CZ2001669A3 - Novel isoxazolinone-based 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

Technical field

The invention relates to novel isoxazolinones, methods for their use and methods for their preparation. The invention provides a compound represented by the general formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ represents

a) H,

b) a C 1-6 alkyl group optionally substituted by one or more of F, Cl, OH, C 1-6 alkoxy and C 1-6 alkyloxy.

c) a C3-Cycloalkyl group; or

d) C 1-6 alkoxy;

L is oxygen or sulfur;

And it means

and)

(b)

c) a 5-membered heteroaromatic group containing one to three heteroatoms selected from the group consisting of S,

N and O, wherein said 5-membered heteroaromatic group is attached via a carbon atom and may additionally be fused to a benzene or naphthyl ring, and said heteroaromatic group is optionally substituted with one to three R e,

d) a 6-membered heteroaromatic group containing at least one nitrogen atom, wherein said heteroaromatic group is attached via a carbon atom and said 6-membered heteroaromatic group may additionally be fused to a benzene or naphthyl ring, and the heteroaromatic group is optionally substituted with one to three R 9 substituents,

e) a group selected from the group consisting of β-carbolin-3-yl or indolizinyl linked via a 6-membered ring and optionally substituted with one to three R g,

F)

6)

or

wherein R 2 and R 3 each independently represent a group consisting of:

and) H, (b) F, C) Cl, (d) Br, E) C 1-6 alkyl, F) NO ₂ , G) AND, (h) C 1-6 alkoxy, and) OH, (j) amino, to) cyan, or 1) R2 and R3 together they are -O (CH 2) h -O; where R4 represents a group from the group consisting of and) H, (b) C 1-2 alkyl, C) F, or (d) OH;

R 5 is a group selected from the group consisting of

a) H,

(b) CF ₃ ;

c) C 1-3 alkyl, optionally substituted with one or more halogen atoms,

d) phenyl, optionally substituted with one or more halogen atoms,

e) R 5 and R 6 together form a 5-, 6-, or 7-membered ring of the general formula

F)

wherein D is S, O or Re 6, wherein R 6 is H or C 1-6 alkyl, or

g) R 5 and R 6 taken together are - (CH 2) k - when R 7 represents an electron withdrawing group;

R 7 and R 7 have the same or different meanings at each occurrence and mean:

a) electron withdrawing group,

b) H,

(c) CF ₃

d) C _1-3 alkyl optionally substituted with one halogen atom,

(e) a phenyl group, provided that at least one of R 6 and R 7 is an electron withdrawing group; or

f) R 6 and R 7 together represent a 5-, 6-, or 7-membered ring of the general formula

O

ΟΥ

U means:

(a) CHz,

b) 0,

(c) S or

d) NR1e;

R16 means:

·· ··· ·

(a) H or

b) a C 1-6 alkyl group;

wherein Re is a group selected from the group consisting of:

(a) carboxy,

(b) halogen,

c) -CN,

(d) mercapto,

e) forms1,

f) CF

(g) NO

h) C 1-6 alkoxy

(i) C 1-6 alkoxycarbonyl,

j) C 1-6 alkylthio,

k) C 1-6 acyl,

(l) -NR17R18;

NOH

II

m) -C-R 87 wherein R 7 is H or C 1-6 alkyl,

n) a C 1-6 alkyl group optionally substituted by the group consisting of OH, sulfamoyl, C 1-6 alkoxy, C 1-6 sacyl and -NR 17 R 18,

o) a C2-alkyl group optionally substituted by one or two R19,

p) a phenyl group optionally substituted with one or two R 19,

q) a 5- or 6-membered saturated or unsaturated heterocyclic group containing one to three atoms selected from the group consisting of S, N and O, optionally substituted with one or two R 19, or

Toto to toto to to toto toto • • • • • • • • • to to • to to to

R17 and R18, at each occurrence, have the same or different meanings and are selected from the group consisting of:

a) H

b) C 1-4 alkyl,

c) C8-ecycloalkyl1, or

d) R 17 and R 16 together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated heterocyclic group which optionally contains another heteroatom selected from the group consisting of S, N, O, and may be further optionally substituted, including substitution at another nitrogen atom, a C 1-3 alkyl, formyl, 5- or 6-membered heteroaromatic group containing 1-3 O, N

II or S, -C-NR 88 R 89 wherein R e and R 89 each independently represent hydrogen or C 1-6 alkyl, SO 2 R 9 O where R 90 is H or C 1-6 alkyl, or C 1-3 acyl optionally substituted with 1 or more F, Cl or OH;

R19 is selected from the group consisting of:

(a) carboxyl,

(b) halogen,

c) -CN,

(d) mercapto,

(e) formyl;

(f) CF3;

(g) NO2;

h) C 1-6 alkoxy

i) C 1-6 alkoxycarbonyl,

• 9999 • 1 and" • · • « • • • » 9 9 • • 99 • 9 ·· ♦ 9 · • 9 9 • • * 9 9 9 • • • 9 9 • • 9 • 99 ··· «· 999

j) C 1-6 alkylthio,

k) C 1-6 acyl,

l) C 1-6 alkyl optionally substituted with OH, C 1-6 alkoxy, C 1-6 sacyl and -NR 17 R 18,

m) phenyl,

n) -C (= O) NR ₂₀ o R 21,

(o) -NR17R18;

p) -N (R ₂₀ ) (-SO ₂ R 22),

q) -SO 2 -NR 2 OR 21 a

r) -S (= O) 1 R 22;

R20 and R21, at each occurrence, have the same or different meanings and are a group consisting of

a) H,

b) C 1-6 alkyl;

c) phenyl;

R22 is selected from the group consisting of

a) C 1-4 alkyl; and

b) phenyl optionally substituted with C 1-4 alkyl;

wherein R 9 is a group selected from the group consisting of

(a) carboxyl,

(b) halogen,

c) -CN,

(d) mercapto,

(e) formyl;

(f) CF3;

g) NO2, ········· 4 4 • 4 4 4 44 ··· · 4 4 4 4 44 • 44 4 4 4 44

h) C 1-6 alkoxy

(i) C 1-6 alkoxycarbonyl

j) C 1-6 alkylthio,

k) C 1-6 acyl,

(l) -NR23R24;

m) C 1-6 alkyl optionally substituted with OH, C 1-6 alkoxy, C 1-6 sacyl and -NR 23 R 24,

n) C 2-8 alkylphenyl optionally substituted with one or two R 25,

o) phenyl, optionally substituted with one or two R 25,

p) a 5- or 6-membered saturated or unsaturated heterocyclic group containing one to three atoms from the group consisting of S, N and O, optionally substituted with one or two R 25. or

q)

R23 and R24, at each occurrence, have the same or different meanings and are selected from the group consisting of:

a) H,

(b) formyl;

c) C 1-4 alkyl,

d) C 1-4 acyl,

(e) phenyl;

f) C 3-6 cycloalkyl; or

g) R 23 and R 24 together with the nitrogen atom form a 5- or 6-membered saturated heterocyclic group which optionally contains another heteroatom selected from the group consisting of S, N, O, and may be further optionally substituted, including substitution at ···· · · Said further nitrogen atom, a group selected from the group consisting of phenyl, pyrimidyl, C 1-3 alkyl and C 1-3 acyl; ;

R25 is selected from the group consisting of:

(a) carboxyl,

(b) halogen,

c) -CN,

(d) mercapto,

(e) formyl;

(f) CF3;

(g) NO2;

h) C 1-6 alkoxy

i) C 1-6 alkoxycarbonyl,

j) C 1-6 alkylthio,

k) C 1-6 acyl,

(l) phenyl;

m) C 1-6 alkyl optionally substituted with OH, azido, C 1-6 alkoxy, C 1-6 sacyl, -NR 32 R 33, -SR 34, -O-SO 2 R 35 or

R36-X> -NHCOO-

(n) —C (= O) NR 26 R 27;

o) -NR 23 R 24

(p) —N (R26) (-SO2R22),

q) -SO 2 -NR 26 R 27, or

r) -S (= O) 1 R 22,

s) -CH ₂ NR 8, or

t) -CH (OH) -SO ₃ R ₃₁ ;

R22 is as defined above;

R26 and R27 each have the same or different at each occurrence. ·································································Lect a group from the group consisting of:

a) H,

b) C 1-6 alkyl,

(c) phenyl; or

d) tolyl;

R28 is selected from the group consisting of:

(a) OH,

(b) benzyloxy,

c) -NH-C (= O) -NH ₂ ,

d) -NH-C (= S) -NH 2, or

e) -NH-C (= NH) -NR 29 R ₃₀ ;

R29 and R30 have the same or different meanings at each occurrence and denote

(a) H or

b) a C 1-4 alkyl group optionally substituted by a phenyl or pyridyl group;

R31 is

(a) H or

b) sodium ion;

R32 and R33 have the same or different meanings at each occurrence and are selected from the group consisting of:

a) H,

(b) formyl;

c) C 1-4 alkyl; - - - - - - - - - - - - - - - · · · · · · · · · · · · · · · · ·

d) C 1-4 acyl,

(e) phenyl;

f) C3-6cycloalkyl,

g) R 32 and R 33 taken together form a 5- or 6-membered saturated heterocyclic group containing one to three atoms selected from the group consisting of S, N, O, optionally substituted, including substitution at the nitrogen atom, with a group selected from phenyl, pyrimidyl, C 1-6 3alkyl, and C 1-3 acyl,

h) -P (O) (OR ₃₇ ) (OR ₃₈ ); or

i) -SO 2 -R 39;

R34 stands for

R 35 represents a C 1-3 alkyl group;

R36 is

a) a C 1-6 alkoxycarbonyl group; or

b) a carboxyl group;

R37 and R38 have the same or different meanings at each occurrence and denote

(a) H or

b) a C 1-3 alkyl group;

R39 is selected from the group consisting of:

• · · · ·

(a) methyl,

(b) phenyl; or

c) tolyl;

K means

a) 0,

(b) S, or

c) NR40 in which R40 represents a radical from the group comprising hydrogen, formyl, Ci-C4alkyl, Ci-4acyl, phenyl, C ₃ -6cykloalkyl ,, -P (0) (0R ₃ 7) (0R ₃ e) and -SO2- R ₃ 9, wherein R ₃ 7, R ₃ 8 and R ₃ 9 are as defined above;

R10, R11, R12, R _3, R 14 and R 15 at each occurrence are the same or different and represent a group selected from the group comprising:

a) H,

(b) formyl;

c) carboxyl,

d) C 1-6 alkoxycarbonyl,

e) C 1-6 alkyl,

f) C 2-6 alkenyl wherein the substituents labeled (e) and (f) are optionally substituted with OH, halogen, C 1-6 alkoxy, C 1-6 acyl, C 1-6 alkylthio, or C 1-6 alkoxycarbonyl, or phenyl optionally substituted with halogen ,

(g) an aromatic group of 6 to 10 carbon atoms optionally substituted by a group selected from the group consisting of carboxyl, halogen, -CN, formyl, CF ₃ , NO 2,

99999

9999

C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylthio, and C 1-6 alkoxycarbonyl;

(h) -NR42R43;

(i) OR44;

j) —S (= O) i -R45,

k) -SO 2 -N (R 46) (R 47), or

(l) a group selected from the following formulas:

R48R49N

R52— (CH2Jt-NN—

X or

R19 is as defined above;

T stands for

a) 0,

(b) S, or

c) SO2;

R 42 and R 43, at each occurrence, have the same or different meanings and are selected from the group consisting of:

a) H,

b) C 3-6 cycloalkyl,

(c) phenyl;

d) C 1-6 acyl,

e) C 1-6 alkyl optionally substituted with OH,

C 1-6 alkoxy optionally substituted by OH, 5 or 6-membered aromatic heterocyclic group containing one to three atoms selected from the group consisting of S, N and O, phenyl optionally substituted by OH, CF 3, halogen, -NO 2, C 1-4 alkoxy, -NR 48 R 49, or

f) In ^R 54 or r ₅₅ -chg)

V means

a) O,

(b) CH2; or

c) NR56;

R48 and R49 may have the same or different meanings at each occurrence and are

(a) H or

b) a C 1-4 alkyl group;

R54 is

(a) OH,

b) C 1-4 alkoxy, or

c) -NR 57 R 58;

99 * 9 9 9 * 9

9 9 9 * · * · · · · · · ·

Rs5 means

(a) H or

b) a C 1-7 alkyl group optionally substituted with indolyl, OH, mercaptyl, imidazolyl, methylthio, amino, phenyl optionally substituted with OH, -C (= O) -NH 2, -CO 2 H or -C (= NH) -NH ₂ ;

Rse means

a) H,

(b) a phenyl group; or

c) C 1-6 alkyl optionally substituted with OH;

R57 and Rse can have the same or different meanings at each occurrence and are

a) H,

b) C 1-6 alkyl,

c) a C 1-3 cycloalkyl group, or

d) phenyl;

R44 stands for

a) C 1-6 alkyl optionally substituted with C 1-6 alkoxy or C 1-6 hydroxy, C 3-6 cycloalkyl, a 6-membered aromatic or benzo-fused heterocyclic group containing one to three nitrogen atoms, which may be substituted with one to three groups of -NO 2, CF 3, halogen, -CN, OH, C 1-6 alkyl,

C 1-5 alkoxy and C 1-5 sacyl,

b) \ ^ N- _(CH2) t- »

(c) a phenyl group; or

d) a pyridyl group;

R45 stands for

a) C 1-6 alkyl group,

b) a C 2-10 alkenyl group wherein substituents (a) and (b) may be optionally substituted with a C 1-6 alkoxycarbonyl group or a 5-, 6- or 7-membered aromatic heterocyclic group containing one to three atoms selected from the group consisting of S, N and O,

(c) an aromatic group of 6 to 10 carbon atoms; or

d) a 5-, 6-, or 7-membered aromatic heterocyclic group containing one to three atoms selected from the group consisting of S, N and O, wherein substituents (c) and (d) may be optionally substituted by a group selected from carboxyl, halogen , -CN, formyl, CF 3, -NO 2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylthio, and C 1-6 alkoxycarbonyl;

R46 and R47 may have the same or different meanings and meanings at each occurrence

a) H,

b) a phenyl group,

c) C 1-6 alkyl, or

d) a benzyl group;

R50 and R51 may have the same or different meanings at each occurrence and are

a) H,

(b) OH,

c) C 1-6 alkyl optionally substituted with -NR 48 R 49 wherein R 48 and R 49 are as defined above,

d) R50 and R51 together are = O;

R 52 represents a group selected from the group consisting of

(a) an aromatic group of 6 to 10 carbon atoms;

b) a 5- or 6-membered aromatic or benzo-fused heterocyclic group containing one to three atoms selected from the group consisting of S, N and O, wherein substituents (a) and (b) may be optionally substituted with one to three groups selected from -NO 2, CF 3, halogen, -CN, OH, phenyl, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 sacyl,

c) morpholines1,

(d) OH,

e) C 1-6 alkoxy,

f) -NR 48 R 49 wherein R 48 and R 49 are as defined above,

g) -C (= O) -R 59, or

(h)

«· ·· · ·

R 53 represents a group selected from the group consisting of

a) H,

(b) formyl;

c) C 1-4 alkyl,

d) C 1-4 acyl,

(e) phenyl;

f) C3-ecycloalkyl,

g) -P (O) (OR 37) (OR 38);

h) -SO 2 R 39, wherein R 37, R 38 and R 39 are as defined above;

R 59 is selected from the group consisting of

(a) morpholinyl,

(b) OH, and

c) C 1-6 alkoxy;

h is 1 or 3;

i is 0, 1 or 2; j is 0, or 1;

k is 3 or 5;

r stands for

2, 3, 4, 5, or 6;

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

u is 1 or 2; and

Q is a group selected from the group consisting of

(a) hydrogen,

(b) halogen,

(c) NO2;

d) N3

ΦΦΦΦ φφφ ·

9 99 · · φ φ φ φ • · ΦΦΦΦ ΦΦΦΦ • · · ΦΦ ΦΦΦφ ·· 99 φφφ φφ φφφ

e) C 1-6 alkylthio,

II

f) C 1 -C 6 alkyl-S-;

It

g) C 1 -C 6 alkyl-S-;

O

h) C 1 -C 6 alkyl

(i) C 1 -C 6 alkoxy,

(j) formyl;

II

k) C 1 -C 6 alkyl-C-

II

l) C1- _C6 alkyl-OC-

(m) -sulfamoyl (H2NSO2-), η) -NHOH,

o) C 1 -C 6 alkyl-C-00

1 «

p) heteroaryl-C-, wherein heteroaryl represents a 5- or 6-membered aromatic heterocyclic group containing 1-3 heteroatoms selected from the group consisting of 0, N or S.

q) CsH5-C-

r) amino,

s) C 1 -C 6 alkylamino-,

t) di (C 1 -C 6 alkyl) amino-, n

u) (C1-C6) alkyl-C-NR6Re1, where T10 and R6i are each independently hydrogen or C1-C6alkyl,

(v) OH,

(w) cyan;

x) hydroxy (C 1 -C 6 alkyl)

O

Π

y) C 1 -C 6 alkyl-S-C-,

II

z) NC- (CH2) r-C-, wherein r is 1-6,

(Aa) C6H5CH2-O-C-,

O

II bb) C 5 H 5 -O-C-, OR 6 4

N n

cc) C 1 -C 6 alkyl-C-, wherein R 84 is hydrogen or

C 1-6 alkyl,

O

II dd) Re5O- (CH2) 1-6-C-, where Res is hydrogen,

C 1-6 alkyl optionally substituted by one or more of F, Cl, OH, C 1-6 alkoxy or C 1-6 alkyloxy, C 3-6 cycloalkyl or C 1-6 alkoxy;

N-OR84

Ee) HC- wherein R 84 is hydrogen or C 1-6 alkyl, ff) substituted or unsubstituted C 6 -C 10 aryl, gg) substituted or unsubstituted monocyclic or bicyclic saturated or unsaturated heterocyclic group containing 1-3 atoms selected from the group consisting of 0 , N and S, wherein said ring is bonded through a ring carbon or nitrogen atom to a phenyl substituent, hh) a monocyclic or bicyclic substituted or unsubstituted heteroaromatic group containing 1-3 atoms selected from the group consisting of 0, N and S, wherein said ring is attached to the phenyl substituent through a ring carbon or nitrogen atom, and wherein the heteroaromatic group may be further fused to a benzene or naphthalene ring;

wherein the substituents for the groups mentioned under (p), (q), (ff), (gg) and (hh) may form 1 or 2 groups selected from the following groups:

1) halogen,

2) C 1-6 alkyl,

3) N0 ₂

4) N ₃ ,

II

5) C1-6alkyl-S-,

II

6) C 1-6 alkyl-S-,

II o

7) formyl,

II

8) C 1-6 alkyl-C 1-8

π

9) C 1-6 alkyl-O-C-,

O

II

10) heteroaryl-C-, wherein heteroaryl is 5- or

A 6-membered aromatic heterocyclic group containing 1-3 heteroatoms selected from the group consisting of O, N and S,

O

11) CsHs-C-

O

II

12) - (C 1 -C 6) alkyl-C-NR 60 R 6i, wherein Reo and R 6i each independently represent hydrogen or C 1 -C 6 alkyl,

13) OH,

14) hydroxy (C 1 -C 6 alkyl),

Ó • J

15) C 1 -C 6 alkyl-S-C-,

O

1 «

16) NC- _(CH2) rOC-, wherein r is 1-6,

O

II

(17) C6H5CH2-O-C-,

18) -CH 2 -R 80, wherein Reo is

(a) -OR 32 where R 32 is as defined above,

b) -SR 32 where R 32 is as defined above,

c) -NR 32 R 33 wherein R 32 and R 33 are as defined above, or

d) 5- or 6-membered heteroaromatic group containing 1-4 atoms of 0, S or N, ^ ORe 4

N

C 1 -C 6 alkyl-L- wherein Re 4 is as defined above, cyano, carboxyl,

CF ₃ ,

O

II

C 1 -C 6 alkyl-C-O-;

C 6 H 8 -O-C-, wherein the phenyl part of the group may be optionally substituted by halogen or (C 1 -C 6) alkyl,

II

NR60R6I-C- wherein Ruo and Rei are as defined above,

O 0

II 11

R91-NH-C- or R91-C-NH-, wherein R91 is 5- or 2-R-

A 6-membered aromatic heterocyclic group containing 1-3 O, N or S atoms,

O

II

C ₆ H ₅ (CH 2) 1-6-OC-, o

II

Re5O- (CH2) 1 -6 ^_ O-C- wherein Res is as defined above,

O

II

S 1 R 99 R 100 R 10 -O-CH 2 -C-, wherein R 99, R 100 and R 101 each independently represent a C 1-6 alkyl group; or ·· ·· · · · · · ·

Q and each R 1 and R 2 together form a -O-CH 2 -O group.

Said derivatives are useful as antimicrobial agents effective against multiple pathogens in human and veterinary medicine, including Gram-positive bacteria such as multidrug-resistant staphylococci, streptococci and enterococci, such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus faecium.

BACKGROUND OF THE INVENTION

A limited number of isoxazolinones for use as pre-emergence herbicides are known in the literature. For example, 2-methyl-4- (trifluoromethyl-m-tolyl) -3-isoxazolin-5-one and 2-methyl-4- (chloro-m-tolyl) -3-isoxazolin-5-one disclosed in US Pat. No. 4,065,463 are suitable for preventing the growth of weeds having an adverse effect on crop yields.

U.S. Patent No. 4,000,155 discloses a related compound,

1,2-dimethyl-4- (trifluoro-m-tolyl) -3-pyrazolin-5-one having the same uses.

The Applicant is not aware of any literature indicating the use of the above compounds as broad-spectrum antibacterial agents. A different ring system is disclosed in WO 98/07708 dealing with the use of isoxazoline derivatives as antibacterial agents wherein W is a substituted aryl or heteroaryl system and V is H, a C 1 -C 4 alkyl group optionally substituted by F, Cl, OH, C 1 -C 4 alkyl group or acyloxy group .

The oxazolidinones of formula (II) shown below are a well known class of orally administered active antibacterial agents. There are multiple references in the art to said compounds, wherein the substituents Y and Z may have more different meanings. Specific substituted oxazolidinones are disclosed in U.S. Patent Nos. 4,705,799 and 5,523,403 (substituted phenyl-2-oxazolidinones), in U.S. Patent Nos. 4,948,801;

5,254,577; and 5,130,316 (arylbenzene-oxazolidinyl compounds) and in European Patent Applications No. 1,697,412; 0,694,544; 0,694,543; and 0,693,491 (5- to 9-membered heteroaryl-substituted oxazolidinones).

In addition, certain compounds containing a substituted furanone ring are reported to exhibit antibiotic activity. WO 97/14690 discloses a compound of the formula

wherein T is hydroxy or NHC (O) C 1 -C 4 alkyl, M and L are each independently hydrogen or fluoro, G and H each independently are hydrogen or methyl, KJ is C = CH, CHCH 2 or C (OH) CH 2 , I is O, SO, SO2 or a substituted nitrogen atom and QR is CH2-CH2 or CH = CH2. Other substituted furanones are disclosed in U.S. Patent No. 5,708,169 and in WO 97/43280 and WO 97/10235.

SUMMARY OF THE INVENTION

The present inventors have now found that certain substituted isoxazolinones are effective as antibacterial agents. In particular, the invention includes compounds of formula (I):

L

Or a pharmaceutically acceptable salt thereof, wherein:

R ¹ represents

a) Η,

b) C 1-6 alkyl optionally substituted by one or more of F, Cl, OH, C 1-6 alkoxy and C 1-6 alkyloxy.

c) a C 3-6 cycloalkyl group;

d) C 1-6 alkoxy;

L is oxygen or sulfur;

And it means

and)

(b)

c) a 5-membered heteroaromatic group containing one to three heteroatoms selected from the group consisting of S, N and O, wherein said 5-membered heteroaromatic group is attached via a carbon atom and may additionally be fused to a benzene or naphthyl ring, and said heteroaromatic the group is optionally substituted with one to three R e substituents,

d) a 6-membered heteroaromatic group containing at least one nitrogen atom, wherein said heteroaromatic group is attached via a carbon atom and said 6-membered heteroaromatic group may additionally be fused to a benzene or naphthyl ring, and the heteroaromatic group is optionally substituted with one to three R 9 substituents,

(e) a group selected from the group consisting of β-carbolin-3-yl or indolizinyl attached to a group of β-carbolin-3-yl or indolizinyl; 9 99 • 9 9 9 9 9 9 9 99 • 9 9 9 9 9 99 • 99 999 99 999 99999 via a 6-membered ring and optionally substituted with one to three Rg,

F)

or

wherein R 2 and R 3 each independently represent a group consisting of:

a) H,

b) F,

c) Cl,

d) Br,

e) C 1-6 alkyl,

(f) NO2;

S) I,

h) C 1-6 alkoxy,

(i) OH,

j) amino,

(k) cyano; or

l) R 2 and R 3 together represent -O (CH 2) h -O;

wherein R 4 is a group selected from the group consisting of

a) H,

b) C 1-2 alkyl,

(c) F, or

d) OH;

R 5 is a group selected from the group consisting of

a) H,

(b) CF3;

c) C 1-3 alkyl, optionally substituted with one or more halogen atoms,

d) phenyl, optionally substituted with one or more halogen atoms,

e) R 5 and R 6 together form a 5-, 6-, or 7-membered ring of the general formula

F)

X wherein D is S, O or Re6, wherein Re6 is H or C1-6alkyl, or

g) R 5 and R 6 taken together are - (CH 2) k - when

R 7 represents an electron withdrawing group;

Rd and R7 have the same or different meanings at each occurrence and mean:

a) electron withdrawing group,

b) H,

c) CF3

d) C 1-3 alkyl optionally substituted by one halogen atom,

(e) a phenyl group, provided that at least one of R 6 and R 7 is an electron withdrawing group; or

f) R 6 and R 7 together represent a 5-, 6-, or 7-membered ring of the general formula

U means:

(a) CH2,

b) O,

(c) S or

d) NRIE;

Rié means:

(a) H or

b) a C 1-6 alkyl group;

wherein Re is a group selected from the group consisting of:

(a) carboxyl,

(b) halogen,

c) -CN,

(d) mercapto,

(e) formyl;

(f) CF3;

(g) NO2;

h) C 1-6 alkoxy,

i) C 1-6 alkoxycarbonyl,

j) C 1-6 alkylthio,

k) C 1-6 acyl,

l) -NR17R18, ·· ···· · ·

NOH ιι

m) -C-R87, wherein _R8 represents H 7 or C-alkyl group, a

n) C 1-6 alkyl optionally substituted with OH, sulfamoyl, C 1-6 alkoxy, C 1-6 sacyl and "NR 17 R 18"

o) C 2-6 alkyl optionally substituted by one or two R 19,

p) a phenyl group optionally substituted with one or two R 19,

q) a 5- or 6-membered saturated or unsaturated heterocyclic group containing one to three atoms selected from the group consisting of S, N and O, optionally substituted with one or two R 19, or

R17 and R18, at each occurrence, have the same or different meanings and are selected from the group consisting of:

a) H

b) C 1-4 alkyl,

c) C5-ecycloalkyl; or

d) R 17 and R 16 together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated heterocyclic group which optionally contains another heteroatom selected from the group consisting of S, N, O, and may be further optionally substituted, including substitution at another nitrogen atom, group selected from the group consisting of Ci-3 alkyl, formyl, a 5- or 6-membered heteroaromatic moiety containing 1-3 0, N | i or S, -C-NR88R89 in which R ₈₈ and R ₈ 9 are each independently ·· · 9999 • 9 They represent hydrogen or C 1-6 alkyl, SO 2 R 90 wherein R 90 is H or C 1-6 alkyl, or C 1-3 acyl optionally substituted with 1 or more F, Cl or OH;

R19 is selected from the group consisting of:

(a) carboxyl,

(b) halogen,

c) -CN,

(d) mercapto,

(e) formyl;

f) cf

(g) NO2;

h) C 1-6 alkoxy,

(i) C 1-6 alkoxycarbonyl,

j) C 1-6 alkylthio,

k) C 1-6 acyl,

l) C 1-6 alkyl optionally substituted with OH, C 1-6 alkoxy, C 1-6 sacyl and -NR 17 R 18,

m) phenyl,

n) -C (= O) NR ₂ OR 21,

(o) -NR17R18;

p) -N (R ₂₀ ) (-SO ₂ R 22),

q) -SO 2 -NR 20 R 21 a

r) -S (= O) 1 R 22;

R20 and R21, at each occurrence, have the same or different meanings and are a group consisting of

a) H,

b) C 1-6 alkyl;

c) phenyl;

R22 is selected from the group consisting of

a) C 1-4 alkyl; and

b) phenyl optionally substituted with a C 1-6 alkyl group;

wherein R 9 is a group selected from the group consisting of

(a) carboxyl,

(b) halogen,

c) -CN,

(d) mercapto,

(e) formyl;

(f) CF3;

(g) NO2;

(h) C1-alkoxy,

i) C 1-6 alkoxycarbonyl,

j) C 1-6 alkylthio,

(k) C1-eacyl,

(l) -NR23R24;

m) C 1-6 alkyl optionally substituted with OH, C 1-6 alkoxy, C 1-6 sacyl and -NR 23 R 24,

n) C 2-8 alkylphenyl optionally substituted with one or two R 25,

o) phenyl, optionally substituted with one or two R 25,

p) a 5- or 6-membered saturated or unsaturated heterocyclic group containing one to three atoms from the group consisting of S, N and O, optionally substituted with one or two R 25, or

q)

· ······························· · »* * * * * * * *» »*»

R23 and R24, at each occurrence, have the same or different meanings and are selected from the group consisting of:

a) H,

(b) formyl;

c) C 1-4 alkyl,

d) C 1-4 acyl,

(e) phenyl;

f) C3-ecycloalkyl1, or

g) R 23 and R 24 together with the nitrogen atom form a 5- or 6-membered saturated heterocyclic group which optionally contains an additional heteroatom selected from the group consisting of S, N, O, and may be further optionally substituted, including substitution on said other nitrogen atom, from the group consisting of phenyl, pyrimidyl, C 1-3 alkyl and C 1-3 acyl;

R25 is selected from the group consisting of:

(a) carboxyl,

(b) halogen,

c) -CN,

(d) mercapto,

(e) formyl;

(f) CF3;

(g) NO2;

h) C 1-6 alkoxy

i) C 1-6 alkoxycarbonyl,

j) C 1-6 alkylthio,

(k) C1-eacyl,

(l) phenyl;

m) C 1-6 alkyl optionally substituted with OH, azido, C 1-6 alkoxy, C 1-6 sacyl, -NR 32 R 33,

• • » ··· « • 9 • · 9 »» « and · <1 • • • ··· • • 9 ♦ E • • · • • • • • • · ·· ··· • r •

-SR34, -O-SO2R35 or

n) -C (= O) NR 26 R 27;

o) -NR 23 R 24

P) -N (R ₂₆ ) (-SO 2 R ₂₂ ),

q) -SO 2 -NR 26 R 27, or

(r) -S (= 0) 1 R 22,

s) -CH ₂ NR 8, or

t) -CH (OH) -SO ₃ R 31;

R22 is as defined above;

R 26 and R 27, at each occurrence, have the same or different meanings and are selected from the group consisting of:

a) H,

b) C 1-6 alkyl,

(c) phenyl; or

d) tolyl;

R28 is selected from the group consisting of:

(a) OH,

(b) benzyloxy,

c) -NH-C (= O) -NH 2,

d) -NH-C (= S) -NH ₂ , or

e) -NH-C (= NH) -NR ₂ 9R3o;

R29 and R30 have the same or different meanings at each occurrence and denote

a) H or ································

b) C 1-4 alkyl optionally substituted by phenyl or pyridyl;

R31 is

(a) H or

b) sodium ion;

R32 and R33 have the same or different meanings at each occurrence and are selected from the group consisting of:

and)

(b)

C)

(d)

E)

F)

G)

(h)

and)

H, forms 1, C 1-4 alkyl, C 1-4 acyl, phenyl,

C 3-6 cycloalkyl,

R32 and R33 together form a 5- or 6-membered saturated heterocyclic group containing one to three atoms selected from the group consisting of S, optionally substituted, including nitrogen substitution, by a group selected from phenyl, pyrimidyl, C1-3alkyl, and C1-3acyl, -P (O) (OR 37) (OR 38), or -SO 2 -R 39;

N, O, atom

R34 stands for

N — N <K.

N (CH ₃ ) ₃ CH ₃

or

R 35 represents a C 1-3 alkyl group;

R36 is

a) a C 1-6 alkoxycarbonyl group; or

b) a carboxyl group;

R37 and R38 have the same or different meanings at each occurrence and denote

(a) H or

b) a C 1-3 alkyl group;

R39 is selected from the group consisting of:

(a) methyl,

(b) phenyl; or

c) tolyl;

K means

a) 0,

(b) S, or

c) NR 40 wherein R 40 is hydrogen, formyl, C 1-4 alkyl, C 1-4 acyl, phenyl, C 3-6 cycloalkyl, -P (O) (OR 37) (OR 37e) and -SO 2 -R 39, wherein R 37, R38 and R39 are as defined above;

R10, R11, R12, R13, R14 and R15 have the same or different meanings at each occurrence and are selected from the group consisting of:

a) H,

b) formyl, ♦ · · · yl yl yl yl yl yl yl yl yl yl yl yl yl

c) carboxyl,

d) C 1-6 alkoxycarbonyl,

e) C 1-6 alkyl,

f) C 2-8 alkenyl wherein the substituents labeled (e) and (f) are optionally substituted with OH, halogen, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylthio, or C 1-6 alkoxycarbonyl, or phenyl optionally substituted with halogen ,

g) an aromatic group of 6 to 10 carbon atoms optionally substituted by a group selected from the group consisting of carboxyl, halogen, -CN, formyl, CF 3, NO 2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylthio, and

C 1-6 alkoxycarbonyl;

(h) -NR42R43;

(i) OR44;

j) -S (= O) 1 -R 45,

k) -SO 2 -N (R 46) (R 47), or

(l) a group selected from the following formulas:

r ~ \ _U—

Q-.

CONH ₂

R48R4 ₉ N - ^^ NHN or ^R 53rd

R53-N N—

RS3 ^U

R19 is as defined above;

T stands for

a) O,

(b) S, or

c) SO2;

R 42 and R 43, at each occurrence, have the same or different meanings and are selected from the group consisting of:

a) H,

b) C 3-6 cycloalkyl,

(c) phenyl;

(d) C1-eacyl,

e) C 1-6 alkyl optionally substituted with OH,

C 1-6 alkoxy optionally substituted with OH, 5 or 6-membered aromatic heterocyclic group containing one to three atoms selected from the group consisting of S, N and O, phenyl optionally substituted with OH, CF 3, halogen, -NO 2, C 1-4 alkoxy,

F)

-NR 48 R 49, or

or

G)

V means

O.

R55-CH-

a) O •

(b) CH2; or

c) NRse;

R48 and R49 may have the same or different meanings at each occurrence and are

(a) H or

b) a C 1-4 alkyl group;

R54 is

(a) OH,

b) C 1-4 alkoxy, or

c) -NR 57 R 58;

R55 is

(a) H or

b) a C 1-7 alkyl group optionally substituted with indolyl, OH, mercaptyl, imidazolyl, methylthio, amino, phenyl optionally substituted with OH, -C (= O) -NH 2, -CO 2 H or -C (= NH) -NH ₂ ;

Rso means

a) H,

(b) a phenyl group; or

c) C 1-6 alkyl optionally substituted with OH;

R57 and R58 may have the same or different meanings at each occurrence and mean:

a) Η,

b) C 1-6 alkyl,

c) a C 1-3 cycloalkyl group, or

d) phenyl;

R44 stands for

a) C 1-6 alkyl optionally substituted with C 1-6 alkoxy or C 1-6 hydroxy, C 3-6 cycloalkyl, a 6-membered aromatic or benzo-fused heterocyclic group containing one to three nitrogen atoms, which may be substituted with one to three groups of -NO 2, CF 3, halogen, -CN, OH, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 sacyl,

(c) a phenyl group; or

d) a pyridyl group;

R45 stands for

a) C 1-6 alkyl,

b) a C 2-10 alkenyl group wherein substituents (a) and (b) may be optionally substituted with a C 1-6 alkoxycarbonyl group or a 5-, 6- or 7-membered aromatic heterocyclic group containing one to three atoms selected from the group consisting of S, N and 0,

(c) an aromatic group of 6 to 10 carbon atoms; or

d) a 5-, 6-, or 7-membered aromatic heterocyclic group containing one to three atoms selected from the group consisting of S, N and O, wherein substituents (c) and (d) may be optionally substituted by a group selected from carboxyl, halogen , -CN, formyl, CF 3, -NO 2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 acyl, C 1-6 alkylthio, and C 1-6 alkoxycarbonyl;

R46 and R47 may have the same or different meanings at each occurrence and are

a) H,

b) a phenyl group,

c) C 1-6 alkyl, or

d) a benzyl group;

R50 and R51 may have the same or different meanings at each occurrence and are

a) H,

(b) OH,

c) a C 1-6 alkyl group optionally substituted by -NR 48 R 49 wherein R 48 and R 49 are as defined above,

d) R50 and R51 together are = O;

R 52 represents a group selected from the group consisting of

(a) an aromatic group of 6 to 10 carbon atoms;

b) a 5- or 6-membered aromatic or benzo-fused heterocyclic group containing one to three atoms selected from the group consisting of:

Comprising S, N and O, wherein substituents (a) and (b) may be optionally substituted with one to three groups selected from the group consisting of -NO 2, CF 3, halogen, -CN, OH , phenyl, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 sacyl,

c) morpholinyl,

(d) OH,

e) C 1-6 alkoxy,

f) -NR 48 R 49 wherein R 48 and R 49 are as defined above,

g) —C (= O) —R 59, or

(h)

R 53 represents a group selected from the group consisting of

a) H,

b) molds1,

c) C 1-4 alkyl,

d) C 1-4 acyl,

(e) phenyl;

f) C3-6cycloalkyl,

g) -P (O) (OR 37) (OR 38);

h) -SO 2 R 39, wherein R 37, R 38 and R 39 are as defined above;

R 59 is selected from the group consisting of

(a) morpholinyl,

(b) OH, and

c) C 1-6 alkoxy;

h means 1, 2 or 3; and means 0, 1 or 2; j means 0, or 1 9 to means 3, 4 or 5; r means 1, 2, 3, 4, 5, or 6; t means 0, 1, 2, 3, 4, 5 or 6; at means 1 or 2; and

Q is a group selected from the group consisting of

(a) hydrogen,

(b) halogen,

(c) NO2;

d) N3

e) C 1-6 alkylthio,

O li

f) C 1 -C 8 alkyl-S-,

g) C 1 -C 6 alkyl-S-,

h) C 1 -C 6 alkyl

(i) C 1 -C 6 alkoxy,

(j) formyl;

O ti

k) C 1 -C 6 alkyl-C-

AND"

l) C 1 -C 6 alkyl-O-C-

(m) -sulfamoyl (H2NSO2-),

η) -NHOH

o) C 1 -C 6 alkyl-C-O 45

4444 • 4 «4 · φ 4 ♦ 4 • • • • 4 4 4 4 • «t • • • 4 4 4 4 4 • ♦ 4 4 4 4 4 4 • • 4 4 4 • 4 4 4 4 e «4 4 * • 4 4

O ιι

p) heteroaryl-C-, wherein heteroaryl represents a 5- or 6-membered aromatic heterocyclic group containing 1-3 heteroatoms selected from the group consisting of 0, N or S.

II

q) C6H5-C-

r) amino,

s) C 1 -C 6 alkylamino-,

t) di (C 1 -C 6 alkyl) amino -;

u) (C 1 -C 6 alkyl-C-NR c R e R 6, wherein R 10 and R 8 each independently represent hydrogen or C 1 -C 6 alkyl,

(v) OH,

(w) cyan;

x) hydroxy (C 1 -C 6 alkyl)

O

II

y) C 1 -C 6 alkyl-S-C-,

O

II

z) NC- (CH2) r-C-, wherein r is 1-6,

II (aa) C6H5CH2-O-C-

II bb) C 6 H 5 -O-C

• 4444 <4 * 4 • * •• 4 4 · 9 44 • 4 4 9 O 9 • 4 • • 4 « • 4 4 4 4 • • • 4 • • 4 4 4 4 • • • • 4 4 • 444 • 44 • 4 «3 · ·· 44 4

^ 0 ^ 8 5

Cc) C 1 -C 6 alkyl-C-, wherein R 84 is hydrogen or

C 1-6 alkyl,

O

II dd) Re5O- (CH2) 6 ^- C ^- where Res represents hydrogen,

A C 1-6 alkyl group optionally substituted by one or more of F, Cl, OH, C 1-6 alkoxy or C 1-6 acyloxy, C 3-6 cycloalkyl or C 1-6 alkoxy;

N-ORe 4

(Ef) substituted or unsubstituted C 6 -C 10 aryl, gg) substituted or unsubstituted monocyclic or bicyclic saturated or unsaturated heterocyclic group containing 1-3 atoms selected from the group consisting of O, (Hh) a monocyclic or bicyclic substituted or unsubstituted heteroaromatic group containing 1-3 atoms selected from the group consisting of O, N and S, wherein said ring is bonded to a phenyl substituent; a phenyl substituent through a ring carbon or nitrogen atom, and wherein the heteroaromatic group may be further fused to a benzene or naphthalene ring;

wherein the substituents for the groups mentioned under (p), (q), (ff), (gg) and (hh) may form 1 or 2 groups selected from the following groups:

1) halogen,

2) C 1-6 alkyl,

3) NO2

4) N3,

O! ·

5) C 1-6 alkyl-S-;

O

II

6) C 1-6 alkyl-S-,

II

O

7) formyl,

O n

8) C 1-6 alkyl-C-

O l>

9) C 1-6 alkyl-O-C-,

O (I

10) heteroaryl-C-, wherein heteroaryl is 5- or

A 6-membered aromatic heterocyclic group containing 1-3 heteroatoms selected from the group consisting of O, N and S,

O

11) CeH 5 -C,

O

II

12) - (C 1 -C 6) alkyl-C-NR 60 R 61, wherein R 60 and R 6 each independently represent hydrogen or C 1 -C 6 alkyl,

13) OH,

14) hydroxy (C 1 -C 6 alkyl), 4 · 4, 4 · 4, 4 · 4 · 44 ···

O

15) C 1 -C 6 alkyl-S-C-,

16) NC - (CH 2) r -O-t-, wherein r is 1-6,

O

(17) C6H5CH2-O-L-,

18) -CH 2 -R 80, wherein Reo is

(a) -OR 32 where R 32 is as defined above,

b) -SR 32 where R 32 is as defined above,

c) -NR 32 R 33 wherein R 32 and R 33 are as defined above, or

d) a 5- or 6-membered heteroaromatic group containing 1-4 O, S or N atoms,

ORs 4 /

N

II

19) C 1 -C 6 alkyl-C- wherein R 84 is as defined above,

20) cyan;

21) carboxy,

22) CF3

O

II

23) C 1 -C 6 alkyl-C-O-,

O

II

24) C 6 H 5 -O-C-, wherein the phenyl moiety of the group may be optionally substituted with halogen or (C 1 -C 6) alkyl,

O

(25) NR60R6I - & - wherein Reo and R6i are as defined above,

(26) R 1i-NH-C- or R91-C-NH-, wherein R91 is a 5- or 6-membered aromatic heterocyclic group containing 1-3 O, N or S atoms,

27) C ₆ H ₅ (CH 2) 1-6-OC-,

1 '

28) R 8 5 O- (CH 2) 1-6 -O-C-, wherein R 5 is as defined above,

29) S 1 R 99 R 100 R 10 -O-CH 2 -C-, wherein R 99, R 100 and R 101 each independently represent a C 1-6 alkyl group; or

Q and each R 1 and R 2 together form a -O-CH 2 -O group.

The compounds of the invention are novel and represent a new class of antibacterial agents. They differ from both the previously disclosed oxazolidinone and isoxazoline antibiotics because they contain an isoxazolinone ring system. They also differ from the already known isoxazolinone herbicides because the ring nitrogen atom in these compounds is necessarily substituted with an amide group as described above.

The compounds of formula (I) are antibacterial agents useful in the treatment of infections in humans and animals caused by various bacteria, in particular methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus faecium.

The invention also encompasses processes for preparing compounds of formula (I) and pharmaceutical compositions comprising the following:

The compound in association with pharmaceutically acceptable carriers or diluents.

Definition

The term pharmaceutically acceptable salt as used herein includes non-toxic acid addition salts including inorganic or organic acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, fumaric, almond, p-toluenesulfonic, methanesulfonic, ascorbic, lactic acid. , gluconic, trifluoroacetic, hydroiodic, hydrobromic and the like. Said salts may be in hydrated form.

The terms halogen or halogen include chlorine, bromine, fluorine and iodine, preferably chlorine or fluorine.

The term aliphatic alkyl groups as used herein refers to straight or branched chain chains containing a specified number of carbon atoms, for example, in the case of C 1 -C 6 alkyl, the alkyl group may contain 1 to 6 carbon atoms.

Similarly, terms such as C 2 -C 8 alkenyls include alkenyl groups having a specified number of carbon atoms containing at least one double bond and C 2 -C 8 alkynyl groups, alkynyl groups containing a specified number of carbon atoms, and at least one triple bond, etc.

The term acyloxy means, unless otherwise indicated,

An O-type CH3AO- group wherein the alkyl group contains a specified number of carbon atoms, for example, a C 1 -C 8 alkoxy group may contain 1-6 carbon atoms. If the carbon chain length is not specified, the chain may contain 1-6 carbon atoms.

The term aryl means, unless otherwise indicated, aromatic carbocyclic rings, ie, phenyl and naphthyl.

The term heteroaromatic as used herein includes an aromatic heterocyclic group containing one or more atoms selected from the group consisting of O, N, S, such as pyridine, thiophene, furan, pyrimidine, and including groups such as 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidinyl,

4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl,

3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl,

3-isoquinolyl, 2-imidazolyl, 4-imidazolyl, 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.

Saturated or unsaturated heterocyclic groups containing 1-3 atoms selected from the group consisting of O, N and S, such as dioxolane, imidazolidine, dithiolane, oxathiolane, oxazolidine, piperidinyl, piperazinyl, morpholine or thiomorpholine, or the corresponding unsaturated heterocyclic groups.

Where possible, the nitrogen and / or sulfur atoms in said heterocyclic groups may be oxidized, and these oxidized compounds are to be considered included in the group of compounds of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Preferred embodiments of the invention include compounds of formula (I) wherein

And it means

wherein Q 1, R 2 and R a are as defined above.

An even more preferred embodiment of the invention comprises a compound of formula (IA)

or a pharmaceutically acceptable salt thereof, wherein

R 1 represents H, C 1-6 alkyl optionally substituted by one or more of F, Cl, OH, C 1-6 alkoxy and C 1-6 alkyloxy, or C 3-6 cycloalkyl or C 1-6 alkoxy;

R2 and R3 are each independently &quot; 999 &quot;

9 · 9 9 9 9 99 9

999 9 9,999,999

9 9 9 9 9 9 99 99 • 9 9 9 9 99

999999 · * * ♦ · 999 9 9

a) Η,

b) F,

c) Cl,

d) Br,

e) C 1-6 alkyl,

f) no

g) I,

h) C 1-6 alkoxy,

(i) OH,

j) amino, or

(k) cyano; and

Q is a group selected from the group consisting of

(a) hydrogen,

(b) halogen,

c) NO2,

d) Na,

e) C 1-6 alkylthio,

II

f) C 1 -C 6 alkyl-S-,

II

g) C 1 -C 6 alkyl-S-;

O

h) C 1 -C 6 alkyl

(i) C 1 -C 6 alkoxy;

(j) formyl;

O ir

k) C 1 -C 6 alkyl-C-,

O

II

l) C 1 -C 6 alkyl-OC-, · · · · «« «« «« «« «« «« «« «« « »» • · * * * * *.......

O

II

m) C 1 -C 6 alkyl-C-O-,

n) heteroaryl-C-, wherein heteroaryl is 5- or

A 6-membered aromatic heterocyclic group containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

if

o) C ₆ H ₅ -C-

p) amino,

q) C 1 -C 6 alkylamino-,

r) di (C 1 -C 6 alkyl) amino-,

II

s) (C 1 -C 6) alkyl-C-NR 60 R 61, wherein Reo and R 6 are each independently hydrogen or C 1 -C 6 alkyl,

(t) OH,

(u) cyan;

(v) hydroxy (C 1 -C 6 alkyl);

II

w) C 1 -C 8 alkyl-S-C-,

Π

x) NC- _(CH2) RC wherein r is 1-6,

II

(y) C6H5CH2-O-C-,

O

H

z) C 8 H 8 -O-C-,

0R ₈ 4

N

II aa) C-Cealkyl-C-, where R ₈ is hydrogen or 4

C 1-6 alkyl,

O (1b) R ₈₅ O- (CH ₂ ) 2-6-C-, where Res is hydrogen,

C ₈ alkyl group optionally substituted by one or more radicals from the group consisting of F, Cl, OH, C ₈ -alkoxy or C ₈ acyloxy, C 3 -C ₈ cycloalkyl or C ₈ alkoxy;

N-OR ₈ 4 cc) HC-, wherein R ₈ 4 is defined as above, dd)

ee) ff gg hh ii)

wherein R92 is H or C1-6alkyl,

tt) uu)

aaa) diazinyl group optionally substituted with X and Y, bbb) triazinyl group optionally substituted with X and Y, ccc) quinolinyl group optionally substituted with X and

Y, ddd) a quinoxalinyl group optionally substituted with X a

Y, eee) a naphthyridyl group optionally substituted with X a

Y, fff) 9) 9) ggg) hhh) iii)

B represents an unsaturated 4-atom linking group containing one nitrogen atom and three carbon atoms;

M means

a) H,

b) a C 1-6 alkyl group,

c) a C 3-8 cycloalkyl group,

d) - (CH 2) m OR 6, or

e) - (CH 2) n R 67 R 68;

Z means

a) O,

(b) S or

c) NM;

W stands for

a) CH,

(b) N or

c) S or O when Z is NM;

X and Y each independently represent a group from the group consisting of

(a) hydrogen,

(b) halogen,

(c) NO2;

d) N3,

e) C 1-6 alkylthio,

II

f) C 1 -C 6 alkyl-S-;

g) C 1 -C 6 alkyl-S-;

O

h) C 1 -C 6 alkyl

(i) C 1 -C 6 alkoxy;

(j) formyl; and

k) C 1 -C 6 alkyl-C- »

l) C1- _C6 alkyl-OC-,

m) heteroaryl-C-, wherein heteroaryl represents a 5- or 6-membered aromatic heterocyclic group containing 1-3 heteroatoms selected from the group consisting of 0, N or S.

n) C ₆ H ₅ -C-

0) amino,

p) C 1 -C 6 alkylamino-,

q) di (C 1 -C 6 alkyl) amino-,

O

r) (C 1 -C 6) alkyl-1-NR 60 R 61, wherein R 60 and R 58 each independently represent hydrogen or C 1 -C 6 alkyl,

(s) OH,

t) hydroxy (C 1 -C 6 alkyl)

O

AT

u) C 1 -C 6 alkyl-S-C-,

O

v) NC- (CH 2) r O-C-, wherein r is 1-6,

O

II

w) C 6 H 5 CH 2 -O-C-, o

II

x) C 6 H 5 -O-C-, OR 6 4

N

AT

y) C 1 -C 6 alkyl-C-, wherein R 4 is as defined above,

z) cyano, aa) carboxyl bb) CF ₃ , cc) mercapto,

O

II dd) C 1 -C 6 alkyl-C-O-,

O

H ee) C 6 H 5 -O-C-, wherein the phenyl moiety may be optionally substituted by halogen or C 1 -C 6 alkyl,

(Ff) C ₆ H ₈ (CH ₂ ) 1-6 O-C-, gg) ResO ^- (CH 2) 1-6-C- wherein Res is as defined above, or

O

AND!

hh) S 1 R 99 R 1 and R 1 o 1 -O-CH 2 -C-, wherein R 99, R 100 and R 101 each independently represent a C 1-6 alkyl group; or

Q and each of R 1 and R 3 form -O-CH ₂ -O;

R62 is

a) H

b) a C 1-6 alkyl group optionally substituted by one or more halogen atoms, or

c) C 1-6 alkyl optionally substituted by one or more OH groups or C 1-6 alkoxy groups;

E stands for

(a) NR9,

b) -S (= O) i, wherein i is 0, 1 or 2, or

c) O;

R 3 is a group selected from the group consisting of

a) H,

(b) C1-6alkyl1,

c) - (CH 2) q -aryl, a

d) halogen;

R 66 represents H or a C 1-6 alkyl group;

R 67 and R 18 each independently represent H or a C 1-4 alkyl group, or NR 6 R 6 together form - (CH 2) b ^- ;

R 9 is a group selected from the group consisting of

a) H,

b) C 1-6 alkyl,

c) - (CH 2) q -aryl,

(d) -CO2R81,

(e) CORe 2;

f) -C (= O) - (CH 2) q -C (= O) R 8,

g) -S (= O) 2 -C 1-6 alkyl,

h) -S (= 0) _z - (CH 2) q -aryl, or

i) - (C = O) j-Het wherein j is 0 or 1;

Zi means

a) -CH 2 - or

b) -CH (R 70) -CH ₂ -;

Z2 stands for

a) -O2S-

b) -0-

c) -S-,

d) -SO-, or

e) -N (R ₇₁ ) -;

Z3 means • ·

a) S,

b) SO,

(c) SO2; or

to;

A 1 is H or CH 3;

A2 means

a) H,

(b) 0H-,

(c) CH3CO2-,

d) CH 3 -.

e) CH ₃ O-,

f) R 72 O-CH ₂ -C (O) -NH-,

g) R ₇ 2 -O-C (O) -NH-,

h) R ₇ 3-C (O) -NH-,

i) (C 1 -C 2) alkyl-O-C (O) -, or

j) HO-CH 2; or

Ai and A2 together mean

and)

b) 0 =;

or

R 4 is H or CH 3 -;

m is 4 or 5;

n is 0, 1, 2, 3, 4, or 5;

y is 0 or 1;

P stands for 0, 1, 2, 3, 4, or 5;

w is 1, 2 or 3;

q is 1, 2, 3, or 4;

z is 0 or 1;

Re 5 means

(a) R74OC (R75) (R76) ^- C (O) -,

(b) R77OC (O) -,

(C) R78 (O) -,

d) R79-SO2-, or

e) Reo-NH-C (O);

R 70 is H or (C 1 -C 3) alkyl;

R71 stands for

(a) R ₇ 4OC (R 75) (R 76) -C (O) -,

(b) R77O-C (O) -,

(c) R ₇ 8-C (O) -, o

(d)

E)

H

O

f) H ₃ CC (O) - (CH 2) 2 -C (O) -,

(g) R79-SO2-;

(h)

O

(i) R ₈ o -NH-C (O) -,

65 • to ··· ·· · · · • · · · · · • ··· · · ··· • · · · · · · · • · · · · R 72 is a) H, b) CH 3, c) phenyl-CH 2 -, or d) CH ₃ C (O) -; R 73 represents (C 1 -C 3) alkyl or phenyl;

R 74 is H, CH 3, phenyl-CH 2 or CH 3 -C (O) -;

R 75 and R 76 each independently represent H or CH 3, or R 75 and R 76 together represent -CH ₂ CH ₂ -;

R77 is (C1-C3) alkyl or phenyl;

R78 represents a group selected from the group consisting of H, (Ci-C4) alkyl, aryl- (CH _{2) n} I, CIH2C, C1 ₂ HC 2 C-, F2HC- and (C ₃ -C ₆₎ cycloalkyl;

R 79 is CH 3; -CH ₂ Cl, -CH ₂ CH = CH ₂ , aryl or -CH ₂ CN;

R eo is - (CH ₂ ) n ¹ -aryl, wherein n ¹ is 0 or 1;

Rei means

a) H,

b) a C 1-6 alkyl group optionally substituted by one or more groups selected from the group consisting of OH, halogen and CN,

c) - (CH ₂ ) q -aryl wherein q is as defined above, or

* · Β β β β β * *

d) - (CH 2) q -OR e 3, wherein q is as defined above;

Re 2 means

a) C 1-6 alkyl optionally substituted by one or more groups selected from OH, halogen and CN;

b) - (CH 2) q -aryl wherein q is as defined above, or

c) - (CH 2) q -OR e 3, wherein q is as defined above;

R83 is selected from the group consisting of

a) H,

b) C 1-6 alkyl,

c) - (CH 2) q -aryl, wherein q is as defined above; or

d) -C (= O) C 1-6 alkyl; and aryl is phenyl, pyridyl or naphthyl, wherein said phenyl, pyridyl or naphthyl may be optionally substituted by one or more of halogen, -CN, OH, SH, C 1-6 alkoxy or C 1-6 alkylthio.

Another preferred embodiment of the invention comprises a compound of formula (IA)

IA ··· · • ·· ···

···· ·· ««! • • · * ♦ ··· 4 * • • • <9 4 • • 9 9 9 ·· • 4 * AT#

or a pharmaceutically acceptable salt thereof, wherein

R 1 represents H, C 1-6 alkyl optionally substituted by one or more of F, Cl, OH, C 1-6 alkoxy and C 1-6 acyloxy, C 3-6 cycloalkyl or C 1-6 alkoxy;

R ₂ and R 3 each independently represent H or F; or _R2 and R3 together are

O-

Q is a group selected from the group consisting of

(a) hydrogen,

(b) halogen,

(c) N3;

d) NO ₂ ,

e) C 1-6 alkylthio

f) C 1 -C 8 alkyl-S-,

h) C 1 -C 8 alkyl

(i) C 1 -C 6 alkoxy;

(j) formyl;

H

k) C 1 -C 6 alkyl-C-, n

1) C 1 -C 6 alkyl-O-C · · · · ·· ·····

O

m) C 1 -C 6 alkyl-C 1 -O-,

n) (C 1 -C 6 alkoxy) 2 N -,

o) a 5- or 6-membered heterocyclic group contains 1-3 O, N, or S, attached to the phenyl substituent via a carbon or nitrogen atom, wherein said heterocyclic group is optionally substituted with R96.

_Z OH

N i ·

p) C 1 -C 6 alkyl-C,

q) phenyl optionally substituted with R 96; or

r) a 5- or 6-membered saturated or unsaturated heterocyclic group containing 1-3 O, N or S and attached to the phenyl substituent via a carbon or nitrogen atom, wherein said heterocyclic group is optionally substituted with R96, and

R96 represents a group selected from the group consisting of

a) C 1 -C 6 alkyl-OH,

b) C 1 -C 8 alkyl-O-C-,

O

O

c) CH3-C-C1- _C6 alkyl-C-,

O

(d) cyano;

e) forms1,

from ^0H N 11 F) H-C-, G) 0 II C 1 -C 6 alkyl-O-C-, (h) SiR99R100R101-O-CH2 0 II -C-, wherein R99, R100 and R101 each independently C 1-6 alkyl,

IIII

i) CH 3 -S-C 1 -C ₆ alkyl-S-,

I »| l oo o

II

(j) HCsCCH2OC-,

O

II

k) C6H5-O-C-, wherein the phenyl group may be optionally substituted by halogen,

O * 1

(l) HO-CH2-C-

m) (C 1 -C 6 alkyl) 2 N -,

n) C 1 -C 6 alkyl-NH-,

o) amino,

O

p) C 1 -C 6 alkyl-S-,

II

q) C6H5CH2OC-, or ······················································ · · ·· o ·· ·· ··· · · ··· o

II

r) R98-C-, wherein R98 represents a phenyl group, a 5- or 6-membered heteroaryl group containing 1-3 O, N or S and attached to the phenyl substituent via a ring carbon atom, or a 5- or 6-membered saturated or unsaturated a heterocyclic group containing 1-4 O, N or S and attached to the phenyl substituent through a ring carbon atom.

Some of the specific preferred embodiments of the invention are set forth in the attached table below:

• ·· ·

···· ·· ····

• 44 • • 4444 • 4

4 4 4 • 4

· 44 4444 · 4 · 4 · 4 · 4 · 4 · 44 · 44 · 44 · 44 · 44 · 44 · 44 · 44 · 44 · 44 · 44 · 44 · 44 · 44 · 44 · 44

· ♦ · ♦ φ ΦΦΦΦ φ · φ · · · · · · · · · · • • • • • • • ·

• 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 ·· · ··

···· ·· 444 « 44 «4 • 4 • WITH 4 4 4 • 444 4 4 4 4 4 »» 4 4 4 4 44 4> 4 • 1 4 «

• ·

• ·

·· ····

The compounds of the invention can be prepared by methods summarized below.

It will be apparent to those skilled in the art that the procedures described below are in fact illustrative and that alternative embodiments are possible.

The isoxazolinones (5) of the invention are preferably prepared by the sequence of reactions depicted in Scheme 1. The arylacetic acids (1) are either commercially available or can be prepared by any of a number of methods known in the chemical literature, including, but not limited to, in Schemes 2 or 3. Isoxazolinone (3) was prepared according to the methods described in Marchesini (J. Org. Chem. 1984, 49, 4227-4290). Treatment of compound (1) with sodium hydride and ethyl formate affords compound (2), which reaction with hydroxylamine affords compound (3). Treatment of compound (3) with a weak base, preferably potassium carbonate, in a suitable solvent, preferably dichloromethane or N, N-dimethylformamide, followed by the addition of compound (4) (prepared as described by Barnes et al., U.S. Pat. No. 5,284), 863) prepare isoxazolinone (5).

Scheme 1

AiA ^ y.COjR NaH Ar 2 O ₂ CO ₂ R H ₂ NOH EtOCHO CHO 1 2

K ₂ CO ₃

AcOCH ₂ NHCOR '

• · · ·

An alternative process for preparing the arylacetic acid esters (1) of the invention is shown in Scheme 2. Treatment of triflate (6) (prepared from methyl-4-hydroxyphenylacetate by methods known to those skilled in the art) with N, N-dialkylamine as described by Buchwald (Tet. Lett., 1997, 38, pp.6363-6366), esters such as compound (7) are prepared. The triflate (6) used in Scheme 2 may be appropriately replaced with aryl bromides, iodides and -chlorides. Said Ν, Ν-dialkylamines used in Scheme 2 are either commercially available or can be prepared by methods described in the literature. The preparation of many cyclic Ν, Ν-dialkylamine according to literature is described in detail in Gadwood (WO 97/10223) and other methods are methods generally known to those skilled in the art.

Scheme 2

Pd ° r ₂ nh

A further alternative preparation of the arylacetic acid esters (1) of the invention is shown in Scheme 3. Treatment of compound (8) with a weak base, preferably potassium carbonate and a primary or secondary amine or thiolate, in a suitable solvent, preferably acetonitrile or v, Ν-dimethylformamide, at a temperature of from 25 ° C to 100 ° C, is prepared compound (9). Compound (8) is commercially available. Compound (9) is then converted to compound (11) or (12) by the methods described in Gravestock (World Patent 97 (14690)).

This sequence of reactions is also known to those skilled in the art as the Wiergerodt reaction. Conversion of compound (11) to compound (12) can be accomplished by various methods known in the chemical literature including, but not limited to, treatment with an acid in a hot alcohol.

Scheme 3

I ² «Sulfur with For11: KOH (aq) HER ____ YEAH morpholine or For12: HCl, EtOH 10

11:

12:

R = H

R = Et

H *. EtOH

L = NRR '. or SR X ₁ = H or F

X 2 ⁼ H or F

The sulfoxides and sulfones (14) and (16) are prepared by treating the corresponding sulfides (13) and (14) with an oxidizing agent such as m-chloroperoxybenzoic acid or osmium tetroxide, by methods known in the art such as Barbachyn (J. Med.Chem). 1996, 39, 680-685).

• · · · · ♦ ··· ·

An alternative method of preparing the compound (18) of the invention is shown in Scheme 5. Treatment of compound (17) with a suitable organostannane affords compound (18). This method is known in the art as the Stille cross coupling reaction.

Scheme 5

RSnBu3

Pd °

DMF

The preparation of compounds (21), (22), (23) and (24) of the invention is shown in Scheme 6. Treatment of compound (19) with trifluoroacetic acid provides compound (20). Compound (20) is then treated with acid chloride, chloroformate, sulfonyl halide, or isocyanate in the presence of triethylamine by methods described in the literature to give the corresponding compounds (21), (22), (23) and (24).

Scheme 6

RCOCI

ROCOC1

RR'NCO

4

444 ♦ 4 ····

The triazole-substituted compounds (27) and (28) are prepared by cyclizing the azide (25) with acetylenes (26) (Scheme 7). It is a standard 3 + 2 cycloaddition sufficiently documented in the chemical literature. Acetylenes (26) are either commercially available or can be prepared by methods known in the literature. For example, cyanacetylene is prepared as described by Murahashi (J. Chem.Soc.Jap., 1956, 77, 1689). The cyclization reaction is 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 product of the cyclization reaction is two adducts (27) and (28) which are separated by preparative HPLC or by trituration with a suitable solvent such as ethyl acetate. Other suitable solvents for trituration include, but are not limited to, methanol, ethanol, diethyl ether, and acetone.

Scheme 7: 1,2,3-triazoles

Azidophenylisoxazolinone (25) is reduced to aminophenylisoxazolinone (29) by any of the many methods known in the literature including, but not limited to, treatment with stannous chloride in a suitable solvent such as a 2: 2 mixture of ethyl acetate and methanol: 1. Treatment of the aminophenylisoxazolinone (29) with

2,5-Dimethoxytetrahydrofurans (30) in acetic acid were prepared by pyrrole-substituted isoxazolinones (31) (Scheme 8). Subsequent conversions of pyrrole (R = CHO) are also possible, for example by heating at reflux with 50% aqueous hydroxylamine in methanol, to prepare the corresponding oxime.

Scheme 8: pyrroles

N-thioacetates can be prepared from the corresponding N-acetates using more literature methods known in the art, for example by heating at reflux with Lawesson's reagent in benzene. Other solvents such as toluene and xylene are also suitable.

Scheme 9: Thioacetates

Lawesson's reagent benzene. reflux

It will be appreciated that some of the substituent groups involved in the above reactions contain reaction-sensitive groups, which could lead to undesired side reactions, but these groups may be protected by commonly used protecting groups known to those skilled in the art. Suitable protecting groups and methods for their removal are disclosed, for example, in Theodor W. Green, Protective Groups in Organic Synthesis, (John Wiley & Sons, 1991). It is believed that such protected intermediates and end products are included within the scope of the invention and the appended claims.

Some desired end products of formula (I) contain an amino group. In these cases, the end product can be obtained in the form of a pharmaceutically acceptable salt, for example by adding a suitable acid such as HCl or methanesulfonic acid to said amine.

It will also be appreciated that certain products within formula (I) may contain as substituents groups which may lead to the formation of optical isomers. It is intended that the invention encompasses all such optical isomers as well as racemic mixtures thereof, i.e., the R- or S-form or the racemic form.

The compounds of the invention are beneficial due to their pharmacological effects on animals, including in particular mammals and especially humans. These novel isoxazolinone derivatives of formula (I), or pharmaceutically acceptable salts or prodrugs thereof, are potent antibiotics for Gram-negative bacteria. Thus, for example, they can be used as additives to animal feed to promote their growth, as food preservatives, as bactericides in industry, for example, water-soluble paints and white water in paper mills to inhibit the growth of harmful bacteria, as disinfectants in medical and dental compositions for destroying or inhibiting harmful bacteria, and in particular may be useful in the treatment of bacterial infections in humans and other animals caused by gram-negative bacteria susceptible to these novel derivatives.

The pharmaceutically active compounds of the invention may be administered alone or may be formulated into a pharmaceutical composition comprising, in addition to the active isoxazolinone component, a pharmaceutically acceptable carrier or diluent. The compounds may be administered by a variety of routes, for example, orally, topically, or parenterally (by intravenous or intramuscular injection). Said pharmaceutical compositions may be formulated into dosage forms such as capsules, tablets, powders, etc., or liquid forms such as solutions, suspensions or emulsions. Compositions for injection may be formulated in single-dose ampoules or in multi-dose vials and may contain ingredients such as suspending, stabilizing and dispersing agents. These compositions can be in the form of ready to use or may be in powder form for ♦ «·· ·· · * • * · · · · · · · · ··· · ♦ · ·· ·« _·># · _φ ; _β reconstitution at the time of use with a suitable vehicle such as sterile water.

In another aspect, the invention provides a method of treating a bacterial infection which comprises administering a therapeutically effective amount of a compound to a host, especially a mammal host, and particularly a human patient. The invention also includes the use of the compounds of the invention as medicaments and the use of the compounds of the invention in the manufacture of a medicament for the treatment of bacterial infections.

The dose administered depends largely on the particular compound to be administered, the particular composition used, the route of administration, the type and condition of the patient and the target organ and organism to which the treatment relates. The choice of individual preferred dosage and method of administration is left to the discretion of the physician or treating physician. In general, the compounds of the invention may be administered to a mammal parenterally or orally in an amount of from about 25 mg / day to about 2 g / day.

The preparation of the pyrazole-substituted compounds is shown in Scheme 10. Compound (29) is diazotized and then reduced to the hydrazine hydrochloride salt of compound (34) by any of the more commonly known methods in the literature including, but not limited to, processing. with sodium nitrite and stannous chloride. Treatment of compound (34) with ethoxycarbonylmalondialdehyde, cyanmalondialdehyde (prepared by the method described by Bertz SH, Dabbagh G. and Cotte P., in J. Org. Chem., 1982, 47, p. 2216) or malondialdehyde (prepared by the method described by Martinez AM (Cushmac GE, Rocek J., in J.Amer.Chem.Soc.1975, 97, p.6502) in the presence of sodium bicarbonate at room temperature, prepare compound (35).

Scheme 10: pyrazoles

NH (CO) R '

NaNO ₂ , SnCl ₂ . 2H ₂ O

HCl

NH (CO) R '

R

OHCl 2 CHO —---- ► NaHCO ₃

·· ···· 4 • 9 9 •

4 «9 9

In vitro activity

Samples of the compounds prepared below according to Examples 1-97 upon dissolution in water and dilution in nutrient broth exhibit the following minimum inhibitory concentrations (MICs) to the microorganisms of interest as determined by dilution in a test tube. MIC values were determined by micro-dilution in broth as recommended by the National Committee for Clinical Laboratory Standards (NCCLS). Medium was used for the assay

Mueller-Hinton with the exception of Streptoccoci species, which were tested in Todd Hewitt soil. The final bacterial inoculum contained about 5. 10 ⁵ cfu (colony forming units) / ml and plates were incubated for 18 hours at 35 ° C in room temperature air (Streptococci in 5% CO 2). The MIC is defined as the lowest concentration preventing visible bacterial growth.

Microorganism MIC value in pg / ml

S. pneumoniae A9585 <.8

E.faecalis A20688 <_16

S-aureus A15090, penicillinase positive <16

DETAILED DESCRIPTION OF THE INVENTION

The following examples are intended to further illustrate the invention but do not limit the invention in any way. Abbreviations used in the examples have the meaning commonly used, and are generally known in the art. Certain abbreviations have the following meanings:

= hour (s)

mo 1 = moles mmo 1 = mmol (mmoles) WITH = gram (grams) min = minute (s) rt = room temperature THF = tetrahydrofuran L = liter (liters) mL = milliliters (milliliters) Et ₂ O = diethyl ether EtOAc = ethyl acetate MeOH = methanol DMF = dimethylformamide

In the examples below, all temperatures are in degrees Celsius. Melting points were determined on a thermoelectric instrument and are not corrected. Proton nuclear magnetic resonance and carbon nuclear ( ¹³ OH and ¹³ C NMR) spectra were recorded in CDCl 3, DMSO-d 6, CD 3 OD or D ² O unless otherwise noted. Chemical shifts are reported in δ units relative to tetramethylsilane (TMS) or the solvent reference peak, and interprotone coupling constants are reported in Hertz (Hz). The type of signal splitting is referred to as: s, singlet; d, duplet; t, triplet; q, quartet, m; m, multiplet; br, broad peak; dd, duplet duplets; dt, duplet of triplets; and app d, apparent duplet, etc. Infrared spectra were determined on a Perkin-Elmer 1800 FTIR spectrometer in the wavelength range of 4000 cm ^-1 to 400 cm ^-1 , calibrated to a polystyrene film with absorption at 1601 cm ^-1 and presented in reciprocal centimeters (cm ^-1 ). Mass spectra were recorded on a Kratos MS-50 or Finnegan 4500 instrument using desorption chemical ionization (DCI, isobutene), fast atom bombardment (FAB), or electron spray (ESI) ionization method. The ultraviolet spectra were determined on a Hewlett Packard 8452 diode array spectrophotometer in the indicated solvent.

Analytical thin layer chromatography (TLC) evaluations were performed on finished silica gel plates (60F-254) with detection by UV light, iodine vapor, and / or staining with a methanolic phosphomolybdic acid solution. Column chromatography, also referred to as flash chromatography, was performed in a glass column packed with finely divided silica gel at pressures slightly higher than atmospheric pressure and using the solvents described herein. Analytical thin layer chromatography using reverse phase was performed on finished reverse phase plates with UV light detection or iodine vapor.

Example 1

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

O

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 under reduced pressure. The residue was then partitioned between methylene chloride and sodium bicarbonate. The organic layer was washed with brine, dried over sulfate

Magnesium, filtered and concentrated to 1.1 g colorless oil (96%). 1 H NMR (300 MHz, CDCl ₃ ) δ 7.22 (s, 4H), 4.15 (q, J = 6 Hz, 2H), 3.57 (s, 2H), 2.47 (s, 3H) 1.25 (t, J = 6Hz, 3H).

B. Ethyl-4-methylthi-α-formyl-phenylacetate

To a solution of ethyl 4-methylthiophenylacetate (1.1 g, 5.2 mmol) in ethyl formate (20 mL) was added a suspension of NaH (0.84 g, 20.8 mmol). The resulting mixture was stirred at room temperature for 1 hour and then a cold solution of 0.5 N HCl (20 mL) was added slowly. The crude reaction mixture was then extracted with ether and the organic layer was washed with sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered, and concentrated to give 1.2 g of ethyl methylthio-α-form-1-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 methanol and 1 mL of water was added hydroxylamine hydrochloride (0.54 g, 7.8 mmol). The resulting mixture was heated at reflux for 1 hour. The solvent was evaporated and trituration of the residue with water gave a precipitate which was then triturated with ether to give 0.48 g (two steps, 44%) of a pale yellow solid. 1 H NMR (300 MHz, MeOH-d ₄ ) δ 8.74 (s, 1H), 7.66 (d, J = 8Hz, 2H), 7.25 (d, J = 8Hz, 2H), 2 46 (s, 3H).

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) chloride. Acetamide acetate (0.64 g, 4.85 mmol). The resulting mixture was stirred at room temperature for 18 hours. It is then poured into 10 ml of 1 N HCl and extracted three times with chloroform. The organic layer was then washed with sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated to give a light brown solid which was then recrystallized from hexane / chloroform. The solid obtained was further purified by trituration with ether to give 0.186 g (69%) of a light brown solid. IR NMR (300 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.72 (d, J = 9 Hz, 2H), 7.28 (d, J = 9 Hz, 2H), 5, O 2 (d, J = 6 Hz, 2H), 2.48 (s, 3H), 1.84 (s, 3H).

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-yl-phenyl) -5-oxo-2-hydroisoxazol-2-yl] -methyl} -acetamide (200 mg, 0.60 mmol) in 50 mL of methanol add magnesium monoperoxyphthalate (300 mg, 0.60 mmol). After 2 hours at room temperature, a white precipitate was filtered off and the filtrate was concentrated. Pass the residue through a layer of basic alumina with dichloromethane. The eluate was concentrated and recrystallized from dichloromethane / hexanes to give 162 mg (44%) of the title compound as a brown solid. 1 H NMR (DMSO-d 6, 300 MHz) δ 9.19 (s, 1H), 9.02 (t, J = 6.1 Hz,

1H), 8.62-8.55 (m, 2H), 7.82-7.75 (m, 2H), 5.09 (d, J = 6.0 Hz, 2H), 4.44 (app) t, J = 11.1 Hz, 2H), 4.08 (a _PP t, J = 9.6 Hz, 2H), 3.78 (app d, J = 11.1 Hz, 2H), 2.89 (app d, J = 10.5Hz, 2H), 1.86 (s, 3H); ESI (M + H) &lt; + & gt ^; = 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, 3.6 mmol) in 50 mL chloroform at 0 ° C was added m-CPBA (1.12 g, 3.6 mmol) in 30 mL chloroform over 2 hours via a linear dispenser. Saturated sodium bicarbonate was then added and the reaction stirred vigorously for 10 minutes, then poured into saturated sodium bicarbonate and chloroform: methanol (4: 1). The organic layer was then washed with brine, dried over magnesium sulfate, filtered, and concentrated. Trituration of the residue with ether gave 800 mg (79%) of the title compound as a colorless solid. 1 H NMR (DMSO-d 6, 300 MHz) δ 9.11 (s, 1H), 8.96 (t, J = 6.1 Hz, 1H), 7.96 (d, J = 6.6 Hz, 2H ), 7.67 (d, J = 6.6 Hz, 2H), 5.03 (d, J = 6.1 Hz, 2H), 2.73 (s, 3H), 1.84 (s, 3H) ); ESI (M + H) &lt; + & gt ^; = 295.

Example 4

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

Ν - {[4- (4-Methyl-thiophenyl) -5-oxo-2-hydroxy-oxazol-2-yl] -methyl} -acetamide (200 mg, 0.72 mmol) in 20 mL of chloroform was added at 0 ° C m-CPBA (450 mg, 1.44 mmol) in 5 mL of 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 treated with acetone / (1: 1) hexanes: ether and in (t, J = 6.1 Hz, 2H), 5.11 (d, (M + H) ⁺ = 311).

112 mg (50%) of the title compound were obtained as a colorless solid.

(s, 1H), 9.01 (d, J = 8.6Hz, (s, 3H); ESI)

1 H NMR (DMSO-d 6, 300 MHz) δ 9.24

1H), 8.02 (d, J = 8.6 Hz, 2H), 7.91 J = 6.2 Hz, 2H), 3.20 (s, 3H), 1.86

Example 5

N - ({4- [4- (1,1-dioxo (1,4-thiazaperhydroin-4-yl)) - 3-fluorophenyl] -5-oxo-2-hydroisoxazol-2-yl} methylacetamide

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 of water and 8 ml of acetone was added N-methylmorpholine N-oxide

100 (98 mg, 0.85 mmol) and then osmium tetroxide (2.5 wt% in isopropanol, 7 μΐ, 0.07 mmol). After 18 hours at room temperature, saturated sodium bisulfite was added and the reaction mixture was extracted with 4: 1 chloroform: methanol. The organic layer was then concentrated to give 85 mg (77%) of the title compound as a colorless solid. 1 H NMR (DMSO-d 6, 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) &lt; + & gt ^; = 384.

Example 6

4- (3-Fluoro-4-morpholin-4-yl-phenyl) -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 refluxed for 3 hours. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel chromatography using methylene chloride and ethyl acetate to give a colorless solid (80 mg, 30%). @ 1 H NMR (300 MHz, CDCl3) .delta. 8.61 (br s, 1H); 8.49 (s, 1H); 7.50 (dd, J = 1.5 and 13.8 Hz, 1H); 40 (dd, J = 1.5 and 10.2 Hz, 1H), 7.12 (t, J = 10.2 Hz, 1H), 5.56 (d, J = 6.3 Hz, 2H), 3.94 (m, 4H), 3.17 (m, 4H), 2.57 (s, 3H).

101

Example 7

N - {[4- (4-Acetylphenyl) -5-oxo-2-hydroxyxazol-2-yl] methyl} acetamide

O

To N - {[4-phenyl-5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (3.0 g, 12.9 mmol) and aluminum chloride (III) (13.8 g, 103.4 Acetyl chloride (7.3 mL, 103.4 mmol) was added dropwise over 10 minutes in 150 mL 1,2-dichloroethane. The resulting red mixture was heated at 80 ° C for 3.5 hours, cooled to room temperature and poured into a rapidly stirred mixture of 20% methanol / chloroform and 1 N hydrochloric acid in an ice bath over 10 minutes. The mixture was then poured into a separate separatory funnel and the layers separated. The aqueous layer was extracted twice with 20% methanol / chloroform and then the combined organics were washed sequentially with 1 N sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was then dried over magnesium sulfate, filtered, and concentrated to give an amorphous yellow solid which was dissolved in 20% methanol / chloroform. Ether was then added and the mixture was left at 0 ° C for 18 hours. The resulting precipitate was filtered off to give 2.48 g (70%) of the title compound as a pale pink solid. 1 H NMR (DMSO-d 6, 300 MHz) 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 = 6.6Hz, 2H), 5.10 (d, J = 6.2Hz, 2H), 2.56 (s, 3H), 1.86 (s, 3H); ESI (M + H) &lt; + & gt ^; = 275.

Example 8

N - ({4- [4 - ((hydroxyimino) ethyl) phenyl] -5-oxo-2-hydroxyisoxyl-2102)

-yl} methyl) acetamide

O

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 at reflux for 1.5 hours, concentrated to near dryness and redissolved in 20% methanol / chloroform. Hexanes are then added until the solution becomes cloudy and the mixture is left at 0 ° C for 3 hours. The precipitate was filtered off

to give 1.42 g (67 %) title compounds in form bl ed E yellow solid. 1H NMR (DMSO- d ₆ , 300 MHz) 6 11.21 (with, 1H), 9.01 (s, 1H); 8.96 (t, J = 6.2 Hz, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.6Hz, 2H) , 5.04 (d, J = 6.2 Hz, 2H) , 2.19 (s, 3H),

1.84 (s, 3H); ESI (M + H) &lt; + & gt ^; = 290.

Example 9

N - {[4- (4- (2-Furyl) phenyl) -5-oxo-2-hydroxy-oxazol-2-ylmethyl] -acetamide

O

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)

103

(77 mg, 0.08 mmol), triphenylarsine (51 mg, 0.17 mmol) and lithium chloride (106 mg, 2.51 mmol) in 5 mL of DMF were purged with nitrogen. The reaction mixture was sealed and stirred at room temperature for 8 hours, then diluted with 20% methanol / chloroform, filtered through celite, and concentrated. The residue was suspended in chloroform and loaded onto a Biotage 40i chromatography module (12M) for flash chromatography over frit and eluted with 50% hexane / ethyl acetate to give a solid whose trituration with chloroform / ether gave 132 mg (53%). the title compound as a colorless solid. NMR (DMSO-d 6, 300 MHz) δ 9.00 (s, 1H), 8.94 (t, J = 6.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H) 7.74-7.70 (m, 2H), 6.95 (d, J = 3.2Hz, 1H), 6.60-6.59 (m, 1H), 5.04 (d, J) = 6.1 Hz, 2H), 1.85 (s, 3H); ESI (M + H) &lt; + & gt ^; = 299.

Example 10

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

O

A mixture of N - {[4- (4-iodo-phenyl) -5-oxo-2-hydroxy-oxazol-2-yl] -methyl-acetamide (300 mg, 0.84 mmol), 2-tributylsilylthiophene (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 of DMF were purged with nitrogen. The reaction mixture was sealed and stirred at room temperature for 8 hours, then diluted with 20% methanol / chloroform, filtered through celite, and concentrated.

104 • «· ·

The residue was suspended in chloroform and loaded onto a Biotage 40i chromatography module (12M) for flash chromatography through a frit, eluting with 15% acetone / chloroform to give a solid whose trituration with chloroform / ether gave 165 mg (63%). the title compound as a colorless solid. 1 H NMR (DMSO-d 6, 300 MHz) δ 9.00 (s, 1H), 8.95 (t, J = 6.0 Hz, 1H), 7.81 (d, J = 7.3 Hz, 2H),

7.68 (d, J = 7.4 Hz, 2H), 7.54-7.52 (m, 2H), 7.15-7.11 (m, 1H),

5.04 (d, J = 6.1 Hz, 2H); 1.85 (s, 3H); ESI (M + H) &lt; + & gt ^; = 315.

Example 11

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

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- 4] -dioxine (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 of DMF was purged with nitrogen. The reaction mixture was sealed and stirred at room temperature for 16 hours, diluted with 20% methanol / chloroform, 10% aqueous potassium fluoride was added, and the mixture was stirred rapidly for 1 hour. The reaction mixture was filtered through celite and concentrated. The black oil obtained was dissolved in 20% methanol / chloroform, absorbed onto silica gel, and loaded onto the Biotage 40i SIM chromatography module for flash chromatography i.

105 ··· ♦ • · «* * 9 9 9 9 9

999 9

Using a 12M silica gel cartridge and using 20% acetone / chloroform as the eluent gave an amber oil which was triturated with ether to give 115 mg (44%) of the title compound as a light brown solid. 1 H NMR (DMSO-d 6, 300 MHz) 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 0.07 (m, 2H); 1.85 (s, 3H); ESI (M + H) &lt; + & gt ^; = 317.

Example 12

N - {[5-oxo-4- (4-pyrazin-2-yl-phenyl) -2-hydroxy-oxazol-2-yl] -methyl} -acetamide, N

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), three phenylarsine (51 mg, 0.17 mmol) and lithium chloride (106 mg, 2.51 mmol) in 5 mL of DMF were added. purged with nitrogen. The reaction mixture was sealed and stirred at room temperature for 16 hours, diluted with 20% methanol / chloroform, 10% aqueous potassium fluoride was added, and the mixture was stirred rapidly for 1 hour. The reaction mixture was filtered through celite and concentrated. The black oil obtained was dissolved in 20% methanol / chloroform, absorbed onto silica gel and loaded onto a Biotage 40i flash chromatography module i. Chromatography was performed using a 12M silica gel cartridge and 25%

106 * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Elution with acetone / chloroform gave an amber oil, from which trituration with ether gave 52 mg (44%) of the title compound as a colorless solid. mass. 1 H NMR (DMSO-d 6, 300 MHz) δ 9.28 (d, J = 1.4 Hz, 1H), 9.11 (s, 1H), 8.97 (t, J = 6.1 Hz, 2H) ), 8.71 (app t, J = 1.9Hz, 1H), 8.59 (d, J = 2.5Hz, 1H), 8.17 (d, J = 8.5Hz, 2H) 7.94 (d, J = 8.5 Hz, 2H), 5.07 (d, J = 6.2 Hz, 2H), 1.86 (s, 3H); ESI (M + H) &lt; + & gt ^; = 311.

Example 13

N - {[5-OXO-4- (4- {4- [2- (1,1,2,2-tetramethyl-1-ilapropoxy) acetyl] piperazinyl} phenyl) -2-hydroxisazol-2-yl] methyl} acetamide

To the 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 of dichloromethane was added triethylamine (0.7 mL, 0.5 mmol) then (tert-butyldimethylsilyloxy) acetyl chloride (1.0 g, 4.8 mmol). The resulting mixture was stirred at room temperature for 1.5 hours and then partitioned between dichloromethane and water. The organic layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with ether to give 0.24 g (49 g (49%) of the title compound. 1 H NMR (methanol-d ₄ , 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.

107 • ··· ·················· · · · · ·

Example 14

N - [(4- {4- [4- (2-Hydroxyacetyl) piperazinyl] phenyl} -5-oxo-2-hydroxisazol-2-yl) methyl] acetamide

N - {[5-oxo-4- (4- (4- [2- (1,1,2,2-tetramethyl-1-silapropoxy) acetyl] piperazinyl} phenyl) -2-hydroxyxazole-2- 1] methyl} acetamide (0.3 g, 0.6 mmol) in 4 mL of dichloromethane was added 4 mL of trifluoroacetic acid After 1 hour the reaction mixture was concentrated, partitioned between dichloromethane and saturated sodium bicarbonate solution and the organic layer was washed with brine. Trituration of the residue with ether gave 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 = 8.7Hz, 2H), 6.97 (d, J = 8.9) Hz, 2H), 4.95 (d, J = 6.2 Hz, 2H), 4.64 (t, J = 5.6 Hz, 1H), 4.13 (d, J = 5, 6 Hz, 2H) , 3.60 (br s, 2H), 3.48 (br s, 2H) 3.17 (br with, 4H), 1.83 (s, 3H); ESI (M + H) &lt; + & gt ^; = 375.

Example 15

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

108

Prepared from ethyl 4-azidophenylacetate by the general method shown in Scheme 1. The starting material was prepared as follows:

Ethyl-4-azidophenylacetate

According to the general method described in Marchesini (J. Org. Chem. 49, 4227-4290, 1984), to a stirred and cooled (0 ° C) mixture of ethyl 4-aminophenylacetate (25 g, 0.14 mol) in 700 mL of TFA was slowly added sodium nitrite (38 g, 0.56 mol). After the addition was complete, the reaction mixture was stirred at 0 ° C for an additional 0.5 h and then sodium azide (27 g, 0.42 mol) was added slowly over 0.5 h. The mixture was then stirred for an additional 2 hours at 0 ° C, then quenched with ice water and the product was extracted with EtOAc. The organic phase was then washed with water, dried over magnesium sulfate, filtered, and concentrated to give 26.5 g (90%) of the title compound as a white solid. ¹ H NMR (300 MHz, DMSO-d 6) δ 7.31 (d, J = 8 Hz, 2H), 7.07 (d, J = 7 Hz, 2H), 4.07 (q, J = 7 Hz) (2H), 3.66 (s, 2H), 1.17 (t, J = 7Hz, 3H).

Example 16

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

ΌΗ

109 • · · ·

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 DMF was heated at 100 ° C for 10 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel; eluting with EtOAc then 10% MeOH / EtOAc) to yield 62 mg of a yellow solid. The @ 1 H-NMR spectrum indicated that the crude product contained a mixture of two triazole isomers. These isomers were separated by preparative HPLC (H 2 O / MeOH) to yield 10 mg (10%) of the title compound as a white solid. 1 H NMR (300 MHz, DMSO-d 6) δ 9.11 (s, 1H), 8.96 (t, J = 6 Hz, 1H), 8.69 (s, 1H), 7.96 (m, 4H) ), 5.07 (d, J = 6Hz, 2H), 4.61 (s, 2H), 1.86 (s, 3H).

Example 17

Methyl 1- (4- (2 - [(acetylamino) methyl] -5-oxo-2-hydroxyxazol-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, 58 mmol) in 3 ml DMF was heated at 50 ° C for 24 hours. Then the reaction mixture was concentrated in vacuo and trituration with EtOAc gave 25 mg (24%) of the title compound as a yellow solid. (An alternative method that is more reliable involves carrying out the reaction at room temperature for 10 days followed by isolation as described above). ¹ H NMR (300 MHz, DMSO-d 6) δ 9.52 (s, 1H), 9.15 (s, 1H), 8.96 (t, J = 6 Hz, 1H), 8.02 (s, 4H), 5.08 (d, J = 6Hz, 2H), 3.90 (s, 3H), 1.87 (s, 3H).

110 • ···· φφ ···· φφ · ··· ··· ΦΦΦΦ • φ · φ · φ ΦΦΦΦ · ΦΦΦΦ φ • · ΦΦ «φφφ ··· ··· ·· ··· φφ φφφ

Example 18

Ν - ({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 3-butin-2-one (0.035 mL, 0 (72 mmol) in 3 mL of DMF was heated at 50 ° C for 24 h. The reaction mixture was then concentrated in vacuo and trituration with EtOAc afforded 60 mg (49%) of the title compound as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6) δ 9.47 (s, 1H), 9.35 (s, 1H), 8.98 (t, J = 6 Hz, 1H), 8.02 (s, 4H) ), 5.08 (d, J = 6Hz, 2H), 3.32 (s, 3H), 1.85 (s, 3H).

Example 19

N - ({4- [4-cyano (1,2,3-triazolyl)) phenyl] -5-oxo-2-hydroxy-oxazol-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 cyanacetylene (prepared according to Murahashi S. Takizawa T., Kurioka S., Maekawa S. in J. Chem.Soc.Jap., 77, p.1689, 1956)

111 in 5 ml DMF was heated at 50 ° C for 48 hours. After cooling, the precipitated solid was filtered off, washed with DMF to give 375 mg (63%) of the title compound as a white solid. 1 H NMR (300 MHz, DMSO-d 6) δ 9.75 (s, 1H), 9.17 (s, 1H), 9.00 (t, J = 6 Hz, 1H), 8.05 (d, J = 9Hz, 2H), 7.95 (d, J = 9Hz, 2H), 5.10 (d, J = 6Hz, 2H), 1.85 (s, 3H).

Example 20

N - {[4- (4-Aminophenyl) -5-oxo-2-hydroxyxazol-2-yl] methyl} acetamide

O

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 SnCl 2. 2H2O (12.5 g, 54.9 mmol). Once all the solids have dissolved, the reaction mixture is concentrated in vacuo and neutralized with saturated aqueous sodium bicarbonate. The resulting mixture was then concentrated again in vacuo and the residue was dissolved in CHCl 3 / MeOH 4: 1. The resulting solution was then filtered through celite and the insolubles removed, and the filtrate was concentrated in vacuo to give 3 g (100%) of the title compound as a yellow solid. 1 H NMR (30 MHz, DMSO-d 6) δ 8.83 (t, J = 6Hz, 1H), 8.55 (s, 1H), 7.43 (d, J = 9Hz, 2H), 6 56 (d, J = 9Hz, 2H), 5.21 (broad s, 2H), 4.91 (d, J = 6Hz, 2H), 1.82 (s, 3H).

Example 21

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

111 · «··· ·

Γ \

To a solution of Κ - {[4- (4-aminophenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (200 mg, 0.81 mmol) in 3 mL of acetic acid is added 2,5-dimethoxy -3-tetrahydrofurancarbaldehyde (184 mg, 1.27 mmol). The mixture was heated at reflux for 0.5 h and then concentrated in vacuo to give the crude product. Purification by silica gel chromatography (eluting with EtOAc then 8% MeOH in EtOAc as eluent) gave 240 mg (91%) of the title compound as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6) δ 9.79 (s, 1H), 9.08 (s, 1H), 9.00 (t, J = 6 Hz, 1H), 8.29 (m, 1H) ), 7.93 (d, J = 9Hz, 2H), 7.74 (d, J = 9Hz, 2H), 7.58 (m, 1H), 6.71 (m, 1H), 5, Δ (d, J = 6 Hz, 2H), 1.86 (s, 3H).

Example 22

N - {[5-oxo-4- (4-pyrrolinylphenyl) -2-hydroxyxazol-2-yl] methyl} acetamide

O

O

The title compound was prepared from N - {[4- (4-aminophenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide as described above for the preparation of N - ({4- [4- (3-formylpyrrolyl) (phenyl) -5-oxo-2-hydroisoxazol-2-yl} methyl) acetamide except that 2,5-dimethoxy-3-tetrahydrofuran is used instead of 2,5-dimethoxy-3-tetrahydrofurancarbaldehyde. 1 H NMR (300 MHz, DMSO-d 6) δ 8.92 (s, 1H), 8.94 (t, J = 6Hz, 1H), 7.85 (d, J = 9Hz, 2H), 7 , 62 (d,

113 • 4

4

J = 9Hz, 2Η), 7.40 (t, J = 2Hz, 2H), 6.27 (t, J = 2Hz, 2Η), 5.04 (d, J = 6Hz, 2H), 1.86 (s, 3H).

Example 23

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

NOH

H

O

A mixture of N - ({4- [4- (3-formylpyrrolyl) phenyl] -5-oxo-2-hydroisoxazol-2-yl} methyl) acetamide (100 mg, 0.30 mmol) and 50% aqueous NH 2 OH (40 mg) (0.60 mmol) in 3 mL of MeOH was heated at reflux for 2 h. The reaction mixture was then concentrated in vacuo and trituration of the residue with ether afforded 96 mg (94%) of the title compound as a yellow solid. ¹ H NMR (300 MHz, DMSO-d 6) δ 10.6 (s, 1H), 9.02 (s, 1H), 8.95 (t, J = 6 Hz, 1H), 8.00 (s, 1H), 7.87 (d, J = 9Hz, 2H), 7.66 (s, 1H), 7.63 (d, J = 9Hz, 2H), 7.45 (m, 1H), 6 50 (m, 1H); 5.04 (d, J = 6Hz, 2H); 1.85 (s, 3H).

Example 24

Tert-Butyl-4- (4- {2 - [(acetylamino) methyl] -5-oxo-2-hydroisoxazol-4-yl} phenyl) piperazine carboxylate

AcOCH ₂ NHAc • NH

114 ·· ♦♦ «4 * 444 · · · 4 * 44 · ♦ · 4 4 444 4 44« 4 4 4 · · 4 »* • ♦ · 4 4 44 ··· 44 44« 44444

To tert-butyl 4- [4- (5-oxo-2-hydroxy-oxazol-4-yl) -phenyl] -piperazinecarboxylate (1.5 g, 4.3 mmol) in 35 mL of 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 off and dried in vacuo to give 1.4 g (77%) of the title compound. ¹ H NMR (methanol-d, 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 = 4.8Hz, 4H), 3.17 (t, J = 5.2Hz, 4H), 1.94 (s, 3H), 1.50 (s, 9H); ESI (M + H) &lt; + & gt ^; = 417.

The default folders are prepared as follows:

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

° ^, ° ΥΊ Ϊ Boc ^ N η

Flask with introduced cesium carbonate (4.6 g, 14.0 mmol), palladium (II) acetate (0.07 g, 0.3 mmol) and (S) -BINAP (0.28 g, 4.5 mmol) is evacuated and purged with dry nitrogen. Then methyl 2- {4 - [(trifluoromethyl) sulfonyloxy] phenyl acetate (3.0 g, 10.0 mmol) and tert-butyl-1-piperazinecarboxylate (2.3 g, 12.0 mmol) were added via syringe. 20 ml of toluene are added and the mixture is stirred at 80 ° C for 16 minutes at room temperature. The reaction mixture was then removed from the water bath, concentrated and chromatographed on silica gel (0 to 30% ethyl acetate / hexane) to give 1.7 g (50%) of the title compound. 1 H NMR (300 MHz, CDCl 3) 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 = 5.0Hz, 4H), 3.57 (s,

115

• ·· 44 • 4 • 9 • • «· 4 4 • 44 » • 4 ··· 4 • • 4 9 • · • • 4 • • * 4 4 4 4 • 44 4 · »· * 4 ^ 44 44 ···

2H), 3.12 (t, J = 5.2Hz, 4H), 1.50 (s, 9H); ESI (M + H) &lt; + & gt ^; = 335.

Ethyl 2- (4- {4 - [(tert-butyl) oxycarbonyl] piperazinyl}) phenyl) -3-oxopropanoate.

O

------->

NaH.

To methyl 2- (4- {4 - [(tert-butyl) oxycarbonyl] piperazinyl} phenyl) acetate (0.67 g, 2.0 mmol) in 8 mL of ethyl formate was added portionwise sodium hydride (60% dispersion). in mineral oil) (0.32 g, 8.0 mmol). 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.

Tert-Butyl-4- [4- (5-oxo-2-hydrosioxazol-4-yl) phenyl] piperazine incarboxylate

h ₂ feet

To ethyl 2- (4- {4 - [(tert-butyl) oxycarbonyl] piperazinyl] phenyl) -3-oxopropanoate (7.8 g, 20.7 mmol) in 140 mL of methanol and 40 mL of water was added hydroxylamine (50% in water). , 3.0 mL, 49.0 mmol). The reaction mixture was heated at reflux for 3 hours, then cooled and concentrated. The residue was triturated with water and the precipitate was filtered off, dried and washed with ether

116 g of the title compound are obtained. Lyophilization of the aqueous solution gave an additional 1.5 g of the title compound. 1 H NMR (methanol-d 4, 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 (brs, 4H), 1.50 (s, 9H); ESI (M + H) &lt; + &gt; = 345.

Example 25

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

To tert-butyl 4- (4- {2 - [(acetylamino) methyl] -5-oxo-2-hydroisoxazol-4-yl} phenyl) piperazinecarboxylate (0.3 g, 0.7 mmol) in 5 mL 2 ml of trifluoroacetic acid are added. After 30 minutes, the reaction mixture was concentrated and trituration with ether gave 0.3 g (97%) of the title compound. 1 H NMR (methanol-d 4, 300 MHz) δ 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 = 8.7Hz, 2H), 5.08 (d, J = 6.2Hz, 2H), 3.45-3.38 (m, 8H), 1, 95 (s. 3H); ESI (M + H) < + & gt ^; = 317.

Example 26

Tert-Butyl-4- (4- {2 - [(acetylamino) methyl] -5-oxo (2-hydroxy-oxazol-4-yl)} - 2-fluorophenyl) piperazine carboxylate

K ₂ COa BocN ' ^Z ' A 0 F ^Z ACOCH2NHAC NH F ^Z U-N N— NH k-

117

They were prepared by the general methods depicted in the schemes

The starting components are prepared as follows:

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

1) HCl

2) NaOH, BOC2O

To tert-butyl 4- [2-fluoro-4- (2-morpholin-4-yl-2-trioxoethyl) phenyl] piperazinecarboxylate (4.2 g, 10 mmol) was added at 0 ° C 22 mL of concentrated hydrochloric acid. The resulting mixture was heated at reflux for 1.5 h, then cooled to 0 ° C and 23 mL of 10 N sodium hydroxide was added to adjust the pH to 14. Then 50 mL of water was added followed by di-tert-butyl dicarbonate (5.6 g, 26.0 mmol) in 5 mL of tetrahydrofuran. The mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 1 hour, then diluted with 200 mL of water. Sodium hydroxide (5 ml) 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 careful addition of 6 N 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 obtained residue was then dissolved in dichloromethane, hexanes were added to form a precipitate which was filtered off to give 3.0 g (89%) of the title compound. 1 H NMR (CDCl 3, 300 MHz) δ 7.04-6.98 (m, 2H), 6.90 (t, J = 8.3 Hz, 1H), 3.60 (m, 6H), 3.02 (t, J = 5.0Hz, 4H), 1.50 (s, 3H); ESI (M + H) &lt; + & gt ^; = 339.

118 · 9 · 4 · 4 · 44 · 44 · 44 · 44 · 44 · 44 · 44

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

Me3SiCHN ₂

To 2- (4- {4 - [(tert-butyl) oxycarbonyl] piperazinyl} -3-fluorophenyl) acetic acid (0.3 g, 1.0 mmol) in 2 mL methanol and 7 mL benzene was added trimethylsilyldiazomethane (0). , 65 mL, 1.30 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated to give 0.36 g (99%) of the title compound. 1 H NMR (CDCl ₃ , 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) &lt; + & gt ^; = 353.

Example 27

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

They are prepared in the general manner shown in Schemes 1 and 2. The starting components are prepared in the following ways:

Methyl 4- (trifluoromethylsulfonyloxyphenyl acetate)

119 • ·· ·

To methyl 4-hydroxyphenyl acetate (20 g, 120 mmol) and pyridine (20 mL, 240 mmol) in 100 mL dichloromethane at 0 ° C was added dropwise over 30 minutes trifluoromethanesulfonic anhydride (23 mL, 132 mmol). The reaction mixture is left for a further 30 minutes at 0 ° C and then for 30 minutes at room temperature, then 1N hydrochloric acid is added and the reaction mixture is extracted with dichloromethane. The organic layer was then washed with 1 N hydrochloric acid, saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated to give 32 g (90%) of the title compound as a yellow solid. NMR (CDCl3, 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, r

BINAP Cs ₂ CO ₃ morpholine

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 were purged with nitrogen and then the reaction mixture was heated at 80 ° C for 6 hours

120 ° C. The reaction mixture was cooled, celite was added and the mixture was concentrated. The residue was chromatographed on a Biotage 40i flash chromatography module as well as introducing dry Celite into the SIM and eluting with 20% ethyl acetate / hexanes (40S cartridge) to give 250 mg (37%) of the title compound as a yellow oil. ¹ H NMR (CDCl 3, 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-hydroxy-oxazol-2-yl] methyl} acetamide

They are prepared by the general methods shown in Schemes 1 and 3.

The default folders are prepared in the following ways:

4-thiomorpholinoacetophenone

K ₂ CO ₃ thiomofoline,

To 4-fluoroacetophenone (20 g, 145 mmol) in 100 mL of dimethylformamide was added potassium carbonate (39 g, 580 mmol) followed by thiomorpholine (87 mL, 870 mmol). The reaction mixture was quenched

121 · 9 9 9 · 9 9 <<<<<9 9 9 <<<<<<<<<<<<<

The mixture was heated at reflux for 24 hours, then cooled to room temperature and partitioned between water and dichloromethane. The organic layer was then dried over magnesium sulfate, filtered, and concentrated. The residue was then dissolved in ether and precipitated with hexanes to give 31 g (96%) of the title compound as a yellow solid. 1 H NMR (CDCl 3, 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-thiomorpholinylphenylthiacetomorpholide

A mixture of 4-thiomorpholinoacetophenone (30 g, 136 mmol), morpholine (16 mL, 180 mmol) and sulfur (6 g, 180 mmol) was refluxed for 6 hours, cooled to 50 θθ and 100 mL of hexanes added. : ethyl acetate 1: 1. The mixture was heated to reflux for 30 minutes and the orange precipitate formed was filtered off. The precipitate was then washed with an additional 1: 1 ether: hexanes to give a yellow-orange product.

31 g (73%) of the title compound. ¹ H NMR (CDCl 3, 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-thiomorpholinylphenyl acetate

122

4444

44 • 444 »4 • 4 • * 4 4 4 444 4 4 • 4 4 4 4 4 • 4 • • 4 44 444 4 «

♦ 4 ···

A solution of 4-thiomorpholinophenylthioacetomorpholide (30 g, 93.2 mmol) in 70 mL of 1: 1 ethanol: sulfuric acid was heated at reflux for 18 h, then cooled to room temperature and solid sodium bicarbonate was slowly added. until the pH of the reaction mixture is 7. Then the reaction mixture is extracted with chloroform and the organic layer is 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 40i flash chromatography module (40M cartridge) and chromatographed with 10% ethyl acetate / hexanes to give 12 g (51%) of the title compound as a yellow oil. ¹ H NMR (CDCl 3, 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-hydroxisazol-2-yl] methyl} acetamide

F

123 ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

They are prepared by the general methods outlined in Schemes 1 and 3. Starting materials are prepared by the following methods:

3-fluoro-4-methylthioacetophenone

To 3,4-difluoroacetophenone (30 g, 192 mmol) in 200 mL of dimethyl sulfoxide was added sodium thiomethoxide (15 g, 211 mmol). The reaction mixture was then heated at 150 ^° C for 2 hours and then partitioned between ethyl acetate and sodium bicarbonate. The organic layer was then washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in ethyl acetate and hexanes precipitated. The precipitate was filtered off to give 25 g (70%) of the title compound as a yellow solid.

3-fluoro-4-methylthiophenylthioacetomorpholide

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) was heated for 4 hours at reflux, then 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 room temperature and the resulting orange precipitate formed.

124 was filtered off. The precipitate was then washed with 1: 1 hexanyl ether to give 10.1 g (73%) of the title compound as a yellow-orange solid. 1 H NMR (DMSO-d 6, 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

KOH

To 3-fluoro-4-methylthiophenylthioacetomorpholide (2.6 g, 90.9 mmol) was added 500 mL of 10% sodium hydroxide. The reaction mixture was then heated at reflux for 3 hours, cooled to room temperature and adjusted to pH 4 by carefully adding 4 N hydrochloric acid. The aqueous solution was then extracted with dichloromethane and the organic layer was extracted with 200 mL of 10% potassium hydroxide. . The pH of the aqueous layer was then adjusted to 4 by careful addition of 2N hydrochloric acid and extracted with dichloromethane. The organic layer was then dried over magnesium sulfate, filtered, and concentrated to afford 10.0 g (55%) of the title compound as a brown oil. 1 H NMR (CDCl ₃ , 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-hydroxisazol-2-yl] methyl} acetamide

125

It is prepared in the general manner shown in Scheme 1. The starting component is prepared as follows:

Ethyl 1- (3-fluoro-4-methoxy) phenyl acetate

K ₂ CO ₃ ch ₃ i

To ethyl (3-fluoro-4-hydroxy) phenyl acetate (2.5 g, 8.9 mmol) in 20 mL of acetone was added potassium carbonate (3.4 g, 24.2 mmol) and iodomethane (1, 2). 5 mL, 24.2 mmol). The reaction mixture was then heated at reflux for 2 hours, then cooled and partitioned between saturated sodium bicarbonate and ether. The organic layer was then washed with brine, dried over magnesium sulfate, filtered and concentrated to give 2.3 g (88%) of the title compound as a yellow oil. ¹ H NMR (CDCl 3, 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 = 7.2Hz, 3H).

Example 31

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

O

126 • 444

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 CH 3 CN and 1 mL of CCl 4 was added polymer-bound triphenylphosphine (400 mg, 1.2 mmol) and the mixture was heated at reflux for 8 h. The reaction mixture was dissolved in ethyl acetate, filtered and concentrated to give a yellow solid. Trituration of this mass with ether afforded 30 mg (32%) of the title compound as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6) δ 9.08 (s, 1H), 8.97 (t, J = 6 Hz, 1H), 8.28 (s, 1H), 7.92 (d, J = 9Hz, 2H), 7.70 (d, J = 9Hz, 2H), 7.59 (m, 1H), 6.74 (m, 1H), 5.06 (d, J = 6Hz) 2H, 1.86 (s, 3H).

Example 32

N - [(4- {4- [3 - ((1E) -2-aza-2-methoxyvinyl) pyrrolyl] phenyl} -5-oxo-2-hydroxisazol-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), HCl.NH 2 OCH 3 (31 mg, 0.37 mmol) and sodium carbonate (20 mg, 0.19 mmol) were dissolved in 3 mL MeOH and 2 mL water. Acetic acid was then added to this mixture to adjust the pH to 5. The reaction mixture was then heated at reflux for 1 hour. The reaction mixture was then cooled to room temperature and the yellow precipitate was filtered off to give 40 mg (36%) of the title compound as a yellow solid. (M + H &lt; + & gt ^; ) = 355

Example 33

127 • · ♦ · · · · φφφ

Ν - {[4- (4- {3 - [(1 E) -2- (acetylamino) -2-aza-vinyl] pyrrolyl} phenyl-5-oxo-2-hydroxisazol-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 EtOH was heated at reflux for 1 h. The reaction mixture was cooled to room temperature and the yellow precipitate was filtered off to give 80 mg (36%) of the title compound. (M + H &lt; + & gt ^; ) = 382.

Example 34

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

O

To a mixture of N - {[4- (4-hydrazinophenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl] acetamide hydrochloride (150 mg, 0.5 mmol) in 3 mL of methanol was added sodium bicarbonate (50 mL). mg, 0.6 mmol) and ethoxycarbonylmalondialdehyde (75 mg, 0.52 mmol). The resulting mixture was stirred at room temperature overnight. The solid was filtered off and then washed with water and dried to give 140

128 • 9 · 9

9

9

9 mg of a purple solid. Chromatography of this crude product on silica gel (ethyl acetate followed by 5% methanol / ethyl acetate) gave 123 mg (66%) of the title compound as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6) δ 9.11 (s, 1H), 9.08 (s, 1H), 8.96 (t, J = 6 Hz, 1H), 8.15 (s, 1H) ), 7.95 (m, 4H), 5.06 (d, J = 6Hz, 2H), 4.28 (q, J = 7Hz, 2H), 1.86 (s, 3H)), 1 31 (t, J = 7Hz, 3H).

The starting material, N - {[4- (4-hydrazinylphenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide hydrochloride, was prepared as follows. 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 and during 5 min. Sodium nitrite (112 mg, 1.6 mmol) in 2 mL of water was added over 1 min. The reaction mixture was then stirred at 0 ° C for 10 min and then SnCl 2 · 2H 2 O (720 mg, 3.2 mmol) in 2 mL concentrated hydrochloric acid was added. The mixture was then stirred at room temperature for 3 hours. The reaction mixture was filtered to separate a yellow solid, which was then washed with 3 mL of water and dried to give 260 mg (55%) of the title compound. ¹ H NMR (300 MHz, DMSO-d 6) δ 10.2 (s, 2H), 8.94 (t, J = 6 Hz, 1H), 8.82 (s, 1H), 8.35 (s, 1H), 7.70 (d, J = 9, 2H), 6.99 (d, J = 9, 2H), 4.99 (d, J = 6Hz, 2H), 1.84 (s, 3H) ).

Example 35

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

129

To a mixture of N - {[4- (4-hydrazinylphenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide hydrochloride (50 mg, 0.17 mmol) in 2 mL of methanol was added 20 mg (0 , 24 mmol) of sodium bicarbonate and cyanmalondialdehyde (30 mg, 0.3 mmol). The resulting mixture was stirred at room temperature overnight. Concentration gave a solid which was washed with water and then methanol to give 42 mg (76%) of the title compound as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6) δ 9.35 (s, 1H), 9.10 (s, 1H), 8.98 (t, J = 6 Hz, 1H), 8.37 (s, 1H), 7.93 (m, 4H), 5.07 (d, J = 6Hz, 2H), 1.86 (s, 3H).

Preparation of cyanmalondialdehyde:

Sodium hydride (0.82 g, 50% suspension in mineral oil, 17 mmol) was added to the dry flask. The sodium hydride was washed three times with 15 mL of ether and then 15 mL of ether was added to the flask. The resulting slurry was cooled to 0 ° C and 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 (linear dispenser) over 2 hours. The mixture was stirred at room temperature for 20 hours and then poured into 100 mL of ice water. The resulting solution was extracted three times with ether and then the ether was removed. The aqueous phase was acidified to pH 3 with concentrated HCl and then extracted with dichloromethane. The organic phase was then dried over MgSO 4, filtered, and concentrated to give 0.3 g of cyanomalone dialdehyde as a yellow solid. A further portion of the product is obtained from the aqueous phase at pH 3: the aqueous phase is concentrated to dryness and then dissolved in 5 ml of methanol.

The inorganic salt was removed by filtration and the filtrate concentrated to give 1 g of cyanomalone dialdehyde as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6) δ 8.94 (s, 2H), 4.95 (br s, 1H).

130 • · · · · ·

Example 36

N - {[5-oxo-4- (4-pyrazolyl-phenyl) -2-hydroxy-isoxazol-2-yl] -methyl} -acetamide.

To a mixture of N - {[4- (4-hydrazinylphenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamido hydrochloride (100 mg, 0.33 mmol) in 3 mL of methanol was added sodium bicarbonate (28 mg, 0.33 mmol) and malondialdehyde (50 mg, 0.35 mmol). The resulting mixture was stirred at room temperature overnight. Concentration gave 120 mg of a yellow oil, which was purified by chromatography on silica gel (using ethyl acetate as eluent) to give 30 mg (30%) of the title compound as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6) δ 9.03 (s, 1H), 8.95 (t, J = 6 Hz, 1H), 8.52 (s, 1H), 7.88 (m, 4H) ), 7.75 (s, 1H), 6.56 (s, 1H), 5.05 (d, J = 6Hz, 2H), 1.86 (s, 3H).

The table below lists the chemical structures, characteristics (MS results) and methods of preparing several typical compounds of the invention, including those prepared according to Examples 1-36 described above.

• ··· <· «·

131

structure MS data preparation scheme no. 1 H3CS ^ >> 9 0 (M + H) &lt; + &gt; = 279 ESI 1 2 pZ ** i / H 0 (M + H) &lt; + &gt; = 352 DCI 3.1 3 O (M + H) &lt; + &gt; = 295 ESI 1.4 4 O (M + H) &lt; + &gt; = 311 ESI 1.4 5 ° θ YXa _o p ^'85 * 1 / H 0 (M + H) &lt; + &gt; = 384 ESI 3,1,4 6 ob o α / ^ν ύ 2Χα f '* ⁸ "' v ° ^{h u} ~ v s (M + H) &lt; + &gt; = 352 ESI 3,1,9 7 0 ° C 0 (M + H) &lt; + &gt; = 275 ESI 1 8 NOH 2 ~ 0 0 (M + H) &lt; + &gt; = 290 ESI 1

132

structure MS data preparation scheme no. 9 0 (+ +) + = 299 ESI 1.5 10 χ. 0 (+ +) + = 315 ESI 1.5 11 ο (+ +) + = 317 ESI 1.5 12 ΟχχΛ 0 (+ +) + = 311 ESI 1.5 13 ’Χ / Νγ ' 0 (+) + = 489 ESI 2,1,6 14 0 JXXXy * δ (+ +) + = 375 ESI 2,1,6 15 Dec χ, ο (+) + = 274 DCI 1 16 X. ^Ν χ 0 (+ +) + = 330 ESI 1.7

133

structure MS data preparation scheme no. 17 N = N 0 (+ +) + = 358 ESI 1.7 18 ΧΧγ. Ύ o (+) + = 342 DCI 1.7 19 Dec N = N 0 (+) + = 325 DCI 1.7 20 May ^Η4Ν Ο- ^ χ «τ ο (+) + = 248 DCI 1.8 21 _Η bbky '0 (+) + = 326 DCI 1.8 22nd Οχυς 0 (+ +) + = 298 ESI 1.8 23 ΓΧ HON / \ _r 0 UY (+ +) + = 341 ESI 1.8 24 0 (+ +) + = 417 ESI 2, 1.6

134

structure MS data preparation scheme no. 25 hn ^ Y o AA AND (M + H) &lt; + &gt; = 317 ESI 2,1,6 26 0 ^h jc 'ý— / m — y \ - <y? HjC-Λ — 0 HjC F Π 0 (M + H) &lt; + &gt; = 435 ESI 3,1,6 27 Mar: ° <Y. YFTES / Y 0 (M + H) &lt; + &gt; = 318 ESI 2.1 28 Y. ~ γ O (M + H) &lt; + &gt; = 334 ESI 3.1 29 / ^S ^ Y _O YYA 0 (M + H) &lt; + &gt; - 297 DCI 3.1 30 A01 pA ⁷ \ / H ^U ^ Y 0 (M + H) &lt; + &gt; = 281 ESI 3.1 31 YY. AND 0 (M + H) &lt; + &gt; = 295 ESI 3.1 32 Yaí Y / ° H 2 Y 0 (M + H) &lt; + &gt; = 323 ESI 1, 8

• • 9 »

135

structure MS data preparation scheme no. 33 O (+) + = 324 DCI 1.8 34 0 (+) + = 265 DCI 1 35 '' Ο-Λ. 0 (Μ + Η) + = 313 DCI 1 36 | / ° Η 0 (+) + = 297 DCI 1 37 ⁰ 0 (+ +) + = 281 ESI 1 38 X. ο (+) + = 293 ESI 1 39 Χν ο (+ +) + = 309 ESI 1 40 'BYE. ^F Ο (+) + = 295 ESI 1

* ♦ * ·· ♦

136 · t t t t t t t t t

· 4 4 4 · 4 4 4 4 4 4 4 4

W *

structure MS data preparation scheme no. 41 • n c ° ý (M + H) &lt; + &gt; = 369 DCI 1 42 AS. T o (M + H) + = 276; 1 43 Aý 0 (M + H) + = 299 ESI 1 44 And. 'r (M + H) + = 233 ESI 1 45 0 (M + H) + = 309 ESI 1 46 (M + H) + = 275 ESI 1 47 AS. 0 (M + H) + = 359 ESI 1 48 AND. T 0 (M + H) + = 277 ESI 1

137

structure MS data preparation scheme no. 49 0 (M + H) &lt; + &gt; = 309 ESI 1 50 ^Br —A v> x <O (M + H) &lt; + &gt; = 312 ESI 1 51 ° άα ^ κ Y (M + H) &lt; + &gt; = 268 ESI 1 52 (M + H) &lt; + &gt; = 268 ESI - 1 53 .AŇ. O (M + H) &lt; + &gt; = 251 ESI 1 54 HiC ^Z ^ a ^{? Z} ^ yy ^H T 0 (M + H) &lt; + &gt; = 247 ESI 1 55 Ay T 0 (M + H) &lt; + &gt; = 277 ESI 1 56 Άΐ o X / t 0 \\ / H AND 0 (M + H) &lt; + &gt; = 371 DCI 1,8

138 9 · 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9

structure MS data preparation scheme no. 57 O ~ \ _ / = \ _ Xo o ^Z 0 (M + H) &lt; + &gt; = 395 ESI 2, 1.6 58 αοα> ^ α _υ «<. 0 (M + H) &lt; + &gt; = 359 ESI 2,1,6 59 0 V / NA ⁰ / ^h aa_H> ^ ⁿ v ^ck · I (M + H) &lt; + &gt; = 399 ESI 2. 1,6 60 _{ρ _υυο} ^ ^{_ν Ο ν_ οΧα ν υ} ^ (M + H) &lt; + &gt; = 455 ESI 2, 1.6 61 Α'Ο'ΥζΑΑγ * --- f 0 H.Č (M + H) &lt; + &gt; = 445 ESI 2, 1.6 62 Vf-x / = \ _ k \ = / 0 (M + H) &lt; + &gt; = 437 ESI 2, 1.6 63 O (M + H) &lt; + &gt; = 375 ESI 2, 1.6 64 ΥΎ 0 17 ^ 1 Y 0 (M + H) &lt; + &gt; = 322 ESI 3. 1

139

structure MS data preparation scheme no. 65 O (M + H) &lt; + &gt; = 370 ESI 3.1 66 A'o (M + H) &lt; + &gt; = 354 ESI 3.1 67 They 0 (M + H) &lt; + &gt; = 350 ESI 3.1 68 θ 'λ 0 ^{ρ /} ^ ^{/ Λ} ^ -Ν N ^ CF 3 Y O (M + H) &lt; + &gt; = 390 ESI 3.1 69 OX o - ^λ λλ Y / h ”^ V 0 (M + H) &lt; + &gt; = 354 ESI 3.1 70 O t 0 O / ^N Y 1 F ^{/> Sa / X} V ° H o (M + H) &lt; + &gt; = 370 ESI 3.1 71 ° AŠ. T 0 (M + H) &lt; + &gt; = 302 ESI 3, 1 72 ° oj. '-'V 0 (M + H) &lt; + &gt; = 316 ESI 3, 1

• ·

140

<structure MS data preparation scheme no. 73 Y 0 (M + H) &lt; + &gt; = 304 ESI 3.1 74 Y (M + H) &lt; + &gt; = 336 ESI 3.1 75 O (M + H) &lt; + &gt; = 352 ESI 3.1 76 O (M + H) &lt; + &gt; = 368 ESI 3.1.4 77 i _{t H} 0 (M + H) &lt; + &gt; = 313 ESI 3.1.4 78 0 -sXZA j? '--IN 0 (M + H) &lt; + &gt; = 329 ESI 3,1,4 79 0 (M + H) &lt; + &gt; = 350 ESI 3, 1.4 80 '-Υ 0 (M + H) &lt; + &gt; = 366 ESI 1.4

141

structure MS data preparation scheme no. 81 0 (+ +) + = 334 ESI 3,1,6 82 ο, ν αλ Λ * ο γ-ντγΥχχγ ο (+ +) + = 377 ESI 3,1,6 83 η Γ ~ \ / = \ _ Α ° ί CH, Ο (+ +) + = 413 ESI 3,1,6 84 ^ / ~ \ _ / = \ Λο HP ^ ^F ο (+ +) + = 463 ESI 3, 1.6 85 0 V Υχλ ° / V lAvi _N r— “0 V— ⁷ of“ '' // ^F ř HC ^u (+ +) + = 417 ESI 3,1,6 86 ‘ΆΑν, Γ \ Λθ ΐ τ 0 (+ +) + = 449 ESI 3, 1.6 87 0 In ^ \ / ^ · Ά ý — Ν Ν — ό. ·. ---'... I r-cT / = Λ F » / \ 0 W (+ +) + = 469 ESI 3,1,6 88 0 H.C Υ / ~ Ν / Ύ Α e> C Ν Ν-Ζ,) --- 6 I W V / γΓνΝ ^ Ν ΐ II 0 (+ +) + = 407 ESI 3, 1.6

142 ·········· 0 · 0 0 · 0 0 · 0 0 · 0 0 · 0 000 000 000

structure MS data preparation scheme no. ⁸⁹ 0 (M + H) &lt; + &gt; = 393 ESI 3. 1,6 90 O (M + H) &lt; + &gt; = 393 ESI 3,1,6 91 IN 0 (M + H) &lt; + &gt; = 429 ESI 3,1,6 92 0 VPHN ^ _N ___, CH ₃ Y 0 (M + H) &lt; + &gt; = 323 ESI 1,8 93 »Γί » Y o (M + H) &lt; + &gt; = 355 ESI 1,8 94 * ARV-CVx of «Mya H 'n _{X z,} N-CH ₃ 0 (M + H) &lt; + &gt; = 382 ESI 1,8 95 free ⁰ H Y 0 (M + H) &lt; + &gt; = 371 DCI 1.9 96 / = ^ ΝΟ-'Χ / Νγί ^ o YPHN N, CH _S Y 0 (M + H) &lt; + &gt; = 324 DCI 1.9

• · · ·. · ·

143 • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

structure MS data 1 preparation scheme no.) 97 0 H «—N n ^ xhj Π 0 (M + H) &lt; + &gt; = 299 ESI 1.9

144

PV 2JQ _O / I _ Q & Q

44 * 4 * 4 * 4 ** 4 * 4 * 4 * 4

Claims (7)

Wherein R92 is H or a C 1-6 alkyl group; substituted X and Y, ddd) quinoxalinyl optionally substituted with X and Y, eee) naphthyridinyl optionally substituted with X and hh), or 173B represents an unsaturated 4-atom linking group containing one nitrogen and three carbon atoms; M is a) H, b) C 1-6 alkyl, c) C 3-8 cycloalkyl, d) - (CH 2) m OR 6, or e) - (CH 2) n R 67 R 6; 7 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 each independently represent a) hydrogen, b) halogen, c) NO2, d) N3, e) C1-6alkylthio, 174; • ··· · 9 99 9 • 9 9 9 9 9 9 • 9 9 9 9 999 999 99 999 f) 0 C 1 -C 6 alkyl-S-, g) 0 II C 1 -C 6 alkyl-S-, 0 h) C 1 - C 1-6 alkyl i) C 1 -C 6 alkoxy, j) formyl, k) 0-10 C 1 -C 6 alkyl-C-1) 8 C 1 -C 6 alkyl-O-C-, m) 0 II heteroaryl-C-, wherein heteroaryl means 5- or ···· 1 ' f) H-C- g) C 1 -C 6 alkyl-O-C-, h) S1R84R85R86-O-C-, wherein Re4, Res and Rs6 each independently represent a C1-6alkyl group, 184 • · · · ⁰ P IIll (i) CH3-S-C1-C6alkyl-S-; IIII OO O II j) HC = CCH ₂ OC-, o H k) C6H5-O-C-, wherein the phenyl group may be optionally substituted by halogen, O (l) HO-CH2-C- m) (C 1 -C 6 alkyl) 2N-, n) C 1 -C 5 alkyl-NH-, o) amino, O n p) C 1 -C 6 alkyl-S-, II q) C6H5CH2OC-, or II r) R98-C-, wherein R98 represents a phenyl group, a 5- or 6-membered heteroaryl group containing 1-3 O, N or S and attached to the phenyl substituent via a ring carbon atom, or a 5- or 6-membered saturated or unsaturated a heterocyclic group containing 1-4 O, N or s attached to the phenyl substituent through a ring carbon atom. 1-3 O, N, or S, attached to the phenyl substituent through a carbon or nitrogen atom, wherein said heterocyclic group is optionally substituted with R96. 183 · ♦ ♦ · • OH N II p) C 1 -C ₆ alkyl-C, q) phenyl optionally substituted with R 96; or r) an S- or 6-membered saturated or unsaturated heterocyclic group containing 1-3 O, N or S and attached to the phenyl substituent via a carbon or nitrogen atom, said heterocyclic group being optionally substituted with R96, and R96 represents a group selected from the group consisting of a) C 1 -C 8 alkyl-OH, b) C 1 -C 8 alkyl-O-C-, c) CH ₃ -C 1 -C ₆ alkyl-R ₆ -, (d) cyano; (e) formyl; OH z N 1 ' y) C 1 -C 6 alkyl-C-, wherein R 4 is as defined above, z) cyano, aa) carboxyl bb) CF 3, cc) mercapto, dd) C 1 -C 6 alkyl-C-O-, O ee) C 6 H 5 -O-C-, wherein the phenyl moiety may be optionally substituted by halogen or C 1 -C 6 alkyl, IIff) C ₆ H ₅ (CH 2) 1-6O-C-, o Gg) Re 50 O - (CH 2) 1 -6-C ^- where Res is as defined above, or O II hh) SiR99R100R1O1-O-CH2-C-, where R99, R100 and R101 each 176 independently represents a C 1-6 alkyl group; or Q and each of R 1 and R a form -O-CH 2 -O; Re 2 means a) H b) C 1-6 alkyl optionally substituted by one or more halogen atoms; or c) C 1-6 alkyl optionally substituted by one or more OH groups or C 1-6 alkoxy groups; E stands for (a) NR69; b) —S (= O) i, wherein i is 0, 1 or 2, or c) 0; R 63 represents a group selected from the group consisting of a) H, b) C 1-6 alkyl, c) - (CH 2) q -aryl, a d) halogen; Re 6 represents H or a C 1-6 alkyl group; R 7 and R 8 each independently represent H or a C 1-6 alkyl group or NR 67 R 68 together form - (CH 2) m ^- ; R 9 is a group selected from the group consisting of a) H, ΧΊΊ • ♦ ··· • · * • 44 • • · • • • · · ·· ♦ 1 ' u) C 1 -C 6 alkyl-S-C-, 175 • ··········. • · · · · ·. • · · ·· ······ ... «, · ·· o II v) NC- (CH 2) r O-C-, wherein r is 1-6, O (w) C6H5CH2-O-C-; O x) C ₆ H ₅ -OC-, OR 6 4 N 1 « C 1 -C 6 alkyl-C- wherein R 4 is as defined above, cyano, carboxyl, CFa, O II C 1 -C 6 alkyl-C-O-, O II C 6 H 6 -O-C-, wherein the phenyl part of the group may be optionally substituted by halogen or (C 1 -C 6) alkyl, O II NReoRei-C- wherein R60 and Rei are as defined above, O O II R91-NH-C- or R91-C-NH-, wherein R91 is 5- or 2-R- 1) halogen, A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R ¹ represents a) H, b) C 1-6 alkyl optionally substituted by one or more of F, Cl, OH, C 1-6 alkoxy and C 1-6 alkyloxy. c) a C 3-6 cycloalkyl group; d) C 1-6 alkoxy; L is oxygen or sulfur; And it means and) (b) c) a 5-membered heteroaromatic group containing one to three heteroatoms selected from the group consisting of S, 145 (d) E) N and O, wherein said 5-membered heteroaromatic group is attached via a carbon atom and may additionally be fused to a benzene or naphthyl ring, and said heteroaromatic group is optionally substituted with one to three substituents R 6, a 6-membered heteroaromatic group containing at least one a nitrogen atom wherein said heteroaromatic group is attached via a carbon atom and said 6-membered heteroaromatic group may additionally be fused to a benzene or naphthyl ring, and the heteroaromatic group is optionally substituted with one to three substituents R 9, a group selected from β -carbolin-3-yl or indolizinyl linked via a 6-membered ring and optionally substituted with one to three R 9, or g) wherein R 2 and R 3 each independently represent a group consisting of: a) H 146 b) F, c) Cl, d) Br, e) C 1-6 alkyl, (f) NO2; g) I, h) C 1-6 alkoxy (i) OH, j) amino, (k) cyano; or l) R 2 and R 3 together represent -O (CH 2) h -O; wherein R 4 is a group selected from the group consisting of a) H, b) C 1-2 alkyl, (c) F, or d) OH; R 5 is a group selected from the group consisting of a) H, b) CF c) C 1-3 alkyl, optionally substituted with one or more halogen atoms, d) phenyl, optionally substituted with one or more halogen atoms, e) R 5 and R 6 together form a 5-, 6-, or 7-membered ring of the general formula 147 f) wherein D is S, O or R 50, wherein R 6 is H or C 1-6 alkyl, or g) R 5 and R 6 taken together are - (CH 2) k - when R 7 represents an electron withdrawing group; Re and R7 have the same or different meanings at each occurrence and are: a) electron withdrawing group, b) H, (c) CF ₃ d) C _1-3 alkyl optionally substituted with one halogen atom, (e) a phenyl group, provided that at least one of R e and R 7 is an electron withdrawing group; or f) R 6 and R 7 together represent a 5-, 6-, or 7-membered ring of the general formula O // <cc _K U means: (a) CH2, b) 0, (c) S or d) NRIE; R16 means: 148 * (a) H or b) a C 1-6 alkyl group; wherein Re is a group selected from the group consisting of: (a) carboxyl, (b) halogen, c) -CN, (d) mercapto, (e) formyl; (f) CF3; (g) NO2; h) C 1-6 alkoxy, (i) C 1-6 alkoxycarbonyl; j) C 1-6 alkylthio, k) C 1-6 acyl, (l) -NR17R18; NOH • 1 m) -C-R 87 wherein R 7 is H or C 1-6 alkyl, n) a C 1-6 alkyl group optionally substituted by the group consisting of OH, sulfamoyl, C 1-6 alkoxy, C 1-6 sacyl and -NR 17 R 18, o) C 2-6 alkyl optionally substituted by one or two R 19, p) a phenyl group optionally substituted with one or two R 19, q) a 5- or 6-membered saturated or unsaturated heterocyclic group containing one to three atoms selected from the group consisting of S, N and O, optionally substituted with one or two R 19, or 149 · «« · ·· <· <· · « R17 and R18, at each occurrence, have the same or different meanings and are selected from the group consisting of: a) H b) C 1-6 alkyl, c) C 5-6 cycloalkyl, or d) R 17 and R 16 together with the nitrogen atom form a 5- or 2-membered group The compound of claim 1, wherein A is wherein Q 1, R 2 and R 3 are as defined above. 2) C 1-6 alkyl, A compound of formula (IA) or a pharmaceutically acceptable salt thereof, wherein R 1 is H, C 1-6 alkyl optionally substituted by one or more of F, Cl, OH, C 1-6 alkoxy and C 1-6 acyloxy, or C 3-6 cycloalkyl or C 1-6 alkoxy; _R2 and R3 are each independently a) H, b) F, c) Cl, d) Br, e) C 1-6 alkyl, (f) NO2; g) I, h) C 1-6 alkoxy, 168 · · · · · · · · (i) OH, j) amino, or (k) cyano; and Q is a group selected from the group consisting of (a) hydrogen, (b) halogen, (c) NO2; d) N ₃ e) C1-6alkylthio, II f) C 1 -C 6 alkyl-S-; AND" g) C 1 -C 6 alkyl-S-, h) C 1 -C 6 alkyl (i) C 1 -C 6 alkoxy; (j) formyl; II k) C 1 -C 6 alkyl-C-, l) C 1 -C 6 alkyl-O-L-, II m) C 1 -C 6 alkyl-C-O-, O | l n) heteroaryl-C-, wherein heteroaryl is 5- or 3) NO2, 4. Compound of formula (IA) O Q IA or a pharmaceutically acceptable salt thereof, wherein R 1 is H, C 1-6 alkyl optionally substituted by one or more of F, Cl, OH, C 1-6 alkoxy or C 1-6 alkyloxy, C 3-6 cycloalkyl or C 1-6 alkoxy; R 2 and R 3 each independently represent H or F; or R2 and R3 together represent O 182 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· · · ··· ·· · · · Q is a group selected from the group consisting of (a) hydrogen, (b) halogen, c) Ns, d) NO ₂ , e) C1-6alkylthio, O (l f) C 1 -C 6 alkyl-S-; O g) C 1 -C 6 alkyl-S-; O h) C 1 -C ₆ alkyl (i) C 1 -C 6 alkoxy; (j) formyl; O II k) C 1 -C 6 alkyl-C-, O AND" l) C1- _C6 alkyl-OC-, O AND" m) C 1 -C 6 alkyl-C-O-, n) (C 1 -C 6 alkoxy) 2 N -, o) a 5- or 6-membered heterocyclic group contains • 4 • «« 4 • « 4 4 4 444 • • • • • 4 4 « • 44 • «• 4 • 4 b) C 1-6 alkyl, c) - (CH 2) q -aryl, (d) -CO2R81, (e) COR82; f) -C (= O) - (CH ₂ ) q C (= O) R _8i , g) -S (= O) _z -C 1-6 alkyl, h) -S (= O) 2 - (CH 2) q -aryl, or i) - (C = O) j-Het wherein j is 0 or 1; Zi means a) -CH 2 - or b) -CH (R ₇₀ ) -CH ₂ -; Z2 stands for a) -O2S- b) -0- c) -S-, (d) —SO—, or e) -N (R ₇₁ ) -; Z3 means a) S, b) SO, (c) SO2; or to; A 1 is H or CH 3; A2 means 178 • ·· « * · • • ··· • · ··· • • • * • • · • · • · · ♦ · ··· ·· > ·· * * · · · · · · ··· a) Η, b) ΟΗ-, (c) CH3CO2-, d) CH3-, (e) CH3O '; f) R ₇₂ O-CH 2 -C (O) -NH-, g) R ₇ 2 -O-C (O) -NH-, h) R ₇ 3-C (O) -NH-, i) (C 1 -C 2) alkyl-O-C (O) -, or j) HO-CH 2; or A 1 and A 2 together represent ⁰ | J or b) 0 =; R 4 is H or CH 3 -; m means 4 or 5; n means 0, 1, 2, 3, 4, or 5; y means 0 or 1; P means 0, 1, 2, 3, 4, or 5; w means 1, 2 or > 3 »» q means 1, 2, 3, or 4; of means 0 or 1; R65 stands for (a) R ₇ 4OC (R 75) (R ₇ 6) ^- C (O) ^- , (b) R7 ₇ OC (O) -, c) R 8 (0) -, 179 (d) R79 ~ SC> 2 ~, or e) R ₈ o -NH-C (O); R 70 is H or (C 1 -C 3) alkyl; R71 stands for (a) R74OC (R75) (R6) -C (O) -, (b) R77O-C (O) -, c) R ₇ 8-C (O) -, d) o f) H ₃ CC (O) - (CH ₂ ) 2 -C (O) -, (g) R79-SO2-; i) R ₈ 0 -NH-C (O) -, R72 stands for a) H, (b) CH ₃ ; c) phenyl-CH2-, or d) CH ₃ C (O) -; R 73 is (C 1 -C 3) alkyl or phenyl; R 74 is H, CH 3, phenyl-CH 2 or CH 3 -C (O) -; 180 · · ··············· · · · R 75 and R 76 each independently represent H or CH 3, or R 75 and R 76 together represent -CH 2 CH 2 -; R77 is (C1-C3) alkyl or phenyl; R78 represents a group selected from the group consisting of H, (C1-C4) alkyl, aryl- _(CH2) n1, CIH2C, CI2HC 2 C-, F2HC-, and (C3-C6) cycloalkyl; R 79 is CH 3; -CH 2 Cl, -CH 2 CH = CH 2, aryl or -CH 2 CN; Reo is - (CH 2) n ¹ -aryl, wherein n ¹ is 0 or 1; Rei means a) H, b) a C 1-6 alkyl group optionally substituted by one or more groups selected from OH, halogen and CN; c) - (CH 2) q -aryl wherein q is as defined above, or d) - (CH 2) q -OR 5, wherein q is as defined above; Re 2 means a) C 1-6 alkyl optionally substituted by one or more groups selected from OH, halogen and CN; b) - (CH 2) q -aryl wherein q is as defined above, or c) - (CH 2) q -OR e 3, wherein q is as defined above; 181 R ₃ is a group selected from the group consisting of a) H, b) C _1-6 alkyl, c) - (CH 2) q -aryl, wherein q is as defined above; or d) -C (= O) C 1-6 alkyl; and aryl is phenyl, pyridyl or naphthyl, wherein said phenyl, pyridyl or naphthyl may be optionally substituted by one or more of halogen, -CN, OH, SH, C 1-6 alkoxy or C 1-6 alkylthio. 4) Na, II 4 4 · ·· c) C1-6alkyl, or d) a benzyl group; R 50 and R 51 can each have the same or different meanings and mean each occurrence a) H, (b) OH, c) a C 1-6 alkyl group optionally substituted by -NR 48 R 49 wherein R 48 and R 49 are as defined above, d) R 50 and R 51 taken together are = O; R 52 represents a group selected from the group consisting of (a) an aromatic group of 6 to 10 carbon atoms; b) a 5- or 6-membered aromatic or benzo-fused heterocyclic group containing one to three atoms selected from the group consisting of S, N and O, wherein substituents (a) and (b) may be optionally substituted with one to three groups selected from -NO 2, CF 3, halogen, -CN, OH, phenyl, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 sacyl, c) morpholinyl, (d) OH, e) C 1-6 alkoxy, f) -NR 48 R 49 wherein R 48 and R 49 are as defined above, g) —C (= O) —R 59, or (h) 161 • · · · R 53 represents a group selected from the group consisting of a) H, b) molds1, c) C 1-4 alkyl, d) C 1-4 acyl, (e) phenyl; f) C3-6cycloalkyl, g) -P (O) (OR 37) (OR 38); h) -SO 2 R 39, wherein R 37, R 38 and R 39 are as defined above; R 59 is selected from the group consisting of (a) morpholinyl, (b) OH, and c) C 1-6 alkoxy; h is 1, 2 or 3; i is 0, 1 or 2; j is 0, or 1; k is 3, 4 or 5; r is 1, 2, 3, 4, 5, or 6; t is 0, 1, 2, 3, 4, 5, or 6; u is 1 or 2; and Q is a group selected from the group consisting of (a) hydrogen, (b) halogen, (c) NO2; d) N3 162 ························· e) C1-6alkylthio, II f) C 1 -C 6 alkyl-S-; g) C 1 -C 8 alkyl-S-, II o h) C 1 -C 6 alkyl (i) C 1 -C 6 alkoxy; (j) formyl; O II k) C 1 -C 8 alkyl-C- II l) Cl-Csalky1-O-C- (m) -sulfamoyl (H2NSO2-), η) -NHOH, O o) C1-C6alkyl-C-O0 II p) heteroaryl-C-, wherein heteroaryl is 5- or 4,444 «« • · 4 4 · 4 «· A compound which is a compound selected from the group of compounds according to Examples 1-97 set forth in the disclosure. 185 ··· · 444444 44 · 4 4 4 4 4 444 4 4 4 4 4 4 44 44 44 444 44444 5) C 1-6 alkyl-S-, A 5-, 6- or 7-membered aromatic heterocyclic group containing one to three atoms selected from the group consisting of S, N and O, (c) an aromatic group of 6 to 10 carbon atoms; or d) a 5-, 6-, or 7-membered aromatic heterocyclic group containing one to three atoms selected from the group consisting of S, N and O, wherein substituents (c) and (d) may be optionally substituted by a group selected from carboxyl, halogen , -CN, formyl, CF 3, -NO 2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylthio, and C 1-6 alkoxycarbonyl; R46 and R47 may have the same or different meanings at each occurrence and are a) H, b) a phenyl group, 160 * 4 44 ··· «• · · ··· 6. A pharmaceutical composition comprising the compound of claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. A 6-membered aromatic heterocyclic group containing 1-3 heteroatoms selected from the group consisting of O, N, or S. II n) CeH 5 -C o) amino, p) C 1 -C 6 alkylamino-, q) di (C 1 -C 6 alkyl) amino-, r) (C 1 -C 6 alkyl-C-NR 6 R 6, wherein R 6 and R 6 each independently represent hydrogen or C 1 -C 6 alkyl, (s) OH, t) hydroxy (C 1 -C 6 alkyl) A 6-membered aromatic heterocyclic group Containing 1-3 heteroatoms selected from the group consisting of 0, N or S. o) C ₆ H5-Cl - p) amino, q) C 1 -C 6 alkylamino-, r) di (C 1 -C 6 alkyl) amino-, AT s) (C 1 -C 6) alkyl-C-NR 6 R e1, wherein Reo and Re 1 are each independently hydrogen or C 1 -C 6 alkyl, (t) OH, (u) cyan; v) hydroxy (C 1 -C 6 alkyl) O w) C 1 -C ₆ alkyl-SC-; O »· x) NC- _(CH2) RC wherein r is 1-6, O l | y) C ₆ H ₅ CH ₂ -OC-, O II z) C6H5-OC-, ₈ ^ 0R 4 N II aa) Cealky1 C-C-, wherein R ₈ is hydrogen or 4 C 1-6 alkyl, O II bb) Re5O- _(CH2) i-6-C-, wherein R ₈ 5 represents hydrogen, C 1-6 alkyl optionally substituted One or more of F, Cl, OH, C 1-6 alkoxy or C 1-6 acyloxy, C 3-8 cycloalkyl or C 1-6 alkoxy; N-ORe 4 II cc) H-C-, where R 4 is as defined above dd) ee) ffgg) hh) ii) j) kk) 11) M IN AND M 171 • · · · · · ♦ mm) X, N — N A 6-membered aromatic heterocyclic group containing 1-3 O, N or S atoms, O C ₆ H ₅ (CH 2) 1-6-OC-, o II R85O- (CH2) 1-6-O-C-, wherein Res is as defined above, O || S 1 R 99 R 100 R 10 -O-CH 2 -C-, wherein R 99, R 100 and R 101 each independently represent a C 1-6 alkyl group; or 167 Q and each R 1 and R 2 together form a -O-CH 2 -O group. 6-membered aromatic heterocyclic group group containing 0 II 1-3 heteroatoms selected 0, N and S, that 11) C6H5-C-, 0 12) - (C 1 -C ₆ ) al cy1-C-NR &lt; 6 &gt; R &lt; 1 &gt; Ré 1 each independently represent hydrogen or C 1 -C 6 alkyl, 13) OH, 14) hydroxy (C 1 -C 6 alkyl), O II 15) C 1 -C 6 alkyl-S-C-; O II 16) NC- _(CH2) rOC-, wherein r is 1-6, O AND" 17) C ₆ H ₅ CH ₂ -OC-, 18) -CH 2 -R 80, wherein Reo is (a) -OR 32 where R 32 is as defined above, b) -SR 32 where R 32 is as defined above, c) -NR 32 R 33 wherein R 32 and R 33 are as defined above, or d) a 5- or 6-membered heteroaromatic group 166 containing 1-4 atoms O, S or N, ^ ORs 4 N 6) C 1-6 alkyl-S-, II 7) formyl, II 8) C 1-6 alkyl-C-, 165 • «· • ···· e · • · · ··· · · ···· • 9 · «··« 9 • ·· • * ♦ <· · 9 • 9 99 99 • 99 • 999 O II 9) C 1-6 alkyl-O-C-, O | l 10) heteroaryl-C-, wherein heteroaryl is 5- or A 6-membered aromatic heterocyclic group containing 1-3 heteroatoms selected from the group consisting of O, N or S. II q) C 6 H 5 -C 1 -amino, s) C 1 -C 6 alkylamino-, t) di (C 1 -C 6 alkyl) amino-, O u) (C 1 -C 6) alkyl-C-NR 60 R 6, wherein R d and R e are each Independently represent hydrogen or a C 1 -C 6 alkyl group; (v) OH, (w) cyan; x) hydroxy (C 1 -C 6 alkyl) O y) C 1 -C 5 alkyl-S-C 1 -; z) NC- _(CH2) RC wherein r is 1-6, aa) C6H5CH2-OC- bb) ₅ CEH? C-, 4-ORs N c) C 1 -C 6 alkyl-C-, wherein R 84 is hydrogen or A C 1-6 alkyl group, II dd) Re5O- (CH2) 1-6-C-, where Res is hydrogen, C ealkylovou group optionally substituted by one or more radicals from the group consisting of F, Cl, OH, Ci-8 alkoxy or C sacyloxy, _C3 -ecykloalkyl or C alkoxy; N-ORe 4 li ee) H-C- wherein Re 4 represents hydrogen or C 1-6 alkyl, ff) substituted or unsubstituted C 6 -C 10 aryl (Gg) a substituted or unsubstituted monocyclic or bicyclic saturated or unsaturated heterocyclic group containing 1-3 atoms selected from the group consisting of 0, N and S, wherein said ring is bonded via a ring carbon atom; or hh) a monocyclic or bicyclic substituted or unsubstituted heteroaromatic group containing 1-3 atoms selected from the group consisting of 0, N and S, wherein said ring is attached to the phenyl substituent via a ring carbon or nitrogen atom, and wherein the heteroaromatic group may be further fused to a benzene or naphthalene ring; wherein the substituents for the groups mentioned under (p), (q), (ff), (gg) and (hh) may form 1 or 2 groups selected from the following groups: A 6-membered saturated or unsaturated heterocyclic group which optionally contains another heteroatom selected from the group consisting of S, N, O, and may be further optionally substituted, including substitution at another nitrogen atom, with a group selected from C 1-3 alkyl, formyl, 5- or 6-membered heteroaromatic group containing 1-3 O, NO atoms II or S, -C-NR 88 R 89 wherein R 86 and R 9 each independently represent hydrogen or C 1-6 alkyl, SO 2 R 90 wherein R 90 is H or C 1-6 alkyl, or C 1-3 acyl optionally substituted with 1 or more F, Cl or OH; R19 is selected from the group consisting of: (a) carboxyl, (b) halogen, c) -CN, (d) mercapto, (e) formyl; (f) CF3; (g) NO2; h) C 1-6 alkoxy, i) C 1-6 alkoxycarbonyl, 150 • <44 · • 4 444 « 44 • · · • 4 4 • 4 * • 4 44 4 • 444 4 4 • «4 4 • 4 4 • 4 • 4 • 4 4 • 4 45 4 4 4 « 44 4 44 4 4 « j) C1-6alkylthio, k) C 1-6 acyl, l) C 1-6 alkyl optionally substituted with OH, C 1-6 alkoxy, C 1-6 sacyl and -NR 17 R 18, m) phenyl, n) -C (= O) NR 20 R 21; (o) -NR17R18; P) -N (R ₂₀ ) (-SO ₂ R 22), q) -SO 2 -NR 20 R 21 a r) -S (= O) 1 R 2 2; R20 and R21, at each occurrence, have the same or different meanings and are a group consisting of a) H, b) C 1-6 alkyl; c) phenyl; R22 is selected from the group consisting of a) C 1-4 alkyl; and b) phenyl optionally substituted with C 1-4 alkyl; wherein R 9 is a group selected from the group consisting of (a) carboxyl, (b) halogen, c) -CN, (d) mercapto, e) forms1, (f) CF3; (g) NO2; 151 • ·· • 44 ·· 9 ♦ · · ··· · · ···· ·· • <· ··· · · • ·· • • • · · · • · · · • • 44 · ♦ · · · ♦ · ♦ · · ··· ·· • ·· 9 h) C 1-6 alkoxy (i) C 1-6 alkoxycarbones 1; j) C 1-6 alkylthio, (k) C1-eacyl, (l) -NR2 3R24; m) C 1-6 alkyl optionally substituted with OH, C 1-6 alkoxy, C 1-6 sacyl and -NR 23 R 24, n) C 2-8 alkylphenyl optionally substituted with one or two R 25, o) phenyl, optionally substituted with one or two R 25, p) a 5- or 6-membered saturated or unsaturated heterocyclic group containing one to three atoms from the group consisting of S, N and O, optionally substituted with one or two R 25, or q) R23 and R24, at each occurrence, have the same or different meanings and are selected from the group consisting of: a) H, (b) formyl; c) C 1-4 alkyl, d) C 1-4 acyl, (e) phenyl; f) C 3-6 cycloalkyl; or g) R 23 and R 24 together with the nitrogen atom form a 5- or 6-membered saturated heterocyclic group which optionally contains another heteroatom selected from the group consisting of S, N, O, and may be further optionally substituted, including substitution at 152 said further nitrogen atom, phenyl, pyrimidyl, C 1-3 alkyl and C 1-3 acyl; R25 is selected from the group consisting of: (a) carboxy, (b) halogen, c) -CN, (d) mercapto, e) forms1, (f) CF3; g) NO h) C 1-6 alkoxy, i) C 1-6 alkoxycarbonyl, j) C 1-6 alkylthio, (k) C1-eacyl, (l) phenyl; m) C 1-6 alkyl optionally substituted with OH, azido, C 1-6 alkoxy, C 1-6 sacyl, -NR 32 R 33, -SR 34, -O-SO 2 R 35 or R36 - <^ ~ ^ ~ ^NH ' ^C0 ~ ⁰ ' n) -C (= O) NR ₂₆ R 27 o) -NR 23 R 24 p) -N (R 26) (-SO ₂ R 22), q) -SO ₂ -NR 26 R 27, or r) -S (= O) 1 R 22, s) -CH ₂ NR 8, or t) -CH (OH) -SO ₃ R 31; R ₂ 2 is as defined above; R26 and R27 have the same or different at each occurrence 153 meaning a means a group selected from the group consisting of: and) H, (b) Ci-6alky1, C) phenyl or (d) toly1; R2 8 means a group selected from the group consisting of: and) OH, (b) benzyloxy, C) -NH-C (= O) -NH ₂ , (d) -NH-C (= S) -NH ₂ , or E) -NH-C (= NH) -NR ₂ 9R3o; R2 9 and R30 have the same or each occurrence different meaning a mean i and) H or (b) C 1 -C 6 alkyl optionally substituted phenyl or pyridyl; R3 1 means and) H or (b) sodium ion; R3 2 and R33 have the same or each occurrence different meaning a means a group selected from the group consisting of: and) H, (b) formyl, C) C1-Aalkyl, 154 • · · · d) C 1-4 acyl, (e) phenyl; f) C3-6cycloalkyl, g) R 32 and R 33 together form a 5- or 6-membered saturated heterocyclic group containing one to three atoms selected from the group consisting of S, N, O, optionally substituted, including substitution at the nitrogen atom, with a group selected from phenyl, pyrimidyl, C 1-6 3alkyl, and C 1-3 acyl, h) -P (O) (OR 37) (OR 38), or i) -SO 2 -R 39; R34 stands for R 35 represents a C 1-3 alkyl group; R36 is a) C 1-6 alkoxycarbonyl; or b) a carboxyl group; R37 and R38 have the same or different meanings and meanings at each occurrence (a) H or b) a C 1-3 alkyl group; R39 is selected from the group consisting of: 155 Φ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · (a) methyl, (b) phenyl; or c) tolyl; K means a) 0, (b) S, or c) NR 40 wherein R 40 is hydrogen, formyl, C 1-4 alkyl, C 1-4 acyl, phenyl, C3-6cycloalkyl, -P (O) (OR37) (OR38) and -SO2-R39, wherein R37, R38 and R39 are as defined above; R10, R11, R12, R13, R14 and R15 have the same or different meanings at each occurrence and are selected from the group consisting of: a) H, (b) formyl; c) carboxy, d) C 1-6 alkoxycarbonyl, e) C 1-6 alkyl, f) C 2-6 alkenyls wherein the substituents designated (e) and (f) are optionally substituted with OH, halogen, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylthio, or C 1-6 alkoxycarbonyl, or phenyl optionally substituted with halogen , (g) an aromatic group of 6 to 10 carbon atoms optionally substituted by a group selected from the group consisting of carboxyl, halogen, -CN, formyl, CF 3, NO 2, 156 99 9 • · · · · · · · · · · · · · C 1-6 alkyl, C 1-6 alkoxy, C 1-6 acyl, C 1-6 alkylthio, and C 1-6 alkoxycarbonyl; (h) -NR42R43; (i) OR44; j) -S (= O) 1 -R 45, k) -SO ₂ -N (R 46) (R 47), or (l) a group selected from the following formulas: R19 is as defined above; T stands for a) 0, (b) S, or c) SO2; R 42 and R 43, at each occurrence, have the same or different meanings and are selected from the group consisting of: a) H, b) C 3-6 cycloalkyl, (c) phenyl; 157 • · · · d) C 1-6 acyl, e) C 1-6 alkyl optionally substituted with OH, C 1-6 alkoxy optionally substituted with OH, 5 or 6-membered aromatic heterocyclic group containing one to three atoms selected from the group consisting of S, N and O, phenyl optionally substituted with OH, -NR 48 R 49, or R54 (f) R55-CH-, ogen, G) V means a) O, (b) CH2; or c) NR 5 6; R48 and R49 may have the same or different meanings at each occurrence and are (a) H or b) a C 1-4 alkyl group; R54 is (a) OH, b) C 1-4 alkoxy, or c) -NR 57 R 58; 158 R55 is (a) H or b) a C 1-7 alkyl group optionally substituted with indolyl, OH, mercaptyl, imidazolyl, methylthio, amino, phenyl optionally substituted with OH, -C (= O) -NH 2, -CO 2 H or -C (= NH) -NH ₂ ; R56 stands for a) H, (b) a phenyl group; or c) C 1-6 alkyl optionally substituted with OH; R57 and R58 may have the same or different meanings at each occurrence and are a) H, b) C 1-6 alkyl, c) a C 1-3 cycloalkyl group, or d) phenyl; R44 stands for a) C 1-6 alkyl optionally substituted with C 1-6 alkoxy or C 1-6 hydroxy, C 3-6 cycloalkyl, a 6-membered aromatic or benzo-fused heterocyclic group containing one to three nitrogen atoms, which may be substituted with one to three groups of -NO 2, CF 3, halogen, -CN, OH, C 1-6 alkyl, 159 • ·· · C 1-6 alkoxy and C 1-6 sacyl, b) in Q 1 N- (CH ₂ ) t -> (c) a phenyl group; or d) a pyridyl group; R45 stands for a) C 1-6 alkyl, b) a C2-1alkenyl group, wherein substituents (a) and (b) may be substituted by C 1-6 alkoxycarbonyl eventual group or 7. A method of treating a bacterial infection in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim 1.