Patent ID: 6515027
Filing Date: 2003-02-04
Classification: A61K,A61P,C07C,C07D

Abstract:
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:Arâ€”Aâ€”Eâ€ƒâ€ƒFormula I in which Ar represents a group selected from (i), (ii) or (iii); in which:R1 and R2 are independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-6cycloalkenyl, aryl, (CH2)aNR7R8, (CH2)aNR7COR9, (CH2)aNR7CO2R10, (CH2)aNR7SO2R11, (CH2)aCONR12R13, hydroxyC1-6alkyl, C1-4alkoxyalkyl (optionally substituted by a C1-4alkoxy or hydroxy group), (CH2)aCO2C1-6alkyl, (CH2)bOC(O)R14, CR15&boxH;NOR16, CNR15&boxH;NOR16, COR17, CONR12R13, CONR12(CH2)cOC1-4alkyl, CONR12(CH2)aCO2R18, CONHNR19R20, CONR12SO2R21, CO2R22, cyano, trifluoromethyl, NR7R8, NR7COR9, NR23CO(CH2)aNR23R24, NR23CONR23R24, NR7CO2R10, NR7SO2R11, N&boxH;CNR23NR23R24, nitro, hydroxy, C1-6alkoxy, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkoxy, OC(O)NR25R26, SR27, SOR28, SO2R28, SO2NR25R26 or halogen; a is 1, 2, 3 or 4; R7 and R8 are independently hydrogen or C1-6alkyl, or NR7R8 forms a heterocyclic ring which has 5 or 6 ring members which, may optionally be substituted by an oxo group and, when there are 6 ring members, may optionally contain in the ring one oxygen or sulfur atom; R9 is hydrogen, C1-6alkyl or C1-4alkoxyalkyl; R10 is C1-6alkyl; R11 is C1-6alkyl or phenyl; R12 and R13 are independently hydrogen or C1-6alkyl, or NR12R13 forms a saturated heterocyclic ring which has 5 or 6 members which, when there are 6 ring members, may optionally contain in the ring one oxygen or sulfur atom; b is 0, 1, 2 or 3; R14 is C1-4alkyl, optionally substituted by a C1-6alkoxy; R15 and R16 are independently hydrogen or C1-6alkyl; R17 is hydrogen or C1-6alkyl; c is 1, 2 or 3; R18 is hydrogen or C1-6alkyl; R19 and R20 are independently hydrogen or C1-6alkyl; R21 is hydrogen or C1-6alkyl; R22 is hydrogen or C1-6alkyl optionally substituted with one or two substituents selected from C1-6alkyl, C1-6alkoxy, hydroxy, or NR7R8; R23 and R24 are independently hydrogen or C1-6alkyl; R25 and R26 are independently hydrogen or C1-6alkyl, or NR25R26 forms a saturated heterocyclic ring which has 5 or 6 members which, when there are 6 ring members, may optionally contain in the ring one oxygen or sulfur atom; R27 is hydrogen or C1-6alkyl; R28 is C1-6alkyl; P is a 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; R3 and R4 are independently hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-6cycloalkenyl, hydroxyC1-6alkyl, C1-6alkylOC1-6alkyl, CONR29R30, CO2R31, cyano, aryl, trifluoromethyl, NR29R30, nitro, hydroxy, C1-6alkoxy, acyloxy or halogen; R29, R30 and R31 are independently hydrogen or C1-6alkyl; R5 is hydrogen, C1-6alkyl, C1-6alkoxy or halogen; R6 is hydrogen, C1-6alkyl, C3-7cycloalkyl (optionally substituted by a hydroxy or an oxo group), hydroxyC1-6alkyl, hydroxyC3-6alkenyl, hydroxyC3-6alkynyl, (CH2)dOR32, (CH2)dCOR33, (CH2)dCR34&boxH;NOR35, CONR36R37, CO2R38, hydroxy, O(CH2)eR39, NR36R37, SR40, SO2NR41R42 or halogen; d is 0, 1, 2, 3, 4, 5, or 6; R32 is C1-6alkyl, hydroxyC1-6alkyl, or C1-4alkanoyl; R33 is hydrogen or C1-6alkyl; R34 is hydrogen or C1-6alkyl; R35 is hydrogen or C1-6alkyl; R36 and R37 are independently hydrogen or C1-6alkyl or NR36R37 forms a saturated heterocyclic ring which has 5 or 6 members, may optionally be substituted by an oxo group and, when there are 6 ring members, may optionally contain one oxygen or sulfur atom or an NH or NR43 where R43 is C1-6alkyl, COR44 or CO2R45 where R44 and R45 are independently hydrogen or C1-6alkyl; R38 is hydrogen or C1-6alkyl; e is 1, 2, 3, 4, 5 or 6; R39 is C1-6alkoxy, CO2H, CO2C1-6alkyl or CONR36R37; R40 is C1-6alkyl; R41 and R42 are independently hydrogen or C1-6alkyl; alternatively, R5 and R6 form a fused benzo ring optionally substituted with C1-6 alkyl, C1-6alkoxy or halogen; when Ar is (i), (ii) or (iii), and A is CONR46, [NHCO, â€”NHCH2,] or CH2NH, where R46 is hydrogen or C1-6alkyl, E represents (a): â€ƒin which R47 and R48 are independently hydrogen or C1-6alkyl; R49 is hydrogen, C1-6alkyl, CO2R53, NHCO2R54, hydroxy, C1-6alkoxy or halogen where R53 is hydrogen or C1-6alkyl and R54 is C1-6alkyl; R50 and R51 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 containing one to two heteroatoms selected from oxygen, nitrogen or sulfur; B is oxygen, S(O)h where h is 0, 1 or 2, CR55&boxH;CR56 or CR55R56 where R55 and R56 are independently hydrogen or C1-6alkyl, or B is NR57 where R57 is hydrogen, C1-6alkyl or phenylC1-6alkyl; R52 is hydrogen or R52 taken together with R46 forms a group D where D is (CR58R59)i where i is 2, 3 or 4 and R58 and R59 are independently hydrogen or C1-6alkyl or D is (CR58R59)jâ€”G where j is 0, 1, 2 or 3 and G is oxygen, sulfur or CR58&boxH;CR59; f is 1 to 4; and g is 1 or 2; provided that the compound of formula (I) is not N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-4â€²-(5-dimethylamino-1,2,4-oxadiazol-3-yl)-2â€²-methylbiphenyl-4-carboxamide; N-[3-(1-Methylazetidin-2-ylmethoxy)-4-methoxyphenyl]-4â€²-(5-methyl-1,2,4-oxadiazol-3-yl)-2â€²-methylbiphenyl-4-carboxamide; [7-(2-Dimethylaminoethoxy)-6-methoxy-3,4-dihydro-2H-quinolin-1-yl]-[2â€²-methyl-[1,2,4]-oxadiazol-3-yl)biphenyl-4-yl]-methanone oxalate; 2,3,6,7-Tetrahydro-1â€²-methyl-5-[2â€²-methyl-4â€²-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl]-furo[2,3-f]indole-3-spiro-3â€²-piperidine oxalate; 5-[4â€²-(5-Methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl]-1â€²-methyl-2,3,6,7-tetrahydrofuro[2,3-f]indole-3-spiro-4â€²-piperidine; 1â€²-Ethyl-5-[2â€²-methyl-4â€²-(5-methyl-1,2,4-oxadiazol-3-yl)-biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospirofuro[2,3-f]indole-3,4â€²-piperidine; N-[2-(2-Dimethylamino)ethoxy-phenyl]-[1,1â€²-biphenyl]-4-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]benzamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-[1,1â€²-biphenyl]-2-carboxamide; N-[3-(2-Diethylamino)ethoxy-4-methoxyphenyl]-4-(methoxy)benzamide; N-[3-(2-Diethylamino)ethoxy-4-methoxyphenyl]-4-(nitro)benzamide; N-[3-(2-Diethylamino)ethoxy-4-methoxyphenyl]-4-(nitro)benzamide; N-[3-(2-Dimethylamino)ethoxy-4-methoxyphenyl]-4-(nitro)benzamide; N-[3-(Dimethylamino)ethoxy-4-methoxyphenyl]-[1,1â€²-biphenyl]-4-carboxamide; N-[3-(2-Dimethylamino)ethoxy-4-methoxyphenyl]-4â€²-chloro-[1,1â€²-biphenyl]-4-carboxamide; N-[3-(2-Diethylamino)ethoxy-4-methoxyphenyl]-4â€²-hydroxy-[1,1â€²-biphenyl]-4-carboxamide; N-[3-(2-Diethylamino)ethoxy-4-methoxyphenyl]-4â€²-acetyl-[1,1â€²-biphenyl]-4-carboxamide; N-[3-(2-Dimethylamino)ethoxy-4-methoxyphenyl]-4â€²-acetyl-[1,1â€²-biphenyl]-4-carboxamide; N-[3-(2-Dimethylamino)ethoxy-4-methoxyphenyl]-3â€²-chloro-[1,1â€²-biphenyl]-4-carboxamide; N-[3-(2-Diethylamino)ethoxy-4-methoxyphenyl]-3â€²-nitro-[1,1â€²-biphenyl]-4-carboxamide; N-[3-(2-Dimethylamino)ethoxy-4-methoxyphenyl]-3â€²-nitro-[1,1â€²-biphenyl]-4-carboxamide; N-[3-(2-Diethylamino)ethoxy-4-methoxyphenyl]-4-iodobenzamide; N-[4-(2-Diethylamino)ethoxy-phenyl]-4-iodobenzamide; N-[2-(2-Diisopropylamino)ethoxy-phenyl]-4-iodobenzamide; N-[4-(2-Diethylamino)ethoxy-phenyl]-3-iodobenzamide; N-[2-(2-Diisopropylamino)ethoxy-phenyl]-3-iodobenzamide; N-[2-(2-Diethylamino)ethoxy-phenyl]-3-iodobenzamide; N-[3-(2-Diethylamino)ethoxy-phenyl]-4-bromobenzamide; N-[2-(2-Diisopropylamino)ethoxy-phenyl]-4-bromobenzamide; N-[2-(2-Diethylamino)ethoxy-phenyl]-4-bromobenzamide; N-[4-(2-Diethylamino)ethoxy-phenyl]-3-bromobenzamide; N-[2-(2-Diisopropylamino)ethoxy-phenyl]-3-bromobenzamide; N-[2-(2-Diethylamino)ethoxy-phenyl]-3-bromobenzamide; N-[3-(2-Diethylamino)ethoxy-4-methoxyphenyl]-4-(dimethylamino)benzamide; N-[4-(2-Diisopropylamino)ethoxy-phenyl]-4-(dimethylamino)benzamide; N-[4-(2-Diethylamino)ethoxy-phenyl]-4-(dimethylamino)benzamide; N-[2-(2-Diisopropylamino)ethoxy-phenyl]-4-(dimethylamino)benzamide; N-[2-(2-Diethylamino)ethoxy-phenyl]-4-(dimethylamino)benzamide; N-[4-(2-Diethylamino)ethoxy-phenyl]-4-(isopropyl)benzamide; N-[2-(2-Diisopropylamino)ethoxy-phenyl]-4-(isopropyl)benzamide; N-[2-(2-Diethylamino)ethoxy-phenyl]-4-(isopropyl)benzamide; N-[3-(2-Diethylamino)ethoxy-phenyl]-4-(cyclohexyl)benzamide; N-[2-(2-Diisopropylamino)ethoxy-phenyl]-4-(cyclohexyl)benzamide; N-[2-(2-Diethylamino)ethoxy-phenyl]-4-(cyclohexyl)benzamide; N-[2-(2-Diisopropylamino)ethoxy-phenyl]-4â€²-ethyl-[1,1â€²-biphenyl]-4-carboxamide; and N-[2-(2-Diethylamino)ethoxy-phenyl]-4â€²-ethyl-[1,1â€²-biphenyl]-4-carboxamide.