EP1107756A1 - Novel isoxazolinone antibacterial agents - Google Patents

Abstract

This invention describes isoxazolinone derivatives which possess antibacterial 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 ISOXAZOLINONE 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

or a pharmaceutically acceptable salt thereof wherein: R-l is a) H, b) C-_|_s alkyl optionally substituted with one or more F, Cl, OH, C-|_8 alkoxy, or Cι_8 acyloxy, c) C3-6 cycloalkyl, or d) C-μs alkoxy;

L is oxygen or sulfur;

A is a)

R₂

^Q"

R₃ b)

c) a 5-membered heteroaromatic moiety having one to three hetero atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom and can additionally have a fused-on benzene or naphthyi ring, and wherein the heteroaromatic moiety is optionally substituted with one to three Re, 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 naphthyi ring, wherein the heteroaromatic moiety is optionally substituted with one to three Rg, e) a β-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three Rg, f)

g)

wherein R₂ and R3 are each independently a) H, b) F, c) Cl, d) Br, e) C|_6 alkyl, f) N0₂, g) I, h) Cι_6 alkoxy, i) OH j) amino, k) cyano, or

I) R₂ and R₃ taken together are -0(CH ) -0; wherein R4 is a) H, b) C-_|_₂ alkyl, c) F. or d) OH;

R₅ 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) R5 and Re taken together are a 5-, 6-, or 7-membered ring of the formula,

f)

in which D is S, O or NR₈e in which R₈e is H or

C-|_6 alkyl, or g) R5 and Re 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) 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) Re and R7 taken together are a 5-, 6-, or 7-membered ring of the formula,

U is a) CH₂, b) 0, c) S or, d) NR₁₆ 00/10566

- 5 -

R₁₆ is a) H or b) C-1.5 alkyl; wherein Ra is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF₃, g) N0₂, h) C-|_e alkoxy, i) C-|_e alkoxycarbonyl, j) C-|_ alkythio, k) Ci^ acyl,

I) -NR-17R18.

NOH

I I m) — C-R₈₇ in which Rs7 is H or Cι_e alkyl n) Ci_e alkyl optionally substituted with OH, sulfamoyl, C-ι_₅ alkoxy, C-|.₅ acyl, or-NR^R^,

0) C₂_8 alkyl optionally substituted with one or two R^g, p) phenyl optionally substituted with one or two R-|g, 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 Rig, or

i7 and R-JS at each occurrence are the same or different and are a) H, b) C-]_ alkyl, ^c) ₅_e cycloalkyl, or d) R-i 7 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, C-\._$ alkyl, formyl, a 5- or 6-membered heteroaromatic moiety

O II containing 1-3 0, N or S, — C-NR₈₈R₈₉ in which R₈₈ and R₈g are each independently hydrogen or C<|_e alkyl, S0 Rgrj in which Rgg is H or C-|_₆ alkyl, or C-1.3 acyl optionally substituted with 1 or more F, Cl or OH;

R-i 9 '^s a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF₃, g) N0₂, h) Cι_e alkoxy, i) Cι_e alkoxycarbonyl, j) C-|_e alkythio, k) C-|_6 acyl,

I) C- e alkyl optionally substituted with OH, C-1.5 alkoxy, C-1.5 acyl, or -NR₁₇R₁₈, m) phenyl, n) -C(=O)NR₂₀R_{21 )} o) -N R17R18,

P) -N(R₂₀)(-SO₂R₂₂), q) -SO₂-NR₂₀R₂₁, or r) -S(=0)iR₂₂;

R₂₀ and R₂₁ at each occurrence are the same or different and are a) H, b) C-|_6 alkyl, or c) phenyl;

R₂ is a) C_|_4 alkyl, or b) phenyl optionally substituted with C^ alkyl; wherein Rg is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF₃, g) N0₂, h) C-|_e alkoxy, i) C-|_6 alkoxycarbonyl, j) C-|.e alkythio, k) ^acyi.

I) -NR₂3R₂4, m) C^e alkyl optionally substituted with OH, C-^ alkoxy, C^ 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 q)

R₂3 and R ₄ at each occurrence are the same or different and are a) H, b) formyl, c) C-_]_4 alkyl, d) C-₎_4 acyl, e) phenyl, f) C3.6 cycloalkyl, or g) R₂ and R₂ 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, C-|_₃ alkyl, or C1.3 acyl;

R₂₅ is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF₃, g) N0₂, h) C^ alkoxy, i) C-|_e alkoxycarbonyl, j) C-|_e alkythio, k) C^e acyl,

I) phenyl, m) C1.6 alkyl optionally substituted with OH, azido, C1.5 alkoxy,

C_π_₅ acyl, -NR3₂R_33ι -SR₃₄, -0-S0₂R₃₅, or

36— ~ NH-CO-O-

n) -C(=0)NR₂₆R₂₇, o) -NR₂3R₂ ,

P) -N(R₂₆)(-S0₂R₂₂), q) -S0₂-NR₂₆R₂₇, or r) -S(=0)iR₂₂, s) -CH=N-R₂₈, or t) -CH(OH)-S0₃R₃₁;

R₂₂ is the same as defined above;

R₂₆ and F \₂ι at each occurrence are the same or different and are a) H, b) C^e 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;

R_2g 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) C-|_4 alkyl, d) C^ acyl, e) phenyl, f) C₃_ cycloalkyl, g) R₃ and R₃₃ taken together are a 5- or 6-membered saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyl, C^_3 alkyl, or C-|_₃ acyl, h) -P(0)(OR₃7)(OR₃₈), or i) -S0₂-R₃₉;

R₃₄ is

R₃₅ is Ci.3 alkyl;

R36 ^is a) C-_|_e alkoxycarbonyl, or b) carboxyl;

R₃₇ and R₃₈ at each occurrence are the same or different and are a) H, or b) C|_3 alkyl; 39 'S a) methyl, b) phenyl, or c) tolyl; wherein K is a) O, b) S, or c) NR₄₀ in which R₄₀ is hydrogen, formyl, C^ alkyl, C< phenyl, C₃.₆ cycloalkyl, -P(0)(OR₃7)(OR₃8) or -S0₂-R₃₉ in which R37, R3₈ and R3g are as defined above; Rιo_ Rn_i R-12. Ri3_, 14 and R15 at each occurrence are the same or different and are a) H, b) formyl, c) carboxyl, d) C-|_e alkoxycarbonyl, e) C-|.₈ alkyl, f) C₂.₈ alkenyl, wherein the substitutents (e) and (f) can be optionally substituted with OH, halo, C-|_6 alkoxyl, C-|.₆ acyl, C|_₆ alkylthio or C<_|_e alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, -CN, formyl, CF₃, N0₂, C-|_₆ alkyl, C-|_6 alkoxy, C-|_e acyl, C1.5 alkylthio, or C-|_e alkoxycarbonyl; h) -NR4₂R43, i) OR44, j) -S(=0)_rR45, k) -S0₂-N(R₄₆)(R47)> or

1) a radical of the following formulas

S3

HN N— R₅₂- (CH₂)t-N N- R53-N N — or R53

R_ιg is the same as defined above;

T is a) O, b) S, or c) S0₂;

R ₂ and R43 at each occurrence are the same or different and are a) H, b) C₃_e cycloalkyl, c) phenyl, d) Cι_e acyl, e) C-|_8 alkyl optionally substituted with OH, C-_|_e alkoxy which can be substituted with OH, a 5- or 6-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF₃, halo, -N0₂, C^

alkoxy,-NR ₈R4g, or

u.

^■'R54

R₅₅-CH- or g)

V N-(CH₂)t—

V is a) O, b) CH₂, or c) NR₅₆;

R48 and R4g at each occurrence are the same or different and are a) H, or b) C.|_4 alkyl;

R₅₄ is a) OH, b) C-|_4 alkoxy, or c) -NR₅₇R₅₈; 55 '^s a) H, or b) Ci_₇ alkyl optionally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C(=0)-NH₂, -C0₂H, or -C(=NH)-NH₂;

Rδ6 ^is a) H, b) phenyl, or c) Cι_6 alkyl optionally substituted by OH; R₅₇ and R58 at each occurrence are the same or different and are a) H, b) Ci.5 alkyl, c) C-]_₃ cycloalkyl, or d) phenyl;

R44 is a) C-|_8 alkyl optionally substituted with C-j.₆ alkoxy or C^e 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,_5 alkyl, C-,.5 alkoxy, or C1-5 acyl, b)

N-(CH₂)t —

c) phenyl, or d) pyridyl; R₄₅ is a) C- β alkyl, b) C₂_ιe alkenyl, wherein the substituents (a) and (b) can be optionally substituted with C^e alkoxycarbonyl, or a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, c) an aromatic moiety having 6 to 10 carbon atoms, or 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, -NO , C-|_e alkyl, Cι_e alkoxy, C^ acyl, C^e alkylthio, or Cι_e alkoxycarbonyl; R ₆ and R47 at each occurrence are the same or different and are a) H, b) phenyl, c) C-|_6 alkyl, or d) benzyl;

R₅₀ and R51 at each occurrence are the same or different and are a) H, b) OH, c) C-|_e alkyl optionally substituted with -NR ₈R4g in which R₄8and R4g are as defined above, d) R₅₀ and R51 taken together are =0; R₅₂ is a) an aromatic moiety having 6 to 10 carbon atoms, 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^s alkyl, C-|_5 alkoxy, or Cι_₅ acyl, c) morpholinyl, d) OH, e) Cι_e alkoxy, f) -NR4₈R49 in which R4₈and R4g are as defined above, g) -C(=0)-R₅₉, or h)

₁₆ )

R53'S a) H, b) formyl, c) C-|_4 alkyl, d) C|_4 acyl, e) phenyl, ) C3-6 cycloalkyl, g) -P(0)(OR₃₇)(OR₃₈), or h) -SO2R39, in which R₃₇, R₃₈ and R₃g are as defined above;

R59'S a) morpholinyl, b) OH, or c) C-|_e alkoxy; his 1, 2, or 3; i is 0, 1, or 2; j is 0, or 1; kis 3, 4, or 5; r is 1,2, 3, 4, 5 or 6; t is 0, 1,2, 3, 4, 5, or 6; u is 1 or 2; and

Qis a) hydrogen, b) halo, c) N0₂, d) N₃. e) C C₆ alkylthio,

O f) C_rC₆alkyl-s-, 0 g) C C₆ alkyl— s—

0 ' h) C_rC₆ alkyl, i) C-j-Ce alkoxy, j) formyl,

0 k) C C_β alkyl-c- ,

0

1) C_rC₆ alkyl-o-C- , m) -sulfamoyl (H₂NS0₂-), n) -NHOH,

O o) C_rC₆ alkyl— c-O—

0

P) heteroaryl — C— in which heteroaryl is a 5- or 6-member aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S,

r) amino, s) C-|-Ce alkylamino-, t) di (C-j-Ce alkyl)amino-,

0 u) (C C₆) alkyl-C-NR₆₀R₆₁ in which R₆o and R₆₁ are each independently hydrogen or C C₆ alkyl, v) OH, w) cyano, x) hydroxy (C-|-Ce alkyl), o y) C C₆ alkyl-S-C— 0 z) NC — (CH₂) -C— in which r is 1-6,

O aa) C₆H₅CH₂-0-C- ,

0 bb) C₆H₅-0-C- ,

_/OR₈₄ N cc) C C₆ alkyl— c— in which R₈₄ is hydrogen or C-|_e alkyl,

0 dd) R₈₅0-(CH₂)ι_₆-C— in which Rss is hydrogen, C-j_₈ alkyl optionally substituted with one or more F, Cl, OH, C-|_8 alkoxy or C-|_8 acyloxy, C3.6 cycloalkyl or C-|_8 alkoxy;

N-OR₈₄ ee) H-C— jn which R84 is hydrogen or Cι_e alkyl, ff) a substituted or unsubstituted Ce-C-io 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 substituents for such p, q, ff, gg and hh moieties being selected from

1 or 2 of the following:

1) halo,

2) C^e alkyl,

3) N0₂, 4) N₃, 0 II

5) C C₆ alkyl - -S-,

0 II

6) C C₆ alkyl- -s It—

0 '

7) formyl,

0

8) C C₆ alkyl - -C-,

0

9) C C₆ alkyl- -0-C-

O

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

O

11) C₆H₅-C-,

O 12) -(C_rC₆) alkyl-C-NR₆₀R₆₁ in which R₆₀ and R₆₁ are each independently hydrogen or C- Ce alkyl,

13) OH,

14) hydroxy (C_rC₆ alkyl),

O

15) C_rC₆ alkyl -S-C-,

O 16) NC-(CH₂)_r-0-C— in which r is 1-6,

O

17) C₆H₅CH₂-O-C-,

18) -CH -R₈o in which R_8u is a) -OR in which R₃₂ is as defined above, b) -SR3₂ in which R₈₂ 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 0, S or N atoms,

_/OR₈₄ N

19) C_rC₆ alkyl— c— in which R₈₄ is as defined above,

20) cyano, 21) carboxyl,

22) CF₃,

O

23) C_rC₆ alkyl— C-O—

O

24) C₆H₅-0-C— in which the phenyl moiety may be optionally substituted by halo or (C-ι-C₆)alkyl,

O 25) NR₆₀R₆₁—C— in which R₆n and Rei are as defined above,

O O

26) R₉₁-NH-C— or R₉₁-C-NH— in which R₉₁ is a 5- or 6- membered aromatic heterocyclic group having 1-3 O, N or S,

O 27) C₆H₅(CH₂)₁^-0-C- ,

O

28) R₈5θ-(CH₂)_1-6— 0-C— in which R₈5 is as defined above,

O

29) SiR₉₉R₁₀₀R₁₀₁-O-CH₂-C— in which Rgg, R_10u and R₁₀ι are each independently Cι_₆ alkyl; or

Q and either R₁ and R taken together form -0-CH -0.

These derivatives are useful as antimicrobial agents which are effective against a number of human and veterinary pathogens, including gram positive bacteria such as multiply-resistant staphylococci, streptococci, and enterococci, such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus faecium.

2. Description of the Prior Art

The literature contains a limited number of isoxazolinones used as pre-emergence herbicides. For example in U.S. Patent 4,065,463, 2- methyl-4-(trifluoromethyl-/r7-tolyl)-3-isoxazolin-5-one and 2-methyl-4- (chloro- -tolyl)-3-isoxazolin-5-one are disclosed as being useful in preventing the growth of weeds which have a deleterious effect on crop production.

U.S. Patent 4,000,155 discloses the related compound 1 ,2- dimethyl-4-(trifluoromethyl-m-tolyl)-3-pyrazolin-5-one for the same utility.

The applicant is not aware of any literature which discloses the use of these compounds as broad spectrum anti-bacterial agents. A different ring system is disclosed in WO 98/07708, which discusses the use of isoxazoline derivatives as anti-bacterial agents,

where W is a substituted aryl or heteroaryl system and V is H, or C1-C4 alkyl optionally substituted with F, Cl, OH, C1-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; 0,694,544; 0694,543; and 0,693,491 (5 to 9-membered heteroaryl substituted oxazolidinones).

Additionally, certain compounds containing a substituted furanone ring have been reported to possess antibiotic activity. WO 97/14690 discloses

where T is hydroxy or NHC(0)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, 1 is O, SO, S02 or a substituted nitrogen, and Q-R is CH₂-CH₂ or CH=CH₂. Other substituted furanones are discussed in U.S. Patent 5,708,169, WO 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:

or a pharmaceutically acceptable salt thereof wherein:

Ri is a) H, b) C^s alkyl optionally substituted with one or more F, Cl, OH,

C<_|_₈ alkoxy, or C-_|_₈ acyloxy, c) C3-6 cycloalkyl, or d) C-_|_₈ alkoxy;

L is oxygen or sulfur;

A is a)

b)

c) a 5-membered heteroaromatic moiety having one to three hetero atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom and can additionally have a fused-on benzene or naphthyi ring, and wherein the heteroaromatic moiety is optionally substituted with one to three R₈, d) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the heteroaromatic moiety is bonded via a carbon atom, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyi ring, wherein the heteroaromatic moiety is optionally substituted with one to three Rg, e) a β-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three Rg,

^Rn R12 ^{w R}13 or g)

wherein R₂ and R3 are each independently a) H, b) F, c) Cl, d) Br, e) C|.₆ alkyl, f) N0₂, g) I, h) Ci_e alkoxy, i) OH j) amino, k) cyano, or I) R₂ and R₃ taken together are -0(CH₂)_n-0; wherein R4 is a) H, b) C-|_₂ alkyl, c) F, or d) OH;

R₅ is a) H, b) CF₃, c) C-1.3 alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) R5 and Re 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

C-|_6 alkyl, or g) R5 and Re taken together are -(CH₂)|<-, when R₇ is an electron-withdrawing group; R₆ and R 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) Re and R7 taken together are a 5-, 6-, or 7-membered ring of the formula,

U is a) CH₂, b) 0, c) S or, d) NR₁₆;

R₁₆ is a) H or b) C-1.5 alkyl; wherein R₈ is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF₃, g) N0₂, h) C-1.5 alkoxy, i) Cι_e alkoxycarbonyl, j) Cι_e alkythio, k) Ci^ acyl,

I) -NRi7R-_|8, NOH

I I m) — C-R₈₇ in which R₈7 is H or C-|_e alkyl, n) C-|_e alkyl optionally substituted with OH, sulfamoyl, C-1.5 alkoxy, C1.5 acyl, or -NR₁₇R₁₈, o) C₂.₈ alkyl optionally substituted with one or two R-|g, p) phenyl optionally substituted with one or two R-jg, q) a 5- or 6-membered saturated or unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or

R-l 7 and R-|₈ at each occurrence are the same or different and are a) H, b) C-,.₄ alkyl, ^c) C5.6 cycloalkyl, or d) R17 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, C1.3 alkyl, formyl, a 5- or 6-membered heteroaromatic moiety

O II containing 1-3 O, N or S, — C-NR₈₈R₈₉ in which R₈₈ and R₈g are each independently hydrogen or C-|_e alkyl, S0₂R₉Q in which Rgn is H or C-|.₆ alkyl, or C-j.3 acyl optionally substituted with 1 or more F, Cl or OH; - .do -

R ^ki1o9 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF₃, g) N0₂, h) C __Q alkoxy, i) Cι_e alkoxycarbonyl, j) C-|.₆ alkythio, k) C-|.₆ acyl,

I) C-|_e alkyl optionally substituted with OH, C-|_₅ alkoxy, C-1.5 acyl, or -NR₁₇R₁₈, m) phenyl, n) -C(=O)NR₂₀R₂₁, o) -N R₁₇R-_|8,

P) -N(R₂₀)(-SO₂R₂₂), q) -SO₂-NR₂₀R₂₁, or r) -S(=0)iR₂₂;

R₂₀ and R₂- I at each occurrence are the same or different and are a) H, b) C^e alkyl, or c) phenyl;

R₂₂ is a) C-|_4 alkyl, or b) phenyl optionally substituted with C-|_4 alkyl; - ^y -

wherein Rg is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, ) CF₃, g) N0₂, h) C-|_ alkoxy, i) C-|_₆ alkoxycarbonyl, j) C-|_e alkythio, k) acyl,

I) -NR₂3R₂4, m) C-|_6 alkyl optionally substituted with OH, C-1.5 alkoxy, C^_₅ acyl, or -NR₂₃R₂₄, n) C .₈ alkenylphenyl optionally substituted with one or two

^R25> o) phenyl optionally substituted with one or two R 5,

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 q)

R₂₃ and R₂₄ at each occurrence are the same or different and are a) H, b) formyl, c) Cι_4 alkyl, d) C-|_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, C-_|.₃ alkyl, or C-_|_3 acyl;

R₂₅ is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF₃, g) N0₂, h) C-|_e alkoxy, i) Cι_e alkoxycarbonyl, j) Cι_e alkythio, k) C-1.6 acyl,

I) phenyl, m) Ci_e alkyl optionally substituted with OH, azido, Cι_₅ alkoxy,

C-1.5 acyl, -NR3₂R_33ι -SR₃₄, -0-SO₂R₃₅, or

R36— ^NH-CO-0-

n) -C(=0)NR₂₆R₂₇,

0) -NR₂3R₂4, 00/10566

- 31 -

P) -N(R₂₆)(-S0₂R₂₂), q) -S0₂-NR₂₆R₂ , or r) -S(=0)iR₂₂, s) -CH=N-R₂₈, or t) -CH(OH)-S0₃R₃ι;

R₂ is the same as defined above;

R₂e and R₂7 at each occurrence are the same or different and are a) H, b) Cι_e alkyl, c) phenyl, or d) tolyl;

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 bb)) C Cιι__44 aallkkyyll ooppttiioonnaallllyy ssuubbssttiittuutteedd wwiitthh pphheennyyll oorr ppyyrriiddyyl;

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) Cι_4 alkyl, d) Cι_4 acyl, e) phenyl, f) C3^ 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 Cι_₃ acyl, h) -P(0)(OR₃₇)(OR₃₈), or i) -S0₂-R3 ;

R₃₄ is

R35 is C1.3 alkyl; 36 ^is a) C _e alkoxycarbonyl, or b) carboxyl; R37 and R3₈ at each occurrence are the same or different and are a) H, or b) Ci_₃ alkyl;

R39 is a) methyl, b) phenyl, or c) tolyl; wherein K is a) O, b) S, or cc)) NNRR4400 iinn wwhich R40 is hydrogen, formyl, C1. alkyl, Cι_4 acyl, phenyl, C₃.₆ cycloalkyl, -P(O)(OR₃₇)(OR₃₈) or -SO₂-R₃₉ in which R37, R₃₈ and R₈₉ are as defined above; R-10, 11_, i2' Ri3, R14 and R15 at each occurrence are the same or different and are a) H, b) formyl, c) carboxyl, d) Cι_e alkoxycarbonyl, e) C^_β alkyl, f) C₂.₈ alkenyl, wherein the substitutents (e) and (f) can be optionally substituted with OH, halo, Cι_e alkoxyl, Cι_e acyl, Cι_e alkylthio or Cι_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, N0 , Cι_e alkyl, C _e alkoxy, C _e acyl, C _₆ alkylthio, or C __Q alkoxycarbonyl; h) -NR₄₂R₄3, i) OR44, j) -S(=0)i-R4₅, k) -S0₂-N(R₄₆)(R₄7), or I) a radical of the following formulas:

Rδ3

HN N— R₅₂ (CH₂)t-N N— 53-N N-

R ₉ is the same as defined above; T is a) O, b) S, or c) S0₂; R4₂ and R43 at each occurrence are the same or different and are a) H, b) C3.6 cycloalkyl, c) phenyl, d) Cι_e acyl, e) C _₈ alkyl optionally substituted with OH, Cι_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, -N0₂, C_1-4

alkoxy,-NR4₈R₄g, or , f)

R55-CH- or g)

V -(CH₂)t-

V is a) O, b) CH₂, or c) NR₅₆;

R4₈ and R4g at each occurrence are the same or different and are a) H, or b) C-|_4 alkyl; R₅₄ is a) OH, b) Cι_4 alkoxy, or c) -NR57R5₈; δδ 's a) H, or b) C C11..77 aallkkyyll ooppttiioonally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C(=0)-NH₂, -CO₂H, or -C(=NH)-NH₂; R₅₆ is a) H, b) phenyl, or c) Cι_e alkyl optionally substituted by OH;

R₅₇ and Rδ₈ at each occurrence are the same or different and are a) H, b) Ci_₅ alkyl, c) C1.3 cycloalkyl, or d) phenyl; R44 is a) Cι_₈ alkyl optionally substituted with C .₆ alkoxy or Cι_₆ hydroxy, C₃_e 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, Cι_₅ alkyl, Cι_₅ alkoxy, or C^s acyl, b)

V N-(CH₂)t

c) phenyl, or d) pyridyl; R₄₅ is a) Cι_₁₆ alkyl, b) C₂_ιe alkenyl, wherein the substituents (a) and (b) can be optionally substituted with Ci_e alkoxycarbonyl, or a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, c) an aromatic moiety having 6 to 10 carbon atoms, or 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,

Ci_e alkyl, C₁^ alkoxy, Cι_₆ acyl, C _₈ alkylthio, or C^ alkoxycarbonyl;

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

R50 and R51 at each occurrence are the same or different and are a) H, b) OH, c) Cι_e alkyl optionally substituted with -NR ₈R g in which R ₈ and R _g are as defined above, d) R50 and R5 taken together are =0; 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, Cι_₅ alkyl, C .5 alkoxy, or C-_|_₅ acyl, c) morpholinyl, d) OH, e) C _e alkoxy, f) -NR₄₈R₄g in which R₄₈ and R₄₉ are as defined above, g) -C(=0)-R₅₉, or h)

Rδ3 is a) H, b) formyl, c) Cι_ alkyl, d) Cι_4 acyl, e) phenyl, f) C₃.₆ cycloalkyl, g) -P(0)(OR₃₇)(OR₃₈), or h) -S0 R_3g, in which R₃₇, R₃₈ and R₃₉ are as defined above;

a) morpholinyl, b) OH, or c) Cι_e alkoxy; h is 1 , 2, or ^■ 3; i is 0, 1 , or 2; j is 0, or 1 ; k is 3, 4, or 5; ris 1,2, 3, 4, 5 or 6; t is 0, 1,2, 3,4, 5, or 6; u is 1 or 2; and

Qis a) hydrogen, b) halo, c) N0₂, d) N₃, e) C_rC₆ alkylthio,

O ) C C₆ alkyl— s— ,

O g) C C₆ alkyl— s—

0 ' h) C C₆ alkyl, i) Cι-C₆ alkoxy, j) formyl,

O k) C C₆ alkyl-c- ,

O

I) C C₆ alkyl-o-C- , m) -sulfamoyl (H₂NS0₂-), n) -NHOH,

O o) C C₆ alkyl— c-O—

O

P) heteroaryl — c— in w aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, - 3

0 q) C6H5-C , amino, s) Cι-C₆ alkylamino-, t) di (Ci-Ce alkyl)amino-,

O u) (C C₆) alkyl- C-NR₆₀R₆₁ in which Reo and Re are each independently hydrogen or C Ce alkyl, v) OH, w) cyano, x) hydroxy (Cι-C₆ alkyl),

0 y) C C₆ alkyl-S-C— ,

0 z) NC — (CH₂) -C— in which r is 1-6,

0 aa) C₆H₅CH₂-0-C- ,

0 bb) C₆H₅-0-C- ,

_/OR₈₄

N cc) C C₆ alkyl— c— in which R₈₄ is hydrogen or Cι_₆ alkyl,

O dd) R₈₅0-(CH₂)ι_₆-C— in which R₈₅ is hydrogen, C _₈ alkyl optionally substituted with one or more F, Cl, OH, Cι_₈ alkoxy or C _₈ acyloxy, C3.5 cycloalkyl or Cι_₈ alkoxy;

N-OR₈₄ ee) H-C— jn which R₈₄ is hydrogen or Cι_₆ alkyl, ff) a substituted or unsubstituted C₆-Cιo 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 substituents for such p, q, ff, gg and hh moieties being selected from 1 or 2 of the following:

1) halo,

2) Cι.₆ alkyl,

3) N0₂,

4) N₃,

O 5) C C₆ alkyl —S— ,

O

6) C C₆ alkyl— s II — o '

7) formyl,

O

8) C C₆ alkyl-c- ,

O

9) C C₆ alkyl-o-C- ,

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

O

11) C₆H₅-C- ,

O

12) -(C C₆) alkyl- C-NR₆₀R₆₁ in which R₆o and R₆ι are each independently hydrogen or Cι-C₆ alkyl, 13) OH,

14) hydroxy (C_rC₆ alkyl),

O

15) C_rC₆ alkyl -S-C- ,

O

16) NC-(CH₂)_r —0-C— in which r is 1-6,

O 17) C₆H₅CH₂-0-C- ,

18) -CH₂-R₈o in which R₈Q is a) -OR3₂ in which R₃ 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 0,

S or N atoms,

_/OR^ N

19) C_rC₆ alkyl— c— in which R₈₄ is as defined above,

20) cyano, 21) carboxyl,

22) CF₃,

O

23) C C₆ alkyl— £-0—

O

24) C₆H₅-0-C— in which the phenyl moiety may be optionally substituted by halo or (Cι-C₆)alkyl,

O 25) NR₆₀R_6f-C— in which R_6Q and R₆ι are as defined above,

O O

26) R₉₁-NH-C— or R₉₁-C-NH— in which R₉₁ is a 5- or 6- membered aromatic heterocyclic group having 1-3 0, N or S, O

27) C₆H₅(CH₂)ι^-0-C- ,

O

28) R8₅θ-(CH₂)₁.₆— 0-C— in which R₈₅ is as defined above,

O

29) SiR₉₉R₁₀₀Rιoι-0-CH₂-C— in which R₉g, R_i0o and R_i0ι are each independently Cι_₆ alkyl; or Q and either Ri and R₂ taken together form -0-CH₂-0.

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 I 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. 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, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p- toluene-sulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic, hydroiodic, hydrobromic, and the like. These salts may be in hydrated form.

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 Ci-Ce alkyl, the alkyl group may have from 1 to 6 carbon atoms.

Similarly, terms such as "C -C₈ alkenyl" refer to at least one double bond alkenyl group having the specified number of carbon atoms, "C₂-C₈ 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-0— where the alkyl group can have the specified number of carbon atoms, e.g. C^Ce 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 naphthyi. "Heteroaromatic" as used herein refers to an aromatic heterocyclic moiety having one or more atoms selected from O, N, S, e.g. pyridine, thiophene, furan, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2- quinolyn, 3-quinolyn, 1-isoquinolyl, 3-isoquinolyl, 2-imadazolyl, 4- imadazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4- pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4- thiazolyl, 5- thiazolyl, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2- benzothiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3- 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-tetrazolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 1-purinyl, 3-isothiazolyl, 4- isothiazolyl, and 5-isothiazolyl.

A saturated or unsaturated heterocyclic group can have 1-3 atoms selected from O, N and S, e.g. dioxolane, imidazolidine, dithiolane, oxathiolane, oxazolidine, piperidinyl, piperazinyl, morpholino or thiomorpholino, or the corresponding unsaturated heterocyclic groups.

Where possible nitrogen and/or sulfur atoms in such heterocyclic moieties may be oxidized and such oxidized compounds are intened to be encompassed within the formula I compounds.

DETAILED DESCRIPTION

Preferred embodiments of the present invention are the compounds of formula I wherein A is in which Q , R , and R₃ are as defined above.

A still more preferred embodiment of the present invention comprises a compound of the formula

or a pharmaceutically acceptable salt thereof, in which

Ri is H, Ci _₈ alkyl optionally substituted with one or more F, Cl, OH, Cι_₈ alkoxy, or Cι_₈ acyloxy, C3.6 cycloalkyl or Cι_₈ alkoxy;

R₂ and R₃ are each independently a) H, b) F, c) Cl, d) Br, e) Cι_e alkyl, f) N0₂, g) I, h) Cι_6 alkoxy, i) OH j) amino, or k) cyano; and Q is a) hydrogen, b) halo, c) N0₂, d) N₃, e) C_rC₆ alkylthio,

0 f) C C₆ alkyl -S- ,

0 g) C C₆ alkyl— s II— ,

0 h) C_rC₆ alkyl, i) Cι-C₆ alkoxy, j) formyl,

O k) C₁-C₆ alkyl-c- ,

O

I) C C₆ alkyl-o-C— ,

O m) C C₆ alkyl-c-O- ,

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

O o) 6^5" O ,

P) amino, q) Ci-Ce alkylamino-, r) di(Cι-C₆ alkyl)amino-, o s) (C_rC₆) alkyl- C-NR₆₀R₆₁, in which R₆o and R₆ι are each independently hydrogen or Cι-C₆ alkyl, t) OH, u) cyano, v) hydroxy (Cι-C₆ alkyl),

O w) C C₆ alkyl— S-C— ,

O x) NC-(CH₂)_r —0-C— in which r is 1-6,

O z) C₆H₅-0-C- ,

OR₈₄

N^κ aa) C C₆ alkyl— c— wherein R₈₄ is hydrogen or C _e alkyl,

O bb) 85θ-(CH₂)-,.₆— C— in which R₈₅ is hydrogen, Cι_₈ alkyl optionally substituted with one or more F, Cl, OH, Cι_₈ alkoxy or Cι_₈ acyloxy, C3_₆ cycloalkyl or Cι_₈ alkoxy,

N-OR₈₄ cc) H-C— in which R₈ is as defined above, dd)

ee)

f )

gg)

Y^

M hh)

jj)

kk)

II)

N-N mm)

N"^ nn)

00)

N-N

¹ ;N

N

I

^R92 in which R₉₂ is H or C^ alkyl,

PP)

N-N qq)

rr)

,N xά

ss)

tt)

uu)

.S N

,_^X vv)

- OU -

ww)

xx)

yy)

zz)

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)

iϋ)

B is an unsaturated 4-atom linker having one nitrogen and three carbons; M is a) H, b) Cι_₈ alkyl, c) C3-₈ cycloalkyl, d) -(CH₂)_mOR₆₆, or e) -(CH₂)_nNR₆₇R₆₈;

Z is a) 0, b) S or c) NM;

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

X and Y are i each independently a) hydrogen, b) halo, c) N0₂, d) N₃. e) Cι_₆ alkythio, -- 52 -

0 f) C C₆ alkyl — S— ,

0 g) C C₆ alkyl-s- ,

0 h) C_rC₆ alkyl, i) Cι-C₆ alkoxy, j) formyl,

0 k) C C₆ alkyl— c—

0

1) C C₆ alkyl— 0-C—

O I I 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) C₆H₅-C- , o) amino, p) Ci-Ce alkylamino-, q) di(Cι-Ce alkyl)amino-,

O I I r) -(C_rC₆) alkyl-C-NR₆₀R₆₁ in which R_6Q and R_6i are each independently hydrogen or C^Ce alkyl, s) OH, t) hydroxy (Cι-C₆ alkyl),

O u) C_rC₆ alkyl —S-C- ,

O v) NC-(CH₂)_r— 0-C— in which r is 1-6,

O w) C₆H₅CH₂-θ-C- , 0

X) C₆H₅-0-C-

_/OR84

N y) C C₆ alkyl- _ _ in which R₈4 is as defined above, z) cyano, aa) carboxyl, bb) CF₃, cc) mercapto,

0 dd) C_rC₆ alkyl- -c-o- o ee) C₆H₅-0-C— in which the phenyl moiety may be optionally substituted by halo or Cι-C₆ alkyl,

O ff) C₆H₅(CH₂)₁^-0-C- ,

O gg) R₈5θ^~(CH₂)₁.₆— C— in which R₈₅ is as defined above, or

O hh) SiR₉₉R₁₀₀R₁₀₁— O-CH₂-C— in which R₉₉, Rι₀o and Rι₀ι

are each independently Cι_₆ alkyl; or

Q and either R<\ and R₃ taken together form -O-CH₂-0; Re is a) H, b) C _s alkyl optionally substituted with one or more halos, or c) Cι_₈ alkyl optionally substituted with one or more OH, or Cι_₈ alkoxy; E is a) NR_69ι b) -S(=0)j in which i is 0, 1 or 2, or c) O; R63 ^is a) H, b) Ci^ alkyl, c) -(CH₂)_q-aryl, or d) halo;

Re6 is H or C _4 alkyl;

R₆₇ and R₆₈ i are each independently H or C^ alkyl, or NR67R68 taken together are -(CH₂)_m-;

R₆₉ is a) H, b) Cι_6 alkyl, c) -(CH₂)_q-aryl, d) -C0₂R₈ , e) COR₈₂, f) -C(=0)-(CH₂)_q-C(=0)R₈ι, g) -S(=0)₂-Ci.₆ alkyl, h) -S(=0)₂-(CH₂)_q-aryl, or i) -(C=0)j-Het in which j is 0 or 1 ;

∑ι is a) -CH₂-, or b) -CH(R₇₀)-CH₂-;

Z₂ is a) -0₂S-, b) -0-, c) -S-, d) -SO-, or e) -N(R₇₁)-; Z₃is a) s, b) so, c) S0₂, or d) O;

Ai is H or CH₃;

A₂ is a) H, b) OH-, c) CH₃C0₂-, d) CH₃-, e) CH3O-, f) R₇₂0-CH₂-C(0)-NH-, g) R₇₃0-C(0)-NH-, h) R₇₃-C(0)-NH-, i) (C_rC₂)alkyl-0-C(0)-, or j) HO-CH₂; or

A and A₂ taken together are a)

b) 0 = ;

Re4 is H or CH₃-; m is 4 or 5; nisO, 1,2, 3, 4 or 5; y is 0 or 1 ; pisO, 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) R74θC(R₇5)(R76)-C(0)-, b) R₇₇OC(0)-, c) R ₈(0)-, d) R₇₉-S0₂-, or e) R₈₀-NH-C(O)-;

R70 is H or (CrCealkyl;

R71 is a) R₇4OC(R75)(R₇₆)-C(O)-, b) R₇₇O-C(0)-, c) R₇₈-C(0)-, d)

e)

f) H₃C-C(0)-(CH₂)₂-C(0)-, g) R7₉-S0₂-, h)

i) R₈₀-NH-C(O)-,

R₇₂ is a) H, b) CH₃, c) phenyl -CH₂-, or d) CH₃C(0)-; R ₃ is (C -C₃)alkyl or phenyl;

R₇₄ is H, CH₃, phenyl-CH₂- or CH₃-C(0)-; R75 and R ₆ are each independently H or CH , or R₇₅ and R₇₆ taken together are -CH₂CH₂-; R77 is (C -C3)alkyl or phenyl;

R₇₈ is H, (C_rC )alkyl, aryl-(CH₂)_nι, CIH₂C, CI₂HC, FH₂C-, F₂HC- or (C₃-Ce)cycloalkyl; R₇₉ is CH₃; -CH₂CI, -CH₂CH=CH₂, aryl or -CH₂CN; R₈₀ is -(CH₂)_nι-aryl where n¹ is 0 or 1 ; R₈₁ is a) H, b) Ci_e 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) C _e 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) C-1.6 alkyl, c) -(CH₂)_q-aryl in which q is as defined above; or d) -C(=0) Cι^ alkyl; and - OO -

aryl is phenyl, pyridyl or naphthyi, said phenyl, pyridyl or naphthyi moieties being optionally substituted by one or more halo, -CN, OH, SH, Cι_e alkoxy or C^ alkylthio.

Another preferred embodiment of the present invention comprises a compound of the formula

or a pharmaceutically acceptable salt thereof, in which

Ri is H, Cι_₈ alkyl optionally substituted with one or more F, Cl, OH, Cι_₈ alkoxy or Cι_₈ acyloxy, C3.6 cycloalkyl or Cι_₈ alkoxy; R₂ and R₃ are each independently H or F; or R₂ and R₃ taken together represent

0—

Q is a) hydrogen, b) halo, c) N₃. d) N0₂, e) C C₆ alkylthio, O f) C C₆ alkyl-s- , O g) C C₆ alkyl— s—

O h) C1-C-6 alkyl, i) C Ce alkoxy, j) formyl,

O k) C C₆ alkyl— c— ,

O I) C C₆ alkyl-o-C-

O m) C₁-C₆alkyl-c-0-₎ n) (C_rC₆ 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 Rge, .OH

N C C₆ alkyl— c

P) 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 Rg₆, and R₉₆ is a) C_rC₆ alkyl-OH, b) C C₆ alkyl- -0-C II-.

O

O c) CH₃-c II- C C₆ alkyl— c— .

O d) cyano, e) formyl,

_N-OH

II f) H-C- ,

O II g) C_rC₆ alkyl- -0-C-, O h) SiR₉₉R₁₀₀Rι₀₁— 0-CH₂-C— in which Rgg, R100 and R101 are each independently C^ alkyl,

O O i) CH₃_s- C C₆ alkyl— s- , o o o j) HC≡CCH₂OC— ,

O k) C₆H₅-0-C— where the phenyl may be optionally substituted by halo,

O I) HO-CH₂-C- , m) (C C₆ alkyl)₂N-, n) C_rC₆ alkyl-NH-, o) amino,

O p) C C₆ alkyl-s- ,

O q) C₆H₅CH₂OC— or

O r) R₉₈-C— 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.

Some specific preferred embodiments of the present invention are listed in the table below.

O

7^/ V

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.

Isoxazolinones 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. Org. Chem. 1984, 49, p. 4287-4290]. Reaction of 1 with sodium hydride and ethyl formate provides 2 which is in turn reacted with hydroxylamine yielding 3. Treatment of 3 with mild base, preferably potassium carbonate, in an appropriate solvent, preferably dichloromethane or N, Λ/-dimethylformamide followed by addition of 4 (prepared by methods described by Barnes et al in US Patent 5, 284, 863) provides isoxazolinone 5.

Scheme 1

2

An alternative way to prepare aryl acetic esters 1 of the present invention is shown in Scheme 2. Treatment of triflate 6 (prepared from methyl 4-hydroxyphenyl acetate by methods known by those skilled in the art) with an N, N- dialkylamine in the manner described by Buchwald [Tet. Lett., 1997, 38, p. 6363-6366] produces esters exemplified by 7. Aryl-bromides, -iodides, and -chlorides are also suitable as replacements for triflate 6 in Scheme 2. The N, N- dialkylamines used in Scheme 2 are either commercially available or are synthesized by literature procedures. Literature preparations of many cyclic N, N- dialkylamines have been detailed by Gadwood (WO 97/10223) and others are well known to those skilled in the art.

Scheme 2

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 suitable solvent, preferably acetonitrile or N, N- dimethylformamide, at a temperature between 25°C and 100°C provides 9. Compound 8 is commercially available. Compound 9 is converted to 11 or 12 by methods described by Gravestock (World Patent 97/14690). This sequence is also known to those skilled in the art as the Willgerodt reaction. Conversion of 11 to 12 can also be accomplished by various methods known in the chemical literature including but not limited to treatment with acid in hot alcohol. Scheme 3

Sulfur morpholine

10

Sulfoxides and sulfones 14 and 16 are prepared by treating sulfides 13 and 15, respectively with an oxidizing agent such as m- chloroperoxybenzoic acid or osmium tetroxide by methods known by those skilled in the art and exemplified by Barbachyn [J. Med. Chem., 1996, 39, 680-685].

Scheme 4

Xi = H or F X₂ = H or F

An alternative method of preparing compound 18 of the present invention is shown in Scheme 5. Treatment of 17 with an appropriate organostannane provides 18. This method is known by those skilled in the art as the Stille cross-coupling reaction.

Scheme 5

Preparation of 21, 22, 23, and 24 of the present invention is described in Scheme 6. Treatment of 19 with trifluoroacetic acid provides 20. Compound 20 is treated with an acid chloride, chloroformate, sulfonyl halide, or isocyanate in the presence of triethylamine by methods well known in the chemical literature to provide 21, 22, 23, and 24, respectively.

Scheme 6

The triazole-substituted compounds 27 and 28 are prepared by cyclization of the azide 25 with acetylenes 26 (Scheme 7). This is a standard 3+2 cycloaddition which is well documented in the chemical literature. The acetylenes 26 are either commercially available or prepared by literature procedures. For example, cyanoacetylene is prepared according to Murahashi [J.Chem. Soc. Jap., 1956, 77, 1689]. 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 methanoi, ethanol, diethyl ether, and acetone.

Scheme 7: 1 ,2,3-Triazoles

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 stannous chloride in a suitable solvent such as a 2:1 combination of ethyl acetate and methanoi . Treatment of aminophenylisoxazolinones 29 with 2,5-dimethoxytetrahydrofurans 30 in acetic acid provide pyrrole- substituted isoxazolinones 31 (Scheme 8). Subsequent conversions of the pyrrole (R = CHO) are also possible, for instance the corresponding oxime can be prepared by refluxing with 50 % aqueous hydroxylamine in methanoi.

Scheme 8: Pyrroles

N-thioacetates 33 may be prepared from the corresponding N- acetates 32 using a variety of well known literature methods, for instance by refluxing in benzene with Lawesson's reagent. Other solvents such as toluene and xylene are also suitable.

Scheme 9: Thioacetates

Lawesson's Reagent benzene, reflux

It will be understood that where the substituent groups used in the above reactions contain certain reaction-sensitive functional groups which might result in undesirable side-reactions, such groups may be protected by conventional protecting groups known to those skilled in the art. Suitable protecting groups and methods for their removal are illustrated, for example, in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons, 1991). It is intended that such "protected" intermediates and end-products are included within the scope of the present disclosure and claims.

Some of the desired end-products of formula I contain an amine. In these cases, the final product may be recovered in the form of a pharmaceutically acceptable acid addition salt, e.g. by addition of the appropriate acid such as HCI, HI or methane-sulfonic acid to the amine.

It will be appreciated that certain products within the scope of formula I may have substituent groups which can result in formation of optical isomers. It is intended that the present invention include within its scope all such optical isomers as well as epimeric mixtures thereof, i.e. R- or S- or racemic forms.

The compounds of the invention are useful because they possess pharmacological activities in animals, including particularly mammals and most particularly, humans. The novel isoxazolinone derivatives of general formula I , or pharmaceutically acceptable salts or prodrugs thereof, are potent antibiotics active against gram-positive bacteria. 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 dental equipment, they are especially useful in the treatment 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 formulated as pharmaceutical compositions comprising, in addition to the active isoxazolinone ingredient, a pharmaceutically acceptable carrier or diluent. The compounds may be administered by a variety of means, for example, orally, topically or parenterally (intravenous or intramuscular injection). The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. Compositions for injection may be prepared in unit dose form in ampules or in multidose containers and may contain additives such as suspending, stabilizing and dispersing agents. The compositions may be in ready-to-use form or in powder form 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 the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 25 mg/day to about 2 g/day.

The preparations of pyrazoles substituted compounds are outlined in Scheme 10. Compound 29 was diazotized and then reduced to form hydrazine hydrochloride salt 34 via one of the many well known methods in the chemical literature including but not limited to the treatment with sodium nitrite and stannous chloride. Treatment of 34 with 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

29

34

35 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 (NCCLS). 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% CO2). The MIC was defined as the lowest drug concentration that prevented visible growth.

i ^" ! ^"" I

Microorganism MIC value in ug/ml

S. pneumoniae A9585 < 8

E. faecalis A20688 | < 16

S. aureus A15090, penicillinase positive ≤ 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: h = hour(s) mol = mole(s) mmol - mmole(s)

9 = gram(s)

5 min = minute(s) rt = room temperature

THF = tetrahydrofuran

L = liter(s) mL = milliliter(s)

) Et₂0 = diethyl ether

EtOAc = ethyl acetate

MeOH = methanoi

DMF = dimethylformamide

In the following examples, all temperatures are given in degrees

Centigrade. Melting points were determined on an electrothermal apparatus and are not corrected. Proton and carbon-13 nuclear magnetic resonance (¹H and ¹³C NMR) spectra were recorded on a Bruker AM-300 or a Varian Gemini 300 spectrometer. All spectra were determined in CDCI₃, DMSO-d₆, CD3OD, or D2O unless otherwise indicated. Chemical shifts are reported in δ 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 5 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"¹ to 400 cm-¹, calibrated to 1601 cm-¹ absorption of a polystyrene film, and are reported in reciprocal centimeters (cm-¹). Mass spectra were recorded on a Kratos MS-50 or a Finnegan 4500 instrument 0 utilizing direct chemical ionization (DCI, isobutene), fast atom bombardment (FAB), or electron ion spray (ESI). 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, and/or staining by heating with methanolic phosphomolybdic acid. Column chromatography, also referred to as flash chromatography, was performed in a glass column using finely divided silica gel at pressures 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.

EXAMPLE 1

N-[[4-(4-methylthiophenyl)-5-oxo-2-isoxazolinyl]methyl]acetamide

A. Ethyl 4-methylthiophenylacetate

To a solution of 4-methylthiophenylacetic acid (1.0 g, 5.48 mmol) in 55 mL of ethanol was slowly added a catalytic amount of concentrated sulfuric acid. The mixture was stirred at room temperature overnight and then concentrated at reduced pressure. The residue was partitioned between methylene chloride and sodium bicarbonate. The organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated to yield 1.1 g of a colorless oil (96%). ¹H NMR (300MHz, CDCI3) δ 7.22 (s, 4 H), 4.15 (q, J=6 Hz, 2 H), 3.57 (s, 2 H), 2.47 (s, 3 H), 1.25 (t, J=6 Hz, 3 H).

B. Ethyl 4-methyIthio-α-formyl-phenylacetate A suspension of NaH (0.84 g, 20.8 mmol) was added at room temperature to a solution of ethyl 4-methylthiophenylacetate (1.1 g, 5.2 mmol) in ethyl formate (20 mL). The mixture was stirred at room temperature for 1 hour and then cold 0.5 N HCI (20 mL) was added slowly. The crude reaction was then extracted with ether, and the organic layer was washed with sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated to yield 1.2 g of ethyl 4-methylthio-α- formyl-phenylacetate as a colorless oil, which was used in the next step without purification.

C. 4-(4-methylthio)-phenylisoxazolin-5-one

To a solution of ethyl 4-methylthio-α-formyl-phenylacetate in 20 mL of methanoi 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. ¹H NMR (300MHz, MeOH-d₄) δ 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 mmol). The mixture was stirred at room temperature for 18 hours. It was then poured into 10 mL of 1N HCI and extracted three times with chloroform. The organic layer was then washed with sodium bicarbonate, brine, dried over magnesium sulfate, filtered, concentrated to yield a tan solid, which was then recrystallized with hexane/chloroform. The resulting solid was further purified by triturating with ether to yield 0.186 g (69%) of a tan solid. ¹H NMR (300MHz, DMSO-d₆) δ 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).

EXAMPLE 2

N-{[4-(3-fluoro-4-oxido-4-morpholin-4-ylphenyl)-5-oxo-2- hydroisoxazol-2-yl]methyl}acetamide

To N-{[4-(3-fluoro-4-morpholin-4-ylphenyl)-5-oxo-2-hydroisoxazol-

2-yl]methyl}acetamide (200 mg, 0.60 mmol) in 50 mL methanoi was added magnesium monoperoxyphthalate (300 mg, 0.60 mmol). After 2 hours at ambient temperature the white precipitate was filtered and the filtrate was concentrated. The remaining residue was pushed through a plug of basic alumina with dichloromethane. The eluant was concentrated and recrystallized from dichloromethane / hexanes to afford 162 mg (44%) of the title compound as a brown solid. ¹H NMR (DMSO- d₆; 300 MHz) δ 9.19 (s, 1 H), 9.02 (t, J = 6.1 Hz, 1H), 8.62-8.55 (m, 2H),

7.82-7.75 (m, 2H), 5.09 (d, J = 6.0 Hz, 2H), 4.44 (app t, J = 11.1 Hz, 2H), 4.08 (app t, J = 9.6 Hz, 2H), 3.78 (app d, J = 11.1 Hz, 2H), 2.89 (app d, J = 10.5 Hz, 2H), 1.86 (s, 3H); ESI (M+H)⁺=352. EXAMPLE 3

N-({4-[4-(methylsulfinyl)phenyl]-5-oxo-2-hydroisoxazol-2- yl}methyl)acetamide

To N-{[4-(4-methylthiophenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide (1.0 g, 3.6mmol) in 50 mL chloroform at 0°C was 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 concentrated. The residue was triturated with ether providing 800 mg (79%) of the title compound as a colorless solid. ¹H NMR (DMSO-d₆; 300 MHz) δ 9.11 (s, 1H), 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.

EXAMPLE 4

N-({4-[4-(methylsulfonyl)phenyl]-5-oxo-2-hydroisoxazol-2- yl}methyl)acetamide

To N-{[4-(4-methylthiophenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide (200 mg, 0.72 mmol) in 20 mL chloroform at 0°C was added m-CPBA (450 mg, 1.44 mmol) in 5 mL chloroform. After 30 minutes saturated sodium bicarbonate was added and the reaction mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was precipitated from acetone / 1:1 hexanes : ether providing 112 mg (50%) of the title compound as a colorless solid. ¹H NMR (DMSO-d₆;

300 MHz) δ 9.24 (s, 1H), 9.01 (t, J - 6.1 Hz, 1 H), 8.02 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 5.11 (d, J = 6.2 Hz, 2H), 3.20 (s, 3H), 1.86 (s, 3H); ESI (M+H) ⁺=311.

EXAMPLE 5

N-({4-[4-(1 ,1 -dioxo(1 ,4-thiazaperhydroin-4-yl))-3-fluoropheny l]-5-oxo- 2-hydroisoxazol-2-yl}methyl)acetamide

To N-{[4-(3-fluoro-4-(1 ,4-thiazaperhydroin-4-yl)phenyl)-5-oxo-2- hydroisoxazol-2-yl]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 μl; 0.07 mmol). After 18 hours at ambient temperature saturated sodium bisulfite was added and the reaction mixture was extracted with 4:1 ch!oroform:methanol. The organic layer was concentrated providing 85 mg (77%) of the title compound as a colorless solid. ¹H NMR (DMSO-d₆;

300 MHz) δ 8.95 (s, 1H), 8.92 (t, J = 6.2 Hz, 1H), 7.62-7.51 (m, 2H), 7.17 (app t, J = 9.2 Hz, 1H), 4.99 (d, J = 6.2 Hz, 2H), 3.52-3.48 (m, 4H), 3.27- 3.23 (m, 4H), 1.82 (s, 3H); ESI (M+H) ⁺=384.

EXAMPLE 6

4-(3-Fluoro-4-morpholin-4-ylphenyl)-2- [(thioxoethyl)amino]methyl}- 2-hydroisoxazol-5-one

Lawesson's Reagent benzene reflux

A mixture of N-{[4-3-fluoro-4-morpholinylphenyl-5-oxo-2- isoxazolinyl]methyl}acetamide (0.25 g, 0.75 mmol) and Lawesson's reagent (0.4 g, 1.0 mmol) in 10 mL of benzene was heated at reflux for 3 hours. The mixture was then concentrated under reduced pressure. The residue was purified using silica gel chromatography eluting with methylene chloride and ethyl acetate to give a colorless solid (80 mg, 30%): ¹H NMR (300 MHz, CDCI₃) δ 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).

EXAMPLE 7

N-{[4-(4-acetylphenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide

To N-{[4-phenyl-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide (3.0 g, 12.9 mmol) and aluminum (III) chloride (13.8 g, 103.4 mmol) in 150 mL 1 , 2-dichloroethane was added acetyl chloride (7.3 mL, 103.4 mmol) dropwise over 10 minutes. The resultant red mixture was heated to 80°C for 3.5 hours, cooled to ambient temperature, and poured over 10 minutes into a rapidly stirring mixture of 20% methanol/chloroform and 1N hydrochloric acid which was immersed in an ice bath. The mixture was poured into a separatory funnel, and the layers were separated. The aqueous layer was extracted twice with 20% methanol/chloroform, and 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. ¹H NMR (DMSO-d₆; 300MHz) δ 9.18 (s, 1H), 9.00 (t, J = 6.1 Hz, 1H), 7.96 (d, J = 6.7 Hz, 2H), 7.91 (d, J = 6.6 Hz, 2H), 5.10 (d, J = 6.2 Hz, 2H), 2.56 (s, 3H), 1.86 (s, 3H); ESI (M+H)⁺=275.

EXAMPLE 8

N-({4-[4-((hydroxyimino)ethyl)phenyl]-5-oxo-2-hydroisoxazol-2- yl}methyl)acetamide

A mixture of N-{[4-(4-acetylphenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide (2.0 g, 7.3 mmol) and 50% aqueous hydroxylamine (1.0 mL, 14.6 mmol) was heated to reflux for 1.5 hours, concentrated to near dryness and redissolved in 20% methanol/chloroform. Hexanes were added until the solution became cloudy and the mixture was stored at 0°C for 3 hours. The precipitate was filtered providing 1.42 g (67%) of the title compound as a pale yellow solid. ¹H NMR (DMSO-d₆; 300MHz) δ

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), 7.66 (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.

EXAMPLE 9

N-{[4-(4-(2-furyl)phenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide

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- tributylstannylfuran (0.26 mL, 0.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (77 mg, 0.08 mmol), triphenylarsine (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) in 5 mL DMF. The reaction mixture was capped and allowed to stir at ambient temperature for 8 hours, at which time it was diluted with 20% methanol/chloroform, filtered thru celite and concentrated. The residue was suspended in chloroform, loaded onto a Biotage flash 40i chromatography module (12M) thru a frit, and eluted with 50% hexane/ethyl acetate providing a solid which was triturated with chloroform/ether to provide 132 mg (53%) of the title compound as a colorless solid. ¹H NMR (DMSO-d₆; 300MHz) δ 9.00 (s, 1H), 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, 1H), 6.60-6.59 (m, 1H), 5.04 (d, J = 6.1 Hz, 2H), 1.85 (s, 3H); ESI (M+H)⁺=299.

EXAMPLE 10

N-{[5-oxo-4-(4-(2-thienyl)phenyl)-2-hydroisoxazol-2- yl]methyl}acetamide

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 mmol), triphenylarsine (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) in 5 mL DMF. The reaction mixture was capped and allowed to stir at ambient temperature for 8 hours, at which time it was diluted with 20% methanol/chloroform, filtered thru celite and concentrated. The residue was suspended in chloroform, loaded onto a Biotage flash 40i chromatography module (12M) thru a frit, and eluted with 15% acetone/chloroform providing a solid which was triturated with chloroform/ether to provide 165 mg (63%) of the title compound as a colorless solid. ¹H NMR (DMSO-d₆; 300MHz) δ 9.00 (s, 1 H), 8.95 (t, J = 6.0 Hz, 1H), 7.81 (d, J = 7.3 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.54-7.52 (m, 2H), 7.15-7.11 (m, 1 H), 5.04 (d, J = 6.1 Hz, 2H), 1.85 (s, 3H); ESI (M+H)⁺=315.

EXAMPLE 11

N-{[4-(4-(2H,3H-1,4-dioxin-5-yl)phenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide

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)-5,6-dihydro-[1 ,4]-dioxin (346 mg, 0.92 mmol), tris(dibenzylideneacetone)dipalladium(0) (77 mg, 0.08 mmol), triphenylarsine (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) in 5 mL DMF. The reaction mixture was capped and allowed to stir at ambient temperature for 16 hours, at which time it was diluted with 20% methanol/chloroform, 10% aqueous potassium fluoride was added and the mixture was allowed to rapidly stir for 1 hours. The reaction mixture was filtered thru celite and concentrated. The resultant black oil was dissolved in 20% methanol/chloroform, adsorbed onto silica gel and loaded into a Biotage flash 40i chromatography module SIM. Chromatography was performed using a 12M silica gel cartridge eluting with 20% acetone/chloroform providing an amber oil which was triturated with ether, yielding 115 mg (44%) of the title compound as a tan solid. ¹H NMR (DMSO-d₆; 300MHz) δ 8.93-8.88 (m, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 6.96 (s, 1H), 5.01 (d, J = 6.2 Hz, 2H), 4.22-4.19 (m, 2H), 4.10-4.07 (m, 2H), 1.85 (s, 3H); ESI (M+H)⁺=317.

EXAMPLE 12

N-{[5-oxo-4-(4-pyrazin-2-ylphenyl)-2-hydroisoxazol-2- yl]methyl}acetamide

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), tris(dibenzylideneacetone)dipalladium(0) (77 mg, 0.08 mmol), triphenylarsine (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) in 5 mL DMF. The reaction mixture was capped and allowed to stir at ambient temperature for 16 hours, at which time it was diluted with 20% methanol/chloroform, 10% aqueous potassium fluoride was added and the mixture was allowed to rapidly stir for 1 hour. The reaction mixture was filtered thru celite and concentrated. The resultant black oil was dissolved in 20% methanol/chloroform, adsorbed onto silica gel and loaded into a Biotage flash 40i chromatography module SIM. Chromatography was performed using a 12M silica gel cartridge eluting with 25% acetone/chloroform providing an amber oil which was triturated with ether, yielding 52 mg (44%) of the title compound as a colorless solid. ¹H NMR (DMSO-d₆; 300MHz) δ 9.28 (d, J = 1.4 Hz, 1 H), 9.11 (s,

1H), 8.97 (t, J = 6.1 Hz, 2H), 8.71 (app t, J = 1.9 Hz, 1H), 8.59 (d, J = 2.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 5.07 (d, J = 6.2 Hz, 2H), 1.86 (s, 3H); ESI (M+H)⁺=311. - y -

EXAMPLE 13

N- [5-oxo-4-(4-{4-[2-(1 ,1 ,2,2-tetramethyM - silapropoxy)acetyl]piperazinyl}phenyl)-2-hydroisoxazol-2- yl]methyl}acetamide

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-butyldimethylsilyloxy)acetyl chloride (1.0 g, 4.8 mmol). The resultant mixture was allowed to stir at ambient temperature for 1.5 hours before being partitioned between dichloromethane and water. The organic layer was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated. The residue was triturated with ether to provide 0.24 g (49%) of the title compound. ¹H NMR (methanol-d₄; 300 MHz) δ 8.49 (s, 1H), 7.66 (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.

EXAMPLE 14

N-[(4- 4-[4-(2-hydroxyacetyl)piperazinyl]phenyl}-5-oxo-2- hydroisoxazol-2-yl)methyl]acetamide

To N-{[5-oxo-4-(4-{4-[2-(1 , 1 ,2,2-tetramethyM - silapropoxy)acetyl]piperazinyl}phenyl)-2-hydroisoxazol-2- yl]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, filtered and concentrated. The residue was triturated with ether to provide 92 mg (40%) of the title compound. ¹H NMR (DMSO-d₆; 300 MHz) δ 8.87 (t, J = 6.2 Hz, 1H), 8.74

(s, 1H), 7.63 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 4.95 (d, J = 6.2 Hz, 2H), 4.64 (t, J = 5.6 Hz, 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); ESI (M+H)⁺=375.

EXAMPLE 15

N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide)

Prepared from ethyl 4-azidophenylacetate according to the general route outlined in Scheme 1. The starting material was prepared as follows: Ethyl 4-Azidophenylacetate

Following the general procedure of Marchesini (J. Qrg. Chem. 49, p. 4287-4290, 1984), sodium nitrite (38 g, 0.56 mol) was slowly added to a stirred and cooled (0°C) mixture of ethyl 4-aminophenylacetate (25 g, 0.14 mol) in 700 mL of TFA. After the addition was complete, the reaction was stirred at 0°C for another 0.5 hour and then sodium azide (27 g, 0.42 mol) was slowly added over a period of 0.5 hours. The mixture was stirred for another 2 hours at 0°C and then quenched with ice water and the product was extracted with EtOAc. The organic phase was washed with water, dried over magnesium sulfate, filtered, concentrated to yield 26.5 g (90%) of the title compound as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.31 (d, J = 8 Hz, 2 H), 7.07 (d, J = 7 Hz, 2 H), 4.07 (q, J = 7 Hz, 2 H), 3.66 (s, 2 H), 1.17 (t, J = 7 Hz, 3 H).

EXAMPLE 16

N-[(4-{4-[4-(hydroxymethyl)(1,2,3-triazolyl)]phenyl}-5-oxo-2- hydroisoxazol-2-yl)methyl]acetamide

A mixture of N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide (80 mg, 0.29 mmol) and propargyl alcohol (0.1 mL, 1.71 mmol) in 3 mL of DMF was heated at 100°C for 10 hours. The reaction mixture was then concentrated in vacuo and purified by flash chromatography (silica gel; eluting with EtOAc followed by 10% MeOH/EtOAc) to yield 62 mg of a yellow solid. The ¹H NMR spectra indicated that the crude product was a mixture of two triazole isomers. These isomers were separated by preparative HPLC (H 0/MeOH) to yield 10 mg (10%) of the title compound as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.11 (s, 1 H), 8.96, (t, J = 6 Hz, 1 H), 8.69, (s, 1 H), 7.96 (m, 4 H), 5.07 (d, J = 6 Hz, 2 H), 4.61 (s, 2 H), 1.86 (s, 3 H).

EXAMPLE 17

Methyl 1 -(4-{2-[(acetylamino)methy l]-5-oxo-2-hydroisoxazol-4- yl}phenyl)-1,2,3-triazole-4-carboxylate

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, 0.58 mmol) in 3 mL DMF was heated at 50°C for 24 hours. The reaction mixture was then concentrated in vacuo and triturated with EtOAc to yield 25 mg (24%) of the title compound as a yellow solid. (An alternate procedure which is more reliable involves conducting the reaction at room temperature for 10 days and then isolating as above.) ¹H NMR (300 MHz, DMSO-d₆) δ 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). EXAMPLE 18

N-({4-[4-(4-acetyl(1,2,3-triazolyl))phenyl]-5-oxo-2-hydroisoxazol-2- yl}methyl)acetamide

A mixture of N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide (100 mg, 0.36 mmol) and of 3-butyn-2-one (0.035 mL, 0.72 mmol) in 3 mL DMF was heated at 50°C for 24 hours. The reaction mixture was concentrated in vacuo and then triturated with EtOAc to yield 60 mg (49%) of the title compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 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).

EXAMPLE 19

N-({4-[4-(4-cyano(1,2,3-triazolyl))phenyl]-5-oxo-2-hydroisoxazol-2- yl}methyl)acetamide

A mixture of N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide (500 mg, 1.83 mmol) and 0.8 mL of cyanoacetylene [prepared according to Murahashi, S.; Takizawa, T.; Kurioka, S.; Maekawa, S.; in J. Chem. Soc. Jap., 77, p, 1689, 1956] in 5 mL of DMF was heated at 50°C for 48 hours. Upon cooling, the precipitated solid was collected by filtration and washed with DMF to yield 375 mg (63%) of the title compound as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.75

(s, 1 H), 9.17, (s, 1 H), 9.00, (t, J = 6 Hz, 1 H), 8.05 (d, J = 9 Hz, 2 H), 7.95 (d, J = 9 Hz, 2 H), 5.10 (d, J = 6 Hz, 2 H), 1.85 (s, 3 H).

EXAMPLE 20

N-{[4-(4-aminophenyl)-5-oxo-2-hydroisoxazol-2-yl]methyl}acetamide

To a mixture of N-{[4-(4-azidophenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide (3 g, 10.98 mmol) in 40 mL EtOAc and 20 mL MeOH was added SnCI₂»2H₂0 (12.5 g, 54.9 mmol). After all of the solid was dissolved, the reaction mixture was concentrated in vacuo and neutralized with saturated aqueous sodium bicarbonate. The mixture was concentrated in vacuo again and the residue was dissolved in a mixture of 4:1 CHCl3/MeOH. The resulting solution was filtered throuth celite, and the insoluble material was discarded. The filtrate was then concentrated in vacuo to yield 3 g (100%) of the title compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 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). EXAMPLE 21

N-({4-[4-(3-formylpyrrolyl)phenyl]-5-oxo-2-hydroisoxazol-2- yl}methyl)acetamide

To a solution of N-{[4-(4-aminophenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide (200 mg, 0.81 mmol) in 3 mL of acetic acid was added 2,5-dimethoxy-3-tetrahydrofurancarboaldehyde (184 mg, 1.27 mmol). This mixture was refluxed for 0.5 hours, and then concentrated in vacuo to give the crude product. Purification by silica gel chromatography (eluting with EtOAc, then 8% MeOH in EtOAc) gave 240 mg (91%) of the title compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 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).

EXAMPLE 22

N-{[5-oxo-4-(4-pyrrolylphenyl)-2-hydroisoxazol-2- yl]methyl}acetamide

This compound was prepared from N-{[4-(4-aminophenyl)-5-oxo-2- hydroisoxazol-2-yl]methyl}acetamide as described above for N-({4-[4-(3- formylpyrrolyl)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. ¹H NMR (300 MHz, DMSO- d₆) δ 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).

EXAMPLE 23

N-[(4- 4-[3-((hydroxyimino)methyl)pyrrolyl]phenyl}-5-oxo-2- hydroisoxazol-2-yl)methyl]acetamide

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 NH₂OH (40 mg, 0.60 mmol) in 3 mL of MeOH was heated at reflux for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was triturated with ether to yield 96 mg (94%) of the title compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 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, 2 H), 1.85 (s, 3 H). EXAMPLE 24

t-Buty! 4-(4-{2-[(acetylamino)methyl]-5-oxo-2-hydroisoxazol-4- yl)phenyl)piperazine carboxylate

To t-butyl 4-[4-(5-oxo-2-hydroisoxazol-4- yl)phenyl]piperazinecarboxylate (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 mmol). After 5 hours the reaction mixture was poured into ice water. After 18 hours the precipitate was filtered and dried in vacuo to provide 1.4 g (77%) of the title compound. ¹H NMR (methanol-d₄; 300 MHz) δ 8.48 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.07 (s, 2H), 3.58 (t, J = 4.8 Hz, 4H), 3.17 (t, J = 5.2 Hz, 4H), 1.94 (s, 3H), 1.50 (s, 9H); ESI (M+H)⁺ = 417.

The starting materials were prepared as follows:

Methyl 2-(4-{4-[(t-butyl)oxycarbonyl]piperazinyl}phenyl) acetate

A flask charged with cesium carbonate (4.6 g, 14.0 mmol), palladium (II) acetate (0.07 g, 0.3 mmol), and (S)-BINAP (0.28 g, 4.5mmol) was evacuated and flushed with dry nitrogen. Methyl 2-{4- [(trifluoromethyl)sulfonyloxy]phenyl} 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 / hexane) providing 1.7 g (50%) of the title compound. ¹ H NMR (300 MHz, CDCI₃) δ 7.20 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 3.70 (s, 3H), 3.59 (t, J = 5.0 Hz, 4H), 3.57 (s, 2H), 3.12 (t, J = 5.2 Hz, 4H), 1.50 (s, 9H); ESI (M+H)⁺ = 335.

Ethyl 2-(4-{4-[(t-butyI)oxycarbonyl]piperazinyl})phenyl)-3-oxopropanoate

To methyl 2-(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)phenyl]piperazinecarboxylate

To ethyl 2-(4-{4-[(t-butyl)oxycarbonyl]piperazinyl})phenyl)-3- oxopropanoate (7.8 g, 20.7 mmol) in 140 mL methanoi and 40 mL water was added hydroxylamine (50% in water, 3.0 mL, 49.0 mmol). The reaction mixture was heated to reflux for 3 hours, cooled and concentrated. The residue was triturated with water and the precipitate was filtered, dried and washed with ether to provide 4.3 g of the title compound. The aqueous solution was lyophilized providing an additional 1.5 g of the title compound. ¹H NMR (methanol-d₄; 300 MHz) δ 8.35 (s, 1H), 7.58 (br d, J = , 2H), 6.96 (d, J = 8.2 Hz, 2H), 3.58 (t, J = 4.6 Hz, 4H), 3.10 (br s, 4H), 1.50 (s, 9H); ESI (M+H)⁺ = 345.

EXAMPLE 25

N-{[5-oxo-4-(piperazinylphenyl)-2-hydroisoxazol-2-yl]methyl} acetamide trifluoroacetate salt

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 concentrated and triturated with ether to provide 0.3 g (97%) of the title compound. ¹H NMR (methanol-d₄; 300 MHz) δ

9.00 (t, J = 6.0 Hz, 1H), 8.23 (s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 5.08 (d, J = 6.2 Hz, 2H), 3.45-3.38 (m, 8H), 1.95 (s, 3H); ESI (M+H)⁺ = 317.

EXAMPLE 26

tert-Butyl 4-(4-{2-[(acetylamino)methyl]-5-oxo(2-hydroisoxazol-4-yl)}- 2-fluorophenyl)piperazinecarboxylate

Prepared according to the general procedures outlined in Schemes 1 , 3, and 6. The starting materials were prepared as follows:

2-(4-{4-[(t-butyl)oxycarbonyl]piperazinyl}-3-fluorophenyl)acetic acid

To t-butyl 4-[2-fluoro-4-(2-morpholin-4-yl-2- thioxoethyl)phenyl]piperazinecarboxyiate (4.2 g, 10 mmol) was added 22 mL of concentrated hydrochloric acid at 0°C. The resulting mixture was heated to reflux for 1.5 hours, cooled to 0°C, and 23 mL of 10N sodium hydroxide was added to bring the pH to 14. Then 50 mL water was added followed by di-t-butyl dicarbonate (5.6 g, 26.0 mmol) in 5 mL tetrahydrofuran. The resulting mixture was allowed to stir at 0°C for 30 minutes and then for 1 hour at ambient temperature at which time it was diluted with 200 mL water. Then 5 mL sodium hydroxide was added to adjust the pH to 14, and the reaction mixture was extracted with ether . The aqueous layer was acidified to pH 3 by the careful addition of 6N hydrochloric acid and then extracted with three portions of ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The resultant residue was dissolved in dichloromethane and hexanes were added to produce a precipitate which was collected by filtration providing 3.0 g (89%) of the title product. ¹H NMR (CDCI₃; 300 MHz) δ 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.

Methyl 2-(4-{4-[(t-butyl)oxycarbonyl]piperazinyl}-3-fluorophenyl)acetate

Me₃SiCHN₂

To 2-(4-{4-[(t-butyl)oxycarbonyl]piperazinyI}-3-fluorophenyl)acetic acid (0.3 g, 1.0 mmol) in 2 mL methanoi and 7 mL benzene was added trimethylsilyldiazomethane (0.65 mL, 1.30 mmol). After stirring at ambient temperature for 1 hour, the reaction mixture was concentrated to provide 0.36 g (99%) of the title compound. ¹H NMR (CDCI₃; 300 MHz) δ 7.00 (m, 2H), 6.90 (t, J = 8.3 Hz, 1H), 3.71 (s, 3H), 3.61 (t, J = 4.9 Hz, 4H), 3.57 (s, 2H), 3.02 (t, J = 5.0 Hz, 4H), 1.50 (s, 9H); ESI (M+H)⁺ = 353. EXAMPLE 27

N-{[4-(4-morpholinylphenyl)-5-oxo-2-isoxazolinyl]methyl}acetamide

Prepared according to the general procedure outlined in Schemes 1 and 2. The starting materials were prepared as follows:

Methyl-4-(trifluoromethylsulfonyloxy)phenyl acetate

To methyl-4-hydroxyphenyl acetate (20 g, 120 mmol) and pyridine (20 mL, 240 mmol) in 100 mL dichloromethane at 0°C was added trifluoromethanesulfonic anhydride (23 mL, 132 mmol) dropwise over 30 minutes. After an additional 30 minutes at 0°C followed by 30 minutes at ambient temperature, 1 N hydrochloric acid was added and the reaction mixture was extracted into dichloromethane. The organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated providing 32 g (90%) of the title compound as a yellow solid. ¹H NMR (CDCI₃; 300 MHz) δ 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 Pd(OAc)₂, morpholine BINAP _Cs2co₃

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 mg, 0.15 mmol), and morpholine (0.35 mL, 4.02 mmol) in 8 mL toluene and the reaction mixture was heated to 80°C for 6 hours. The reaction was then cooled, celite was added, and the mixture was concentrated. Chromatography was performed on a Biotage flash 40i chromatography module by loading the dried celite into a SIM and eluting with 20% ethyl acetate / hexanes (40S cartridge) providing 250 mg (37%) of the title compound as a yellow oil. ¹H NMR (CDCI₃; 300 MHz) δ 7.19

(d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 3.89-3.85 (m, 4H), 3.69 (s, 3H), 3.56 (s, 2H), 3.17-3.13 (m, 4H).

EXAMPLE 28

N-{[4-(4-(1,4-thiazaperhydroin-4-yl)phenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl)acetamide

Prepared according to the general procedures outlined in Schemes 1 and 3. The starting materials were prepared as follows: 4-Thiomorpholinoacetophenone

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 reflux 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. ¹H NMR (CDCI₃; 300

MHz) δ 7.87 (d, J = 9.0 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 3.81-3.78 (m, 4H), 2.73-2.69 (m, 4H), 2.53 (s, 3H).

4-Thiomorpholinophenylthioacetomorpholide

Sulfur

Morpholine

A mixture of 4-thiomorpholinoacetophenone (30 g, 136 mmol), morpholine (16 mL, 180 mmol) and sulfur (6 g, 180 mmol) was heated to reflux for 6 hours, cooled to 50°C, and 100 mL 1:1 hexanes:ethyl acetate was added. The reaction mixture was again brought to reflux for 30 minutes, cooled, and the resultant orange precipitate was collected via filtration. The precipitate was washed with additional 1 :1 ether / hexanes providing 31 g (73%) of the title compound as a yellow-orange solid. ¹H NMR (CDCI₃; 300 MHz) δ 7.21 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.1 Hz, 2H), 4.35 (t, J = 4.8 Hz, 2H), 4.27 (s, 2H), 3.74 (t, J = 4.8 Hz, 2H), 3.65 (t, J = 4.2 Hz, 2H), 3.52 (t, J = 5.1 Hz, 4H), 3.41 (t, J = 5.4 Hz, 2H), 2.77- 2.71 (m, 2H).

Ethyl-4-thiomorpholinophenyl acetate

A solution of 4-thiomorpholinophenylthioacetomorpholide (30 g, 93.2 mmol) in 70 mL 1:1 ethanol:sulfuric acid was heated to reflux for 18 hours, cooled to room temperature and solid sodium bicarbonate was slowly added to the reaction until it reached pH 7. The reaction mixture 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. ¹H NMR (CDCI₃; 300 MHz) δ 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).

EXAMPLE 29

N-{[4-(3-fluoro-4-methylthiophenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide

Prepared according to the general procedures outlined in Schemes 1 and 3. The starting materials were prepared as follows:

3-Fluoro-4-methylthioacetophenone

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 between 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-methylthiophenylthioacetomorpholide

Sulfur

Moφholine A mixture of 3-fluoro-4-methylthioacetophenone (9.0 g, 48.9 mmol), morpholine (5.7 mL, 65.0 mmol), and sulfur (2.1 g, 65.0 mmol) were heated to reflux for 4 hours, cooled to 50°C, and 1 :1 hexanes : ethyl acetate was added. The reaction mixture was again heated to reflux for 30 minutes, cooled to ambient temperature, and the resultant orange precipitate was collected by filtration. The precipitate was washed with 1:1 hexanes : ether providing 10.1 g (73%) of the title compound as a yellow-orange solid. ¹H NMR (DMSO-d₆; 300 MHz) δ 7.36-7.29 (m, 1H),

7.20-7.15 (m, 2H), 4.27 (s, 2H), 4.22 (t, J = 4.8 Hz, 2H), 3.73 (t, J = 4.5 Hz, 2H), 3.65 (t, J = 4.8 Hz, 2H), 3.47 (t, J = 5.1 Hz, 2H), 2.47 (s, 3H).

3-Fluoro-4-methylthiophenylacetic acid

To 3-fluoro-4-methylthiophenylthioacetomorpholide (2.6 g, 90.9 mmol) was added 500 mL 10% potassium hydroxide. The reaction mixture was heated to reflux for 3 hours, cooled to ambient temperature, and adjusted to pH 4 by the careful addition of 2N hydrochloric acid. The aqueous solution was extracted with dichloromethane and the organic layer was then extracted with 200 mL 10% potassium hydroxide. The aqueous layer was then brought to pH 4 by the careful addition of 2N hydrochloric acid and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated providing 10.0 g (55%) of the title compound as a brown oil. ¹H NMR (CDCI₃; 300 MHz) δ 7.24-7.21 (m, 1H), 7.04-6.99 (m, 2H), 3.63 (s, 2H), 2.46 (s, 3H). EXAMPLE 30

N-{[4-(3-fluoro-4-methoxyphenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl}acetamide

Prepared according to the general procedure outlined in Schemes 1. The starting material was prepared as follows:

Ethyl-(3-Fluoro-4-methoxy)phenyl acetate

To ethyl-(3-fluoro-4-hydroxy)phenyl acetate (2.5 g, 8.9 mmol) in

20mL acetone was added potassium carbonate (3.4 g, 24.2 mmol) and iodomethane (1.5 mL, 24.2 mmol). The reaction mixture was heated to reflux for 2 hours, cooled, and partitioned between saturated sodium bicarbonate and ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated providing 2.3 g (88%) of the title compound as a yellow oil. ¹H NMR (CDCI₃; 300 MHz) δ 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). EXAMPLE 31

N-({4-[4-(3-cyanopyrrolyl)phenyl]-5-oxo-2-hydroisoxazol-2- yl}methyl)acetamide

To a mixture of N-[(4-{4-[3-((hydroxyimino)methyl)pyrrolyl]phenyl}- 5-oxo-2-hydroisoxazol-2-yl)methyl]acetamide (100 mg, 0.29 mmol) in 3 ml of CH₃CN and 1 ml of CCI₄ was added polymer-bound triphenylphosphine (400 mg, 1.2 mmol) and the mixture was heated at reflux for 8 hours. It was then dissolved in ethyl acetate, filtered, and concentrated to yield a yellow solid. This solid was then triturated with ether to obtain 30 mg (32 %) of the title compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.08 (s, 1 H), 8.97 (t, J = 6 Hz, 1 H), 8.28,

(s, 1 H), 7.92 (d, J = 9 Hz, 2 H), 7.70 (d, J = 9 Hz, 2 H), 7.59 (m, 1 H), 6.74 (m, 1 H), 5.06 (d, J = 6 Hz, 2 H), 1.86 (s, 3 H).

EXAMPLE 32

N-[(4-{4-[3-((1E)-2-aza-2-methoxyvinyl)pyrrolyl]phenyl}-5-oxo-2- hydroisoxazol-2-yl)methyl]acetamide

A mixture of N-({4-[4-(3-formylpyrrolyl)phenyl]-5-oxo-2- hydroisoxazol-2-yl}methyl)acetamide (100 mg, 0.3 mmol), HCI.NH₂OCH₃ (31 mg, 0.37 mmol) and sodium carbonate (20 mg, 0.19 mmol) was dissolved in 3 mL of MeOH and 2 mL of water. To this mixture was added acetic acid to adjust the pH to 5. The reaction was heated at reflux for 1 hour. The reaction was cooled to room temperature, and the yellow precipitate was collected by filtration to give 40 mg (36 %) of the title compound as a yellow solid. (M+H⁺)= 355.

EXAMPLE 33

N-{[4-(4-{3-[(1E)-2-(acetylamino)-2-azavinyl]pyrrolyl)phenyl)-5-oxo-2- hydroisoxazol-2-yl]methyl}acetamide

A mixture of N-({4-[4-(3-formylpyrrolyl)phenyl]-5-oxo-2- 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 reflux for 1 hour. The reaction was cooled to room temperature, and the yellow precipitate was collected by filtration to give 80mg (36 %) of the title compound. (M+H⁺)=382.

EXAMPLE 34

Ethyl 1-(4-{2-[(acetylamino)methyl]-5-oxo-2-hydroisoxazol-4- yl}phenyl)pyrazole- 4-carboxylate

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 methanoi was added sodium bicarbonate (50 mg, 0.6 mmol) and ethoxycarbonylmalondialdehyde (75 mg, 0.52 mmol). The mixture was stirred at room temperature overnight. The solid was collected by filtration and then washed with water, and dried to yield 140 mg of a purple solid. The crude product was subjected to silica gel chromatography (eluting with ethyl acetate followed by 5% methanol/ethyl acetate) to yield 123 mg (66%) of the title compound as a yellow solid. ¹H NMR (300 MHz, DMSO- d₆) δ 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 starting material, N-{[4-(4-hydrazinylphenyl)-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 0°C over 5 minutes. The reaction was stirred for an additional 10 minutes at 0°C, and then SnCI₂»2H₂0 (720 mg, 3.2 mmol) in 2 mL of concentrated hydrochloric acid was added. This mixture was stirred at room temperature for 3 hours. The reaction mixture was then filtered to collect a yellow solid which was washed with 3 mL of water and dried to yield 260 mg (55%) of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 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).

EXAMPLE 35

N-({4-[4-(4-cyanopyrazolyl)phenyl]-5-oxo-2-hydroisoxazol-2- yl}methyl)acetamide

To a mixture of N-{[4-(4-hydrazinylphenyl)-5-oxo-2-hydroisoxazol- 2-yl]methyl}acetamide hydrochloride (50 mg, 0.17 mmol) in 2 mL of methanoi 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 methanoi to give 42 mg (76%) of the title compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 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, 2 H), 1.86 (s, 3 H). Preparation of cyanomalondialdehyde. To a dried flask was added sodium hydride (0.82 g, 50% suspended in mineral oil, 17 mmol). The sodium hydride was washed three times with 15 mL of ether, and then 15 mL of ether was added to the flask. After cooling the slurry to 0°C, ethyl 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 cyanomalondialdehyde 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 methanoi. The inorganic salt was removed by filtration, and the filtrate was concentrated to yield 1 g of cyanomalondialdehyde as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.94 (s, 2 H), 4.95 (br s, 1 H).

EXAMPLE 36

N-{[5-oxo-4-(4-pyrazolylphenyl)-2-hydroisoxazol-2- yl]methyl}acetamide

To a mixture of N-{[4-(4-hydrazinylphenyl)-5-oxo-2-hydroisoxazol- 2-yl]methyl}acetamide hydrochloride (100 mg, 0.33 mmol) in 3 mL of methanoi was added sodium bicarbonate (28 mg, 0.33mmol) and malondialdehyde (50 mg, 0.35 mmol). The mixture was stirred at room temperature overnight. It was then concentrated to yield 120 mg of a yellow oil, which was then purified by silica gel chromatography (eluting with ethyl acetate) to obtain 30 mg (30%) of the title compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 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), 1.86 (s, 3 H).

The table below shows the chemical structures, characterizing properties (MS data) and preparative method for several representative compounds of the present invention, including those of Examples 1-36 described above.

Claims

CLAIMSWe claim:

1. A compound of the formula

or a pharmaceutically acceptable salt thereof wherein:

R-l is a) H, b) C-^8 alkyl optionally substituted with one or more F, Cl, OH, C-|_8 alkoxy, or C^._Q acyloxy, c) C3-6 cycloalkyl, or d) C.|_8 alkoxy;

L is oxygen or sulfur;

A is a)

b)

c) a 5-membered heteroaromatic moiety having one to three hetero atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom and can additionally have a fused-on benzene or naphthyi ring, and wherein the heteroaromatic moiety is optionally substituted with one to three Ra, 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 naphthyi ring, wherein the heteroaromatic moiety is optionally substituted with one to three Rg, e) a β-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three Rg, f)

9)

wherein R₂ and R3 are each independently a) H, b) F, c) Cl, d) Br, e) C.|_₆ alkyl, f) N0₂, - 1 8 -

g) i. h) C^ alkoxy, i) OH j) amino, k) cyano, or

I) R₂ and R₃ taken together are -0(CH₂) -0; wherein R4 is a) H, b) C-,_₂ alkyl, c) F, or d) OH; R₅ 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) R5 and R_Q taken together are a 5-, 6-, or 7-membered ring of the formula,

)

in which D is S, O or NR₈e in which R₈6 is H or

C-|_6 alkyl, or g) R5 and Re taken together are -(CH₂)|<-, when R7 is an electron-withdrawing group; R5 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 R_Q and R is an electron- withdrawing group, or f) Rg and R 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) CL₅ alkyl; wherein Rs is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF₃, g) NO₂, h) C-^ alkoxy, i) Cι_6 alkoxycarbonyl, j) Ci_e alkythio, ) Ci^ acyl, I) -NR₁₇R₁₈₎

NOH

II m) — C-R₈₇ in which R₈₇ is H or C^ alkyl, ⁿ) C-i.R alkyl optionally substituted with OH, sulfamoyl, C1.5 alkoxy, C-[.₅ acyl, or-NR₁₇R₁₈, o) C₂_s alkyl optionally substituted with one or two R_ιg, p) phenyl optionally substituted with one or two R-jg, q) a 5- or 6-membered saturated or unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two Rig, or

(CHzfiJ

» d R₁₈ at each occurrence are the same or different and are a) H, b) C^ alkyl, c) C5.6 cycloalkyl, or d) R₁ 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

O II containing 1-3 O, N or S, — C-NR₈₈R₈₉ in which R₈s and Ra are each independently hydrogen or C<\__e alkyl, S0₂Rgn in which Rg₀ is H or Cι_₆ alkyl, or C-_j.₃ acyl optionally substituted with 1 or more F, Cl or OH; R₁₉ is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF₃, g) N0₂. h) C^ alkoxy, i) C-_|_R alkoxycarbonyl, j) C-|_6 alkythio, k) C^ acyl,

I) C^ alkyl optionally substituted with OH, C^s alkoxy, Cι_₅ acyl, or -NR₁₇R₁₈, m) phenyl, n) -C(=O)NR₂₀R₂₁, o) -N R-|₇Ri8.

P) -N(R₂₀)(-SO₂R₂₂), q) -SO₂-NR₂₀R₂ι, or r) -S(=0)iR₂₂;

R₂0 and R₂- I at each occurrence are the same or different and are a) H, b) C-|_6 alkyl, or c) phenyl;

R ₂ is a) -i- alkyl, or b) phenyl optionally substituted with C^ alkyl; wherein Rg is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, ) CF₃, g) N0₂, h) C|__fi alkoxy, i) C^ alkoxycarbonyl, j) C^ alkythio, k) C^ acyl,

I) -NR ₃R₂₄, m) C^e alkyl optionally substituted with OH, C-|_₅ alkoxy, C-j.₅ acyl, or -NR ₃R₂ , 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 q)

R₂₃ and R₂ at each occurrence are the same or different and are a) H, b) formyl, c) C^ alkyl, d) C-^ 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, C-j.₃ alkyl, or C-_|.₃ acyl;

R₂₅ is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF_3> g) N0₂, h) C-]^ alkoxy, i) C-_|__fi alkoxycarbonyl,

J) Cι_6 alkythio, k) C^ acyl,

I) phenyl, m) C^._Q alkyl optionally substituted with OH, azido, C-₎.₅ alkoxy,

C^s acyl, -NR₃₂R₃₃₎ -SR₃₄, -0-S0₂R₃₅, or

36— - NH-CO-O-

n) -C(=0)NR₂₆R_27>

0) -NR₂3R₂₄, p) -N(R₂₆)(-S0₂R₂₂), q) -S0₂-NR₂₆R₂₇, or s) -CH=N-R₂₈, or t) -CH(OH)-S0₃R₃₁; R₂₂ is the same as defined above; R₂₆ and R at each occurrence are the same or different and are a) H, b) C|.₆ alkyl, c) phenyl, or d) tolyl;

R₂₈ is a) OH, b) benzyloxy, c) -NH-C(=0)-NH₂, d) -NH-C(=S)-NH₂, or e) -NH-C(=NH)-NR₂₉R₃₀;

R_2g and R₃₀ i at each occurrence are the same or different and are a) H, or b) C^_4 alkyl optionally substituted with phenyl or pyridyl;

R₃₁ is a) H, or b) a sodium ion;

R₃₂ and R₃₃ at each occurrence are the same or different and are a) H, b) formyl, c) C-1. alkyl, d) C- 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, C-j.₃ alkyl, or C-_|_₃ acyl, h) -P(0)(OR₃₇)(OR₃₈), or i) -S0₂-R₃₉; R34 's

R₃₅ is 0^3 alkyl;

R36 ^is a) C<|_6 alkoxycarbonyl, or b) carboxyl; R3₇ and R₃s at each occurrence are the same or different and are a) H, or b) C-|_3 alkyl;

R39 'S a) methyl, b) phenyl, or c) tolyl; wherein K is a) 0, b) S, or cc)) NNRR₄₄Q₀ iinn wwhich R₄₀ is hydrogen, formyl, C-^ alkyl, C-j_4 acyl, phenyl, C₃.₆ cycloalkyl, -P(0)(0R₃₇)(0R₃₈) or -S0₂-R₃g in which R₃ , R₃₈ and R₃g are as defined above; R-JO, Rn, R12. R13, R14 ^ar|d R15 at each occurrence are the same or different and are a) H, b) formyl, c) carboxyl, d) Cι_e alkoxycarbonyl, e) C^s alkyl, f) C₂_8 alkenyl, wherein the substitutents (e) and (f) can be optionally substituted with OH, halo, C-_|_R alkoxyl, C<\__Q acyl, C-₎_R alkylthio or C-^ alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, -CN, formyl, CF₃, N0₂, C-|_6 alkyl, C-^R alkoxy, C-_|_₆ acyl, C-_|_R alkylthio, or C-_|_R alkoxycarbonyl; h) -NR₄₂R₄₃₎ i) OR^, j) -S(=0)_rR₄₅, k) -S0₂-N(R₄₆)(R₄₇), or I) a radical of the following formulas:

R53

/ — \ / \

HN N— R₅₂ (CH₂)t— N N— R53-N N—

R_ιg is the same as defined above; T is a) O, b) S, or c) S0₂; R ₂ and R₄3 at each occurrence are the same or different and are a) H, b) C3._fi cycloalkyl, c) phenyl, d) Cι.,6 acyl, e) C-j.8 alkyl optionally substituted with OH, C-j.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, -N0₂, C-

alkoxy,-NR₄₈R₄g, or

f)

g)

V N-(CH₂)t—

V is a) 0, b) CH₂, or c) NR₅₆;

R₄8 and R₄g at each occurrence are the same or different and are a) H, or b) C-)^ alkyl; R₅₄ is a) OH, b) C-|_4 alkoxy, or c) -NR5₇Rδ8; R55 is a) H, or b) C C--_j)__ aallkkyyll ooppttiioonally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C(=0)-NH₂, -CO₂H, or -C(=NH)-NH₂; R₅₆ is a) H, b) phenyl, or c) Cι_₆ alkyl optionally substituted by OH;

R5₇ and R₅₃ at each occurrence are the same or different and are a) H, b) CL5 alkyl, ^c) C-|.₃ cycloalkyl, or d) phenyl; R^ is a) C-ι_8 alkyl optionally substituted with C-|.₆ alkoxy or C^ 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, C-1.5 alkoxy, or C^_δ acyl, b)

c) phenyl, or d) pyridyl; R₄₅ is a) C^-,6 alkyl, b) C₂. ₆ alkenyl, wherein the substituents (a) and (b) can be optionally substituted with Cι_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;

R₄6 and R at each occurrence are the same or different and are a) H, b) phenyl, c) C|__fi alkyl, or d) benzyl;

R50 and R51 at each occurrence are the same or different and are a) H, b) OH, c) Cι_6 alkyl optionally substituted with -NR ₃R₄g in which R₄₈ and R₄g are as defined above, d) R50 and R₅ taken together are =0; 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-j.s alkyl, C-).₅ alkoxy, or C-j.₅ acyl, c) morpholinyl, d) OH, e) C^ alkoxy, f) -NR ₃R₄g in which R ₈ and R _g are as defined above, g) -C(=0)-R₅₉, or h)

CO

Rδ3 's a) H, b) formyl, c) C_1- alkyl, d) C-|_4 acyl, e) phenyl, f) C₃-6 cycloalkyl, g) -P(0)(OR₃₇)(OR₃8), or h) -S0₂R3g, in which R3 , R₃₈ and R₃g are as defined above;

R59 IS a) morpholinyl, b) OH, or c) C-|_₆ alkoxy; h is 1 , 2, or ^■ 3; i is 0, 1 , or 2; j is 0, or 1; k is 3, 4, oi r5; r is 1,2, 3, 4, 5 or 6; tisO, 1,2, 3,4, 5, or 6; u is 1 or 2; and

Qis a) hydrogen, b) halo, c) N0₂, d) ₃, e) Cι-C₆ alkylthio,

O f) C C₆ alkyl-s- ,

O g) C C₆ alkyl— s —

0 ' h) C_rC₆ alkyl, i) C1-C5 alkoxy, j) formyl,

O k) C C₆ alkyl-c- ,

O

I) C Cβalkyl-o-C-, m) -sulfamoyl (H₂NS0₂-), n) -NHOH,

O o) C_rC₆ alkyl— c-O—

O

P) heteroaryl — C— in w aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, 0 II q) 06^₅-0— , r) amino, s) C Ce alkylamino, t) d^C- Ce alkyl)amino-,

0 I I u) (C-i-C₆) alkyl-C-NR₆₀R₆₁ in which R₆o and R₆-| are each independently hydrogen or C-j-Ce alkyl, v) OH, w) cyano, x) hydroxy (C-j-Ce alkyl),

0 y) C_rC₆ alkyl-S-C— ,

0 z) NC — (CH₂) -C— in which r is 1-6, 0 aa) C₆H₅CH₂-0-C- ,

0 bb) C₆H₅-0-C- ,

_/OR₈₄ N cc) C_rC₆ alkyl— c— in which R₃₄ is hydrogen or C-1.5 alkyl,

O dd) R₈₅0-(CH₂)₁_₆-C— in which R₈s is hydrogen, C^s alkyl optionally substituted with one or more F, Cl, OH, Cι_₈ alkoxy or C-|_₈ acyloxy, C₃_6 cycloalkyl or C^s alkoxy;

N-OR₈₄ ee) H-C— in which R₈₄ is hydrogen or C-_|.6 alkyl, ff) a substituted or unsubstituted C₆-C-|o 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 substituents for such p, q, ff, gg and hh moieties being selected from 1 or 2 of the following:

1) halo,

2) C^R alkyl,

3) N0₂,

4) N₃,

O 5) C C₆ alkyl —S— ,

O

6) C C₆ alkyl— s—

O '

7) formyl,

O

8) C C₆ alkyl-c- ,

O

9) C C₆ alkyl-o-C- ,

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

O

11) C₆H₅-C- ,

O

12) -(C.,-C₆) alkyl-C-NR₆₀R₆₁ in which R₆₀ and R₆₁ are each independently hydrogen or C-|-C₆ alkyl, 13) OH,

14) hydroxy (C C₆ alkyl),

0

15) C C₆ alkyl -S-C- ,

O

16) NC-(CH₂)_r —0-C— in which r is 1-6,

O 17) C₆H₅CH₂-0-C- ,

18) -CH₂-R₈o in which R_8u is a) -OR₃₂ in which R₃ is as defined above, b) -SR₃₂ in which R₃ is as defined above, c) -NR₃ R₃₃ in which R₃ and R₃₃ are as defined above, or d) 5- or 6-membered heteroaromatic containing 1-4 0, S or N atoms,

_/OR84

N

19) C_rC₆ alkyl— c— in which R₃₄ is as defined above,

20) cyano, 21) carboxyl,

22) CF₃,

O

23) C C₆ alkyl— 6-0—

O

24) C₆H₅-0-C— in which the phenyl moiety may be optionally substituted by halo or (C-j-CβJalkyl,

O 25) NR₆₀R_6T— C— in which R₆₀ and R₆ are as defined above,

O O

26) R₉₁-NH-C— or R₉₁-C-NH— in which R₉₁ is a 5- or 6- membered aromatic heterocyclic group having 1-3 O, N or S, O

27) C₆H₅(CH₂)₁_₆-0-C- ,

O

28) R₈₅ -(CH₂)ι.₆— 0-C— in which R₃5 is as defined above,

O

29) SiR99R₁₀oRιoι^~O^~CH2^{~c— in} which Rgg, R₁₀o and R-|₀₁ are each independently C-j._fi alkyl; or Q and either R<_\ and R₂ taken together form -0-CH -0.

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

R- is H, C-|_8 alkyl optionally substituted with one or more F, Cl, OH, C-|_₈ alkoxy, or C^._Q acyloxy, C₃__R cycloalkyl or C^s alkoxy;

R and R₃ are each independently a) H, b) F, c) Cl, d) Br, e) C^ alkyl, f) N0₂,

9) I, h) C-|__fi alkoxy, i) OH j) amino, or k) cyano; and

Qis a) hydrogen, b) halo, c) N0₂, d) N₃, e) C_rC₆ alkylthio,

O f) C C₆ alkyl — S— ,

O g) C C₆ alkyl-s II-,

O h) C_rC₆ alkyl, i) C_rC₆ alkoxy, j) formyl,

O k) c C₆ alkyl-c-,

O I) C_rC₆ alkyl-o-C- ,

O m) C C₆ alkyl-c-O- , O n) heteroaryl— C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S,

O o) C₆H₅-C- , p) amino, q) C-j-Ce alkylamino-, r) di(Cι-C₆ alkyl)amino-,

O s) (C-pCe) alkyl-C-NR₆₀R₆₁,in which R₆₀ and R₆₁ are each independently hydrogen or C C₆ alkyl, t) OH, u) cyano, v) hydroxy (C-|-C₆ alkyl),

O w) C C₆ alkyl— S-C— ,

O x) NC-(CH₂)_r —0-C— in which r is 1-6,

O y) C₆H₅CH₂-0-C- ,

O z) C₆H₅-0-C- ,

_/ORδ4 N aa) C C₆ alkyl— c— wherein R₃₄ is hydrogen or C-|_₆ alkyl,

O bb) R8_δO-(CH₂)₁.₆— C— in which R₃s is hydrogen, C-|.₈ alkyl optionally substituted with one or more F, Cl, OH, C._j_₈ alkoxy or C-|_8 acyloxy, C₃_6 cycloalkyl or C-|_₈ alkoxy,

N-OR^ cc) H-C— in which R₃₄ is as defined above, dd)

ee)

^N

ff)

gg)

I M hh)

ii)

jj)

kk)

il)

N-N mm)

nn)

oo)

N-N

,N

N

I

^R92 in which R₉₂ is H or C-_j._fi alkyl,

PP)

qq)

rr)

ss)

tt)

uu)

< fc hx w)

N-

- .-

ww)

xx)

yy)

zz)

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) Ci.8 alkyl, c) C₃.8 cycloalkyl, d) -(CH₂)_mOR₆₆, or e) -(CH )_nNRe₇R68:

Zis a) o, b) Sor c) NM;

Wis a) CH, b) Nor c) S or 0 when Z is NM;

X and Y are each independently a) hydrogen, b) halo, c) N0₂₎ d) N₃. e) C-|__fi alkythio,

O f) C C₆ alkyl — S— ,

O g) C C₆ alkyl-s- ,

0 h) C_rC₆ alkyl, i) C-i-Cβ alkoxy, j) formyl,

O k) C C₆ alkyl— c—

O

I) C C₆ alkyl— 0-C—

O I I 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 II n) o) amino,

P) C- Ce alkylamino-, q) di (C-i-Cβ alkyhamino-, O r) -(C C₆) alkyl-C-NR₆₀R₆₁ in which R₆₀ and R₆₁ are each independently hydrogen or Cj-Cg alkyl, s) OH, t) hydroxy (C C₆ alkyl),

O u) C C₆ alkyl— S-C— ,

O v) NC-(CH₂)_r —0-C— in which r is 1-6,

O w) c₆H₅CH₂-0-C- ,

O x) C₆H₅-0-C- ,

_/OR84

N y) C C₆ alkyl— c— in which R₃₄ is as defined above, z) cyano, aa) carboxyl, bb) - CF₃, cc) mercapto,

O dd) C C₆ alkyl— c-O—

O ee) C₆H₅-0-C— in which the phenyl moiety may be optionally substituted by halo or C C₆ alkyl,

O ff) C₆H₅(CH₂)₁_₆-0-C- ,

O gg) R₈₅0-(CH₂)₁.₆— C— in which R₃5 is as defined above, or

O hh) SiR₉₉R₁₀₀R₁₀ι— 0-CH₂-C— in which Rgg, R ₀₀ and R₁₀ι are each independently C-|_₆ alkyl; or

Q and either R-_| and R₃ taken together form -0-CH₂-0; R₆₂ is a) H, b) C-|_8 alkyl optionally substituted with one or more halos, or c) C-|_8 alkyl optionally substituted with one or more OH, or C-j.8 alkoxy;

E is a) NR_69ι b) -S(=0)_j in which i is 0, 1 or 2, or c) O;

R63 ^is a) H, b) C|__fi alkyl, c) -(CH₂)_q-aryl, or d) halo;

R₆₆ is H or C-i^ alkyl;

R₆₇ and R₆₈ ■ are each independently H or C-^ alkyl, or NR₆ R₆8 taken together are -(CH₂)_m-; δθ is a) H, b) C-|__fi alkyl, c) -(CH₂)_q-aryl, d) -C0₂R8i, e) COR₈₂, f) -C(=0)-(CH₂)_q-C(=0)R₈₁, g) -S(=0)_z-C₁.₆ alkyl, h) -S(=0)₂-(CH₂)_q-aryl, or i) -(C=0)j-Het in which j is 0 or 1 ; a) -CH₂-, or b) -CH(R₇₀)-CH₂-;

Z₂ is a) -0₂S-, b) -0-, c) -S-, d) -SO-, or e) -N(R₇₁)-;

Z₃ is a) S, b) so, c) S0₂, or d) O;

A-_] is H or CH₃;

A₂ is a) H, b) OH-, c) CH₃C0₂-, d) CH₃-, e) CH₃0-, f) R₇₂0-CH₂-C(0)-NH-, g) R₇₃0-C(0)-NH-, h) R₇₃-C(0)-NH-, i) (C_rC₂)alkyl-0-C(0)-, or j) HO-CH₂; or

A-_| and A₂ taken together are - OO -

a)

b) 0 = ;

Re₄ is H or CH₃-; m is 4 or 5; nisO, 1,2, 3, 4 or 5; y is 0 or 1 ; pis 0,1,2, 3,

4 or 5; w is 1 , 2 or 3; q is 1,2, 3 or 4; zis Oor 1;

R65^is a) R₇₄OC(R₇₅)(R₇₆)-C(0)-, b) R₇₇OC(0)-, c) R 8(0)-, d) R₇₉-S0₂-, or e) R₈₀-NH-C(O)-;

R₇0 is H or (C C₃)alkyl;

R₇1 is a) R₇₄OC(R₇₅)(R₇₆)-C(0)-, b) R₇₇0-C(0)-, c) R₇8-C(0)-, d) - lot -

e)

f) H₃C-C(0)-(CH₂)₂-C(0)-, g) R₇g-S0₂-, h)

i) R₈₀-NH-C(O)-,

R₇₂ is a) H, b) CH₃, c) phenyl -CH₂-, or d) CH₃C(0)-;

R₇₃ is (C-]-C₃)alkyl or phenyl; R₇₄ is H, CH₃, phenyl-CH₂- or CH₃-C(0)-; R₇₅ and R ₆ are each independently H or CH₃, or R ₅ and R ₆ taken together are -CH₂CH₂-; R ₇ is (C-|-C₃)alkyl or phenyl;

R₇₈ is H, (C C₄)alkyl, aryl-(CH₂)_nι, CIH₂C, CI₂HC, FH₂C-, F₂HC- or (C₃-C6)cycloalkyl; R₇₉ is CH₃; -CH₂CI, -CH₂CH=CH₂, aryl or -CH₂CN; R₈o is -(CH₂)_nι-aryl where n¹ is 0 or 1; R₈₁ is a) H, b) Cι_5 alkyl optionally substituted with one or more OH, halo or CN, c) -(CH₂)_q-aryl in which q is as defined above, or d) -(CH )_q-OR₈₃ in which q is as defined above;

R₈₂ is a) C-j._fi 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;

Rδ3 is a) H, b) C-,.6 alkyl, c) -(CH )_q-aryl in which q is as defined above; or d) -C(=0) Cι_6 alkyl; and aryl is phenyl, pyridyl or naphthyi, said phenyl, pyridyl or naphthyi moieties being optionally substituted by one or more halo, -CN, OH, SH, C-|__fi alkoxy or C-i^ alkylthio.

A compound of the formula

or a pharmaceutically acceptable salt thereof, in which

R-_j is H, C-|_₈ alkyl optionally substituted with one or more F, Cl, OH, Cι_₈ alkoxy or C-|_₈ acyloxy, C₃_6 cycloalkyl or C-j_s alkoxy; R₂ and R₃ are each independently H or F; or R₂ and R₃ taken together represent

0—

Q is a) hydrogen, b) halo, c) N₃> d) N0₂, e) C_rC₆ alkylthio,

O f) C C₆ alkyl-s- ,

O g) C C₆ alkyl— s —

0 ' h) C_rC₆ alkyl, i) C-j-Ce alkoxy, j) formyl,

O k) C C₆ alkyl-c- ,

O i) C_rC₆ alkyl-o-C—

O m) C_rC₆ alkyl-c-0- , n) (C_rC₆ alkoxy)₂N-, o) 5- or 6-membered he linked to the phenyl substituent via a carbon or nitrogen, said heterocycle moiety being optionally substituted by Rgg, .OH

N I I

C_rC₆ alkyl-

P) -C q) phenyl optionally substituted by Rgø, 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 Rg₆, and

a) C_rC₆ alkyl-OH, b) C C₆ alkyl- -0-C II - .

0

0 c) CH₃-c II- C C₆ alkyl— c-.

O d) cyano, e) formyl, _N-OH n f) H-C- ,

O g) C_rC₆ alkyl- -0-C- , O h) SiR₈ R₈₅R₈₆-0-C— in which R₈₄, Rsβ and R₈6 are each independently C-|-C₆ alkyl,

O O i) CH₃-_S' _ C C₆ alkyl-s- ,

I I I I o o

0 j) HC≡CCH₂OC— ,

O k) C₆H₅-0-C— _wnere th_e ph_eny| _{may De} optionally substituted by halo,

O I) HO-CH₂-C- , m) (C_rC₆ alkyl)₂N-, n) C C₆ alkyl-NH-, o) amino.

O p) C C₆ alkyl-s- ,

O q) C₆H₅CH₂OC— , or

O r) R₉₈-C— in which R_g8 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.