CA2341271A1 - Novel isoxazolinone antibacterial agents - Google Patents

Abstract

This invention describes isoxazolinone derivatives which possess antibacteri al activity and are useful in the treatment of bacterial diseases. More particularly, new isoxazolinones are provided having general formula (I), wherein A and R1 are as described in the specification.

Description

NOVEL iS'~OXAZOL1NONE ANTIBACTERIAL AGENTS
BACKGROUND OF THE INVENTION
1. Field of the Invention 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 , O
~L-N R~
L
Za or a pharmaceutically acceptable salt thereof wherein:
R~ is a) H, b) C~_$ alkyl optionally substituted with one or more F, C1, OH, C~_$ alkoxy, or C~_$ acyfoxy, C) C3~ CyClOallCyl, Or d) C~_g alkoxy;
L is oxygen or sulfur;
A is a) rR2 b) R' \ /
Rs c) a 5-membered heteroaromatic moiety having one to three hetero atoms selected from the group consisting of S, N, and CJ, wherein the 5-membered heteroaromatic moiety is banded via a carbon atom and can additionally have a fusedl-on benzene or naphthyl ring, and wherein the heteroaromatic moiety is optionally substituted with one to three R8, d) a fi-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 2g naphi:hyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three Rg, e) a ~3-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three Rg, R R~~~~R12 ~o~ \~/
f 1 R~4 ~C ~J
R~3 , Or 9) R1 \ /R'I2 N
R~5 C
T
R~3 ' wherein R2 and R3 are each independently a) H, b) F, d} Br, e) C~_6 alkyl, N02, g) h} C~~ alkoxy, i) OH
10 j) amino, k) cyano~, or l) R2 and R3 taken together are -O(CH2)~,-O;
wherein R4 is a) H, b) C~_z alkyl, c) F, or d) OH;

R~ is a} H, b} CFg, c) C~_3 alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) R~ and R6 taken together are a 5-, 6-, or 7-membered ring ofi they fiormula, o= ,c=c~
~U ~c~r2~n, in which D is S, O or NR~6 in which R86 is H or C~~ alkyl, or g) R~ and R6 taken together are -(CH~)k-, when R7 is an electron-withdrawing group;
R6 and R~ at each occurrence are the same or different and are a) an elE;ctron-withdrawing group, b} H, c} CF3, d) C~_3 alkyl optionally substituted with one halo, e) phenyl, provided at least ane ofi R6 and R~ is an electron-withdrawing group, or f) R6 and R7 taken together are a 5-, fi-, or 7-membered ring of the formula, -~r~
(Cti2)r .
U is a} CH2, b} O, c} S or, d} NR16;

R1g is a) H or b) C~_~ alkyl;
wherein Rg is a) carboxyl, b) halo, c) -CN, d) merc;apto, e) formyl, f) CF3, g) NOz, h) C~_6 ~alkoxy, i) C~.~ alkoxycarbonyl, j) C~~ alkythio, k) C 1 _6 <~cyl, I) -NR~;~R~g, NoH

m) -C-R8~ in which Rg~ is H or C~_6 alkyl, n) C~~ alkyl optionally substituted with OH, sulfamoyl, C~_~

alkox!,r, C~_~ acyl, or-NR~~R~g, o) C2_$ alkyl optionally substituted with one or two Rig, p) phenyl optionally substituted with one or two Rig, 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~9, or (CH~~--a 6 - fi PCT/US99/19265 R~~ and Rig at each occurrence are the same or different and are a) H, b) C~..~ ;alkyl, c) C5~ cycloalkyl, or d) R~7 and R~$ taken together with the nitrogen atom is a 5- or fi-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, C~_3 alkyl, formyl, a 5- or fi-membered heteroaromatic moiety containing 1-3 O, N or S, -C-NR88R89 in which R8$ and Rgg are each independently hydrogen or C~~ alkyl, S02Rgp in whiich Rg~ is H or C~~ alkyl, or C1_3 acyl optionally substituted with 1 or more F, CI or OH;
R~ g is a) carboxyl, b) halo, c) -CN, d) mercapto, e) forrnyl, f) CF3, g) N02, h) C~~ alkoxy, i) C~~ alkoxycarbony(, j) C~-6 aikythio, k) C~_g ~clcyl, l) C~~ alkyl optionally substituted with OH, C~_5 alkoxy, C'_~

acyl, or-NR~7R~s, m) phenyl, n} -C(=~O)NR2pR2~, ) -N R17R18 p) -N(R2o){-S02R22), q) -SO~~-NR2pR21, or r) -S{=f~)~R22~

R2p and R2 ~ at each occurrence are the same or different and are a) H, b) C~_6 alkyl, or c) phenyl;
R22 is a) C~~ alkyl, or b} phenyl optionally substituted with C~~ alkyl;
wherein Rg is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, 9) N~2, h) C~~ ;alkoxy, i) C~~ alkoxycarbonyl, j) C~-6 ~alkythio, k) C~_g ;acyl, I) -NR2;3R24=

m) C1:6 alkyl optionally substituted with OH, C~_5 afkoxy, C~_~

aryl, or -NR23R24~

WO 00/1O5b6 PCT/US99119265 - $ _ n) C2_~; aikenylphenyl optionally substituted with one or two R2~, o) phenyl optionally substituted with one or two R2~, p) a 5- or 6-rnembered saturated or unsaturated heterocyciic moiEay having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R2~, or q) t~~; \
R23 and R24 at each occurrence are the same or different and are a) f-I, b) formyl, c) C~~ alkyl, d) C~~ acyl, '15 e) phenyl, f) Cg~ cycloalkyl, or g) R23 and R24 taken together with the nitrogen atom is a 5- or 6-me~mbered saturated heterocyclic maiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and. can in turn be optionaNy substituted with; including on the further nitrogen atom, phenyl, pyrimidyl, C~_3 alkyl, or C~_3 acyl;
R2~ is a) carboxyl, b) halo, c) -CN, d) merc~apto, e) formyl, CF3, 9) N~2 h} C~~ alkoxy, i} C~~ alkoxycarbonyl, b j) C~_6 alkythio, k) C~_6 acyl, 1) phenyl, m} C~..g ;alkyl optionally substituted with OH, azido, C~_5 alkoxy, C~_~ ;acyl, -NR32R33, -SR34, -O-S02R35, or Ras- ~ ~ H~-co-o-n} -C(=O}NR2~R27, o} -NR2;3Rz4~

p) -N(R2s}(-SO2R22)~

4) -SC)2..NR26R27~ or r} -S(=O};Rzz~

s} -CH=N-R28, or t) -CH(OH}-S03R3~;

R22 is the ame as defned above;
s R~~ and R2~
at each occurrence are the same or different and are a} H, b) C~_6 alkyl, c} phenyl, or d) tolyl;

R2$ is a) OH, b) benzyloxy, c) -NH-C:{=O}-NH2, WO flfl/1fl566 - ,~ O - PCT/US99/19265 d) -NH-G(=S)-NHS, or e) -NH-C(=NH)-NRZ9R3p;
R29 and R3p at each occurrence are the same or different and are a) H, or b) C~.,q, alkyl optionally substituted with phenyl or pyridyl;
R3~ is a) H, or b) a sodium ion;
R32 and R33 at each occurrence are the same or different and are a) H, b) formyl, c} C~~ alkyl, d) C~.~ acyl, e) phenyl, f) C3~ c:ycloaikyl, g) R32 and R~3 taken together are a 5- or 6-membered saturated heterocyclic moiety having one to three atoms seleci;ed from the group consisting of S, N, O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyi, C~_g alkyl, or C~_3 acyl, h) -P{O)I;OR3~)(OR3g), or 'SO2'R39~
Rg4 is NN ~ ~ CH C' ' ~ ~ \ N~ I N~ .
N t 3f3 S ~ ~ N , or ~ N
t I

R3~ is C~_g alkyl;
R3g is a) G~~ alkoxycarbonyl, or b) carboxyl;
R37 and R38 at each occurrence are the same or different and are a) H, or b) C~_3 alkyl;
R3g is a) methyl, b) phenyl, or c) tolyl;
wherein K is a) O, !, b) S, or c) NR4p in which R4o is hydrogen, formyl, G1~ alkyl, C~~ acyl, phenyl, C3~ cycloalkyl, -P(O}(OR37)(OR3$} or -S02-R39 in which R3~, Rg8 and R3~ are as defined above;
Rya, R~ ~, R~2, R~3, R~4 and R~~ at each occurrence are the same or different and are a} H, b) formyl, c) carboxyl, d) C~~ alkoxycarbonyl; I
e) C~_g alkyl, C2_$ alkenyl, wherein the substitutents (e} and {f) can be optionally substituted with OH, halo, C~_6 alkoxyl, C~_g acyl, C~_6 alkylthio or C~_6 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, NO2, C~_s alkyl, C~~ alkoxy, C~_~ acyl, C~_6 alkylthio, or C~~
alkoxycarbonyl;

- '12 h) -NR42R43~
i) OR4~~, l) -SC=«)i R45 k) -S02-N~Ra6)~R47)~ or I) a radical of the following formulas:
UN- ~ CN ~O~CN' \CONH2 ' O
Raa~sN ~ \ N-- R5o Rs~

H ~N- ' R$2--(CHy)t-N N- R$g-N N-or R5~)a , Rig iS the same as defrned above;
T is 7 0 a) O, b) S, or c) S02;
R42 and R43 at each occurrence are the same or different and are a) H, '! 5 b) C3_g cycioalkyl, c) phenyl, d) C~_6 acyl, e) C~_8 alkyl optionally substituted with OH, C~_~ 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 PCT/US991t9265 substituted with OH, CF3, halo, -N02, C~~
alkoxy,-NR4$R49, or o o~
~~--Rat R55 ~'H~ , Or g) ~/N-(GHy)t- .
V IS
a) ~a b) CH2, or c) NR56;
R4$ and R49 at each occurrence are the same or difFerent and are a) H, or b) C~~ alkyl;
R~4 is ~ a) OH, b) C~~ alkoxy, or c) -NR~~~R58;
R~~ is a) H, or b) C~_~ alkyl optionally substituted with indolyl, OH, mercaptyl, imidaroly, rnethylthio, amino, phenyl optionally substituted with OH, -C(=O)-NH2, -C02H, or -C{=NH)-NH2;
Rg~ is a) H, b) phenyl, or c) C~..6 alkyl optionally substituted by OH;

R5~ and R58 at each occurrence are the same or different and are a) H, b) C~_5 alkyl, c) C~_3 cycloalkyl, or d) phenyl;
R~ is a) C'_8 alkyl optionally substituted with C~_6 alkoxy or C~~
hydroxy, C3_6 cycloalkyl, a 6-membered aromatic optionally benz:o-fused heterocyclic moiety having one to three nitrogen atoms, which can in turn be substituted with one or two -N02, CFg, halo, -CN, OH, C~_~ alkyl, C~_5 alkoxy, or C~_5 acyl, b) ~/N-(CHy)t-c) phenyl, or d) pYridyl;
R4~ is a) C~_~E; alkyl, b) C~_~~, alkenyl, wherein the substil:uents (a} and (b) can be optionally substituted with C~_6 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 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~~ alkoxy, C~~ acyl, C~_~ alkylthio, or C~~
alkoxycarbonyl;
R4~ and R47 at each occurrence are the same or different and are a) H, b) phenyl, c) C~~ alkyl, or d) benzyi;
Rya and R~1 at each occurrence are the same or different and are a) H, b) OH, c) C~_g alkyl optionally substituted with-NR4gR~9 in which R4gand R49 are as defined above, d) R5p and R5~ taken together are =O;
R52 is 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 with one or three -N02, CF3, halo, -CN, OH, phenyl, C~_~

alkyl, C~_5 alkoxy, or C~_5 acyl, c) morpholinyl, d) OH, e} C~~ alkoxy, f) -NR4;BR4g in which R48and R4s are as defined above, g} -C(=)-Rss, or h) o~~

WO 00110566 - 1 fi - PCT/US99119265 R~3 is a) H, b) formyl, c) C~~ alkyl, d) C~..~ acyl, e) phenyl, f} Cg_6 cycloalkyl, 9) 'P~~)'~OR37)tOR3s), or h) -S02R3g, in which R3~, R3g and Rig are as defined above;

R59 is a) morpholinyl, b) OH, or c) C ~ _~ a I koxy;
h is 1, 2, or 3;
i is 0, 1, or 2;
jis0,orl;
k is 3, 4, or 5;
r is 1, 2, 3, 4, 5 or 6;
t is 0, 1, 2, 3, 4, 5, or fi;
a is 1 or 2; and Q is a) hydrogen, b) halo, c) N02, d) Ng, e) C~-Cg alkylthio, O

C~-C6 alkyl-S-, O
g) C~-C~ alkyl-S-O ' h) C1-CE; alkyl, t) C1-CEi alkoxy, j) formyl, O

k) C'-Cf; alkyl-C- , O

~~ C1"(''Ei alkyl-O-C-, m) -sulfa;moyl (HzNS02-), n) -NHOH, O

o) C~-CE~ alkyl-C-O-O

1~ p) heterc~aryl -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

G) C6H~wC-r) amino, 1 ~ s) C1-C6 alkylamino-, t) di (C1~-Cs alkyl)amino-, O

u) (C~-C,~) alkyl-C-NRsoRs~ in which Rgo and R61 are each indepE:ndently hydrogen or C1-C~ alkyl, v) OH, 20 w) cyano, x) hydroxy (C1-C6 alkyl), y) C~-C6 alkyl-S-C- , WO OOIIOS66 - ~ $ - PCT/US99/19265 O
z) NC--(CH2)r C- in which r is 1-6, O
aa) C6H5CH2-O-C- , O
bb) CsH~-O-C- , ~OR$a N
cc) C~-CE; alkyl-C- in which R84 is hydrogen or C~_6 alkyl, O
dd) R8s0~-(GH2)~_s-C- in which Rg5 is hydrogen, C~_$ alkyl optionally substituted with one or more F, Cl, OH, C~_8 alkox,~ or C~_8 acyloxy, C3~ cycloalkyi or C~_~ alkoxy;

ee) H-C-- in which R~ is hydrogen or C~_6 alkyl, ff) a substituted or unsubstituted C6-C~c aryl moiety, 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 heteroarornatic 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 heterctaromatic 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 1 or 2 of the following:

1 ) halo, 2) C~_6 alkyl, 3) NOz, 2~ 4) Ng, WO 00/t0566 PCT/US99/19265 O
5) C~-Cb alkyl -S- , O
fi) C1-C~s alkyl-g-O
7) formyl, O

8) C~-CE; alkyl-C- , O

9) C'-Cf; alkyl-O-C- , O

10) heteroaryi-C- in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, p "

11) C6H~-C-, O

12) -(C~-C:6) alkyl-C-NR6oR6~ in which R6p and Rg~ are each independently hydrogen or C~-C6 alkyl, 13) OH, 14) hydro:xy (C~-Cg alkyl), O

15) C~-CE~ alkyl-S-C-, O

16) NC-(CH2)~ -O-C- in which r is 1-fi, O

17) C6H5CH2-O-C- , 18) -CH2-Rgp in which Rgp 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 above, or - 20 .:
d) 5- or 6-membered heteroaromatic containing 1-4 O, S or N atoms, N~ORsa 19) C~-C6 alkyl-~- in which R84 is as defined above, 20) cyano, 21 ) carboxyl, 22) CF3, O

23) C~-C6 alkyl-C-O-O

24) C6H~,-O-C- in which the phenyl moiety may be optionally substituted by halo or (C~-C6)alkyl, O

25) NR6oR6.r-C- in which R6o and R6~ are as defined above, O O

26) R9~ IVH-C- or Rg~-C-NH- in which R9~ is a 5- or 6-membered aromatic heterocyclic group having 1-3 O, N or S, O

27) CsHs(CH2)~-~-O-C-, O

28) R8~C)--(CH2)~_6-O-C- in which R$5 is as defined above, O

29) SiR9~R~ooR~o~-O-CH2-C- in which R99, R~oo and R~o~
are a<~ch independently C~_6 alkyl; or Q and either R~ and R2 taken together form -O-CH2-O.
These derivatives are usefiul as antimicrobial agents which are effective against a number of human and veterinary pathogens, including gram positive bactE:ria such as multiply-resistant staphylococci, streptococci, and enterococci, such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus faecium.
2. Descrijption of the Prior Art The literature contains a limited number of isoxazolinones used as pre-emergence herbicides. For example in U.S. Patent 4,065,463, 2-methyl-4-(trifluoromethyl-m-tolyt)-3-isoxazolin-5-one and 2-methyl-4-(chloro-m-tolyl}-3-isoxazolin-5-one are disclosed as being useful in preventing the growth of weeds which have a deleterious effect on crop production.
/ ° o ° /
''. ~~ I .,., 0 FCC L---N\
CI ~ N
CH3 \CHa U.S. Patent 4,000,155 discloses the related compound 1,2 dimethyl-4-(trifluoromethyl-m-tolyl)-3-pyrazolin-5-one for the same utility.
°
/CHI
' N
FCC
~cH~
The appiicar~t 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 C~-C4 alkyl optionally substituted with F, Cl, OH, C~-C4 alkoxy, or acyloxy.

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.
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,:144; 0694,543; and 0,693,491 (5 to 9-membered heteroaryl substituted oxazolidinones}.

Y
~'N~O
H
N

Additionally" certain compounds containing a substituted furanone ring have been reported to possess antibiotic activity. WO 97114690 discloses H' T
where T is hydroxy or NHC(O)C~-C4 alkyl, M and L are each independently hydrogen or fluoro, G and H are are each independently hydrogen or methyl!, K-J is of the formula C=CH, CHCH2 or C(OH}CH2, I
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
97/43280 and WO !97/10235.

SUMMARY OF THE INVENTION
It has now been found that certain substituted isoxazolinones are effective as antibacterial agents. Specifically, the invention covers compounds of the formula I:

~o N w..,.-- N R~
L
f or a pharmaceutically acceptable salt thereof wherein:
R~ is a) H, b) C~_8 alkyl optionally substituted with one or more F, CI, OH, C~_g ~alkoxy, or C~_g acyloxy, c) C3_6 cycloalkyl, or d) C~_8 alkoxy;
1 ~ L is oxygen or sulfur;
A is a) r_~_ b) Ra ~ Rs c) a 5-membered heteroaromatic moiety having one to three hete~ro 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 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 naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three Rg, e) a ~i-c;arbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three Rg, Rlp~
j R1s , or g) _~N ~~
R15 ~ J
T

wherein R2 and R3 are each independently a) H, b) F, c) Cl, d) Br, e) C~~ alkyl, f) N02, 2~ g) I, WO 00110566 - 2~ - PCT/US99/19265 h) C1_g ;alkoxy, i) OH
j) amino, k) cyano, or !) R2 and R3 taken together are -O(CH2)h-O;
wherein R,~ is a} H, b) C1_2 alkyl, c) F, or d} OH;

R~ is a) H, b) CF3, c} C~_3 alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) R~ and R~ taken together are a 5-, 6-, or 7-membered ring of the formula, o ,c-c, ~CH2~h U~ ' D
- in which D is S, O or NR86 in which R86 is H or C1_6 alkyl; or g) R~ and R~ taken together are -(GH2)k-, when R7 is an electiron-withdrawing group;
R6 and R7 at each occurrence are the same or different and are a) an electron-withdrawing group, b) H, c) CF3, d) C~_3 alkyl optionally substituted with one halo, e) phenyl, provided at least one of R6 and R7 is an electron-withdrawing group, or f) Rg and R7 taken together are a 5-, 6-, or 7-membered ring b of thE: formula, 1!
-c, ~CH2)r U iS
a) CH2, b) O, c) S or, d) NR~B;;
Rig IS
a) H or b) C~_5 alkyl;

wherein R8 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, g) N02, h) C~_s alkoxy, i) C~_6 alkoxycarbonyl, j) C~~ alkythio, k) C~_g acyl, i) -NR17R18~

WO 00/10566 - 27 - PCTlUS99/19265 NOH
ii m) -~wRs7 in which R87 is H or C~_g alkyl, n) C~~ alkyl optionally substituted with OH, sulfamoyl, C~_~
alkoxy, C~_5 acyl, or-NR~7R~8, o) CZ_g alkyl optionally substituted with one or two Rig, p) phenyl optionally substituted with one or two Rig, q) a 5- or 6-membered saturated ar unsaturated heterocyclic moiety having one to three atoms selected from the group consiisting of S, N, and O, optionally substituted with one or two R' g, or (cH~~-- w R~7 and R~$ at each occurrence are the same or different and are a) H, b) G~~ alkyl, c) C5~ cycloalkyl, or d) R~7 and R~8 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, C~_3 alkylv formyl, a 5- or fi-membered heteroaromatic moiety O
~~
containing 1-3 O, N or S, -C-NR88R89 in which Rgg and Rgg are each independently hydrogen or C~_6 alkyl, S02Rga in which Rgp is H or C~..6 alkyl, or C~_3 acyl optionally substituted with 1 or more F, CI or OH;

WO OOI10566 - 2$ - PCT/US99/19265 R1g is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, 9) N02 h) C1~ alkoxy, 't 0 i) C1 ~ alkoxycarbonyl, j) C1_6 alkythio, k) C1_6 acyi, I) C1-6 alkyl optionally substituted with OH, C1_5 alkoxy, C1_5 acyl, or-NR17R1$, 'I5 m) phenyl, n) -C(=n)NRzoR21~

o) -N R 1 ~R1 s, P) -N(R:2o)(-SO2Rz2), g) -SOz-NRzpR2l, or 20 r) -S(=O);Rz2 Rzp and Rz1 at each occurrence are the same or different and are a) H, b) C1 _g alkyl, or c) phenyl;
25 Rzz is a) C1~ alkyl, or b) phenyl optionally substituted with C1~ alkyl;
~x::~f.:

wherein Rg is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, g) NO~, h) C~~ alkoxy, i) C~_s alkoxycarbonyl, j) C'.~ alkythio, k) C~_6 acyl, I) -NR~gR2~~

m) C~..6 alkyl optionally substituted with OH, C~_~ alkoxy, C~_~

acyl, or -NR2gR~4, n) C2_8 alkenylphenyl optionally substituted with one or two o) phenyl optionally substituted with one or two R25, p) 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 R25, or G) (C

R23 and R24 at each occurrence are the same ar different and are a) H, b) formyl, - 30 - PCT/US99l19265 c) C~~ alkyl, d) C'.~ acyl, e) phenyl, f) C3~ cycioalkyl, or g) R~3 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, phenyl, pyrimidyl, G~_3 alkyl, or C~_3 acyl;
R25 is a) carboxyl, b) halo, c) -CN, d) merc:apto, e) formyl, f) CF3, g) N02, h) C~~ alkoxy, i} C~~ alkoxycarbonyl, j) C~~ alkythio, k) C~~ acyl, 1) phenyl, m) C~..6 alkyl optionally substituted with OH, azido, C~_5 alkoxy, G~_5 acyl, -NR32R33, -SR34, -O-S02R3~, or Rgg ~ ~ Nli-c0-O-, n) -C(=O)NR2gR27~

o) -NR''3R24' p) -N(R26)(-S02R22), 4) -SO~~-NR2gR27, or r) 'S(W~)iR22~

s) -CH~N-R2g, or t) -CH(OH)-S03R3~;

R22 is the same as defined above;

R26 and R2~
at each occurrence are the same or different and are a) H, b) C~_g alkyl, c} phenyl, or d} tolyl;

R2g is a) OH, b} benz:yloxy, c) -NH-C(=O)-NH2, d) -NH-C(=S)-NH2, or e} -NH-C(=NH)-NR29R3o;
Rz9 and R3p at each occurrence are the same or different and are a) H, or b) C~~ alkyl optionally substituted with phenyl or pyridyl;
Rg~ is a) H, or b) a sodium ion;
R32 and R33 at each occurrence are the same or different and are a) H, b) formyl, c) C~.~ alkyl, d) C~~ acyl, e} phenyl, f} C~~ 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 ~ subsirituted with, including on the nitrogen atom, phenyl, pyrimidyl, C~_3 alkyl, or C~_3 acyl, h) 'P~~,I(~R37}(~R38), or 'S~2'R39~
R34 is N"N 'N-N ~ N CN
N~ ~ ~-- ~--~N~ ~ (CH3)3C~S~ ~ ~ ~ N- , or I N' CH3 CHg CH3 R35 is C~_3 alkyl;
R36 1s a) C~~ alkoxycarbonyl, or b) carboxyl;
R3~ and R38 at each occurrence are the same or different and are a) H; or b) C~_3 alkyl;
R3g IS
a) methyl, b) phenyl, or c) tolyl;
wherein K is a) O, b) S, or c) NR4p in which R4p is hydrogen, formyl, C1~ alkyl, C~~ acyl, phenyl, C3_6 cycloalkyl, -P(O}(OR37)(OR3$) or -SO2-R3g in whicih R37, R3g and R3g are as defined above;

R10, R11, R12~ R13, R14 and R~~ at each occurrence are the same or different and are a) H, b) formyl, c) carboxyl, d) C1.~ alkoxycarbonyl, e) C~_$ alkyl, f) C2_$ ~alkenyl, wherein the substitutents (e} and (f) can be optionally substituted with OH, halo, C~_g alkoxyl, C~~ acyl, C~_~ alkylthio or C~_6 alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 7 0 carbon atoms optionally substituted with carboxyl, halo, -CN, formyl, CF3, N02, C~_6 alkyl, C'~ alkoxy, C~_6 acyl, C~_6 alkylthio, or C~~
1 ~ alkoxycarbonyl;
h) -NR4~R43, i) ORS, J) -S(=O);-R~5, k) -S02-N(R4s)(Ra7)~ or I) a radical of the following formulas:

UN- , ~~ , ~ ~~VN- , R48R49N ~/ \ N- R50 > > R51 HN N- Ray-(CHy)t-N N- R53-N N-or ~) , R~9 is the same as defined above;

T is a) O, b} S, or c) S02;
R42 and R43 at each accurrence are the same or different and are a} H, b) C3_6 cycloalkyl, c) phenyl, d) C~~ acyl, e} C~_8 alkyl optionally substituted with OH, C~_6 aikoxy 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 optianally substituted with OH, CFA, halo, -NO2, C~~
alkox -NR R o Y~ 48 49~ ar , o~
~'-R~
R5g-~H- ~ ar g) /-\ _ CG~Z)~
V IS
a) O, b) CH2, or c) N Rig;

R4g and R49 at each occurrence are the same or different and are a} H, or b} C~~ aikyl;

R~4 is a) OH, b) C~.~ alkoxy, or c) -NR~;7R~g;
R5~ is a) ~ H, or b) C~_7 alkyl optionally substituted with indoiyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C~=O)-NH2, -C02H, or -C(=NH)-NH2;
R5g is a) H, b) phenyl, or c) C~~ alkyl optionally substituted by OH;

R~7 and R~$
at each occurrence are the same or different and are a) H, b) C~_~ alkyl, c) C~_3 cycloalkyl, or d) phenyl;

a) C~_$ alkyl optionally substituted with C~~ alkoxy or C~_s 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, C~_~ alkyl, C1_5 alkoxy, or C~_5 acyl, b) ~N-(CHy)t-c) phenyl, or WO 00/x0566 _ 3s _ PCTIUS99/19265 d) pyridyl;
R45 is a) C~_'~ alkyl, b) C2_~~, alkenyl, wherein the substii:uents (a) and (b) can be optionally substituted with C~_6 alkoxycarbonyl, or a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, I

N, and O, c) an aromatic moiety having 6 to 10 carbon atoms, or d) a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group of S, N, and O, I

wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, -CN, formyl, CFg, -N02, C'_~ alkyl, C~~ alkoxy, C~_6 acyl, C~_6 alkylthio, or C~~

alkoxycarbonyl;

Rq,s and R4~ at each occurrence are the same or different and are ', a) b) phenyl, . ', c) C'_6 alkyl, or d} benzyl;

R5o and R~~ at each occurrence are the same or different and are a} H, b) OH, c) C~..6 alkyl optionally substituted with -NR4gR4s in which R~8 and R4~ are as defined above, d) Rip and R5~ taken together are =O;

R52 is a) an aromatic moiety having 8 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 with one or three -NOz, CF3, halo, -CN, OH, phenyl, C~_5 alkyl, C~_5 alkoxy, or C~_5 acyl, c) morpholinyl, d) OH, e) C~_6 alkoxy, f) -NR48R4g in which R48 and R4g are as defined above, g) -C{=)-RSg, or h) o~~
o a) H, b) formyl, c) C~-a alkyl, d) C1~ acyl, e) phenyl, f) C3_g cycloalkyl, g) -P{O.)(OR37)(OR3a), or h) -SO~R~g, in which R3~, R38 and R3g are as defined above;

R5g is a) morpholinyl, b) OH, or c) C~_6 alkoxy;
h is 1, 2, or 3;
i is 0, 1; or 2;

WO 00/10566 - 3$ - PCT/US99/19265 jis0,or1;

k is 3, 4, or 5;

r is 1, 2, 3, 4, 5 or Ei;

t is 0, 1, 2, 3, 4, 5, or 6;

a is 1 or 2; and Q is a) hydragen, b) halo, c) N 02, d) N3, e) C1-Ch alkylthio, O

f) C~-C,s alkyl-S-, O

g) C~-Cs alkyl-S-O

h) C1-Ch alkyl, i) C1-CE; alkoxy, j) formyl, O

k) C1-C,~ alkyl-C-, O

C~-C,; alkyl--O-C-, m) -suifamoyl (H2NS02-), 2Q n) -NHOH, O
o) C~-Cs alkyl-C-p-O
p) heteroaryl -C- in which heteroaryi is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, WO 00/10566 - ~9 - PCT/US99119265 G) C6H5 C-r) amino, s) C~-Cg alkylamino-, t) di (C.~-Cg alkyl)amino-, O
u) (C~-t:6) alkyl-C-NR6oR6~ in which Rgp and Rg~ are each independently hydrogen or C~-C6 alkyl, v) OH, w) cyano, x) hydroxy (C~-C6 alkyl), O
y) C~-C6 alkyl-S-C- , O
z) NC--(CH2)~ C- in which r is 1-6, O
aa} C6H~;CH2-O-C-, O
bb} C6H~, O-C- , ~OR~
N
cc) C~-C6 alkyl-~- in which R$4 is hydrogen or C~_6 alkyl, O
dd) RgSG~--(CH2)1_6--C- in which Rg~ is hydrogen, C~_g alkyl optionally substituted with one or more F, CI, OH, C~_8 alkoxy or C~_8 acyloxy, C~.~ cycloalkyl or C~_8 alkoxy;
N--OR~
ee) H"C"- in which R84 is hydrogen or C~_6 alkyl, ff} a substituted or unsubstituted C6-Cep aryl moiety, 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 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;

the substitu ents for such p, q, ff, gg and hh moieties being selected from 1 or 2 of the following:

1 ) halo, 2) C~_~ alkyl, 3) NO~"

4) Ng, 5) C~-Ca alkyl -S- , O
g) C~-to alkyl-S-O ' 7) formyl, O
8) C~-Ca alkyl-C- , O
9) C~-C;6 alkyl-p-C-, O
10) heteroaryl-C- in which heteroaryl is a 5- or 6-membered aramatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, O
11 ) C6H,~-C- , O
12) -(C~--C6) alkyl-C-NR6oR6~ in which R6p and R~~ are each independently, hydrogen or C~-C6 alkyl, 13) OH, 14) hydroxy (C~-Cg alkyl), O
15) C~-Cs alkyl-S-C-, O

16) NC-(CH2)~ -O-C- in which r is 1-6, O

17) C6H;;CH2-p-C- , 18) -CH2-Rgp in which Rgp is a) -ORg2 in which R32 is as defined above, b) -SRg2 in which R32 is as defined above, c) -NR32R~3 in which R32 and R33 are as defined above, or d) 5- or 6-membered heteroaromatic containing 1-4 O, S or N atoms, ~OR~

N

19) C~-C:6 alkyl-C- in which R84 is as defined above, 20) cyano, 21 ) carboxyl, 22) CF3, O

23} C~-C6 alkyl=C-O-O

24} C6N,;-O-C- in which the phenyl moiety may be optionally substituted by halo or (C1-Cp)alkyl, O
25) NR6~?R6.i--C- in which Rpp and R~~ are as defined above, O O
26) R~~-NH-C- or R9~-C-NH- in which Rp~ is a 5- or 6-membered aromatic heterocyclic group having 1-3 O, N or S, O
27) c6H~~cH2),..~-o-~-a 28) RgSO-~CH2)1_s-O-C-- in which Rg5 is as defined above, O
29) SiRs9R~ooR~a~-O-CH2-C- in which R9g, Rtoo and R~o~
are Each independently C'_6 alkyl; or Q and either R~ and RZ 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 oxazolidinone and isoxazoline antibiotics since they incorporate 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 E are antibacterial agents useful in the 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 compounds of formula I and pharmaceutical compositions containing said compounds in combination with pharmaceutically acceptable carriers or diluents.

WO 00/1OS66 - 43 - PCTlUS99/19265 DEFINITIONS
The term "pharmaceutically acceptable salt" as used herein is intended to include the non-toxic acid addition salts with inorganic or organic acids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric, malefic, acetic, citric, succinic, benzoic, fumaric, mandelic, p-toluene-sulfonic, rnethanesulfonic, ascorbic, lactic, giuconic, trifluoroacetic, hydroiodic, hydrobromic, and the like. These salts may be in hydrated form.
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 branched chains having the specified number of carbon atoms, e.g. in the case of C~-Cg alkyl, the alkyl group may have from 1 to 6 carbon atoms.
Similarly, terms such as "C2-C$ alkenyl" refer to at least one double bond alkenyl group having the specified number of carbon atoms, "C2-C$
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
the type CH3C-O- where the alkyl group can have the specified number of carbon atoms, e.g. C~-C~ 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.

WO 00/10566 - 44. - PCT/US99I19265 "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-pyrimidinyi, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyn, 3-quinolyn, 1-isoquinolyl, 3-isoquinolyl, 2-imadazolyi, 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- thiazolyi, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-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-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-tetrazoiyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 1-purinyl, 3-isothiazolyl, isothiazolyl, and 5-isothiazoiyl:
A saturated ar unsaturated heterocycfic group can have 1-3 atoms selected from O, N and S, e.g. dioxolane,, imidazolidine, dithiolane, oxathiolane, oxaz~olidine, piperidinyl, piperazinyl, rnorpholino or thiomorpholino, or the corresponding unsaturated heterocyclic groups.
Where possible nitrogen andlor sulfur atoms in such heterocyclic moieties may be oxidized and such oxidized compounds are intened to be encompassed within the formula I compounds.

Preferred embodiments of the present invention are the compounds of formula I wherein A is WO 00/10566 _ 45 _ PCT/US99/19265 Q _~_ in which Q~, R2, and R3 are as defined above.
A still more preferred embodiment of the present invention comprises a compound of the formula NON R~

IA
or a pharmaceutically acceptable salt thereof, in which Ry is H, C~_g alkyl optionally substituted with one or more F, CI, OH, C~_~
aikoxy, or C~_8 acyloxy, C3_6 cycloalkyl or C~_$ alkoxy;
R2 and R3 are each independently a) H, b) F, c) CI, d) Br, e) C~..~ alkyl, f) N02, g) l, h) C~..~ alkoxy, i) OH

j) amino, or k) cyano; and Q IS
a) hydrogen, b) halo, c) No2 d) N3, e) C~-C6 alkylthio, O

f) C~-G6 alkyl -S- , O

g) C~-C6 alkyl-S-, O

h) C~-C6 alkyl, i) C~-Cg alkoxy, j} formyl, O

k) C~-G6 alkyl-C-, O

I} C~-G6 alkyl-O-C- , O

m) C~-G6 alkyl-C-O-, O

n) heteroaryl-C- in which heteroaryl is a 5- or 6-membered aramatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, O

o) C6H~; C- , p) amino, p) C~-C6 alkylamino-, r} di(C~-C6 alkyl}amino-, O

s C -C alk i-C-NR R in which R and R are each } ~ 1 6} Y 60 61. 60 6'1 independently hydrogen or C~-C6 alkyl, t) OH, u) cyano, v) hydroxy (C~-C6 alkyl), O

w) C~-C:6 alkyl -S-C- , O

x) NC-~(CH2)~ -O-C- in which r is 1-6, O

Y) CsH~CH2-O-C- , z) C6Ha O-C- , N~OR8a aa) C~-C:6 alkyl-C- wherein Rg,~ is hydrogen or C~_g alkyl, O
bb) R8~C)-{CFi2)~_s-C- in which R85 is hydrogen, C~_8 alkyl optionally substituted with one or more F, CI, OH, C~_8 aikooy or C~_g acyloxy, C3_g cycloalkyl or C~_8 alkoxy, cc) H-C- in which R84 is as defined above, dd) ee) Y\~-~
X <~~~,-._ '~ _~ Y
X
Y~ '~.-X
,Z

WO 00/10566 _ 4$ _ PCTIL3S99/19265 9J) Y~ j x N
M
, hh}
x Y,.r' ~-,~--,N
Z
5 II}
X.
~ N. N
I
M
lJ) X ~l~ ~'N
,N
N
M
, kk}
x N. ~~J
M Y
~I}
~o~
N-N X
mm}
~ N~ N
~N J X
, nn}
~N
~N
~N'~
X
, WO 00/10566 _ 49 r PCTlUS99/19265 OO) N-N
~N
N
I
z in which R92 is H or C~~ alkyl, PP) ,s -~ -x N-N

qq) x ~~

-N
J

Y

rr) ~N,,N~X
~a Y

SS) r,.N
~
'~~ N

X , tt) x ~~ N

-N
'~-~ N

Y

uu) ,s, N
I~ X
~

j-vv) ~N~ N

~~ Y

X

WO 00/10566 _ 50 _ PCT/US99/19265 WW) X
.W., / ~1 < ~~J
N' Y
) ~~'iX
~y l z YY) oRs2 / w __)_ u}
~~H2)n i R63 E ~(t:H2)P
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, ~2 A1'a {CH2~~) Y
9gg) z2~ ~o, Y
~~~{CHI=~~
s WO 00/10566 _ 51 - PCT/US99/19265 hhh) Z3_~
.~.y Ny0)Y
Or Rss ~
N ' ~~rO,Y I
v..1~ .
, B is an unsaturated 4-atom linker having one nitrogen and three carbons;
M is a) H, b) C~_8 alkyl, c) C3_8 cycloalkyl, d} -(CH2)mOR66, or e) -(CH2)nNF~'67R68~

Z is a) O, b} S
or c) NM;

W is a) CH, b) N or c) S or O when Z is NM;

X and Y
are each independentiy a) hydrogen, b) halo, c) N02"

d) N3, e) C~_6 alkythio, O
c,-c:6 alkyl -S-, O
g) C~-C;6 alkyl-S-, O
h) C~-Cg alkyl, i) C~-C~ alkoxy, j) formyl, O

k) C~-C;~ alkyl-C---, O

I) C~-C:6 alkyl-O-C-O

m} 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

"
n) C6H;-,-,-C-, o) amino, p) C~-C6 alkylamino-, q) di(C~-Cs alkyl)arnino-, O

r) -(C~-~C6) alkyl-C-NRsoRs~ in which R6p and R~~ are each independently hydrogen or C~-C6 alkyl, s) OH, t) hydroxy (C~-C6 alkyl), O

u) C~-C~ alkyl--S-C-, O

v) NC-(CH2)~-O-C- in which r is 1-6, O

w) C6H;;CH2-O-C- .

O
X) CsH~-O-C- , N~ORg4 y) C~-t)6 alkyl-C- in which R~ is as defined above, z) cyano, aa) carboxyl, bb) CF3, cc) merc:apto, O
dd) C~-C;6 alkyl-C-O-O
ee) C6H5-O-C- in which the phenyl moiety may be optionally substituted by halo or C~-C6 alkyl, O
f~ C6Hs(CHz)~..sr0-C-, O
gg) R8~C)-(CH2)~-s C- in which Rg5 is as defined above, or O
hh) SiR99R~ooR~o~-O-CH2-C- in which R99, R~oo and R~o~
are each independently C~_6 alkyl; or Q and either R~ and R~ taken together form -O-CHz-O;
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, ar C~_$ alkoxy;
E is a) NRgc~
b) -S(=cJ); in which i is 0, 1 or 2, or c) O;

Rg3 IS
a) H, b) C~.~ alkyl, c) -(CH2)q-aryl, or d) halo;
R66 is H or C~.,~ alkyl;
Rg7 and Rgg are each independently H or C~~ alkyl, or NRg~Rs$ taken together arf: -(CH2},~-;
R6g is a) H, b) C' _6 alkyl, c} -(CH2)q-aryl, d) -GO~>R8~, e} COR~2, ~ -c(=O)-(cH2)g-c{~o)R$~, g) -S{=~~)z'C1_s alkyl, h) -S(=O}Z-{CH2)~-aryl, or i} -{C=O)j-Het in which j is 0 or 1;

Z~ is a) -CHI,-, or b) -CH(R7o)-CH2-;
Z2 is a) -O~S.-, b} -O-, c) -S-, d) -SO-, or e) -N(R~~)-;

WO 00/10566 - 5~ - PCT/US99/19265 a) S, b) SO, c) SO2, or a) o;
A~ is H or CH3;
A2 is a) H, b) OH-, c) CH3C02-, d) CHI-, e) CH30-, R~ZtJ-C Hz-C ( O)-NH-, 9) R73-C(O)-NH-, 1 ~ h) R~3-C(O)-NH-, i) (C~-C2)alkyl-O-C{O)-, or j) HO-CH2; or A1 and A2 taken together are a) Rs~ ~~o 0 ~ '~ or b) O=;
R~ is H or CHg-;
m is 4 or 5;
n is 0, 1, 2, 3, 4 or b;
yis0orl;
pis0, 1,2,3,4or5;
wisl,2or3;
q is 1, 2, 3 or 4;

WO 00/10566 - ~~ - PCT/US99/19265 zis0orl;
R6~ is a) R74C)C(R75)(R7s)-C(G)-~

b) R77GC(O)-, b ~) ~78(~)-~

d) R7g-aG2-, or e) Rsa-t~H-C(O)-;

R7p is H (C~-C3)alkyl;
or R7~ is a) R74GC(R75)(R7s)-C(~)-~
b) R~7G-C(G)-, c) R7$-C(O)-, d) H
e) H
H3C-C(G)-(CH2)2-C(G)-~
9) R7g-;302-, h) ~o~~ w .rr i) R$p-MH-C(O)-, R72 is a) HB
b) CH3, WO 00/10566 - 5,~ PCT/US99/19265 c) phenyl -CH2-, or d) CH3C(O)-;
R73 is (C~-C3)alkyl or phenyl;
R74 is H, CH3, phenyl-CH2- or CH3-C{O)-;
R75 and R?6 are each independently H or CH3, or R~5 and R76 taken together are -CH2CH2-;
R~~ is (C~-C3}alkyl or phenyl;
R78 is H, (C~-C4)alkyl, aryl-(CH2)n~, CIH2C, C12HC, FH2C-, F2HC- or (C3-Cg)cycloalkyl;
R79 is CH3; -CH2C1, -CHzCH=CH2, aryl or -CH2CN;
Rso is-(CH2)n1-aryl where n~ is 0 or 1;
Rg~ is a) H, b) C~~ alkyl optionally substituted with one or more OH, halo or CN, c) -(CH2)q-aryl in which q is as defined above, or d) -(CHI2)g-OR$3 in which q is as defined above;
Rg2 is a) C~_6 alkyl optionally substituted with one or more OH, halo or C1N, b) -{CH2)q-aryl in which q is as defined above, or c) -(CH2)q-OR$3 in which q is as defined above;
Rgg is a) H, b) C~_g alkyl, c) -(CH2}q-aryl in which q is as defined above; or d) -C{=~0) C'_6 alkyl; and WO 00/I0566 - 5$ _ _ PCT/US99119265 aryl is phenyl, pyridyl or naphthyl, said phenyl, pyridyl or naphthyl moieties being optionally substituted by one or more halo, -CN, OH, SH, C~~ alkoxy or C~.~ alkylthio.
Another preferred embodiment of the present invention comprises a compound of the formula ~ ~ ~ t O
N~N~R~
R ~3 IA O
or a pharmaceutically acceptable salt thereof, in which 'I0 R~ is H, C~_8 alkyl optionally substituted with one or more F, CI, OH, C~_a alkoxy or C.~_$ acyloxy, C3_6 cycloalkyl or C~_8 alkoxy;
R2 and R3 are each independently H or F; or R2 and R3 taken together represent o~..
~o~ .
Q is a} hydrogen, b) halo, c} N3, d) NOz, e) C~-Cg alkylthio, O

f) C~-C6 alkyl-S-, O
g} C~-Ca alkyl-~-~ ' h) C~-C6 alkyl, i) C~-C6 alkoxy, .

j) formyl, O
k) C~-C;6 alkyl-G-, O
C~-C;6 alkyl-O-C-O
m) C~-C;s alkyl---~-O-n) (C~-C6 alkoxy)2N-, o) 5- or 6-membered heterocyclic containing '!-3 O, N or S and linked to the phenyl substituent via a carbon or nitrogen, said heterocycle moiety being optionally substituted by R96, ,O H
N
P) C~-C;s alkyl-~C
q) phenyl optionally substituted by Rg6, or r) 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 R96 is a) C~-C6 alkyl-OH, b) C~-C:6 alkyl-O-C-, O
O
c) CH3._C- C~_C6 alkyl-C-, O
d) cyano, e) formyl, N.OH
H_C_ O
g) C~-Cs alkyl-O-C-, WO 00/10566 - 6o PCT/US99/19265 O
h) SiR99R~ooR~o~"O-CH2-C- in which R99, R~oo and R~o~
are each independently C~~ alkyl, O O
i) CH~._S- C~-C6 alkyl-S-, j) HC=CCH20C-, O
k) C6H;;-O-C- where the phenyl may be optionally substituted by halo, O
f) HO-CH2-C- , m) (C~-C6 alkyl)2N-, n} C~-C,o alkyl-NH-, 0) amino, O
p) Ci-C6 alkyl-S-O
q) C6H~CH20C- or O
r) R98-~C- in which Rgg is phenyl, 5- or 6-membered heteroaryl containing 1-3 O, N or S and linked to the phenyl ~ 5 subst:ituent via a ring carbon atom or 5- or 6-membered saturated or unsaturated heterocyclic containing 1-4 0, N or S and finked to the phenyl substituent via a ring carbon atom..
Some speciiric preferred embodiments of the present invention are listed in the table below.

WO 00/10566 ' 6,~ _ PCT/US99/19265 o ... ~O N
~,U
O
O"
'~''~/ ~ a F w 1.-NO N
a O
O
,/S '/ O

w ~ NO N
O
O
.. IS / O

w ~ NO N
O
O
Oi ~N / 0 F ' P H
NON
OO
~N / 1 0 F .-.., ~NO N
a S
O
O
O H
uN
O
NOH
/ O
O N
U
O
/o ~ / ' a w NO N
~/
O

WO 00110566 _ 62 w PCT/US99119265 / o N N
U
p ~O

~o ri N
/ O
~N 1 H N

O
ta3uMezSiO~ ~ ~ ~ O
~ P H
O
O~
~ /-'. ~O

N3 ~ O
''-NO N
O
N=N
FIO' J N / O

N N
U
O
N=N
t / 1 a a ~-.. , o M
N~

N=N
~33C~N
O ' N N
U

WO OOIIOSb6 _ 63 ' PCT/US99/19265 N=N
O
PJC''~N
''-N N
a O
O
EIZN / ~ ~ N N
O
f'~~N / O
rl' O s ~ O
H
'v/
O
O
O
N N
U
O
H I~N / O
IHC~
~N N
O
O

v ~~
O
HN~ O
~N
w ~N N
\/
O
O
O
HsC ~ ~N 0 sC.~O ~ ~ ~ ~ N~N~CHs HOC p O
O~ O
N / ~
~N N
O

WO 00/10566 _ 64 _ PCT/US99I19265 s~ / o NO N
U
O
S ~ O
F ~ 1' N N
U
O
/ O
F '\ ~ NO N
O
/ O
W
F w ~1V N
a O
NC"~ / ~ O
w ~N N
a O
/ O
~.. N
U
O
H''~ / O
.~N H
O
O
''-N N
''~ ~a t,~~ / o ~N ~
~F
IIO

WO 00/10566 _ 6~ _ PCT/US99/19265 o ~N N
O
O
~N N
O
O

n ./O ~ O
N N
O
F
p F ~ ' N N
O
O
N N
a O
N U / O
~' ~ NO N
\/
a o NP N
\/
1 ~ o NO N
U
O

- fib -o o N N
O
O
W ~O N
\/
O
/ O
O W ~ O H
NON
ll~fO
O
O F w ~ ~ O
~N N
U
O
Br / O
O
N N
U
O
/ O
CI
O
CI / O
W ~N N
O
O
F '-N O N
O
/ O
HsC w ~ NO N
O

o / t o ~ No ~.~C~N O
O ~ ~ ~O H
O
~C iS~tJ~.~N-i~j.--r \ ~
O ~/, \~ ; ~N~N~~
i:
n a ~ - ,, , ~o HaC tJ~N \ /.'.-~~N~./N~CHa O

o /-1 ~ ,,1 0 O
O
O /'-~. i= , _ t\ N N--C' ~~~---;. O
1\'r-p~ ~'~- ~= :~N~N~/~
,~. O

, !1 ;N /r.~0 ' i / \' N~N~~
~O
N,O
O
O ~~. ~. 0 ~'--N 'N ~
'''; ~N~NU~a O
O
\'~N ---~~,'N~\
O~ /~, O
O

WO 00/10566 _ 6$ _ PCT/US99/19265 0/~'1 L N / o F \ ~ NON H
O
C~ / O
F w ~N . N
~ ~'a O
O/~ / O
~N N
~F
O/
O
/~
F \ ~N N
v O
O/ O
/~
F ~ ~N CF3 O
F
O/

F ~.' ~ NO N
\/
O
F
O
F '-N N
v 1/
Il0 O
NO N
O
O
NO N
O

WO 00/10566 - 69 _ PCT/US99/19265 / o N N
O

F \ I N N
\/
S~
/ o I
F ~ N N
U
O
O:aS ' O
~N / ~
N N
a O
O
O
/ I
O
N N
O
O
I
C$ / O
F ~ ~ NO N
O
~:S O
I
~O H
~,j~N~
1~~(O
O
O/:~N / I O
~.. ~O H
51~--NON
l~~fO
HN \ O
~N / t F \ 'NO H
O

WO OO/1O5b6 PCT/US99/19265 ~ ' ,~ o -N N
° ~.._..,/ ~ / ,~~N N
F/
O
O
r~C~S-N .~.,,N J~,.-c., O
O
~,i N~~ N
O

O~N~.N ~..~-.-/~O
,/~ ~~N~N
F
O _ \~--.N~,vN ~,-,., , O
I
O ~ ~~-"NON
F~ ~ ~
HC: O
O
HsC .~0~ /_-\~N~~N-; "--.! 10 ~NVN~~~~
F
O
O
r--~
~N N~' ''\. i ~N~N
F
O
O
i~
Ii~C~o~N~ N~~~i~ O
\:~ N~ N
F

O
O'~N ~'~.N-~ ~ ,~~0 ~,C~ ~ '~ ''. ~'' ~'\';i N N
~!'~s F~ ;i O
O
O\ ~\ ~,,., ~~ O
HO ~ \'jN~j~'~.~N~N C
F~
O

~~N~ ~
'~ w './N ~ ~ O
O
~ H
NON
~,'(O
NC~N / . I O
\ O
H
N~H~CH3 ~O
H3C.0 N
N / O
H
O H
N~N~CH~
~O
O'I
HsC~H.N I " N
O
H
O
N,v N"CHs ~O
IEtO~ N
/ O
O \( p H
N~,N~CH3 ~O
N
NC~N / I O
~ H
N~N~CH3 ~O
cN
/ I O
O
1 N~N~CH3 ~O

WO 00/10566 _ 72 _ PCT/US99119265 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 described herein are representative in nature and that alternative procedures are feasible.
Isoxazolinemes 5 of the present invention are preferably prepared via the sequence outlined in Scheme 1. Aryl acetic acids 1 are either 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. ~rg. Chem. 7 984, 49, p. 4287-4290]. Reaction of 1 with sodium hydride and ethyl formate provides 2 which is in turn reacted with hydroxylarnine yielding 3. Treatment of 3 with milts base, preferably potassium carbonate, in an appropriate solvent, preferably dichloromethane or N, N dimethylformamide followed by addition of 4 {prepared by methods described by Barnes et al in US Patent 5, 284, 863) provides isoxazolinone 5.
Schr~ma 4 NaH Ar~C02R H2NOH
Ar~t:02R '~' ...
EtOCHO CHO

o KZCOg Ar Ar ~O \ N
AcOCH2NHCOR' -NH 4 \--NH
R

WO 00/IOSG6 - 73 PCTlUS99/19265 An alternative way to prepare aryl acetic esters 1 of the present invention is shown in Scheme 2. Treatment of tritlate 6 {prepared from methyl 4-hydroxyphenyl acetate by methods known by those skilled in the art) with an N, N dialkylamine in the manner described by Buchwald [Tet. Lett., 1997, ;38, p. 6363-6366] produces esters exemplified by ?.
Aryl-bromides, -iodides, and -chlorides are also suitable as replacements for triflate 6 in Scheme 2. The N, N dialkylarnines used in Scheme 2 are either commercially available or are synthesized by literature procedures.
Literature preparations of many cyclic N, N- dialkylamines have been detailed by Gadwood (V110 97110223) and others are well known to those skilled in the art.
Scheme 2 Tf0 ~ pd° R2N
C02Me R2NH ~ / C02Me Another alternative to prepare aryl acetic esters 1 of the present invention is shown in Scheme 3. Treatment of 8 with a mild base, preferably potassium carbonate, and a primary or secondary amine or thiolate, in a suitak~le solvent, preferably acetonitriie 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).
This sepuence is alsa 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 - ~4 - PCT/US99l19265 Scheme 3 x~' x2 Base CH3CN or DMF x O RR'NH or RSNa O

x2 Sulfur ~ \ S For 11: KOH {aq) morpholline X I i or For 12: HCI, EtOH
O

p x9~~~~oR~ L = NRR' or SR
X~=HorF
X2=H orF
11: R"=H
12: R"=Et .~ H;' EtOH
5 Sulfoxides and sulfones 14 and 9 6 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 they art and exemplified by Barbachyn [J. Med. Chem., 7 996, 39, 680-685).
'i 0 Scheme 4 S C) (O~S~
~N / 1 ~ ~ m-CPBA (n=1) 1~N / ' o ~( o X~ ' ~.N~ or X~
NH Os04, NMO (n=2) L--NH
R R
13 ~ 14: n=1, 2 X~=HorF
X2=HorF
XZ X
/ c~ to)n z o s ~ ~s /
o m-CPBA
X~ ' 'N X~ ' N
\--NH \-NH
R~ , O R
1S 16: n=1, 2 0 An alternative method of preparing compound 18 of the present invention is shown in Scheme 5. Treatment of 1? with an appropriate organostannane provides 18. This method is known by those skilled in the art as the StillE: cross-coupling reaction.
Scheme 5 x x ~ o RSnBug R
Pd° x ~ ~ ~°
\_NH DMF '-NH
17 Q R 1$ p' R, WO 00/10566 _ 7~ , PCT/US99/19265 Preparation of 21, 22, 23, and 24 of the present invention is described in Sch~:me 6. Treatment of 19 with trifluoroacetic acid provides 20. Compound 20 is treated with an acid chloride, chloroformate, sulfonyl haiide, or isocyanate in the presence of triethylamine by methods well 5 known in the chemical literature to provide 29, 22, 23, and 24, respectively.

WO 00/10566 - 77 - PCTli1S99/19265 Scheme 6 Bx, ~N % HN~ / O
O
_ ~ TFA
X ~ ~O -.----~ ~ 5, O
N x v ~N
~--NH ~NH
~-R. R.
19 p~ 20 O
O
RCOCI x R~ N~ 0 ~N /
x 'w.
i N
~NH
-R' O
~ X
RO" N~ O
~N
X w ~.O
i N
~-NH
--R' O
R~O.N~ X O
~N i ~
x -., ~ .o N
~--NH
R

O
~ X
R'RN~N~ O
~N
X w ~ _O
i N
~-NH
R

The triazolE:-substituted compounds 27 and 28 are prepared by cyclization of the azide 25 with acetylenes 26 (Scheme 7). This is a WO 00/10566 - 7$ _ PCTlUS99/19265 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, T7, 1689].
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 solvents for trituration include but are not limited to methanol, ethanol, diethyl ether, and acetone.
Scheme 7: 1,2,3-Triazoles N_-_N
R~N / O

N / ~ O H ~ R \ , ~ H
26 N~N~R' ~+
H H R. DMF, rt-80 °C 27 O
N=N
O
R ~ C
~o N~N~R' 15 2s o0 The azidophenylisoxazolinone 25 is reduced to aminophenylisoxazolinone 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 aminophenylisoxazoEinones 29 with 2,5-dimethoxytetrahydrofurans 30 in acetic acid provide pyrrole-substituted isoxazolinones 31 (Scheme 8). Subsequent conversions of the pyrrole (R = (~HO) are also possible, for instance the corresponding oxime can be prepared by refluxing with ~0 % aqueous hydroxylamine in methanol.
Scheme 8: Pyrrotes Na / ~ O HxN
O
\ o H SnClx~2H20 \ O

N~N~R" 1 N N R' 2s o 2s R ~_ R
N / O
/~
HgCO O OCH3 30 \ p acetic aced, reflex, 0.5 h , N ~ ~ R' O
N-thioacetates 33 may be prepared from the corresponding N-'10 acetates 32 using a variety of welt known literature methods, for instance by refluxing in benzene with Lawesson's reagent. Other solvents such as toluene and xylene are also suitable.
Scheme 9: Thioacetates O i_awesson's O
Reagent Ar Ar o H benzene, reflex ~ H
NvN, CH3 ~ NON CHg It will be understood that where the substituent groups used in the above reactions contain certain reaction-sensitive functional groups which WO 00/1O5b6 - $~ - 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 Prytective Groups in Qrganic Synthesis, Theodora W.
Greene (John WiiE:y & 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.
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 wil! be appreciated that certain products within the scope of 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 racemtc forms.
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 l , or pharmaceutically acceptable salts or prodrugs thereof, are potent antibiotics active against gram-positive bacteria.
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 medical and denta'd equipment, they are especially useful in the treatment WO OO/1O5b6 - $1 - PCTIUS99119265 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 used alone or forrnulated 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 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 additiives such as suspending, stabilizing and dispersing agents. The compositions may be in ready-to-use form or in powder form 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 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 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 particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of WO 00/1O5b6 _ ~2 - PCT/US99/192b5 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 mglday to about 2 glday.
The preparations of pyrazoles substituted compounds are outlined in Scheme 10. Compound 29 was diazotized and then reduced to form hydrazine hydroclhloride salt 34 via one of the many well known methods in the chemical literature including but not Limited to the treatment with sodium nitrite andl stannous chloride. Treatment of 34 with 9 0 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 provides compound 35.
Scheme 10: Pyrazoles NaN02, SnClz . 2H20 H2N / \ , o N~ NH(CO)R' HCi R
O
OHC~CHO
H2N-HN / \ , O ~"".
~ HCI N~ NH(CO)R' NaHC03 ~N~N / \ o ,N
R ~ NH(CO)R' WO 00/10566 - $3 - 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 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 (NCCL,S). Mueller-Hinton medium was used except for 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%
C02).
The M1C was defined as the lowest drug concentration that prevented visible growth.
Microorganism MIC value in ug/ml I i S. pneumoniae A9585 ~ g E. faecalis A20688 ~ < 16 S. aureus A15090, penicillinase positive i < 16 ILLUSTRATIVE EXAMPLES
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:

WO OOIlOS66 - $4 - PCT/US99/19265 h - hour(s) mol - mole(s) mmol - mmole(s) 9 - gram(s) min - minute(s) - room temperature THF - tetrahydrofuran - liter(s) mL - milliliters) Et20 - diethyl ether EtOAc - ethyl acetate MeOH - methanol DMF - dimethylformamide 15 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 nuctear magnetic resonance (~ H and ~3C NMR) spectra were recorded on a Bruker AM-300 or a Varian Gemini 300 spectrometer. All spectra were determined in 20 CDCl3, DMSO-dg, CD30D, or D20 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 25 doublets; dt, doublet of triplets; and app d, apparent doublet, etc.
Infrared spectra were determined on a Perkin-Elmer 1800 FT-IR spectrometer from 4000 cm-~ to 400 cm-~, calibrated to 1601 cm-~ absorption of a polystyrene film, and are reported in reciprocal centimeters (cm-~). Mass spectra were recorded on a Kratos MS-50 or a Finnegan 4500 instrument 30 utilizing direct chemical ionization (DCI, isobutene), fast atom bombardment (FAB), or electron ion spray (ESl). Ultraviolet spectra were determined on a Hewlett Packard 8452 diode array spectrophotometer in the solvent indicated.
Analytical thin-layer chromatography (TLC) was carried out on precoated silica gel plates (60F-254) and visualized using UV light, iodine vapors, andlor staining by heating with methanolic phosphomolybdic acid.
Column chromatography, also referred to as filash chromatography, was performed in a glass column using finely divided silica gel at pressures 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.

N-[[4-(4-methylthi~henyl)-5-oxo-2-isoxazolinyl]methyl~acetamide / ~ 1 0 NON
O
A. Ethyl4-methylthiophenylacetate To a solution of 4-methylthiophenylacetic acid (1.0 g, 5.48 mmol) in 55 mL of ethanol eras slowly added a catalytic amount of concentrated sulfuric acid. The mixture was stirred at room temperature overnight and 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%). ~ H NMR (300MHz, CDC13} b 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. Ethyl4-methylthio-a-formy!-phenylacetate A suspension of NaH (0.84 g, 20.8 mmol) was added at room temperature to a solution of ethyl 4-methyithiophenylacetate (1.1 g, 5.2 mmoi) 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 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-phenylaceitate as a coioriess oil, which was used in the next step without purification.
C. 4-(4-methytthio)-phenylisoxazolin-5-one To a solution of ethyl 4-methyithio-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 a precipitate, which was then further triturated with ether to yield 0.48 g (two steps, 44%) of a pale yellow solid. ~ H NMR (300MHz, MeOH-d4) &
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 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 mmoi). The mixture was stirred at room temperature for 18 hours. It was then poured into 10 mL of 1 N HCI and extracted three times with chloroform. The organic layer was then washed with sodium WO 00/10566 - $7 - PCT/US99/19265 bicarbonate, brine, dried over magnesium sulfate, filtered, concentrated to yield a tan solid, which was then recrystallized with hexanelchiorofom~.
The resulting solid was further purified by triturating with ether to yield 0.18fi g (69%) of a tan solid. ~ H NMR (300MHz, DMSO-d6) 8 8.93 (s, 1 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, 3 H), 1.84 (s, 3 H).

N-~t4-(3-fiuoro-4.-oxido-4-morpholin-4-ylphenyl)-5-oxo-2-hydroisoxazol-2_ yl~methyl}acetamide o~*.o' MMPP ~ , F v 1! 'O
~N~N
O
15 To N-{[4-(~~-fluoro-4-morpholin-4-y(phenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (200 mg, 0.60 mmol) in 50 mL methanol was added magnesiurn 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 plug of basic alumina with dichloromethane. The eluant was concentrated and recrystallized from dichloromethane ! hexanes to afford 162 mg (44%) of ithe title compound as a brown solid. ~ H NMR (DMSO-d6; 300 MHz) 8 9.19 (s, 7 H), 9.02 (t, J = 6.1 Hz, 1 H), 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), 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); ES1 (M+H)~=352.

WO 00/1OS66 - $$ - PCTIUS99/19265 N-({4-[4-(methylsulfinyl)phenyl-5-oxo-2-hydroisoxazol-2-yl}meth~~l)acetamide iS ~ C) i O m-CPBA
_N~-N
O
To N-~[4-(~G-methylthiophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamiide (1.0 g, 3.6mmol) in 50 mL chloroform at 0°C was 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, filtered and concE~ntrated. The residue was triturated with ether providing 800 mg (79%) of 'the title compound as a colorless solid. ~ H NMR
(DMSO-dg; 300 MHz) b 9.11 (s, 1 H), 8.96 (t, J = 6.1 Hz, 1 H), 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.

N-(~4-(4-(methylsulfonyl)phenyl-5-oxo-Z-hydroisoxazol-2-~rl}methyl acetamide WO 00/10566 - $9 - PCT/US99/19265 O m-CPBA
~N~N N
o O
To N-~[4-(4-methylthiophenyl)-5-oxo-2-hydroisoxazol-2-ylJmethyl}acetam~de (200 mg, 0.72 mmol) in 20 mL chloroform at 0°C was 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 extraECted with chloroform. The organic layer was washed with brine, dried aver magnesium sulfate, filtered, and concentrated. The residue was precipitated from acetone / 1:1 hexanes : ether providing 112 mg (50%) of the title compound as a colorless solid. ~H NMR (DMSO-ds;
300 MHz) S 9.24 I;s, 1 H), 9.01 (t, J = 6.1 Hz, 1 H), 8.02 (d, J = 8.6 Hz, 2H}, 7.91 (d, J = 8.6 H:z, 2H), 5.11 (d, J = 6.2 Hz; 2H), 3.20 (s, 3H), 1.86 (s, 3H); ESI (M+H) +~=311.

\ o N-(~4-j4-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))-3-fluorophenyl] 5 oxo 2-hydroisoxazol-2-yt}methyt)acetamide oa~
~N \ O
oso4 H NMO F ~ N H
N~ ~N~

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 pl; 0.07 mmol). After 18 hours at ambient temperature saturated sodium bisulfite was added and the reaction mixture was extracted with 4:1 chloroform:methanol. The organic layer was concentrated providing 85 mg {77%) of the title compound as a colorless solid. ~ H NMR (DMSO-d6;
300 MHz) 8 8.95 (s, 1 H), 8.92 (t, J = 6.2 Hz, 1 H), 7.62-7.51 {m, 2H), 7.17 (app t, J = 9.2 Hz, 1 H}, 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.

4-(3-Fluoro-4-morphotin-4-ylphenyl)-2-{[(thioxoethyl)amino]methyl 2-hydroisoxazol-~5-one ~N
O' Lawesson's ~ N ~ O
/ ~O Reagent i benzene F ~ ~ H
reflux NON
IOI ~(S
A mixture of N-{[4-3-fluoro-4-morpholinylphenyl-5-oxo-2-isoxazolinylJmethyl}acetamide (0.25 g, 0.75 mmol) and Lawesson's reagent {0.4 g, 1.0 mmoi) 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%): ~H NMR (300 MHz, CDCi3} 8 8.61 (br s, 1 H), 8.49 (s, 1 H), 7.50 {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).

N-{(4-(4-acetyl~ahenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide O
-N N
O
To N-{(4-phenyl-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (3.0 g, 12.9 mmol) and aluminum (Ill) chloride (13.8 g, 103.4 mmol) in 150 rnL
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
for 3.5 hours, cooled to ambient temperature, and poured over 10 minutes into a rapidly stirring mixture of 20% methanol/chioroforrn and 1 N
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 the combined organics were then washed successively with 1 N 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 resultant precipitate was filtered to provide 2.48 g (70%) of the title compound as a pale pink solid. ~ H NMR (DMSO-ds; 300MHz) 8 9.18 (s, 1 H}, 9.00 (t, J = Ei.1 Hz, 1 H), 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); ES1 (M+H)~=275.

N-(~4-[4-((hydro~yimino)ethyl)phenyl-5-oxo-2-hydroisoxazoi-2-yi}methyl)acetamide HO-N
1 / ' O
~, -O
~N~N
O
A mixture of N-{[4-(4-acetyfphenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (2.0 g, 7.3 mmol} and 50% aqueous hydroxylamine (1.0 mL, 14.6 mmol) was heated to reflex for 1.5 hours, concentrated to near dryness and redissolved in 20% methanol/chloroform. Hexanes were added until i:he 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. ~H NMR (DMSO-d6; 300MHz) 8 11.21 (s, 1 H), 9.01 (s, 1 H), 8.96 (t, J = 6.2 Hz, 1 H), 7.78 (d, J = 8.6 Hz, 2H), 7.fi6 (d, J = 8.6 Hz, 2H), 5.04 (d, J = 6.2 Hz, 2H), 2.19 (s, 3H}, 1.84 (s, 3H}; ESI (M+H)+=290.

N.~[4-(4-(2-furyl)phenyl)-5-oxo-2-h~,rdroisoxazol-2-~rl]methyl}acefiamide O O
O
' ~N N
a O
Nitrogen was bubbled through a mixture of N-{[4-(4-iodophenyl)-5-oxo-2-hydroisoxazol-2-ylJmethyi}acetamide (300 mg, 0.84 mmol), 2-tributylstannylfur~an (0.26 mf_, 0.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (77 mg, 0.08 mmol), triphenylarsine (~i1 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) in 5 mL DIMF. The reaction mixture was capped and allowed to stir at ambient tempE:rature for 8 hours, at which time it was diluted with 20%
10 methanollchloroform, filtered thru celite and concentrated. The residue was suspended in chioroform, loaded onto a Biotage flash 40i chromatography module {12M) thru a frit, and eluted with 50%
hexanelethyl acetate providing a solid which was triturated with chloroform/ether to provide 132 mg (53%) of the title compound as a 15 colorless solid. ~ H NMR (DMSO-dg; 300MHz) 8 9.00 (s, 1 H), 8.94 (t, J =
6.0 Hz, 1 H), 7.82 {d, J = 8.4 Hz, 2H), 7.74-7.70 (m, 2H), 6.95 (d, J = 3.2 Hz, 1 H), 6.60-6.59 (m, 1 H), 5.04 (d, J = 6.1 Hz, 2H), 1.85 {s, 3H); ESI
(M+H)+=299.

N-~[5-oxo-4-(4-(2-thienyl)phenyl)-2-hydroisoxazol-2-r~ll methyl}acetamide O
s ~ 1 ~ -o ~N~,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-tributylstannylthiophene (0.27 mL, 0.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (77 mg, 0.08 mmoi), triphenylarsine (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) in 5 mL DAIfF. The reaction mixture was capped and allowed to stir at ambient temperature for 8 hours, at which time it was diluted with 20%
methanollchloroform, filtered thru celite and concentrated. The residue was suspended in chloroform, loaded onto a Biotage flash 40i chromatography rnodule (12M) thru a frit, and eluted with 15%
acetonelchloroform providing a solid which was triturated with chloroforrnlether to provide 165 mg (63%) of the title compound as a colorless solid. ~ hI NMR (DMSO-d6; 300MHz) 8 9.00 (s, 1 H), 8.95 (t, J =
6.0 Hz, 1 H), 7.81 (d, J = 7.3 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.54-7.52 (m, 2H), 7.15-7.1 if (m, 1 H), 5.04 (d, J = 6.1 Hz, 2H}, 1.85 (s, 3H); ESI
(M+H)+=315.

N-~[4-(4-(2H,3H-1,4-dioxin-5-yljphenyly-5-oxo-2-hydroisoxazol-2-yI]methyl}acetamide WO 00/10566 - g5 - PCTIUS99/19265 ~O

o ~ 1 '--N N

Nitrogen was bubbled through a mixture of N-{[4-(4-iodophenyl)-5-oxo-2-hydroisoxa:~o1-2-yl)methyl}acetamide (300 mg, 0.84 mmol), 2-(tributylstannyl)-5,6-dihydro-[1,4]-dioxin (346 mg, 0.92 mmol), tris(dibenzylideneacetone)dipalladium(0) {77 mg, 0.08 mmol), triphenylarsine (5'I 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 20% methanollchloroform, 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% methanollchloroform, adsorbed onto silica gel and loaded into a Biotage flash 40i chromatography module SIM.
Chromatography was performed using a 12M silica gel cartridge eluting with 20% acetone~'chloroform providing an amber oil which was triturated with ether, yielding 1'15 mg (44%) of the title compound as a tan solid. ~H
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, 1 H), 5.01 (d, J = 6.2 Hz, 2H), 4.22-4.19 {m, 2H), 4.10-4.07 (m, 2H), 1.85 (s, 3H); ESI (M+H)+=317.

N-{[5-oxo-4-(4-pyrazin-2-ylphenyl)-2-hydroisoxazol-2-~methyl3acetamide ~N
d O
~N ~ 1 -N 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-(tributylstannyl)pyrazine (340 mg, 0.92 mmol), Iris(dibenzyiideneacetone)dipalladium(0) (77 mg, 0.08 mmol}, triphenylarsine (5'I 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 20% methanol/chloroform, 10% aqueous potassium fluoride was added and the mixture w,as allowed to rapidly stir for 1 hour. The reaction mixture was filtered thru celite and concentrated. The resultant black oil was dissolved in 2,0% methanollchlorofoml, adsorbed onto silica gel and loaded into a Biotage flash 40i chromatography module SIM.
Chromatography vvas performed using a 12M silica gel cartridge eluting with 25% acetonelchloroform providing an amber oil which was triturated with ether, yielding 52 mg (44%) of the title compound as a colorless solid. ~ H NMR (DMSO-dg; 300MHz) 8 9.28 (d, J = 1.4 Hz, 1 H), 9.11 (s, 1 H), 8.97 (t, J = 6.1 Hz, 2H), 8.71 (app t, J = 1.9 Hz, 1 H), 8.59 (d, J =
2.5 Hz, 1 H), 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.

N-~[5-oxo..4-(4-{4~-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ace~t~Ijpiperazinyl~phenyl)-2-hydroisoxazo!-2-yl]methyl~acetarnide t BuMe2SiO~N~
' N / O
~/
'~ , 0 NON
~'O
To N-{[5-oxo-4-(piperazinylphenyl}-2-hydroisoxazol-2-yl]methyl}
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-butyldimethyisilyloxy)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 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. ~H NMR (methanol-d4; 300 MHz) 8 8.49 (s, 1 H), 7.fi6 (d, J = 8.8 Hz, 2H}, 7.00 (d, J = 8.8 Hz, 2H), 5.07 (s, 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.

N-[(4-{4-[4-(2-h~droxyacetyl)piperazinyl~phenyl}-5-oxo-2-hydroisoxazol-2-yl)methyl]acetamide WO 00/10566 - 9$ - PCT/US99119265 o HO~
N O
~N
~NO N
O
To N-{j5-oxo-4-(4-{4-[2-(1,1,2,2-tetramethyl-1-silapropoxy)acetyljpiperazinyl}phenyl)-2-hydroisoxazol-2-yi)methyl}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, fiiltered and concentrated. The 10 residue was triturated with ether to provide 92 mg'(40%) of the title compound. ~H NMR (DMSO-d6; 300 MHz) 8 8.87 (t, J = 6.2 Hz, 1 H), 8.74 {s, 1 H), 7.63 (d, ~' = 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, 1 H), 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); ES1 (M+H)+=375.

N-{j4-(4-azidoph~enyl)-5-oxo-2-hydroisoxazol-2-yi]methyl}acetamide) O
N3 / \ N N
\/
O
Prepared from ethyl 4-azidophenylacetate according to the general route outlined in ~>cheme 1. The starting material was prepared as follows:

WO 00/10566 - 9~ - PCT/US99/19265 Ethyl 4-Azidophenylacetate NaN02, TFA, NaN3 H2N~ OEt N3 OEt 0°C
5 Following the general procedure of Marchesini (J. Org. Chem. 49, p. 4287-4290, 7 984), sodium nitrite (38 g, 0.56 mol) was slowly added to a stirred and cooled (0°G) 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°(: for another 0.5 hour and then sodium azide (27 g, 0.42 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 ~:xtracted 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. ~H NMR (300 MHz, DMSO-dg) 8 7.31 (d, J = 8 Hz, 2 H), 7.07 (d, J = 7 Hz, 2 H), 4.07 (q, J = 7 Hz,2H),3.66(s,2H),1.17(t,J=7Hz,3H).

N-[(4-{4-[4-(h~dr~oxymethyij(1,2,3-triazolylj]phenyl}-5-oxo-2-hydroisoxazol-2~)methyl]acetamide / \
~N'N ~ ~ H
N / N~,N
OH 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 - PCTIUS99119265 1.71 mmol) in 3 rnL 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 ~H NMR spectra indicated that the crude product was a mixture of two triazole isomers.
These isomers were separated by preparative HPLC (HzO/MeOH) to yield 10 mg (10°/<>) of the title compound as a white solid. ~H 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.t)7 (d, J = 6 Hz, 2 H), 4.61 (s, 2 H), 1.86 (s, 3 H).

Methyl 1-(4-~2-[(acetylamino)methyl]-5-oxo-2-hydroisoxazol-4-yt~phenyl)-1,2,3.~triazote-4-carboxylate N-N
H3C0 ~ p i~ N /
O ...'.. 1 ~O H
NON
~0 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 its more reliable involves conducting the reaction at room temperature for 10 days and then isolating as above.) ~ H NMR {300 MHz, 25 DMSO-dg) 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}.

N-({4-j4-(4-acetyN(1,2,3-triazolyl)}phenyll-5-oxo-2-hydroisoxazo_1_-2-yl~methyt acetamide NN-N ~
N~,N
Oi w ~~'(O
A mixture of N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2-ylJmethyl}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. ~ H
NMR (300 MHz, DMSO-ds) 8 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-triazotyl))phenyl]-5-oxo-2-hydroisoxazol-2-yl}methyl~acetamude N N ~ ~ , N N
v CN
O
A mixture oiE N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (500 mg, 1.83 mmol) and 0.8 mL of cyanoacetylene [prepared according to Murahashi, S.; Takizawa, T.; Kurioka, S.;
Maekawa, S.; in _l. Chem. Soc. Jap., ?7, p, 1689, 195fi] in 5 mL of DMF
was heated at 50°C for 48 hours. Upon cooling, the precipitated solid was collected by ~Fltration and washed with DMF to yield 375 mg (63%) of the title compound as a white solid. ~H NMR (300 MHz, DMSO-dg) 8 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).

N-~(4-(4-aminoEhenyl}-5-oxo-2-hydroisoxazol-2-yl~methyl}acetamide O
H2N / \ , N N
v ll O
To a mixture of N-~[4-(4-azidophenyl}-5-oxo-2-hydroisoxazol-2-yl]methyl~acetami~9e (3 g, 10.98 mmol) in 40 mL EtOAc and 20 mL MeOH
was added SnCIzH2H20 (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 concentrated in vacuo again and the residue was dissolved in a mixture of 4:1 CHCI3/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. ~ H
NMR (300 MHz, DMSO-d6) 8 8.83, (t, J = 6 Hz, 1 H), 8.55, (s, 1 H), 7.43 (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 - ,~ 03 - PCT/US99/19265 N-({4-[4-(3-formq~lpyrroly!)phenyl]-5-oxo-2-hydroisoxazol-2-yl}methyl)acetamide O
O
N ~ ~ O
N N
O
To a solutuon of N-{(4-(4-aminophenyl)-5-oxo-2-hydroisoxazoi-2-yljmethyl}acetamide (200 mg, 0.81 mmol) in 3 mL of acetic acid was added 2,5-dimeth.oxy-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 ge! chromatography (eluting with EtOAc, then 8% MeOH in EtOAc) gave 240 mg (91 %) of the title compound as a yellow solid. ~ H NMR (300 MHz, DMSO-d6) 8 9.79 (s, 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).

[5-oxo-4-(4-pyrrotylphenyl)-2-hydroisoxazot-2-yl~methyl acetarr~ide O
~N N
O

WO 00/10566 - 1 a4 - 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-formylpyrroly!)phenyl]-5-oxo-2-hydroisoxazol-2-yl}methyl)acetamide except that 2,5-dimethoxy-3-tetrahydrofuran was used in place of 2,5-dimethoxy-3-tetrahydrofurancarboaldehyde. ~H 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 = 6 Hz, 2 H), '1.86 (s, 3 H).

N-[(4 4-[3-S(hydr_oxyimino)methyl)pyrrolvllahenyl}-5-oxo-2-hydroisoxazol-2 ~I)methyl]acetamide NOH
N O
.~ N / \ O
N N
O
A mixture of N-({4-[4-(3-formylpyrrolyl)phenyl]-5-oxo-2-hydroisoxazol-2-yl}methyl)acetamide (100 mg, 0.30 mmol) and 50%
aqueous NH20H (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. ~H NMR (300 MHz, DMSO-d6) b 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, 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, :? H), 1.85 (s, 3 H).

t-Butyl 4-(4-{2-((acetylamino)methyll-5-oxo-2-hydroisoxazol-4-yl}phenyl)piperazine carboxytate Bot ~ ~ BotN~ , N
KzCO~ 1 N / ' O
w ~/O
AcOCH NHAt NH Z i N
~NH
O
To t-butyl 4-[4-{5-oxo-2-hydroisoxazol-4-yl)phenyljpiperazinecarboxylate (1.5 g, 4.3 mmol) in 35 mL
dimethylformamide was added N-(hydroxymethyl}acetamide acetate (2.9 g, 22.0 mmol) followed by potassium carbonate (3.0 g, 22.0 rnmol). 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. ~H NMR (methanol-d4; 300 MHz) 8 8.48 (s, 1H), 7.fi6 (d, J = 8.8 Hz, 2Hy, 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.
The starting materials were prepared as follows:
Methyl 2-(4-~4-[(t-br~tyl)oxycarbonyljpiperazinyl)phenyi) acetate Bot.N
Tf0 O~ ~ {~
\~~~~~Oi WO 00/10566 - 1 O~ PCT/US99/19265 A flask charged with cesium carbonate (4.6 g, 14.0 mmol}, palladium (11) 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-[(trifluoromethyl)sulfonyloxyjphenyl} acetate (3.0 g, 10.0 mmol) and t-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 1.7 g (50%) of the: title compound. ~H NMR (300 MHz, CDC13) 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}f =
335.
Ethyl2-(4-{4-j(t-b~.rtyl)oxycarbonyl]piperazinyl})phenyl}-3-oxopropanoate soc~ O
~O~H Boc~N
N
O --~ N \
~ NaH. I o r cH0 To methyl :?-(4-{4-[(t-butyl)oxycarbonyl]piperazinyl}phenyl) acetate (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 concentrated. The crude product was used directly in the next step without further purification.
t-Butyl 4-[4-(5-oxo-2-hydroisoxazol-4.-yl)phenylJpiperazinecarboxylate Boc N
N ~ O HZNOH Boc ~ O
N
/ O~ "~' 1l o CHO ~NH
To ethyl 2-(4-{4-[(t-butyl)oxycarbonylJpiperazinyl~)phenyl)-3-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 mrnol). The reaction mixture was heated to reflex 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. ~ H NMR (methanol-d4; 300 MHz) b 8.35 (s, 1 H), 7.58 (br d, J = , 2H), 6.9fi (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.

N-{[5-oxo-4-(piperazinylphenyl)-2-hydroisoxazol-2-yl]methyl acetamide trifluoroacetate salt BocN , O HN ' O
N
I TFA ~ N /
--~N~ ~TFA \'N~

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 trifluoroacetic acid. After 30 minutes, the reaction mixture was cancentrated and triturated with ether to provide WO 00/10566 - 1 O$ - PCT/US99/19265 0.3 g (97%) of thE; title compound. ~ H NMR (methanol-d4; 300 MHz} 8 9.00 {t, J = 6.0 Hz, 1 H), 8.23 (s, 1 H), 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.

tent-Butyl 4-(4-~2~.[(acetylamino)methyl'~-5-oxo(2-hydroisoxazol-4-yi)}-2-fluor~ hen r~iperazinecarboxytate N /
O K CO BoCN~ O
z a ~N
O
F ~~ AcOCH2NHAc 1'' ~~ O
NH F ~ L--N
'-NH
O
Prepared according to the general procedures outlined in Schemes 1, 3, and 6. The si:arting materials were prepared as follows:
2-(4-(4-[(t-butyl}oxycarbonyl]piperazinyl)-3-fluorophenyl)acetic acid eoc N~ Boc~N
~N 1) HCI ~
\S '\iN\O
F ~ / ~ N 2) NaOH, Boc20 F ~~~"~OH
~O
To t-butyl 4-[2-fluoro-4-(2-morpholin-4-yl-2-thioxoethyl}phenyl;tpiperazinecarboxylate (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 addled to bring the pH to 14. Then 50 mL water was WO 00/10566 PCTlUS99/19265 added followed by di-t-butyl Bicarbonate {5.6 g, 26.0 mmol) in 5 mL
tetrahydrofuran. The resulting mixture was allowed to stir at 0°C for 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 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 concentratedl. The resultant residue was dissolved in dichloromethane and hexanes were added to produce a precipitate which was collected by filtration providing 3.0 g (89%) of the title product. ~H
NMR (CDC13; 300 MHz) s 7.04-6.98 {m, 2H}, 6.90 (t, J = 8.3 Hz, 1 H}, 3.60 (m, 6H), 3.02 (t, J = 5.0 Hz, 4H), 1.50 (s, 3H); ESI (M+H)*=339.
Methyl2-(4-{4-j(t-butyl)oxycarbonylJpiperazinyl}-3-fluorophenyl)acetate Boc.N~ Boc,N
~N ~ \ Me3SiCHN2 ~N
O O
F OH F ~ Oi To 2-(4-{4-~[(t-butyl)oxycarbonylJpiperazinyl~-3-fluorophenyl)acetic 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. ~H NMR (CDCIg; 300 MHz) 8 7.00 {m, 2H), 6.90 (t, J = 8.3 Hz, 1 H), 3.71 (s, 3H), 3.61 (t, J = 4.9 Hz, 4H), 3,57 (s, 2H), 3.02 (t, J = 5.0 Hz, 4H), 1.50 (s, 9H); ESI (M+H)* = 353.

N-~(4-(4-morphntinylphenyl)-5-oxo-2-isoxazotinyt~methyl~acetamide o i H

Prepared according to the general procedure outlined in Schemes 1 and 2. The starting materials were prepared as follows:
Methyl-4-{trifiuoromethylsuifonyloxy)phenyl acetate HO ~ O Tf20 F C-S'O
s ~~ O
i pyridine O
O V 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 trifluoromethanes;ulfonic anhydride (23 mL, 132 mmol) dropwise over 30 minutes. After an additional 30 minutes at 0°C followed by 30 minutes at ambient temperature, 1 N hydrochloric acid was added and the reaction mixture was extracted info dichloromethane. The organic layer was 20 washed with 1 N 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. ~ H NMR (CDC13; 300 MHz) s 7.38 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 3.72 {s, 3H), 3.66 (s, 2H).
Methyl-4-morpholinophenyl acetate WO 00!10566 PCT/US99l19265 O
i=3C-S'O I ~ p Pd(OAc)2, morpholine Q N
O ~~ ~ ~- ~ O
O QINAP CSZCOg I i O
Nitrogen was bubbled through a mixture of methyl-4-(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 md, 0.15 mmol), and morpholine (0.35 mL, 4.02 mmol) in 8 mL toluene and the reaction mixture was heated to 80°G for 6 hours. The reaction was then cooled, celite was added, and the mixture was concentrated. Chromatography was performed on a Biotage flash 40i chromatography rnodule 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. ~H NMR (CDCI3; 300 MHz) 8 7.19 (d, J = 8.4 Hz, 2H;1, 6.87 (d, J = 8.3 Hz, 2H), 3.89-3.85 (m, 4H), 3.69 (s, 3H), 3.56 (s, 2H), 3.17-3.13 (m, 4H).

N-~[4-(4-(1,4-thia~:aperhydroin-4-yl)phenyl)-5-oxo-2-hydroisoxazol-2-yi~meth I acetam~ide S
~N
Prepared according to the general procedures outlined in Schemes 1 and 3. The starting materials were prepared as follows:

4-Thiomorpholinoacetophenone F S
K2COs Thiomorphoiine i O
O
To 4-fluoroacetophenone (20 g, 145 mmol) in 100 mL
dimethylformamide was added potassium carbonate (39 g, 580 mmol) followed by thiomorpholine (87 mL, 870 mmol). The reaction mixture was heated to reflex and after 24 hours, it was cooled to ambient temperature and partitioned between water and dichloromethane. The organic layer 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. ~H 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 ~N \
S
~r Morphoiine N
O ~O
A mixture of 4-thiomorpholinoacetophenone (30 g, 136 mmol), morpholine (16 miL, 180 mmol) and sulfur (6 g, 180 mmol) was heated to reflex for 6 hours, cooled to 50°C, and 100 mL 1:1 hexanes:ethyl acetate was added. The reaction mixture was again brought to reflex for 30 minutes, cooled, and the resultant orange precipitate was collected via fsltration. The precipitate was washed with additional 1:1 ether / hexanes WO 00/1O5b6 - 113 - pCT/US991192b5 providing 31 g (T3%) of the title compound as a yellow-orange solid. ~H
NMR (CDCI3; 300 MHz) 8 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), 2.7?-2.71 (m, 2H).
Ethyl-4.-thiomorpholinopheny! acetate s~ s~
~N .~ w S H2SOa ~N
O
N~ Ethanol 1~..~~0~
~.O
A solution of 4-thiomorpholinophenylthioacetomorpholide (30 g, 93.2 mmol) in 70 mL 1:1 ethanolaulfuric acid was heated to reflex for 18 hours, cooled to room temperature and solid sodium bicarbonate was slowiy 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 %) of the title compound as a yellow oil. ~H NMR (CDC13; 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).

N-~[4-(3-fluoro-4-methylthiophenyl)-5-oxo-2-hydroisoxazot-2-yl~methyt~acetarnide Prepared according to the general procedures outlined in Schemes 1 and 3. The starting materials were prepared as follows:
3-Ftuoro-4-methylthioacetophenone F~ ,S
NaSCH3 F~ ~ F
O O
To 3, 4-difluoroacetophenone (30 g, 192 mmol} in 200 mL
dimethylsulfoxide was added sodium thiomethoxide (15 g; 211 mmol).
The reaction mixture was heated to 150°C for 2 hours and then partitioned betwef:n ethyl acetate and sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and 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-methyljthiophenylthioacetomorpholide ~S ~ W Sulfur ~ ~S ~ ~ S
i F ~ Morpholine F

WO 00/10566 PCTlUS99l192b5 A mixture of 3-fluoro-,4-methyfthioacetophenone (9.0 g, 48.9 mmol}, morpholine (5.7 mL, 65.0 mmol}, and sulfur (2.1 g, 65.0 mmol) were heated to reflex for 4 hours, cooled to 50°C, and 1:1 hexanes :
ethyl acetate was added. The reaction mixture was again heated to reflex for 30 minutes, cooled to ambient temperature, and the resultant orange precipitate was collected by filtration. The precipitate was washed with 1:1 hexanes : ethE:r providing 10.1 g (73%) of the title compound as a yellow-orange solid. ~ H NMR (DMSO-dg; 300 MHz) 8 7.36-7.29 (m, 1 H), 7.20-7.15 (m, 2H), 4.27 (s, 2H), 4.22 (t, J = 4.8 Hz, ZH}, 3.73 (t, J = 4.5 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 ,S ~
KoH ~S I w o F ~ OH
To 3-fluoro-4-methylthiophenylthioacetomorpholide (2.6 g, 90.9 mmol) was added 500 ml_ 10% potassium hydroxide. The reaction mixture was heated to reflex for 3 hours, cooled to ambient temperature, and adjusted to pHl 4 by the careful addition of 2N hydrochloric acid. The aqueous solution was extracted with dichloromethane and the organic Payer 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 10.0 g (55%} of the title compound as a brown oil. ~ H NMR (CDC13; 300 , MHz) s 7.24-7.21 (im, 1 H), 7.04-6.99 (m, 2H), 3.63 (s, 2H}, 2.46 (s, 3H).

WO flfl/10566 PCTlUS99/19265 N-~(4-(3-fluoro-4-methoxyphenyl)-5-oxo-2-hydroisoxazol-2-y!]meth, i]acetarnide o w ~0 N
a Prepared according to the general procedure outlined in Schemes 1. The starting material was prepared as follows:
Ethyl-(3-Fluoro-4-rnethoxy)phenyl acetate HO ~ O K2CO3 ~O
,- ~ l w O
O~ CH31 ~ 5 To ethyl-(3-iiuoro-4-hydroxy)phenyl acetate (2.5 g, 8.9 mmol) in 20mL acetone was added patassium carbonate (3.4 g, 24.2 mmol} and iodomethane (1.5 rnL, 24.2 mmol). The reaction mixture was heated to reflux for 2 hours, cooled, and partitioned between saturated sodium bicarbonate and etlher. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated providing 2.3 g (88%) of the title compound as a yellow oil. ~H NMR (CDCI3; 300 MHz) 8 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).

N-({4-[4-(3-cyanopyrrolyl)phenyl-5-oxo-2-hydroisoxazol-2-yl}methyl)aceta,mide He ~N ~. o W
O H
N~N~CH3 ~O
To a mixture of N-[(4-{4-[3-((hydroxyimino)methyl)pyrrolyl)phenyl}-5-oxo-2-hydroisoxazoi-2-yi}methyl]acetamide (100 mg, 0.29 mmol) in 3 mI
of CH3CN and 1 ml of CCI~ 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. ~ H
15 NMR (300 MHz, IDMSO-d6) 8 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.CI6 (d, J = 5 Hz, 2 H), 1.86 (s, 3 H).

N-[(4-~4-[3-((1 E)-2-aza-2-methoxyvinyl)p~~rrolyl]phenyl}-5-oxo-2-hydroisoxazol-2.-yt)methyl]acetamide WO 00/10566 - 1 ~ $ PCT/US99/19265 fi3C~0, N /~
\~r~N / O
H
H
N~N\ 'CH3 ~O
A mixture of N-({4-[4-(3-formylpyrrolyl)phenyl~-5-oxo-2 hydroisoxazol-2-yl}methyl)acetamide (100 mg, 0.3 mmol), HCl.NH20CH3 (31 mg, 0.37 mmoi) 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 reflex 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 compound as a yellow solid. (M+H'~)= 355.

N-~[4-(4-~3-[(1E)..2-(acetytamino)-2-azaviny_ llpyrrolyl}phenyl)-5-oxo-2 hydroisoxazol-2-girl}methyl}acetamide H3C:~H~N
/ O
H ~ I
~ H
N~N~CH3 ~O
A mixture of N-(t4-[4-(3-formylpyrrolyl)phenylj-5-oxo-2-20 hydroisoxazol-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 reflex for 1 hour. The reaction was coated to room temperature, and the yellow WO 00/10566 - 11 g - PCT/US99/19265 precipitate was c~allected by filtration to give 80mg (36 %) of the title compound. (M~-HI+)=382.

Ethyl1-(4-~2-[(ac:etylamino)methyt~-5-oxo-2-hydroisoxazol-4-yl}phenyl)pyrazole- 4-carboxylate ~H
Et0 ~r~ N
O ~ / ~ O
O H
N~ N~CH~
~'O
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 ternperature overnight. The solid was collected by filtration 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. ~ H NMR (300 MHz, DMSO-d~) & 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 (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 startincl material, N-{[4-(4-hydrazinyiphenyl)-5-oxo-2 hydroisoxazol-2-yl]methyl}acetamide hydrochloride, was prepared as 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 at 0oC over 5 minutes. The reaction was stirred for an additional 10 minutes at 0°C, and then SnC12.2H~0 (720 mg, 3.2 mrnol) 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 collect a yellow solid which was washed with 3 mL. of water and dried to yield 260 mg (55a/o) of the title compound. sH NMR (300 MHz, DMSO-dg) s 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).

N-((4-(4- 4-cyanopyrazolyl)phenyt~-5-oxo-2-hydroisoxazol-2-yl~methyl)acetarnide N
NC~N /
~ O
~N~,N CH3 To a mixture of N-~[4-(4-hydrazinylphenyl)-5-oxo-2-hydroisoxazol-2-ylJmethyl}acetamide hydrochloride (50 mg, 0.17 mmol) in 2 m!. of methanol was added 20 mg (0.24 mmol) of sodium bicarbonate and 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. ~ H NMR {300 MHz, DMSO-ds) 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), 5.07 (d, J = 6 Hz, :? H), 1.86 (s, 3 H).

Preparation of cyanomalondialdehyde. To a dried flask was added sodium hydride (~D.82 g, 50% suspended in mineral oil, 17 mmol). The sodium hydride ~nras washed three times with 15 mL of ether, and then 15 mL of ether was ;added to the flask. After cooling the slurry to O~C, ethyl 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 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 cyanornalondialdE:hyde as a yellow solid. Additional product was recovered from the pH 3 aqueous phase: the aqueous phase was 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 cyanomalondialdehyde as a yellow solid. ~ H NMR (300 MHz, DMSO-ds) Fi 8.94 (s, 2 H), 4.95 (br s, 1 H).

N-~[5-oxo-4-(4-pyrazolylphenyl)-2-hydroisoxazol-2-yt~methyl}acetamide CN
N
/ I O
H
N~N~GHg To a mixture of N-{[4-(4-hydraziny(phenyl)-5-oxo-2-hydroisoxazol-2-yljmethyl}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 oii, which eras then purifred by silica gel chromatography (eluting with ethyl acetate) to obtain 30 mg {30%} of the title compound as a yellow solid. ~H NMR (300 MHz, DMSO-d6) 8 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, J = 6 Hz, 2 H}, 1.t36 {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 described above.

- '123 -Structure MS data prepared via Schemes) 1 ~ 1 ~ H (M+H)+
= 279 O

0~'"1 i ~N / ' 2 (M+H)+
= 352 E ~ No N L7CI 3' 1 O

O
O
~

3 .," o (M+H}+
= 295 1, 4 N ~N~ ESI
I
I

O

-.,S / 0 4 0 ~, ~ (M+H)+
= 311 ~N~,"J~ ESI 1' 4 's~1 OG ~ N ~ O
~ ' 5 (M+H}+
= 384 N ESI 3~ 1, 4 /

' g (M+H)+
= 352 1 ES! 3. 1, 9 ~ ~

N
~

s i 7 ~~ o (M+H)+
= 275 ~~N ES! 1 NOH
O

o (M+H)+
= 290 NON ESt 1 Structure MS data ~'rePared via Schemes) / ~ / ' o 9 ~. , o (M+H)+
= 299 5 ~N ESi ~

/ , /
o 10 ~ (M+H)+
~. ~o - 315 1 H S
~

~ ESI ' ~
~j ~~
o 11 / (M+H)+
~ ' o = 317 1 S

v~
II ESI ' N
/ o ~

N M+H + =
12 w ( o 311 1 ( ) 5 H ESI , two 13 ~ ' 1 (M+H)+
= 489 0 2~ 1 6 ESI ' o 14 ,w_,. 375 0 (M+H
N~~:-;
~-- ~
N
~

JN~ ESI 2~ 1~ 6 , ~
Ho IJs~' O

15 ~ ' o H (M+H)+
= 274 NvN~ DCI 1 I!

~_N
HO' / /N
' 16 ~ (M+H)+ 1 7 1 p H - 330 N~N~ ESI ' II

O

WO 00/10566 _ ,) 2~ _ PCT/US99/19265 Structure MS data Prepared via Schemes) H~
N /' o 17 0 '~- 'o (M+H)+
' N = 358 7 ESI , !N-N _ HaC~~N / ~ O

18 ~. 'o - (M+H}+
= 342 1 II DCl ' I~N

NC~,N ~

19 .,, o (M+H)+
= 325 7 DCl , O

p HZN ' (M+H)+
= 248 v ~ DCI ~

~N / O
/
v 21 / (M+H)+ 1 0 = 326 8 w.
1 o H DCI ~
~N

~..~ O
~N~- ~

+
22 ~, 1 ~o (M H)+=2981 H ESl , N~~

H~~ / O

23 ~ ~ ~o (M+H)+=3411 N

~ ESI , ~
~( O

'~ 0 24 ~ ~ (M+H)+
= 417 1 ~, ESl 2' 1' 6 WO 00/10566 _ ,~ ~~ ~ PCT/US99119265 Structure MS data ~'rePared via _ Scherne(s) HN~ N / O
25 ~. ' , ~o " (M+H)+ = 317 2; 1 r 6 ESI

26 " ~~ ~'"U ~ j \ ~ N (M+H)+ = 435 ~N~ ~o"~ ESI 3' 1' 6 il~C 1IF
O
O O
/
27 ...~, 1 0 (M+H)+ = 318 ESI 2, 1 O
S' 1 O

28 '~ 1 ~ " (M+H)+ = 334 3 1 N~"~ ESI

/s i, o 29 ~~ ' ~~ o (M+H)+ = 297 ~N N SCI
O
O / O
'O
30 F ~ ~ " (M+H)+ = 281 N~N~ ESI 3, 1 31 ~ 1 ~o (M+H)+ = 295 N N ESI 3, 1 o _ 32 w I 1 0 " (M+H)+ = 323 1, 8 N ESI

WO 00/1056b - 127 - PCTIUS99/19265 Structure MS data prepared via ----- , Schemes) =N
o ~~ ~

33 (M+H)+ =

DCI 1'8 H3cs~ /

34 ~ ~ ~ H (M+H)+ =

N~N~H DCI 1 ~

O

~ r~ O , 35 ~ ~ ~ H (M+H)+ =

M~N~a ~ DCi 1 36 ~"' ~ ~ H (M+H)+ =

~N~F DCI 1 O

a / o o +

37 L / H (M H)+ =

N~N~ ESI 1 o 38 ~' ~ ~ H (M+H)+ =

NuN~ ESI 1 O

o 39 ~ ~' ~ a ~ (M+H)+ =

ESI

40 F \~ \ ~ H (M+H)+ =

N~''N~ ESI 1 Structure 1 MS data Prepared via Schemes) F
O

41 -.. 1 0 (M+H)+
= 369 F ' H DCI

o _ ' 42 o H (M+H)+
~ = 276 1 ~

N ~N ~ ESl O

N~ ' / a _ , 43 ~ (M+H)+ 1 ' o H = 299 r~~~~ ESI
II

O

'~'' ~ - p (M+H)+
= 233 " ESI

i \ ~ i o ~

45 ~- (M+H)+
= 309 1 ~N~ ESI
Il o ~~

46 ~ (M+H)+
~"'' \ ~ H = 275 ~vN ~ ESt II

o _.

47 ~' ~ ~ ~ (M+H)+
= 359 N~N~ ESI
I' O

O

48 \ ~ H (M+H)+
= 277 N ~N ESI

O

WO 00/10566 _ ,~ 2~ _ PCT/US99/19265 Structure MS data ~'rePared via Schemes) o 49 o F~ ~ ~p ~ (M+H)+
= 309 ESI

O

Br / O
~

50 ~ ~o (M+M)+
~ = 312 rv ~N ESI 1 O

51 of ~ ~a H (M+H)+
= 268 o 52 ~ ~ H (M+H)+
= 268 N'~..~N~ ESI 1 o 53 ~ p (M+H)+
~ = 251 ~ w."~N ESI

54 ~~ ~ N (M+H)+
= 247 H3o ESl 1 w.."

ow / t o 55 ~ ~ ~ H (M+H)+
= 277 .

o a ' 56 0 ' (M+H)+
t ~o = 371 t~ DCI ' WO 00/10566 _ ~ ~O PCT/US99/19265 Structure MS data Prepared via Schemes) ~cls.~ /~ o ~

57 / ~ N ~ (M+H}+ =
0' VN ~ 395 1 s Esl , , a 58 N (M+H}+ =
i~" 359 " \' ~~ c,~
/ \
U

~c 2, 1, 6 ESI

o ~\ ~\ ~c 59 r (M+H}+ =
~-O N~-% "~~~~~~, N~N~c~a 399 ESI 2' 1' 6 60 F ~ ~ _or ~i ' ~ ~ N.~."~~ (M+H)+ = 2 1 o ESI ' ' '~
"
~' ~," ~~~~"

61 ,' (M+H)+ _ ~ ~5 ~-~ 2, 1' 6 ESI

o~ ,-',, ~,-, \~o ~
N
N~

62 ~,-",..~" ;%~ (M+H)+ =
'~-J 437 ~-~
~~~- ~

2 1, 6 o ESI ' 0\' o /y /-v ~o -"

63 ~ (M+H)+ =

~/,~H..
~H c~

~c- 2~ 1 .. ES l (M+H)+ = 1 , N.,~r~~rr ESI ' II

WO 00/1 OSb6 - 131 - PCT/US99119265 Structure MS data prepared via Schemes) o~

o ~..~N ~ i 65 ~ 370 (M+H

F ESI 3~ 1 , ~ ~
~ ~a ~N' ~ I

66 F, ~ t a H (M+H)+ =

N~N~F ESI , '~~~( ~

o~

o ~N~ / I

67 , w o (M+H)+ =

~

N. N ESI ' o~
_.

o ~N' /
' 68 1 (M+H)+ =
o 390 , ESI
H
N.~N~CF3 ~
( I' O

p o ~N_ /
t 69 w (M+H)+ =

F, 3 1 _ ESI ' ' o H
L-N~N~
i!

O

S O

'1! N." /

70 (M+H)+ =
~ 370 3 N N ESI ' ~N~ / O
' 71 w (M+H)+ =
o 302 , 3, 1 H ESI
~i,~N~

~N
/ o _ 72 ' (M+H)+ =
~.. t o 316 1 ESI , WO 00/10566 _ ~ 32 PCT/US99/19265 Structure MS data prepared via Schemes) J ~ O

~

73 ~ o (MfH)+=304 NON ESf 3, 1 a a ~

74 a (M+H)+
~ = 336 F ESI ' ) NON

75 , w o (M+H)+
= 352 ri~,N ESl 3, 1 0.

t5 ~~ O
~I /

76 ~ (M+H)'~
= 368 , 3, 1, 4 ESl ~ ~

s / o /
~
, 77 o (M+H)+
~ = 313 -N N~ ESI 3, 1, 4 ~IU

O

O
/ O
)S
( ~
' 78 ~ Mthi)+
o = 329 F ~--N \~, N ~ ESI ' ' 4 O

O

79 ~. (M~-H)+
p = 350 3 ESI , 1, 4 o~
O
/

O
, ~N~ / ~

80 (M+H)+
= 366 ESI 3, 1, 4 Structure MS data prepared via ' Schemes) HN~ O
Li ~ ~
81 ~ o (M+H)+ = 334 3 1, 6 F ' ~ ESI ' - ~o 82 ~ ~ ~,N ~ / ~ Nw..- c {M+H)+ = 377 , 1, 6 c N~. ~ ESl 3 F
O
O
O
83 ~c-s- ~" ~~/ ~ N (M+H)+ = 413 o w.-"~cH, ESI 3' 1' 6 F
O
O
OY--N \N~.. i O
84 .1,..' -''o '-~ -.-(~~~'%"~.~"~c,~, (M+H)+ = 463 3, 1, 6 o ESI

85 i'-" ~" ', a {M+H)+ = 417 o ~ 1\ / \ "~"~~ ESI 3, 1, 6 F

86 "'c~o~ U"y\~,'o~ {M+H)+ = 449 F~ ~'"~ j~~ ESI 3' 1' 6 O
O
i ~ _.~O
87 ,_p ",-." /~i' ''.~-N.~", {M+H)+ = 469 i-=' F to ~' ESI 3, 1, 6 ~\

v O~-IV N ;~ O
88 L-o ~~ ~/~-NON (M+H)+ = 407 Yes'' ESI 3. 1, 6 WO 00/1O5b6 _ ,~ 34 _ PCT/US99/19265 Structure MS data Prepared via .~ Scheme(s) ~o 393 N~ (M+H

89 H,c~Q \,-/ E 3 ~~N~N 1 ~ 6 ~~ SI , 5 , l O

O
90 O _ (M+H)+
N = 393 ~

\ / \ ~, N g~ 1, 6 Ho ~/
' ~ ~c", ESI

' ., 91 ~ / o (M+H)+ 1 0 ~ l o = 429 6 " ESI , .

NON
~''( O

~

HC
~H / O

92 w ~ (M+H)+
= 323 1 ~ N N CH ESi ' ~".i ~ 3 O

N' nN
~CO

s o 93 \ I 355 (M+H

~N~CH~
~

O

O
H N N

/ O
94 1 (M+H)+
H = 382 ~
~ o ESI 1 8 N~N~CH~
~

O

/ O

95 ~ ~ (M+M)+
= 371 N DCI

N
CH
~- ~. s _ o =N
NC~
H

~
/
O

96 I (M+H)+
w = 324 O

Structure MS data ~ Prepared via Schemes) -N
~
N

/ O
~

97 w ~ (M+H)+ =

H ESI

N N CH

O

Claims (9)

We claim:

1. A compound of the formula or a pharmaceutically acceptable salt thereof wherein:
R1 is a) H, b) C1-8 alkyl optionally substituted with one or more F, Cl, OH, C1-8 alkoxy, or C1-8 acyloxy, c) C3-6 cycloalkyl, or d) C1-8 alkoxy;
L is oxygen or sulfur;
A is 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 fused-on benzene or naphthyl ring, and wherein the heteroaromatic moiety is optionally substituted with one to three R8, 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 naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three R9, a .beta.-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three R9, wherein R2 and R3 are each independently a) H, b) F, c) Cl, d) Br, e) C1-6 alkyl, f) NO2, g) I, h) C1-6 alkoxy, i) OH
j) amino, k) cyano, or l) R2 and R3 taken together are -O(CH2)h-O;
wherein R4 is a) H, b) C1-2 alkyl, c) F, or d) OH;
R5 is a) H, b) CF3, c) C1-3 alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) R5 and R6 taken together are a 5-, 6-, or 7-membered ring of the formula, f) in which D is S, O or NR86 in which R86 is H or C1-6 alkyl, or g) R5 and R6 taken together are -(CH2)k-, when R7 is an 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;
d) C1-3 alkyl optionally substituted with one halo, e) phenyl, provided at least one of R6 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, U is a) CH2, b) O, c) S or, d) NR16;
R16 is a) H or b) C1-5 alkyl;
wherein R8 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, g) NO2, h) C1-6 alkoxy, i) C1-6 alkoxycarbonyl, j) C1-6 alkythio, k) C1-6 acyl, l) -N17R18, m) in which R87 is H or C1-6 alkyl, n) C1-6 alkyl optionally substituted with OH, sulfamoyl, C1-5 alkoxy, C1-5 acyl, or -NR17R18, o) C2-8 alkyl optionally substituted with one or two R19, 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 two R19, or R17 and R18 at each occurrence are the same or different and are a) H, b) C1-4 alkyl, c) C5-6 cycloalkyl, or 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 alkyl, formyl, a 5- or 6-membered heteroaromatic moiety containing 1-3 O, N or S, in which R88 and R89 are each independently hydrogen or C166 alkyl, SO2R90 in which R90 is H or C1-6 alkyl, or C1-3 acyl optionally substituted with 1 or more F, Cl or OH;

-141-~

R19 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, g) NO2, h) C1-6 alkoxy, i) C1-6 alkoxycarbonyl, j) C1-6 alkythio, k) C1-6 acyl, l) C1-6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, or ~NR17R18, m) phenyl, n) -C(=O)NR20R21, o) -N R17R18, p) -N(R20)(-SO2R22), q) -SO2-NR20R21, or r) -S(=O)i R22;
R20 and 21 at each occurrence are the same or different and are a) H, b) C1-6 alkyl, or c) phenyl;
R22 is a) C1-4 alkyl, or b) phenyl optionally substituted with C1-4 alkyl;

wherein R9 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, g) NO2, h) C1-6 alkoxy, i) C1-6 alkoxycarbonyl, j) C1-6 alkythio, k) C1-6 aryl, l) -NR23R24, m) C1-6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 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 moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R25, or R23 and R24 at each occurrence are the same or different and are a) H, b) formyl, c) C1-4 alkyl, d) C1-4 acyl, 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 consisting of S, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, phenyl, pyrimidyl, C1-3 alkyl, or C1-3 acyl;
R25 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, g) NO2, h) C1-6 alkoxy, i) C1-6 alkoxycarbonyl, j) C1-6 alkythio, k) C1-6 acyl, l) phenyl, m) C1-6 alkyl optionally substituted with OH, azido, C1-5 alkoxy, C1-5 acyl, -NR32R33, -SR34, -O-SO2R35, or n) -C(=O)NR26R27, o) -NR23R24, p) -N(R26)(-SO2R22), q) -SO2-NR26R27, or r) -S(=O)i R22, s) -CH=N-R28, or t) -CH(OH)-SO3R31;
R22 is the same as defined above;
R26 and R27 at each occurrence are the same or different and are a) H, b) C1-6 alkyl, c) phenyl, or d) tolyl;
R28 is a) OH, b) benzyloxy, c) -NH-C(=O)-NH2, d) -NH-C(=S)-NH2, or e) -NH-C(=NH)-NR29R30;
R29 and R30 at each occurrence are the same or different and are a) H, or b) C1-4 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 a) H, b) formyl, c) C1-4 alkyl, d) C1-4 acyl, e) phenyl, 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, C1-3 alkyl, or C1-3 acyl, h) -P(O)(OR37)(OR38), or i) -SO2-R39;
R34 is R35 is C1-3 alkyl;
R36 is a) C1-6 alkoxycarbonyl, or b) carboxyl;
R37 and R38 at each occurrence are the same or different and are a) H, or b) C1-3 alkyl;
R39 is a) methyl, b) phenyl, or c) tolyl;
wherein K is a) O, b) S, or c) NR40 in which R40 is hydrogen, formyl, C1-4 alkyl, C1-4 acyl, phenyl, C3-6 cycloalkyl, -P(O)(OR37)(OR38) or -SO2-R39 in which R37, R38 and R39 are as defined above;

R10, R11, R12, R13, R14 and R15 at each occurrence are the same or different and are a) H, b) formyl, c) carboxyl, d) C1-6 alkoxycarbonyl, e) C1-8 alkyl, f) C2-8 alkenyl, wherein the substitutents (e) and (f) can be optionally substituted with OH, halo, C1-6 alkoxyl, C1-6 acyl, C1-6 alkylthio or C1-6 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, NO2, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, C1-6 alkylthio, or C1-6 alkoxycarbonyl;
h) -NR42R43, i) OR44, j) -S(=O)i-R45, k) -SO2-N(R46)(R47), or l) a radical of the following formulas:
R19 is the same as defined above;

T is a) O, b) S, or c) SO 2;
R42 and R43 at each occurrence are the same or different and are a) H, b) C3-6 cycloalkyl, c) phenyl, d) C1-6 acyl, e) C1-8 alkyl optionally substituted with OH, C1-6 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, C1-4 alkoxy,-NR48R49, or a) O, b) CH2, or c) NR56;
R48 and R49 at each occurrence are the same or different and are a) H, or b) C1-4 alkyl;

R54 is a) OH, b) C1-4 alkoxy, or c) -NR57R58;

R55 is a) H, or b) C1-7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C(=O)-NH2, -CO2H, or-C(=NH)-NH2;

R56 is a) H, b) phenyl, or c) C1-5 alkyl optionally substituted by OH;
R57 and R58 at each occurrence are the same ar different and are a) H
b) C1-5 alkyl, c) C1-3 cycloalkyl, or d) phenyl;
R44 is a) C1-8 alkyl optionally substituted with C1-6 alkoxy or C1-6 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 -NO2, CF3, halo, -CN, OH, C1-5 alkyl, C1-5 alkoxy, or C1-5 acyl, b) c) phenyl, or d) pyridyl;
R45 is a) C1-16 alkyl, b) C2-16 alkenyl, wherein the substituents (a) and (b) can be optionally substituted with C1-6 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 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, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, C1-6 alkylthio, or C1-6 alkoxycarbonyl;

R46 and R47 at each occurrence are the same or different and are a) H, b) phenyl, c) C1-6 alkyl, or d) benzyl;

R50 and R51 at each occurrence are the same or different and are a) H, b) OH, c) C1-6 alkyl optionally substituted with -NR48R49 in which R48 and R49 are as defined above, d) R50 and R51 taken together are =O;
R52 is 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 with one or three -NO2, CF3, halo, -CN, OH, phenyl, C1-5 alkyl, C1-5 alkoxy, or C1-5 acyl , c) morpholinyl, d) OH, e) C1-6 alkoxy, f) -NR48R49 in which R48 and R49 are as defined above, g) -C(=O)-R59 or R53 is a) H, b) formyl, c) C1-4 alkyl, d) C1-4 acyl, e) phenyl, f) C3-6 cycloalkyl, g) -P(O)(OR37)(OR38), or h) -SO2R39, in which R37, R38 and R39 are as defined above;
R59 is a) morpholinyl, b) OH, or c) C1-6 alkoxy;
h is 1, 2, or 3;
i is 0, 1, or 2;

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;
a is 1 or 2; and Q IS
a) hydrogen, b) hallo, c) NC)2, d) N3, e) C~~-Cg alkylthio, h) C~..C6 alkyl, i) C~-~C6 alkoxy, j) forrnyl, m) -sullfamoyl (H2NS02-), n) -Nl-fOH, p) heteroaryl:l MG:in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, q) C6H5- r) amino, s) C1-C6 alkylamino, t) di(C1-C6 alkyl)amino-, u) (C1-C6) alkyl-NR60R61 in which R60 and R61 are each independently hydrogen or C1-C6 alkyl, v) OH, w) cyano, x) hydroxy (C1-C6 alkyl), y) C1-C6 Z) NC-(CH2)r- In which r is 1-6, aa) C6H5CH2-O- bb) C6H5-O- cc) C1-C6 alkyl- in which R84 is hydrogen or C1-6 alkyl, dd) R85 O-(CH2)1-6- in which R85 is hydrogen, C1-8 alkyl optionally substituted with one or more F, Cl, OH, C1-8 alkoxy or C1-8 acyloxy, C3-6 cycloalkyl or C1-8 alkoxy;
ee) H- in which R84 is hydrogen or C1-6 alkyl, ff) a substituted or unsubstituted C6-C10 aryl moiety, 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 heteroarornatic 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;

the substituents for such p, q, ff, gg and hh moieties being selected from.
1 or 2 of the following:

1) halo, 2) C1-6 alkyl, 3) NO2, 4) N3, 5) C1-C6 alkyl 6) C1-C6 7) formyl, 8) C1-C6 alkyl- 9) C1-C6 alkyl- 10) heteroalyl- in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, 11) C6H5- 12) -(C1-C6) alkyl--NR60R61 in which R60 and R61 are each independently hydrogen or C1-C6 alkyl, 13) OH, 14) hydroxy (C1-C6 alkyl), 15) C1-C6 alkyl- 16) NC-(CH2)r- in which r is 1-6, 17) -C6H5-CH2-O- 18) -CH2-R80 in which R80 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 above, or d) 5- or 6-membered heteroaromatic containing 1-4 O, S or N atoms, 19) C1-C6 alkyl- in which R84 is as defined above, 20) cyano, 21) carboxyl, 22) CF3, 23) C1-C6 alkyl- 24) C6H5-O- in which the phenyl moiety may be optionally substituted by halo or (C1-C6)alkyl, 25) NR60-R61- in which R60 and R61 are as defined above, 26) R91-NH- or R91--NH- in which R91 is a 5- or 6-membered aromatic heterocyclic group having 1-3 O, N or S, 27) 28) in which R85 is as defined above, 29) in which R99, R100 and R101 are each independently C1-6 alkyl; or Q and either R1 and R2 taken together form -O-CH2-O.

2. A compound of claim 1 wherein A is in which Q, R2 and R3 are as defined in claim 1.

3. A compound of the formula or a pharmaceutically acceptable salt thereof, in which R1 is H, C1-8 alkyl optionally substituted with one or more F, Cl, OH, C1-8 alkoxy, or C1-8 acyloxy, C3-6 cycloalkyl or C1-8 alkoxy;
R2 and R3 are each independently a) H, b) F, c) Cl, d) Br, e) C1-6 alkyl, f) NO2, g) l, h) C1-6 alkoxy, i) OH
j) amino, or k) cyano; and Q is a) hydrogen, b) halo, c) NO2, d) N3, e) C1-C6 alkylthio, f) C1-C6 g) C1-C6 h) C1-C6 alkyl, i) C1-C6 alkoxy, j) formyl, k) C1-C6 l) C1-C6 m) C1-C6 n) in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, p) amino, q) C1-C6 alkylamino-, r) di(C1-C6 alkyl)amino-, s) (C1-C6) in which R60 and R61 are each independently hydrogen or C1-C6 alkyl, t) OH, u) cyano, v) hydroxy (C1-C6 alkyl), w) C1-C6 alkyl x) in which r is 1-6, y) z) aa) C1-C6 wherein R84 is hydrogen or C1-6 alkyl, bb) in which R85 is hydrogen, C1-8 alkyl optionally substituted with one or more F, Cl, OH, C1-8 alkoxy or C1-8 acyloxy, C3-6 cycloalkyl or C1-8 alkoxy, cc) in which R84 is as defined above, ll) mm) nn) oo) pp) qq) rr) ss) 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, fff) ggg) hhh) iii) B is an unsaturated 4-atom linker having one nitrogen and three carbons;
M is a) H, b) C1-8 alkyl, c) C3-8 cycloalkyl, d) -(CH2)m OR66, or e) -(CH2)n NR67R68;
Z is a) O, b) S or c) NM;
W is a) CH, b) N or c) S or O when Z is NM;
X and Y are each independently a) hydrogen, b) halo, c) NO2, d) N3, e) C1-6 alkythio, f) C1-C6 alkyl g) C--C6 alkyl h) C1-C6 alkyl, i) C1-C6 alkoxy, j) formyl, k) C1-C6 alkyl l) C1-C6 alkyl m) heteroaryl in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetera atoms selected from O, N or S, n) o) amino, p) C1-C6 alkylamino-, q) di (C1-C6 alkyl)amino-, r) -(C1-C6) in which R60 and R61 are each independently hydrogen or C1-C6 alkyl, s) OH, t) hydroxy (C1-C6 alkyl), u) C1-C6 ~
v) in which r is 1-6, in which R84 is as defined above, z) cyano, aa) carboxyl, bb) CF3, cc) mercapto, dd) C1-C6 in which the phenyl moiety may be optionally substituted by halo or C1-C6 alkyl, in which R85 is as defined above, or hh) in which R99, R100 and R101 are each independently C1-6 alkyl; or Q and either R1 and R3 taken together form -O-CH2-O;

R62 is a) H, b) C1-8 alkyl optionally substituted with one or more halos, or c) C1-8 alkyl optionally substituted with one or more OH, or C1-8; alkoxy;
E is a) NR69, b) -S(=O)i in which i is 0, 1 or 2, or c) O;
R63 is a) H, b) C1-6 alkyl, c) -(CH12)q-aryl, or d) halo;
R66 is H or C1-4 alkyl;
R67 and R68 are each independently H or C1-4 alkyl, or NR67R68 taken together are -(CH2)m-;
R69 is a) H, b) C1-6 alkyl, c) -(CH2)q-aryl, d) -CO2R81, e) COR82, f) -C(=O)-(CH2)q-C(=O)R81, g) -S(=O)z-C1-6 alkyl, h) -S(=O)z-(CH2)q-aryl, or i) -(C=O)j-Het in which j is 0 or 1;

Z1 is a) -CH2-, or b) -CH(R70)-CH2-;
Z2 is a) -O2S-, b) -O-, c) -S-d) -SO-, or e) -N(R71)-;

Z3 is a) S, b) SO, c) SO2, or d) O;
A1 is H or CH3;
A2 is a) H, b) OH-, C) CH3CO2-, d) CH3-, e) CH3O-, f) R72O-CH2-C(O)-NH-, g) R73O-C(O)-NH-, h) R73-C(O)-NH-, i) (C1-C2)alkyl-O-C(O)-, or j) HO-CH2; or A1 and A2 taken together are a) or b) O =;
R64 is H or CH3-;
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;
w is 1, 2 or 3;
q is 1,2,3 or 4;
z is 0 or 1;
R65 is a) R74OC(R75)(R76)-C(O)-, b) R77OC(O)-, c) R78(O)-, d) R79-SO2-, or e) R80-NH-C(O)-;
R70 is H or (C1-C3)alkyl;
R71 is a) R74OC(R75)(R76)-C(O)-, b) R77O-C(O)-, c) R78-C(O)-, d) e) H3C-C(O)-(CH2)2-C(O)-, g) R79-SO2-, h) i) R80-NH-C(O)-, R72 is a) H, b) CH3, c) phenyl -CH2-; or d) CH3C(O)-;
R73 is (C1-C3)alkyl or phenyl;
R74 is H, CH3, phenyl-CH2- or CH3-C(O)-;
R75 and R76 are each independently H or CH3, or R75 and R76 taken together are -CH2CH2-;
R77 is (C1-C3)alkyl or phenyl;
R78 is H, (C1-C4)alkyl, aryl-(CH2)n1, CIH2C, C12HC, FH2C-, F2HC- or (C3-C6)cycloalkyl;
R79 is CH3; -CH2Cl, -CH2CH=CH2, aryl or -CH2CN;
R80 is -(CH2)n1-aryl where n1 is 0 or 1;
R81 is a) H, b) C1-6 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-OR83 in which q is as defined above;
R82 is a) C1-6 alkyl optionally substituted with one or more OH, halo 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, b) C1-6 alkyl, c) -(CH2)q-aryl in which q is as defined above; or d) -C(=O)C1-6 alkyl; and aryl is phenyl, pyridyl or naphthyl, said phenyl, pyridyl or naphthyl moieties being optionally substituted by one or mare halo, -CN, OH, SH, C1-6 alkoxy or C1-6 alkylthio.

4. A compound of the formula or a pharmaceutically acceptable salt thereof, in which R1 is H, C1-8 alkyl optionally substituted with one or more F, Cl, OH, C1-8 alkoxy or C1-8 acyloxy, C3-6 cycloalkyl or C1-8 alkoxy;

R2 and R3 are each independently H or F; or R2 and R3 taken together represent Q is a) hydrogen, b) halo, c) N3, d) NO2, e) C1-C6 alkylthio, f) g) h) C1-C6 alkyl, i) C1-C6 alkoxy;
j) formyl, k) l) m) n) (C1-C6 alkoxy)2N-, o) 5- or 6-membered 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, p) q) phenyl optionally substituted by R96, or r) 5- or S-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 R96 is a) C1-C6 alkyl-OH, b) , c) , d) cyano, e) formyl, f) , g) , h) in which R84, R85 and R86 are each independently C1-C6 alkyl, i) , j) , k) where the phenyl may be optionally substituted by halo, l) , m) (C1-C6 alkyl)2N-, n) C1-C6 alkyl-NH-, o) amino.
r) in which R98 is phenyl, 5- or 6-membered heteroaryl containing 1-3 O, 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 Claim 1 in admixture with a pharmaceutically acceptable adjiwant, diluent or carrier.

7. A method of treating a bacterial infection in a mammal which comprises administering a therapeutically effective amount of a compound of Claim 1 to a mammal in need thereof.

8. Use of an effective amount of a compound of claim 1 to treat a bacterial infection in a mammal.

9. Use of an effective amount of a compound of claim 1 in the manufacture of a medicament to treat a bacterial infection in a mammal.