NZ509867A

NZ509867A - Isoxazolinone antibacterial agents

Info

Publication number: NZ509867A
Application number: NZ509867A
Authority: NZ
Inventors: Lawrence B Snyder; Zhizhen Zheng
Original assignee: Bristol Myers Squibb Co
Priority date: 1998-08-24
Filing date: 1999-08-23
Publication date: 2003-08-29
Also published as: CO5160266A1; CN1314813A; EP1107756A4; UY25677A1; AU748750B2; PE20001063A1; KR20010072945A; PL346267A1; TW572757B; EP1107756A1; AR020250A1; HUP0103433A3; WO2000010566A1; JP2002523369A; CZ2001669A3; ZA200101505B; NO20010916D0; NO20010916L; HUP0103433A2; AU5783399A

Abstract

Isoxazolinone derivatives of formula (I) that possess antibacterial activity and are useful in the treatment of bacterial diseases are disclosed, wherein A and R1 are as described in the specification.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 509867 WO 00/10566 - 1 - PCT/US99/19265 5 NOVEL ISOXAZOLINONE ANTIBACTERIAL AGENTS 10 20 BACKGROUND OF THE INVENTION 1. Field of the Invention 15 The present invention is directed toward new isoxazolinones, methods for their use, and processes for their production. The present invention provides for a compound represented by the general formula .A "-V l I or a pharmaceutical^ acceptable salt thereof wherein: R-i is a) H, b) C-|_8 alkyl optionally substituted with one or more F, CI, OH, 25 C-j_8 alkoxy, or acyloxy, WO 00/10566 - 2 - PCT/US99/19265 c) C3_6 cycloalkyl, or d) C-|_8 alkoxy; L is oxygen or sulfur; A is a) b) *2 Ra R4 r7 )=A_/ re r5 c) a 5-membered heteroaromatic moiety having one to three 10 hetero atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom and can additionally have a fused-on benzene or naphthyl ring, and wherein the heteroaromatic moiety is optionally substituted with one to 15 three Rg, d) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the heteroaromatic moiety is bonded via a carbon atom, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or 20 naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three Rg, e) a p-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three Rg, WO 00/10566 - 3 - PCT/US99/19265 f) r13 ; 5 wherein R2 and R3 are each independently a) H- b) F, c) CI, d) Br, e) C-J.Q alkyl, f) no2> g) I, h) alkoxy, i) oh j) amino, k) cyano, or i) R2 and R3 taken together are -0(CH2)h-0; wherein R4 is a) H, 20 b) C-|_2 alkyl, c) F, or d) OH; R5 is a) H, 25 b) CF3, WO 00/10566 - 4 - PCT/US99/19265 c) C-|_3 alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) R5 and Rg taken together are a 5-, 6-, or 7-membered ring of the formula, _ / o=OoH2,h, " // ( in which D is S, O or NR86 in which R86 is H or C-|_g alkyl, or g) R5 and R5 taken together are -(CH2)k-, when R7 is an 10 electron-withdrawing group; R6 and R7 at each occurrence are the same or different and are a) an electron-withdrawing group, b) H, c) CF3, 15 d) C-j_3 alkyl optionally substituted with one halo, e) phenyl, provided at least one of Rg and R7 is an electron-withdrawing group, or f) R6 and R7 taken together are a 5-, 6-, or 7-membered ring of the formula, o ii ^ z-c-c, ( (CH2)r 20 ; U is a) CH2l b) O, c) S or, 25 d) NR16; WO 00/10566 - 5 - PCT/US99/19265 Rig is a) H or b) C^s alkyl; wherein Rg is 5 a) b) c) d) e) 10 f) 9) h) ') j) 15 k) ') m) n) 20 o) P) q), carboxyl, halo, -CN, mercapto, formyl, CF3I no2, C-i_6 alkoxy, alkoxycarbonyl, C-|_g alkythio, 0^6 acyl, -NR17R18, noh —C-R87 in which Rg7 is H or Ci_g alkyl, alkyl optionally substituted with OH, sulfamoyl, C-|_5 alkoxy, acyl, or-NR17R18, C2-8 alkyl optionally substituted with one or two R-jg, phenyl optionally substituted with one or two R19, a 5- or 6-membered saturated or unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R-jg, or o WO 00/10566 - 6 - PCT/US99/19265 R17 and R18 at each occurrence are the same or different and are a) H, b) C-|_4 alkyl, c) C5_e cycloalkyl, or 5 d) R17 and R18 taken together with the nitrogen atom is a 5- or 6-membered saturated or unsaturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, C1.3 10 alkyl, formyl, a 5- or 6-membered heteroaromatic moiety O II containing 1-3 O, N orS, —c-nr88r89 in which R88 and R89 are each independently hydrogen or Ct_6 alkyl, SO2R90 in which Rg0 is H or C-^ alkyl, or C1.3 acyl optionally substituted with 1 or more F, CI or OH; 15 R19 is a) carboxyl, b) halo, c) -CN, d) mercapto, 20 e) formyl, D CF3, g) no2, h) alkoxy, i) C-|_6 alkoxycarbonyl, 25 j) alkythio, k) Ci_6 acyl, I) C-|_q alkyl optionally substituted with OH, alkoxy, C^s acyl, or-NR17R18, WO 00/10566 - 7 - PCT/US99/19265 m) phenyl, n) -C(=O)NR20R21, o) -N R17R18. P) -N(R20)(-SO2R22). 5 q) -SO2-NR20R2i, or r) -S(=0)iR22; R2o and R2i at each occurrence are the same or different and are a) H, b) C-|_6 alkyl, or 10 c) phenyl; R22 is a) Ci_4 alkyl, or b) phenyl optionally substituted with alkyl; wherein Rg is 15 a) carboxyl, b) halo, c) -cn, d) mercapto, e) formyl, 20 f) cf3, g) no2, h) G-)_g alkoxy, i) C-|.6 alkoxycarbonyl, j) c-j.6 alkythio, 25 k) acyl, I) -nr23R24, m) alkyl optionally substituted with oh, Ci_5 alkoxy, acyl, or -nr23r24, WO 00/10566 - 8 - PCT/US99/19265 n) C2.8 alkenylphenyl optionally substituted with one or two r25- o) phenyl optionally substituted with one or two R25, p) a 5- or 6-membered saturated or unsaturated heterocyclic 5 moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R25, or q) V (ch^iJ) I 10 R23 and R24 at each occurrence are the same or different and are a) H, b) formyl, c) C1-4 alkyl, d) acyl, 15 e) phenyl, f) C3-6 cycloalkyl, or g) R23 and R24 taken together with the nitrogen atom is a 5- or 6-membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group 20 consisting of S, N, O, and. can in turn be optionally substituted with, including on the further nitrogen atom, phenyl, pyrimidyl, C-1.3 alkyl, or C-|_3 acyl; R25 is a) carboxyl, 25 b) halo, c) -CN, d) mercapto, e) formyl, WO 00/10566 - 9 - PCT/US99/19265 10 f) cf3, g) no2, h) alkoxy, i) Ci_6 alkoxycarbonyl, j) C-]^ alkythio, k) C-,.6 acyl, I) phenyl, m) C-i^ alkyl optionally substituted with OH, azido, C-|_5 alkoxy, C-|_5 acyl, -NR32R33i -SR34, -O-SO2R35, or r36—<\ /)—nh-co-o- n) -C(=0)NR26R27, o) -NR23R24. P) -N(R26)(-S02R22), q) -S02-NR26R27, or 15 r) -S(=0)ir22, s) -CH=N-R28, or t) -CH(0H)-S03R31; R22 is the same as defined above; R20 and R27 at each occurrence are the same or different and are 20 a) H, b) Ct_6 alkyl, c) phenyl, or d) tolyl; R28 is 25 a) OH, b) benzyloxy, c) -NH-C(=0)-NH2, WO 00/10566 - 10 - PCT/US99/19265 d) -NH-C(=S)-NH2, or e) -NH-C(=NH)-NR29R30; R2g and R30 at each occurrence are the same or different and are a) H, or 5 b) C-|_4 alkyl optionally substituted with phenyl or pyridyl; R31 is a) H, or b) a sodium ion; R32 and R33 at each occurrence are the same or different and are 10 a) H, b) formyl, c) C-m alkyl, d) C-j_4 acyl, e) phenyl, 15 f) C3_6 cycioalkyl, g) R32 and R33 taken together are a 5- or 6-membered saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, O, optionally substituted with, including on the nitrogen atom, phenyl, 20 pyrimidyl, alkyl, or C-^ acyl, h) -P(0)(OR37)(OR38), or i) -S02-R3g; R34 is n-n n-n ^n >- a j— rt >— r * n ' (chafec s ' \^^~n ■or n I 11 ch3 ch3 ch3 25 R35 is C-).3 alkyl; R36 is a) C-i^ alkoxycarbonyl, or WO 00/10566 - 11 - PCT/US99/19265 b) carboxyl; R37 and R33 at each occurrence are the same or different and are a) H, or b) C-1.3 alkyl; 5 R39 is a) methyl, b) phenyl, or c) tolyl; wherein K is 10 a) O, b) S, or c) NR40 in which R40 is hydrogen, formyl, C-j^ alkyl, acyl, phenyl, C3.6 cycioalkyl, -P(0)(OR37)(OR38) or-S02-R3g in which R37, R38 and R3g are as defined above; 15 R10> R11 R-12- R13, R14 and R15 at each occurrence are the same or different and are a) H, b) formyl, c) carboxyl, . 20 d) alkoxycarbonyl, e) Ci_8 alkyl, f) C2.8 alkenyl, wherein the substitutents (e) and (f) can be optionally substituted with OH, halo, C-1.5 alkoxyl, acyl, C-|_6 alkylthio or C<|_6 alkoxycarbonyl, or 25 phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, -CN, formyl, CF3, N02, C-\.q alkyl, Ci_5 alkoxy, C^g acyl, C-^g alkylthio, or C^ alkoxycarbonyl; WO 00/10566 - 12 - PCT/US99/19265 h) -NR42R43, i) OR44, j) -S(=0)rR45l k) -S02-N(R46)(R47), or I) a radical of the following formulas: rv rW o / \ conh2 \ \ / \ / \ f ■w-O5-. "">0-. R53 /—\ /—\ HN N— RS2 (CH2)t—N N— R53-N N— N—f - M7). ■ or >V) : ' R53 u R19 is the same as defined above; Tis 10 a) O, b) S, or c) SO2; R42 and R43 at each occurrence are the same or different and are a) H, 15 b) C3.6 cycloalkyl, c) phenyl, d) C^e acyl, e) C-|_8 alkyl optionally substituted with OH, C-)_e alkoxy which can be substituted with OH, a 5- or 6-membered aromatic 20 heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally WO 00/10566 - 13 - PCT/US99/19265 f) g) substituted with OH, CF3, halo, -NO2, <°1 alkoxy,-NR45R49, or o Yr* R55-OH— ( or V N-(CH2)t- V is a) O, b) CH2, or 10 c) NR56; R48 and R4g at each occurrence are the same or different and are a) H, or b) alkyl; R54 is 15 a) OH, b) C-j.4 alkoxy, or c) -NR57R58; R55 is a) H, or 20 b) C-|_7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C(=0)-NH2, -C02H, or -C(=NH)-NH2; R56 is a) H, 25 b) phenyl, or c) C-]_6 alkyl optionally substituted by OH; WO 00/10566 - 14 - PCT/US99/19265 R57 and R58 at each occurrence are the same or different and are a) H, b) C-1.5 alkyl, c) C<i_3 cycloalkyl, or 5 d) phenyl; R44 is a) C-f_8 alkyl optionally substituted with Ci_g alkoxy or Ci_6 hydroxy, C3.0 cycloalkyl, a 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three 10 nitrogen atoms, which can in turn be substituted with one or two -NO2, CF3, halo, -CN, OH, Ci_5 alkyl, C-^ alkoxy, or 0^5 acyl, b) v N-(CH2)t- 15 c) phenyl, or d) pyridyl; R45's a) C-M6 alkyl, b) C2.16 alkenyl, 20 wherein the substituents (a) and (b) can be optionally substituted with C^g alkoxycarbonyl, or a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, c) an aromatic moiety having 6 to 10 carbon atoms, or 25 d) a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group of S, N, and O, wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, -CN, formyl, CF3, -N02, WO 00/10566 - 15 - PCT/US99/19265 C-|_6 alkyl, C-|_6 alkoxy, C^ acyl, C1.5 alkylthio, or alkoxycarbonyl; R46 and R47 at each occurrence are the same or different and are a) H, 5 b) phenyl, c) C-^ alkyl, or d) benzyl; R50 and R51 at each occurrence are the same or different and are a) H, 10 b) OH, c) C-|_6 alkyl optionally substituted with -NR48R49 in which R48and R49 are as defined above, d) R50 and R51 taken together are =0; R52 is 15 a) an aromatic moiety having 6 to 10 carbon atoms, b) a 5- or 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the substituents (a) and (b) can in turn be optionally substituted 20 with one or three -N02, CF3, halo, -CN, OH, phenyl, C^ alkyl, C-|_5 alkoxy, or C^ acyl, c) morpholinyl, d) OH, e) C-|_6 alkoxy, 25 f) -NR4gR4g in which R48and R49 are as defined above, g) -C(=0)-R59, or h) 0 WO 00/10566 - 16 - PCT/US99/19265 R53 is a) H, b) formyl, c) alkyl, 5 d) CM acyl, e) phenyl, f) C3.6 cycloalkyl, g) -P(0)(0R37)(0R38), or h) -SO2R39, in which R37, R38 and R39 are as defined above; 10 R59 is a) morpholinyl, b) OH, or c) Ci_g alkoxy; h is 1, 2, or 3; 15 i is 0,1, or 2; j is 0, or 1; kis 3, 4, or 5; r is 1, 2, 3, 4, 5 or 6; tisO, 1,2, 3, 4, 5, or 6; 20 u is 1 or 2; and Q is 25 a) hydrogen, b) halo, c) no2, d) n3, e) CrC0 alkylthio, f) o CrC6 alkyl—s- WO 00/10566 - 17 - PCT/U S99/19265 0 9) C-j-Og alkyl—s— O ' h) C1-C6 alkyl, i) C-i-Cq alkoxy, j) formyl, O 5 k) CrC6 alkyl—C—, O ') CrC6 alkyl-o-C—. m) -sulfamoyl (H2NSO2-), n) -NHOH, O o) CrC6 alkyl—c-O— O 10 p) heteroaryl —C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, O q) C6H5~C—, r) amino, 15 s) CrCs alkylamino- t) di (Ci-C6 alkyl)amino-O 11 u) (C-pCs) alkyl-C-NR6oR6i 'n which Rqq and R51 are each independently hydrogen or CrC6 alkyl, v) OH, 20 w) cyano, x) hydroxy (CrC6 alkyl), O y) C.t-C6 alkyl-S-C—, WO 00/10566 - 18 - PCT/US99/19265 o z) NC—(CH2)r—C— in which r is 1-6, O aa) CgHgCh^-O C , O bb) C6H5-0-C-, OR34 ■ N' cc) CrC6 alkyl—c— in which R84 is hydrogen or C^ alkyl, O 11 5 dd) Rg50~(CH2)i-6—C— in which R85 is hydrogen, C^ alkyl optionally substituted with one or more F, CI, OH, C^g alkoxy or C-|.8 acyloxy, C3_e cycloalkyl or C^s alkoxy; N-OR84 ee) H-C— jn which R^ is hydrogen or C^e alkyl, ff) a substituted or unsubstituted C6-C10 aryl moiety, 10 gg) a substituted or unsubstituted monocyclic or bicyclic, saturated or unsaturated, heterocyclic moiety having 1-3 atoms selected from O, N or S, said ring being bonded via a ring carbon or nitrogen to the phenyl substituent, hh) a monocyclic or bicyclic substituted or unsubstituted 15 heteroaromatic moiety having 1-3 hetero atoms selected from O, N or S, said ring being bonded via a ring carbon or nitrogen to the phenyl substituent and wherein the heteroaromatic moiety can additionally have a fused-on benzene or naphthalene ring; 20 . the substituents for such p, q, ff, gg and hh moieties being selected from 1 or 2 of the following: 1) halo, 2) C^ alkyl, 3) N02l 25 4) N3, WO 00/10566 PCT/US99/19265 - 19 - O 5) CrC6 alkyl —S—, O 6) CrC6 alkyl—s— O ' 7) formyl, O 8) CrC6 alkyl—c—, O 5 9) CrC6 alkyl—o-C—. O 10) heteroaryl—C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, O 11) C6H5-C—, O 10 12) -(Ci-Ce) alkyl-C-NR60RB1 in which R6o and R6i are each independently hydrogen or CrC6 alkyl, 13) OH, 14) hydroxy (CrC6 alkyl), O 15) CrC6 alkyl-S-C-, O 15 16) NC-(CH2)r— O-C— in which r is 1-6, O 17) C6H5CH2-0-C-, 18) -CH2-R8O m which R8q is a) -OR32 in which R32 is as defined above, b) -SR32 in which R32 is as defined above, 20 c) -NR32R33 in which R32 and R33 are as defined above, or WO 00/10566 - 20 - PCT/US99/19265 20 d) 5- or 6-membered heteroaromatic containing 1-4 0, S or N atoms, N 19) CrC6 alkyl—c— in which Rg4 is as defined above, 20) cyano, 5 21) carboxyl, 22) CF3, O 23) C-j-Cg alkyl—C-0— » O 11 24) C6H5-0-C— in which the phenyl moiety may be optionally substituted by halo or (C-i-CgJalkyl, O 10 25) NR60R6r-C— in which R60 and R81 are as defined above, 9 9 26) RS1-NH-C— or R91-C-NH— in which R91 is a 5- or 6-membered aromatic heterocyclic group having 1-3 O, N or S, O 15 27) C6H5(CH2)i-g—O-C—, O 28) R850-(CH2)1.6—O-C— in which R85 is as defined above, O 29) SiR99R100R10-O-CH2-C in which Rgg, R-ioo anci R101 are each independently alkyl; or Q and either R-i and R2 taken together form -0-CH2-0. These derivatives are useful as antimicrobial agents which are effective against a number of human and veterinary pathogens, including gram positive bacteria such as multiply-resistant staphylococci, WO 00/10566 - 21 - PCT/US99/19265 streptococci, and enterococci, such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus faecium. 2. Description of the Prior Art The literature contains a limited number of isoxazoiinones used as pre-emergence herbicides. For example in U.S. Patent 4,065,463, 2-methyl-4-(trifluoromethyl-m-tolyl)-3-isoxazoiin-5-one and 2-methyl-4-(chloro-m-tolyl)-3-isoxazolin-5-one are disclosed as being useful in 10 preventing the growth of weeds which have a deleterious effect on crop production. U.S. Patent 4,000,155 discloses the related compound 1,2-dimethyl-4-(trifluoromethyl-m-tolyI)-3-pyrazolin-5-one for the same utility. The applicant is not aware of any literature which discloses the use of these compounds as broad spectrum anti-bacterial agents. A different ring system is disclosed in WO 98/07708, which discusses the use of isoxazoline derivatives as anti-bacterial agents, where W is a substituted aryl or heteroaryl system and V is H, or C1-C4 alkyl optionally substituted with F, CI, OH, C1-C4 alkoxy, or acyloxy. 5 15 20 .v WO 00/10566 - 22 - PCT/US99/19265 Oxazolidinones II shown below are a well known class of orally active antibacterial agents. The prior art contains numerous references to these compounds where Y and Z can include a wide variety of substituents. Specific substituted oxazolidinones are discussed in U.S. 5 Patent Nos. 4,705,799 and 5,523,403 (substituted phenyl 2- oxazolidinones), U.S. Patent Nos. 4,948,801; 5,254,577; and 5,130,316 (arylbenzene oxazolidinyl compounds), and European Patent Applications 0,697,412; 0,694,544; 0694,543; and 0,693,491 (5 to 9-membered heteroaryl substituted oxazolidinones). Additionally, certain compounds containing a substituted furanone ring have been reported to possess antibiotic activity. WO 97/14690 discloses 15 where T is hydroxy or NHC(0)Ci-C4 alkyl, M and L are each independently hydrogen orfluoro, G and H are are each independently hydrogen or methyl, K-J is of the formula C=CH, CHCH2 or C(OH)CH2,1 is O, SO, S02 or a substituted nitrogen, and Q-R is CH2-CH2 or CH=CH2 Other substituted furanones are discussed in U.S. Patent 5,708,169, WO 20 97/43280 and WO 97/10235. Q 10 g WO 00/10566 - 23 - PCT/US99/19265 SUMMARY OF THE INVENTION It has now been found that certain substituted isoxazoiinones are effective as antibacterial agents. Specifically, the invention covers 5 compounds of the formula I: o l I or a pharmaceutical^ acceptable salt thereof wherein: R<l is 10 a) H, b) C*i_8 alkyl optionally substituted with one or more F, CI, OH, C-I.B alkoxy, or C-^s acyloxy, c) C3_5 cycloalkyl, or d) C-i.g alkoxy; 15 L is oxygen or sulfur; A is a) j! r3 b) r4 c) a 5-membered heteroaromatic moiety having one to three hetero atoms selected from the group consisting of S, N, WO 00/10566 - 24 - PCT/US99/19265 and O, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom and can additionally have a fused-on benzene or naphthyl ring, and wherein the heteroaromatic moiety is optionally substituted with one to 5 three Rg, d) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the heteroaromatic moiety is bonded via a carbon atom, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or 10 naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three Rg, e) a p-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three R9, P R!1 ,R12 Rl4 15 R13 , or 9) R11 R12 R13 • 1 wherein R2 and R3 are each independently a) H, 20 b) F, c) CI, d) Br, e) C-i.6 alkyl, f) N02, 25 g) I, WO 00/10566 - 25 - PCT/US99/19265 h) alkoxy, i) OH j) amino, k) cyano, or 5 I) R2 and R3 taken together are -0(CH2)h-0; wherein R4 is a) H, b) Ci_2 alkyl, c) F, or 10 d) OH; R5 is a) H, b) CF3, c) C-].3 alkyl optionally substituted with one or more halo, 15 d) phenyl optionally substituted with one or more halo, e) R5 and Rg taken together are a 5-, 6-, or 7-membered ring of the formula, / Q—r'C=Cv D_c (CH2)h f) -+S v ,T~YJ D 20 — in which D is S, O or NRg6 in which Rgg is H or C1-6 alkyl, or g) R5 and R6 taken together are -(CH2)|<;-, when R7 is an electron-withdrawing group; R6 and R7 at each occurrence are the same or different and are 25 a) an electron-withdrawing group, b) H, c) CF3, WO 00/10566 - 26 - PCT/US99/19265 d) e) f) 5 U is a) b) 10 c) d) Ri6 is a) b) 15 wherein Rg is a) carboxyl, b) halo, 0) -cn, d) mercapto, e) formyl, f) cf3, g) no2, h) c-J.Q alkoxy, 0 c-j.g alkoxycarbonyl j) alkythio, k) c^ acyl, D -nr17r18, C-|_3 alkyl optionally substituted with one halo, phenyl, provided at least one of Rq and R7 is an electron-withdrawing group, or Re and R7 taken together are a 5-, 6-, or 7-membered ring of the formula, o J-S O"* 1 ch2, o, S or, nr16; Hor C-j.5 alkyl; WO 00/10566 - 27 - PCT/US99/19265 noh II m) — C-R87 in which R37 is H or alkyl, n) alkyl optionally substituted with OH, sulfamoyl, C1.5 alkoxy, C-^5 acyl, or-NR17R18, o) C2-8 alkyl optionally substituted with one or two Rig, 5 p) phenyl optionally substituted with one or two R-jg, q) a 5- or 6-membered saturated or unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R-ig, or V (CH2)i X) 10 N—' ; R17 and R-jg at each occurrence are the same or different and are a) H, b) alkyl, c) C5_6 cycloalkyl, or 15 d) R17 and R18 taken together with the nitrogen atom is a 5- or 6-membered saturated or unsaturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, 20 alkyl, formyl, a 5- or 6-membered heteroaromatic moiety o ii containing 1-3 O, N or S, —c-nr88r89 in which R8g and R89 are each independently hydrogen or C-|_6 alkyl, SO2Rg0 in which Rg0 is H or alkyl, or C-j.3 acyl optionally substituted with 1 or more F, CI or OH; WO 00/10566 - 28 - PCT/US99/19265 R19 is a) carboxyl, b) halo, c) -CN, 5 d) mercapto, e) formyl, f) cf3, 9) N02. h) C^ alkoxy, 10 i) C-j.6 alkoxycarbonyl, j) C^ alkythio, k) C-i.6 acyl, I) C-j-6 a'M optionally substituted with OH, Ci_5 alkoxy, C-j.5 acyl, or-NR17R18, 15 m) phenyl, n) -C(=0)NR2oR21> o) -N R17R18' P) -N(R2o)(-S02R22), q) -SO2-NR20R21. or 20 r) -S(=0)jR22; R2o and R2i at each occurrence are the same or different and are a) H, b) C-|_6 alkyl, or c) phenyl; 25 R22 is a) C1m4 alkyl, or b) phenyl optionally substituted with Ci_4 alkyl; WO 00/10566 - 29 - PCT/US99/19265 wherein Rg is a) carboxyl, b) halo, c) -CN, 5 d) mercapto, e) formyl, f) CF3, 9) no2, h) alkoxy, 10 i) alkoxycarbonyl, j) C-i.6 alkythio, k) C^ acyl, I) -NR23R24, m) C-|_6 alkyl optionally substituted with OH, C-1.5 alkoxy, C-1.5 15 acyl, or-NR23R24, n) C2.8 alkenylphenyl optionally substituted with one or two R25> o) phenyl optionally substituted with one or two R25, p) a 5- or 6-membered saturated or unsaturated heterocyclic 20 moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R25, or q) 1 25 R23 and R24 at each occurrence are the same or different and are a) H, b) formyl, WO 00/10566 - 30 - PCT/US99/19265 c) C-j.4 alkyl, d) acyl, e) phenyl, f) 03^ cycloalkyl, or 5 g) R23 and R24 taken together with the nitrogen atom is a 5- or 6-membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, 10 phenyl, pyrimidyl, C-j.3 alkyl, or C^ acyl; R25 is a) carboxyl, b) halo, c) -CN, 15 d) mercapto, e) formyl, f) CF3, g) no2, h) C-i_6 alkoxy, 20 i) C-|_6 alkoxycarbonyl, j) C-i.6 alkythio, k) C^ acyl, I) phenyl, m) Ci_e alkyl optionally substituted with OH, azido, alkoxy, 25 C-j_5 acyl, -NR32R33) -SR34, -O-SO2R35, or R36—/J— NH-CO-Q- n) -C(=0)NR2eR27, o) -NR23R24, WO 00/10566 - 31 - PCT/US99/19265 P) -N(R26)(-S02R22). c|) -s02-nr26r27i of r) -S(=0)iR22, s) -CH=N-R28, or 5 t) -CH(0H)-S03R31; R22 is the same as defined above; R26 and R27 at each occurrence are the same or different and are a) H, b) C-,.6 alkyl, 10 c) phenyl, or d) tolyl; R28 is a) OH, b) benzyloxy, 15 c) -NH-C(=0)-NH2, d) -NH-C(=S)-NH2, or e) -NH-C(=NH)-NR29R30; R29 and R3q at each occurrence are the same or different and are a) H, or 20 b) C-|_4 alkyl optionally substituted with phenyl or pyridyl; R31 is a) H, or b) a sodium ion; R32 and R33 at each occurrence are the same or different and are 25 a) H, b) formyl, c) alkyl, d) acyl, e) phenyl, WO 00/10566 - 32 - PCT/US99/19265 f) C3_6 cycloalkyl, g) R32 and R33 taken together are a 5- or 6-membered saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyl, C-j.3 alkyl, or C-|_3 acyl, h) -P(0)(0R37)(0R38), or i) -S02-R39; R34 is n-n n-n -n " *v fx>- Cv- s ' \^-n or n n ' (ch3)3c I Y i 10 ch3 ch3 ch3 R35 is C-,_3 alkyl; R36 is a) C-j^ alkoxycarbonyl, or b) carboxyl; 15 R37 and R38 at each occurrence are the same or different and are a) H, or b) C-j.3 alkyl; R39 is a) methyl, 20 b) phenyl, or c) tolyl; wherein K is a) O, b) S, or 25 c) NR40 in which R40 is hydrogen, formyl, C-|_4 alkyl, C^ acyl, phenyl, C3.6 cycloalkyl, -P(0)(0R37)(0R38) or -S02-R3g in which R37, R38 and R39 are as defined above; WO 00/10566 - 33 - PCT/US99/19265 Rio, Rn, Ri2> r13, r14 and R15 at each occurrence are the same or different and are a) H, b) formyl, 5 c) carboxyl, d) C-|_6 alkoxycarbonyl, e) alkyl, f) C2.8 alkenyl, wherein the substitutents (e) and (f) can be optionally substituted with 10 OH, halo, C-i_5 alkoxyl, C-|_g acyl, C^6 alkylthio or C^g alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, -CN, formyl, CF3, N02, C^ alkyl, Ct_g alkoxy, Ci_g acyl, C^ alkylthio, or C^ 15 alkoxycarbonyl; h) -NR42R43. i) OR44, j) -S(=0)rR45l k) -S02-N(R46)(R47), or 20 I) a radical of the following formulas: °^n- Qr , 00-. "conh2 R53. / \ /~\ hn n— r52 {ch2)t—n n— R53-n n— Rig is the same as defined above; WO 00/10566 - 34 - PCT/US99/19265 Tis a) O, b) S, or c) S02; 5 R42 and R43 at each occurrence are the same or different and are a) H, b) C3.5 cycloalkyl, c) phenyl, d) acyl, 10 e) C^g alkyl optionally substituted with OH, C-1.5 alkoxy which can be substituted with OH, a 5- or 6-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF3, halo, -N02, C1-4 o 15 alkoxy,-NR48R49, or ° f) g) 20 Vis YRS4 r55-ch- or /—\ V^N-(CH2)t— a) O, b) CH2, or c) NR56; R48 and R4g at each occurrence are the same or different and are 25 a) H, or b) C-j.4 alkyl; WO 00/10566 - 35 - PCT/US99/19265 R54 is a) OH, b) Ct_4 alkoxy, or c) -NR57R58; 5 R55 is a) H, or b) C<|_7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C(=0)-NH2, -C02H, or-C(=NH)-NH2; 10 R56 is a) H, b) phenyl, or c) C^ alkyl optionally substituted by OH; R57 and R58 at each occurrence are the same or different and are 15 a) H, b) alkyl, c) C<|_3 cycloalkyl, or d) phenyl; R44 is 20 a) Ci_8 alkyl optionally substituted with Ci_6 alkoxy or hydroxy, C3_6 cycloalkyl, a 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three nitrogen atoms, which can in turn be substituted with one or two -N02, CF3, halo, -CN, OH, C1.5 alkyl, C^s alkoxy, or 25 C-).5 acyl, b) V^ \i-(CH2)t > c) phenyl, or WO 00/10566 - 36 - PCT/US99/19265 d) pyridyl; R45 is a) C.,_16 alkyl, b) C2_16 alkenyl, 5 wherein the substituents (a) and (b) can be optionally substituted with Ci_e alkoxycarbonyl, or a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, c) an aromatic moiety having 6 to 10 carbon atoms, or 10 d) a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group of S, N, and O, wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, -CN, formyl, CF3, -NO2, C-|_6 alkyl, C-|_6 alkoxy, C-j.6 acyl, C-|_6 alkylthio, or C^ 15 alkoxycarbonyl; R4e and R47 at each occurrence are the same or different and are a) H, b) phenyl, c) C-|_g alkyl, or 20 d) benzyl; R50 and R51 at each occurrence are the same or different and are a) H, b) OH, c) C-|_6 alkyl optionally substituted with -NR48R49 in which R48 25 and R4g are as defined above, d) R50 and R51 taken together are =0; R52 is a) an aromatic moiety having 6 to 10 carbon atoms, WO 00/10566 PCT/US99/19265 • Of ■ b) a 5- or 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and 0, wherein the substituents (a) and (b) can in turn be optionally substituted 5 with one or three -N02, CF3, halo, -CN, OH, phenyl, C^s alkyl, C^5 alkoxy, or C-|_5 acyl, c) morpholinyl, d) OH, e) C-)^ alkoxy, 10 f) -NR48R49 in which R4g and R49 are as defined above, g) -C(=0)-R59, or h) CO- 1 R53 is 15 a) H, b) formyl, c) C^ alkyl, d) C-,.4 acyl, e) phenyl, 20 f) C3.5 cycloalkyl, g) -P(0)(OR37)(OR38), or h) -SO2R39, in which R37, R38 and R3g are as defined above; R59 ^ a) morpholinyl, 25 b) OH, or c) C-|_6 alkoxy; his 1,2, or3; i is 0, 1, or 2; WO 00/10566 - 38 - PCT/US99/19265 j is 0, or 1; k is 3,4, or 5; r is 1, 2, 3, 4, 5 or 6; t is 0, 1, 2, 3,4, 5, or 6; 5 u is 1 or 2; and Q is a) hydrogen, b) halo, c) no2, 10 d) n3, e) C-pCg alkylthio, f> O CrC6 alkyl—S—. g) O C-j-Cg alkyl—s— O ' h) CrC6 alkyl, 15 i) CrC6 alkoxy, j) formyl, k) O CrC6 alkyl—C—, i) O C-|-Cg alkyl—O-C—. m) -sulfamoyl (H2NSO2-) 20 n) -NHOH, °) O C-j-Cg alkyl—C-0— O p) heteroaryl —C— >n which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, WO 00/10566 - 39 - PCT/US99/19265 o q) C6H5-C , r) amino, s) CrC6 alkylamino-, t) di (C-j-Cg alkyl)amino-, O 5 u) (C-j-Cg) alkyl-C-NR60R61 in which Rgo and Rg<| are each independently hydrogen or CrC6 alkyl, v) OH, w) cyano, x) hydroxy (C-j-Cg alkyl), 9 10 y) CrC6 alkyl-S-C-, 0 z) NC—(CH2)r— C— in which r is 1-6, O aa) C6H5CH2-0-C-, 0 bb) C6H5-0-C-, /ORw N cc) CrC6 alkyl—c— in which R84 is hydrogen or alkyl, O 15 dd) RB50-(CH2)1.6-C— in which R85 is hydrogen, C-^g alkyl optionally substituted with one or more F, CI, OH, C-]_8 alkoxy or C^g acyloxy, C3.6 cycloalkyl or C^g alkoxy; n-or84 ee) H-C— in which R^ is hydrogen or C-|_6 alkyl, ff) a substituted or unsubstituted Cg-C-io aryl moiety, 20 gg) a substituted or unsubstituted monocyclic or bicyclic, saturated or unsaturated, heterocyclic moiety having 1-3 WO 00/10566 - 40 - PCT/US99/19265 atoms selected from O, N or S, said ring being bonded via a ring carbon or nitrogen to the phenyl substituent, hh) a monocyclic or bicyclic substituted or unsubstituted heteroaromatic moiety having 1-3 hetero atoms selected 5 from 0, N or S, said ring being bonded via a ring carbon or nitrogen to the phenyl substituent and wherein the heteroaromatic moiety can additionally have a fused-on benzene or naphthalene ring; the substituents for such p, q, ff, gg and hh moieties being selected from 10 1 or 2 of the following: 1) halo, 2) C^e alkyl, 3) N02, 4) N3, O 15 5) CrC6 alkyl-S-, O 6) CrC6 alkyl—s— O ' 7) formyl, O 8) CrC6 alkyl—c—, O 9) CrC6 alkyl—o-C—. O 20 10) heteroaryl—C—in which heteroaryl is a 5-or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, O 11) C6H5-C—, o ii 12) -(C-j-Cg) alkyl-C-NR60R61 in which Rgo and Rei are each 25 independently hydrogen or C^Cq alkyl, WO 00/10566 - 41 - PCT/US99/19265 13) OH, 14) hydroxy (C-|-C6 alkyl), O 15) CrC6 alkyl-S-C-, O 16) NC-(CH2)r -O-C— in which r is 1-6, 0 5 17) C6H5CH2-0-C-, 18) -CH2-R8o in which Rgo is a) -OR32 in which R32 is as defined above, b) -SR32 in which R32 is as defined above, c) -NR32R33 in which R32 and R33 are as defined 10 above, or d) 5- or 6-membered heteroaromatic containing 1-4 0, S or N atoms, ORb4 N 19) CrC6 alkyl—c— in which is as defined above, 20) cyano, 15 21) carboxyl, 22) CF3, O 23) C-j-Cg alkyl—C-O— O 11 24) C6H5-0-C— in which the phenyl moiety may be optionally substituted by halo or (Ci-C6)alkyl, O 20 25) NRgoRg-r-C— in which R60 and Rei are as defined above, O O 26) R91-NH-C— or R91-C-NH— in which R91 is a 5- or 6-membered aromatic heterocyclic group having 1-3 O, N or S, WO 00/10566 - 42 - PCT/US99/19265 o 27) CeH5(CH2)i_g—O-C—, O 28) Rg§0 (CH2)'].6—O"C— in which R85 is as defined above, O 29) SiRg9R100Rioi 0-CH2 C in which Rgg, R100 and R101 are each independently Ci_6 alkyl; or 5 Q and either R.) and R2 taken together form -O-CH2-O. The compounds of this invention are novel and represent a new class of antibacterial agents. They are distinct from both the previously reported oxazoiidinone and isoxazoline antibiotics since they incorporate 10 the isoxazolinone ring system. They differ from the prior art isoxazolinone herbicides since the ring nitrogen must be substituted with an amide moiety as defined above. The compounds of formula I are antibacterial agents useful in the 15 treatment of infections in humans and other animals caused by a variety of bacteria, particularly methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Also included in the invention are processes for preparing the 20 compounds of formula I and pharmaceutical compositions containing said compounds in combination with pharmaceutical^ acceptable carriers or diluents. WO 00/10566 PCT/US99/19265 - 43 - DEFINITIONS The term "pharmaceutically acceptable salt" as used herein is intended to include the non-toxic acid addition salts with inorganic or 5 organic acids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p-toluene-sulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic, hydroiodic, hydrobromic, and the like. These salts may be in hydrated form. 10 The terms "halo" or "halogen" includes chloro, bromo, fluoro and iodo, and is preferably chloro or fluoro. The aliphatic "alkyl" groups as used herein means straight or 15 branched chains having the specified number of carbon atoms, e.g. in the case of C-|-C6 alkyl, the alkyl group may have from 1 to 6 carbon atoms. Similarly, terms such as "C2-C8 alkenyl" refer to at least one double bond alkenyl group having the specified number of carbon atoms, "C2-C8 20 alkenyl" refers to at least one triple bond alkynyl group having the specified number of carbons, etc. The term "acyloxy" unless otherwise defined refers to a group of O ii the type CH3C-0— where the alkyl group can have the specified number 25 of carbon atoms, e.g. C-pC5 alkoxy would have 1-6 carbons. Where not specified the carbon length is from 1-6 carbons. Unless otherwise indicated the term "aryl" refers to aromatic carbocyclic rings, i.e. phenyl and naphthyl. 30 WO 00/10566 - 44 - PCT/US99/19265 "Heteroaromatic" as used herein refers to an aromatic heterocyclic moiety having one or more atoms selected from O, N, S, e.g. pyridine, thiophene, furan, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-5 quinolyn, 3-quinolyn, 1-isoquinolyl, 3-isoquinolyl, 2-imadazolyl, 4- imadazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-10 pyrrolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-thiazol-3-yl, 1,2,4-thiazol-5-yl, 1,2,3,4-tetrazol- 5-yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazoIyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-tetrazolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 1-purinyl, 3-isothiazolyl, 4-isothiazolyl, and 5-isothiazolyl. 15 A saturated or unsaturated heterocyclic group can have 1-3 atoms selected from O, N and S, e.g. dioxolane. imidazolidine, dithioiane, oxathiolane, oxazolidine, piperidinyl, piperazinyl, morpholino or thiomorpholino, or the corresponding unsaturated heterocyclic groups. 20 Where possible nitrogen and/or sulfur atoms in such heterocyclic moieties may be oxidized and such oxidized compounds are intened to be encompassed within the formula I compounds. 25 DETAILED DESCRIPTION Preferred embodiments of the present invention are the compounds of formula I wherein A is WO 00/10566 - 45 - PCT/US99/19265 r2 r3 in which Q-j, R2, and R3 are as defined above. A still more preferred embodiment of the present invention 5 comprises a compound of the formula or a pharmaceutically acceptable salt thereof, in which 10 Rf is H, C-j_e alkyl optionally substituted with one or more F, CI, OH, C-^ alkoxy, or C-^g acyloxy, C3.6 cycloalkyl or Ci_8 alkoxy; R2 and R3 are each independently a) H, 15 b) F, c) CI, d) Br, e) C-,.6 alkyl, f) N02, 20 g) I, h) C-j_6 alkoxy, i) OH j) amino, or k) cyano; and WO 00/10566 - 46 - PCT/US99/19265 Q is a) hydrogen, b) halo, c) N02, 5 d) N3, e) CrC6 alkylthio, 9 f) CrC6 alky! —S—, 9 g) CrC6 alkyl—s—, O h) CrC6 alkyl, 10 i) C-j-Ce alkoxy, j) formyl, 9 k) CrC6 alkyl—c—, O I) 0-,-Cg alkyl—o-C—. 9 m) CrC6 alkyl—c-O—. 9 15 n) heteroaryl— C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, O o) C6H5-C-, p) amino, 20 q) C-j-Cg alkylamino-, r) di(Ci-C6 alkyl)amino-, O ii s) (C-j-Cg) alkyl-C-NR60R61,in which Rgg and Rgi are each independently hydrogen or CrC6 alkyl, WO 00/10566 PCT/US99/19265 - 47 - t) OH, u) cyano, v) hydroxy (C-pCg alkyl), O w) CrC6 alkyl-S-C—, O 5 x) NC-(CH2)r -O-C— in which r is 1-6, O y) O0H5CH2—o-c—1 o z) C6H5-0-C , /0R84 N aa) CrC6 alkyl—c— wherein R84 is hydrogen or C-|_e alkyl, O bb) R850-(CH2)i.6—C— in which R85 is hydrogen, C^g alkyl 10 optionally substituted with one or more F, CI, OH, Ci_8 alkoxy or C^s acyioxy, C3.6 cycloalkyl or C^.8 alkoxy, N-ORg4 cc) H-C— in which R^ is as defined above, dd) 15 ee) ff) \\ r x n/ Q X Y WO 00/10566 - 48 - PCT/US99/19265 gg) hh) Y-J^X X ^ N I M x ii) 10 jj) kk) ID >n,n I M x^T» V" I M CQ ' Y M T ^°ix > N-N 15 mm) nn) / -- N N JIx s -sd N L 'Vi K5 I WO 00/10566 ,Q PCT/US99/19265 - 49 - oo) PP) qq) rr) ss) tt) N-N A* I r92 in which Rg2 is H or alkyl, V^x N-N X "V Y ,N * -N ft N >7 \=,J —N I \^-N 10 X , uu) 15 w) A \=^-N Y A \JhX ,«*N NX=^Y X WO 00/10566 - 50 - PCT/US99/19265 15 WW) /Y*- Y XX) yy) zz) /(CH2)n^ E\ (CH2)p^<\ i aaa) a diazinyl group optionally substituted with X and Y, 10 bbb) a triazinyl group optionally substituted with X and Y, ccc) a quinolinyl group optionally substituted with X and Y, ddd) a quinoxalinyl group optionally substituted with X and Y, eee) a naphthyridinyl group optionally substituted with X and Y, fff) Ai (CH2)w /f\i ggg) 1 .kr™ R64 (CHjfc \jj" WO 00/10566 - 51 - PCT/US99/19265 hhh) N- y AO) y , or R65v 0)y 5 B is an unsaturated 4-atom linker having one nitrogen and three carbons; M is a) H, b) Ci_8 alkyl, c) C3.8 cycloalkyl, 10 d) -(CH2)mOR66> or e) -(CH2)nNR67R68; Zis a) O, b) S or 15 c) NM; Wis a) CH, b) Nor c) S or O when Z is NM; 20 X and Y are each independently a) hydrogen, b) halo, c) N02, d) N3, 25 e) C-i.6 alkythio, WO 00/10566 - 52 - PCT/US99/19265 0 f) CrC6 alkyl — S—, 0 g) CrC6 alkyl—s—, 0 h) CrC6 alkyl, i) C-j-Cg alkoxy, 5 j) formyl, 0 k) CrC6 alkyl—c— t O I) CrC6 alkyl—o-C— j 0 m m) heteroaryl—C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms 10 selected from O, N or S, O n) C6H5-C—, o) amino, p) C-)-Cg alkylamino-, q) dKCfCg alkyl)amino-, O ii 15 r) -(Ci-C6) alkyl-C-NR6oR6i 'n which Rgo and Rgi are each independently hydrogen or CrC6 alkyl, s) OH, t) hydroxy (CrC6 alkyl), O u) CrC6 alkyl —S-C—, O 20 v) NC-(CH2)r—o-c—in which r is 1-6, O w) CQH5CH2—O-C—. WO 00/10566 - 53 - PCT/US99/19265 0 x) C6H5-0-C-, ,ORg4 n' y) CrC6 alkyl—Q— in which Rg4 is as defined above, z) cyano, aa) carboxyl, 5, bb) CF3, cc) mercapto, O dd) CrC6 alkyl—c-O— t 0 ii ee) C6H5-0-C— in which the phenyl moiety may be optionally substituted by halo or CrC6 alkyl, O 10 ff) C6H5(CH2)1_£r-0-C—, O gg) R850-(CH2)1.6—C— in which R85 is as defined above, or O ii hh) SiRggR-jpgR^Q-j 0-CH2 C in which R991 R100 and R101 are each independently alkyl; or Q and either R-) and R3 taken together form -O-CH2-O; 15 R62 is a) H, b) C-).g alkyl optionally substituted with one or more halos, or c) C-).g alkyl optionally substituted with one or more OH, or C.j.8 alkoxy; 20 Eis a) NRgg, b) -S(=0)j in which i is 0, 1 or 2, or c) O; - 54 - # 10 15 20 R63is a) H, b) alkyl, c) -(CH2)q-aryl, or d) halo; Rgg is H or C-|_4 alkyl; R67 and Re8 are each independently H or alkyl, or R67R68 taken together are -(CH2)m-; R69 is a) H, b) alkyl, c) -(CH^q-aiyl, d) -CO2R81. e) CORg2, f) -C(=0)-(CH2)q-C(=0)R81, 9) -S(=0)2-C1.g alkyl, h) -S(=0)z-(CH2)q-aryl, or 0 -(C=0)j-Het in which j is 0 or 1 and Het is a saturated or unsaturated 5- or 6-membered heterocyclic group having 1-3 hetero atoms selected from 0, N or S; a) -CH2-, or b) -CH(R70)-CHr; Z2is a) -02S-, b) -0-, c) -S-, d) -SO-, or e) -N(R71)r; WO 00/10566 - 55 - PCT/US99/19265 Z3 is a) s. b) so, c) S02, or 5 d) o; a-j is H or CH3; a2 is a) H, b) OH-, 10 c) CH3CO2-, d) ch3-, e) ch3o-, f) R720-CH2-C(0)-NH-, g) R730-C(0)-NH-, 15 h) R73-C(0)-NH-, i) (CrC2)alkyl-0-C(0)-, or j) HO-CH2; or A<[ and A2 taken together are a) b) 0 =; Rq4 is H or CH3-; m is 4 or 5; n is 0, 1, 2, 3, 4 or 5; 25 y is 0 or 1; p is 0, 1, 2, 3, 4 or 5; w is 1,2 or 3; q is 1, 2, 3 or 4; WO 00/10566 - 56 - 10 15 z is 0 or 1; R65'S a) R740C(R75)(R76)-C(0)-, b) R770C(0)-, c) R78(0)-, d) R79-S02-, or e) R80-NH-C(O)-; R7q is H or (C-|-C3)alkyl; R71 is a) R740C(R75)(R76)-C(0)-, b) R770-C(0)-, c) R78-C(0)-, d) f) H3C-C(0HCH2)2-C(0)-, g) R7g-S02-, h) o o i) R80-NH-C(O)-, R72 is a) H, b) CH3, WO 00/10566 - 57 - PCT/US99/19265 c) phenyl-CH2-, or d) CH3C(0)-; R73 is (C^CsJalkyl or phenyl; R74 is H, CH3, phenyl-CH2- or CH3-C(0)-; 5 R75 and R76 are each independently H or CH3, or R75 and R78 taken together are -CH2CH2-; R77 is (Ci-C3)alkyl or phenyl; R78 is H, (CrC4)alkyl, aryl-(CH2)ni, C!H2C, CI2HC, FH2C-, F2HC- or (C3-C6)cycloalkyl; 10 R79 is CH3; -CH2CI, -CH2CH=CH2, aryl or -CH2CN; R80 is -(CH2)ni-aryl where n1 is 0 or 1; R8i is a) H, b) Ci_6 alkyl optionally substituted with one or more OH, halo 15 or CN, c) -(CH2)q-aryl in which q is as defined above, or d) -(CH2)q—ORg3 in which q is as defined above; R82 is a) C-|^ alkyl optionally substituted with one or more OH, halo 20 or CN, b) -(CH2)q-aryl in which q is as defined above, or c) -(CH2)q-OR83 in which q is as defined above; R83 is a) H, 25 b) C^ alkyl, c) -(CH2)q-aryl in which q is as defined above; or d) -C(=0) Ci_6 alkyl; and WO 00/10566 - 58 - PCT/US99/19265 20 aryl is phenyl, pyridyl or naphthyl, said phenyl, pyridyl or naphthyl moieties being optionally substituted by one or more halo, -CN, OH, SH, C-|_0 alkoxy or C^ alkylthio. Another preferred embodiment of the present invention comprises a compound of the formula r2 o or a pharmaceutical^ acceptable salt thereof, in which 10 R1 is H, Ci_g alkyl optionally substituted with one or more F, CI, OH, Ci_g alkoxy or C-i_8 acyioxy, C3.5 cycloalkyl or C-).g alkoxy; R2 and R3 are each independently H or F; or R2 and R3 taken together represent o— V. 1 15 Q is a) hydrogen, b) halo, c) n3. d) no2, e) CrC6 alkylthio, f) O CrC6 alkyl—s— g) O C^Cg alkyl—s— 11 O h) C1-C6 alkyl, 0 CrC6 alkoxy, WO 00/10566 j) k) I) m) 5 n) o) P) 10 q) r) 15 Rge is a> b) c) d) 20 e) f) g) PCT/US99/19265 - 59 - formyl, O C-j-Cq alkyl—c— i O C-)-Cg alkyl—O-C— j O CrC6 alkyl—C~0—, (CrC6 alkoxy)2N-, 5- or 6-membered heterocyclic containing 1-3 0, N or S and linked to the phenyl substituent via a carbon or nitrogen, said heterocycle moiety being optionally substituted by Rgq, .OH N CrC6 alkyl—c > phenyl optionally substituted by Rg6, or 5- or 6-membered saturated or unsaturated heterocyclic containing 1-3 O, N or S and linked to the phenyl substituent via a carbon or nitrogen, said heterocycle moiety being optionally substituted by R96, and CrC6 alkyl-OH, CrC6 alkyl—o-C—. II O 0 ch3-C— CrC6 alkyl—C-. ii O cyano, formyl, n-oh il H-C- , O CrC6 alkyl—O-C—, WO 00/10566 - 60 - PCT/U S99/19265 o h) SiRggRiggR-joi 0-CH2 C in which Rggi R100 and R^oi are each independently alkyl, O O i) CH3_s— CrC6 alkyl—s—, ii ii 0 o o II j) hocch2oc— , o 5 k) C6H5-0-C— where the phenyl may be optionally substituted by halo, O i) ho-ch2-c- , m) (Ci~C6 alkyl)2N-, n) CrC6 alkyl-NH-, 10 o) amino, O p) CrC6 alkyl—s—, O C|) c6h5ch2oc— or i O • i r) R98-C— in which Rg8 is phenyl, 5- or 6-membered heteroaryl containing 1-3 O, N or S and linked to the phenyl 15 substituent via a ring carbon atom or 5- or 6-membered saturated or unsaturated heterocyclic containing 1-4 O, N or S and linked to the phenyl substituent via a ring carbon atom. 20 Some specific preferred embodiments of the present invention are listed in the table below. WO 00/10566 - 61 - PCT/US99/19265 WO 00/10566 - 62 - PCT/US99/19265 WO 00/10566 - 63 - PCT/US99/19265 n=n v „N y *06» N. M r 0 / h N. -N hon >^0 ^ ' h o - o \y « Y °' 1 n—t( ,) <x i W V-^ -ch3 hjc V- n n HaC-^—O ^ f h3c f r WO 00/10566 - 64 - PCT/US99/19265 WO 00/10566 - 65 - PCT/US99/19265 Y" ft O \ / h Y\ /°Y« f' h F N. M ° h n. ,n r r n ^ r WO 00/10566 - 66 - PCT/US99/19265 (-Y \ \\ p h Y -c\!-. «—N. M CI \\ /° h r ^ Nv n "V h3c n 'V WO 00/10566 - 67 - PCT/US99/19265 WO 00/10566 - 68 - PCT/US99/19265 WO 00/10566 - 69 0/ \ O v'° h v -N. M. Y CV\ 0 iv o ft / h M Y 0assr/r"""\ o onY\ " H o & / h -n. r r o4_/n Y HN/^~A o ^/NY\ - \\ _/° h —n- -n r PCT/US99/19265 WO 00/10566 - 70 - PCT/US99/19265 ac—s-n n- ii \ / O N W // 'N, .N V CH, N. \\ /\ /*—\ /' '0 V—N • ' «,C r o CHj V* n-C ■ -nx. hc o H3C CHjO, ^ H,C—( y—N N- N—0 X ' 0 W /-o -<• I ' »N. ■ i o %—N N- / \ / .^r 'NX^Nx ^ \\ =r\ /) r 0 o =■■. Kr H.C W ••„ / W 0 -o' w )J "-V-K V ch, V-N N >1 (v 0 k H,C-o HO O °w h-° V N N—U >} > x—'' }-* x^'nv/Nv.ch3 WO 00/10566 - 71 - PCT/US99/19265 WO 00/10566 - 72 - PCT/US99/19265 The compounds of the present invention can be made by the methods summarized below. It will be apparent to those skilled in the art that the procedures 5 described herein are representative in nature and that alternative procedures are feasible. Isoxazoiinones 5 of the present invention are preferably prepared via the sequence outlined in Scheme 1. Aryl acetic acids 1 are either 10 commercially available or prepared by one of many well known methods in the chemical literature including but not limited to the sequence shown in Scheme 2 or 3. Isoxazolinone 3 is prepared by methods described by Marchesini [J. Org. Chem. 1984,49, p. 4287-4290]. Reaction of 1 with sodium hydride and ethyl formate provides 2 which is in turn reacted with 15 hydroxylamine yielding 3. Treatment of 3 with mild base, preferably potassium carbonate, in an appropriate solvent, preferably dichloromethane or N, A/-dimethylformamide followed by addition of 4 (prepared by methods described by Barnes et al in US Patent 5, 284, 863) provides isoxazolinone 5. 20 Scheme 1 1 2 o 4 3 5 O >-R' WO 00/10566 - 73 - PCT/US99/19265 An alternative way to prepare aryl acetic esters 1 of the present invention is shown in Scheme 2. Treatment of triflate 6 (prepared from methyl 4-hydroxyphenyl acetate by methods known by those skilled in the 5 art) with an N, N- dialkylamine in the manner described by Buchwald [Tet. Lett., 1997, 38, p. 6363-6366] produces esters exemplified by 7. Aryl-bromides, -iodides, and -chlorides are also suitable as replacements for triflate 6 in Scheme 2. The N, N- dialkylamines used in Scheme 2 are either commercially available or are synthesized by literature procedures. 10 Literature preparations of many cyclic N, N- dialkylamines have been detailed by Gadwood (WO 97/10223) and others are well known to those skilled in the art. Scheme 2 15 Another alternative to prepare aryl acetic esters 1 of the present invention is shown in Scheme 3. Treatment of 8 with a mild base, 20 preferably potassium carbonate, and a primary or secondary amine or thiolate, in a suitable solvent, preferably acetonitrile or N, N-dimethylformamide, at a temperature between 25°C and 100°C provides 9. Compound 8 is commercially available. Compound 9 is converted to 11 or 12 by methods described by Gravestock (World Patent 97/14690). 25 This sequence is also known to those skilled in the art as the Willgerodt reaction. Conversion of 11 to 12 can also be accomplished by various methods known in the chemical literature including but not limited to treatment with acid in hot alcohol. WO 00/10566 - 74 - PCT/US99/19265 Scheme 3 Base CH3CN or DMF RR'NH or RSNa Sulfur morpholine X2 o For 11: KOH (aq) or For 12: HCI, EtOH 10 : X2 OR" 11: R'-H 12 L = NRR' or SR X! = H or F X2 = H or F : R'-H —, : R"=Et _J H+"Et0H 5 Sulfoxides and sulfones 14 and 16 are prepared by treating sulfides 13 and 15, respectively with an oxidizing agent such as m-chloroperoxybenzoic acid or osmium tetroxide by methods known by those skilled in the art and exemplified by Barbachyn [J. Med. Chem., 1996,39,680-685]. 10 WO 00/10566 - 75 - PCT/US99/19265 Scheme 4 m-CPBA (n=1) or 13 NH 0s04l NMO (n=2) 14: n=1, 2 Xi = H or F X2 = H or F m-CPBA An alternative method of preparing compound 18 of the present invention is shown in Scheme 5. Treatment of 17 with an appropriate organostannane provides 18. This method is known by those skilled in the art as the Stille cross-coupling reaction. 10 Scheme 5 RSnBu3 Pd° DMF 15 WO 00/10566 - 76 - PCT/US99/19265 Preparation of 21, 22, 23, and 24 of the present invention is described in Scheme 6. Treatment of 19 with trifluoroacetic acid provides 20. Compound 20 is treated with an acid chloride, chioroformate, sulfonyi halide, or isocyanate in the presence of triethylamine by methods well 5 known in the chemical literature to provide 21, 22, 23, and 24, respectively. WO 00/10566 - 77 PCT/US99/19265 Scheme 6 boc-n^ RCOCI Rocoa RO-V-! x Rsc^a o ii v X R 11 ° 23 o NH y* RR'NCO R'RN N 24 O The triazole-substituted compounds 27 and 28 are prepared by cyclization of the azide 25 with acetylenes 26 (Scheme 7). This is a WO 00/10S66 - 78 - PCT/US99/19265 standard 3+2 cycloaddition which is well documented in the chemical literature. The acetylenes 26 are either commercially available or prepared by literature procedures. For example, cyanoacetylene is prepared according to Murahashi [J.Chem. Soc. Jap., 1956, 77, 1689]. 5 The cyclization reaction was usually carried out in a suitable solvent such as DMF, at a temperature between 25°C and 80°C. Other suitable solvents include but are not limited to DMSO, NMP, and DMA. The two cyclization adducts 27 and 28 were separated using preparative HPLC or by triturating with a suitable solvent such as ethyl acetate. Other suitable 10 solvents for trituration include but are not limited to methanol, ethanol, diethyl ether, and acetone. Scheme 7: 1,2,3-Triazoles N=N 26 DMF, rt-80 °C 15 The azidophenylisoxazolinone 25 is reduced to aminophenylisoxazoiinone 29 via one of the many well known methods in the chemical literature including but not limited to the treatment with 20 stannous chloride in a suitable solvent such as a 2:1 combination of ethyl acetate and methanol. Treatment of aminophenylisoxazolinones 29 with 2,5-dimethoxytetrahydrofurans 30 in acetic acid provide pyrrole-substituted isoxazoiinones 31 (Scheme 8). Subsequent conversions of WO 00/10566 - 79 - PCMJS99/19265 the pyrrole (R = CHO) are also possible, for instance the corresponding oxime can be prepared by refluxing with 50 % aqueous hydroxylamine in methanol. Scheme 8: Pyrroles SnCI2-2H20 h3co o och3 30 acetic acid, reflux, 0.5 h N-thioacetates 33 may be prepared from the corresponding N-10 acetates 32 using a variety of well known literature methods, for instance by refluxing in benzene with Lawesson's reagent. Other solvents such as toluene and xylene are also suitable. 15 Scheme 9: Thioacetates ar h ^-n n ch3 T Lawesson's Reagent benzene, reflux U 32 33 y0Hs s It will be understood that where the substituent groups used in the above reactions contain certain reaction-sensitive functional groups which WO 00/10566 - 80 - PCT/US99/19265 might result in undesirable side-reactions, such groups may be protected by conventional protecting groups known to those skilled in the art. Suitable protecting groups and methods for their removal are illustrated, for example, in Protective Groups in Organic Synthesis, Theodora W. 5 Greene (John Wiley & Sons, 1991). It is intended that such "protected" intermediates and end-products are included within the scope of the present disclosure and claims. Some of the desired end-products of formula I contain an amine. 10 In these cases, the final product may be recovered in the form of a pharmaceutically acceptable acid addition salt, e.g. by addition of the appropriate acid such as HCI, HI or methane-sulfonic acid to the amine. It will be appreciated that certain products within the scope of 15 formula I may have substituent groups which can result in formation of optical isomers. It is intended that the present invention include within its scope all such optical isomers as well as epimeric mixtures thereof, i.e. R-or S- or racemic forms. 20 The compounds of the invention are useful because they possess pharmacological activities in animals, including particularly mammals and most particularly, humans. The novel isoxazolinone derivatives of general formula I, or pharmaceutically acceptable salts or prodrugs thereof, are potent antibiotics active against gram-positive bacteria. 25 While they may be used, for example, as animal feed additives for promotion of growth, as preservatives for food, as bactericides in industrial applications, for example in waterbased paint and in the white water of paper mills to inhibit the growth of harmful bacteria, and as disinfectants for destroying or inhibiting the growth of harmful bacteria on 30 medical and dental equipment, they are especially useful in the treatment WO 00/10566 - 81 - PCT/US99/19265 of bacterial infections in humans and other animals caused by the gram-positive bacteria sensitive to the new derivatives. The pharmaceutically active compounds of this invention may be 5 used alone or formulated as pharmaceutical compositions comprising, in addition to the active isoxazolinone ingredient, a pharmaceutically acceptable carrier or diluent. The compounds may be administered by a variety of means, for example, orally, topically or parenterally (intravenous or intramuscular injection). The pharmaceutical compositions may be in 0 solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. Compositions for injection may be prepared in unit dose form in ampules or in multidose containers and may contain additives such as suspending, stabilizing and dispersing agents. The compositions may be in ready-to-use form or in powder form 5 for reconstitution at the time of delivery with a suitable vehicle such as sterile water. Thus, according to another aspect of the invention, there is provided a method of treating a bacterial infection which comprises 0 administering a therapeutically effective amount of the compound to a host, particularly a mammalian host and most particularly a human patient. The use of the compounds of the present invention as pharmaceuticals and the use of the compounds of the invention in the manufacture of a medicament for the treatment of bacterial infections are :5 also provided. The dosage to be administered depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the >0 particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of WO 00/10566 - 82 - PCT/US99/19265 the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 25 mg/day to about 2 g/day. 5 The preparations of pyrazoles substituted compounds are outlined in Scheme 10. Compound 29 was diazotized and then reduced to form hydrazine hydrochloride salt 34 via one of the many well known methods in the chemical literature including but not limited to the treatment with sodium nitrite and stannous chloride. Treatment of 34 with 10 ethoxycarbonylmalondiadehyde, cyanomalondiadehyde [prepared according to Bertz, S.H., Dabbagh, G. and Cotte, P. in J. Org. Chem, 1982, 47, p. 2216,] or malondiadehyde [prepared according to Martinez,A.M., Cushmac, G.E., Rocek, J. in J. Amer. Chem. Soc, 1975, 97, p. 6502] in the presence of sodium bicarbonate at room temperature 15 provides compound 35. Scheme 10: Pyrazoles h2n-\ W o o NaN02, SnCI2 . 2H20 ^ N^NH(CO)R' HCI 29 h2n-hn-/\-/vo r ohc^cho \\ y * n^NH(CO)R- NaHC03 •HCI 34 WO 00/10566 - 83 - PCT/US99/19265 In Vitro Activity Samples of the compounds prepared below in Examples 1-97 after solution in water and dilution with Nutrient Broth were found to 5 exhibit the following ranges of Minimum Inhibitory Concentrations (MIC) versus the indicated microorganisms as determined by tube dilution. The MICs were determined using a broth micro dilution assay in accordance with that recommended by the National Committee for Clinical Laboratory Standards (NCCLS). Muelfer-Hinton medium was used except for 10 Streptococci which was tested in Todd Hewitt broth. The final bacterial inoculate contained approximately 5 x 105 cfu/ml and the plates were incubated at 35°C for 18 hours in ambient air (Streptococci in 5% CO2). The MIC was defined as the lowest drug concentration that prevented visible growth. 15 Microorganism MIC value in ug/ml S. pneumoniae A9585 < 8 E. faecalis A20688 <16 S. aureus A15090, penicillinase positive <16 ILLUSTRATIVE EXAMPLES 20 The following examples illustrate the invention, but are not intended as a limitation thereof. The abbreviations used in the examples are conventional abbreviations well-known to those skilled in the art. Some of the abbreviations used are as follows: 25 WO 00/10566 - 84 - PCT/US99/19265 h = hour(s) mol = mole(s) mmol = mmole(s) g = gram(s) min = minute(s) rt = room temperature THF = tetrahydrofuran L = liter(s) mL = milliliters) Et20 = diethyl ether EtOAc = ethyl acetate MeOH = methanol DMF = dimethylformamide In the following examples, all temperatures are given in degrees Centigrade. Melting points were determined on an electrothermal apparatus and are not corrected. Proton and carbon-13 nuclear magnetic resonance (1H and 13C NMR) spectra were recorded on a Bruker AM-300 or a Varian Gemini 300 spectrometer. All spectra were determined in CDCI3, DMSO-d6, CD3OD, or D2O unless otherwise indicated. Chemical shifts are reported in 8 units relative to tetramethylsilane (TMS) or a reference solvent peak and interproton coupling constants are reported in Hertz (Hz). Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; dd, doublet of doublets; dt, doublet of triplets; and app d, apparent doublet, etc. Infrared spectra were determined on a Perkin-Elmer 1800 FT-1R spectrometer from 4000 cm'1 to 400 cm'1, calibrated to 1601 cm'1 absorption of a polystyrene film, and are reported in reciprocal centimeters (cm-1). Mass spectra were recorded on a Kratos MS-50 or a Finnegan 4500 instrument utilizing direct chemical ionization (DCI, isobutene), fast atom WO 00/10566 - 85 - PCT/US99/19265 bombardment (FAB), or electron ion spray (ESI). Ultraviolet spectra were determined on a Hewlett Packard 8452 diode array spectrophotometer in the solvent indicated. 5 Analytical thin-layer chromatography (TLC) was carried out on precoated silica gel plates (60F-254) and visualized using UV light, iodine vapors, and/or staining by heating with methanolic phosphomolybdic acid. Column chromatography, also referred to as flash chromatography, was performed in a glass column using finely divided silica gel at pressures 10 somewhat above atmospheric pressure with the indicated solvents. Reversed-phase analytical thin-layer chromatography was carried out on precoated reverse phase plates and visualized using UV light or iodine vapors. 15 EXAMPLE 1 N-[[4-(4-methylthiophenyl)-5-oxo-2-isoxazolinyl]methyl]acetamide o 20 A. Ethyl 4-methylthiophenyiaeetate To a solution of 4-methylthiophenylacetic acid (1.0 g, 5.48 mmol) in 55 mL of ethanol was slowly added a catalytic amount of concentrated sulfuric acid. The mixture was stirred at room temperature overnight and 25 then concentrated at reduced pressure. The residue was partitioned between methylene chloride and sodium bicarbonate. The organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated to yield 1.1 g of a colorless oil (96%). 1H NMR (300MHz, WO 00/10566 PCT/US99/19265 - 86 - CDCI3) 6 7.22 (s, 4 H), 4.15 (q, J=6 Hz, 2 H), 3.57 (s, 2 H), 2.47 (s, 3 H), 1.25 (t, J=6 Hz, 3 H). B. Ethyl 4-methyIthio-a-formyl-phenylacetate 5 A suspension of NaH (0.84 g, 20.8 mmol) was added at room temperature to a solution of ethyl 4-methylthiophenylacetate (1.1 g, 5.2 mmol) in ethyl formate (20 mL). The mixture was stirred at room temperature for 1 hour and then cold 0.5 N HCI (20 mL) was added slowly. The crude reaction was then extracted with ether, and the organic 10 layer was washed with sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated to yield 1.2 g of ethyl 4-methylthio-a-formyl-phenylacetate as a colorless oil, which was used in the next step without purification. 15 C. 4-(4-methylthio)-phenylisoxazolin-5-one To a solution of ethyl 4-methylthio-a-formyl-phenylacetate in 20 mL of methanol and 1 mL of water was added hydroxylamine hydrochloride (0.54 g, 7.8 mmol). The mixture was heated to reflux for 1 hour. The solvent was evaporated and the residue was triturated with water to afford 20 a precipitate, which was then further triturated with ether to yield 0.48 g (two steps, 44%) of a pale yellow solid. 1H NMR (300MHz, MeOH-d4) 6 8.74 (s, 1 H), 7.66 (d, J=8 Hz, 2 H), 7.25 (d, J=8 Hz, 2 H), 2.46 (s, 3 H). D. N-[[4-(4-methylthiophenyl)-5-oxo-2-isoxazolinyl]methyl]acetamide 25 To a solution of 4-(4-methylthio)-phenylisoxazolin-5-one (0.2 g, 0.97 mmol) in 10 mL of methylene chloride was added potassium carbonate (0.67 g, 4.85 mmol) and N-(hydroxymethyl) acetamide acetate (0.64 g, 4.85 mmol). The mixture was stirred at room temperature for 18 hours. It was then poured into 10 mL of 1N HCI and extracted three times 30 with chloroform. The organic layer was then washed with sodium WO 00/10566 - 87 - PCT/US99/19265 bicarbonate, brine, dried over magnesium sulfate, filtered, concentrated to yield a tan solid, which was then recrystallized with hexane/chloroform. The resulting solid was further purified by triturating with ether to yield 0.186 g (69%) of a tan solid. 1H NMR (300MHz, DMSO-d6) 5 8.93 (s, 1 5 H), 7.72 (d, J=9 Hz, 2 H), 7.28 (d, J=9 Hz, 2 H), 5.02 (d, J=6 Hz, 2 H), 2.48 (s, 3H), 1.84 (s, 3 H). EXAMPLE 2 10 N-{[4-(3-fluoro-4-oxido-4-morpholin-4-ylphenyl)-5-oxo-2-hydroisoxazol-2-yl3methyl}acetamide 15 To N-{[4-(3-fluoro-4-morpholin-4-ylphenyl)-5-oxo-2-hydroisoxazol- 2-yl]methyl}acetamide (200 mg, 0.60 mmol) in 50 mL methanol was added magnesium monoperoxyphthalate (300 mg, 0.60 mmol). After 2 hours at ambient temperature the white precipitate was filtered and the filtrate was concentrated. The remaining residue was pushed through a 20 plug of basic alumina with dichloromethane. The eluant was concentrated and recrystallized from dichloromethane / hexanes to afford 162 mg (44%) of the title compound as a brown solid. 1H NMR (DMSO-d6; 300 MHz) 6 9.19 (s, 1H), 9.02 (t, J= 6.1 Hz, 1H), 8.62-8.55 (m, 2H), 7.82-7.75 (m, 2H), 5.09 (d, J = 6.0 Hz, 2H), 4.44 (app t. J- 11.1 Hz, 2H), 25 4.08 (app t, J = 9.6 Hz, 2H), 3.78 (app d, J = 11.1 Hz, 2H), 2.89 (app d, J = 10.5 Hz, 2H), 1.86 (s, 3H); ESI (M+H)+=352. WO 00/10566 - 88 - PCT/OS99/19265 EXAMPLE 3 N-({4-[4-(methylsulfinyl)phenyl]-5-oxo-2-hydroisoxazol-2-yl}methyl)acetamide 5 O m-CPBA O To N-{[4-(4-methylthiophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (1.0 g, 3.6mmol) in 50 mL chloroform at 0°C was 10 added m-CPBA (1.12 g, 3.6 mmol) in 30 mL chloroform via syringe pump over 2 hours. Saturated sodium bicarbonate was added and the reaction mixture was stirred vigorously for 10 minutes at which time it was poured into saturated sodium bicarbonate and 4:1 chloroform:methanol. The organic layer was washed with brine, dried over magnesium sulfate, 15 filtered and concentrated. The residue was triturated with ether providing 800 mg (79%) of the title compound as a colorless solid. 1H NMR (DMSO-d6; 300 MHz) 8 9.11 (s, 1H), 8.96 (t, J = 6.1 Hz, 1H), 7.96 (d, J = 6.6 Hz, 2H), 7.67 (d, J = 6.6 Hz, 2H), 5.03 (d, J = 6.1 Hz, 2H), 2.73 (s, 3H), 1.84 (s, 3H); ESI (M+H)+=295. 20 EXAMPLE 4 N-({4-[4-(methylsulfonyl)phenyl]-5-oxo-2-hydroisoxazol-2-yl)methyl)acetamide 25 WO 00/10566 - 89 - PCT/US99/19265 To N-{[4-(4-methylthiophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (200 mg, 0.72 mmol) in 20 mL chloroform at 0°C was 5 added m-CPBA (450 mg, 1.44 mmol) in 5 mL chloroform. After 30 minutes saturated sodium bicarbonate was added and the reaction mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was precipitated from acetone /1:1 hexanes : ether providing 112 10 mg (50%) of the title compound as a colorless solid. 1H NMR (DMSO-d6; 300 MHz) 5 9.24 (s, 1H), 9.01 (t, J - 6.1 Hz, 1H), 8.02 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 5.11 (d, J = 6.2 Hz, 2H), 3.20 (s, 3H), 1.86 (s, 3H); ESI (M+H) +=311. 15 EXAMPLE 5 N-({4-[4-(1,1 -dioxo(1,4-thiazaperhydroin-4-yl))-3-fluorophenyl1-5-oxo-2-hydroisoxazol-2-yl)methyl)acetamide 20 WO 00/10566 - 90 - PCT/US99/19265 To N-{[4-(3-fluoro-4-(1,4-thiazaperhydroin-4-yl)phenyl)-5-oxo-2-hydroisoxazol-2-yI]methyl}acetamide (100 mg, 0.29 mmol) in 2 mL water and 8 mL acetone was added N-methylmorpholine N-oxide (98 mg, 0.85 mmol) followed by osmium tetroxide (2.5 wt% in isopropanol; 7 nl; 0.07 5 mmol). After 18 hours at ambient temperature saturated sodium bisulfite was added and the reaction mixture was extracted with 4:1 chlorofomrmethanol. The organic layer was concentrated providing 85 mg (77%) of the title compound as a colorless solid. 1H NMR (DMSO-dgl 300 MHz) 5 8.95 (s, 1H), 8.92 (t, J = 6.2 Hz, 1H), 7.62-7.51 (m, 2H), 7.17 10 (app t, J = 9.2 Hz, 1H), 4.99 (d, J = 6.2 Hz, 2H), 3.52-3.48 (m, 4H), 3.27-3.23 (m, 4H), 1.82 (s, 3H); ESI (M+H) +=384. EXAMPLE 6 15 4-(3-Fluoro-4-morpholin-4-ylphenyl)-2-([(thioxoethyl)amino]methyl)-2-hydroisoxazol-5-one Lawesson's Reagent benzene reflux 20 25 A mixture of N-{[4-3-fluoro-4-morpholinylphenyl-5-oxo-2-isoxazolinyl]methyl}acetamide (0.25 g, 0.75 mmol) and Lawesson's reagent (0.4 g, 1.0 mmol) in 10 mL of benzene was heated at reflux for 3 hours. The mixture was then concentrated under reduced pressure. The residue was purified using silica gel chromatography eluting with methylene chloride and ethyl acetate to give a colorless solid (80 mg, 30%): 1H NMR (300 MHz, CDCI3) 6 8.61 (br s, 1 H), 8.49 (s, 1 H), 7.50 WO 00/10566 - 91 - PCT/US99/19265 (dd, J = 1.5 and 13.8 Hz, 1 H), 7.40 (dd,J= 1.5 and 10.2 Hz, 1 H), 7.12 (t, J= 10.2 Hz, 1 H), 5.56 (d, J= 6.3 Hz, 2 H), 3.94 (m, 4 H), 3.17 (m, 4 H), 2.57 (s, 3 H). 5 EXAMPLE 7 N-{[4-(4-acetylphenyl)-5-oxo-2-hydroisoxazol-2-yl]methyI)acetamide n o 10 To N-{[4-phenyl-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (3.0 g, 12.9 mmol) and aluminum (III) chloride (13.8 g, 103.4 mmol) in 150 mL 1, 2-dichloroethane was added acetyl chloride (7.3 mL, 103.4 mmol) dropwise over 10 minutes. The resultant red mixture was heated to 80°C 15 for 3.5 hours, cooled to ambient temperature, and poured over 10 minutes into a rapidly stirring mixture of 20% methanol/chloroform and 1N hydrochloric acid which was immersed in an ice bath. The mixture was poured into a separatory funnel, and the layers were separated. The aqueous layer was extracted twice with 20% methanol/chloroform, and 20 the combined organics were then washed successively with 1N sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was then dried over magnesium sulfate, filtered, and concentrated to an amorphous yellow solid which was dissolved in 20% methanol/chloroform. Ether was added and the mixture was stored at 0°C for 18 hours. The 25 resultant precipitate was filtered to provide 2.48 g (70%) of the title compound as a pale pink solid. 1H NMR (DMSO-d6; 300MHz) 8 9.18 (s, WO 00/10566 - 92 - PCT/US99/19265 1H), 9.00 (t, J = 6.1 Hz, 1H), 7.96 (d, J = 6.7 Hz, 2H), 7.91 (d, J = 6.6 Hz, 2H), 5.10 (d, J = 6.2 Hz, 2H), 2.56 (s, 3H), 1.86 (s, 3H); ESI (M+H)+=275. N-({4-[4-((hydroxyimino)ethyl)phenyl]-5-oxo-2-hydroisoxazol-2-yl}methyl)acetamide A mixture of N-{[4-(4-acetylphenyl)-5-oxo-2-hydroisoxazol-2-yl]methyi}acetamide (2.0 g, 7.3 mmol) and 50% aqueous hydroxylamine (1.0 mL, 14.6 mmol) was heated to reflux for 1.5 hours, concentrated to near dryness and redissolved in 20% methanol/chloroform. Hexanes 15 were added until the solution became cloudy and the mixture was stored at 0°C for 3 hours. The precipitate was filtered providing 1.42 g (67%) of the title compound as a pale yellow solid. 1H NMR (DMSO-dg; 300MHz) 8 11.21 (s, 1H), 9.01 (s, 1H), 8.96 (t, J = 6.2 Hz, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 5.04 (d, J = 6.2 Hz, 2H), 2.19 (s, 3H), 1.84 20 (s, 3H); ESI (M+H)+=290. EXAMPLE 8 5 O 10 EXAMPLE 9 N-{[4-(4-(2-furyl)phenyl)-5-oxo-2-hydroisoxazol-2- 25 yl]methyl)acetamide WO 00/10566 - 93 - PCT/US99/19265 O Nitrogen was bubbled through a mixture of N-{[4-(4-iodophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (300 mg, 0.84 mmol), 2-5 tributylstannylfuran (0.26 mL, 0.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (77 mg, 0.08 mmol), triphenylarsine (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) in 5 mL DMF. The reaction mixture was capped and allowed to stir at ambient temperature for 8 hours, at which time it was diluted with 20% 10 methanol/chloroform, filtered thru celite and concentrated. The residue was suspended in chloroform, loaded onto a Biotage flash 40i chromatography module (12M) thru a frit, and eluted with 50% hexane/ethyl acetate providing a solid which was triturated with chloroform/ether to provide 132 mg (53%) of the title compound as a 15 colorless solid. 1H NMR (DMSO-d6; 300MHz) 5 9.00 (s, 1H), 8.94 (t, J = 6.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.74-7.70 (m, 2H), 6.95 (d, J = 3.2 Hz, 1H), 6.60-6.59 (m, 1H), 5.04 (d, J = 6.1 Hz, 2H), 1.85 (s, 3H); ESI (M+H)+=299. 20 EXAMPLE 10 N-{[5-oxo-4-(4-(2-thienyl)phenyl)-2-hydroisoxazol-2-yl]methyl)acetamide 25 WO 00/10566 - 94 - PCT/US99/19265 Nitrogen was bubbled through a mixture of N-{[4-(4-iodophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (300 mg, 0.84 mmol), 2-5 tributylstannylthiophene (0.27 mL, 0.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (77 mg, 0.08 mmol), triphenylarsine (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) in 5 mL DMF. The reaction mixture was capped and allowed to stir at ambient temperature for 8 hours, at which time it was diluted with 20% 10 methanol/chloroform, filtered thru celite and concentrated. The residue was suspended in chloroform, loaded onto a Biotage flash 40i chromatography module (12M) thru a frit, and eluted with 15% acetone/chloroform providing a solid which was triturated with chloroform/ether to provide 165 mg (63%) of the title compound as a 15 colorless solid. 1H NMR (DMSO-d6; 300MHz) 5 9.00 (s, 1H), 8.95 (t, J = 6.0 Hz, 1H), 7.81 (d, J = 7.3 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.54-7.52 (m, 2H), 7.15-7.11 (m, 1H), 5.04 (d, J = 6.1 Hz, 2H), 1.85 (s, 3H); ESI (M+H)+=315. 20 EXAMPLE 11 N-{[4-(4-(2H,3H-1,4-dioxin-5-yl)phenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide WO 00/10566 - 95 - PCT/US99/19265 n o Nitrogen was bubbled through a mixture of N-{[4-(4-iodophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (300 mg, 0.84 mmol), 2-5 (tributylstannyl)-5,6-dihydro-[1,4]-dioxin (346 mg, 0.92 mmol), tris(dibenzylideneacetone)dipalladium(0) (77 mg, 0.08 mmol), triphenylarsine (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) in 5 mL DMF. The reaction mixture was capped and allowed to stir at ambient temperature for 16 hours, at which time it was diluted with 10 20% methanol/chloroform, 10% aqueous potassium fluoride was added and the mixture was allowed to rapidly stir for 1 hours. The reaction mixture was filtered thru celite and concentrated. The resultant black oil was dissolved in 20% methanol/chloroform, adsorbed onto silica gel and loaded into a Biotage flash 40i chromatography module SIM. 15 Chromatography was performed using a 12M silica gel cartridge eluting with 20% acetone/chloroform providing an amber oil which was triturated with ether, yielding 115 mg (44%) of the title compound as a tan solid. 1H NMR (DMSO-d6; 300MHz) 8 8.93-8.88 (m, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 6.96 (s, 1H), 5.01 (d, J = 6.2 Hz, 2H), 4.22-4.19 20 (m, 2H), 4.10-4.07 (m, 2H), 1.85 (s, 3H); ESI (M+H)+=317. EXAMPLE 12 N-{[5-oxo-4-(4-pyrazin-2-ylphenyl)-2-hydroisoxazol-2- 25 yl]methyl)acetamide WO 00/10566 - 96 - PCT/US99/19265 Nitrogen was bubbled through a mixture of N-{[4-(4-iodophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (300 mg, 0.84 mmol), 2-5 (tributylstannyl)pyrazine (340 mg, 0.92 mmol), tris(dibenzy!ideneacetone)dipalladium(0) (77 mg, 0.08 mmol), triphenylarsine (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) in 5 mL DMF. The reaction mixture was capped and allowed to stir at ambient temperature for 16 hours, at which time it was diluted with 10 20% methanol/chloroform, 10% aqueous potassium fluoride was added and the mixture was allowed to rapidly stir for 1 hour. The reaction mixture was filtered thru celite and concentrated. The resultant black oil was dissolved in 20% methanol/chloroform, adsorbed onto silica gel and loaded into a Biotage flash 40i chromatography module SIM. 15 Chromatography was performed using a 12M silica gel cartridge eluting with 25% acetone/chloroform providing an amber oil which was triturated with ether, yielding 52 mg (44%) of the title compound as a colorless solid. 1H NMR (DMSO-d6; 300MHz) 8 9.28 (d, J = 1.4 Hz, 1H), 9.11 (s, 1H), 8.97 (t, J = 6.1 Hz, 2H), 8.71 (app t, J = 1.9 Hz, 1H), 8.59 (d, J = 2.5 20 Hz, 1H), 8.17 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 5.07 (d, J = 6.2 Hz, 2H), 1.86 (s, 3H); ESI (M+H)+=311. WO 00/10566 - 97 - PCT/US99/19265 EXAMPLE 13 N-ft5-oxo-4-(4-{4-[2-( 1,1,2,2-tetramethyM -silapropoxy)acetynpiperazinyl}phenyl)-2-hydroisoxazol-2-5 yl]methyl}acetamide o t-BuMo2SiOx/l^ '~V o To N-{[5-oxo-4-(piperazinylphenyl)-2-hydroisoxazol-2-yl]methyl} 10 acetamide trifluoroacetate salt (0.43 g, 1.0 mmol) in 2 mL of dimethylformamide and 10 mL dichloromethane was added triethylamine (0.7 mL, 0.5 mmol) followed by (t-butyldimethylsilyloxy)acetyl chloride (1.0 g, 4.8 mmol). The resultant mixture was allowed to stir at ambient temperature for 1.5 hours before being partitioned between 15 dichloromethane and water. The organic layer was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated. The residue was triturated with ether to provide 0.24 g (49%) of the title compound. 1H NMR (methanol-d4; 300 MHz) 8 8.49 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 5.07 (s, 20 2H), 4.42 (s, 2H), 3.73 (t, J = 4.9 Hz, 4H), 3.24 (t, J = 4.9 Hz, 4H), 1.94 (s, 3H), 0.95 (s, 9H); ESI (M+H)+ = 489. EXAMPLE 14 25 N-[(4-{4-[4-(2-hydroxyacetyl)piperazinyl1phenyl}-5-oxo-2- hydroisoxazol-2-yl)methyl]acetamide WO 00/10566 - 98 - PCT/US99/19265 O r o To N-{[5-oxo-4-(4-{4-[2-(1,1,2,2-tetramethyl-1-silapropoxy)acetyl]piperazinyl}phenyl)-2-hydroisoxazol-2-5 yl]methyi}acetamide (0.3 g, 0.6 mmol) in 4mL dichloromethane was added 4 mL trifluoroacetic acid. After 1 hour, the reaction was concentrated, the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The 10 residue was triturated with ether to provide 92 mg (40%) of the title compound. 1H NMR (DMSO-d6; 300 MHz) 5 8.87 (t, J = 6.2 Hz, 1H), 8.74 (s, 1H), 7.63 (d, J = 8.7 Hz, 2H), 6.97 (d. J = 8.9 Hz, 2H), 4.95 (d, J = 6.2 Hz, 2H), 4.64 (t, J = 5.6 Hz, 1H), 4.13 (d, J = 5.6 Hz, 2H), 3.60 (br s, 2H), 3.48 (br s, 2H), 3.17 (br s, 4H), 1.83 (s, 3H); ESI (M+H)+=375. N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide) 15 EXAMPLE 15 O O 20 Prepared from ethyl 4-azidophenylacetate according to the general route outlined in Scheme 1. The starting material was prepared as follows: WO 00/10566 - 99 - PCT/US99/19265 Ethyl 4-Azidophenylacetate O o i-Q-A OEt 'OEt 5 Following the general procedure of Marchesini (J. Org. Chem. 49, p. 4287-4290,1984), sodium nitrite (38 g, 0.56 mol) was slowly added to a stirred and cooled (0°C) mixture of ethyl 4-aminophenylacetate (25 g, 0.14 mol) in 700 mL of TFA. After the addition was complete, the reaction was stirred at 0°C for another 0.5 hour and then sodium azide (27 g, 0.42 10 mol) was slowly added over a period of 0.5 hours. The mixture was stirred for another 2 hours at 0°C and then quenched with ice water and the product was extracted with EtOAc. The organic phase was washed with water, dried over magnesium sulfate, filtered, concentrated to yield 26.5 g (90%) of the title compound as a white solid. 1H NMR (300 MHz, 15 DMSO-d6) 8 7.31 (d, J = 8 Hz, 2 H), 7.07 (d, J = 7 Hz, 2 H), 4.07 (q, J = 7 Hz, 2 H), 3.66 (s, 2 H), 1.17 (t, J = 7 Hz, 3 H). 20 N-[(4-{4-[4-(hydroxymethyl)(1,2,3-triazolyl)]phenyl}-5-oxo-2-hydroisoxazol-2-yl)methyl]acetamide EXAMPLE 16 o 25 A mixture of N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide (80 mg, 0.29 mmol) and propargyl alcohol (0.1 mL, WO 00/10566 - 100 - PCT/US99/19265 1.71 mmol) in 3 mL of DMF was heated at 100°C for 10 hours. The reaction mixture was then concentrated in vacuo and purified by flash chromatography (silica gel; eluting with EtOAc followed by 10% MeOH/EtOAc) to yield 62 mg of a yellow solid. The 1H NMR spectra 5 indicated that the crude product was a mixture of two triazole isomers. These isomers were separated by preparative HPLC (H^O/MeOH) to yield 10 mg (10%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 9.11 (s, 1 H), 8.96, (t, J = 6 Hz, 1 H), 8.69, (s, 1 H), 7.96 (m, 4 H), 5.07 (d, J = 6 Hz, 2 H), 4.61 (s, 2 H), 1.86 (s, 3 H). Methyl 1 -(4-{2-[(acety lamino)methy l]-5-oxo-2-hydroisoxazol-4-yl}phenyl)-1,2,3-triazole-4-carboxylate 15 A mixture of N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (80 mg, 0.29 mmol) and methyl propionate (0.05 mL, 20 0.58 mmol) in 3 mL DMF was heated at 50°C for 24 hours. The reaction mixture was then concentrated in vacuo and triturated with EtOAc to yield 25 mg (24%) of the title compound as a yellow solid. (An alternate procedure which is more reliable involves conducting the reaction at room temperature for 10 days and then isolating as above.) 1H NMR (300 MHz, 25 DMSO-d6) 8 9.52 (s, 1 H), 9.15, (s, 1 H), 8.96, (t, J = 6 Hz, 1 H), 8.02 (s, 4 H), 5.08 (d, J = 6 Hz, 2 H), 3.90 (s, 3 H), 1.87 (s, 3 H). 10 EXAMPLE 17 o WO 00/10566 PCT/US99/19265 - 101 - EXAMPLE 18 N-({4-[4-(4-acetyl(1,2f3-triazolyl))phenyl]-5-oxo-2-hydroisoxazol-2-yl)methyl)acetamide A mixture of N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (100 mg, 0.36 mmol) and of 3-butyn-2-one (0.035 mL, 0.72 mmol) in 3 mL DMF was heated at 50°C for 24 hours. The reaction mixture was concentrated in vacuo and then triturated with EtOAc to yield 60 mg (49%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 6 9.47 (s, 1 H), 9.35, (s, 1 H), 8.98, (t, J = 6 Hz, 1 H), 8.02 (s, 4 H), 5.08 (d, J = 6 Hz, 2 H), 3.32 (s, 3 H), 1.85 (s, 3 H). N-({4-[4-(4-cyano(1,2,3-triazolyl))phenyl]-5-oxo-2-hydroisoxazol-2-yl)methyl)acetamide o EXAMPLE 19 0 A mixture of N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (500 mg, 1.83 mmol) and 0.8 mL of cyanoacetylene WO 00/10566 - 102 - PCT/US99/19265 [prepared according to Murahashi, S.; Takizawa, T.; Kurioka, S.; Maekawa, S.; in J. Chem. Soc. Jap., 77, p, 1689, 1956] in 5 mL of DMF was heated at 50°C for 48 hours. Upon cooling, the precipitated solid was collected by filtration and washed with DMF to yield 375 mg (63%) of 5 the title compound as a white solid. 1H NMR (300 MHz, DMSO-dg) 6 9.75 (s, 1 H), 9.17, (s, 1 H), 9.00, (t, J = 6 Hz, 1 H), 8.05 (d, J = 9 Hz, 2 H), 7.95 (d, J = 9 Hz, 2 H), 5.10 (d, J = 6 Hz, 2 H), 1.85 (s, 3 H). EXAMPLE 20 10 N-fr4-(4-aminophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide H2N-Ot^ h *-N Y O 15 To a mixture of N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide (3 g, 10.98 mmol) in 40 mL EtOAc and 20 mL MeOH was added SnCl2*2H20 (12.5 g, 54.9 mmol). After all of the solid was dissolved, the reaction mixture was concentrated in vacuo and neutralized with saturated aqueous sodium bicarbonate. The mixture was 20 concentrated in vacuo again and the residue was dissolved in a mixture of 4:1 CHCl3/MeOH. The resulting solution was filtered throuth celite, and the insoluble material was discarded. The filtrate was then concentrated in vacuo to yield 3 g (100%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 8.83, (t, J = 6 Hz, 1 H), 8.55, (s, 1 H), 7.43 25 (d, J = 9 Hz, 2 H), 6.56 (d, J = 9 Hz, 2 H), 5.21, (broad s, 2 H), 4.91 (d, J = 6 Hz, 2 H), 1.82 (s, 3 H). WO 00/10566 - 103 - PCT/US99/19265 EXAMPLE 21 N-({4-[4-(3-formylpyrrolyl)phenyl]-5-oxo-2-hydroisoxazol-2- yl}methyl)acetamide 5 20 ,JW \ ? H r To a solution of N-{[4-(4-aminophenyI)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (200 mg, 0.81 mmol) in 3 mL of acetic acid was 10 added 2,5-dimethoxy-3-tetrahydrofurancarboaldehyde (184 mg, 1.27 mmol). This mixture was refluxed for 0.5 hours, and then concentrated in vacuo to give the crude product. Purification by silica gel chromatography (eluting with EtOAc, then 8% MeOH in EtOAc) gave 240 mg (91%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-dg) 8 9.79 (s, 15 1 H), 9.08, (s, 1 H), 9.00, (t, J = 6 Hz, 1 H), 8.29, (m, 1 H), 7.93 (d, J = 9 Hz, 2 H), 7.74 (d, J = 9 Hz, 2 H), 7.58, (m, 1 H), 6.71 (m, 1 H), 5.06 (d, J = 6 Hz, 2 H), 1.86 (s, 3 H). EXAMPLE 22 N-{[5-oxo-4-(4-pyrrolylphenyI)-2-hydroisoxazol-2-yl]methyl)acetamide o WO 00/10566 - 104 - PCT/US99/19265 This compound was prepared from N-{[4-(4-aminophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide as described above for N-{{4-[4-(3-formylpyrrolyl)phenyi]-5-oxo-2-hydroisoxazol-2-yl}methyl)acetamide 5 except that 2,5-dimethoxy-3-tetrahydrofuran was used in place of 2,5-dimethoxy-3-tetrahydrofurancarboaldehyde. 1H NMR (300 MHz, DMSO-d6) 8 8.92, (s, 1 H), 8.94, (t, J = 6 Hz, 1 H), 7.85 (d, J = 9 Hz, 2 H), 7.62 (d, J = 9 Hz, 2 H), 7.40, (t, J = 2 Hz, 2 H), 6.27 (t, J = 2 Hz, 2 H), 5.04 (d, J = 6Hz,2H), 1.86 (s, 3 H). 10 EXAMPLE 23 N-[(4-{4-r3-((hydroxyimino)methyl)pyrrolyl]phenyl)-5-oxo-2-hydroisoxazol-2-yl)methyl]acetamide 15 NOH T O A mixture of N-({4-[4-(3-formytpyrrolyl)phenyl]-5-oxo-2-hydroisoxazol-2-yl}methyl)acetamide (100 mg, 0.30 mmol) and 50% 20 aqueous NH2OH (40 mg, 0.60 mmol) in 3 mL of MeOH was heated at reflux for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was triturated with ether to yield 96 mg (94%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 8 10.6 (s, 1 H), 9.02, (s, 1 H), 8.95, (t, J = 6 Hz, 1 H), 8.00, (s, 1 H), 7.87 (d, J = 9 Hz, 25 2 H), 7.66, (s, 1 H), 7.63 (d, J = 9 Hz, 2 H), 7.45, (m, 1 H), 6.50 (m, 1 H), 5.04 (d, J = 6 Hz, 2 H), 1.85 (s, 3 H). WO 00/10566 - 105 - PCT/US99/19265 EXAMPLE 24 t-Butyl 4-(4-{2-[(acetylamino)methyl]-5-oxo-2-hydroisoxazol-4-yl>phenyl)piperazine carboxyiate 5 To t-butyl 4-[4-(5-oxo-2-hydroisoxazol-4-yl)phenyl]piperazinecarboxylate (1.5 g, 4.3 mmol) in 35 mL 10 dimethylformamide was added N-(hydroxymethyl)acetamide acetate (2.9 g, 22.0 mmol) followed by potassium carbonate (3.0 g, 22.0 mmol). After 5 hours the reaction mixture was poured into ice water. After 18 hours the precipitate was filtered and dried in vacuo to provide 1.4 g (77%) of the title compound. 1H NMR (methanol-d4; 300 MHz) 5 8.48 (s, 1H), 7.66 15 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.07 (s, 2H), 3.58 (t, J = 4.8 Hz, 4H), 3.17 (t, J ~ 5.2 Hz, 4H), 1.94 (s, 3H), 1.50 (s, 9H); ESI (M+H)+ = 417. ^—nh y~ o The starting materials were prepared as follows: ■20 Methyl 2-(4-{4-[(t-butyl)oxycarbonyl]piperazinyl}phenyl) acetate Boc^ ■Ux. Wxx WO 00/10566 - 106 - PCT/US99/19265 A flask charged with cesium carbonate (4.6 g, 14.0 mmol), palladium (II) acetate (0.07 g, 0.3 mmol), and (S)-BINAP (0.28 g, 4.5mmol) was evacuated and flushed with dry nitrogen. Methyl 2-{4-[(tr'rfluoromethyl)sulfonyloxy]phenyl} acetate (3.0 g, 10.0 mmol) and t-5 butyl-1-piperazinecarboxylate (2.3 g, 12.0 mmol) in 20 mL toluene was added via syringe and the resultant mixture was stirred at ambient temperature for 30 minutes and at 80°C for 16 hours. The reaction mixture was removed from the heating bath, concentrated, and chromatographed on silica gel (0 to 30% ethyl acetate I hexane) providing 10 1.7 g (50%) of the title compound. 1H NMR (300 MHz, CDCI3) 8 7.20 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 3.70 (s, 3H), 3.59 (t, J = 5.0 Hz, 4H), 3.57 (s, 2H), 3.12 (t, J = 5.2 Hz, 4H), 1.50 (s, 9H); ESI (M+H)+ -335. 15 Ethyl 2-(4-{4-[(t-butyI)oxycarbonyl]piperazinyl})phenyl)-3-oxopropanoate 20 (0.67 g, 2.0 mmol) in 8 mL ethyl formate was added sodium hydride (60% dispersion in mineral oil) (0.32 g, 8.0 mmol) portionwise. After 1.5 hours, the reaction mixture was poured into saturated sodium bicarbonate, and extracted three times with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and 25 concentrated. The crude product was used directly in the next step without further purification. o CHO To methyl 2-(4-{4-[(t-butyl)oxycarbonyl]piperazinyl}phenyl) acetate t-Butyl 4-[4-(5-oxo-2-hydroisoxazol-4-yl)phenyl]piperazinecarboxylate WO 00/10566 - 107 - PCT/US99/19265 BocN^ ~\ _ To ethyl 2-(4-{4-[(t-butyl)oxycarbony!]piperazinyl})phenyl)-3-5 oxopropanoate (7.8 g, 20.7 mmol) in 140 mL methanol and 40 mL water was added hydroxylamine (50% in water, 3.0 mL, 49.0 mmol). The reaction mixture was heated to reflux for 3 hours, cooled and concentrated. The residue was triturated with water and the precipitate was filtered, dried and washed with ether to provide 4.3 g of the title 10 compound. The aqueous solution was lyophilized providing an additional 1.5 g of the title compound. 1H NMR (methanol^; 300 MHz) 8 8.35 (s, 1H), 7.58 (br d, J = , 2H), 6.96 (d, J = 8.2 Hz, 2H), 3.58 (t, J = 4.6 Hz, 4H), 3.10 (br s, 4H), 1.50 (s, 9H); ESI (M+H)+ = 345. 15 EXAMPLE 25 N-{[5-oxo-4-(piperaziny[phenyl)-2-hydroisoxazol-2-yl]methyl} acetamide trifluoroacetate salt 0 tca ^ NH TFA \ r To t-butyl 4-(4-{2-[(acetylamino)methyl]-5-oxo-2-hydroisoxazol-4-yl}phenyl)piperazine carboxylate (0.3 g, 0.7 mmol) in 5 mL dichloromethane was added 2 mL trifiuoroacetic acid. After 30 minutes, 25 the reaction mixture was concentrated and triturated with ether to provide Boc. "Gjl ~ h*noh o CHO bocn'^I _ _ ^—NH oh WO 00/10566 - 108 - PCT/US99/19265 10 15 0.3 g (97%) of the title compound. 1H NMR (methanol-d4; 300 MHz) 5 9.00 (t, J = 6.0 Hz, 1H), 8.23 (s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 5.08 (d, J = 6.2 Hz, 2H), 3.45-3.38 (m, 8H), 1.95 (s, 3H); ESI (M+H)+ = 317. EXAMPLE 26 tert-Butyl 4-(4-{2-[(acetylamino)methyl]-5-oxo(2-hydroisoxazol-4-yl)}-2-fluorophenyl)piperazinecarboxylate O BocN^^ 0 F' Ln'h ACOCH2NHAC y~ N —NH O Prepared according to the general procedures outlined in Schemes 1, 3, and 6. The starting materials were prepared as follows: 2-(4-{4-[(t-butyl)oxycarbonyl]piperazinyl}-3-fluoropheny])acetic acid Boc^ N^-\ Boc. 21 NaOH, BoC20 0> 20 To t-butyl 4-[2-fluoro-4-(2-morpholin-4-yl-2- thioxoethyl)phenyl]piperazinecarboxylate (4.2 g, 10 mmol) was added 22 mL of concentrated hydrochloric acid at 0°C. The resulting mixture was heated to reflux for 1.5 hours, cooled to 0°C, and 23 mL of 10N sodium hydroxide was added to bring the pH to 14. Then 50 mL water was WO 00/10566 - 109 - PCT/US99/19265 added followed by di-t-butyl dicarbonate (5.6 g, 26.0 mmol) in 5 mL tetrahydrofuran. The resulting mixture was allowed to stir at 0°C for 30 minutes and then for 1 hour at ambient temperature at which time it was diluted with 200 mL water. Then 5 mL sodium hydroxide was added to 5 adjust the pH to 14, and the reaction mixture was extracted with ether. The aqueous layer was acidified to pH 3 by the careful addition of 6N hydrochloric acid and then extracted with three portions of ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The resultant residue was dissolved in 10 dichloromethane and hexanes were added to produce a precipitate which was collected by filtration providing 3.0 g (89%) of the title product. 1H NMR (CDCI3; 300 MHz) 5 7.04-6.98 (m, 2H), 6.90 (t, J = 8.3 Hz, 1H), 3.60 (m, 6H), 3.02 (t, J = 5.0 Hz, 4H), 1.50 (s, 3H); ESI (M+H)+=339. 15 Methyl 2-(4-{4-[(t-butyl)oxycarbonyl]piperazinyl}-3-fluorophenyl)acetate 20 acid (0.3 g, 1.0 mmol) in 2 mL methanol and 7 mL benzene was added trimethylsilyldiazomethane (0.65 mL, 1.30 mmol). After stirring at ambient temperature for 1 hour, the reaction mixture was concentrated to provide 0.36 g (99%) of the title compound. 1H NMR (CDCl3; 300 MHz) 6 7.00 (m, 2H), 6.90 (t, J = 8.3 Hz, 1H), 3.71 (s, 3H), 3.61 (t, J = 4.9 Hz, 4H), 3.57 (s, 25 2H), 3.02 (t, J = 5.0 Hz, 4H), 1.50 (s, 9H); ESI (M+H)+ = 353. To2-(4-{4-[(t-butyl)oxycarbonyl]piperazinyl}-3-fluorophenyl)acetic WO 00/10566 PCT/US99/19265 - 110 -EXAMPLE 27 N-fl4-(4-morpholinylphenyt)-5-oxo-2-isoxazolinyl]methy1)acetamide Prepared according to the general procedure outlined in Schemes 1 and 2. The starting materials were prepared as follows: 10 Methyl-4-(trifluoromethylsulfonyloxy)phenyl acetate H Vi s t,2° . *4 pyridine O To methyl-4-hydroxyphenyl acetate (20 g, 120 mmol) and pyridine 15 (20 mL, 240 mmol) in 100 mL dichloromethane at 0°C was added trifluoromethanesulfonic anhydride (23 mL, 132 mmol) dropwise over 30 minutes. After an additional 30 minutes at 0°C followed by 30 minutes at ambient temperature, 1N hydrochloric acid was added and the reaction mixture was extracted into dichloromethane. The organic layer was 20 washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated providing 32 g (90%) of the title compound as a yellow solid. 1H NMR (CDCI3; 300 MHz) 8 7.38 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 3.72 (s, 3H), 3.66 (s, 2H). 25 Methyl-4-morpholinophenyl acetate WO 00/10566 - 111 - PCT/US99/19265 9 o °^i 0 Pd(OAc)2, morpholine L^n O ^ BINAP CS.C03 "" QJk^ Nitrogen was bubbled through a mixture of methyl-4-5 (trifluoromethylsulfonyloxy)phenyl acetate (1.0 g, 3.35 mmol), cesium carbonate (1.6 g, 4.69 mmol), palladium (II) acetate (22 mg, 0.10 mmol), (S)-BINAP (93 mg, 0.15 mmol), and morpholine (0.35 mL, 4.02 mmol) in 8 mL toluene and the reaction mixture was heated to 80°C for 6 hours. The reaction was then cooled, celite was added, and the mixture was 10 concentrated. Chromatography was performed on a Biotage flash 40i chromatography module by loading the dried celite into a SIM and eluting with 20% ethyl acetate / hexanes (40S cartridge) providing 250 mg (37%) of the title compound as a yellow oil. 1H NMR (CDCI3; 300 MHz) 8 7.19 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 3.89-3.85 (m, 4H), 3.69 (s, 15 3H), 3.56 (s, 2H), 3.17-3.13 (m, 4H). EXAMPLE 28 N-{[4-(4-(1,4-thiazaperhvdroin-4-yl)phenyl)-5-oxo-2-hydroisoxazol-2-20 yl]methyl)acetamide 25 Prepared according to the general procedures outlined in Schemes 1 and 3. The starting materials were prepared as follows: WO 00/10566 - 112 - PCT/US99/19265 4-Thiomorpholinoacetophenone 15 k2co3 Thiomorphoiine 5 To 4-fluoroacetophenone (20 g, 145 mmol) in 100 mL dimethylformamide was added potassium carbonate (39 g, 580 mmol) followed by thiomorphoiine (87 mL, 870 mmol). The reaction mixture was heated to reflux and after 24 hours, it was cooled to ambient temperature and partitioned between water and dichloromethane. The organic layer 10 was dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in ether and precipitated with hexanes providing 31 g (96%) of the title compound as a yellow solid. 1H NMR (CDCI3; 300 MHz) 8 7.87 (d, J = 9.0 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 3.81-3.78 (m, 4H), 2.73-2.69 (m, 4H), 2.53 (s, 3H). 4-Thiomorpholinophenylthioacetomorpholide Sulfur Morpholine k/O 20 A mixture of 4-thiomorpholinoacetophenone (30 g, 136 mmol), morpholine (16 mL, 180 mmol) and sulfur (6 g, 180 mmol) was heated to reflux for 6 hours, cooled to 50°C, and 100 mL 1:1 hexanes:ethyl acetate was added. The reaction mixture was again brought to reflux for 30 minutes, cooled, and the resultant orange precipitate was collected via 25 filtration. The precipitate was washed with additional 1:1 ether / hexanes WO 00/10566 - 113 - PCT/US99/19265 providing 31 g (73%) of the title compound as a yellow-orange solid. 1H NMR (CDCI3; 300 MHz) 5 7.21 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.1 Hz, 2H), 4.35 (t, J = 4.8 Hz, 2H), 4.27 (s, 2H), 3.74 (t, J = 4.8 Hz, 2H), 3.65 (t, J = 4.2 Hz, 2H), 3.52 (t, J = 5.1 Hz, 4H), 3.41 (t, J = 5.4 Hz, 2H), 2.77-5 2.71 (m, 2H). Ethyl-4-thiomorpholinophenyl acetate A solution of 4-thiomorpholinophenylthioacetomorpholide (30 g, 93.2 mmol) in 70 mL 1:1 ethanol:sulfuric acid was heated to reflux for 18 hours, cooled to room temperature and solid sodium bicarbonate was slowly added to the reaction until it reached pH 7. The reaction mixture 15 was extracted with chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to a yellow residue. The residue was then dissolved in chloroform, loaded onto a Biotage flash 40i chromatography module (40M cartridge) and chromatographed with 10% ethyl acetate / hexanes providing 12 g (51%) 20 of the title compound as a yellow oil. 1H NMR (CDCI3; 300 MHz) 8 7.18 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.54-3.50 (m, 6H), 2.76-2.73 (m, 4H), 1.25 (t, J = 7.2 Hz, 3H). < 10 EXAMPLE 29 25 N-{[4-(3-fluoro-4-methylthiophenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide WO 00/10566 PCT/US99/19265 - 114 - Prepared according to the general procedures outlined in Schemes 1 and 3. The starting materials were prepared as follows: dimethylsulfoxide was added sodium thiomethoxide (15 g, 211 mmol). The reaction mixture was heated to 150°C for 2 hours and then partitioned between ethyl acetate and sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and 15 concentrated. The residue was dissolved in ethyl acetate and precipitated with hexanes. The precipitate was collected by filtration providing 25 g (70%) of the title compound as a yellow solid. 3-Fluoro-4-methylthiophenylthioacetomorpholide 5 3-Fluoro-4-methylthioacetophenone 10 To 3, 4-difluoroacetophenone (30 g, 192 mmol) in 200 mL 20 WO 00/10566 - 115 - PCT/US99/19265 A mixture of 3-fluoro-4-methylthioacetophenone (9.0 g, 48.9 mmol), morpholine (5.7 mL, 65.0 mmol), and sulfur (2.1 g, 65.0 mmol) were heated to reflux for 4 hours, cooled to 50°C, and 1:1 hexanes : ethyl acetate was added. The reaction mixture was again heated to reflux for 5 30 minutes, cooled to ambient temperature, and the resultant orange precipitate was collected by filtration. The precipitate was washed with 1:1 hexanes : ether providing 10.1 g (73%) of the title compound as a yellow-orange solid. 1H NMR (DMSO-d6; 300 MHz) 5 7.36-7.29 (m, 1H), 7.20-7.15 (m, 2H), 4.27 (s, 2H), 4.22 (t, J = 4.8 Hz, 2H), 3.73 (t, J = 4.5 10 Hz, 2H), 3.65 (t, J = 4.8 Hz, 2H), 3.47 (t, J = 5.1 Hz, 2H), 2.47 (s, 3H). 3-Fluoro-4-methylthiophenylacetic acid To 3-fluoro-4-methylthiophenylthioacetomorpholide (2.6 g, 90.9 mmol) was added 500 mL 10% potassium hydroxide. The reaction mixture was heated to reflux for 3 hours, cooled to ambient temperature, and adjusted to pH 4 by the careful addition of 2N hydrochloric acid. The 20 aqueous solution was extracted with dichloromethane and the organic layer was then extracted with 200 mL 10% potassium hydroxide. The aqueous layer was then brought to pH 4 by the careful addition of 2N hydrochloric acid and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated providing 25 10.0 g (55%) of the title compound as a brown oil. 1H NMR (CDCI3; 300 MHz) 5 7.24-7.21 (m, 1H), 7.04-6.99 (m, 2H), 3.63 (s, 2H), 2.46 (s, 3H). KOH 15 WO 00/10566 PCT/US99/19265 - 116 - EXAMPLE 30 N-([4-(3-fluoro-4-methoxyphenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl)acetamide 10 Prepared according to the general procedure outlined in Schemes 1. The starting material was prepared as follows: Ethyl-(3-Fluoro-4-methoxy)phenyl acetate H°v^ n K2C03 CH3I Xa 15 To ethyl-(3-fluoro-4-hydroxy)phenyl acetate (2.5 g, 8.9 mmol) in 20mL acetone was added potassium carbonate (3.4 g, 24.2 mmol) and iodomethane (1.5 mL, 24.2 mmol). The reaction mixture was heated to reflux for 2 hours, cooled, and partitioned between saturated sodium bicarbonate and ether. The organic layer was washed with brine, dried 20 over magnesium sulfate, filtered and concentrated providing 2.3 g (88%) of the title compound as a yellow oil. 1H NMR (CDCI3; 300 MHz) 5 7.06-6.88 (m, 3H), 4.15 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.54 (s, 2H), 1.26 (t, J = 7.2 Hz, 3H). WO 00/10566 - 117 - PCT/U S99/19265 EXAMPLE 31 N-({4-[4-(3-cyanopyrrolyl)phenyl]-5-oxo-2-hydroisoxazoI-2-yl}methyl)acetamide NC\./" P H N N CH3 T To a mixture of N-[(4-{4-[3-((hydroxyimino)methyl)pyrrolyI]phenyl}-5-oxo-2-hydroisoxazol-2-yl)methyl]acetamide (100 mg, 0.29 mmol) in 3 ml 10 of CH3CN and 1 ml of CCI4 was added polymer-bound triphenylphosphine (400 mg, 1.2 mmol) and the mixture was heated at reflux for 8 hours. It was then dissolved in ethyl acetate, filtered, and concentrated to yield a yellow solid. This solid was then triturated with ether to obtain 30 mg (32 %) of the title compound as a yellow solid. 1H 15 NMR (300 MHz, DMSO-d6) 6 9.08 (s, 1 H), 8.97 (t, J = 6 Hz, 1 H), 8.28, (s, 1 H), 7.92 (d, J = 9 Hz, 2 H), 7.70 (d, J = 9 Hz, 2 H), 7.59 (m, 1 H), 6.74 (m, 1 H), 5.06 (d, J = 6 Hz, 2 H), 1.86 (s, 3 H). EXAMPLE 32 20 N-[(4-{4-[3-((1E)-2-aza-2-methoxyvinyl)pyrrolyl]phenyl}-5-oxo-2-hydroisoxazol-2-yl)methyl]acetamide WO 00/10566 - 118 - PCT/US99/19265 A mixture of N-({4-[4-(3-formylpyrrolyl)phenyl]-5-oxo-2-hydroisoxazol-2-yl}methyl)acetamide (100 mg, 0.3 mmol), HCUNH2OCH3 5 (31 mg, 0.37 mmol) and sodium carbonate (20 mg, 0.19 mmol) was dissolved in 3 mL of MeOH and 2 mL of water. To this mixture was added acetic acid to adjust the pH to 5. The reaction was heated at reflux for 1 hour. The reaction was cooled to room temperature, and the yellow precipitate was collected by filtration to give 40 mg (36 %) of the title 10 compound as a yellow solid. (M+H+)= 355. EXAMPLE 33 N-([4-(4-(3-[(1E)-2-(acetylamino)-2-azaviny{]pyrrolyl}phenyl)-5-oxo-2-15 hydroisoxazol-2-yl]methyI}acetamide A mixture of N-({4-[4-(3-formylpyrrolyI)phenyl]-5-oxo-2-20 hydroisoxazo!-2-yl]methyl)acetamide (100 mg, 0.30 mmol) and acetic hydrazide (28 mg, 0.38 mmol) in 3 mL of EtOH was heated at reflux for 1 hour. The reaction was cooled to room temperature, and the yellow WO 00/10566 ... PCT/US99/19265 - 119 - precipitate was collected by filtration to give 80mg (36 %) of the title compound. (M+H+)=382. EXAMPLE 34 5 Ethyl 1 -(4-{2-[(acetylamino)methyl]-5-oxo-2-hydroisoxazol-4-yl}phenyl)pyrazole- 4-carboxylate EtO 10 To a mixture of N-{[4-(4-hydrazinylphenyl)-5-oxo-2-hydroisoxazol- 2-yl]methyl}acetamide hydrochloride (150 mg, 0.5 mmol) in 3 mL of methanol was added sodium bicarbonate (50 mg, 0.6 mmol) and ethoxycarbonylmalondialdehyde (75 mg, 0.52 mmol). The mixture was stirred at room temperature overnight. The solid was collected by filtration 15 and then washed with water, and dried to yield 140 mg of a purple solid. The crude product was subjected to silica gel chromatography (eluting with ethyl acetate followed by 5% methanol/ethyl acetate) to yield 123 mg (66%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 9.11 (s, 1 H), 9.08 (s, 1 H), 8.96 (t, J = 6 Hz, 1 H), 8.15 (s, 1 H), 7.95 20 (m, 4 H), 5.06 (d, J = 6 Hz, 2 H), 4.28, (q, J = 7 Hz, 2 H), 1.86 (s, 3 H), 1.31 (t, J = 7 Hz, 3 H). The starting material, N-{[4-(4-hydrazinylphenyl)-5-oxo-2-hydroisoxazoI-2-yl]methyl}acetamide hydrochloride, was prepared as 25 follows. Sodium nitrite (112 mg, 1.6 mmol) in 2 mL of water was added to a solution of N-{[4-(4-aminophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (400 mg, 1.6 mmol) in concentrated hydrochloric acid WO 00/10566 - 120 - PCT/US99/19265 at 0°C over 5 minutes. The reaction was stirred for an additional 10 minutes at 0°C, and then SnCl2«2H20 (720 mg, 3.2 mmol) in 2 mL of concentrated hydrochloric acid was added. This mixture was stirred at room temperature for 3 hours. The reaction mixture was then filtered to 5 collect a yellow solid which was washed with 3 mL of water and dried to yield 260 mg (55%) of the title compound. 1H NMR (300 MHz, DMSO-dg) 5 10.2 (s, 2 H), 8.94 (t, J = 6 Hz, 1 H), 8.82, (s, 1 H), 8.35 (s, 1 H), 7.70 (d, J = 9, 2 H), 6.99 (d, J = 9, 2 H), 4.99 (d, J = 6 Hz, 2 H), 1.84 (s, 3 H). 10 EXAMPLE 35 N-({4-[4-(4-cyanopyrazolyl)phenyl]-5-oxo-2-hydroisoxazol-2-yl}methyl)acetamide 15 To a mixture of N-{[4-(4-hydrazinylphenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide hydrochloride (50 mg, 0.17 mmol) in 2 mL of methanol was added 20 mg (0.24 mmol) of sodium bicarbonate and 20 cyanomalondialdehyde (30 mg, 0.3 mmol). The mixture was stirred at room temperature overnight. It was then concentrated to give a solid which was washed with water then methanol to give 42 mg (76%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 8 9.35 (s, 1 H), 9.10 (s, 1 H), 8.98 (t, J = 6 Hz, 1 H), 8.37 (s, 1 H), 7.93 (m, 4 H), 25 5.07 (d, J = 6 Hz, 2 H), 1.86 (s, 3 H). WO 00/10566 - 121 - PCT/US99/19265 Preparation of cyanomaiondialdehyde. To a dried flask was added sodium hydride (0.82 g, 50% suspended in mineral oil, 17 mmol). The sodium hydride was washed three times with 15 mL of ether, and then 15 mL of ether was added to the flask. After cooling the slurry to 0°C, ethyl 5 formate (10.4 g, 140 mmol) was added. To this mixture was added 3,3-diethoxypropionitrile (2 g, 14 mmol) in 10 ml of ether over 2 hours (syringe pump). The mixture was stirred at room temperature for 20 hours, and then poured into 100 mL of ice water. This solution was extracted three times with ether, and then the ether extracts were discarded. The 10 aqueous phase was acidified to pH 3 with concentrated HCI and extracted with dichloromethane. The organic phase was dried over MgS04, filtered, and concentrated to yield 0.3 g of cyanomaiondialdehyde as a yellow solid. Additional product was recovered from the pH 3 aqueous phase: the aqueous phase was 15 concentrated to dryness, and then dissolved in 5 mL of methanol. The inorganic salt was removed by filtration, and the filtrate was concentrated to yield 1 g of cyanomaiondialdehyde as a yellow solid. 1H NMR (300 MHz, DMSO-dg) 8 8.94 (s, 2 H), 4.95 (br s, 1 H). 20 EXAMPLE 36 N-{[5-oxo-4-(4-pyrazolylphenyl)-2-hydroisoxazol-2-yl]methyl}acetamide :N 25 o WO 00/10566 - 122 - PCT/US99/19265 To a mixture of N-{[4-(4-hydrazinylphenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide hydrochloride (100 mg, 0.33 mmol) in 3 mL of methanol was added sodium bicarbonate (28 mg, 0.33mmol) and malondialdehyde (50 mg, 0.35 mmol). The mixture was stirred at room 5 temperature overnight. It was then concentrated to yield 120 mg of a yellow oil, which was then purified by silica gel chromatography (eluting with ethyl acetate) to obtain 30 mg (30%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 9.03 (s, 1 H), 8.95 (t, J = 6 Hz, 1 H), 8.52 (s, 1 H), 7.88 (m, 4 H), 7.75 (s, 1 H), 6.56 (s, 1 H), 5.05 (d, 10 J = 6 Hz, 2 H), 1.86 (s, 3 H). The table below shows the chemical structures, characterizing properties (MS data) and preparative method for several representative compounds of the present invention, including those of Examples 1-36 15 described above. WO 00/10566 - 123 - PCT/U S99/19265 Structure MS data Prepared via Scheme(s) 1 ~"0^. 0 (M+H)+ = 279 ESI 1 2 WN+-0I 0 (M+H)+ = 352 DCI 3,1 3 n-^n"Y--0 (M+H)+ = 295 ESI 1,4 4 0 (M+H)+ = 311 ESI 1,4 5 V"~"\ 0^ONV\! F//^as/^ % > H 0 (M+H)+ = 384 ESI 3,1,4 6 °w. s (M+H)+ = 352 ES! 3, 1,9 7 0 (M+H)+ = 275 ESI 1 8 NOH o (M+H)+ = 290 ESI 1 WO 00/10566 - 124 - PCT/US99/19265 Structure MS data Prepared via Scheme(s) g o (M+H)+ = 299 ESI 1.5 10 0 (M+H)+ = 315 ESI 1.5 11 X O (M+H)+ = 317 ESI 1.5 12 )=° XZ I Oz (M+H)+ = 311 ESI 1,5 13 0 (M+H)+ = 489 ESI 2,1,6 14 * V /~X /— N N~\-. /} < w ru HO—/ \_/ \J 0 (M+H)+ = 375 ESI 2,1,6 15 0 (M+H)+ = 274 DCI 1 16 v° XZ P~> 0=V-J (M+H)+ = 330 ESI 1,7 00/10566 - 125 - PCT/US99/19265 Structure MS data Prepared via Scheme(s) 17 N=N 0 0 (M+H)+ = 358 ESI 1,7 18 N=N "jcKI V ° vWjp H 0 (M+H)+ = 342 DCI 1.7 19 N=N NC-*A^n'~/?s^| ? 0 (M+H)+ = 325 DCI 1,7 20 ^ H — N\/NN/ T (M+H)+ = 248 DCI 1,8 21 O X/VD \\ / H 0 (M+H)+ = 326 DCI 1,8 22 0 (M+H)+ = 298 ESI 1,8 23 Hv—0 HON 0 (M+H)+ = 341 ESI 1,8 24 ,wt>04. ^Y 0 (M+H)+ = 417 ESI 2, 1,6 WO 00/10566 - 126 - PCT/US99/19265 Structure MS data Prepared via Scheme(s) 25 T (M+H)+ = 317 ESI 2,1,6 26 HjC F fl 0 (M+H)+ = 435 ESI 3, 1,6 27 ^-v 0 (M+H)+ = 318 ESI 2,1 28 n\^nN/ T 0 {M+H)+ = 334 ESI 3, 1 29 /S^0-A c / H 0 (M+H)+ = 297 DCI 3,1 30 A01 \ /° H N^V O (M+H)+ = 281 ESI 3,1 31 ^o-y^ j? \ P H 0 (M+H)+ = 295 ESI 3,1 32 •cC^l 1 y - ^Y 0 (M+H)+ = 323 ESI 1,8 WO 00/10566 - 127 - PCT/US99/1926S Structure MS data Prepared via Scheme(s) 33 0 (M+H)+ = 324 DCI 1,8 34 HsCS-^/^l j? T (M+H)+ = 265 DCI 1 35 ~o-^. L-N^NyNQ 0 (M+H)+ = 313 DCI 1 36 O (M+H)+ = 297 DCI 1 37 LnX/nY^ 0 (M+H)+ = 281 ESI 1 38 LNx/NY^ o (M+H)+ = 293 ESI 1 39 0 (M+H)+ = 309 ESI 1 40 0 (M+H)+ = 295 ESI 1 WO 00/10566 - 128 - PCT/U S99/19265 Structure MS data Prepared via Scheme(s) 41 F H "~Y 0 (M+H)+ = 369 DCI 1 42 >-0i O (M+H)+ = 276 ESI 1 43 vnY\a 0 (M+H)+ = 299 ESI 1 44 ° ^,, T (M+H)+ = 233 ESI 1 45 (M+H)+ = 309 ESI 1 46 (M+H)+ = 275 ESI 1 47 0 (M+H)+ = 359 ESI 1 48 ? H 0 (M+H)+ = 277 ESI 1 00/10566 - 129 - PCT/US99/19265 Structure MS data Prepared via Scheme(s) 49 VYXA ^ v o (M+H)+ = 309 ESI 1 50 •~o^>, ■~v o (M+H)+ = 312 ESI 1 51 o X r"*0 < zx (M+H)+ = 268 ESI 1 52 A' •. I (M+H)+ = 268 ESI 1 53 T <M+H)+ = 251 ESI 1 54 (M+H)+ = 247 ESI 1 55 o (M+H)+ = 277 ESI 1 56 (M+H)+ = 371 DCI 1,8 WO 00/10566 - 130 - PCT/US99/19265 Structure MS data Prepared via Scheme(s) 57 o \ /=\ Ao O WN"\J ..CH, T 0 (M+H)+ = 395 ESI 2,1,6 58 0 y1 N N—~v. //—\\ 1 ru ^ W yCH, O (M+H)+ = 359 ESI 2,1,6 59 0 HC^ 0 (M+H)+ = 399 ESI 2,1, 6 60 0 Wn'^Z}~v^nyc^ (M+H)+ = 455 ESI 2,1,6 61 V ^ •—' 0 (M+H)+ = 445 ESI 2,1,6 62 /=* K> rv7""wHLrvi W^° « (M+H)+ = 437 ESI 2,1,6 63 0 °\\ /=\_>o 0 (M+H)+ = 375 ESI 2,1,6 64 T 0 (M+H)+ = 322 ESI 3, 1 WO 00/10566 - 131 - PCT/US99/19265 Structure MS data Prepared via Scheme(s) 65 °W>. """n m yv 0 (M+H)+ = 370 ESI 3,1 66 u. zz / u. 0 (M+H)+ = 354 ESI 3, 1 67 0a \ I / u. 0 (M+H)+ = 350 ESI 3, 1 68 n n cfj T 0 (M+H)+ = 390 ESI 3,1 69 <0 -k o VvHYlA 0 (M+H)+ = 354 ESI 3,1 70 O .k o \l ? h N~Y 0 (M+H)+ = 370 ESI 3, 1 71 c"^tv 0 (M+H)+ = 302 ESI 3,1 72 "~Y 0 <M+H)+ = 316 ESI 3,1 WO 00/10566 - 132 - PCT/US99/19265 Structure MS data Prepared via Scheme(s) 73 t 0 (M+H)+ = 304 ESI 3,1 74 o/ \ o T (M+H)+ = 336 ESI 3, 1 75 V0 xz g=\ -j -.2 0 (M+H)+ = 352 ESI 3,1 76 0 (M+H)+ = 368 ESI 3,1,4 77 0 ~v 0 (M+H)+ = 313 ESI 3,1,4 IB x "~Y (M+H)+ = 329 ESI 3, 1,4 79 °-Q^ i (M+H)+ = 350 ESI 3, 1,4 80 >0X^a 0 (M+H)+ = 366 ESI 3,1,4 WO 00/10566 - 133 - PCT/US99/19265 Structure MS data Prepared via Scheme(s) 81 0 (M+H)+ = 334 ESI 3,1,6 82 0 V_/—x _/=vJ^° y—N N—(. ,)—(v I W |iV'vy, o (M+H)+ = 377 ESI 3, 1,6 83 ° ^ H.C-S-N N—(. ,) (x I 0 (M+H)+ = 413 ESI 3,1,6 84 0 V ^ F 4 (M+H)+ = 463 ESI 3,1,6 85 V ^ ^vJ^° y—N N—(x ,) (v ! /-» (M+H)+ = 417 ESI 3,1,6 86 0 / r 0 (M+H)+ = 449 ESI 3,1,6 87 0 V ^ ^0 ,*=r< F Ii / \ 0 V/ (M+H)+ = 469 ESI 3,1,6 88 0 H.C % ^ .^0 *Vf V-N N—(. ,) t I ^0~w y/v^N F T 0 (M+H)+ = 407 ESI 3, 1,6 WO 00/10566 - 134 - PCT/US99/19265 Structure MS data Prepared via Scheme(s) 89 0 V_ ' 0 N—(■- /- t. I H,C.0/ v_/ v* F r 0 (M+H)+ = 393 ESI 3,1.6 90 o (M+H)+ = 393 ESI 3, 1,6 91 */ ! H N^Y 0 (M+H)+ = 429 ESI 3,1,6 92 NC--^?ny^\ O ^""1% H ^-N^N CK3 T O (M+H)+ = 323 ESI 1,8 93 "^VOvi ° H UkA„ ^-Nv/NyCH, O (M+H)+ = 355 ESI 1,8 94 O 0 kXJ^0 H SvO|, T 0 (M+H)+ = 382 ESI 1,8 95 ■vCU s 0 - T 0 (M+H)+ = 371 DCI 1,9 96 NC-^VNV^\ 0 H '-N^N^CHj T 0 (M+H)+ = 324 DCI 1,9 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 00/10566 - 135 - PCT/US99/19265 Structure MS data Prepared via Scheme(s) 97 /=rN H n-^-n^-ch3 n 0 (M+H)+ = 299 ESI 1,9 WO 00/10566 PCT/US99/19265 - 136 - CLAIMS We claim: 5 1. A compound of the formula o or a pharmaceutically acceptable salt thereof wherein: Ri is a) H, b) C-j.8 a'kyl optionally substituted with one or more F, CI, OH, C-j.8 alkoxy, or C^ acyioxy, c) C3-6 cycloalkyl, or d) C-|_8 alkoxy; L is oxygen or sulfur; A is a) j* Q<l>- Rs b) *6 R5 10 15 20 WO 00/10566 - 137 - PCT/US99/19265 c) a 5-membered heteroaromatic moiety having one to three hetero atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom and can additionally have a 5 fused-on benzene or naphthyl ring, and wherein the heteroaromatic moiety is optionally substituted with one to three R8, d) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the heteroaromatic moiety is bonded 10 via a carbon atom, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three Rg, e) a p-carbolin-3-yl, or indolizinyl bonded via the 6-membered 15 ring, optionally substituted with one to three R9, f) g) e RV /R12 R10W<^ ' ct-1 R14 R13 R11 r12 N- or 7s Rl3 • J 20 wherein R2 and R3 are each independently a) H, b) F, c) CI, d) Br, 25 e) C^ alkyl, f) N02, WO 00/10566 - 138 - PCT/US99/19265 g) i. h) C-|_e alkoxy, i) OH j) amino, 5 k) cyano, or I) R2 and R3 taken together are -0(CH2)h-0; wherein R4 is a) H, b) C<|_2 alkyl, 10 c) F, or d) OH; R5 is a) H, b) CF3, 15 c) C1.3 alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) R5 and Rg taken together are a 5-, 6-, or 7-membered ring of the formula, ,c=cf 0~\j^JCH2,h 20 f) ■CH N— > in which D is S, O or NRg6 in which Rgg is H or C-|_e alkyl, or g) R5 and Rg taken together are -(CH2)k-, when R7 is an electron-withdrawing group; 25 Re and R7 at each occurrence are the same or different and are a) an electron-withdrawing group, b) H, WO 00/10566 - 139 - PCT/US99/19265 c) cf3, d) ci.3 alkyl optionally substituted with one halo, e) phenyl, provided at least one of rg and r7 is an electron- withdrawing group, or f) rg and r7 taken together are a 5-, 6-, or 7-membered ring of the formula, 0 /-c-cx 1 U is a) CH2, 10 b) O, c) S or, d) NR16; R16is a) H or 15 b) C^s alkyl; wherein R8 is a) carboxyl, b) halo, c) -CN, 20 d) mercapto, e) formyl, f) cf3, g) no2. h) Ci^ alkoxy, 25 i) C-j^ alkoxycarbonyl, j) Cve alkythio, k) C^ acyl, WO 00/10566 - 140 - PCT/US99/19265 I) -NR17R13, NOH II m) — C-R87 in which R87 is H or alkyl, n) C1-6 alkyl optionally substituted with OH, sulfamoyl, C1.5 alkoxy, C1.5 acyl, or-NR17R18, 5 0) C2.8 alkyl optionally substituted with one or two R-jg, p) phenyl optionally substituted with one or two R19, q) a 5- or 6-membered saturated or unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or 10 two R-jg, or V (CHjJij} » R17 and R-)8 at each occurrence are the same or different and are a) H, b) C1>4 alkyl, 15 c) C5_e cycloalkyl, or d) R-J7 and R18 taken together with the nitrogen atom is a 5- or 6-membered saturated or unsaturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and can in turn be optionally 20 substituted with, including on the further nitrogen atom, C1.3 alkyl, formyl, a 5- or 6-membered heteroaromatic moiety o II containing 1-3 O, N or S, —C-NR88R89 in which R88 and R89 are each independently hydrogen or C-j.5 alkyl, S02R9o in which R90 is H or C-i.6 alkyl, or C-j_3 acyl optionally 25 substituted with 1 or more F, CI or OH; WO 00/10566 - 141 - PCT/US99/19265 Rigis a) carboxyl, b) halo, c) -CN, 5 d) mercapto, e) formyl, f) CF3, 9) no2, h) C^ alkoxy, 10 i) C-|_6 alkoxycarbonyl, j) C-i.6 alkythio, k) C^ acyl, I) Ci_e alkyl optionally substituted with OH, C^ alkoxy, C-|_5 acyl, or-NR17R18, 15 m) phenyl, n) -C(=O)NR20R21, o) -N R^R-jg, P) -N(R2o)(-S02R22), CJ) -SO2-NR20R2i, or 20 r) -S(=0)jR22; R20 and R2-| at each occurrence are the same or different and are a) H, b) Ci_6 alkyl, or c) phenyl; 25 R22 is a) C^ alkyl, or b) phenyl optionally substituted with C^ alkyl; WO 00/10566 - 142 - PCT/US99/19265 wherein Rg is a) carboxyl, b) halo, c) -CN, 5 d) mercapto, e) formyl, f) cf3, g) no2, h) C<j_g alkoxy, 10 i) Ci_e alkoxycarbonyl, j) C^ alkythio, k) C^ acyl, I) -NR23R241 m) C-|_5 alkyl optionally substituted with OH, C1.5 alkoxy, C1.5 15 acyl, or-NR23R24, n) C2-8 alkenylphenyl optionally substituted with one or two r25> o) phenyl optionally substituted with one or two R25, p) a 5- or 6-membered saturated or unsaturated heterocyclic 20 moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R25, or q) (CH^) j 25 R23 and R24 at each occurrence are the same or different and are a) H, b) formyl, WO 00/10566 - 143 - PCT/US99/19265 c) C^ alkyl, d) C1jt acyl, e) phenyl, f) C3.6 cycloalkyl, or 5 g) R23 and R24 taken together with the nitrogen atom is a 5- or 6-membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, 0, and can in turn be optionally substituted with, including on the further nitrogen atom, 10 phenyl, pyrimidyl, C^ alkyl, or Ci_3 acyl; R25 is a) carboxyl, b) halo, c) -CN, 15 d) mercapto, e) formyl, f) cf3, 9) no2, h) C<|_g alkoxy, 20 i) C-j.0 alkoxycarbonyl, j) C-)^ alkythio, k) C-j_6 acyl, I) phenyl, m) Ci_e alkyl optionally substituted with OH, azido, C-|.5 alkoxy, 25 Ci_5 acyl, -NR32R33i -SR34, -O-SO2R35, or R36~~S^ ^—NH-CO-O- n) -C(=0)NR26R27. o) -NR23R24. WO 00/10566 - 144 - PCT/US99/19265 p) -N(R26)(-S02R22), q) -S02-NR2gR27, or r) -S(=0)jR22, s) -CH=N-R28, or 5 t) -CH(0H)-S03R31; R22 is the same as defined above; R26 and R27 at each occurrence are the same or different and are a) H, b) alkyl, 10 c) phenyl, or d) tolyl; R28 is a) OH, b) benzyloxy, 15 c) -NH-C(=0)-NH2, d) -NH-C(=S)-NH2, or e) -NH-C(=NH)-NR29R30; R2g and R30 at each occurrence are the same or different and are a) H, or 20 b) C-i_4 alkyl optionally substituted with phenyl or pyridyl; R31 's a) H, or b) a sodium ion; R32 and R33 at each occurrence are the same or different and are 25 a) H, b) formyl, c) Ct_4 alkyl, d) acyl, e) phenyl, WO 00/10566 - 145 - PCT/U S99/19265 f) C3_0 cycloalkyl, g) R32 and R33 taken together are a 5- or 6-membered saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, O, optionally 5 substituted with, including on the nitrogen atom, phenyl, pyrimidyl, Ci_3 alkyl, or C-j.3 acyl, h) -P(0)(0R37)(0R38), or i) -SO2-R39; R34 is N-N N-N ^^-N r^-N N' fCH , C ^ or C ^ ■ N » (C"3)3C s » •or N » l I I 10 ch3 ch3 ch3 R35 is 0^3 alkyl; R36is a) C-i^ alkoxycarbonyl, or b) carboxyl; 15 R37 and R38 at each occurrence are the same or different and are a) H, or b) 0^3 alkyl; R39 is a) methyl, 20 b) phenyl, or c) tolyl; wherein K is a) O, b) S, or 25 c) NR40 in which R40 is hydrogen, formyl, C-)^ alkyl, acyl, phenyl, C3.6 cycloalkyl, -P(0)(0R37)(0R38) or -S02-R3g in which R37, R38 and R3g are as defined above; WO 00/10566 - 146 - PCT/US99/19265 Rio, Rn, R-)2> R13, R14 and R15 at each occurrence are the same or different and are a) H, b) formyl, d) Ci_g alkoxycarbonyl, e) C-j_8 alkyl, f) C2-8 alkenyl, wherein the substitutents (e) and (f) can be optionally substituted with 10 OH, halo, C-|_6 alkoxyl, acyl, alkylthio or alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally 5 c) carboxyl, 15 substituted with carboxyl, halo, -CN, formyl, CF3, NO2, C^ alkyl, Ci„6 alkoxy, C-1.5 acyl, C^ alkylthio, or C-j^ alkoxycarbonyl; 20 h) -NR42R43, i) OR44, j) -S(=0)rR45, k) -S02-N(R46){R47), or I) a radical of the following formulas: 0 N— N— HN N— R52 (CH2)t—N R-19 is the same as defined above; WO 00/10566 - 147 - PCT/US99/19265 Tis a) 0, b) S, or c) S02; 5 R42 and R43 at each occurrence are the same or different and are a) H, b) C3_6 cycloalkyl, c) phenyl, d) acyl, 10 e) Ci_b alkyl optionally substituted with OH, C-1.5 alkoxy which can be substituted with OH, a 5- or 6-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF3, halo, -NO2, C-m o 15 alkoxy,-NR48R49, or o 9) 20 Vis o. ^ R54 r5s-ch— ^ or /—\ Y_yN~(CH2)t" a) O, b) CH2, or c) NR56; R48 and R49 at each occurrence are the same or different and are 25 a) H, or b) C-1.4 alkyi; WO 00/10566 - 148 - PCT/US99/19265 R54 is a) OH, b) Ci_4 alkoxy, or c) -NR57R58; 5 R55 is a) H, or b) C1.7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C(=0)-NH2, -C02H, or-C(=NH)-NH2; 10 R56 is a) H, b) phenyl, or c) Ci_g alkyl optionally substituted by OH; R57 and R58 at each occurrence are the same or different and are 15 a) H, b) C-|_5 alkyl, c) C<i_3 cycloalkyl, or d) phenyl; R44 is 20 a) alkyl optionally substituted with C-|_6 alkoxy or C-|_6 hydroxy, C3.6 cycloalkyl, a 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three nitrogen atoms, which can in turn be substituted with one or two -N02, CF3, halo, -CN, OH, C1.5 alkyl, Ci_5 alkoxy, or 25 C-|_5 acyl, b) /—\ V N-(CH2)t- c) phenyl, or WO 00/10566 - 149 - PCT/US99/19265 d) pyridyl; R45 is a) C-ms alkyl, b) C2_16 alkenyl, 5 wherein the substituents (a) and (b) can be optionally substituted with C-).g alkoxycarbonyl, or a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, c) an aromatic moiety having 6 to 10 carbon atoms, or 10 d) a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group of S, N, and O, wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, -CN, formyl, CF3, -N02, C^ alkyl, C-j.6 alkoxy, C^ acyl, C^ alkylthio, or C^ 15 alkoxycarbonyl; R46 and R47 at each occurrence are the same or different and are a) H, b) phenyl, c) C-]_6 alkyl, or 20 d) benzyl; R50 and R51 at each occurrence are the same or different and are a) H, b) OH, c) C-|_g alkyl optionally substituted with -NR48R49 in which R48 25 and R49 are as defined above, d) R50 and R51 taken together are =0; R52 is a) an aromatic moiety having 6 to 10 carbon atoms, WO 00/10566 PCT/US99/19265 - 150 - 5 10 b) a 5- or 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the substituents (a) and (b) can in turn be optionally substituted with one or three -NO2, CF3, halo, -CN, OH, phenyl, C1.5 alkyl, C-|_5 alkoxy, or C1.5 acyl, c) morpholinyl, d) OH, e) Ci_e alkoxy, f) -NR48R49 in which R48 and R49 are as defined above, g) -C(=0)-R59, or h) a) H, b) formyl, c) C1>4 alkyl, d) C^ acyl, e) phenyl, f) C3-6 cycloalkyl, g) -P(0)(0R37)(0R38), or h) -SO2R39, in which R37, R38 and R3g are as defined above; a) morpholinyl, b) OH, or c) C-|_g alkoxy; i is 1, 2, or 3; isO, 1, or 2; r53's R59 is WO 00/10566 - 151 - PCT/US99/19265 jisO, or1; k is 3, 4, or 5; r is 1, 2, 3,4, 5 or 6; t is 0, 1, 2, 3, 4, 5, or 6; 5 u is 1 or 2; and Q is a) hydrogen, b) halo, c) N02> 10 d) N3) e) C<|-C6 alkylthio, O f) C-|-C6 alkyl—S—, O 9) CrC6 alkyl—s— O ' h) CrC6 alkyl, 15 i) Ci-C6 alkoxy, j) formyl, O k) CrC6 alkyl—c—, O •) CrC6 alkyl—o-C—, m) -sulfamoyl (H2NSO2-), 20 n) -NHOH, O o) CrC6 alkyl—c-O— O p) heteroaryl —c— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, WO 00/10566 - 152 - PCT/US99/19265 o q) C6H5-C , r) amino, s) C-i-Cg alkylamino, t) di(C.j-Cg alkyl)amino-, O 5 u) (CrC6) alkyi-C-NR60R61 in which Rgo and R61 are each independently hydrogen or C-j-Cg alkyl, v) OH, w) cyano, x) hydroxy (C^-Cg alkyl), 9 10 y) CrC6 alkyl-S-C-, O z) NC—(CH2)r—C— in which r is 1-6, O aa) C6H5CH2-0-C—, 0 bb) C6H5-0-C—, xORg4 N cc) CrC6 alkyl—c— in which Rg4 is hydrogen or C^.g alkyl, O 15 dd) R850-(CH2)-j_6-C— in which R85 is hydrogen, C^ alkyl optionally substituted with one or more F, CI, OH, Ci.g alkoxy or C-]_8 acyioxy, C3^ cycloalkyl or C^g alkoxy; N-ORw ee) H-C— in which Rg4 is hydrogen or C-]_6 alkyl, ff) a substituted or unsubstituted Cg-Cio aryf moiety, 20 gg) a substituted or unsubstituted monocyclic or bicyclic, saturated or unsaturated, heterocyclic moiety having 1-3 WO 00/10566 - 153 - PCT/US99/19265 atoms selected from 0, N or S, said ring being bonded via a ring carbon or nitrogen to the phenyl substituent, hh) a monocyclic or bicyclic substituted or unsubstituted heteroaromatic moiety having 1-3 hetero atoms selected 5 from O, N or S, said ring being bonded via a ring carbon or nitrogen to the phenyl substituent and wherein the heteroaromatic moiety can additionally have a fused-on benzene or naphthalene ring; the substituents for such p, q, ff, gg and hh moieties being selected from 10 1 or 2 of the following: 1) halo, 2) alkyl, 3) n02, 4) N3, O 15 5) CrC6 alkyl-S-, O 6) CrC6 alkyl—s— O ' 7) formyl, O 8) CrC6 alkyl—c—, O 9) CrC6alkyl-o-C-, O 20 10) heteroaryl—C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, O 11) c6h5-c-, O ii 12) -(C-pCg) alkyl-C-NR60R61 in which Re0 and R6i are each 25 independently hydrogen or C-pCg alkyl, WO 00/10566 - 154 - PCT/US99/19265 13) OH, 14) hydroxy (CrC6 alkyl), 0 15) CrC6 alkyl-S-C-, O 16) NC-(CH2)r -O-C— in which r is 1-6, O 5 17) C6H5CH2-0-C-, 18) -CH2-R80 in which R8o is a) -OR32 in which R32 is as defined above, b) -SR32 in which R32 is as defined above, c) -NR32R33 in which R32 and R33 are as defined 10 above, or d) 5- or 6-membered heteroaromatic containing 1-4 0, S or N atoms, /ORg4 N 19) Ci~C6 alkyl—c— in which Rg4 is as defined above, 20) cyano, 15 21) carboxyl, 22) CF3, O 23) C^-Og alkyl—C~0— 1 O 11 24) C6H5-0-C— in which the phenyl moiety may be optionally substituted by halo or (C-j-CgJalkyl, O 20 25) NRgoRef— C— in which R60 and Rg-j are as defined above, O O 26) R91-NH-C— or R91-C-NH— in which R91 is a 5- or 6-membered aromatic heterocyclic group having 1-3 0, N or S, WO 00/10566 - 155 - PCT/US99/19265 0 27) C6H5(CH2)1.g-0-C-, O 28) R850~(CH2)-t-6—O-C— in which Rgs is as defined above, O 29) SiRg9R100R10i 0-CH2—C— in which R99, R-ioo and R101 are each independently C^ alkyl; or 5 Q and either R-j and R2 taken together form -O-CH2-O.
2. A compound of claim 1 wherein A is r2 qhC|}- r3 10 in which Q, R2 and R3 are as defined in claim 1.
3. A compound of the formula 15 or a pharmaceutically acceptable salt thereof, in which R-i is H, Ci_s alkyl optionally substituted with one or more F, Ci, OH, C-|_8 20 alkoxy, or C-]_8 acyioxy, C3^ cycloalkyl or C^.g alkoxy; R2 and R3 are each independently a) H, WO 00/10566 - 156 - PCT/US99/19265 b) c) d) e) 5 f) 9) h) 0 j) 10 k) Q is a) b) c) 15 d) e) f) g) h) 20 i) j) k) I) m) F, CI, Br, Ci_6 alkyl, N02, I, C-i^ alkoxy, OH amino, or cyano; and hydrogen, halo, N02, n3. CrC6 alkylthio, O C^-Cq alkyl —S—, O CrC6 alkyl—s—, ti O C-j-Cg alkyl, Ci-Cg alkoxy, formyl, O C1-C5 alkyl—c— 1 O CrC6 alkyl—O-C—, O C-i-Cg alkyl—c-O—, WO 00/10566 - 157 - PCT/U S99/19265 o n) heteroaryl—C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, O o) C6H5-C , 5 p) amino, q) CfCe alkylamino-, r) di(C-i-C6 alkyl)amino-, O ii s) (CrC6) alkyl-C-NR60R61,in which R60 and Rqi are each independently hydrogen or C-|-C6 alkyl, 10 t) OH, u) cyano, v) hydroxy (C-|-C6 alkyl), O w) CrC6 alkyl—S-C—, 0 x) NC-(CH2)r -O-C— in which r is 1-6, O 15 y) c6H5CH2-0-C-, O z) C6H5-0-C—, /OR84 N aa) CrC6 alkyl—c— wherein R84 is hydrogen or alkyl, O bb) R85°-(CH2)i^—C— in which R85 is hydrogen, C-).8 alkyl optionally substituted with one or more F, CI, OH, Ct_8 20 alkoxy or Ci_8 acyioxy, C3.0 cycloalkyl or C-j_8 alkoxy, N-ORs4 cc) H-C— in which R^ is as defined above, WO 00/10566 - 158 - PCT/U S99/19265 dd) V ^ ee) 10 fl) gg) hh) ii) /T~^ N 3 \=|=^Y X Y^W-^X N. Z'X Y^-3Lx X > N I M X VN \-n i M jj) 15 kk) x^i*! V" I M <X!r WO 00/10566 - 159 - PCT/US99/19265 H) mm) nn) oo) PP) qq) rr) 15 ss) * n-n -nn J-X N V -n n N-N 11 vn I r92 in which R92 is H or C-|_6 alkyl, -irVx 10 n-n X /Vn "\\J Y -N'V?X ,N^N —N , \^-N X WO 00/10566 - 160 - PCT/US99/19265 tt) uu) w) ww) XX) yy) 22) X —N i V^-N Y -(SsN I Jhx 7^V <T N^> ^4. Y -CO 10 2 9R62 °tb yiOH2)n\^ E\ L*" (CH2)p/\ 15 aaa) a diazinyl group optionally substituted with X and Y, bbb) a triazinyl group optionally substituted with X and Y, ccc) a quinolinyl group optionally substituted with X and Y, ddd) a quinoxalinyl group optionally substituted with X and Y, eee) a naphthyridinyl group optionally substituted with X and Y, WO 00/10566 - 161 - PCT/US99/19265 ffi) A2 (CH2)W jq> ggg) ?2 x Rfi4 (CHjJj y hhh) Z3''N^h . or Hi) Rcsx > B is an unsaturated 4-atom linker having one nitrogen and three carbons; 10 M is a) H, b) C-,.8 alkyl, c) C3_g cycloalkyl, d) -(CH2)mOR56, or 15 e) -(CH2)nNR67R68; Zis a) O, b) S or c) NM; 20 Wis a) CH, b) N or WO 00/10566 - 162 - PCT/US99/19265 c) S or O when Z is NM; X and Y are each independently a) hydrogen, b) halo, 5 c) N02, d) N3, e) C-|_6 alkythio, O f) CrC6 alkyl —S—, O g) CrC6 alkyl—s—, 6 10 h) CrC6 alkyl, i) CrC6 alkoxy, j) formyl, O k) CrC6 alkyl—c— O I) C-j-Ce alkyl—O-C— i O ii 15 m) heteroaryl—C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from 0, N or S, O n) C6H5-C-. o) amino, 20 p) CrCe alkylamino-, q) di (C-j-Cg alkyl)amino-, WO 00/10566 - 163 - PCT/US99/19265 o II r) -(CrC6) alkyl-C-NR60R61 in which Rso and R61 are each independently hydrogen or C-pCe alkyl, s) OH, t) hydroxy (C-)-C6 alkyl), O 5 u) CrC6 alkyl— S-C—, O v) NC-(CH2)r —O-C— in which r is 1-6, O w) c6H5CH2-0-C- , O x) C6Hs-0-C-, /ORm N y) C1-C6 alkyl—c— in which Rg4 is as defined above, 10 z) cyano, aa) carboxyl, bb) CF3, cc) mercapto, O dd) CrC6 alkyl—c-O— > O ii 15 ee) C6H5-0-C—in which the phenyl moiety may be optionally substituted by halo or C-pCg alkyl, 9 ff) C6H5(CH2)i-6—O-C ' o II 99) R85O—(CH2)i_g—C— in which Rg5 is as defined above, or O hh) SiR99R100R10i-O-CH2-C— in which R99, R10q and R10t 20 are each independently C^ alkyl; or Q and either R1 and R3 taken together form -0-CH2-0; - 164 - received Rq2 is a) H, b) Ci_g alkyl optionally substituted with one or more halos, or c) C-|_8 alkyl optionally substituted with one or more OH, or 5 C-j.g alkoxy; B is a) NRe9, b) -S(=0)j in which i is 0,1 or 2, or c) O; 10 R63 is a) H, b) alkyl, c) -(CH2)q-aryl, or d) halo; 15 Rge is H or alkyl; R67 and R®8 are each independently H or C-j^ alkyl, or R67R68 taken together are R69 » a) H, 20 b) alkyl, c) -(CH2)q-aryl, d) -CO2R81, e) COR^, f) -C(=0)-(CH2)q-C(=0)R81, 25 g) -S^O^-C^ alkyl, h) -S(=0)2-(CH2)q-aryl, or 0 -(C=0)j-Het in which j is 0 or 1 and Het is a saturated or unsaturated 5- or 6-membered heterocyclic group having 1-3 hetero atoms selected from O, N or S; WO 00/10566 - 165 - Z-i is a) -CH2-, or b) -CH(R70)-CH2-; Z2 is 5 a) -02S-, b) -0-, c) -S-, d) -SO-, or e) -N(R7i)-; 10 Z3 is a) s, b) SO. c) S02, or d) O; 15 A-| is H or CH3; A2 is a) H, b) OH-, c) ch3co2-, 20 d) ch3-, e) ch3o-, f) R720-CH2-C(0)-NH-, g) R730-C(0)-NH-, h) R73-C(0)-NH-, 25 0 (CrC2)alkyl-0-C(0)-, or j) HO-CH2; or A-i and A2 taken together are WO 00/10566 - 166 - PCT/US99/19265 a) b) O =; Rg4 is H or CH3-; 5 m is 4 or 5; n is 0,1,2, 3,4 or 5; y is 0 or 1; p is 0, 1, 2, 3, 4 or 5; wis 1, 2 or3; 10 q is 1,2, 3 or 4; z is 0 or 1; Res is a) R740C(R75)(R76)-C(0)-, b) R770C(0)-, 15 c) R78(OK d) R79-SO2-, or e) R80-NH-C(O)-; R7o is H or (CrC3)alkyl; R71 is 20 a) R740C(R75)(R76)-C(0)-, b) R770-C(0)-, c) R7g-C(0)-, d) i WO 00/10566 - 167 - PCT/US99/19265 e) H f) H3C-C(0)-(CH2)2-C(0)-, g) R79-SO2-, h) i) R80-NH-C(O)-, R72 is a) H, 10 b) CH3, c) phenyl -CH2-, or d) CH3C(0)-; R73 is (C-j-C^alky) or phenyl; R74 is H, CH3, phenyl-CH2- or CH3-C(0)-; 15 R75 and R76 are each independently H or CH3, or R75 and R78 taken together are -CH2CH2-; R77 is (CrC3)alkyl or phenyl; R78is H, (CrC4)alkyl, aryKCH2)nl, CIH2C, CI2HC, FH2C-, F2HC- or (C3-C6)cycloalkyl; 20 R79 is CH3; -CH2CI, -CH2CH=CH2, aryl or -CH2CN; R30 is -(CH2)ni-aryl where n1 is 0 or 1; R81 is a) H, WO 00/10566 - 168 - PCT/US99/19265 b) Ci_g alkyl optionally substituted with one or more OH, halo or CN, c) -(CH2)q-aryl in which q is as defined above, or d) -(CH2)q—OR53 in which q is as defined above; 5 R82 is a) C-)_g alkyl optionally substituted with one or more OH, halo or CN, b) -(CH^q-aryl in which q is as defined above, or c) -(CH2)q-ORg3 in which q is as defined above; 10 R83 is a) H, b) C^ alkyl, c) -(CH2)q-aryl in which q is as defined above; or d) -C(=0) Ci_e alkyl; and 15 aryl is phenyl, pyridyl or naphthyl, said phenyl, pyridyl or naphthyl moieties being optionally substituted by one or more halo, -CN, OH, SH, C-|_g alkoxy or C^ alkylthio.
4. A compound of the formula 20 r2 O or a pharmaceutically acceptable salt thereof, in which 25 R-| is H, C-|_8 alkyl optionally substituted with one or more F, CI, OH, C-j_8 alkoxy or C-j.g acyioxy, C3_6 cycloalkyl or C-]_8 alkoxy; WO 00/10566 - 169 - PCT/US99/19265 R2 and R3 are each independently H or F; or R2 and R3 taken together represent o~~ v. > Q is 5 a) hydrogen, b) halo, c) N3, d) N02, e) CrCe alkylthio, 0 10 f) C-j-C6 alkyl—s—, O 9) CrC6 alkyl—s— O ' h) CrC6 alkyl, i) C-j-Cg alkoxy, j) formyl, O 15 k) CrC6 alkyl—c—, O I) CrC6 alkyl—o-C— ' 1 O m) CrC6 alkyl-c-O—, n) (CrC6 alkoxy)2N-, o) 5- or 6-membered heterocyclic containing 1-3 O, N or S and 20 linked to the phenyl substituent via a carbon or nitrogen, said heterocycle moiety being optionally substituted by Rgg, OH P) N CrC6 alkyl—c WO 00/10566 - 170 - PCT/US99/19265 q) phenyl optionally substituted by Rg6, or r) 5- or 6-membered saturated or unsaturated heterocyclic containing 1-3 0, n or S and linked to the phenyl substituent via a carbon or nitrogen, said heterocycle moiety being 5 optionally substituted by Rg6, and Rg6 is a) CrC6 alkyl-OH, b) CrC6 alkyl—o-C— - ii O o c) CH3—0— CrC6 alkyl—c—, II O 10 d) cyano, e) formyl, n-oh f) H-C- , O g) CrC6 alkyl-O-C—, O h) SiR^RgsRgg-O-C— in which Rg4, Rg5 and R86 are each 15 independently C^Cg alkyl, O O i) CH3—s— CrC6 alkyl—s—, n II O 0 0 j) hc^cch2oc— , o k) C6H5-0-C— where the phenyl may be optionally substituted by halo, O 20 i) ho-ch2-c-, m) (CrC6 alkyl)2N-, - 171 - n) 0,-Cg alkyl-NH-, o) amino. O p) CrC6 alkyl—s—. O (]) C6H5CH2OC , or 0 r) Rgg—C— in which R93 is phenyl, 5- or 6-membered heteroaryl containing 1-3 0, N or S and linked to the phenyl substituent via a ring carbon atom or 5- or 6-membered saturated or unsaturated heterocyclic containing 1-4 O, N or S and linked to the phenyl substituent via a ring carbon atom.
5. A compound selected from the group consisting of the compounds of Examples 1-97 described in the specification.
6. A pharmaceutical composition comprising a compound of any one of Claims 1 to 5 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
7. Use of a compound of any one of Claims 1 to 5 in the manufacture of a medicament for treating a bacterial infection in a mammal. received </div>