US2003144263A1PendingUtilityA1
Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them
Est. expiryJun 5, 2018(expired)· nominal 20-yr term from priority
Inventors:Michael Barry Gravestock
A61P 31/04C07D 413/12C07F 9/65583C07D 231/12C07F 9/59C07D 413/14C07D 487/08C07D 233/56C07D 417/12C07D 249/08C07D 451/02C07D 417/14
50
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Claims
Abstract
Compounds of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein, for example, X is —O— or —S—; HET is an optionally substituted C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S; Q is selected from, for example, Q1 and Q2 R 2 and R 3 are independently hydrogen or fluoro; T is selected from a range of groups, for example, an N-linked (fully unsaturated) 5-membered heteroaryl ring system or a group of formula (TC5): wherein Rc is, for example, R 13 CO—, R 13 SO 2 — or R 13 CS—; wherein R 13 is, for example, optionally substituted (1-10C)alkyl or R 14 C(O)O(1-6C)alkyl wherein R 14 is optionally substituted (1-10C)alkyl; are useful as antibacterial agents; and processes for their manufacture and pharmaceutical compositions containing them are described.
Claims
exact text as granted — not AI-modified1 . A compound of the formula (I),
or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein
X is —O—, —S—, —SO—, or —SO 2 —;
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 C 1-4 alkyl, amino, C 1-4 alkylamino, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, and halogen, and/or on an available nitrogen atom by C 1-4 alkyl, provided that the ring is not thereby quaternized;
R 2 and R 3 are independently hydrogen or fluoro;
T is selected from TCa, TCb, and TCc;
TCa is an optionally substituted, fully saturated 4-membered monocyclic ring containing 1 heteroatom selected from O, N, and S that is optionally oxidized, and linked via a ring nitrogen or sp 3 carbon atom;
TCb is an optionally substituted 5-membered monocyclic ring containing 1 heteroatom selected from O, N, and S that is optionally oxidized, and linked via a ring nitrogen atom or a ring sp 3 or sp 2 carbon atom, which monocyclic ring is fully saturated other than at a linking sp 2 carbon atom;
TCc is an optionally substituted 6- or 7-membered monocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S that is optionally oxidized, and linked via a ring nitrogen atom or a ring sp 3 or sp 2 carbon atom, which monocyclic ring is fully saturated other than at a linking sp 2 carbon atom.
2 . A compound of the formula (I),
or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein
X is —O—, —S—, —SO—, or —SO 2 —;
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 C 1-4 alkyl, amino, C 1-4 alkylamino, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, and halogen, and/or on an available nitrogen atom by C 1-4 alkyl, provided that the ring is not thereby quaternized;
R 2 and R 3 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;
>represents two single bonds;
wherein in TC1: >A 3 -B 3 — is >C(Rq)-CH(Rr)- and G is —O—, —S—, —SO—, —SO 2 —, or >N(Rc);
wherein in TC2: >A 3 -B 3 — is >C═C(Rr)- or >C(Rq)-CH(Rr)- and G is —O—, —S—, —SO—, —SO 2 —, or >N(Rc);
wherein in TC3: >A 3 -B 3 — is >C(Rq)-CH(Rr)-, Rq and Rr are not both hydrogen, and G is —O—, —S—, —SO—, —SO 2 —, or >N(Rc);
wherein in TC4: >A 3 -B 3 — is >C═C(Rr)-, >C(Rq)-CH(Rr)-, or >N—CH 2 —; and Rp is hydrogen, C 1-4 alkyl (other than when such substitution is defined by >A 3 -B 3 —), hydroxy, C 1-4 alkoxy, or C 1-4 alkanoyloxy, and G is —O—, —S—, —SO—, —SO 2 —, or >N(Rc); or
wherein in TC1, TC2, and TC4: >A 3 -B 3 — is >N—CH 2 — and G is >C(R 11 )(R 12 ), >C═O, >C—OH, >C—C 1-4 alkoxy, >C═N—OH, >C═N—C 1-4 alkoxy, >C═N—NH—C 1-4 alkyl, >C═N—N—CO—C 1-4 alkoxy, or >C═N—N(C 1-4 alkyl) 2 wherein the N(C 1-4 alkyl) 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, C 1-4 alkyl, or C 1-4 alkanoyloxy;
Rr is independently hydrogen or C 1-4 alkyl;
R 11 is hydrogen, C 1-4 alkyl, fluoroC 1-4 alkyl, C 1-4 alkylthioC 1-4 alkyl, or hydroxyC 1-4 alkyl;
R 12 is —(C(Rr)(Rr))m 2 -N(Rr)(Rc); and
other than the ring substitution defined by G, >A 3 -B 3 —, and Rp, each ring system may be optionally further substituted on a carbon atom not adjacent to the link at >A 3 - by up to two substituents independently selected from C 1-4 alkyl, fluoroC 1-4 alkyl, C 1-4 alkylthioC 1-4 alkyl, hydroxyC 1-4 alkyl, amino, aminoC 1-4 alkyl, C 1-4 alkanoylamino, C 1-4 alkanoylaminoC 1-4 alkyl, carboxy, C 1-4 alkoxycarbonyl, 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 phenylC 1-4 alkyl, 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 C 1-6 alkyl, optionally substituted by one or more C 1-4 alkanoyl groups, optionally geminally substituted by C 1-4 alkanoyl groups, and optionally monosubstituted by cyano, C 1-4 alkoxy, trifluoromethyl, C 1-4 alkoxycarbonyl, optionally substituted phenyl, and C 1-4 alkylS(O) q —; or, on any but the first carbon atom of the C 1-6 alkyl 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, C 1-6 alkanoylamino, C 1-4 alkoxycarbonylamino, N —C 1-4 alkyl- N —C 1-6 alkanoylamino, C 1-4 alkylS(O) p NH—, or C 1-4 alkylS(O) p —(C 1-4 alkyl)N—;
Rc2 is R 13 CO—, R 13 SO 2 —, or R 13 CS—;
R 13 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, C 1-4 alkoxycarbonyl, trifluoromethyl, —NRvRw, ethenyl, 2-C 1-4 alkylethenyl, 2-cyanoethenyl, 2-cyano-2-(C 1-4 alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-(C 1-4 alkyl)ethenyl, 2-(C 1-4 alkylaminocarbonyl)ethenyl, 2-(C 1-4 alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, or 2-(AR2a)ethenyl;
Rc2c is C 1-10 alkyl optionally substituted by one or more groups, optionally geminally disubstituted, each independently selected from hydroxy, C 1-10 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkanoyl, phosphoryl (—O—P(O)(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), phosphiryl (—O—P(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), and amino; and optionally substituted by one group selected from carboxy, phosphonate (phosphono, —P(O)(OH) 2 , and mono- and di-C 1-4 alkoxy derivatives thereof), phosphinate (—P(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), cyano, halo, trifluoromethyl, C 1-4 alkoxycarbonyl, C 1-4 alkoxy-C 1-4 alkoxycarbonyl, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxycarbonyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkanoylamino, C 1-4 alkoxycarbonylamino, N —C 1-4 alkyl- N —C 1-6 alkanoylamino, C 1-4 alkylaminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylS(O) p NH—, C 1-4 alkylS(O) p —(C 1-4 alkyl)N—, fluoroC 1-4 alkylS(O) p NH—, fluoroC 1-4 alkylS(O) p (C 1-4 alkyl)N—, C 1-4 alkylS(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 R 14 C(O)OC 1-6 alkyl;
R 14 is AR1, AR2, C 1-4 alkylamino, benzyloxy-C 1-4 alkyl, or C 1-10 alkyl optionally substituted by one or more groups, optionally geminally disubstituted, each independently selected from hydroxy, C 1-10 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkanoyl, phosphoryl (—O—P(O)(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), phosphiryl (—O—P(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), and amino; and optionally substituted by one group selected from carboxy, phosphonate (phosphono, —P(O)(OH) 2 , and mono- and di-C 1-4 alkoxy derivatives thereof), phosphinate (—P(OH)2 and mono- and di-C 1-4 alkoxy derivatives thereof), cyano, halo, trifluoromethyl, C 1-4 alkoxycarbonyl, C 1-4 alkoxy-C 1-4 alkoxycarbonyl, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxycarbonyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkanoylamino, C 1-4 alkoxycarbonylamino, N —C 1-4 alkyl- N —C 1-6 alkanoylamino, C 1-4 alkylaminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylS(O) p NH—, C 1-4 alkylS(O) p —(C 1-4 alkyl)N—, fluoroC 1-4 alkylS(O) p NH—, fluoroC 1-4 alkylS(O)p(C 1-4 alkyl)N—, C 1-4 alkylS(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 R 15 O—;
R 15 is benzyl, CY1, CY2, AR2b, or C 1-6 alkyl, optionally substituted by one or more groups, optionally geminally disubstituted, each independently selected from hydroxy, C 1-10 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkanoyl, phosphoryl (—O—P(O)(OH) 2 , and mono- and di-C 1-4 alkoxy derivatives thereof), phosphiryl (—O—P(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), and amino; and optionally substituted by one group selected from carboxy, phosphonate (phosphono, —P(O)(OH) 2 , and mono- and di-C 1-4 alkoxy derivatives thereof), phosphinate (—P(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), cyano, halo, trifluoromethyl, C 1-4 alkoxycarbonyl, C 1-4 alkoxy-C 1-4 alkoxycarbonyl, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxycarbonyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkanoylamino, C 1-4 alkoxycarbonylamino, N—C 1-4 alkyl-N—C 1-6 alkanoylamino, C 1-4 alkylaminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylS(O) p NH—, C 1-4 alkylS(O) p —(C 1-4 alkyl)N—, fluoroC 1-4 alkylS(O) p NH—, fluoroC 1-4 alkylS(O) p (C 1-4 alkyl)N—, C 1-4 alkylS(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-(C 1-4 alkyl)ethenyl, 2-(C 1-4 alkylaminocarbonyl)ethenyl, 2-(C 1-4 alkoxycarbonyl)ethenyl, 2-nitroethenyl, 2-nitro-2-(C 1-4 alkyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, or Rc3 a;
Rc3a is
X 00 is —OR 17 , —SR 17 , —NHR 17 , or —N(R 17 ) 2 ;
R 17 is hydrogen when X 00 is —NHR 17 or —N(R 17 ) 2 ; or R 17 is C 1-4 alkyl, phenyl, or AR2 when X 00 is —OR 17 , —SR 17 , and —NHR 17 ;
R 16 is cyano, nitro, C 1-4 alkylsulfonyl, C 4 7 cycloalkylsulfonyl, phenylsulfonyl, C 1-4 alkanoyl, and C 1-4 alkoxycarbonyl;
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 C 1-6 alkyl;
Re is hydrogen or C 1-6 alkyl; or Rd and Re together form a C 3-4 alkylene chain;
Rf is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, —NRvRw, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, hydroxyC 2-6 alkoxy, C 1-4 alkylaminoC 2-6 alkoxy, or di-C 1-4 alkylaminoC 2-6 alkoxy;
Rg is C 1-6 alkyl, hydroxy, or C 1-6 alkoxy;
Rh is hydrogen or C 1-6 alkyl;
Ri is hydrogen, C 1-6 alkyl, AR1, AR2, AR2a, or AR2b;
Rj is hydrogen or C 1-6 alkyl;
Rv is hydrogen or C 1-4 alkyl;
Rw is hydrogen or C 1-4 alkyl;
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.
3 . A compound of claim 1 , or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein the groups in TCa, TCb, and TCc are selected from TC5, TC6, TC7, TC8, TC9, TC10, and TC11:
wherein
Rc is selected from Rc1, Rc2, Rc3, Rc4, and Rc5;
Rc1 is C 1-6 alkyl, optionally substituted by one or more C 1-4 alkanoyl groups, optionally geminally substituted by C 1-4 alkanoyl groups, and optionally monosubstituted by cyano, C 1-4 alkoxy, trifluoromethyl, C 1-4 alkoxycarbonyl, optionally substituted phenyl, C 1-4 alkylS(O) q —; or, on any but the first carbon atom of the C 1-6 alkyl chain, optionally substituted by one or more groups and optionally geminally substituted by one or more groups each independently selected from hydroxy and fluoro, and optionally monosubstituted by oxo, —NRvRw, C 1-6 alkanoylamino, C 1-4 alkoxycarbonylamino, N —C 1-4 alkyl- N —C 1-6 alkanoylamino, C 1-4 alkylS(O) p NH—, or C 1-4 alkylS(O) p —(C 1-4 alkyl)N—;
Rc2 is R 13 CO—, R 13 SO 2 —, or R 13 CS—;
R 13 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, C 1-4 alkoxycarbonyl, trifluoromethyl, —NRvRw, ethenyl, 2-C 1-4 alkylethenyl, 2-cyanoethenyl, 2-cyano-2-(C 1-4 alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-(C 1-4 alkyl)ethenyl, 2-(C 1-4 alkylaminocarbonyl)ethenyl, 2-(C 1-4 alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, or 2-(AR2a)ethenyl;
Rc2c is C 1-10 alkyl, optionally substituted by one or more groups, optionally geminally disubstituted, each independently selected from hydroxy, C 1-10 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkanoyl, phosphoryl (—O—P(O)(OH) 2 , and mono- and di-C 1-4 alkoxy derivatives thereof), phosphiryl (—O—P(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), and amino; and optionally substituted by one group selected from carboxy, phosphonate (phosphono, —P(O)(OH) 2 , and mono- and di-C 1-4 alkoxy derivatives thereof), phosphinate (—P(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), cyano, halo, trifluoromethyl, C 1-4 alkoxycarbonyl, C 1-4 alkoxy-C 1-4 alkoxycarbonyl, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxycarbonyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkanoylamino, C 1-4 alkoxycarbonylamino, N—C 1-4 alkyl-N—C 1-6 alkanoylamino, C 1-4 alkylaminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylS(O) p NH—, C 1-4 alkylS(O) p —(C 1-4 alkyl)N—, fluoroC 1-4 alkylS(O) p NH—, fluoroC 1-4 alkylS(O) p (C 1-4 alkyl)N—, C 1-4 alkylS(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 R 14 C(O)OC 1-6 alkyl;
R 14 is AR1, AR2, C 1-4 alkylamino, benzyloxy-C 1-4 alkyl, or C 1-10 alkyl optionally substituted by one or more groups, optionally geminally disubstituted, each independently selected from hydroxy, C 1-10 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkanoyl, phosphoryl (—O—P(O)(OH) 2 , and mono- and di-C 1-4 alkoxy derivatives thereof), phosphiryl (—O—P(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), and amino; and optionally substituted by one group selected from carboxy, phosphonate (phosphono, —P(O)(OH) 2 , and mono- and di-C 1-4 alkoxy derivatives thereof), phosphinate (—P(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), cyano, halo, trifluoromethyl, C 1-4 alkoxycarbonyl, C 1-4 alkoxy-C 1-4 alkoxycarbonyl, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxycarbonyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkanoylamino, C 1-4 alkoxycarbonylamino, N—C 1-4 alkyl-N—C 1-6 alkanoylamino, C 1-4 alkylaminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylS(O) p NH—, C 1-4 alkylS(O) p —(C 1-4 alkyl)N—, fluoroC 1-4 alkylS(O) p NH—, fluoroC 1-4 alkylS(O) p (C 1-4 alkyl)N—, C 1-4 alkylS(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 R 15 O—;
R 15 is benzyl, CY1, CY2, AR2b, or C 1-6 alkyl, optionally substituted by one or more groups, optionally geminally disubstituted, each independently selected from hydroxy, C 1-10 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkanoyl, phosphoryl (—O—P(O)(OH) 2 , and mono- and di-C 1-4 alkoxy derivatives thereof), phosphiryl (—O—P(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), and amino; and optionally substituted by one group selected from carboxy, phosphonate (phosphono, —P(O)(OH) 2 , and mono- and di-C 1-4 alkoxy derivatives thereof), phosphinate (—P(OH) 2 and mono- and di-C 1-4 alkoxy derivatives thereof), cyano, halo, trifluoromethyl, C 1-4 alkoxycarbonyl, C 1-4 alkoxy-C 1-4 alkoxycarbonyl, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxycarbonyl, C 1-4 alkylamino, di(C 1-4 alkyl) amino, C 1-6 alkanoylamino, C 1-4 alkoxycarbonylamino, N—C 1-4 alkyl-N—C 1-6 alkanoylamino, C 1-4 alkylaminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylS(O) p NH—, C 1-4 alkylS(O) p —(C 1-4 alkyl)N—, fluoroC 1-4 alkylS(O) p NH—, fluoroC 1-4 alkylS(O) p (C 1-4 alkyl)N—, C 1-4 alkylS(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-(C 1-4 alkyl)ethenyl, 2-(C 1-4 alkylaminocarbonyl)ethenyl, 2-(C 1-4 alkoxycarbonyl)ethenyl, 2-nitroethenyl, 2-nitro-2-(C 1-4 alkyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, or Rc3a;
Rc3a is
X 00 is —OR 17 , —SR 17 , —NHR 17 , or —N(R 17 ) 2 ;
R 17 is hydrogen when X 00 is —NHR 17 or —N(R 17 ) 2 ; or R 17 is C 1-4 alkyl, phenyl, or AR2 when X 00 is —OR 17 , —SR 17 , and —NHR 17 ; and
R 16 is cyano, nitro, C 1-4 alkylsulfonyl, C 4-7 cycloalkylsulfonyl, phenylsulfonyl, C 1-4 alkanoyl, and C 1-4 alkoxycarbonyl;
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 C 1-6 alkyl;
Re is hydrogen or C 1-6 alkyl; or Rd and Re together form a C 3-4 alkylene chain;
Rf is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, —NRvRw, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, hydroxyC 2-6 alkoxy, C 1-4 alkylaminoC 2-6 alkoxy, or di-C 1-4 alkylaminoC 2-6 alkoxy;
Rg is C 1-6 alkyl, hydroxy or C 1-6 alkoxy;
Rh is hydrogen or C 1-6 alkyl;
Ri is hydrogen, C 1-6 alkyl, AR1, AR2, AR2a, or AR2b;
Rj is hydrogen or C 1-6 alkyl;
Rv is hydrogen or C 1-4 alkyl;
Rw is hydrogen or C 1-4 alkyl;
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 comprising 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 comprising 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.
4 . A compound of claim 2 , represented by the formula (IC):
or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein
HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl, or 1,2,5-thiadiazol-3-yl;
R 2 and R 3 are independently hydrogen or fluoro;
Rp1 and Rp2 are independently hydrogen, AR-oxymethyl, AR-thiomethyl, C 1-4 alkyl, carboxy, C 1-4 alkoxycarbonyl, hydroxymethyl, C 1-4 alkoxymethyl, or carbamoyl;
AR is phenyl, phenyl-C 1-4 alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, or thiophene;
Rcp is cyano, pyrimidin-2-yl, 2-cyanoethenyl, 2-cyano-2-(C 1-4 alkyl)ethenyl, R 13p CO—, R 13p SO 2 —, R 13p CS—, or RfC(═O)C(═O)—;
R 13p is hydrogen or C 1-5 alkyl optionally substituted by one or more groups, each independently selected from hydroxy and amino, or optionally monosubstituted by C 1-4 alkoxy, C 1-4 alkylS(O) q —, C 1-4 alkylamino, C 1-4 alkanoyl, naphthoxy, C 2-6 alkanoylamino, or C 1-4 alkylS(O) p NH—, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, pyridoimidazole, pyrimidoimidazole, quinoxaline, quinazoline, phthalazine, cinnoline, naphthyridine, or R 14p C(O)OC 1-6 alkyl;
R] 14p is C 1-6 alkyl; and
Rf is C 1-6 alkoxy.
5 . A compound of claim 2 , selected from
5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)-oxazolidin-2-one; or 5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-one; or pharmaceutically acceptable salts or an in vivo hydrolysable esters thereof.
6 . A compound of claim 2 , selected from
5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one; 5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one; 5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-diphosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one; or 5 (R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-diphosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one; or pharmaceutically acceptable salts thereof.
7 . A process for the preparation of a compound of claim 2 , comprising
(a) reacting a compound of claim 2 with a suitable reagent, resulting in a modification of a substituent in or introduction of a substituent into a compound of claim 2; (b) reacting a compound of formula (II) wherein Yp is hydroxy with a compound of the formula (b1) HET-OH or (b2) HET-Lg, wherein Lg is a suitable leaving group; (c) reacting a compound of formula (II) wherein Yp is a leaving group with a metal alkoxide compound of the formula HET-OM where M is an alkali metal or another metal known to promote O-alkylation; (d) reacting a compound of the formula Q-Zp wherein Zp is an isocyanate or amine group with an epoxide of the formula CH 2 (O)CH—CH 2 O-HET; (e) when X is —S—, using a process analogous to process (c) using (e1) a metal thioxide compound of the formula HET-SM where M is an alkali metal or another metal known to promote S-alkylation; or using (e2) HET-SH and a compound of formula (II) in which Yp is a suitable leaving group; (f) when X is —SO— or —SO 2 — , oxidizing a compound of formula (I) wherein X is —S—; (g) converting of a compound of formula (I) in which the ring HET bears a quaternary nitrogen to a non-quaternary compound; (h) when HET is an isoxazole ring, reacting a compound of the formula (II) in which Yp is —O—CH═N—OH with an acetylene; or (i) reacting a urethane compound of formula (III) with a compound of formula (IV) wherein R 21 is C 1-6 alkyl or benzyl; and thereafter if necessary removing any protecting groups or forming a pharmaceutically acceptable salt or forming an in vivo hydrolysable ester.
8 . A method for producing an antibacterial effect in a warm blooded animal which comprises administering to said animal in need thereof an effective amount of a compound as claimed in any one of claim 1 to 6 .
9 . A pharmaceutical composition which comprises a compound as claimed in any one of claim 1 to 6 , and a pharmaceutically acceptable diluent or carrier.
10 . A method of manufacturing a medicament, comprising combining a compound of any of claim 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
11 . A compound of claim 2 , or a pharmaceutically acceptable salt, or an in vivo hydrolyzable ester thereof,
wherein
AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, and CY2 are optionally substituted on a carbon atom, valence and stability permitting, by up to three substituents independently selected from C 1-4 alkyl, trifluoromethyl, hydroxy, halo, nitro, cyano, thiol, C 1-4 alkoxy, C 1-4 alkanoyloxy, dimethylaminomethyleneaminocarbonyl, di(N-(C 1-4 alkyl)aminomethylimino, carboxy, C 1-4 alkoxycarbonyl, C 1-4 alkanoyl, C 1-4 alkylSO 2 amino, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkanoylamino, oxo (═O), thioxo (═S), C 1-4 alkanoylamino, C 1-4 alkylS(O) q —, —CONRvRw, and —NRvRw;
wherein,
the C 1-4 alkyl substituents are optionally substituted by at least one substituent independently selected from hydroxy, trifluoromethyl, C 1-4 alkylS(O) q —, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, cyano, nitro, C 1-4 alkanoylamino, —CONRvRw, and —NRvRw;
the C 2-4 alkenyl substituent is optionally substituted by carboxy or C 1-4 alkoxycarbonyl;
in the C 1-4 alkanoylamino substituent, the C 1-4 alkanoyl group is optionally substituted by hydroxy;
in the C 1-4 alkylS(O) q — substituent, the C 1-4 alkyl group is optionally substituted by one or more groups independently selected from cyano, hydroxy, and C 1-4 alkoxy;
Rv is hydrogen or C 1-4 alkyl;
Rw is hydrogen or C 1-4 alkyl; and
q is 0, 1, or2.
12 . A compound of claim 2 , or a pharmaceutically acceptable salt, or an in vivo hydrolyzable ester thereof,
wherein
AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2, and alkyl groups are optionally substituted on a carbon atom, valence and stability permitting, by up to three substituents independently selected from trifluoromethoxy, benzoylamino, benzoyl, phenyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyiminoC 1-4 alkyl, C 1-4 alkoxyiminoC 1-4 alkyl, halo-C 1-4 alkyl, C 1-4 alkanesulfonamido, and —SO 2 NRvRw;
wherein
the phenyl substituent is optionally substituted by up to three substituents independently selected from halo, C 1-4 alkoxy, or cyano;
Rv is hydrogen or C 1-4 alkyl;
Rw is hydrogen or C 1-4 alkyl; and
q is 0, 1,or2.
13 . A compound of claim 2 , or a pharmaceutically acceptable salt, or an in vivo hydrolyzable ester thereof,
wherein
AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, and AR4a are optionally substituted on a nitrogen atom, valence and stability permitting, by C 1-4 alkyl, C 1-4 alkanoyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxycarbonyl, or oxo (to form an N-oxide),
wherein
the substitution does not result in quaternization of the nitrogen atom;
C 1-4 alkyl and C 1-4 alkanoyl substituents are optionally substituted by substituents independently selected from cyano, hydroxy, nitro, trifluoromethyl, C 1-4 alkylS(O) q —, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, C 1-4 alkanoylamino, —CONRvRw, and —NRvRw;
Rv is hydrogen or C 1-4 alkyl;
Rw is hydrogen or C 1-4 alkyl; and
q is 0, 1 or 2.
14 . A compound of claim 2 , or a pharmaceutically acceptable salt, or an in vivo hydrolyzable ester thereof,
wherein AR is optionally substituted phenyl; optionally substituted phenylC 1-4 alkyl; optionally substituted naphthyl; optionally substituted 5- or 6-membered heteroaryl, having 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur and being fully aromatic; optionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system comprising a 6-membered ring fused to either a 5-membered ring or another 6-membered ring, the bicyclic ring system containing from 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) saturated.
15 . A compound of claim 2 , or a pharmaceutically acceptable salt, or an in vivo hydrolyzable ester thereof, wherein
AR2 is selected from furan, pyrrole, thiophene, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, oxazole, isoxazole, oxazine, thiazole, isothiazole, 1,2,4-thiadiazole, and 1,3,4-thiadiazole; AR2a is selected from dihydropyrrole and tetrahydropyridine; AR2b is selected from tetrahydrofuran, pyrrolidine, morpholine, thiomorpholine, piperazine, imidazoline, piperidine, 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl, and 1,4-dioxan-2-yl; AR3 is selected from a bicyclic benzo-fused system containing a 5- or 6-membered heteroaryl ring containing one nitrogen atom and optionally one to three further heteroatoms chosen from oxygen, sulfur, and nitrogen; a 5/5-, 5/6 and 6/6 bicyclic ring system containing heteroatoms in both of the rings; a bicyclic heteroaryl ring system with at least one bridgehead nitrogen and optionally a further one to three heteroatoms chosen from oxygen, sulfur, and nitrogen; and AR4 is selected from pyrrolo[a]quinoline, 2,3-pyrroloisoquinoline, pyrrolo[a]isoquinoline, 1H-pyrrolo[1,2-a]benzimidazole, 9H-imidazo[1,2-a]indole, 5H-imidazo[2,1-a]isoindole, 1H-imidazo[3,4-a]indole, imidazo[1,2-a]quinoline, imidazo[2,1-a]isoquinoline, imidazo[1,5-a]quinoline and imidazo[5,1-a]isoquinoline.
16 . A compound of claim 2 , or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein HET is pyrazole, imidazole, oxazole, isoxazole, 1,2,4- oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, isothiazole, or 1,2,5-thiadiazole.
17 . A compound of claim 16 , or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein HET is isoxazole.
18 . A compound of claim 2 , or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein X is —O—.
19 . A compound of claim 18 , or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl, or 1,2,5-thiadiazol-3-yl.
20 . A compound of claim 19 , or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein HET is isoxazol-3-yl.
21 . A compound of the formula (IP), or a pharmaceutically acceptable salt or an in vivo hydrolyzable ester thereof,
wherein
X is —O—, —S—, —SO—, or —SO 2 —;
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 C 1-4 alkyl, amino, C 1-4 alkylamino, C 1-4 alkoxy, and halogen, and/or on an available N atom by C 1-4 alkyl, provided that the nitrogen atom is not thereby quaternized;
R 2 and R 3 are independently hydrogen or fluoro;
Rp is hydrogen, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, or C 2-4 alkanoyloxy;
>A-B— is of the formula >CC(Rr)-, >CHCHRr-, >C(OH)CHRr-, or >N—CH 2 —;
>represents two single bonds;
Rr is hydrogen or C 1-4 alkyl;
D is —O—, —S—, —SO—, —SO 2 —, or >NRcp;
Rp1 and Rp2 are independently oxo (═O), except when Rcp is PC, C 1-4 alkyl, C 1-4 alkanoylamino-C 1-4 alkyl, hydroxy-C 1-4 alkyl, carboxy, C 1-4 alkoxycarbonyl, 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-(C 1-4 alkoxycarbonyl)ethenyl, 2-cyanoethenyl, 2-cyano-2-(C 1-4 alkyl)ethenyl, or 2-(C 1-4 alkylaminocarbonyl)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 C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkanoyl, wherein the tetrazole ring system is joined to the nitrogen in >NRcp by a ring carbon atom;
PC is R 13p CO—, R 13p SO 2 —, or R 13p CS—;
R 13p 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 C 1-4 alkyl, hydroxy, C 1-4 alkoxy, C 1-4 alkylthio, acetamido, C 1-4 alkanoyl, 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 C 1-4 alkyl;
PCc is hydrogen, C 1-4 alkoxycarbonyl, trifluoromethyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)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 C 1-4 alkoxy, halo, cyano, and, for the phenyl substituent only, C 1-4 alkylsulfonyl;
PCd is C 1-10 alkyl, 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, C 1-10 alkoxy, trifluoromethyl, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkanoylamino, C 1-4 alkoxycarbonylamino, N —C 1-4 alkyl- N —C 2-6 alkanoylamino, C 1-4 alkylS(O) p NH—, C 1-4 alkylS(O) p —, (C 1-4 alkyl)N—, fluoroC 1-4 alkylS(O) p NH—, fluoroC 1-4 alkylS(O) p (C 1-4 alkyl)N—, phosphono, C 1-4 alkoxy(hydroxy)phosphoryl, di-C 1-4 alkoxyphosphoryl, C 1-4 alkylS(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 C 1-4 alkoxy, halo, and cyano;
p is 1 or 2;
q is 0, 1,or 2;
PCe is R 14p C(O)OC 1-6 alkyl;
R 14 is an optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl, C 1-4 alkylamino, benzyloxy-C 1-4 alkyl, or optionally substituted C 1-10 alkyl;
PCf is R 15p O—;
R 15p is benzyl or optionally substituted C 1-6 alkyl;
PD is RdOC(Re)═CH(C═O)—, RfC(═O)C(═O)—, RgN═C(Rh)C(═O)—, or RiNHC(Rj)═CHC(═O)—;
Rd is C 1-6 alkyl and Re is hydrogen or C 1-6 alkyl; or Rd and Re together form a C 3-4 alkylene chain;
Rf is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, hydroxyC 2-6 alkoxy, C 1-4 alkylaminoC 2-6 alkoxy, or di-C 1-4 alkylaminoC 2-6 alkoxy;
Rg is C 1-6 alkyl, hydroxy, or C 1-6 alkoxy;
Rh is hydrogen or C 1-6 alkyl;
Ri is hydrogen, C 1-6 alkyl, 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 C 1-6 alkyl;
PE is R 16p CH(R 17p )(CH 2 ) mp —;
R 16p is hydrogen or C 1-4 alkyl;
R 17p is fluoro, cyano, C 1-4 alkoxy, C 1-4 alkylsulfonyl, C 1-4 alkoxycarbonyl or hydroxy, provided that when mp is 0, R 17p is not fluoro or hydroxy;
mp is 0 or 1;
AR is optionally substituted phenyl, optionally substituted phenylC 1-4 alkyl, 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, C 1-4 alkyl, acyl, oxo, and nitro-C 1-4 alkyl, and when CY is a cycloalkyl or cycloalkenyl ring, optionally geminally disubstituted by substituents selected from C 1-4 alkyl, halo, C 1-4 alkyl, acyl, oxo, and nitro-C 1-4 alkyl;
wherein the optional substituents for alkyl, phenyl, phenyl containing moieties, naphthyl groups, and ring carbon atoms in mono- or bicyclo-heteroaryl rings in R 14p , R 15p , Ri, and AR are selected from halo, C 1-4 alkyl, hydroxy, nitro, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl S(O) q —, carboxy, C 1-4 alkoxycarbonyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkanoyl, C 1-4 alkoxy, C 1-4 alkylS(O) 2 amino, C 1-4 alkanoylamino, benzoylamino, benzoyl, phenyl, optionally substituted by up to three substituents selected from halo, C 1-4 alkoxy, or cyano, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyiminoC 1-4 alkyl, C 1-4 alkoxyiminoC 1-4 alkyl, hydroxy-C 1-4 alkyl, halo-C 1-4 alkyl, nitroC 1-4 alkyl, aminoC 1-4 alkyl, cyanoC 1-4 alkyl, C 1-4 alkanesulfonamido, aminosulfonyl, C 1-4 alkylaminosulfonyl, and di-(C 1-4 alkyl)aminosulfonyl.
22 . A compound of any of claim 2 , or 11 to 20 , wherein the compound is the pure enantiomer depicted in formula (IA)
23 . A compound of claim 2 , wherein the compound is in the form of an in vivo hydrolyzable ester, or a pharmaceutically acceptable salt thereof, selected from
(i) for a compound containing a carboxy group: a C 1-6 alkoxymethyl ester, a C 1-6 alkanoyloxymethyl ester, a phthalidyl ester, a C 3-8 cycloalkoxycarbonyloxyC 1-6 alkyl ester; a 1,3-dioxolan-2-onylmethyl ester, and a C 1-6 alkoxycarbonyloxyethyl ester; or (ii) for a compound containing a hydroxy group: a phosphate ester, a phosphoramidic cyclic ester, a phosphoryl ester (—O—P(O)(OH) 2 ), a phosphiryl ester (—O—P(OH) 2 ), an α-acyloxyalkyl ether, and an ester formed with the hydroxy group by reaction with C 1-10 alkanoyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl, C 1-10 alkoxycarbonyl, or di-C 1-4 alkylcarbamoyl, N-(di-C 1-4 alkylaminoethyl)-N—C 1-4 alkylcarbamoyl, di-C 1-4 alkylaminoacetyl, or carboxyacetyl; wherein the substituents on benzoyl are selected from chloromethyl, aminomethyl, C 1-4 alkylaminomethyl, di-(C 1-4 alkyl)aminomethyl, morpholino, and piperazino, linked from a ring nitrogen atom via a methylene linking group to the 3- or 4-position of the benzoyl ring.
24 . A compound of claim 2 , containing a 1,2-diol group, wherein the compound is in the form of an in vivo hydrolyzable ester, or a pharmaceutically acceptable salt thereof, in which the 1,2-diol group is cyclized to form a cyclic ester of formula (PD1) or a pyrophosphate of formula (PD2):Join the waitlist — get patent alerts
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