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CA2338764A1 - Substituted anilide compounds and methods - Google Patents

Substituted anilide compounds and methods Download PDF

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Publication number
CA2338764A1
CA2338764A1 CA002338764A CA2338764A CA2338764A1 CA 2338764 A1 CA2338764 A1 CA 2338764A1 CA 002338764 A CA002338764 A CA 002338764A CA 2338764 A CA2338764 A CA 2338764A CA 2338764 A1 CA2338764 A1 CA 2338764A1
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CA
Canada
Prior art keywords
methoxyphenyl
methylethyl
ethoxy
bis
amino
Prior art date
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Abandoned
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CA002338764A
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French (fr)
Inventor
Thomas W. Ku
William E. Bondinell
Michael J. Neeb
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SmithKline Beecham Corp
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Individual
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Publication date
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Publication of CA2338764A1 publication Critical patent/CA2338764A1/en
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Abstract

This invention relates to substituted anilide compounds which are modulators, agonists or antagonists, of the CCR5 receptor. In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5.

Description

COMPOUNDS AND METHODS
FIELD OF THE INVENTION
This invention relates to substituted anilide compounds which are modulators, agonists or antagonists, of the CC chemokine receptor CC-CKRS now designated as CCRS (Nature Medicine 1996, 2, 1174-8). In addition; this invention relates to the treatment and prevention of disease states mediated by CCRS.
BACKGROUND OF THE INVENTION
T cells are not only key regulators of the immune response to infectious agents but are believed critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases. Increased numbers or enhanced activation state of T cells, especially CD4+ T cells, have been demonstrated in the synovium of individuals with rheumatoid arthritis (M.J.
Elliott and R. N. Maini, Int. Arch. Allergy Immunol 104: 112-1125, 1994), in the bronchial mucosa of asthmatics (C.J. Corrigan and A.B. Kay, Immunol. Todav 13:501-506, 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarIand, Crit. Rev.
Clin. Lab. Sci. 32: 121-182, 1995), in psoriatic lesions (J.L. Jones, J. Berth-Jone, A.
Fletcher and P.E. Hutchinson, J. Pathol. 174: 77-82, 1994) and in the fatty streaks of atherosclerosis (R. Ross, Annu. Rev. Physiol. 57: 791-804, 1995).
T cells, as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors. Among these factors are a superfamily of 8-12 kDa proteins known as the chemokines. These proteins share structural features such as the presence of 3-4 conserved cysteine residues.
RAIVTES, which stands for Regulated upon Activation Normal T cell Expressed and Secreted, is an 8 kDa protein member of CC branch of the chemokine family.
These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors. The CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues and members of this family predominately elicit the migration of mononuclear cells, eosinophils and basophils (M. Baggiolini, B. Dewald, and B. Moser, Adv. Immunol. 55: 97-179, 1994; and J.J. Oppenheim, C.O.C. Zachariae, N. Mukaida, and K. Matsushima, Annu. Rev. Immunol. 9: 617-648, 1991).
RANTES potently produces chemotaxis of T cells, basophils, eosinophils, monocytes and mast cells. RANT'ES was originally identified as gene product induced late after antigen activation of T-cells (T.J. Schall, J. Jongstra, B.J. Dyer, J.
Jorgensen, et al., J. Immunol. 141:1018-1025, 1988), however, RAIVTES has been shown to be synthesized and secreted by a diverse group of cells that include SUBSTITUTE SHEET (RULE 26) epithelial and endothelial cells (C. Stellato, L.A. Beck, G.A. Gorgone, D.
Proud, et al., J. Immunol. 155: 410-418, 1995; and A. Marfaing-Koka, O. Devergne, G.
Gorgone, A. Portier, et al., J. Immunol. 154: 1870-1878, 1994), synovial fibroblasts (P. Rathanaswami, M. Hachicha, M. Sadick, T.J. Schall, et al., J. Biol. Chem.
268:
5834-5839, 1993) and dermal fibroblasts (M. Sticherling, M. Kupper, F.
Koltrowitz, E. Bornscheuer, et al., J. Invest. Dermatol. 105: 585-591, 1995), mesangial cells (G.
Wolf, S. Aberle, F. Thaiss, et al., Kidney Int. 44: 795-804, 1994) and platelets (Y.
Koameyoshi, A. Dorschner, A.I. Mallet, E. Christophers, et al., J. Exp. Med.
176:
587-592, 1992). In these cells RANTES mRNA is rapidly upregulated in response to IL-1 or TNF~. Although RANTES mRNA is not usually detected in normal tissues (J.M. Patdson, P.J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995), increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate. For example, RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J.M. Pattison, P.J.
Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995; and K.C. Nadeau, H. Azuma and N.I. Tilney, Proc. Natl. Acad. USA 92: 8729-8733, 1995) in the skin of atopic dermatitis patients after exposure to antigen (S. Ying, L. Taborda-Barata, Q.
Meng, M. Humbert, et al., J. Exp. Med. 181: 2153-2159, 1995), and in endothelial cells of coronary arteries undergoing accelerated atherosclerosis after cardiac transplant (J.M. Pattison, P.J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995).
Further, increased immunoreactive protein for RAN'TES has been detected in bronchoalveolar lavage fluid (R. Alam, J. York, M. Boyers, et al., Am. J.
Resp. Crit.
Care Med. 149: A95I, 1994) and sputum from asthmatic individuals (C.M. Gelder, P.S. Thomas, D.H. Yates, LM. Adcock, et al., Thorax 50: 1033-1037, 1995).
Several receptors have been identified that bind RAIV'I'ES. In particular, CCRS, when expressed in either HEK 293 cells or CHO cells, binds RAN'TES. This receptor is expressed in T-cells and in monocytes and macrophages, immune/inflammatory cells which are important in the maintenance of a chronic inflammatory reaction. Pharmacological characterization of CCRS indicates similarities to the RANTES binding site observed on isolated T cells.
Therefore, antagonism of RAN1'ES' action on CCRS, as well as antagonism of other natural modulators of CCRS, should inhibit the recruitment and activation of T cells and macrophages into inflammatory lesions and provide a novel therapeutic approach for the treatment of atopic and autoimmune disorders.
Since T cells and macrophages express CCRS, selective receptor modulators of CCRS, particularly antagonists, are likely to provide beneficial effects in diseases including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, SUBSTITUTE SHEET (RULE 26) atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, preferably humans. Furthermore, since CD8+ T cells and macrophages have been implicated in COPD, CCRS may play a role in their recruitment and therefore antagonists to CCRS could provide potential therapeutic in the treatment of COPD. Also, since CCRS is a co-receptor for the entry of HIV into cells, selective receptor modulators may be useful in the treatment of HIV infection.
Surprisingly, it has now been discovered that this class of non-peptide compounds, in particular substituted anilide compounds of this invention, function as CCRS receptor modulators, and therefore, have utility in the treatment and prevention of disease states mediated by CCRS receptor mechanisms.
SUMMARY OF THE INVENTION
In one aspect, the present invention is to novel compounds of formula (1), or pharmaceutically active salts thereof, and their novel use in treating the above-mentioned CCRS-mediated disease states:
(R~a, (R~b~
P2 A P~ L-~
Formula I
wherein:
the basic nitrogen in moiety E may be optionally quaternized with C 1 _6alkyl or is optionally present as the N-oxide;
P1 and P2 are independently phenyl, fused bicyclic aryl, a monocyclic heterocyclic ring of 5- to 7-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or a fused bicyclic heterocyclic ring of 8 to 11-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
A is C(R4 j2, CR4 (ORS'), CO, C=NORS', NR~', oxygen, or S(O)c ;
L is a group of formula -C(=V)-DR8'-, -DR9'-C(=V)-, -CH2NH-, or -NHCH2-;
V is oxygen or sulfur;
D is nitrogen, carbon, or a CH group, R 1 ~ and R2' are independently hydrogen, C 1-6alkyl, C2-6alkenyl, C2_ galkynyl, C3-~cycloalkyl, C3_~cycloalkenyl, aryl, (CH2)d'NR10~R11'~
(CH2)d'NR IO~COR 12~, (CH2)d'NR 10~C02R 13', (CH2)d'NR 1 O~S02R 14~, SUBSTITUTE SHEET (RULE 26) (CH2)d~CONR 15'R 16', hydroxyC 1 _6alkyl, C 1 ~alkoxyalkyl (optionally substituted by a Cl~alkoxy or hydroxy group), (CH2)d~C02C1-6~Y1~ (CH2)e~OC(O)R17;
CR 18 =NOR 19'. CNR20'--NOR 19', COR21', CONR 15'R 16', CONR 15 (CH2) flOC 1 _ 4alkyl, CONR15'(CH2)d~C02R22', CONHNR23 R24', CONR15'S02R25', C02R26', cyano, trifluoromethyl, NR 10'R 11'~ NR 10 COR 12'~
NR27 CO(CH2)d~NR27'R28 ; NR27'CONR27'R2g', NR10'C02R13 ;
~ 10'S02R 14', N=CNR271VR27'R28', vitro, hydroxy, C 1 _6alkoxy, hydroxyC 1 _ 6alkoxy, C1_6alkoxyCl_6alkoxy, OC(O)NR29R30', SR31', SOR32; S02R32', S02NR33'R34', halogen, C1_6alkanoyl, C02(CH2)d~OR35 ; or R1' is an optionally substituted S to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;
R3'is hydrogen, Cl_6alkyl, C3_6cycloalkyl, C3_6cycloalkenyl, hydroxyCl_ 6~kYl. C1-6alkYlOC1_6alkyl, CONR36'R37', C02R38', cyano, aryl, trifluoromethyl, NR39'R40', vitro, hydroxy, C 1 _6alkoxy, C 1 _6alkanoyl, acyloxy, or halogen;
R4', RS'~ R6'~ R7'~ R 18'~ R 19'~ R20'~ R21 ~ R22'~ R23'~ R24'~ R27 ~ R28'~
R31', R35 ~ R36'~ R37 ~ R38 ~ R39 ~ ~d R40' ~ independently hydrogen or C1_6alkyl;
R8' is hydrogen or C1_6aikyl, providing that D is nitrogen or a CH group;
R9' is hydrogen or C 1 _6alkyl, providing that D is nitrogen or a CH group;
R 10' and R 11' are independently hydrogen or C 1 _6alkyl, or R 10' and R 11' together with the nitrogen to which they are attached, foams a 5- to 6-membered heterocyclic ring, which may optionally be substituted by an oxo group, and, when there are six members, may optionally contain in the ring one oxygen or one sulfur atom;
R 12' is hydrogen, C 1 _6alkyl, or C 1 ~alkoxyalkyl;
R 13'~ R25 ~ ~d R32' ~ independently C 1 _6alkyl;
R 14' is C 1 _6alkyl or phenyl;
R 15' and R 16' are independently hydrogen or C 1 _balkyl, or R 15' and R 16' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when there are 6 ring members, may optionally contain in the ring one oxygen or one sulfur atom;
R 17' is C 1-4alkyl, optionally substituted by C 1 _6alkoxy;
R26' is hydrogen or C 1 _6alkyl optionally substituted with one or two substituents selected from C 1 _6alkyl, C 1 _6alkoxy, hydroxy, or NR 10~ 11'~
R29' and R30' are independently hydrogen or C 1 _6alkyl, or R29' and R30' together with the nitrogen to which they are attached form a 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom;
SUBSTITUTE SHEET (RULE 26) R33' and R34' are independently hydrogen or C 1 _6alkyl, or R33' and R34' together with the nitrogen to which they are attached form 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring 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;
f is 1, 2, or 3;
E represents (a):
B- (CR~Rz)s -NR3R4 Re (a);
in which B is oxygen, S(O)c, CR7=CRB, or CR7R8, or B is NR9;
R 1 and R2 are independently hydrogen or C 1 _6alkyl; alternatively B(CR 1 R2)a is OCR 1 R2CR 1 (OH)CR 1 R2 or OCR 1 R2CR 1 (OCOCH3)CR 1 R2;
R3 and R4 are independently hydrogen, C 1 _6alkyl, C3_~cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C 1 _6alkyl, aryl, CONR 1 OR 11 ~ ~ l OR 11 ~ hy~xy, OCOR 12, NHCOCO_ 6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHS02R 13, and NHC02R 14;
RS is hydrogen, C 1 _6alkyl, aryl, CN, CONR 1 SR 16, C02R 17~
trifluoromethyl, NHC02R 18, hydroxy, C 1 _6alkoxy, benzyloxy, OCH2C02C 1 _ 6alkyl, OCF3, S(O)dRl9, S02NR20R21 or halogen;
R6 is hydrogen, C 1 _6alkyl, aryl, trifluoromethyl, hydroxy, C 1 _6alkoxy or halogen, or R6 taken together with R8' forms a group D where D is (CR22R23)e or D is (CR22R23) f G where G is oxygen, sulfur or CR22=CR23, CR22=N, =CR220, =CR22S, or =CR22_NR23;
R7, R8, R 10, R 11, R 12, R 1 S, R 16, R 17, R20, R21, R22, and R23 are independently hydrogen or C 1 _6alkyl;
R9 is hydrogen, C 1 _6alkyl, or phenylC 1 _6alkyl;
R 13 ~ R 14~ R 18~ ~d R 19 ~ independently C 1 _6alkyl;
a is 1, 2, 3, or 4;
b is 1 or 2;
SUBSTITUTE SHEET (RULE 26) c and d are independently 0, 1 or 2;
a is 2, 3 or 4;
fis0, l,2or3;
alternatively, E represents (b):
R~R~C~
R28R2'C NR~
i (CR24R~)9 J
(b);
R24~ R25~ R26~ R27~ R28~ R29~ R31 ~ ~d R32 ~.e independently hydrogen or c 1 _6alkyl;
R30 is hydrogen, C1_6alkyl, or C3_7cycloalkyl;
R33 is hydrogen, C1_6alkyl, trifluoromethyl, hydroxy, or halogen, or R33 and R8' together form a group -K- where K is (CR34R35)i or K is (CR34R35)j _M
and M is oxygen, sulfur, CR34=CR35, CR34=N, or N=N;
J is oxygen, CR36R37, or NR38, or J is a group S(O)k;
R34~ R35~ R36~ R37~ ~d R38 ~ independently hydrogen or C1_6allcyl;
g is 1, 2 or 3;
h is 1, 2 or 3;
i is 2, 3, or 4;
j is 0, 1, 2, or 3;
k is 0, 1 or 2;
alternatively, E represents (c):
p- (CR3sRoo)i R4~
(R'~m R'~ (c);
in which:
Q is oxygen, S(O)n, CRS=CR45, CR'~R45, or Q is NR46;
R39 and R40 are independently hydrogen or C 1 _6alkyl;
R41 is a group of formula (d):
(C~"~2)0 (CH2)P (CH2)q N (d) or R41 is a group of formula (e):
SUBSTITUTE SHEET (RULE 26) ~~CH2)~
~..N
R4~ (e) R42 is hydrogen, CI_6alkyl, aryl, CN, CONR48R49, C02R50, trifluoromethyl, NHC02R51, hydroxy, C 1 _6alkoxy, benzyloxy, OCH2C02C 1 _ 6alkyl, OCF3, S(O)sR52, S02NR53R54, or halogen;
R43 is hydrogen or R43 together with R8' forms a group R where R is CR55=CR56, CRSS=CR56CRSSR56, or (CRSSR56)t;
R44, R45, R46~ R48~ R49, R50~ R53~ R54~ R55~ ~d R56 ~ independently hydrogen or C 1 _6alkyl;
R47 is hydrogen, C1_6alkyl, or C3_7 cycloallcyl;
RS 1 and R52 are independently C 1 _6alkyl;
lis0, 1,2,or3;
m is I or 2;
nis0, l,or2 o, p, and q are independently integers having the value 1, 2, or 3;
r is 0,1, 2, or 3;
sis0, l,or2;
tis2or3;
alternatively, E represents (f):
W-~CRs~Rse)~ NR~R~
/ O
T
R57 and R58 are independently hydrogen or C 1 _6alkyl;
R59 and R60 are independently hydrogen, C 1 _6alkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C 1 _6alkyl, aryl, CONR61 R62~ NR61 R62~ hydroxy, OCOR63, NHCOCO_6alkyI where alkyl is optionally substituted by OH, NHCOCF3, NHS02R64, and NHC02R65;
T is -(CR66R67)v_ or -O(CR66R67)w_~
W is oxygen, S(O)x, NR68, or W is CR69=CR70 or CR69R70;
R6I, R62, R63~ R66, R67 R68~ R69~ ~d R70 ~.e independently hydrogen or C 1 _6alkyl;
R64 and R65 are independently C 1 _6alkyl;
a is 1 to 4;
SUBSTITUTE SHEET (RULE 26) vis2or3;
wis 1,2,or3;
x is 0, 1 or 2;
alternatively, E represents a group (g):
R~~
w (R~)'' (g):
R71 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 R71 is an optionally substituted 6,6 or 6,5 bicyclic ring containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulfur;
R72 is hydrogen, C 1 _6alkyl, aryl, CN, CONR74R75, C02R76, trifluoromethyl, NHC02R77, hydroxy, C 1 _6alkoxy, benzyloxy, OCH2C02C 1 _ 6~k3'1~ 0~3~ S(O)zR78~ S02NR79R80~ or halogen;
R73 is hydrogen, C 1 _6alkyl, hydroxy, C 1 _6allcoxy or halogen, or R73 and R8'taken together from a group -X- where X is (CR81R82)~ or X is (CR81R82)ab' Y and Y is oxygen, sulfur or CR81=CR82;
R74, R75, R76, R79, R80, R81, and R82 are independently hydrogen or C 1 6~Y1:
R77 and R78are independently C 1 _6alkyl;
y is 1 or 2;
z is 0, 1, or 2;
as is 2, 3 or 4;
abis0, l,2or3;
alternatively, E represents group (h):
Z (CR~R~)8~- NR~R~
Rep (h)~
R83 and R84 are independently hydrogen or C 1 _6alkyl;
R85 and R86 are independently hydrogen, C 1 _6alkyl, Cg_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include Cl_6alkyl, aryl, CONR88R89, NR90R91, hy~oxy, OCOR92, NHCOCp_6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHS02R93, and NHC02R94;
SUBSTITUTE SHEET (RULE 26) WO 00/0614b PC'T/US99/17121 R8~ is hydrogen or C I _6alkyl, C I _6alkoxy, or halogen, or R8~ together with R8' forms a group -AA- where AA is (CR95R96)ad or AA is (CR95=CR96)ae-AB
and AB is oxygen, sulfur, CR95=CR96, CR95=N, CR95NR96 or N=N;
Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
R88, R89, R90, R91 ~ R92~ R95, ~d R96 ~.e independently hydrogen or C 1 _ 6~k3'l~
R93 and R94 are independently C 1 _6alkyl;
acisOto4;
ad is l, 2 or 3;
ae is 0, 1 or 2;
alternatively, E represents group (i):
(CH2)efNR~R~
i (CH2)8A
/ \A~(CR~R'oo)ah R~o~
(i);
R9~ and R98 are independently hydrogen, C1_6alkyl, C3_~cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocycIic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C 1 _6alkyl, aryl, CONR 1028103 ~ Ng 1048105 hy~xy, OCOR I ~, NHCOCO_balkyl where alkyl is optionally substituted by OH, NHCOCF3, NHS02 R10~, and NHC02RI08;
R99 and R I ~ are independently hydrogen or C 1 _6alkyl;
R 101 is hydrogen or C I _6alkyl or R I01 and R8' together form a group -AD-where AD is (CRI09R110)~ or AD is (CRI~RI10)aj_AE and AE is oxygen, sulfur or CR I I~=CR I 10;
AC is oxygen, CR I 1 I R 112 or NR I I3 or AC is a group S(O)S;
R102~ R103~ R104~ R105~ R106~ R109~ RI10~ R111~ R112~ ~d R113 ~.e independently hydrogen or C 1 _6alkyl;
R I0~ and R I08 are independently C 1 _6alkyl;
of is 0, 1, 2, 3, or 4;
ag is I, 2, or 3;
ah is I, 2, 3 or 4;
ai is 2, 3 or 4;
aj is 0, 1, 2, or 3; and ak is 0, 1 or 2.
SUBSTITUTE SHEET (RULE 26) In another aspect, the present invention is to a method of treating CCRS
mediated disease states, including, but not limited to, COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease and HIV infection, all in mammals, preferably humans, comprising administering to such mammal in need thereof, a anilide of formula (I), or pharmaceutically active salts thereof.
In yet another aspect, the present invention is to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier therefor.
In particular, the pharmaceutical compositions of the present invention are used for treating CCRS-mediated disease states, including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, COPD and HIV all in mammals, preferably 1 S humans.
DETAILED DESCRIPTION OF THE INVENTION
It has now been discovered that substituted anilides of formula (I) are CCRS
receptor modulators. It has also now been discovered that selective inhibition of CCRS
receptor mechanisms by treatment with the receptor modulators of formula (1), or a pharmaceutically acceptable salt thereof, represents a novel therapeutic and preventative approach to the treatment of a variety of disease states, including, but not limited to, COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, preferably humans ("CCRS-mediated diseases"). Also, since CCRS is a co-receptor for the entry of HIV into cells, selective receptor modulators may be useful in the treatment of HIV infection.
The term "alkyl" is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
The terms "cycloalkyl" and "cyclic alkyl" are used herein at all occurrences to mean cyclic radicals, preferably comprising 3 to 7 carbon atoms which may be mono-or bicyclo-fused ring systems which may additionally include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.
The terms "halo" or "halogen" are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
SUBSTITUTE SHEET (RULE 26) The term "heterocyclic ring" is used herein at all occurrences to mean a saturated or partially saturated 5-, 6-, or 7-membered ring system (unless the cyclic ring system is otherwise limited) in which the ring system contains one to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which ring system may be optionally substituted with Cl_ S 6alkyl or C3_~cycloalkyl. Examples of such rings include, but are not limited to, piperidine, tetrahydropyridine, and piperazine. When the heterocyclic ring is fused to a phenyl group, the term "heterocyclic ring", together with the phenyl ring to which it is fused, forms a ring which includes, but is not limited to, dihydro-1,4-benzoxazine and 1,2,3,4-tetrahydroquinoline, which may be optionally substituted by Cl_6alkyl or oxo.
The term "6,6 or 6,5 bicyclic ring" means a 6,6 or 6,5-bicyclic ring system containing a nitrogen atom and optionally a further heteroatom selected from nitrogen, oxygen, or sulfur, which ring system may be optionally substituted with C 1 _6alkyl.
Examples of such ring systems include, but are not limited to, tropane, isoquinuclidine and granatane rings.
The term "CCRS mediated disease state" is used herein at all occurrences to mean any disease state which is mediated (or modulated) by CCRS.
The term "monocyclic heterocyclic ring" is used herein at all occurrences to mean a single aromatic ring of S to 7 members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur represented by P 1 and/or P2 including thienyl, furyl, pyrrolyi, and pyridyl.
The term "fused bicyclic heterocyclic ring" is used herein at all occurrences to mean a fused bicyclic ring system of $ to 11 members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur including indole, benzofuran, benzothiophene, quinoline, and isoquinoline rings.
Suitably, pharmaceutically acceptable salts of formula (I) include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate, and stearate.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. The stereocenters may be of any combination of R and S configuration, for example, (R,R), (R,S), (S,S) or (S,R).
All of these compounds are within the scope of the present invention.

SUBSTITUTE SHEET (RULE 26) WO 00/06146 PCTlUS99/17121 For the compounds of formula (I) various embodiments are as follows. It will be understood that the basic nitrogen in moiety E may be optionally quaternized with C1_ 6alkyl or is optionally present as the N-oxide.
P1 and P2 are suitably independently phenyl, fused bicyclic aryl, a monocyclic heterocyclic ring of S- to 7-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or a fused bicyclic heterocyclic ring of 8 to 11-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur. Preferably, P 1 is phenyl and P2 is phenl or quinoxalinyl. More preferably P 1 and P2 are phenyl.
When R 1' is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, suitable heterocyclic rings include aromatic groups such as thienyl, furyl, pyrrolyl, triazolyl, 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, in particular rings including an oxo or thioxo moiety such as lactams and thiolactams. Suitably, the heterocyclic ring can be linked to the remainder of the molecule via a carbon atom, or, when present, a nitrogen atom. Suitable substituents for these rings include one to two of R3'.
A is C(R4 j2, CR4'(ORS'), CO, C=NOR6', NR~', oxygen, or S(O)c'.
Preferably A is C(R4')2, CO, C=NORS', NR~', oxygen, or sulfur. More preferably, A is CH2, CO, C=NOH, oxygen or sulfur. Most preferably, A is CH2, CO, oxygen or sulfur. Preferably, A is attached to P 1 meta or para to L, more preferably, A is attached to P 1 para to L.
L is suitably a group of formula -C(=V)-DR8 =, -DR9'-C(=V)-, -CH2NH-, or -NHCH2-. L is preferably -C(=V)-DR8'-.
V is suitably oxygen or sulfur. V is preferably oxygen.
D is suitably nitrogen, carbon or a CH group. D is preferably nitrogen.
R 1' and R2' are suitably independently hydrogen, C 1 _6alkyl, C2_6alkenyl, C2_6alkynyl, C3_~cycloalkyl, C3_~cycloalkenyl, aryl, (CH2)d'NR10'R11'~
(CH2)d'NR 10'COR 12'~ (CH2)d'NR 10'C02R 13'. (CH2)d'NR 10~S02R 14'~
(CH2)d'CONR 15'R 16', hydroxyC 1 _6alkyl, C 1 ~,alkoxyalkyl (optionally substituted by a C 1 ~alkoxy or hydroxy group), (CH2)d'C02C 1 _6alkyl, (CH2)e'OC(O)R 1 ~', CR 18'=NOR 19', CNR20'=NOR 19', COR21', CONR 15'R 16', CONR 15'(CH2)pOC 1 _ 4alkyl, CONR15'(CH2)d'C02R22', CONHNR23'R24', CONR15'S02R25', C02R26', cyano, trifluoromethyl, NR10'Rl 1'~ NR10'COR12'~
NR2~'CO(CH2)d'NR2~'R2$', NR2~'CONR2~'R28', NR10'C02R13', NR 10'S02R 14', N=CNR2~'NR2~'R28', nitro, hydroxy, C 1 _6aikoxy, hydroxyC 1 _ 6alkoxy, C1_6alkoxyCl_6alkoxy, OC(O)NR29'R30', SR31', SOR32', S02R32', SUBSTITUTE SHEET (RULE 26) S02NR33'R34'~ h~ogen, CI_6alkanoyl, C02(CH2)d~OR35', or RI' is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur. R I' and R2' are preferably hydrogen, C I
_6alkyl, hydroxy, or halogen.
R3' is suitably hydrogen, C 1 _6alkyl, C3_6cycloalkyl, C3_6cycloalkenyl, hydroxyC I _6alkyl, C I _6a1ky10C I _6allcyl, CONR36~t37', C02R38'~ cy~o~ ~.yh trifluoromethyl, NR39'R40', vitro, hydroxy, C I _6alkoxy, C I _6alkanoyl, acyloxy, or halogen. R3' is preferably hydrogen, vitro, sulfamoyl or C I _6alkylamino.
R4'~ RS ~ R6'~ R7'~ R 18'~ R 19'~ R20'~ R21'~ R22'~ R23 ~ R24'. R27', R28'~ R3 I' R35', R36 ; R37'~ R38 ~ R39', ~d R40' ~ suitably independently hydrogen or C
1_ 6alkyl;
R8' is suitably hydrogen or C I _6alkyl, providing that D is nitrogen or a CH
group. R8' is preferably hydrogen.
R9' is suitably hydrogen or C I _6alkyl, providing that D is nitrogen or a CH
I S group.
RIO' and RI I' are suitably independently hydrogen or Cl_6alkyl, or RIO' and R I I' together with the nitrogen to which they are attached, forms a 5- to 6-membered heterocyclic ring, which may optionally be substituted by an oxo group, and, when there are six members, may optionally contain in the ring one oxygen or one sulfur atom.
R I2' is suitably hydrogen, C 1 _6alkyl, or C I ~alkoxyallryl.
R I 3 ~ R25'~ ~d R32' ~ suitably independently C I _6alkyl.
R I4' is suitably C I _6alkyl or phenyl.
R I 5' and R I 6' are suitably independently hydrogen or C I _6alkyl, or R I
5' and R I6' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when there are 6 ring members, may optionally contain in the ring one oxygen or one sulfur atom.
. . RITis suitably CI''Ialkyl, optionally substituted by C1_6alkoxy.
R26' is suitably hydrogen or C I _6alkyl optionally substituted with one or two substituents selected from C I _6alkyl, C I _6alkoxy, hydroxy, or NR I0'R I
1', R29' and R30' are suitably independently hydrogen or C I _6alkyl, or R29' and R30' together with the nitrogen to which they are attached form a 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom.
R33' and R34' are suitably independently hydrogen or C I _6alkyl, or R33' and R34' together with the nitrogen to which they are attached form 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom.

SUBSTITUTE SHEET (RULE Z6) 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.
S f is suitably 1, 2, or 3.
E suitably represents (a):
B- (CR~R2)a-NR3R4 ~R5~b R~
(a);
in which B is suitably oxygen, S(O)c, CRS=CR8~ or CR~Rg, or B is NR9. B is preferably CR~R8, or oxygen. More preferably, B is CH2 or oxygen.
R1 and R2 are suitably independently hydrogen or C1-6alkyl; alternatively B(CR 1 R2)a is OCR 1 R2CR 1 (OH)CR 1 R2 or OCR 1 R2CR 1 (OCOCH3)CR 1 R2.
Preferably, R 1 and R2 are hydrogen.
R3 and R4 are suitably independently hydrogen, C1_6alkyl, C3-~cycloalkyl, 1 S aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted S- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C 1 alkyl, aryl, CONR 1 OR 11 ~ NR l OR 11 ~ hy~xy, OCOR
12, NHCOCO_6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHS02 R 13, and NHC02R 14. Preferably R3 and R4 are both C 1 _6alkyl, or together with the nitrogen atom to which they are attached form an optionally substituted S-to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur. More preferably, R3 and R4 are C3_6alkyl, or together with the nitrogen to which they are attached form a 6-membered ring, 2S optionally substituted with one or more of C 1 _6alkyl, N-acetarnido, or hydroxy.
Most preferably, R3 and R4 are isopropyl or R3 is isopropyl and R4 is tert-butyl, or together with the nitrogen to which they are attached are 1-(2,2,6,6-tetramethylpiperidinyl), 1-(4-acetamido-2,2,6,6-tetramethylpiperidinyl), 1-(4-hydroxy-2,2,6,6-tetramethylpiperidinyl), or 1-(4-hydroxy-2,2,4,6,6-pentamethylpiperidinyl).
Preferably, B-(CR 1 R2)a-NR3R4 is ortho to RS, meta to L, and para to R6, and RS is para to L.
RS is suitably hydrogen, C 1 _6alkyl, aryl, CN, CONR 1 SR 16, C02R 1 ~, trifluoromethyl, NHC02R 1 g, hydroxy, C 1 _6alkoxy, benzyloxy, OCH2C02C 1 _ 3S 6alkyl, OCF3, S(O)dRl9, S02NR20R21~ or halogen. RS is preferably C1_6alkoxy, SUBSTITUTE SHEET (RULE 26) SC 1 _6alkyl, or halogen; more preferably methoxy, methylthio, or iodo, most preferably methoxy. When RS is methoxy, it is preferably para to L.
R6 is suitably hydrogen, C 1 _6alkyl, aryl, trifluoromethyl, hydroxy, C 1 _ 6alkoxy, or halogen, or R6 taken together with R8' forms a group D where D is (CR22R23)e or D is (CR22R23) f G where G is oxygen, sulfur, or CR22=CR23, CR22=N, =CR220, =CR22S, or =CR22_~23, preferably, R6 is hydrogen.
R7~ R8~ R10~ R11, R15, R16~ R17, R20, R21~ R22, and R23 are independently hydrogen or C 1 _6alkyl.
R9 is hydrogen, C 1 _6alkyl, or phenylC 1 _6alkyl.
R 12, R 13, R 14~ R 18~ ~d R 19 ~.e independently C 1 _6alkyl.
a is suitably 1, 2, 3, or 4. Preferably, a is 2 or 3, more preferably, a is 2 or 3 when B is oxygen and a is 2 when B is CH2, most preferably, a is 2 when B is oxygen.
b is suitably 1 or 2. Preferably, b is 1.
c and d are suitably independently 0, 1, or 2.
a is suitably 2, 3, or 4.
f is suitably 0, 1, 2, or 3.
alternatively, E suitably represents (b):
R~R~C~
R~Rz'C NR~
i \ -(CR24R~)o ,( J
Rte, R25, R26, R27~ R28~ R29~ R31 ~ ~d R32 ~ suitably independently hydrogen or C1_6alkyl. R24, R25, R26, R27, R28, R29, R31, and R32 are preferably hydrogen.
R30 is suitably hydrogen, C1_6alkyl, or C3_7cycloalkyl. Preferably, R30 is C1_6alkyl, more preferably, R30 is C3_6alkyl, most preferably, R30 is isopropyl.
R33 is suitably hydrogen, C 1 _6alkyl, trifluoromethyl, hydroxy, or halogen, or R33 and R8' together form a group -K- where K is (CR34R35)i or K is (CR34R35)j _M and M is oxygen, sulfur, CR34=CR35, CR34=N, or N=N.
Preferably, R33 is hydrogen.
J is suitably oxygen, CR36R37, or NR38, or J is a group S(O)k, Preferably, J is oxygen. Preferably, J is para to L.
R34~ R35~ R36, R37~ R38 ~.e suitably independently hydrogen or C1_6alkyl.
g is suitably 1, 2, or 3. Preferably, g is 2 or 3, more preferably 2.
h is suitably 1, 2, or 3. Preferably, h is 1.
i is suitably 2, 3, or 4.
j is suitably 0, 1, 2, or 3.
SUBSTITUTE SHEET (RULE 16) k is suitably 0, 1 or 2.
Known compounds overlapping with the scope of the instant invention are as follows.
A subgenus of formula (I) wherein: the basic nitrogen in moiety E may be optionally quatennized with C 1 _6alkyl or is optionally present as the N-oxide; E is (b); J is CH2; g is 1, 2, or 3; h is 1, 2, or 3; R24, R25, R26~ R27~ R28~ R29~
R31 ~ ~d R32 are hydrogen; R30 is hydrogen or C 1 _6alkyl; R33 is hydrogen, C 1 _6alkyl, trifluoromethyl, or halogen; L is CONRB' or NR9'CO; R8' and R9' are independently hydrogen or C 1 _6alkyl; P 1 and P2 are phenyl; A is CO, O or S(O)0_2; R 1' is hydrogen; R2' is hydrogen or 1, 2, or 3 of hydroxy, C 1 _3alkyl, cyano, halogen, or trifluoromethyl; R3' is hydrogen or 1 or 2 of hydroxy, cyano, halogen, trifluoromethyl, CONR36*R37*, COC1_SalkYl, C02R38*, C1_6alkoxy, or phenyl;
and R36*, R37*, and R38* are independently hydrogen or C1_6alkyl, has been described in WO 98/25604, published 18 June 1998, as chemokine receptor modulators.
Further, a subgenus of formula (I) wherein: the basic nitrogen in moiety E
may be optionally quaternized with C 1 _6alkyl or is optionally present as the N-oxide; E is (b); J is CH2~ g is 1, 2, or 3; h is 1, 2, or 3; R24, R25~ R26~
R27~ R28 R29~ R31~ ~d R32 ~ hy~.ogen; R30 is hydrogen or C1_6alkyl; R33 is hydrogen, C 1 _6allcyl, trifluoromethyl, or halogen; L is CH2NH; P 1 is heteroaryl, wherein heteroaryl is selected from the group consisting of benzimidazolyl, benzofuranyl, benzooxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl; A is CO, O or S(O)~2; P2 is phenyl; R1 * is hydrogen or one of hydroxy, cyano, halogen, trifluoromethyl, NR10*COR12*, NR10*C02R13*, NR27*CONHR28*, NHS(O)p_2R14*, CONR15*R16*, COC1_ S~YI~ CO2R26*, Cl_6alkoxy, SR31*, SOR32*, S02R32*, or phenyl, or R1* is an optionally substituted heterocyclic ring selected from furanyl, imidazoiyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl; R2* is hydrogen or l, or 2 of hydroxy, cyano, halogen, trifluoromethyl, NR10*COR12*, NR10*C02R13*, NR27*CONHR28*, NHS(O)0_2R14*, CONR15*R16*, COC1_ Salkyl, C02R26*, C1_6alkoxy, SR31*, SOR32*, S02R32*, or phenyl; R3' is hydrogen or 1 or 2 of hydroxy, cyano, halogen, trifluoromethyl, CONR36*R37*~
COC1_Salkyl, C02R38*, C1_6alkoxy, or phenyl; R10*, R12*~ R15*~ R16*~ R27*~
R28*, R31*~ R36*, R37*, ~d R38* ~ independently hydrogen or Cl_6alkyl; R13*
and R32* are independently C 1 _6alkyl; R 14* is C 1_6alkyl or phenyl; and R26* is hydrogen or C1_6alkyl optionally substituted with one or two of hydroxy, has been SUBSTITUTE SHEET (RULE 26) described in WO 98/25604, published 18 June 1998, as chemokine receptor modulators.
A preferred subgenus of the compounds of formula (I) are compounds of formula (Ia) in which R 1', R2', R3', p 1, P2, A, a ; b', L, R24, R25~ R26, R27, R28, R29, R30, R31~ R32~ R33~ J, g~ ~d h are defined as above:
(R2~'~ (R37b~ R~R~C~C\NR~
(CR24R2s)a ~CR3~ R~)h J
R~
Formula (Ia) Among the preferred compounds of the 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( I-methylethyl)amino]ethoxy]phenyl]-4-phenoxybenzamide;
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)benzamide;
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-(phenylmethyl)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;

SUBSTITUTE SHEET (RULE Z6) N-[3-[2-[Bis( 1-methylethyI)amino)ethoxy)-4-methoxyphenylJ-4-(3-hydroxyphenoxy)benzamide;
N-[3-[2-[Bis( 1-methylethyl)amino]ethoxy)-4-methoxyphenyl]-4-[(4-chlorophenyl)sulfinyl ]-3-nitrobenzamide;
N-j3-[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]ethoxyJ-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)aminoJpropyl]-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]benzamide;
N-[3-j3-[Bis( 1-methyiethyl)amino]propylJ-4-methoxyphenylJ-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)aminoJethoxy]-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-methoxyphenylJ-5-butylamino-4-phenoxy-3-(sulfamoyl)benzamide;
N-[3-[2-[Bis( 1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(4-chlorophenoxy)-3-nitrobenzamide;

SUBSTITUTE SHEET (RULE 26) N-[3-[3-[Bis( 1-methylethyl)aminoJpropyl]-4-methoxyphenylJ-4-(4-chlorophenoxy)-3-nitrobenzamide;
N-[3-(2-(2,2,6,6-Tetramethyl-1-piperidinyl)ethoxyJ-4-methoxyphenylJ-4-(4-chlorophenoxy)-3-nitrobenzamide;
N-[3-[2-[Bis( 1-methylethyl)aminoJethoxy]-4-methoxyphenyl]-4-(2-quinoxalinylamino)benzamide;
N-[3-[3-[Bis( 1-methylethyl)amino]propyl]-4-methoxyphenylJ-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-methoxyphenylJ-4-[(4-methylphenyl)sulfonyl]-3-nitrobenzanude;
1S 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)aminoJethoxyJ-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-methoxyphenylJ-4-(phenylamino)benzamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxyJ-4.-methoxyphenyl]-4-(phenylthio)benzamide;
2S N-[3-[2-(Bis(1-methylethyl)amino]ethoxyJ-4-methoxyphenyl]-4-(phenylsulfonyl)benzamide;
N-[3-[2-[Bis( 1-methylethyl)amino)ethoxy]-4-methoxyphenylJ-4-(phenylsulfinyl)benzamide;
N-[3-[2-[Bis( 1-methylethyl)amino]ethoxy]-4-methoxyphenylJ-4-[(hydroxyimino)phenylmethylJbenzamide;
N-[3-[2-[Bis( 1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(hydroxyphenylmethyl)benzamide;
N-[1'-( 1-Methylethyl)spiro[benzofuran-3(2H),4'S-piperidin]-S-yl]-4-benzoylbenzamide trifluoroacetate;
N-[1'-(1-Methylethyl)spiro[benzofuran-3(2H),4'S-piperidin]-S-yl]-4-phenoxybenzamide; and N-[1=(1-Methylethyl)spiro[benzofuran-3(2H),4'S-piperidin]-S-yl]-4-(phenylthio)benzamide.

SUBSTITUTE SHEET (RULE 26) Among the more preferred compounds of this invention are the following compounds:
N-[3-[2-[Bis( 1-methylethyl)aminoJethoxy]-4-methoxyphenyl]-3-phenoxybenzamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(phenylmethyl)benzamide;
N-[3-[2-[Bis( 1-methylethyl)aminoJethoxy]-4-methoxyphenyl]-4-phenoxybenzamide methiodide N-[3-[3-[Bis( 1-methylethyl)amino]propyl)-4-methoxyphenylJ-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-methoxyphenylJ-4-benzoylbenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-1-piperidinyl)ethoxy)-4-methoxyphenylJ-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-(phenyimethyl)benzamide;
N-[3-[2-(2,2,6,6-Tetramethyi-1-piperidinyl)ethoxy]-4-methoxyphenyl]-5-butyiamino-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-methoxyphenylJ-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'S-piperidin]-5-yl]-4-benzoylbenzamide trifluoroacetate;
SUBSTITUTE SHEET (RULE 26) N-[1=(1-Methylethyl)spiro[benzofuran-3(2H),4'S-piperidin]-5-yl]-4-phenoxybenzamide; and N-[1=(1-Methylethyl)spiro[benzofuran-3(2H),4'S-piperidin]-5-yl]-4.-(phenylthio)benzamide.
Among the most preferred compounds of this invention are the following compounds:
N-[ 1'-( 1-Methylethyl)spiro[benzofuran-3(2H),4'S-piperidinj-5-yl]-4-benzoylbenzamide trifluoroacetate;
N-[1=(1-Methylethyl)spiro[benzofuran-3(2H),4'S-piperidin]-5-yl]-4-phenoxybenzamide;and N-[ 1'-( 1-Methylethyl)spiro[benzofuran-3(2H),4'S-piperidin]-5-yl]-4-(phenylthio)benzamide.
Among compounds excluded from this 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 effective compounds of this invention (and the pharmaceutically acceptable salts thereof) are administered in conventional dosage forms prepared by combining a compound of this invention ("active ingredient") in an amount sufficient to treat COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV infection, {"CCRS-mediated disease states") with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra albs, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or SUBSTITUTE SHEET {RULE 26) WO 00/0614b PGT/US99/17121 diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid Garner will vary widely but preferably will be from about 25 mg to about 1000 mg.
When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
The active ingredient may also be administered topically to a mammal in need of treatment or prophylaxis of CCRS mediated disease states. The amount of active ingredient required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the disease state being treated and the mammal undergoing treatment, and is ultimately at the discretion of the physician. A suitable dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily.
By topical administration is meant non-systemic administration and includes the application of the active ingredient externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.
While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The active ingredient may comprise, for topical administration, from 0.001 % to 10% w/w, e.g.
from 1 % to 2% by weight of the formulation although it may comprise as much as 10%
w/w but preferably not in excess of 5% w/w and more preferably from 0.1 % to 1 % w/w of the formulation.
The topical formulations of the present invention, both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable carriers) therefor and optionally any other therapeutic ingredient(s). The carriers) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.

SUBSTITUTE SHEET (RULE 26) Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcoholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01 %) and chlorhexidine acetate (O.OI %). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis. The basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
The active ingredient may also be administered by inhalation. By "inhalation"
is meant intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques. The daily dosage amount of the active ingredient administered by inhalation is from about 0.1 mg to about 100 mg per~day, preferably about 1 mg to about 10 mg per day.

SUBSTITUTE SHEET (RULE 26) In one aspect, this invention relates to a method of treating COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV infection, all in mammals, preferably humans, which comprises administering to such mammal an effective amount of a CCRS receptor modulator, in particular, a compound of this invention.
By the term "treating" is meant either prophylactic or therapeutic therapy.
Such compound can be administered to such mammal in a conventional dosage form prepared by combining the compound of this invention with a conventional pharmaceutically acceptable Garner or diluent according to known techniques.
It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable Garner or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The compound is administered to a mammal in need of treatment for COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic diseases, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV infection, in an amount sufficient to decrease symptoms associated with these disease states. The route of administration may be oral or parenteral.
The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, infra-rectal, intravaginal or intraperitoneal administration.
The subcutaneous and intramuscular forms of parenteral administration are generally preferred. The daily parenterai dosage regimen will preferably be from about 30 mg to about 300 mg per day of active ingredient. The daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day of active ingredient.
It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of this invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
Methods of Preparation SUBSTITUTE SHEET (RULE 26) Compounds of formula (1) are prepared by condensing suitably substituted aryl or heteroarylcarboxylic acids and suitably substituted anilines, which are commercially available or synthesized by methods known to the art from commercially available starting materials, using methods known to the art. For example, suitably substituted aryl or heteroarylcarboxylic acids are treated with a suitable reagent, such as thionyl chloride, at a suitable temperature, such as at reflux, to afford aryl or heteroarylcarbonyl chlorides, and the aryl- or heteroarylcarbonyl chlorides are condensed with suitably substituted anilines in the presence of a suitable base, such as diisopropylethylamine, in a suitable solvent, such as dichloromethane, to give compounds of formula (1). Many additional methods for converting a carboxylic acid to an amide are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I-VI
(published by Wiley-Interscience).
Compounds of formula (I) are also prepared using solid-phase chemistry as described in Scheme I and using the general method described in international patent application WO 99/01127, published 14 January 1999. For example, in Scheme 1, an appropriately substituted 3-(2-aminoethoxy)-4-methoxyaniline I-2, such as 3-[2-(diisopropylamino)ethoxy]-4.-methoxyaniline, which is synthesized from the commercially available 2-methoxy-5-nitrophenol, I-1, according to the procedures described in WO 99/01127, is attached to a polymer support such as Merrifield resin-bound aldehyde I-3, which is synthesized according to the general protocol of Boojamra et al., (J. Org. Chem., 1995, 60, 5742-3) by reductive amination employing a reducing agent such as sodium triacetoxyborohydride in dimethylformamide with 1 % acetic acid to give I-4. The resulting resin-bound aniline I-4 is acylated with a commercially available or synthetically accessible, suitably substituted aryl or heteroaryl carboxylic acid I-5, for example 4-phenoxybenzoic acid, using, for example, N-bromo succinimide and triphenylphosphine in dichloromethane, or in dichloromethane in combination with dimethylformamide, in the presence of an organic base such as pyridine to afford I-6. For example, l-4 is treated with a ten-fold excess of an equimolar mixture of a 3-aryl- or heteroaryl carboxylic acid, triphenylphosphine and N-bromosuccinimide, in a suitable solvent, such as dichloromethane, after which a ten-fold excess of a suitable base, such as pyridine, is added, and the mixture is gently agitated for a suitable time, for example, forty-eight hours, to afford the resin-bound amide 1-6.
Optionally, dimethylformamide may be added to the resulting mixture to increase the solubility of the 3-aryl- or heteroaryl carboxylic acid. Treatment of I-6 with a mixture of a strong organic acid and organic solvent, such as trifluoroacetic SUBSTITUTE SHEET (RULE 26) acid:dichloromethane:water {50:48:2), resulted in cleavage of the desired compound from the polymer support and afforded carboxanilide I-7, a compound of formula I.
Sch, eme I:

H OCH~ O~N\R4 C
a-b , OCH3 02N ~N \ ~ c Rs 2 [a3 11 ~ R3 _N_~
O~N\ R4 (R~~~ (R~')b~ R4 OCH
P~ O H (R2~8' (R~~

HN \
OCH3 5 r R ' PZ A P' d Merrifieid nnerri0eld O~N\R4 (Rr)~, (R~)b, O / OCH3 R' PZ A P~
S
a) Cl(CH2)2NR3R4, K2C03, CH3COCH3; {b) H2, 5% Pd/C, MeOH; (c) Merrifield resin bound aldehyde (3); NaBH(OAc)3, 1% HOAc, DMF; (d) aryl/heteroaryl carboxylic acid, NBS, Ph3P, pyridine; (e) TFA, CH2Cl2, H20.
The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. In the Examples, mass spectra were performed upon a VG
Zab mass spectrometer using fast atom bombardment, unless otherwise indicated.
EXAMPLES
Preuaration 1 Preparation of 4-(Methylphenvlamino)benzoic acid SUBSTITUTE SHEET (RULE Z6) A solution of ethyl 4-(methylphenylamino)benzoate (2.65 g, 10 mmol) (Tetrahedron Lett. 1997, 38, 6359-6362) in tetrahydrofuran (SO mL), ethanol (25 mL), and water (5 mL) was treated with 1 N sodium hydroxide (84 mL) and heated to 50°C for 20 h. The mixture was reduced in volume in vacuo, diluted with water, and extracted three times with ethyl acetate. The aqueous phase was acidified with acetic acid to pH~6 and the white solid which precipitated was isolated by filtration, washed with water, and dried to give the title compound (1.95 g). MS (ES) m/e 227.8 (M+H)+.
Preparation 2 Preparation of 1=(1-Methylethy~pirofbenzofuran-3(2Hl 4=piperidinl 5 amine a) 5- and 7-nitrospiro[benzofuran-3(2H),4'-piperidine]
A solution of 1'-methyl-5- and 7-nitrospiro[benzofuran-3(2H),4 =piperidine]
(WO 96/11934) (~ g, 12 mmol) and diisopropylethylamine (2.5 g, 19 mmol) in 1,2-dichloroethane (80 mL) was treated with 1-chloroethyl chloroformate (2.3 g, 16 mmol) at RT, stirred for 1 h, and heated to reflux for 20 min. The mixture was cooled, concentrated in vacuo, and the residue was dissolved in methanol and heated to reflux for 2 h, concentrated in vacuo, and the residue was partitioned between dichloromethane (250 mL) and 5% sodium bicarbonate (50 mL). The organic phase was washed with 5% sodium bicarbonate (50 mL) and the combined aqueous phase was extracted with dichloromethane (2 X 50 mL). The combined organic phase was dried (Na2S04) and concentrated to afford 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 treated with di-tert-butyl dicarbonate (2.6 g, 12 mmol) and stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was crystallized from methanol to afford the title compound (2.1 g).
c) 5-nitrospiro[benzofuran-3(2H),4 =piperidine]
A solution of the compound of Preparation 2(b)(2.1 g, 6.3 mmol) in dichloromethane (50 mL) and trifluoroacetic acid ( 10 mL) was kept at RT for 5 h, concentrated in vacuo, 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 phase was dried (Na2S04) and concentrated in vacuo to give the title compound (1.45 g). MS(ES) m/e 235.1 [+H]+.
d) 1'-(1-methylethyl)-5-nitrospiro[benzofuran-3(2H),4'-piperidine]
A mixture of the compound of Preparation 2(c) (1.45 g, 6.2 mmol), powdered potassium carbonate (0.86 g, 6.2 mmol) and dimethylformamide {50 mL) SUBSTITUTE SHEET (RULE 26) containing 2-iodopropane ( 1.1 g, 6.4 mmol) was stirred and heated to 50°C for 4 h, treated with 2-iodopropane (0.17 g, 1 mmol) at 50°C for 90 min, and treated with 2-iodopropane (0.1 g, 1 mmol) at 50°C for 2 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (20 mL). The organic phase was washed, dried (MgS04), concentrated in vacuo, and the residue was chromatographed (silica gel, 5% methanol:dichloromethane) to give the title compound (0.85 g).
e) 1=(1-methylethyl)spiro[benzofuran-3(2H),4=piperidin]-5-amine A solution of the compound of Preparation 2(d) (0.78 g, 2.8 mmol) in methanol (250 mL) containing 10% palladium-on-carbon (0.375 g) was shaken in a hydrogen atmosphere (40 psi) for 40 min, filtered, and concentrated in vacuo to afford the title compound (0.6 g).
Preuaration 3 Preparation of 7-Amino-3.4-dihydro-N N-bis(1-methylethyl)-ll2H) quinolineethanamine a) 3,4-dihydro-N,N-bis(1-methylethyl)-7-nitro-1(2H)-quinolineethanamine Sodium carbonate (2.9 g, 27 mmol) was added to a mixture of 7-nitro-1,2,3,4-tetrahydroquinoline (1.2 g, 6.7 mmol) (United States Patent 5696133), (diisopropylamino)ethyl chloride hydrochloride (4.0 g, 20 mmol), and ethanol (25 mL). The mixture was heated at reflux for 3 h, filtered, and concentrated in vacuo.
The crude product was purified by chromatography (silica gel, dichloromethane followed by 5% methanol:dichloromethane) to afford 1.4 g (68%) of the title compound as a yellow oil. MS(ES) m/e 306.1 [M+H]+.
b) 7-amino-3,4-dihydro-N,N-bis(1-methylethyl)-1(2H)-quinolineethanamine 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 in vacuo to afford the title compound.
~'reuaration 4 Preparation of 2-(Phenylmethyl)-4.-thiazolecarboxylic Acid A solution of benzeneethanethioamide ( 1.0 g, 6.6 mmol) in dioxane (25 mL) was treated with bromopyruvic acid ( 1.1 g, 6.6 mmol) and heated to 90°C for 4 h.
The mixture was diluted with water and the tan crystals which formed were collected by filtration to afford the title compound.
Example 1 Preparation of N-t3-f2-(Diethvlamino)ethoxyl-4-methoxyphenyll-4 phenoxvbenzamide a) 3-[2-(diethylamino)ethoxy]-4-methoxyaniline/[4-formyl-3,5-{dimethoxy)phenoxy]-Mernfield resin adduct SUBSTITUTE SHEET (RULE 26) A mixture of [4-formyl-3,5-(dimethoxy)phenoxy)-Merrifield resin (Boojamra et al., J. Org. Chem. 1995, 60, 5742-3), 3-[2-(diethylamino)ethoxy]-methoxyaniline (WO 95/15954), and sodium triacetoxyborohydride in dimethylformamide containing 1 % acetic acid was shaken to afford the title adduct.
b) N-[3-[2-(diethylamino)ethoxy]-4-methoxyphenyl]-4-phenoxybenzamide/[4-formyi-3,5-(dimethoxy)phenoxy]-Merrifield resin adduct The resin of Example 1 (a) was placed in an Iron MicroKan and treated with a ten-fold molar excess of an equimolar mixture of 4-chlorocinnamic acid, N-bromosuccinimide, and triphenylphosphine in dichloromethane, followed by addition of a ten-fold excess of pyridine. The mixture was gently agitated for 48 h after which the resin was washed three-times, sequentially with dimethylforrnamide, dichloromethane, and methanol to afford the title adduct.
c) N-[3-[2-(diethylamino~thoxy)-4-methoxyphenyl]-4-phenoxybenzamide The resin of Example 1 (b) was stirred in a mixture of trifluoroacetic acid:dichloromethane:water (50:48:2), filtered, and the filtrate concentrated in vacuo to afford the title compound. MS (ES) m/e 435.0 (M+H)+.
Examples 2-30 Following the procedure of Example 1 (a)-(c), except using 4-[(2-diisopropylanuno)ethoxy]aniline (WO 99/01127), 4-[2-(diethylamino)ethoxy]aniline (J. Med Chem. 1995, 38, 1657-65), 3-[(2-diisopropylamino)ethoxy]aniline (WO
99/01127), 3-[(2-diisopropylamino)ethoxy)-4-methoxyaniline (WO 95/15954), 3-[2-(2,2,6,6-tetramethyl-1-piperidinylJethoxy]-4-methoxyaniline (WO 99/01127), and [(3-diisopropylamino)propyl]-4-methoxyaniline (WO 99/01127) in addition to 3-[2-(diethylamino)ethoxy)-4-methoxyaniline, and except using 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-methylphenyl)sulfonyl]-3-nitrobenzoic acid in addition to 4-phenoxybenzoic acid, gave the title compounds:
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 (M+H)+;
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)+;

SUBSTITUTE SHEET (RULE 26) 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 502.9 (M+H)+;
N-[3-[2-(2,2,6,6-tetramethyl-1-piperidinyl)ethoxy]-4-methoxyphenyl]-4-phenoxybenzamide: MS (ES) m/e 503.3 (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)ethoxyJ-4-methoxyphenylJ-4-benzoylbenzamide: M5 (ES) m/e 515.3 (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)aminoJethoxy]-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)+;
SUBSTITUTE SHEET (RULE 26) 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-jbis( 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-tetramethyi-1-piperidinylJethoxy]-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-f3-12-Bisll-methylethyl)aminolethoxvl-4-methoxyphenyll 3 phenoxybenzamide 3-Phenoxybenzoyl chloride, prepared from 3-phenoxybenzoic acid (0.11 g, 0.5 mmol) and thionyl chloride ( 5 mL) heated to reflux for 30 nun, concentrated in vacuo and concentrated in vacuo from dichloromethane, was dissolved in dichloromethane (5 mL) and treated with 3-[{2-diisopropylanuno)ethoxy]-4.-methoxyaniline (0.14 g, 0.5 mmol) and diisopropylethylamine (0.07 g, 0.5 mmol). The mixture was stirred at RT for 16 h, and washed twice with 5% sodium carbonate and with water. The organic phase was dried (MgS04) and concentrated in vacuo to afford a residue that 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)+.
Example 32-35 Following the procedure of Example 31 except substituting 4-phenoxybenzoic acid, 4-(phenylmethyl)benzoic acid, 4-(phenylthio)benzoic acid, and 4-(phenylsulfonyl)benzoic acid (Chim. Ther. 1973, 8, 340-1) for 3-phenoxybenzoic acid, gave the title compounds:
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 510.7 (M+H)+.
Example 36 SUBSTITUTE SHEET (RULE 2b) Preparation of N-f3-f2-fBisll-methvlethyl)aminolethoxyl-4 methoxyphenvll-4 l3 h droxyphenoxy)benzamide A solution of 4-(3-hydroxyphenoxy)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 (20 mL) was treated with S triethylamine (0.2 g, 2 mmol) and stirred at RT for 16 h. The mixture was diluted with dichloromethane and filtered. The filtrate was washed with water, dried (MgS04), and concentrated in vacuo to afford a residue that was purified by HPLC
(ODS-A, 20 X 50 mm, A:acetonitrile B:water-0.1% trifluoroacetic acid, 10-90%
during 10 min, UV detection at 254 nm) to afford the title compound. MS (ES) m/e 478.8 (M+H)+.
Examples 37-43 Following the procedure of Example 36, except substituting 4-[(4-chlorophenyl)sulfinyl]-3-nitrobenzoic acid, 4-[(2,4-dichlorophenyl)sulfinyl]-3-nitrobenzoic acid, 4-benzoylbenzoic acid, 3-benzoylbenzoic acid, the compound of Preparation 1, 4-(phenylamino)benzoic acid, and 4-(phenylsulfinyl)benzoic acid (Synthesis 1990, 847-9) for 4-(3-hydroxyphenoxy)benzoic acid, afforded the title compounds:
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]ethvxy]-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-(methylphenyiamino)benzamide: MS (ES) m/e 475.9 (M+H)+;
N-[3-[2-[bis( 1-methylethyl)amino]ethoxy]-4-mcthoxyphenyl]-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 494.7 (M+H)+.
Example 44 Preparation of N-f3-f3-fBisll-methylethyl aminolpropvll-4 methoxyphe~ll 4 phenoxybenzamide Following the procedure of Example 36, except substituting 4-phenoxybenzoic acid for 4-(3-hydroxyphenoxy)benzoic acid and 3-[(3-diisopropylamino)propyl]-4-methoxyaniiine for 3-[(2-diisopropylamino)ethoxy]-4-methoxyaniline, afforded the title compound. MS (ES) m/e 461.3 (M+H)+.
Examale 45 SUBSTITUTE SHEET (RULE 26) Preparation of N I3-f2-fBis(1-meth~lethyl)aminolethoxyl-4 methoxyphenyll-4 ((hvdroxvimino~phenylmethyllbenzamide A solution of the compound of Example 39 (0.24 g, 0.5 mmol), hydroxylamine hydrochloride (0.17 g), and triethylamine (0.24 mL) in ethanol ( 10 mL) was heated to reflux for 20 h. The mixture was concentrated in vacuo 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-f3-f2-fBis(1-methylethyl)anunolethoxyl-4-methoxyphen)rll-4 (hvdrox3rphenyImethyl)benzamide A mixture of the compound of Example 39 (0.24 g, 0.5 mmol), ethanol {21 mL), water (7 mL), methanol (5 mL), and dichloromethane (5 mL) was treated with sodium borohydride (0.13 g, 3.5 mmol) and stirred at RT for 2 h. The mixture was diluted with water, reduced in volume in vacuo, and extracted three times with dichloromethane. The combined organic phase was washed with brine, dried (MgS04), and concentrated in vacuo to give the title compound (40 mg). MS (ES) m/e 477.2 (M+H)+.
Examale 47 Preparation of N-f 1=ll-Methvleth)!1)spirofbenzofuran-3(2H) 4'S-piperidinl 5 yll-4 benzoylbenzamide trifluoroacetate A solution of 4-benzoylbenzoic acid (55 mg, 0.254 mmol), the compound of Preparation 2(e) (60 mg, 0.24 mmol), and BOP
reagent ( 108 mg, 0.24 mmol) in acetonitrile (5 mL) was treated with triethylamine (50 mg, 0.5 mmol) and stirred at RT for 16 h. The mixture was quenched with brine and extracted with ethyl acetate. The organic extract was washed with 5%
sodium carbonate and with brine, dried (MgS04), and concentrated in vacuo. The residue was purified by HPLC (ODS-A, 20 X 50 mm, A:acetonitrile B:water-0.1%
trifluoroacetic acid, 10-90% during 10 min, UV detection at 254 nm) to give the title compound. MS (ES) m/e 455.1 (M+H)+.
Examples 4$-49 Preparation of N-f 1=ll-Methvlethyl)spirofbenzofuran-312H14'S piperid_ inl 5 yll-4-uhenoxybenzamide and N-f 1=(1-Methylethyl)spirofbenzofuran 312H14'S piperidinl 5-vll-4-(ghen l~hio)benzamide Following the procedure of Example 47, except substituting 4-phenoxybenzoic acid and 4-(phenylthio)benzoic acid for 4-benzoylbenzoic acid, gave the title compounds:
N-[ 1'-( 1-methylethyl)spiro [benzofuran-3 (2H),4'S-piperidinJ-5-y1J-4-phenoxybenzamide: MS (ES) m/e 443.1 (M+H)+; and N-[ 1'-( 1-methylethyl)spiro[benzofuran-3(2H),4'S-piperidinJ-5-yl]-4-(phenylthio)benzamide: MS (ES) m/e 459.1 (M+H)+.
Example 50 SUBSTITUTE SHEET (RULE Z6) Preparation of N-f 1-f2-fBis(1-methylethyl)aminolethyll 1 2 3 4 tetrahydroguinol 7 l~phenoxybenzamide Following the procedure of Example 3I, except substituting 4-phenoxybenzoic acid for 3-phenoxybenzoic acid and substituting the compound of Preparation 3(b) for 3-[(2-diisopropylamino)ethoxy]-4-methoxyaniline, gave the title compound. MS (ES) m/e 472.2 (M+H)+.
Examole Sl Preparation of N-f3-f2-fBis(1-methylethyl)aminolethoxyl-4 methox~rphenyll-4-phenoxybenzamide Methiodide The compound of Example 32 (93 mg, 0.2 mmol) in methanol (3 mL) was treated with iodomethane (8 mL), maintained at RT for 4 d, concentrated in vacuo, and the residue was triturated with ethyl acetate and then withl:l ethyl acetate:ether. The residue was stirred with 1:1 ethyl acetate:ether for several hours and filtered to afford the title compound. MS (ES) m/e 477 (M+H}+.
Examine 52 Preparation of N-f3-f2-fBisf 1-methylethyl)aminolethoxyl-4 methoxyphenvll 2 (phenvlmethyl)thiazole-4-carboxamide hydrochloride Following the procedure of Example 31, except substituting the compound of Preparation 4 for 3-phenoxybenzoic acid, afforded the title compound. MS (ES) m/e 468.0 (M+H)+.
Biological Data:
CCRS Receptor Bindin Assay CHO cell membranes (0.25 x106 cell equivalents) derived from CHO cells stably transfected with CCRS were incubated with 0.3 '~I-RAh1'fES in a 96 well plate for 45 min at room temperature (final reaction volume 200 ul).
The reaction was terminated by filtration and the filters (GF/C} were washed twelve times with a solution of phosphate buffered saline containing 0.1 % bovine serum albumin and 0.05 %
NaN3. The radioactivity bound to filters was measured by liquid scintillation spectrometry.
Non-specific binding was determined in the presence of unlabelled RAN'TES ( 10 or 30 nM) and averages 30-50% of total binding.
CCRS Receptor Functional Assay The cellular functional assay used to assess antagonist activity of compounds was RANTES-induced Ca2+ mobilization in RBL 2H3 cells stably expressing the hCCRS
receptor (RBL 2H3 hCCRS). Agonist activity is determined by Ca2+ mobilization in the same cells which is inhibitable by a selective CCRS antagonist. Cells were grown to 80-100% confluency in T-150 flasks and washed with phosphate-buffered saline.
Cells were lifted from the flasks by treating with 3 mL of 1 mM EDTA for 3 min at room temperature and diluting to 2 X 106 cells/mL with Krebs Ringer Henseleit buffer (KRH; 118 mM
NaCI, 4.6 mM KCI, 25 mM NaHC03, 1 mM KH2P04 and 11 mM glucose) containing 5 SUBSTITUTE SHEET (RULE 26) mM HEPES (pH 7.4), 1 mM CaCl2, 1 mM MgCl2 and 0.1 % BSA and centrifuged at 200g for 3 min. Cells were resuspended at 2 X 106 cells/mL in the same buffer with 2 p.M Fura-2AM, and incubated for 35 min at 370 C. Cells were centrifuged at 200 x g for 3 min and resuspended in the same buffer without Fura-2AM, then incubated for 15 min at 370 C to complete the hydrolysis of intracellular Fura-2AM, and then centrifuged as before. Cells ( 106 cells/mL) were resuspended in cold KRH with 5 mM HEPES (pH 7.4), 1 mM
CaCl2, 1 mM MgCl2 and 0.1 % gelatin and maintained on ice until assayed. For antagonist studies, aliquots (2 mL) of cells were prewarmed at 370 C for 5 min in 3 mL
plastic cuvettes and fluorescence measured in a fluorometer (Johnson Foundation Biomedical Group, Philadelphia, PA, USA) with magnetic stirring and temperature maintained at 370 C. Excitation was set at 340 nm and emission set at 510 nm. Various concentrations of antagonists or vehicle were added and fluorescence monitored for --15 sec to ensure that there was no change in baseline fluorescence, followed by the addition of 33 nM RANZ'ES.
Maximal Ca2+ attained after 33 nM RAI~TfES stimulation was calculated as described by Grynkiewicz et al., ( 1985). The percent of maximal RANTES-induced Ca2+ was determined for each concentration of antagonist and the IC50~ defined as the concentration of test compound that inhibits 50% of the maximal 33 nM RANTES response, obtained from the concentration-response curves (5-7 concentrations of antagonists).
The compounds of this invention show CCRS receptor modulator activity having ICgO values in the range of 0.0001 to 100 Er,M. The full structure/activity relationship has not yet been established for the compounds of this invention. However, given the disclosure herein, one of ordinary skill in the art can utilize the present assays in order to determine which compounds of this invention are modulators of the CCRS
receptor and which bind thereto with an IC50 value in the range of 0.0001 to 100 ~i,M.
All publications, including, but not limited to, patents and patent applications cited in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration it is believed that one skilled in the art can, given the preceding description, utilize the present invention to its fullest extent. Therefore any examples are to be construed as merely illustrative and not a limitation on the scope of the present invention in any way.
The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.
SUBSTITUTE SHEET (RULE 26)

Claims (5)

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

wherein:
the basic nitrogen in moiety E may be optionally quaternized with C1-6alkyl or is optionally present as the N-oxide;
P1 and P2 are independently phenyl, fused bicyclic aryl, a monocyclic heterocyclic ring of 5- to 7-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or a fused bicyclic heterocyclic ring of 8 to 11-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
A is C(R4')2, CR4'(OR5'), CO, C=NOR6', NR7', oxygen, or S(O)c';
L is a group of formula -C(=V)-DR8'-, -DR9'-C(=V)-, -CH2NH-, or -NHCH2-;
V is oxygen or sulfur;
D is nitrogen, carbon, or a CH group, R1' and R2' are independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, aryl, (CH2)d'NR10'R11', (CH2)d'NR10'COR12', (CH2)d'NR 10'CO2R13', (CH2)d'NR10'SO2R14', (CH2)d'CONR15'R16', hydroxyC1-6alkyl, C1-4alkoxyalkyl (optionally substituted by a C1-4alkoxy or hydroxy group), (CH2)d'CO2C1-6alkyl, (CH2)e'OC(O)R17', CR18'=NOR19', CNR20'=NOR19', COR21', CONR15'R16', CONR15'(CH2)fOC1-4alkyl, CONR15'(CH2)d'CO2R22', CONHNR23'R24', CONR15'SO2R25', CO2R26', cyano, trifluoromethyl, NR10'R11', NR10'COR12', NR27'CO(CH2)d'NR27'R28', NR27'CONR27'R28', NR10'CO2R13', NR10'SO2R14', N=CNR27'NR27'R28', nitro, hydroxy, C1-6alkoxy, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkoxy, OC(O)NR29'R30', SR31', SOR32', SO2R32', SO2NR33'R34', halogen, C1-6alkanoyl, CO2(CH2)d'OR35', or R1' is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;
R3'is hydrogen, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, hydroxyC1-6alkyl, C1-6alkylOC1-6alkyl, CONR36'R37', CO2R38', cyano, aryl, trifluoromethyl, NR39'R40; nitro, hydroxy, C1-6alkoxy, C1-6alkanoyl, acyloxy, or halogen;
R4', R5', R6', R7', R18', R19', R20', R21', R22', R23', R24', R27', R28', R31', R35', R36', R37', R38', R39', and R40' independently hydrogen or C1-6alkyl;
R8' is hydrogen or C1-6alkyl, providing that D is nitrogen or a CH
group;
R9' is hydrogen or C 1-6alkyl, providing that D is nitrogen or a CH , group;
R10' and R11' are independently hydrogen or C1-6alkyl, or R10' and R11' together with the nitrogen to which they are attached, forms a 5- to 6-membered heterocyclic ring, which may optionally be substituted by an oxo group, and, when there are six members, may optionally contain in the ring one oxygen or one sulfur atom;
R12' is hydrogen, C1-6alkyl, or C1-4alkoxyalkyl;
R13', R25', and R32' are independently C1-6alkyl;
R14' is C1-6alkyl or phenyl;
R15' and R16' are independently hydrogen or C1-6alkyl, or R15' and R16' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when there are 6 ring members, may optionally contain in the ring one oxygen or one sulfur atom;
R17' is C1-4alkyl, optionally substituted by C1-6alkoxy;
R26' is hydrogen or C1-6alkyl optionally substituted with one or two substituents selected from C1-6alkyl, C1-6alkoxy, hydroxy, or NR10'R11';
R29' and R30' are independently hydrogen or C1-6alkyl, or R29' and R30' together with the nitrogen to which they are attached form a 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom;
R33' and R34' are independently hydrogen or C1-6alkyl, or R33' and R34' together with the nitrogen to which they are attached form 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring 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;
f' is 1,2,or 3;
E represents (a):

in which B is oxygen, S(O)c, CR7=CR8, or CR7R8, or B is NR9;
R1 and R2 are independently hydrogen or C1-6alkyl; alternatively B(CR1R2)a is OCR1R2CR1(OH)CR1R2 or OCR1R2CR1(OCOCH3)CR1R2;
R3 and R4 are independently hydrogen, C1-6alkyl, C3-7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C1-6alkyl, aryl, CONR10R11, NR10R11 hydroxy, OCOR12, NHCOC0-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2R13, and NHCO2R14;
R5 is hydrogen, C1-6alkyl, aryl, CN, CONR15R16, CO2R17, trifluoromethyl, NHCO2R18, hydroxy, C1-6alkoxy, benzyloxy, OCH2CO2C1-6alkyl, OCF3, S(O)dR19, SO2NR20R21 or halogen;
R6 is hydrogen, C1-6alkyl, aryl, trifluoromethyl, hydroxy, C1-6alkoxy or halogen, or R6 taken together with R8' forms a group D where D is (CR22R23)e or D is (CR22R23)f-G where G is oxygen, sulfur or CR22-CR23, CR22=N, =CR22O, =CR22S, or =CR22-NR23;
R7, R8, R10, R11, R12, R15. R16, R17, R20, R21, R22, and R23 are independently hydrogen or C1-6alkyl;
R9 is hydrogen, C1-6alkyl, or phenylC1-6alkyl;
R13, R14, R18, and R19 are independently C1-6alkyl;
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;
f is 0, 1,2 or 3;
alternatively, E represents (b):

R24, R25, R26, R27, R28, R29, R31, and R32 are independently hydrogen or C1-6alkyl;
R30 is hydrogen, C1-6alkyl, or C3-7cycloalkyl;
R33 is hydrogen, C1-6alkyl, trifluoromethyl, hydroxy, or halogen, or R33 and R8' together form a group -K- where K is (CR34R35)i or K is (CR34R35)j-M and M is oxygen, sulfur, CR34=CR35, CR34=N, or N=N;
J is oxygen, CR36R37, or NR38, or J is a group S(O)k;
R34, R35, R36, R37, and R38 independently hydrogen or C1-6alkyl;
g is 1, 2 or 3;
h is 1,2 or 3;
i is 2, 3, or 4;
j is 0, 1, 2, or 3;
k is 0, 1 or 2;
alternatively, E represents (c):

in which:
Q is oxygen, S(O)n, CR44=CR45, CR44R45, or Q is NR46;
R39 and R40 are independently hydrogen or C1-6alkyl;
R41 is a group of formula (d):

or R41 is a group of formula (e):

R42 is hydrogen, C1-6alkyl, aryl, CN, CONR48R49, CO2R50, trifluoromethyl, NHCO2R51, hydroxy, C1-6alkoxy, benzyloxy, OCH2CO2C1-6alkyl, OCF3, S(O)sR52, SO2NR53R54, or halogen;
R43 is hydrogen or R43 together with R8' forms a group R where R is CR55=CR56, CR55=CR56CR55R56, or (CR55R56)t;
R44, R45, R46, R48, R49, R50, R53, R54, R55, and R56 are independently hydrogen or C1-6alkyl;
R47 is hydrogen, C1-6alkyl, or C3-7 cycloalkyl;
R51 and R52 are independently C1-6alkyl;
1 is 0, 1,2, or 3;
m is 1 or 2;
n is 0, 1, or 2 o, p, and q are independently integers having the value 1, 2, or 3;
r is 0, 1, 2, or 3;
s is 0, 1, or 2;
t is 2 or 3;
alternatively, E represents (f):

R57 and R58 are independently hydrogen or C1-6alkyl;
R59 and R60 are independently hydrogen, C1-6alkyl, C3-7cycloallcyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C1-6alkyl, aryl, CONR61R62, NR61R62, hydroxy, OCOR63, NHCOC0-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2R64, and NHCO2R65;
T is -(CR66R67)v- or -O(CR66R67)w-;
W is oxygen, S(O)x, NR68, or W is CR69=CR70 or CR69R70;
R61, R62, R63, R66, R67 R68, R69, and R70 are independently hydrogen or C1-6alkyl;
R64 and R65 are independently C1-6alkyl;
u is 1 to 4;
v is 2 or 3;
w is 1, 2, or 3;
x is 0, 1 or 2;

alternatively, E represents a group (g):

R71 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 R71 is an optionally substituted 6,6 or 6,5 bicyclic ring containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulfur;
R72 is hydrogen, C1-6alkyl, aryl, CN, CONR74R75, CO2R76, trifluoromethyl, NHCO2R77, hydroxy, C1-6alkoxy, benzyloxy, OCH2CO2C1-6alkyl, OCF3, S(O)zR78, SO2NR79R80, or halogen;
R73 is hydrogen, C1-6alkyl, hydroxy, C1-6alkoxy or halogen, or R73 and R8' taken together from a group -X- where X is (CR81R82)aa or X is (CR81R82)ab-Y and Y is oxygen, sulfur or CR81=CR82;
R74, R75, R76, R79, R80, R81, and R82 are independently hydrogen or C1-6alkyl;
R77 and R78are independently C1-6alkyl;
y is 1 or 2;
z is 0, 1, or 2;
aa is 2, 3 or 4;
ab is 0, 1,2 or 3;
alternatively, E represents group (h):

R83 and R84 are independently hydrogen or C1-6alkyl;
R85 and R86 are independently hydrogen, C1-6alkyl, C3-7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C1-6alkyl, aryl, CONR88R89, NR90R91, hydroxy, OCOR92, NHCOCp0-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2R93, and NHCO2R94;
R87 is hydrogen or C1-6alkyl, C1-6alkoxy, or halogen, or R87 together with R8' forms a group -AA- where AA is (CR95R96)ad or AA is (CR95=CR96)ae-AB and AB is oxygen, sulfur, CR95=CR96, CR95=N, CR95NR96 or N=N;

Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
R88, R89, R90, R91, R92, R95, and R96 are independently hydrogen or C1-6alkyl;
R93 and R94 are independently C1-6alkyl;
ac is 0 to 4;
ad is 1, 2 or 3;
ae is 0, 1 or 2;
alternatively, E represents group (i):

R97 and R98 are independently hydrogen, C1-6alkyl, C3-7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C1-6alkyl, aryl, CONR102R103, NR104R105, hydroxy, OCOR106, NHCOC0-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2R107, and NHCO2R108;
R99 and R 100 are independently hydrogen or C1-6alkyl;
R101 is hydrogen or C1-6alkyl or R101 and R8' together form a group -AD- where AD is (CR109R110)ai or AD is (CR109R110)aj-AE and AE is oxygen, sulfur or CR109=CR110;
AC is oxygen, CR111R112 or NR113 or AC is a group S(O)ak;
R102, R103, R104, R105, R106, R109, R110, R111, R112, and R113 are independently hydrogen or C1-6alkyl;
R107 and R108 are independently C1-6alkyl;
of 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, l, 2, or 3; and ak is 0, 1 or 2.
2. The method of claim 1 wherein the compound of formula (I) is selected from a subgenus of formula (Ia) or a pharmaceutically acceptable salt thereof:

wherein:
R1', R2', R3', P1, P2, A, a', b', L, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, J, g, and h are defined in claim 1.
3. The method as claimed in claim 1 wherein the compound is selected from:
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-phenoxybenzamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methaxyphenyl]-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)benzamide;
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-(phenylmethyl)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-methoxyphenyl]-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-methyIethyl)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]benzamide;
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-methoxyphenyl]-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]-4-(phenylthio)benzamide;
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 wherein the CCR5-mediated disease state is selected from COPD, asthma and atopic disorders, rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV.
5. A compound of formula (I) selected from:
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-phenoxybenzamide;
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)benzamide;
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-(phenylmethyl)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-methoxyphenyl]-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]benzamide;
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-methoxyphenyl]-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]-4-(phenylthio)benzamide.
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Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6025154A (en) 1995-06-06 2000-02-15 Human Genome Sciences, Inc. Polynucleotides encoding human G-protein chemokine receptor HDGNR10
PL365183A1 (en) * 2000-07-31 2004-12-27 Smithkline Beecham P.L.C. Carboxamide compounds and their use as antagonists of a human 11cby receptor
AU2002235277A1 (en) * 2000-10-23 2002-05-06 Smith Kline Beecham Corporation Compounds and methods
US7067539B2 (en) 2001-02-08 2006-06-27 Schering Corporation Cannabinoid receptor ligands
US7507767B2 (en) 2001-02-08 2009-03-24 Schering Corporation Cannabinoid receptor ligands
US7175988B2 (en) 2001-02-09 2007-02-13 Human Genome Sciences, Inc. Human G-protein Chemokine Receptor (CCR5) HDGNR10
PL369952A1 (en) 2001-11-14 2005-05-02 Schering Corporation Cannabinoid receptor ligands
US7393934B2 (en) 2001-12-21 2008-07-01 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
CA2487346A1 (en) 2002-06-19 2003-12-31 Schering Corporation Cannabinoid receptor agonists
EP2385040A1 (en) 2003-03-14 2011-11-09 ONO Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
TW200505902A (en) 2003-03-20 2005-02-16 Schering Corp Cannabinoid receptor ligands
EP1619193A4 (en) 2003-04-18 2010-08-11 Ono Pharmaceutical Co Spiropiperidine compound and medicinal use thereof
CN1925854A (en) * 2003-11-14 2007-03-07 沃泰克斯药物股份有限公司 Thiazoles and oxazoles useful as modulators of ATP-binding cassette transporters
US7544803B2 (en) * 2004-01-23 2009-06-09 Amgen Inc. Vanilloid receptor ligands and their use in treatments
WO2005105841A2 (en) 2004-03-12 2005-11-10 Human Genome Sciences, Inc. Human g-protein chemokine receptor (ccr5) hdgnr10
WO2006023852A2 (en) 2004-08-19 2006-03-02 Vertex Pharmaceuticals, Incorporated Modulators of muscarinic receptors
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
BRPI0515164A (en) 2004-09-13 2008-07-08 Ono Pharmaceutical Co nitrogenous heterocyclic derivative and medicine containing the same as an active ingredient
KR20070086756A (en) 2004-11-29 2007-08-27 버텍스 파마슈티칼스 인코포레이티드 Modulators of muscarinic receptors
US20110052612A1 (en) 2005-05-31 2011-03-03 Ono Pharmaceutical Co., Ltd. Spiropiperidine compound and medicinal use thereof
EA200801025A1 (en) * 2005-10-06 2008-12-30 Юниверсити Оф Массачусетс COMPOSITION AND SYNTHESIS OF NEW REAGENTS FOR THE INHIBITION OF HIV REPLICATION
DK1942108T3 (en) 2005-10-28 2013-12-09 Ono Pharmaceutical Co Compound containing basic group and use thereof
EP1961744B1 (en) 2005-11-18 2013-04-17 Ono Pharmaceutical Co., Ltd. Basic group-containing compound and use thereof
WO2007076070A2 (en) 2005-12-22 2007-07-05 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
AU2007221220A1 (en) 2006-02-22 2007-09-07 Vertex Pharmaceuticals Incorporated Spiro condensed piperidnes as modulators of muscarinic receptors
US8003660B2 (en) 2006-02-22 2011-08-23 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
RU2008140144A (en) 2006-03-10 2010-04-20 Оно Фармасьютикал Ко., Лтд. (Jp) NITROGEN CONTAINING HETEROCYCLIC DERIVATIVE AND PHARMACEUTICAL PRODUCT INCLUDING SUCH DERIVATIVE AS AN ACTIVE INGREDIENT
WO2007132846A1 (en) 2006-05-16 2007-11-22 Ono Pharmaceutical Co., Ltd. Compound having acidic group which may be protected, and use thereof
CA2656183A1 (en) 2006-06-29 2008-01-10 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
JP5245827B2 (en) 2006-07-31 2013-07-24 小野薬品工業株式会社 Compound containing spiro-bonded cyclic group and use thereof
AU2007284548A1 (en) 2006-08-15 2008-02-21 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
EP2051715A2 (en) 2006-08-18 2009-04-29 Vertex Pharmceuticals Incorporated Modulators of muscarinic receptors
GB0625523D0 (en) * 2006-12-21 2007-01-31 Ge Healthcare Ltd In vivo imaging agents
CA2700724A1 (en) 2007-10-03 2009-04-09 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
WO2010129351A1 (en) 2009-04-28 2010-11-11 Schepens Eye Research Institute Method to identify and treat age-related macular degeneration
EP2741777B1 (en) 2011-08-12 2017-01-18 INSERM - Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for treatment of pulmonary hypertension
FR2984323B1 (en) 2011-12-16 2019-08-30 L'oreal STRUCTURE COUPLER 7 AMINO-1,2,3,4-TETRAHYDROQUINOLINES, TINCTORIAL COMPOSITION COMPRISING THE SAME, METHODS AND USES
FR2984318B1 (en) 2011-12-16 2014-06-27 Oreal CATIONIC AMINO-1,2,3,4-TETRAHYDROQUINOLINE 7 STRUCTURE COUPLER, TINCTORIAL COMPOSITION COMPRISING THE SAME, METHODS AND USES
FR3072286B1 (en) 2017-10-13 2022-08-12 Oreal PARTICULAR 7-AMINO-1,2,3,4-TETRAHYDROQUINOLEINS, METHOD AND COMPOSITION
US11629196B2 (en) 2020-04-27 2023-04-18 Incelldx, Inc. Method of treating SARS-CoV-2-associated hypercytokinemia by administering a human monoclonal antibody (PRO-140) that inhibits CCR5/CCL5 binding interactions

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK189677A (en) * 1976-05-07 1977-11-08 Sumitomo Chemical Co M-PHENOXYBENZAMIDE DERIVATORS
ZA985542B (en) * 1997-07-03 1999-04-07 Smithkline Beecham Corp Substituted benzanilides as CCR5 receptor ligands antiinflammatory agents and antiviral agents

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