(CH₂)_{f '} OC_1-4Alkyl, CONR^{15 '}(CH₂)_{d '}CO₂R^{22 '}, CONNHN
R^{23 '}R^{24 '}, CONR^{15 '}SO₂R^{25 '}, CO₂R^{26 '}, Cyano,
Trifluoromethyl, NR^{10 '}R^{11 '}, NR^{10 '}COR^{12 '}, NR^{27 '} CO (CH₂)_{d '}NR^{27 '}R^{28 '}, NR^{27 '}CONR^{27 '}R^{28 '},
NR^{10 '}CO₂R^{13 '}, NR^{10 '}SO₂R^{14 '}, N = CNR^{27 '}NR ^{27 '} R^{28 '}, Nitro, hydroxy, C_1-6Alkoxy, hydroxy C_{1- 6} Alkoxy, C_1-6Alkoxy C_1-6Alkoxy, OC (O) NR^{29 '}R ^{30 '} , SR^{31 '}, SOR^{32 '}, SO₂R^{32 '}, SO₂NR^{33 '}R^{34 '} , Halogen, C_1-6Alkanoyl, CO₂(CH₂)_{d '}OR^{35 '}Is
Or R^{1 '}Is 1 to 4 hetero atoms selected from oxygen, nitrogen or sulfur
An optionally substituted 5- to 7-membered heterocycle containing atoms; R^{3 '}Is hydrogen, C_1-6Alkyl, C_3-6Cycloalkyl, C_3-6Cyclo
Alkenyl, hydroxy C_1-6Alkyl, C_1-6Alkyl OC_1-6Archi
LE, CONR^{36 '}R^{37 '}, CO₂R^{38 '}, Cyano, aryl, trifluoro
Lomethyl, NR^{39 '}R^{40 '}, Nitro, hydroxy, C_1-6Alkoxy, C _1-6 R is alkanoyl, acyloxy or halogen; R^{4 '}, R^{5 '}, R^{6 '}, R^{7 '}, R^{18 '}, R^{19 '}, R^{20 '}, R^{21 '} , R^{22 '}, R^{23 '}, R^{24 '}, R^{27 '}, R^{28 '}, R^{31 '}, R^{35 '},
R^{36 '}, R^{37 '}, R^{38 '}, R^{39 '}And R^{40 '}Is independently hydrogen
Or C_1-6Alkyl; R is R when D is a nitrogen or CH group;^{8 '}Is hydrogen or C_1-6Alkyl
When D is a nitrogen or CH group, R^{9 '}Is hydrogen or C_1-6Alkyl
R; R^{10 '}And R^{11 '}Is independently hydrogen or C_1-6Is alkyl
Or R^{10 '}And R^{11 '}Together with the nitrogen to which they bind
Forming a 5- to 6-membered heterocyclic ring which may be substituted by a xo group,
When there is one ring atom, the ring contains one oxygen or one sulfur atom.
May be R^{12 '}Is hydrogen, C_1-6Alkyl or C_1-4An alkoxyalkyl
R^{13 '}, R^{25 '}And R^{32 '}Is independently C_1-6R is alkyl;^{14 '}Is C_1-6R is alkyl or phenyl;^{15 '}And R^{16 '}Is independently hydrogen or C_1-6Is alkyl
Or R^{15 '}And R^{16 '}Together with the nitrogen to which they bind
Forming a-to 6-membered saturated heterocyclic ring and, when there are 6 ring atoms, 1
May contain one oxygen or one sulfur atom; R^{17 '}Is C_1-6C optionally substituted with alkoxy_1-4Alkyl
R; R^{26 '}Is hydrogen or C_1-6Alkyl, C_1-6Alkoxy, hydroxy
Or NR^{10 '}R^{11 '}Substituted with one or two substituents selected from
May be C_1-6R is alkyl;^{29 '}And R^{30 '}Is independently hydrogen or C_1-6Is alkyl
Or R^{29 '}And R^{30 '}Together with the nitrogen to which they bind
Forming a-to 6-membered heterocycle and having six ring atoms, one ring in the ring;
May contain oxygen or one sulfur atom; R^{33 '}And R^{34 '}Is independently hydrogen or C_1-6Is alkyl
Or R^{33 '}And R^{34 '}Together with the nitrogen to which they bind
Forming a-to 6-membered heterocycle and having six ring atoms, one ring in the ring;
A 'and b' are independently 1, 2 or 3; c 'is 0, 1 or 2; d' is 1, E 'is 0, 1, 2 or 3; f' is 1, 2 or 3; E is of the formula (a):(Where B is oxygen, S (O)_c, CR⁷= CR⁸Or CR⁷R⁸Or B is
NR⁹R¹And R²Is independently hydrogen or C_1-6Alkyl;
To B (CR¹R²)_aIs OCR¹R²CR¹(OH) CR¹R²Or OCR¹R² CR¹(OCOCH₃) CR¹R²R³And R⁴Is independently hydrogen, C_1-6Alkyl, C_3-7Cycloal
Kill, aralkyl, or together with the nitrogen atom to which they are attached,
May contain additional heteroatoms selected from oxygen, nitrogen or sulfur
To form an optionally substituted 5- to 7-membered heterocycle, wherein
The group is C_1-6Alkyl, aryl, CONR¹⁰R¹¹, NR¹⁰R¹¹, Hid
Roxy, OCOR¹², NHCOC_0-6Encompasses alkyl, where alkyl is
Is OH, NHCOCF₃, NHSO₂R¹³And NHCO₂R¹⁴Is replaced by
May be R⁵Is hydrogen, C_1-6Alkyl, aryl, CN, CONR^FifteenR¹⁶, CO ₂ R¹⁷, Trifluoromethyl, NHCO₂R¹⁸, Hydroxy, C_1-6Al
Coxy, benzyloxy, OCH₂CO₂C_1-6Alkyl, OCF₃, S (O) _d R¹⁹, SO₂NR²⁰R²¹Or halogen; R⁶Is hydrogen, C_1-6Alkyl, aryl, trifluoromethyl, hydroxy
, C_1-6Alkoxy or halogen, or R⁶Is R^{8 '}Together with
To form a group D, wherein D is (CR²²R²³)_eOr D is (C
R²²R²³)_f-G, where G is oxygen, sulfur, CR²²= CR²³, CR²²
= N, = CR²²O, = CR²²S or = CR²²-NR²³R⁷, R⁸, R¹⁰, R¹¹, R¹², R^Fifteen, R¹⁶, R¹⁷, R²⁰, R ²¹ , R²²And R²³Is independently hydrogen or C_1-6R is alkyl;⁹Is hydrogen, C_1-6Alkyl or phenyl C_1-6R is alkyl;¹³, R¹⁴, R¹⁸And R¹⁹Is independently C_1-6Alkyl
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; 0, 1, 2, or 3); alternatively, E is a group represented by the formula (b):(Where: R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³¹And R³²Is
Independently hydrogen or C_1-6R is alkyl;³⁰Is hydrogen, C_1-6Alkyl or C_3-7R is cycloalkyl;³³Is hydrogen, C_1-6Alkyl, trifluoromethyl, hydroxy or ha
Rogen or R³³And R^{8 '}Together form a group: -K-
, Where K is (CR³⁴R³⁵)_iOr K is (CR³⁴R³⁵)_j−
M, where M is oxygen, sulfur, CR³⁴= CR³⁵, CR³⁴= N or N = N
Yes; J is oxygen, CR³⁶R³⁷Or NR³⁸Or J is a group: S (O)_k R³⁴, R³⁵, R³⁶, R³⁷And R³⁸Is independently hydrogen or C_{1 -6} 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; And E is a group represented by the formula (c):(Where Q is oxygen, S (O)_n, CR⁴⁴= CR⁴⁵, CR⁴⁴R⁴⁵Or
Q is NR⁴⁶R³⁹And R⁴⁰Is independently hydrogen or C_1-6R is alkyl;⁴¹Is represented by the formula (d):Or a group represented by R⁴¹Is represented by the formula (e):R is a group represented by⁴²Is hydrogen, C_1-6Alkyl, aryl, CN, CONR⁴⁸R⁴⁹, C
O₂R⁵⁰, Trifluoromethyl, NHCO₂R⁵¹, Hydroxy, C_1-6A
Lucoxy, benzyloxy, OCH₂CO₂C_1-6Alkyl, OCF₃, S (
O)_sR⁵², SO₂NR⁵³R⁵⁴Or halogen; R⁴³Is hydrogen or R⁴³Is R^{8 '}Forms a group R together with
Where R is CR⁵⁵= CR⁵⁶, CR⁵⁵= CR⁵⁶CR⁵⁵R⁵⁶Or (C
R⁵⁵R⁵⁶) t; R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁸, R⁴⁹, R⁵⁰, R⁵³, R⁵⁴, R⁵⁵ And R⁵⁶Is independently hydrogen or C_1-6R is alkyl;⁴⁷Is hydrogen, C_1-6Alkyl or C_3-7R is cycloalkyl;⁵¹And R⁵²Is independently C_1-6L is 0, 1, 2 or 3; m is 1 or 2; n is 0, 1 or 2 o, p and q are independently 1, 2 or 3 R is 0, 1, 2 or 3; s is 0, 1 or 2; t is 2 or 3); or E is a group represented by the formula ( f): embedded image(Where: R⁵⁷And R⁵⁸Is independently hydrogen or C_1-6R is alkyl;⁵⁹And R⁶⁰Is independently hydrogen, C_1-6Alkyl, C_3-7Cyclo
Alkyl, aralkyl or together with the nitrogen atom to which they are attached
May contain additional heteroatoms selected from oxygen, nitrogen or sulfur
Form an optionally substituted 5- to 7-membered heterocycle, wherein any
The substituent is C_1-6Alkyl, aryl, CONR⁶¹R⁶², NR⁶¹R⁶²,
Hydroxy, OCOR⁶³, NHCOC_0-6Alkyl, including the alkyl
Is OH, NHCOCF₃, NHSO₂R⁶⁴And NHCO₂R⁶⁵Is replaced by
T is-(CR⁶⁶R⁶⁷)_v-Or -O (CR⁶⁶R⁶⁷)_wW is oxygen, S (O)_x, NR⁶⁸Or W is CR⁶⁹= CR⁷⁰Also
Is CR⁶⁹R⁷⁰R⁶¹, R⁶², R⁶³, R⁶⁶, R⁶⁷, R⁶⁸, R⁶⁹And R⁷⁰Is
Independently hydrogen or C_1-6R is alkyl;⁶⁴And R⁶⁵Is independently C_1-6U is 1 to 4; v is 2 or 3; w is 1, 2 or 3; x is 0, 1 or 2); , E are of the formula (g):(Where: R⁷¹Represents one to three heteroatoms selected from nitrogen, oxygen or sulfur
An optionally substituted 5- to 7-membered saturated or partially saturated heterocycle
Or R⁷¹Is selected from one nitrogen atom and oxygen, nitrogen or sulfur
6,6 or more optionally substituted heteroatoms containing
Or 6,5 bicyclic; R⁷²Is hydrogen, C_1-6Alkyl, aryl, CN, CONR⁷⁴R⁷⁵, C
O₂R⁷⁶, Trifluoromethyl, NHCO₂R⁷⁷, Hydroxy, C_1-6A
Lucoxy, benzyloxy, OCH₂CO₂C_1-6Alkyl, OCF₃, S (
O) zR⁷⁸, SO₂NR⁷⁹R⁸⁰Or halogen; R⁷³Is hydrogen, C_1-6Alkyl, hydroxy, C_1-6Alkoxy or ha
Rogen or R⁷³And R^{8 '}Together form a group: -X-
, Where X is (CR⁸¹R⁸²)_aaOr X is (CR⁸¹R⁸²)_{a b} --Y is oxygen, sulfur or CR⁸¹= CR⁸²R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁹, R⁸⁰, R⁸¹And R⁸²Independently
, Hydrogen or C_1-6R is alkyl;⁷⁷And R⁷⁸Is independently C_1-6Y 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 is represented by the formula (h):(Where: R⁸³And R⁸⁴Is independently hydrogen or C_1-6R is alkyl;⁸⁵And R⁸⁶Is independently hydrogen, C_1-6Alkyl, C_3-7Cyclo
Alkyl, aralkyl or together with the nitrogen atom to which they are attached
Containing one further heteroatom selected from oxygen, nitrogen or sulfur
To form an optionally substituted 5- to 7-membered heterocycle, wherein
Optional substituent is C_1-6Alkyl, aryl, CONR⁸⁸R⁸⁹, NR⁹⁰R ⁹¹ , Hydroxy, OCOR⁹², NHCOC_0-6Including alkyl, where
Alkyl is OH, NHCOCF₃, NHSO₂R⁹³And NHCO₂R⁹⁴ R may be substituted with⁸⁷Is hydrogen, C_1-6Alkyl, C_1-6Is alkoxy or halogen
Or R⁸⁷Is R^{8 '}And forms a group: -AA-, where AA is
(CR⁹⁵R⁹⁶)_adOr AA is (CR⁹⁵= CR⁹⁶)_ae-AB
And AB is oxygen, sulfur, CR⁹⁵= CR⁹⁶, CR⁹⁵= N, CR⁹⁵NR ⁹⁶ Or N = N; Z contains 1-3 heteroatoms selected from oxygen, nitrogen or sulfur
R to form an optionally substituted 5- to 7-membered heterocycle;⁸⁸, R⁸⁹, R⁹⁰, R⁹¹, R⁹², R⁹⁵And R⁹⁶Independently
, Hydrogen or C_1-6R is alkyl;⁹³And R⁹⁴Is independently C_1-6Ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2); or E is a group represented by the formula (i) :(Where: R⁹⁷And R⁹⁸Is independently hydrogen, C_1-6Alkyl, C_3-7Cyclo
Alkyl, aralkyl or together with the nitrogen atom to which they are attached
Containing one further heteroatom selected from oxygen, nitrogen or sulfur
To form an optionally substituted 5- to 7-membered heterocycle, wherein
Optional substituent is C_1-6Alkyl, aryl, CONR¹⁰²R¹⁰³, NR^{1 04} R¹⁰⁵, Hydroxy, OCOR¹⁰⁶, NHCOC_0-6Includes alkyl
And the alkyl here is OH, NHCOCF₃, NHSO₂R¹⁰⁷And NH
CO₂R¹⁰⁸R may be substituted with⁹⁹And R¹⁰⁰Is independently hydrogen or C_1-6R is alkyl;¹⁰¹Is hydrogen or C_1-6Alkyl or R¹⁰¹And R^{8 '} Together form a group: -AD-, where AD is (CR¹⁰⁹R¹¹⁰)
_aiOr AD is (CR¹⁰⁹R¹¹⁰)_aj-AE, where AE is
Oxygen, sulfur or CR¹⁰⁹= CR¹¹⁰AC is oxygen, CR¹¹¹R¹¹²Or NR¹¹³Or AC is a group
: S (O)_akR¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁹, R¹¹⁰,
R¹¹¹, R¹¹²And R¹¹³Is independently hydrogen or C_1-6Alkyl
R¹⁰⁷And R¹⁰⁸Is independently C_1-6Af is 0, 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 represents 0, 1, 2 or 3; ak represents 0, 1 or 2), or a pharmaceutically acceptable salt thereof. Do
Method. 2. The compound of formula (I) is a subgroup of formula (Ia): [Wherein, R ^{1 ′} , R ^{2 ′} , R ^{3 ′} , P ¹ , P ² , A, a ′, b ′, L, R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , J, g
And h are the same as defined in claim 1.] or a pharmaceutically acceptable salt thereof. 3. The compound is: N- [4- [2- (dimethylamino) ethyl] -3,4-dihydro-2H-1,4-
Benzoxazin-6-yl) -4-phenoxybenzamide; N- [3- [2- (diethylamino) ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide; N- [4- [2- [bis (1 -Methylethyl) amino] ethoxy] phenyl]]-4-
Phenoxybenzamide; N- [4- [2- (diethylamino) ethoxy] phenyl] -4-phenoxybenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] phenyl] -4-phenoxy N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-phenoxybenzamide; N- [3- [2- (diethylamino) ethoxy] -4- Methoxyphenyl] -3-phenoxybenzamide; N- [4- [2- [bis (1-methylethyl) amino] ethoxy] phenyl] -3-phenoxybenzamide; N- [4- [2- [bis (1- Methylethyl) amino] ethoxy] phenyl] -4- (
Phenylmethyl) benzamide; N- [2- [2- (diethylamino) ethoxy] phenyl] -4- (phenylmethyl)
N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide; N- [3- [2- [bis (1-methylethyl) Amino] ethoxy] -4-methoxyphenyl] -4- (phenylmethyl) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -2- (phenyl Methyl) thiazole-4-carboxamide hydrochloride; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide methiodide; N- [1 -[2- [bis (1-methylethyl) amino] ethyl] -1,2,3,4-tetrahydroquinol-7-yl] -4-phenoxybenzamide; N- [3- [2- [bis (1 -Methylethyl) amino] ethoxy] -4-methoxy Phenyl] -4- (3-hydroxyphenoxy) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(4-chlorophenyl) sulfinyl] -3-nitrobenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(2,4-dichlorophenyl) sulfinyl] -3-nitrobenzamide N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3-phenoxybenzamide; N- [3- [2- (2,2,6,6- Tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -3-phenoxybenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-phenoxybenzamide; N- [3- [2 -(2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-phenoxybenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-benzoylbenzamide; N- [3- [3 -[Bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-benzoylbenzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy] ]-
4-methoxyphenyl] -4-benzoylbenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (phenylmethyl) benzamide; N- [3 -[2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (phenylmethyl) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(4-chlorophenyl) sulfonyl N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-[(4-chlorophenyl) sulfonyl] benzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-[(4-chlorophenyl) sulfonyl] benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -5-butylamino- 4-phenoxy-3- (sulfamoyl) benzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -5-butylamino-4-phenoxy-3- ( Sulfamoyl) benzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -5-butylamino-4-phenoxy-3- (sulfamoyl) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4 -(4-chlorophenoxy) -3-nitrobenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (4-chlorophenoxy) -3 -Nitrobenzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (4-chlorophenoxy) -3-nitrobenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- ( 2-quinoxalinylamino) benzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (2-quinoxalinylamino) benzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (2-quinoxalinylamino) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[( 4-methylphenyl) sulfonyl] -3-nitrobenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-[(4-methylphenyl) sulfonyl ] -3-nitrobenzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-[(4-methylphenyl) sulfonyl] -3-nitrobenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl]- 3-benzoylbenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (methylphenylamino) benzamide; N- [3- [2- [ Bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylamino) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxy Phenyl] -4- (phenylthio) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylsulfonyl) benzamide; N- [3- [2- [bis (1-methylethyl ) Amino] ethoxy] -4-methoxyphenyl] -4- (phenylsulfinyl) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- [ (Hydroxyimino) phenylmethyl] benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (hydroxyphenylmethyl) benzamide; N- [1 ′ -(1-methylethyl) spiro [benzofuran-3 (2H), 4'5-piperidin] -5-yl] -4-benzoylbenzamide trifluoroacetate; N- [1 '-(1-methylethyl) spiro [Benzofuran-3 (2H), 4'5-piperidin] -5-yl] -4-phenoxybenzamide; and N- [1 '-(1-methylethyl) spiro [benzofuran-3 (2H), 4'5 -Piperidin] -5-yl]- - (phenylthio) benzamide; or is selected from a pharmaceutically acceptable salt thereof, The method of claim 1, wherein. 4. The CCR5-mediated condition is COPD, asthma and atopic disorders, rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrosis-type diseases, psoriasis, autoimmune diseases such as multiple sclerosis The method of claim 1, wherein the method is selected from inflammatory bowel disease and HIV. 5. N- [4- [2- (dimethylamino) ethyl] -3,4-dihydro-2H-1,4-
Benzoxazin-6-yl) -4-phenoxybenzamide; N- [3- [2- (diethylamino) ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide; N- [4- [2- [bis (1 -Methylethyl) amino] ethoxy] phenyl]]-4-
Phenoxybenzamide; N- [4- [2- (diethylamino) ethoxy] phenyl] -4-phenoxybenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] phenyl] -4-phenoxy N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-phenoxybenzamide; N- [3- [2- (diethylamino) ethoxy] -4- Methoxyphenyl] -3-phenoxybenzamide; N- [4- [2- [bis (1-methylethyl) amino] ethoxy] phenyl] -3-phenoxybenzamide; N- [4- [2- [bis (1- Methylethyl) amino] ethoxy] phenyl] -4- (
Phenylmethyl) benzamide; N- [2- [2- (diethylamino) ethoxy] phenyl] -4- (phenylmethyl)
N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide; N- [3- [2- [bis (1-methylethyl) Amino] ethoxy] -4-methoxyphenyl] -4- (phenylmethyl) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -2- (phenyl Methyl) thiazole-4-carboxamide hydrochloride; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-phenoxybenzamide methiodide; N- [1 -[2- [bis (1-methylethyl) amino] ethyl] -1,2,3,4-tetrahydroquinol-7-yl] -4-phenoxybenzamide; N- [3- [2- [bis (1 -Methylethyl) amino] ethoxy] -4-methoxy Phenyl] -4- (3-hydroxyphenoxy) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(4-chlorophenyl) sulfinyl] -3-nitrobenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(2,4-dichlorophenyl) sulfinyl] -3-nitrobenzamide N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3-phenoxybenzamide; N- [3- [2- (2,2,6,6- Tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -3-phenoxybenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-phenoxybenzamide; N- [3- [2 -(2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-phenoxybenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-benzoylbenzamide; N- [3- [3 -[Bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-benzoylbenzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy] ]-
4-methoxyphenyl] -4-benzoylbenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (phenylmethyl) benzamide; N- [3 -[2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (phenylmethyl) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[(4-chlorophenyl) sulfonyl N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-[(4-chlorophenyl) sulfonyl] benzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-[(4-chlorophenyl) sulfonyl] benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -5-butylamino- 4-phenoxy-3- (sulfamoyl) benzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -5-butylamino-4-phenoxy-3- ( Sulfamoyl) benzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -5-butylamino-4-phenoxy-3- (sulfamoyl) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4 -(4-chlorophenoxy) -3-nitrobenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (4-chlorophenoxy) -3 -Nitrobenzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (4-chlorophenoxy) -3-nitrobenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- ( 2-quinoxalinylamino) benzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4- (2-quinoxalinylamino) benzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4- (2-quinoxalinylamino) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4-[( 4-methylphenyl) sulfonyl] -3-nitrobenzamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -4-[(4-methylphenyl) sulfonyl ] -3-nitrobenzamide; N- [3- [2- (2,2,6,6-tetramethyl-1-piperidinyl) ethoxy]-
4-methoxyphenyl] -4-[(4-methylphenyl) sulfonyl] -3-nitrobenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl]- 3-benzoylbenzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (methylphenylamino) benzamide; N- [3- [2- [ Bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylamino) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxy Phenyl] -4- (phenylthio) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (phenylsulfonyl) benzamide; N- [3- [2- [bis (1-methylethyl ) Amino] ethoxy] -4-methoxyphenyl] -4- (phenylsulfinyl) benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- [ (Hydroxyimino) phenylmethyl] benzamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -4- (hydroxyphenylmethyl) benzamide; N- [1 ′ -(1-methylethyl) spiro [benzofuran-3 (2H), 4'5-piperidin] -5-yl] -4-benzoylbenzamide trifluoroacetate; N- [1 '-(1-methylethyl) spiro [Benzofuran-3 (2H), 4'5-piperidin] -5-yl] -4-phenoxybenzamide; and N- [1 '-(1-methylethyl) spiro [benzofuran-3 (2H), 4'5 -Piperidin] -5-yl]- - (phenylthio) formula selected from benzamide compounds of formula (I).