Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them

A compound of the formula (I),

• 49
• or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein
• X is —O—, —S—, —SO—, or —SO2—;
• HET is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O, and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from C1-4alkyl, amino, C1-4alkylamino, C1-4alkoxy, C1-4alkoxycarbonyl, and halogen, and/or on an available nitrogen atom by C1-4alkyl, provided that the ring is not thereby quaternized;
• 50
• R2 and R3 are independently hydrogen or fluoro;
• T is selected from TC1, TC2, TC3, and TC4, or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof;
• 51
• >represents two single bonds;
• wherein in TC1:
• >A3-B3— is >C(Rq)-CH(Rr)- and G is —O—, —S—, —SO—, —SO2—, or >N(Rc);
• wherein in TC2:
• >A3-B3— is >C═C(Rr)- or >C(Rq)-CH(Rr)- and G is —O—, —S—, —SO—, —SO2—, or >N(Rc);
• wherein in TC3:
• >A3-B3— is >C(Rq)-CH(Rr)-, Rq and Rr are not both hydrogen, and G is —O—, —S—, —SO—, —SO2—, or >N(Rc);
• wherein in TC4:
• >A3-B3— is >C═C(Rr)-, >C(Rq)-CH(Rr)-, or >N—CH2—;
• and Rp is hydrogen, C1-4alkyl (other than when such substitution is defined by >A3-B3—), hydroxy, C1-4alkoxy, or C1-4alkanoyloxy, and G is —O—, —S—, —SO—, —SO2—, or >N(Rc);
• or
• wherein in TC1, TC2, and TC4:
• >A3-B3— is >N—CH2— and G is >C(R11)(R12), >C═O, >C—OH, >C—C1-4alkoxy, >C═N—OH, >C═N—C1-4alkoxy, >C═N—NH—C1-4alkyl, >C═N—N—CO—C1-4alkoxy, or >C═N—N(C1-4alkyl)2 wherein the N(C1-4alkyl)2 alkyl groups are optionally substituted by hydroxy;
• m1 is 0, 1, or2;
• m2 is 0, 1, or 2;
• n1 is 1 or2;
• o1 is 1 or2;
• and
• n1+o1 is 2 or 3;
• Rq is hydrogen, hydroxy, halo, C1-4alkyl, or C1-4alkanoyloxy;
• Rr is independently hydrogen or C1-4alkyl;
• R11 is hydrogen, C1-4alkyl, fluoroC1-4alkyl, C1-4alkylthioC1-4alkyl, or hydroxyC1-4alkyl;
• R12 is —(C(Rr)(Rr))m2-N(Rr)(Rc);
• and
• other than the ring substitution defined by G, >A3-B3—, and Rp, each ring system may be optionally further substituted on a carbon atom not adjacent to the link at >A3- by up to two substituents independently selected from C1-4alkyl, fluoroC1-4alkyl, C1-4alkylthioC1-4alkyl, hydroxyC1-4alkyl, amino, aminoC1-4alkyl, C1-4alkanoylamino, C1-4alkanoylaminoC1-4alkyl, carboxy, C1-4alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl, Rc, and oxo (═O), except when G is >N—Rc and Rc is Rc2, and if G is —O— or —S—, then hydroxy or halo;
• and
• wherein AR is optionally substituted phenyl, optionally substituted phenylC1-4alkyl, optionally substituted naphthyl, optionally substituted 5- or 6-membered heteroaryl;
• or optionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system, in which the bicyclic heteroaryl ring systems may be linked via an atom in either of the rings comprising the bicyclic system, and wherein both the mono- and bicyclic heteroaryl ring systems are linked via a ring carbon atom and may be partially hydrogenated;
• Rc is selected from Rc1, Rc2, Rc3, Rc4, and Rc5;
• Rc1 is C1-6alkyl, optionally substituted by one or more C1-4alkanoyl groups, optionally geminally substituted by C1-4alkanoyl groups, and optionally monosubstituted by cyano, C1-4alkoxy, trifluoromethyl, C1-4alkoxycarbonyl, optionally substituted phenyl, and C1-4alkylS(O)q—;
• or, on any but the first carbon atom of the C1-6alkyl chain, optionally substituted by one or more groups each independently selected from hydroxy and fluoro, optionally geminally substituted by one or more groups each independently selected from hydroxy and fluoro, and optionally monosubstituted by oxo, —NRvRw, C1-6alkanoylamino, C1-4alkoxycarbonylamino, N—C1-4alkyl-N—C1-6alkanoylamino, C1-4alkylS(O)pNH—, or C1-4alkylS(O)p—(C1-4alkyl)N—;
• Rc2 is R13CO—, R13SO2—, or R13CS—;
• R13 is selected from Rc2a, Rc2b, Rc2c, Rc2d, and Rc2e;
• Rc2a is AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, or CY2;
• Rc2b is hydrogen, C1-4alkoxycarbonyl, trifluoromethyl, —NRvRw, ethenyl, 2-C1-4alkylethenyl, 2-cyanoethenyl, 2-cyano-2-(C1-4alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-(C1-4alkyl)ethenyl, 2-(C1-4alkylaminocarbonyl)ethenyl, 2-(C1-4alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, or 2-(AR2a)ethenyl;
• Rc2c is C1-10alkyl optionally substituted by one or more groups, optionally geminally disubstituted, each independently selected from hydroxy, C1-10alkoxy, C1-4alkoxy-C1-4alkoxy, C1-4alkoxy-C1-4alkoxy-C1-4alkoxy, C1-4alkanoyl, phosphoryl (—O—P(O)(OH)2 and mono- and di-C1-4alkoxy derivatives thereof), phosphiryl (—O—P(OH)2 and mono- and di-C1-4alkoxy derivatives thereof), and amino;
• and optionally substituted by one group selected from carboxy, phosphonate (phosphono, —P(O)(OH)2, and mono- and di-C1-4alkoxy derivatives thereof), phosphinate (—P(OH)2 and mono- and di-C1-4alkoxy derivatives thereof), cyano, halo, trifluoromethyl, C1-4alkoxycarbonyl, C1-4alkoxy-C1-4alkoxycarbonyl, C1-4alkoxy-C1-4alkoxy-C1-4alkoxycarbonyl, C1-4alkylamino, di(C1-4alkyl)amino, C1-6alkanoylamino, C1-4alkoxycarbonylamino, N—C1-4alkyl-N—C1-6alkanoylamino, C1-4alkylaminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alkylS(O)pNH—, C1-4alkylS(O)p—(C1-4alkyl)N—, fluoroC1-4alkylS(O)pNH—, fluoroC1-4alkylS(O)p(C1-4alkyl)N—, C1-4alkylS(O)q—, CY1, CY2, AR1, AR2, AR3, AR1-O—, AR2-O—, AR3-O—, AR1-S(O)q—, AR2-S(O)q—, AR3-S(O)q—, AR1-NH—, AR2-NH—, AR3-NH—, AR2a, AR2b, AR3a, and AR3b;
• Rc2d is R14C(O)OC1-6alkyl;
• R14 is AR1, AR2, C1-4alkylamino, benzyloxy-C1-4alkyl, or C1-10alkyl optionally substituted by one or more groups, optionally geminally disubstituted, each independently selected from hydroxy, C1-10alkoxy, C1-4alkoxy-C1-4alkoxy, C1-4alkoxy-C1-4alkoxy-C1-4alkoxy, C1-4alkanoyl, phosphoryl (—O—P(O)(OH)2 and mono- and di-C1-4alkoxy derivatives thereof), phosphiryl (—O—P(OH)2 and mono- and di-C1-4alkoxy derivatives thereof), and amino;
• and optionally substituted by one group selected from carboxy, phosphonate (phosphono, —P(O)(OH)2, and mono- and di-C1-4alkoxy derivatives thereof), phosphinate (—P(OH)2 and mono- and di-C1-4alkoxy derivatives thereof), cyano, halo, trifluoromethyl, C1-4alkoxycarbonyl, C1-4alkoxy-C1-4alkoxycarbonyl, C1-4alkoxy-C1-4alkoxy-C1-4alkoxycarbonyl, C1-4alkylamino, di(C1-4alkyl)amino, C1-6alkanoylamino, C1-4alkoxycarbonylamino, N—C1-4alkyl-N—C1-6alkanoylamino, C1-4alkylaminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alkylS(O)pNH—, C1-4alkylS(O)p—(C1-4alkyl)N—, fluoroC1-4alkylS(O)pNH—, fluoroC1-4alkylS(O)p(C1-4alkyl)N—, C1-4alkylS(O)q—, CY1, CY2, AR1, AR2, AR3, AR1-O—, AR2-O—, AR3-O—, AR1-S(O)q—, AR2-S(O)q—, AR3-S(O)q—, AR1-NH—, AR2-NH—, AR3-NH—, AR2a, AR2b, AR3a, and AR3b;
• Rc2e is R15O—;
• R15 is benzyl, CY1, CY2, AR2b, or C1-6alkyl, optionally substituted by one or more groups, optionally geminally disubstituted, each independently selected from hydroxy, C1-10alkoxy, C1-4alkoxy-C1-4alkoxy, C1-4alkoxy-C1-4alkoxy-C1-4alkoxy, C1-4alkanoyl, phosphoryl (—O—P(O)(OH)2, and mono- and di-C1-4alkoxy derivatives thereof), phosphiryl (—O—P(OH)2 and mono- and di-C1-4alkoxy derivatives thereof), and amino;
• and optionally substituted by one group selected from carboxy, phosphonate (phosphono, —P(O)(OH)2, and mono- and di-C1-4alkoxy derivatives thereof), phosphinate (—P(OH)2 and mono- and di-C1-4alkoxy derivatives thereof), cyano, halo, trifluoromethyl, C1-4alkoxycarbonyl, C1-4alkoxy-C1-4alkoxycarbonyl, C1-4alkoxy-C1-4alkoxy-C1-4alkoxycarbonyl, C1-4alkylamino, di(C1-4alkyl)amino, C1-6alkanoylamino, C1-4alkoxycarbonylamino, N—C1-4alkyl-N—C1-6alkanoylamino, C1-4alkylaminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alkylS(O)pNH—, C1-4alkylS(O)p—(C1-4alkyl)N—, fluoroC1-4alkylS(O)pNH—, fluoroC1-4alkylS(O)p(C1-4alkyl)N—, C1-4alkylS(O)q—, CY1, CY2, AR1, AR2, AR3, AR1-O—, AR2-O—, AR3-O—, AR1-S(O)q—, AR2-S(O)q—, AR3-S(O)q—, AR1-NH—, AR2-NH—, AR3-NH—, AR2a, AR2b, AR3a, and AR3b;
• Rc3 is hydrogen, cyano, 2-cyanoethenyl, 2-cyano-2-(C1-4alkyl)ethenyl, 2-(C1-4alkylaminocarbonyl)ethenyl, 2-(C1-4alkoxycarbonyl)ethenyl, 2-nitroethenyl, 2-nitro-2-(C1-4alkyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, or Rc3 a;
• Rc3a is
• 52
• X00 is —OR17, —SR17, —NHR17, or —N(R17)2 ;
• R17 is hydrogen when X00 is —NHR17 or —N(R17)2;
• or R17 is C1-4alkyl, phenyl, or AR2 when X00 is —OR17, —SR17, and —NHR17;
• R16 is cyano, nitro, C1-4alkylsulfonyl, C47cycloalkylsulfonyl, phenylsulfonyl, C1-4alkanoyl, and C1-4alkoxycarbonyl;
• Rc4 is trityl, AR1, AR2, AR2a, AR2b, AR3, AR3a, or AR3b;
• Rc5 is RdOC(Re)═CH(C═O)—, RfC(═O)C(═O)—, RgN═C(Rh)C(═O)—, or RiNHC(Rj)═CHC(═O)—;
• Rd is C1-6alkyl;
• Re is hydrogen or C1-6alkyl;
• or Rd and Re together form a C3-4alkylene chain;
• Rf is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxyC1-6alkyl, —NRvRw, C1-6alkoxy, C1-6alkoxyC1-6alkoxy, hydroxyC2-6alkoxy, C1-4alkylaminoC2-6alkoxy, or di-C1-4alkylaminoC2-6alkoxy;
• Rg is C1-6alkyl, hydroxy, or C1-6alkoxy;
• Rh is hydrogen or C1-6alkyl;
• Ri is hydrogen, C1-6alkyl, AR1, AR2, AR2a, or AR2b;
• Rj is hydrogen or C1-6alkyl;
• Rv is hydrogen or C1-4alkyl;
• Rw is hydrogen or C1-4alkyl;
• AR1 is an optionally substituted phenyl or optionally substituted naphthyl;
• AR2 is an optionally substituted 5- or 6-membered, fully unsaturated monocyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N, and S, but not containing any O—O, O—S, or S—S bonds, and linked via a ring carbon atom, or a ring nitrogen atom if the nitrogen atom is not thereby quaternized;
• AR2a is a partially hydrogenated version of AR2, linked via a ring carbon atom or linked via a ring nitrogen atom if the nitrogen atom is not thereby quaternized;
• AR2b is a fully hydrogenated version of AR2, linked via a ring carbon atom or linked via a ring nitrogen atom;
• AR3 is an optionally substituted 8-, 9-, or 10-membered, fully unsaturated bicyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N, and S, but not containing any O—O, O—S, or S—S bonds, and linked via a ring carbon atom in either of the rings of the bicyclic system;
• AR3a is a partially hydrogenated version of AR3, linked via a ring carbon atom, or linked via a ring nitrogen atom if the nitrogen atom is not thereby quaternized, in either of the rings comprising the bicyclic system;
• AR3b is a fully hydrogenated version of AR3, linked via a ring carbon atom, or linked via a ring nitrogen atom, in either of the rings having the bicyclic system;
• AR4 is an optionally substituted 13- or 14-membered, fully unsaturated tricyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N, and S, but not containing any O—O, O—S, or S—S bonds, and linked via a ring carbon atom in any of the rings comprising the tricyclic system;
• AR4a is a partially hydrogenated version of AR4, linked via a ring carbon atom, or linked via a ring nitrogen atom if the nitrogen atom is not thereby quaternized, in any of the rings comprising the tricyclic system;
• CY1 is an optionally substituted cyclobutyl, cyclopentyl, or cyclohexyl ring;
• and
• CY2 is an optionally substituted cyclopentenyl or cyclohexenyl ring.

A compound of the formula (IP), or a pharmaceutically acceptable salt or an in vivo hydrolyzable ester thereof,

• 58
• wherein
• X is —O—, —S—, —SO—, or —SO2—;
• HET is a C-linked 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from N, O, and S, with the proviso that there are no O—O, O—S, or S—S bonds, which ring is optionally substituted on any available C atom, provided that when an N atom is adjacent to the X-link, there is no substitution on any C atom that is adjacent to this N atom, by 1 or 2 substituents independently selected from C1-4alkyl, amino, C1-4alkylamino, C1-4alkoxy, and halogen, and/or on an available N atom by C1-4alkyl, provided that the nitrogen atom is not thereby quaternized;
• R2 and R3 are independently hydrogen or fluoro;
• Rp is hydrogen, C1-4alkyl, hydroxy, C1-4alkoxy, or C2-4alkanoyloxy;
• >A-B— is of the formula >CC(Rr)-, >CHCHRr-, >C(OH)CHRr-, or >N—CH2—;
• >represents two single bonds;
• Rr is hydrogen or C1-4alkyl;
• D is —O—, —S—, —SO—, —SO2—, or >NRcp;
• Rp1 and Rp2 are independently oxo (═O), except when Rcp is PC, C1-4alkyl, C1-4alkanoylamino-C1-4alkyl, hydroxy-C1-4alkyl, carboxy, C1-4alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl, or independently as defined for Rcp hereinbelow, with the proviso that Rp1 and Rp2 are not phenyl, benzyl, AR, a tetrazole ring system, cyclopentyl, or cyclohexyl;
• and when D is —O— or —S—, Rp1 and Rp2 are additionally independently hydroxy or bromo;
• Rcp is selected from PA, PB, PC, PD, and PE;
• PA is hydrogen, cyano, 2-(C1-4alkoxycarbonyl)ethenyl, 2-cyanoethenyl, 2-cyano-2-(C1-4alkyl)ethenyl, or 2-(C1-4alkylaminocarbonyl)ethenyl;
• PB is phenyl, benzyl, AR, or a tetrazole ring system optionally mono-substituted in the 1- or 2-position of the tetrazole ring by C1-4alkyl, C2-4alkenyl, C2-4alkynyl, or C1-4alkanoyl, wherein the tetrazole ring system is joined to the nitrogen in >NRcp by a ring carbon atom;
• PC is R13pCO—, R13pSO2—, or R13pCS—;
• R13p is selected from PCa, PCb, PCc, PCd, PCe, and PCf;
• PCa is AR;
• PCb is cyclopentyl, cyclohexyl, 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl, or 1,4-dioxan-2-yl, optionally mono- or di-substituted by substituents independently selected from C1-4alkyl, hydroxy, C1-4alkoxy, C1-4alkylthio, acetamido, C1-4alkanoyl, cyano and trifluoromethyl, except 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl, or 1,4-dioxan-2-yl substituted by hydroxy, and optionally geminally substituted by C1-4alkyl;
• PCc is hydrogen, C1-4alkoxycarbonyl, trifluoromethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, 2-(5- or 6-membered heteroaryl)ethenyl, 2-(5- or 6-membered partially hydrogenated heteroaryl)ethenyl, or 2-phenylethenyl, wherein the heteroaryl or phenyl substituent is optionally substituted, valence and stability permitting, by up to three substituents independently selected from C1-4alkoxy, halo, cyano, and, for the phenyl substituent only, C1-4alkylsulfonyl;
• PCd is C1-10alkyl, optionally substituted by one or more groups each independently selected from hydroxy and amino, and optionally geminally di-substituted by two or more groups independently selected from hydroxy and amino, or optionally monosubstituted by cyano, halo, C1-10alkoxy, trifluoromethyl, C1-4alkoxy-C1-4alkoxy, C1-4alkoxy-C1-4alkoxy-C1-4alkoxy, C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4alkylamino, di(C1-4alkyl)amino, C1-6alkanoylamino, C1-4alkoxycarbonylamino, N—C1-4alkyl-N—C2-6alkanoylamino, C1-4alkylS(O)pNH—, C1-4alkylS(O)p—, (C1-4alkyl)N—, fluoroC1-4alkylS(O)pNH—, fluoroC1-4alkylS(O)p(C1-4alkyl)N—, phosphono, C1-4alkoxy(hydroxy)phosphoryl, di-C1-4alkoxyphosphoryl, C1-4alkylS(O)q—, phenyl, naphthyl, phenoxy, naphthoxy, phenylamino, naphthylamino, phenylS(O)q—, naphthylS(O)q—, or CY, wherein the phenyl and naphthyl groups are optionally substituted by up to three substituents independently selected from C1-4alkoxy, halo, and cyano;
• p is 1 or 2;
• q is 0, 1,or 2;
• PCe is R14pC(O)OC1-6alkyl;
• R14 is an optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl, C1-4alkylamino, benzyloxy-C1-4alkyl, or optionally substituted C1-10alkyl;
• PCf is R15pO—;
• R15p is benzyl or optionally substituted C1-6alkyl;
• PD is RdOC(Re)═CH(C═O)—, RfC(═O)C(═O)—, RgN═C(Rh)C(═O)—, or RiNHC(Rj)═CHC(═O)—;
• Rd is C1-6alkyl and Re is hydrogen or C1-6alkyl;
• or Rd and Re together form a C3-4alkylene chain;
• Rf is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxyC1-6alkyl, amino, C1-4alkylamino, di-C1-4alkylamino, C1-6alkoxy, C1-6alkoxyC1-6alkoxy, hydroxyC2-6alkoxy, C1-4alkylaminoC2-6alkoxy, or di-C1-4alkylaminoC2-6alkoxy;
• Rg is C1-6alkyl, hydroxy, or C1-6alkoxy;
• Rh is hydrogen or C1-6alkyl;
• Ri is hydrogen, C1-6alkyl, optionally substituted phenyl, an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted partially hydrogenated 5- or 6-membered heteroaryl;
• Rj is hydrogen or C1-6alkyl;
• PE is R16pCH(R17p)(CH2)mp—;
• R16p is hydrogen or C1-4alkyl;
• R17p is fluoro, cyano, C1-4alkoxy, C1-4alkylsulfonyl, C1-4alkoxycarbonyl or hydroxy, provided that when mp is 0, R17p is not fluoro or hydroxy;
• mp is 0 or 1;
• AR is optionally substituted phenyl, optionally substituted phenylC1-4alkyl, optionally substituted naphthyl, optionally substituted 5- or 6-membered heteroaryl or AR is an optionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system, in which the bicyclic heteroaryl ring systems may be linked via an atom in either of the rings comprising the bicyclic system, and wherein both the mono- and bicyclic heteroaryl ring systems are linked via a ring carbon atom and may be partially hydrogenated;
• wherein when AR is optionally substituted 5- or 6-membered heteroaryl, it is a 5- or 6-membered aryl ring wherein 1, 2, or 3 of the ring atoms are selected from nitrogen, oxygen, and sulfur and the rings are fully aromatic;
• when AR is optionally substituted 5/6 or 6/6 bicyclic heteroaryl, it is an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5-membered ring or another 6-membered ring, the bicyclic ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur in which the bicyclic heteroaryl ring systems may be linked via an atom in either of the rings comprising the bicyclic system, and wherein both the mono- and bicyclic heteroaryl ring systems are linked via a ring carbon atom and may be partially hydrogenated;
• CY is selected from:
• (i) cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl ring;
• (ii) 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryloxy, 5- or 6-membered heteroaryl-S(O)q—, 5- or 6-membered heteroarylamino, or partially hydrogenated 5- or 6-membered heteroarylamino;
• and
• (iii) 5/6 or 6/6 bicyclic heteroaryl, 5/6 or 6/6 bicyclic heteroaryloxy, 5/6 or 6/6 bicyclic heteroaryl-S(O)q—, 5/6 or 6/6 bicyclic heteroarylamino, or partially hydrogenated 5/6 or 6/6 bicyclic heteroarylamino;
• q is 0, 1 or2;
• wherein CY is optionally substituted by up to three substituents independently selected from halo, C1-4alkyl, acyl, oxo, and nitro-C1-4alkyl, and when CY is a cycloalkyl or cycloalkenyl ring, optionally geminally disubstituted by substituents selected from C1-4alkyl, halo, C1-4alkyl, acyl, oxo, and nitro-C1-4alkyl;
• wherein the optional substituents for alkyl, phenyl, phenyl containing moieties, naphthyl groups, and ring carbon atoms in mono- or bicyclo-heteroaryl rings in R14p, R15p, Ri, and AR are selected from halo, C1-4alkyl, hydroxy, nitro, carbamoyl, C1-4alkylcarbamoyl, di-(C1-4alkyl)carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkyl S(O)q—, carboxy, C1-4alkoxycarbonyl, C2-4alkenyl, C2-4alkynyl, C1-4alkanoyl, C1-4alkoxy, C1-4alkylS(O)2amino, C1-4alkanoylamino, benzoylamino, benzoyl, phenyl, optionally substituted by up to three substituents selected from halo, C1-4alkoxy, or cyano, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyiminoC1-4alkyl, C1-4alkoxyiminoC1-4alkyl, hydroxy-C1-4alkyl, halo-C1-4alkyl, nitroC1-4alkyl, aminoC1-4alkyl, cyanoC1-4alkyl, C1-4alkanesulfonamido, aminosulfonyl, C1-4alkylaminosulfonyl, and di-(C1-4alkyl)aminosulfonyl.