Patent ID: 6313312
Filing Date: 2001-11-06
Classification: A61P,C07D

Abstract:
A compound of the formula I ##STR259##wherein the ""Ar"" ring represents an optionally benzo-fused phenyl or 5- or 6-membered heteroaryl ring;R.sup.1 when taken alone is H, halogen, NO.sub.2, NH.sub.2, NY.sup.2 WY.sup.1, Het.sup.1, AD, CO.sub.2 R.sup.7, C(O)R.sup.8, C(.dbd.NOH)R.sup.8, or OE,Y.sup.2 is H, C.sub.1-6 alkyl, C.sub.3-6 alkenyl (each of which alkyl and alkenyl is optionally substituted by aryl, aryloxy or Het.sup.1),W is SO.sub.2, CO, C(O)O, P(Y.sup.1).dbd.O, P(Y.sup.1).dbd.S,Y.sup.1 is C.sub.1-10 alkyl (optionally substituted by one or more substituents independently selected from halogen, OH, C.sub.1-4 alkoxy, C.sub.1-6 alkanoyloxy, CONH.sub.2, C.sub.1-6 alkoxycarbonyl, NH.sub.2, aryl, mono- or di(C.sub.1-4 alkyl)amino, C.sub.3-8 cycloalkyl, phthalimidyl, Het.sup.1), Het.sup.1, aryl (optionally substituted by one or more substituents independently selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl and halogen), NH.sub.2, N(C.sub.1-6 alkyl).sub.2 or NH(C.sub.1-6 alkyl),Het.sup.1 is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (preferably a heteroaryl group, optionally benzo- or pyrido-fused heteroaryl), optionally substituted by one or more substituents independently selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 haloalkoxy, C.sub.1-6 haloalkyl, C.sub.3-6 halocycloalkyl, .dbd.O, OH, halogen, NO.sub.2, SiR.sup.19a R.sup.19b R.sup.19c, CON.sup.20a R.sup.20b, NR.sup.20a R.sup.20b, SR.sup.21a, NR.sup.21b SO.sub.2 R.sup.22a, NR.sup.21c C(O)OR.sup.22b, NR.sup.21d COR.sup.22d, and C.sub.1-6 alkoxycarbonyl, and if a S atom is present in a ring, it can be present as part of a --S--, S(O)-- or --S(O.sub.2)-- group, and carbon atoms in the ring can be present as a part of a carbonyl moiety;R.sup.19a, R.sup.19b, R.sup.19c each independently represent C.sub.1-6 alkyl or aryl,R.sup.20a and R.sup.20b each independently represent H, C.sub.1-6 alkyl, aryl, (C.sub.1-4 alkyl)phenyl, each of which alkyl, aryl and alkylphenyl are optionally substituted by one or more C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OH, NO.sub.2, NH.sub.2 and/or halogen, or R.sup.20a and R.sup.20b can be taken together with the N atom to which they are attached, to form a 4- to 6-membered ring optionally substituted by one or more substituents independently selected from one or more C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OH, .dbd.O, NO.sub.2, NH.sub.2 and/or halogen,R.sup.21a, b, c and d each independently represent H, C.sub.1-6 alkyl, aryl or C.sub.1-4 alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OH, NO.sub.2, halogen, NH.sub.2,R.sup.22a, b and c each independently represent C.sub.1-6 alkyl, aryl or C.sub.1-4 alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OH, NO.sub.2, halogen, NH.sub.2,A is C.sub.1-4 alkylene, C.sub.2-4 alkenylene or C.sub.2-4 alkynylene, each of which is optionally substituted by one or more C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen and/or OH,D is H, OH, CN, NR.sup.25 R.sup.26, CONR.sup.25 R.sup.26, NHR.sup.27, CO.sub.2 R.sup.28, COR.sup.29,C(.dbd.NOH)R.sup.29,or AD is CN, NR.sup.25 R.sup.26, CONR.sup.25 R.sup.26,where R.sup.25 and R.sup.26 are either each independently H, C.sub.1-3 alkyl, C.sub.3-8 cycloalkyl, aryl, C.sub.1-4 alkylphenyl (each of which C.sub.1-3 alkyl, C.sub.3-8 cycloalkyl, aryl and C.sub.1-4 alkylphenyl are optionally substituted by one or more NO.sub.2, halogen, C.sub.1-4 alkyl and/or C.sub.1-4 alkoxy, (each of which latter C.sub.1-4 alkyl and C.sub.1-4 alkoxy is optionally substituted by one or more halogen)),or R.sup.25 and R.sup.26 are taken together with the N atom to which they are attached and can form a 4- to 7-membered heterocyclic ring optionally incorporating one or more further hetero atoms selected from N, O and S, and which ring is optionally substituted by one or more C.sub.1-4 alkyl, OH, .dbd.O, NO.sub.2, NH.sub.2 and/or halogen,R.sup.27 is COR.sup.30, CO.sub.2 R.sup.31a, SO.sub.2 R.sup.31b,R.sup.28 and R.sup.29 are each independently H, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, aryl or C.sub.1-4 alkylphenyl, each of which C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, aryl and C.sub.1-4 alkylphenyl are optionally substituted by one or more NO.sub.2, halogen, C.sub.14 alkyl, C.sub.1-4 alkoxy (each of which latter C.sub.1-4 alkyl and C.sub.1-4 alkoxy are optionally substituted by one or more halogen),R.sup.30 is H, C.sub.1-4 alkyl, C.sub.3-8 cycloalkyl, C.sub.1-4 alkoxy, C.sub.3-8 cycloalkyloxy, aryl, aryloxy, C.sub.1-4 alkylphenyl, phenyl(C.sub.1-4)alkoxy, (each of which C.sub.14 alkyl, C.sub.3-8 cycloalkyl, C.sub.1-4 alkoxy, C.sub.3-8 cycloalkyloxy, aryl, aryloxy, C.sub.1-4 alkylphenyl and phenyl(C.sub.1-4)alkoxy are optionally substituted by one or more NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy (which latter alkyl and alkoxy are optionally substituted by one or more halogen)),R.sup.31a and R.sup.31b are each independently C.sub.1-4 alkyl, C.sub.3-8 cycloalkyl, aryl or C.sub.1-4 alkylphenyl, each of which is optionally substituted by one or more NO.sub.2, halogen, C.sub.1-4 alkyl or C.sub.1-4 alkoxy, each of which latter alkyl and alkoxy is optionally substituted by one more halogenE is H, CONR.sup.32 R.sup.33, CSNR.sup.32 R.sup.33, COR.sup.34, CO.sub.2 R.sup.34, COCH(R.sup.34a)NH.sub.2, R.sup.35, CH.sub.2 CO.sub.2 R.sup.35a, CHR.sup.35b CO.sub.2 R.sup.35a, CH.sub.2 OCO.sub.2 R.sup.35c, CHR.sup.35d OCO.sub.2 R.sup.35c, COCR.sup.36.dbd.CR.sup.37 NH.sub.2, COCHR.sup.36 CHR.sup.37 NH.sub.2, or PO(OR.sup.38).sub.2,R.sup.32 and R.sup.33 are each independently H, C.sub.3-10 alkylalkenyl, C.sub.3-7 cycloalkyl (optionally substituted by C.sub.1-4 alkyl), phenyl (optionally substituted by (X).sub.n), C.sub.1-10 alkyl (optionally substituted by C.sub.4-7 cycloalkyl (optionally substituted by C.sub.1-4 alkyl) or phenyl optionally substituted by (X).sub.n),or R.sup.32 and R.sup.33 can be taken together with the N atom to which they are attached and can form a 5- to 8-membered heterocycle optionally comprising further hetero atoms selected from N, O and S, which heterocycle is optionally substituted by C.sub.1-4 alkyl, optionally substituted by one or more halogen,R.sup.34 is H, C.sub.4-7 cycloalkyl (optionally substituted by one or more C.sub.1-4 alkyl), phenyl (optionally substituted by (X).sub.n, C.sub.1-4 alkanoyloxy, NR.sup.32 R.sup.33, CONR.sup.32 R.sup.33 and/or OH), or C.sub.1-6 alkyl (optionally substituted by one or more halogen, C.sub.4-7 cycloalkyl (optionally substituted by one or more C.sub.1-4 alkyl), or phenyl (optionally substituted by (X).sub.n, C.sub.1-4 alkanoyloxy, NR.sup.32 R.sup.33 CONR.sup.32 R.sup.33 and/or OH)),R.sup.34a is H, C.sub.1-6 alkyl (optionally substituted by one or more halogen, C.sub.4-7 cycloalkyl (optionally substituted by one or more C.sub.1-4 alkyl), or phenyl (optionally substituted by (X).sub.n, C.sub.1-4 alkanoyloxy, NR.sup.32 R.sup.33, CONR.sup.32 R.sup.33 and/or OH)), C.sub.4-7 cycloalkyl (optionally substituted by one or more C.sub.1-4 alkyl), phenyl (optionally substituted by (X).sub.n, C.sub.1-4 alkanoyloxy, NR.sup.32 R.sup.33, CONR.sup.32 R.sup.33 and/or OH) or a naturally occuring amino acid substituent,R.sup.35 is C.sub.4-7 cycloalkyl optionally substituted by one or more C.sub.1-4 alkyl, phenyl (optionally substituted by one or more (X).sub.n, C.sub.1-4 alkanoyl, NHR.sup.32, CON(R.sup.32).sub.2, and/or OH), C.sub.1-6 alkyl (optionally substituted by C.sub.4-7 cycloalkyl optionally substituted by one or more C.sub.1-4 alkyl, or phenyl (optionally substituted by one or more (X).sub.n, C.sub.1-4 alkanoyl, NHR.sup.32, CON(R.sup.32).sub.2, and/or OH)), C.sub.1-4 alkoxy(C.sub.1-4 alkyl), phenyl(C.sub.1-4)alkyloxy(C.sub.1-4)alkyl, tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl,R.sup.35a,b,c and d are each independently H, C.sub.4-7 cycloalkyl optionally substituted by one or more C.sub.1-4 alkyl, phenyl optionally substituted by one or more (X).sub.n or C.sub.1-6 alkyl (optionally substituted by C.sub.4-7 cycloalkyl optionally substituted by one or more C.sub.1-4 alkyl, or phenyl optionally substituted by one or more (X).sub.n),R.sup.36 and R.sup.37 each independently represent H, C.sub.3-6 alkylalkenyl, C.sub.4-7 cycloalkyl, phenyl optionally substituted by one or more (X).sub.n, or C.sub.1-6 alkyl (optionally substituted by C.sub.4-7 cycloalkyl optionally substituted by one or more C.sub.1-4 alkyl, or phenyl optionally substituted by one or more (X).sub.n),R.sup.38 is C.sub.4-7 cycloalkyl optionally substituted by one or more C.sub.1-4 alkyl, phenyl optionally substituted by one or more (X).sub.n, or C.sub.1-6 alkyl (optionally substituted by C.sub.4-7 cycloalkyl optionally substituted by one or more C.sub.1-4 alkyl, or phenyl optionally substituted by one or more (X).sub.n),R.sup.2 when taken alone is H or halogen;or R.sup.1 and R.sup.2, when attached to adjacent carbon atoms, can be taken together with the carbon atoms to which they are attached, and may represent Het.sup.1a ;Het.sup.1a is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (and is preferably an optionally benzo-fused 5- to 7-membered heterocyclic ring) and which group is optionally substituted by one or more substituents independently selected from OH, .dbd.O, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy, which C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy groups can be optionally substituted by one or more C.sub.3-6 cycloalkyl, aryl(C.sub.1-6)alkyl, which aryl group is optionally substituted by one or more halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy,which latter C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy groups can be optionally substituted by one or more NR.sup.23 R.sup.24, NR.sup.23 S(O).sub.n R.sup.24, NR.sup.23 C(O).sub.m R.sup.24, and if a S atom is present in a ring, it can be present as part of a --S--, S(O)-- or --S(O.sub.2)-- group,which R.sup.23 and R.sup.24 when taken alone independently represent H, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl,or R.sup.23 and R.sup.24 can be taken together with the N atom to which they are attached, to form a 4- to 6-membered heterocyclic ring optionally comprising one or more further heteroatoms selected from, N, O, or S, and which heterocyclic ring is optionally substituted by one or more halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and/or C.sub.1-4 haloalkoxy groups,R.sup.3 is C.sub.1-6 alkyl optionally substituted by one or more CN, halogen, OH, C.sub.1-6 alkoxy, C.sub.1-6 alkoxycarbonyl, C.sub.2-6 alkyloxycarbonyloxy, C.sub.1-6 alkanoyl, C.sub.1-6 alkanoyloxy, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyloxy, C.sub.4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR.sup.12 R.sup.13, CONR.sup.12 R.sup.13 and/or NY.sup.2 WY.sup.1,R.sup.4 is C.sub.1-10 alkyl, C.sub.3-10 alkenyl or C.sub.3-10 alkynyl each of which groups is linked to the N atom via a sp.sup.3 carbon, and which is optionally substituted by one or more OH, CN, halogen, C.sub.1-6 alkoxy (optionally substituted by aryl), aryloxy (optionally substituted by one or more halogen, C.sub.1-6 alkyl(optionally substituted by one or more CN and/or halogen), C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, OH, .dbd.O and/or NY.sup.2 WY.sup.1), C.sub.1-6 alkoxycarbonyl, C.sub.2-6 alkanoyl, C.sub.2-6 alkanoyloxy, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyloxy, C.sub.4-9 cycloalkanoyl, aryl (optionally substituted by one or more halogen, C.sub.1-6 alkyl(optionally substituted by one or more CN and/or halogen), C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, OH, .dbd.O and/or NY.sup.2 WY.sup.1), C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, OH, C.sub.1-4 haloalkoxy, and/or NY.sup.2 WY.sup.1), heterocycle (optionally benzo-fused and optionally substituted by one or more halogen, C.sub.1-6 alkyl (optionally substituted by one or more CN and/or halogen), C.sub.1-4 alkoxy, OH, .dbd.O, C.sub.1-4 haloalkoxy, and/or NY.sup.2 WY.sup.1), heterocyclyloxy (optionally substituted by one or more halogen, C.sub.1-6 alkyl (optionally substituted by one or more CN and/or halogen), C.sub.1 4 alkoxy, OH, .dbd.O, C.sub.1-4 haloalkoxy, and/or NY.sup.2 WY.sup.1), adamantyl or ZBNR.sup.14 R.sup.15,Z is a direct bond, CO or S(O).sub.n group,B is (CH.sub.2).sub.p,R.sup.12 and R.sup.13 each independently represent Hl or C.sub.1-4 alkyl,or R.sup.12 and R.sup.13 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from NR.sup.16, O and/or S, and which is optionally substituted by one or more C.sub.1-4 alkyl,R.sup.14 and R.sup.15 each independently represent H, C.sub.1-10 alkyl, C.sub.3-10 alkenyl, C.sub.3-10 alkynyl, C.sub.3-8 cycloalkyl, aryl or heteroaryl,or R.sup.14 and R.sup.15 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from NR.sup.16, O and/or S, and which is optionally substituted by one or more C.sub.1-4 alkyl,R.sup.16 is H, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, (C.sub.1-6 alkylene)(C.sub.3-8 cycloalkyl) or (C.sub.1-6 alkylene)aryl,R.sup.5 and R.sup.8 when taken separately are each independently H, C.sub.1-6 alkyl,R.sup.5 and R.sup.8 can be taken together with the carbon atoms to which they are joined to form a C.sub.3-8 cycloalkyl ring,R.sup.6, R.sup.7, R.sup.9 and R.sup.10 when taken separately are H,R.sup.5 and R.sup.6 or R.sup.7 can be taken together with the carbon atoms to which they are joined to form a C.sub.3-8 cycloalkyl ring,X is halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl or C.sub.1-4 haloalkoxy,m is 1 or 2;n is 0, 1 or 2;p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;q is 0 or 1;""Naturally occuring amino acid substituent"" means the (.alpha.-substituent that occurs in any one of the following natural amino acids, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine or proline;""Heteroaryl"" represents an aromatic ring containing up to four heteroatoms independently selected from N, O and S, and if a S atom is present in the ring, it can be present as part of a --S--, S(O)-- or --S(O).sub.2 -- group, and which may be joined to the remainder of the compound via any available atom(s);""Heterocycle"" is a group containing 1, 2 or 3 rings, and which contains up to 4 ring heteroatoms selected from N, O and S and up to 18 ring carbon atoms;""Aryl"", including in the definitions of ""aryloxy"", etc., means a group comprising a phenyl ring and which may incorporate a further carbocyclic ring fused to said phenyl ring and which may be joined to the remainder of the compound via any available atom(s) (examples of such groups include naphthyl, indanyl, etc.);""Alkyl"", ""alkenyl"" and ""alkynyl"" groups can be linear or branched if the number of carbon atoms allows;""Cycloalkyl"" groups can be polycyclic if the number of carbon atoms allows;or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof.