KR20010072945A - Novel isoxazolinone antibacterial agents - Google Patents

Abstract

The present invention relates to isooxazolinone derivatives having antibacterial activity and useful for the treatment of bacterial diseases. More specifically, the novel isooxazolinones of the present invention have the general formula (I):

[Formula I]

In the formula, A and R ₁ are as described in the detailed description of the invention.

Description

New isoxoxazolinone antibacterial agent {NOVEL ISOXAZOLINONE ANTIBACTERIAL AGENTS}

The text includes a limited number of isoxazolinones used as pre-expressing herbicides. For example, US Pat. No. 4,065,463 discloses 2-methyl-4- (trifluoromethyl-m-tolyl) -3-isoxazolin-5-one and 2-methyl-4- (chloro-m- Tolyl) -3-isooxazolin-5-one is expected to be useful in inhibiting the growth of weeds that adversely affect crop production.

US Pat. No. 4,000,155 discloses related compounds, 1,2-dimethyl-4- (trifluoroethyl-m-tolyl) -3-pyrazolin-5-one, for the same use as follows.

Applicant has not seen in any of the literature that these compounds have been disclosed for use as a wide range of anti-bacterial agents. Ring systems of different structures, such as the use of isoxazoline derivatives as anti-bacterial agents are disclosed in WO 98/07708,

Wherein W is substituted or unsubstituted heteroaryl based and V is H or C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or acyloxy optionally substituted with F, Cl, OH.

The following oxazolidinone II is well known as an orally active antimicrobial agent. The prior art includes a number of references to such compounds in which Y and Z include various substituents in the formulas below. Particularly substituted oxazolidinones include US Pat. Nos. 4,705,799 and 5,523,403 (substituted phenyl 2-oxazolidinones), US Pat. No. 4,948,801; 5,254,577 and 5,130,316 (arylbenzene oxazolidinyl compounds) and US Patent Application 0.697,412; 0,694,544; 0,694,543 and 0,693,491 (5- to 9-membered heteroaryl substituted oxazolidinones).

In addition, certain compounds, including substituted furanone rings, are known to have antibiotic activity. WO 97/14690 discloses the following compounds

Wherein T is hydroxy or NHC (O) C ₁ -C ₄ alkyl, M and L are each independently hydrogen or fluoro, G and H are each independently hydrogen or methyl, and KJ is C = CH, CHCH ₂ or C (OH) have the formula CH _2, I is O, SO, SO ₂ or substituted nitrogen, QR is a CH ₂ -CH ₂ or CH = CH _2. Another substituted furanones are disclosed in US Pat. No. 5,708,169, WO 97/43280 and WO 97/10235.

The present invention relates to novel isoxoxazolinones, methods of use thereof and methods of preparation thereof. The present invention provides a compound having the formula (I) or a pharmaceutically acceptable salt thereof:

Where R ₁ is

a) H,

b) C _1-8 C alkyl, C _1-8 alkoxy or C _1-8 acyloxy, optionally substituted with one or more F, Cl, OH,

c) C _3-8 cycloalkyl, or

d) a C _1-8 alkoxy group;

L is oxygen or sulfur;

A is

a) ,

b) ,

c) optionally 1 to 3 selected from the group consisting of S, N and O, optionally substituted with 1 to 3 R ₈ groups, which may additionally have a fused benzene or naphthyl ring and are bonded via a carbon atom; 5-membered heteroaromatic group having 3 hetero atoms,

d) a 6-membered heteroaromatic group having one or more nitrogen atoms, optionally substituted with one to three R ₉ groups, which may additionally have a fused benzene or naphthyl ring and is bonded via a carbon atom; ,

e) indolinyl, or β-carbolin-3-yl, optionally substituted with one to three R ₉ groups, and bonded through a six-membered ring,

f) , or

g) ego;

Wherein R ₂ and R ₃ are each independently,

a) H,

b) F,

c) Cl,

d) Br,

e) C _1-2 alkyl,

f) NO ₂ ,

g) I,

h) C _1-6 alkoxy,

i) OH,

j) amino,

k) cyano, or

l) R ₂ and R ₃ taken together are —O (CH ₂ ) _h —O;

Where R ₄ is

a) H,

b) C _1-6 alkyl,

c) F, or

d) OH;

R ₅ is

a) H,

b) CF ₃ ,

c) C _1-3 alkyl optionally substituted with one or more halo,

d) phenyl optionally substituted with one or more halo,

e) R ₅ and R ₆ taken together are a 5-, 6- or 7-membered ring having the formula

;

f) , Wherein D is S, O or NR ₈₆ , wherein R ₈₆ is H or C _1-6 alkyl, or

g) when R ₇ is an electron-withdrawing group, R ₅ and R ₆ taken together are — (CH ₂ ) _k —;

R ₆ and R ₇ are the same or different at each position,

a) e-trailer,

b) H,

c) CF ₃ ,

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

e) if at least one of R ₆ and R ₇ is an electron-drawing group, phenyl, or

f) R ₆ and R ₇ taken together are a 5-, 6- or 7-membered ring having the formula:

;

U is

a) CH ₂ ,

b) O,

c) S or

d) NR ₁₆ ;

R ₁₆ is

a) H or

b) C _1-5 alkyl;

Wherein R ₁₈ is

a) carboxyl,

b) halo,

c) -CN,

d) mercapto,

e) formyl,

f) CF ₃ ,

g) NO ₂ ,

h) C _1-6 alkoxy,

i) C _1-6 alkoxycarbonyl,

j) C _1-6 alkylthio,

k) C _1-6 acyl,

l) -NR ₁₇ R ₁₈ ,

m) Wherein R ₈₇ is H or C _1-6 alkyl

n) C _1-6 alkyl, sulfamoyl, C _1-5 alkoxy, —C _1-5 acyl, or NR ₁₇ R ₁₈ optionally substituted with OH,

o) C _2-8 alkyl optionally substituted with one or two R ₁₉ ,

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

q) Or a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 3 atoms selected from the group consisting of S, N and O, optionally substituted with one or two R ₁₉ ;

At each position R ₁₇ and R ₁₈ are the same or different,

a) H,

b) C _1-4 alkyl,

c) C _5-6 cycloalkyl, or

d) R ₁₇ and R ₁₈ taken together with a nitrogen atom are 5- or 6-membered saturated or unsaturated heterocyclic groups having additional hetero atoms optionally selected from the group consisting of S, N, O, and then optionally further nitrogen atoms Including C _1-3 alkyl, formyl, 5- or 6-membered heteroatoms containing 1-3 O, N or S, Wherein R ₈₈ and R ₈₉ are each independently hydrogen or C _1-6 alkyl, SO ₂ R ₉₀ (wherein R ₉₀ is H or C _1-6 alkyl), or optionally one or more F, Cl or Optionally substituted with C _1-3 acyl optionally substituted with OH;

R ₁₉ is

a) carboxyl,

b) halo,

c) -CN,

d) mercapto,

e) formyl,

f) CF ₃ ,

g) NO ₂ ,

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, C _1-5 alkoxy, C _1-5 acyl, or NR ₁₇ R ₁₈ , optionally substituted with OH,

m) phenyl,

n) -C (= 0) NR ₂₀ R ₂₁ ,

o) -NR ₁₇ R ₁₈ ,

p) -N (R ₂₀ ) (-SO ₂ R ₂₂ ),

q) -SO ₂ -NR ₂₀ R ₂₁ , or

r) -S (= 0) _i R ₂₂ ;

At each position R ₂₀ and R ₂₁ are the same or different,

a) H,

b) C _1-6 alkyl, or

c) phenyl;

R ₂₂ is

a) C _1-4 alkyl, or

b) phenyl optionally substituted with C _1-4 alkyl;

Wherein R ₉ is

a) carboxyl,

b) halo,

c) -CN,

d) mercapto,

e) formyl,

f) CF ₃ ,

g) NO ₂ ,

h) C _1-6 alkoxy,

i) C _1-6 alkoxycarbonyl,

j) C _1-6 alkylthio,

k) C _1-6 acyl,

l) -NR ₁₇ R ₁₈ ,

m) C _1-6 alkyl, C _1-5 alkoxy, C _1-5 acyl, or —NR ₂₃ R ₂₄ , optionally substituted with OH,

n) C _2-8 alkenylphenyl 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 having 1 to 3 atoms selected from the group consisting of S, N and O, optionally substituted with one or two R ₂₅ , or

q) ego;

At each position R ₂₃ and R ₂₄ are the same or different,

a) H,

b) formyl,

c) C _1-4 alkyl,

d) C _1-4 acyl,

e) phenyl,

f) C _3-6 cycloalkyl, or

d) R ₂₃ and R ₂₄ taken together with a nitrogen atom are 5- or 6-membered saturated or unsaturated heterocyclic groups having additional hetero atoms optionally selected from the group consisting of S, N, O, and then optionally further nitrogen Atoms may be substituted with phenyl, pyrimidyl, C _1-3 alkyl, or C _1-3 acyl;

R ₂₅ is

a) carboxyl,

b) halo,

c) -CN,

d) mercapto,

e) formyl,

f) CF ₃ ,

g) NO ₂ ,

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, azido, C _1-5 alkoxy, C _1-5 acyl, —NR ₃₂ R ₃₃ , —SR ₃₄ , —O—SO ₂ R ₃₅ , optionally substituted with OH or ,

n) -C (= 0) 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) iR ₂₂ ,

s) -CH = NR ₂₈ , or

t) -CH (OH) -SO ₃ R ₃₁ ;

R ₂₂ is as described above;

At each position R ₂₆ and R ₂₇ are the same or different,

a) H,

b) C _1-6 alkyl, or

c) phenyl, or

d) tolyl;

R ₂₈ is

a) OH,

b) benzyloxy,

c) -NH-C (= 0) -NH ₂ ,

d) -NH-C (= S) -NH ₂ , or

e) -NH-C (= NH) -NR ₂₉ R ₃₀ ;

At each position R ₂₉ and R ₃₀ are the same or different,

a) H, or

b) C _1-4 alkyl optionally substituted with phenyl or pyridyl;

R ₃₁ is

a) H, or

b) sodium ions;

At each position R ₃₂ and R ₃₃ are the same or different,

a) H,

b) formyl,

c) C _1-4 alkyl,

d) C _1-4 acyl,

e) phenyl,

f) C _3-6 cycloalkyl,

g) R ₃₂ and R ₃₃ taken together are a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 3 atoms, optionally selected from the group consisting of S, N, O, optionally comprising further nitrogen atoms May be substituted with phenyl, pyrimidyl, C _1-3 alkyl, or C _1-3 acyl,

h) -P (O) (OR ₃₇ ) (OR ₃₈ ), or

i) -SO ₂ -R ₃₉ ;

R ₃₄ ego;

R ₃₅ is C _1-3 alkyl;

R ₃₆ is

a) C _1-6 alkoxycarbonyl, or

b) carboxyl;

At each position R ₃₇ and R ₃₈ are the same or different,

a) H, or

b) C _1-3 alkyl;

R ₃₉ is

a) methyl,

b) phenyl, or

c) tolyl;

Where K is

a) O,

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 ₃₈ ) Or -SO-R ₃₉ , wherein R ₃₇ , R ₃₈ and R ₃₉ are as described above);

At each position R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are the same or different,

a) H,

b) formyl,

c) carboxyl,

d) C _1-6 alkoxycarbonyl,

e) C _1-8 alkyl,

f) C _2-8 alkenyl,

Wherein the substituents (e) and (f) are optionally OH, halo, C _1-6 alkoxy, C _1-6 acyl, C _1-6 alkylthio or C _1-6 alkoxycarbonyl, or phenyl optionally substituted with halo May be substituted with),

g) optionally carboxyl, halo, -CN, formyl, CF ₃ , NO ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 alkylthio or C _1-6 alkoxy Aromatic groups having 6 to 10 carbon atoms substituted with carbonyl;

h) -NR ₄₂ R ₄₃ ,

i) OR ₄₄ ,

j) -S (= O) _i -R ₄₅ ,

k) -SO ₂ -N (R ₄₆ ) (R ₄₇ ), or

l) a substituent having the formula:

;

R ₁₉ is as described above;

T

a) O,

b) S, or

c) SO ₂ ;

At each position R ₄₂ and R ₄₃ are the same or different,

a) H,

b) C _3-6 cycloalkyl,

c) phenyl,

d) C _1-6 acyl,

e) 5- or 6-membered aromatic heteroaryl having 1 to 3 atoms selected from the group consisting of C _1-8 alkyl optionally substituted with OH, C _1-6 alkoxy which may be substituted with OH, S, N and O Phenyl, phenyl optionally substituted with OH, CF ₃ , halo, —NO ₂ , C _1-4 alkoxy, —NR ₄₈ R ₄₉ or ,

f) , or

g) ego;

V is

a) O,

b) CH ₂ , or

c) NR ₅₆ ;

At each position R ₄₈ and R ₄₉ are the same or different,

a) H, or

b) C _1-4 alkyl;

R ₅₄ is

a) OH,

b) C _1-4 alkoxy, or

d) -NR ₅₇ R ₅₈ ;

R ₅₅ is

a) H, or

b) C _1-7 alkyl, mercaptyl, imidazolyl, methylthio, amino, optionally substituted with OH, phenyl optionally substituted with OH, -C (= 0) -NH ₂ , -CO ₂ H, or -C (= NH) -NH ₂ ;

R ₅₆ is

a) H,

b) phenyl, or

c) optionally OH substituted C _1-6 alkyl;

At each position R ₅₇ and R ₅₈ are the same or different,

a) H,

b) C _1-5 alkyl,

c) C _1-3 cycloalkyl, or

d) phenyl;

R ₄₄ is

a) C _1-8 alkyl, C _3-6 cycloalkyl, 6-membered aromatic optionally benzo-fused with 1 to 3 nitrogen atoms, optionally substituted with C _1-6 alkoxy or C _1-6 hydroxy Heterocyclic group, which may be further substituted with one or two —NO ₂ , CF ₃ , halo, —CN, OH, C _1-5 alkyl, C _1-5 alkoxy or C _1-5 acyl ,

b) ,

c) phenyl, or

d) pyridyl;

R ₄₅ is

a) C _1-16 alkyl,

b) C _2-16 alkenyl,

Wherein the substituents (a) and (b) are optionally C _1-6 alkoxycarbonyl, or 5-, 6- or 7-membered aromatic hetero having 1 to 3 atoms selected from the group consisting of S, N and O Cyclic group),

c) aromatic groups having 6 to 10 carbon atoms, or

d) a 5-, 6- or 7-membered aromatic heterocyclic group having 1 to 3 atoms selected from S, N and O, wherein substituents (c) and (d) are optionally carboxyl, halo,- May be substituted with CN, formyl, CF ₃ , -NO ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 alkylthio or C _1-6 alkoxycarbonyl) ;

At each position R ₄₆ and R ₄₇ are the same or different,

a) H,

b) phenyl,

c) C _1-6 alkyl or

d) benzyl;

At each position R ₅₀ and R ₅₁ are the same or different,

a) H,

b) OH,

c) C _1-6 alkyl optionally substituted with NR ₄₈ R ₄₉ , wherein R ₄₈ and R ₄₉ are as described above,

d) R ₅₀ and R ₅₁ taken together are ═O;

R ₅₂ is

a) an aromatic group having 6-10 carbon atoms,

b) 5-, or 6-membered aromatic optionally benzo-fused heterocyclic groups having 1 to 3 atoms selected from the group consisting of S, N and O, wherein substituents (a) and (b) Optionally optionally substituted with 1 to 3 —NO ₂ , CF ₃ , halo, —CN, OH, phenyl, C _1-5 alkyl, C _1-5 alkoxy, or C _1-5 acyl),

c) morpholinyl,

d) OH,

e) C _1-6 alkoxy,

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

g) -C (= 0) -R ₅₉ , or

h) ego;

R ₅₃ is

a) H,

b) formyl,

c) C _1-4 alkyl,

d) C _1-4 acyl,

e) phenyl,

f) C _3-6 cycloalkyl,

g) -P (O) (OR ₃₇ ) (OR ₃₈ ), or

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

R ₅₉ is

a) morpholinyl,

b) OH, or

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;

Q is

a) hydrogen,

b) halo,

c) NO ₂ ,

d) N ₃ ,

e) C ₁ -C ₆ alkylthio,

f) ,

g) ,

h) C ₁ -C ₆ alkyl,

i) C ₁ -C ₆ alkoxy,

j) formyl,

k) ,

l) ,

m) sulfamoyl (H ₂ NSO _2- ),

n) -NHOH,

o) ,

p) Wherein heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S),

q) ,

r) amino,

s) C ₁ -C ₆ alkylamino-,

t) di (C ₁ -C ₆ alkyl) amino-,

u) (Wherein R ₆₀ and R ₆₁ are each independently hydrogen or C ₁ -C ₆ alkyl),

v) OH,

w) cyano,

x) hydroxy (C ₁ -C ₆ alkyl),

y) ,

z) (Where r is 1-6),

aa) ,

bb) ,

cc) Wherein R ₈₄ is hydrogen or C _1-6 alkyl

dd) Wherein R ₈₅ is hydrogen, C _1-8 alkyl, C _1-8 alkoxy or C _1-8 acyoxy, C _3-6 cycloalkyl or C _1-8 alkoxy, optionally substituted with one or more F, Cl, OH being),

ee) Wherein R ₈₄ is hydrogen or C _1-6 alkyl

ff) substituted or unsubstituted C ₆ -C ₁₀ aryl group,

gg) 1-3 atoms selected from O, N or S, substituted or unsubstituted monocyclic or bicyclic, saturated or unsaturated, in which the ring is bonded to a phenyl substituent via a ring carbon or nitrogen Heterocyclic group having,

hh) a heteroatom group having 1-3 atoms selected from O, N or S, in which the ring is bonded to a phenyl substituent via ring carbon or nitrogen and the heteroatom can be added to the fused or benzene or naphthalene ring Is a substituted or unsubstituted monocyclic or bicyclic group;

Substituents for such groups p, q, ff, gg and hh are selected from one or two of the following:

1) halo,

2) C _1-6 alkyl,

3) NO ₂ ,

4) N ₃ ,

5) ,

6) ,

7) formyl,

8) ,

9) ,

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

11) ,

12) (Wherein R ₆₀ and R ₆₁ are each independently hydrogen or C ₁ -C ₆ alkyl),

13) OH,

14) hydroxy (C ₁ -C ₆ alkyl),

15) ,

16) (Where r is 1-6),

17) ,

18) -CH ₂ -R ₈₀ , wherein R ₈₀ is

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

b) -SR ₃₂ (where R ₃₂ is as described above),

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

d) 5- or 6-membered heteroaromatic groups having 1-4 O, S or N atoms,

19) (Wherein R ₈₄ is as described above),

20) cyano,

21) carboxyl,

22) CF ₃ ,

23) ,

24) Wherein the phenyl group may be optionally substituted with halo or (C ₁ -C ₆ ) alkyl),

25) (Wherein R ₆₀ and R ₆₁ are as described above),

26) Wherein R ₉₁ is a 5- or 6-membered aromatic heterocyclic group having 1-3 O, N or S,

27) ,

28) (Wherein R ₈₅ is as described above),

29) Wherein R ₉₉ , R ₁₀₀ and R ₁₀₁ are each independently C _1-6 alkyl; or

One of Q and R ₁ and R ₂ together form —O—CH ₂ —O.

These derivatives are effective antimicrobials against many human and veterinary pathogens, including enterococci such as methisilane-resistant Staphylococcus aureus or vancomycin-resistant stool enterococci and gram positive bacteria such as streptococci and multi-resistant staphylococci. Useful as

Summary of the Invention

We have now found that certain substituted oxazolines are effective as antibacterial agents. In particular, the present invention provides a compound having the formula (I) or a pharmaceutically acceptable salt thereof:

[Formula I]

Wherein R ₁ is

a) H,

b) C _1-8 alkyl, C _1-8 alkoxy or C _1-8 acyloxy, optionally substituted with one or more F, Cl, OH,

c) C _3-8 cycloalkyl, or

d) a C _1-8 alkoxy group;

L is oxygen or sulfur;

A is

a)

b)

c) 1 to 3 heteroatoms selected from the group consisting of S, N and O, optionally substituted with 1 to 3 R ₈ groups, which may additionally have a benzene or naphthyl ring fused and bonded via a carbon atom 5-membered heteroaromatic group having,

d) a 6-membered heteroaromatic group having one or more nitrogen atoms, optionally substituted with 1 to 3 R ₉ groups, which may additionally have a fused or benzene or naphthyl ring, and is bonded via a carbon atom,

e) indolinyl, or β-carbolin-3-yl, optionally substituted with one to three R ₉ groups, and bonded through a six-membered ring,

f) , or

g) ego;

Wherein R ₂ and R ₃ are each independently,

a) H,

b) F,

c) Cl,

d) Br,

e) C _1-6 alkyl,

f) NO ₂ ,

g) I,

h) C _1-6 alkoxy,

i) OH,

j) amino,

k) cyano, or

l) R ₂ and R ₃ taken together are —O (CH ₂ ) _h —O;

Where R ₄ is

a) H,

b) C _1-2 alkyl,

c) F, or

d) OH;

R ₅ is

a) H,

b) CF ₃ ,

c) C _1-3 alkyl optionally substituted with one or more halo,

d) phenyl optionally substituted with one or more halo,

e) R ₅ and R ₆ taken together are a 5-, 6- or 7-membered ring having the formula:

f) , Wherein D is S, O or NR ₈₆ , wherein R ₈₆ is H or C _1-6 alkyl, or

g) when R ₇ is an electron-withdrawing group, R ₅ and R ₆ taken together are — (CH ₂ ) _k —;

R ₆ and R ₇ are the same or different at each position,

a) e-trailer,

b) H,

c) CF ₃ ,

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

e) if at least one of R ₆ and R ₇ is an electron-drawing group, phenyl, or

f) R ₆ and R ₇ taken together are a 5-, 6- or 7-membered ring having the formula:

;

U is

a) CH ₂ ,

b) O,

c) S, or

d) NR ₁₆ ;

R ₁₆ is

a) H or

b) C _1-5 alkyl;

Wherein R ₁₈ is

a) carboxyl,

b) halo,

c) -CN,

d) mercapto,

e) formyl,

f) CF ₃ ,

g) NO ₂ ,

h) C _1-6 alkoxy,

i) C _1-6 alkoxycarbonyl,

j) C _1-6 alkylthio,

k) C _1-6 acyl,

l) -NR ₁₇ R ₁₈ ,

m) Wherein R ₈₇ is H or C _1-6 alkyl

n) C _1-6 alkyl, sulfamoyl, C _1-5 alkoxy, —C _1-5 acyl, or NR ₁₇ R ₁₈ , optionally substituted with OH,

o) C _2-8 alkyl optionally substituted with one or two R ₁₉ ,

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

q) Or a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 3 atoms selected from the group consisting of S, N and O, optionally substituted with one or two R ₁₉ ;

At each position R ₁₇ and R ₁₈ are the same or different,

a) H,

b) C _1-4 alkyl,

c) C _5-6 cycloalkyl, or

d) R ₁₇ and R ₁₈ taken together with a nitrogen atom are 5- or 6-membered saturated or unsaturated heterocyclic groups having additional heteroatoms optionally selected from the group consisting of S, N, O, and then optionally further nitrogen atoms Including C _1-3 alkyl, formyl, 5- or 6-membered heteroatoms containing 1-3 O, N or S, Wherein R ₈₈ and R ₈₉ are each independently hydrogen or C _1-6 alkyl, SO ₂ R ₉₀ (wherein R ₉₀ is H or C _1-6 alkyl), or optionally one or more F, Cl or Optionally substituted with C _1-3 acyl optionally substituted with OH;

R ₁₉ is

a) carboxyl,

b) halo,

c) -CN,

d) mercapto,

e) formyl,

f) CF ₃ ,

g) NO ₂ ,

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, sulfamoyl, C _1-5 alkoxy, —C _1-5 acyl, or NR ₁₇ R ₁₈ optionally substituted with OH,

m) phenyl,

n) -C (= 0) NR ₂₀ R ₂₁ ,

o) -NR ₁₇ R ₁₈ ,

p) -N (R ₂₀ ) (-SO ₂ R ₂₂ ),

q) -SO ₂ -NR ₂₀ R ₂₁ , or

r) -S (= 0) iR ₂₂ ;

At each position R ₂₀ and R ₂₁ are the same or different,

a) H,

b) C _1-6 alkyl, or

c) phenyl;

R ₂₂ is

a) C _1-4 alkyl, or

b) phenyl optionally substituted with C _1-4 alkyl;

Wherein R ₉ is

a) carboxyl,

b) halo,

c) -CN,

d) mercapto,

e) formyl,

f) CF ₃ ,

g) NO ₂ ,

h) C _1-6 alkoxy,

i) C _1-6 alkoxycarbonyl,

j) C _1-6 alkylthio,

k) C _1-6 acyl,

l) -NR ₁₇ R ₁₈ ,

m) C _1-6 alkyl, sulfamoyl, C _1-5 alkoxy, —C _1-5 acyl, or NR ₁₇ R ₁₈ , optionally substituted with OH,

n) C _2-8 alkenylphenyl 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 having 1 to 3 atoms selected from the group consisting of S, N and O, optionally substituted with one or two R ₂₅ , or

q) ego;

At each position R ₂₃ and R ₂₄ are the same or different,

a) H,

b) formyl,

c) C _1-4 alkyl,

d) C _1-4 acyl,

e) phenyl,

f) C _3-6 cycloalkyl, or

d) R ₂₃ and R ₂₄ taken together with a nitrogen atom are 5- or 6-membered saturated or unsaturated heterocyclic groups having additional hetero atoms optionally selected from the group consisting of S, N, O, and then optionally further nitrogen Atoms may be substituted with phenyl, pyrimidyl, C _1-3 alkyl, or C _1-3 acyl;

R ₂₅ is

a) carboxyl,

b) halo,

c) -CN,

d) mercapto,

e) formyl,

f) CF ₃ ,

g) NO ₂ ,

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, azido, C _1-5 alkoxy, C _1-5 acyl, —NR ₃₂ R ₃₃ , —SR ₃₄ , —O—SO ₂ R ₃₅ , optionally substituted with OH or ,

n) -C (= 0) 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) iR ₂₂ ,

s) -CH = NR ₂₈ , or

t) -CH (OH) -SO ₃ R ₃₁ ;

R ₂₂ is as described above;

At each position R ₂₆ and R ₂₇ are the same or different,

a) H,

b) C _1-6 alkyl, or

c) phenyl, or

d) tolyl;

R ₂₈ is

a) OH,

b) benzyloxy,

c) -NH-C (= 0) -NH ₂ ,

d) -NH-C (= S) -NH ₂ , or

e) -NH-C (= NH) -NR ₂₉ R ₃₀ ;

At each position R ₂₉ and R ₃₀ are the same or different,

a) H, or

b) C _1-4 alkyl optionally substituted with phenyl or pyridyl;

R ₃₁ is

a) H, or

b) sodium ions;

At each position R ₃₂ and R ₃₃ are the same or different,

a) H,

b) formyl,

c) C _1-4 alkyl,

d) C _1-4 acyl,

e) phenyl,

f) C _3-6 cycloalkyl,

g) R ₃₂ and R ₃₃ taken together are a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 3 atoms, optionally selected from the group consisting of S, N, O, and optionally comprising further nitrogen atoms May be substituted with phenyl, pyrimidyl, C _1-3 alkyl, or C _1-3 acyl,

h) -P (O) (OR ₃₇ ) (OR ₃₈ ), or

i) -SO ₂ -R ₃₉ ;

R ₃₄ ego;

R ₃₅ is C _1-3 alkyl;

R ₃₆ is

a) C _1-6 alkoxycarbonyl, or

b) carboxyl;

At each position R ₃₇ and R ₃₈ are the same or different,

a) H, or

b) C _1-3 alkyl;

R ₃₉ is

a) methyl,

b) phenyl, or

c) tolyl;

Where K is

a) O,

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 ₃₈ ) Or -SO-R ₃₉ , wherein R ₃₇ , R ₃₈ and R ₃₉ are as described above);

At each position R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are the same or different,

a) H,

b) formyl,

c) carboxyl,

d) C _1-6 alkoxycarbonyl,

e) C _1-8 alkyl,

f) C _2-8 alkenyl,

Wherein the substituents (e) and (f) are optionally OH, halo, C _1-6 alkoxy, C _1-6 acyl, C _1-6 alkylthio or C _1-6 alkoxycarbonyl, or phenyl optionally substituted with halo May be substituted with),

g) optionally carboxyl, halo, -CN, formyl, CF ₃ , NO ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 alkylthio or C _1-6 alkoxy Aromatic groups having 6 to 10 carbon atoms substituted with carbonyl;

h) -NR ₄₂ R ₄₃ ,

i) OR ₄₄ ,

j) -S (= O) _i -R ₄₅ ,

k) -SO ₂ -N (R ₄₆ ) (R ₄₇ ), or

l) a substituent having the formula:

;

R ₁₉ is as described above;

T

a) O,

b) S, or

c) SO ₂ ;

At each position R ₄₂ and R ₄₃ are the same or different,

a) H,

b) C _3-6 cycloalkyl,

c) phenyl,

d) C _1-6 acyl,

e) 5- or 6-membered aromatic heteroaryl having 1 to 3 atoms selected from the group consisting of C _1-8 alkyl optionally substituted with OH, C _1-6 alkoxy which may be substituted with OH, S, N and O Phenyl, phenyl optionally substituted with OH, CF ₃ , halo, —NO ₂ , C _1-4 alkoxy, —NR ₄₈ R ₄₉ or ,

f) , or

g) ego;

V is

a) O,

b) CH ₂ , or

c) NR ₅₆ ;

At each position R ₄₈ and R ₄₉ are the same or different,

a) H, or

b) C _1-4 alkyl;

R ₅₄ is

a) OH,

b) C _1-4 alkoxy, or

d) -NR ₅₇ R ₅₈ ;

R ₅₅ is

a) H, or

b) C _1-7 alkyl, mercaptyl, imidazolyl, methylthio, amino, optionally substituted with OH, phenyl optionally substituted with OH, -C (= 0) -NH ₂ , -CO ₂ H, or -C (= NH) -NH ₂ ;

R ₅₆ is

a) H,

b) phenyl, or

c) optionally OH substituted C _1-6 alkyl;

At each position R ₅₇ and R ₅₈ are the same or different,

a) H,

b) C _1-5 alkyl,

c) C _1-3 cycloalkyl, or

d) phenyl;

R ₄₄ is

a) C _1-8 alkyl, C _3-6 cycloalkyl, 6-membered aromatic optionally benzo-fused with 1 to 3 nitrogen atoms, optionally substituted with C _1-6 alkoxy or C _1-6 hydroxy Heterocyclic group, which may be further substituted with one or two —NO ₂ , CF ₃ , halo, —CN, OH, C _1-5 alkyl, C _1-5 alkoxy or C _1-5 acyl ,

b) ,

c) phenyl, or

d) pyridyl;

R ₄₅ is

a) C _1-16 alkyl,

b) C _2-16 alkenyl,

Wherein the substituents (a) and (b) are optionally C _1-6 alkoxycarbonyl, or 5-, 6- or 7-membered aromatic hetero having 1 to 3 atoms selected from the group consisting of S, N and O Cyclic group),

c) aromatic groups having 6 to 10 carbon atoms, or

d) 5-, 6- or 7-membered aromatic heterocyclic groups having 1 to 3 atoms selected from the group consisting of S, N and O, wherein substituents (c) and (d) are optionally carboxyl, To be substituted with halo, -CN, formyl, CF ₃ , -NO ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 alkylthio or C _1-6 alkoxycarbonyl Can be);

At each position R ₄₆ and R ₄₇ are the same or different,

a) H,

b) phenyl,

c) C _1-6 alkyl or

d) benzyl;

At each position R ₅₀ and R ₅₁ are the same or different,

a) H,

b) OH,

c) C _1-6 alkyl optionally substituted with NR ₄₈ R ₄₉ , wherein R ₄₈ and R ₄₉ are as described above,

d) R ₅₀ and R ₅₁ taken together are ═O;

R ₅₂ is

a) an aromatic group having 6 to 10 carbon atoms,

b) 5-, or 6-membered aromatic optionally benzo-fused heterocyclic groups having 1 to 3 atoms selected from the group consisting of S, N and O, wherein substituents (a) and (b) are further Optionally substituted with 1 to 3 -NO ₂ , CF ₃ , halo, -CN, OH, phenyl, C _1-5 alkyl, C _1-5 alkoxy, or C _1-5 acyl),

c) morpholinyl,

d) OH,

e) C _1-6 alkoxy,

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

g) -C (= 0) -R ₅₉ , or

h) ;

R ₅₃ is

a) H,

b) formyl,

c) C _1-4 alkyl,

d) C _1-4 acyl,

e) phenyl,

f) C _3-6 cycloalkyl,

g) -P (O) (OR ₃₇ ) (OR ₃₈ ), or

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

R ₅₉ is

a) morpholinyl,

b) OH, or

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;

Q is

a) hydrogen,

b) halo,

c) NO ₂ ,

d) N ₃ ,

e) C ₁ -C ₆ alkylthio,

f) ,

g) ,

h) C ₁ -C ₆ alkyl,

i) C ₁ -C ₆ alkoxy,

j) formyl,

k) ,

l) ,

m) sulfamoyl (H ₂ NSO _2- ),

n) -NHOH,

o) ,

p) Wherein heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S),

q) ,

r) amino,

s) C ₁ -C ₆ alkylamino-,

t) di (C ₁ -C ₆ alkyl) amino-,

u) (Wherein R ₆₀ and R ₆₁ are each independently hydrogen or C ₁ -C ₆ alkyl),

v) OH,

w) cyano,

x) hydroxy (C ₁ -C ₆ alkyl),

y) ,

z) (Where r is 1-6),

aa) ,

bb) ,

cc) Wherein R ₈₄ is hydrogen or C _1-6 alkyl

dd) Wherein R ₈₅ is hydrogen, C _1-8 alkyl, C _1-8 alkoxy or C _1-8 acyoxy, C _3-6 cycloalkyl or C _1-8 alkoxy, optionally substituted with one or more F, Cl, OH being),

ee) Wherein R ₈₄ is hydrogen or C _1-6 alkyl

ff) substituted or unsubstituted C ₆ -C ₁₀ aryl group,

gg) heterocy, having 1-3 atoms selected from O, N or S, substituted or unsubstituted monocyclic or bicyclic, saturated or unsaturated, in which the ring is bonded to a phenyl substituent via a ring carbon or nitrogen; Clicker,

hh) a heteroatom group having 1-3 atoms selected from O, N or S, in which the ring is bonded to a phenyl substituent via ring carbon or nitrogen and the heteroatom can be added to the fused or benzene or naphthalene ring Is a substituted or unsubstituted monocyclic or bicyclic group;

Substituents for such groups p, q, ff, gg and hh are selected from one or two of the following:

1) halo,

2) C _1-6 alkyl,

3) NO ₂ ,

4) N ₃ ,

5) ,

6) ,

7) formyl,

8) ,

9) ,

10) Wherein heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 heteroatoms selected from O, N or S,

11) ,

12) (Wherein R ₆₀ and R ₆₁ are each independently hydrogen or C ₁ -C ₆ alkyl),

13) OH,

14) hydroxy (C ₁ -C ₆ alkyl),

15) ,

16) (Where r is 1-6),

17) ,

18) -CH ₂ -R ₈₀ , wherein R ₈₀ is

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

b) -SR ₃₂ (where R ₃₂ is as described above),

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

d) 5- or 6-membered heteroaromatic groups having 1-4 O, S or N atoms,

19) (Wherein R ₈₄ is as described above),

20) cyano,

21) carboxyl,

22) CF ₃ ,

23) ,

24) Wherein the phenyl group may be optionally substituted with halo or (C ₁ -C ₆ ) alkyl),

25) (Wherein R ₆₀ and R ₆₁ are as described above),

26) Wherein R ₉₁ is a 5- or 6-membered aromatic heterocyclic group having 1-3 O, N or S,

27) ,

28) (Wherein R ₈₅ is as described above),

29) Wherein R ₉₉ , R ₁₀₀ and R ₁₀₁ are each independently C _1-6 alkyl; or

One of Q and R ₁ and R ₂ together form —O—CH ₂ —O.

The compounds of the present invention are novel substances and represent new species of antimicrobial agents. These have an isoxoxazolinone ring system and are therefore clearly distinguished from both previously known oxazolidinone and isoxazoline antibiotics. In addition, they are completely different from the isoxazolinone herbicides according to the prior art because the ring nitrogen is substituted with an amide group as described above.

The compounds of formula (I) are useful for treating the symptoms of infection of humans and other animals caused by various bacteria, in particular methicillin-resistant Staphylococcus aureus and vancomycin-resistant stoolcocci.

The present invention also includes a method for preparing a pharmaceutical composition comprising the above formula (I) and the compound and a pharmaceutically acceptable carrier or excipient.

Term Definition

As used herein, "pharmaceutically acceptable salts" means non-toxic acid addition salts with inorganic or organic acids, such as hydrochloric acid, phosphoric acid, sulfuric acid, maleic acid, acetic acid, citric acid, succinic acid, benzoic acid, fumaric acid, mandelic acid, and salts with acids such as p-toluene-sulfonic acid, methanesulfonic acid, ascorbic acid, lactic acid, glycolic acid, trifluoroacetic acid, iodic acid, bromic acid and the like.

The term "halo" or "halogen" in the text refers to chloro, bromo, fluoro and iodine, preferably chloro or fluoro.

Aliphatic "alkyl" as used herein means a straight or branched chain having a certain number of carbon atoms, e.g. for C ₁ -C ₆ alkyl, it may have from 1 to 6 carbon atoms. do.

Likewise, "C ₂ -C ₈ alkenyl" refers to at least one double bond alkenyl group having a specific number of carbon atoms, and "C ₂ -C ₈ alkynyl" refers to a specific number of carbon atoms At least one having a triple bond alkynyl group and the like.

Unless otherwise specified, the term "alkoxy" in the text refers to an alkyl group having a certain number of carbon atoms By referring to a substituent of the type, for example, C ₁ -C ₆ alkoxy may have 1-6 carbon atoms. Unless otherwise specified, carbon lengths are included in 1-6 carbon atoms.

Unless otherwise specified, the term "aryl" in the text refers to aromatic carbocyclic rings, ie phenyl and naphthyl.

"Heteroaromatic" herein refers to aromatic heterocyclic groups having one or more atoms selected from O, N, S, such as pyridine, thiophene, furan, pyrimidine, 2-pyridyl, 3-pyridyl, 4 -Pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinoline, 3-quinoline, 1-isoquinoyl, 3-isoquinolyl, 2-imidazolyl, 4-imidazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 30pyrazolyl, 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-5-yl , 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-thiazol-3-yl, 1,2,4-thiazole -5-day, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrole , 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, 5-isothiazolyl and the like.

Saturated or unsaturated heterocyclic groups may have 1-3 atoms selected from O, N, and S, such as dioxolane, imidazolidine, dithiolane, oxathiolane, oxazolidine, piperidinyl, pyre Laginyl, pyrerazinyl, morpholino, or thiomorpholino, or corresponding unsaturated heterocyclic groups.

Nitrogen and / or sulfur atoms usable in such heterocyclic groups may be oxidized and such oxidized compounds are also within the scope of the compounds of formula I of the present invention.

details

One preferred embodiment of the invention is a compound of formula I wherein A is

In formula, Q <_1> , R <_1> and R <_1> are as above-mentioned.

A more preferred example of the invention consists of a compound having the formula (IA) or a pharmaceutically acceptable salt thereof:

Wherein R ₁ is H, C _1-8 alkyl optionally substituted with one or more F, Cl, OH, C _1-8 alkoxy or C _1-8 acyloxy, C _3-8 cycloalkyl, or C _1-8 An alkoxy group;

R ₂ and R ₃ are each independently,

a) H,

b) F,

c) Cl,

d) Br,

e) C _1-6 alkyl,

f) NO ₂ ,

g) I,

h) C _1-6 alkoxy,

i) OH,

j) amino, or

k) cyano; And

Q is

a) hydrogen,

b) halo,

c) NO ₂ ,

d) N ₃ ,

e) C ₁ -C ₆ alkylthio,

f) ,

g) ,

h) C ₁ -C ₆ alkyl,

i) C ₁ -C ₆ alkoxy,

j) formyl,

k) ,

l) ,

m) ,

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

o) ,

p) amino,

q) C ₁ -C ₆ alkylamino-,

r) di (C ₁ -C ₆ alkyl) amino-,

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

t) OH,

u) cyano,

v) hydroxy (C ₁ -C ₆ alkyl),

w) ,

x) (Where r is 1-6),

y) ,

z) ,

aa) Wherein R ₈₄ is hydrogen or C _1-6 alkyl

bb) Wherein R ₈₅ is hydrogen, C _1-8 alkyl, C _1-8 alkoxy or C _1-8 acyoxy, C _3-6 cycloalkyl or C _1-8 alkoxy, optionally substituted with one or more F, Cl, OH being),

cc) (Wherein R ₈₄ is as described above),

dd) ,

ee) ,

ff) ,

gg) ,

hh) ,

ii) ,

jj) ,

kk) ,

ll) ,

mm) ,

nn) ,

oo) Wherein R ₉₂ is H or C _1-6 alkyl

pp) ,

qq) ,

rr) ,

ss) ,

tt) ,

uu) ,

vv) ,

ww) ,

xx) ,

yy) ,

zz) ,

aaa) a diazinyl group, optionally substituted with X and Y,

bbb) triazinyl groups, optionally substituted with X and Y,

ccc) a quinolinyl group, optionally substituted with X and Y,

ddd) a quinooxalinyl group, optionally substituted with X and Y,

eee) a naphthyridinyl group, optionally substituted with X and Y,

fff) ,

ggg) ,

hhh) , or

iii) ego;

B is an unsaturated four-membered linker having one nitrogen atom and three carbons;

M is

a) H,

b) C _1-8 alkyl,

c) C _3-8 cycloalkyl,

d)-(CH ₂ ) _m OR ₆₆ , or

e)-(CH ₂ ) _n NR ₆₇ R ₆₈ ;

Z is

a) O,

b) S or

c) NM;

W is

a) CH,

b) N or

c) O or S when Z is NM;

X and Y are each independently

a) hydrogen,

b) halo,

c) NO ₂ ,

d) N ₃ ,

e) C _1-6 alkylthio,

f) ,

g) ,

h) C ₁ -C ₆ alkyl,

i) C ₁ -C ₆ alkoxy,

j) formyl,

k) ,

l) ,

m) Wherein heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S),

n) ,

o) amino,

p) C ₁ -C ₆ alkylamino-,

q) di (C ₁ -C ₆ alkyl) amino-,

r) (Wherein R ₆₀ and R ₆₁ are each independently hydrogen or C ₁ -C ₆ alkyl),

s) OH,

t) hydroxy (C ₁ -C ₆ alkyl),

u) ,

v) (Where r is 1-6),

w) ,

x) ,

y) (Wherein R ₈₄ is as described above),

z) cyano,

aa) carboxyl,

bb) CF ₃ ,

cc) mercapto,

dd) ,

ee) Wherein the phenyl group may be optionally substituted with halo or C ₁ -C ₆ alkyl

ff) ,

gg) Where R ₈₅ is as described above, or

hh) Wherein R ₉₉ , R ₁₀₀ and R ₁₀₁ are each independently C _1-6 alkyl; or

One of Q and R ₁ and R ₂ together form —O—CH ₂ —O,

R ₆₂ is

a) H,

b) C _1-8 alkyl optionally substituted with one or more halo, or

c) C _1-8 alkyl, or C _1-8 alkoxy, optionally substituted with one or more OH;

E is

a) NR ₆₉ ,

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

c) O;

R ₆₃ is

a) H,

b) C _1-6 alkyl,

c)-(CH ₂ ) _q -aryl, or

d) halo;

R ₆₆ is H or C _1-4 alkyl;

R ₆₇ and R ₆₈ are each independently H or C _1-4 alkyl or NR ₆₇ R ₆₈ is- (CH ₂ ) _m -taken together;

R ₆₉ is

a) H,

b) C _1-6 alkyl,

c)-(CH ₂ ) _q -aryl,

d) -CO ₂ R ₈₁ ,

e) COR ₈₂ ,

f) -C (= O)-(CH ₂ ) _q -C (= O) R ₈₁ ,

g) -S (= 0) _Z- C _1-6 alkyl,

h) -S (= 0) _Z- (CH ₂ ) _q -aryl, or

i)-(C = O) _j -Het, where j is 0 or 1;

Z ₁ is

a) -CH _2- , or

b) -CH (R ₇₀ ) -CH _2- ;

Z is

a) -O ₂ S-,

b) -O-,

c) -S-,

d) -SO-, or

e) -N (R ₇₁ )-;

Z ₃ is

a) S,

b) SO,

c) SO ₂ , or

d) O;

A ₁ is H or CH ₃ ;

A ₂ is

a) H,

b) OH-,

c) CH ₃ CO _2- ,

d) CH _3- ,

e) CH ₃ O-,

f) R ₇₂ O-CH ₂ -C (O) -NH-,

g) R ₇₃ OC (O) -NH-,

h) R ₇₃ -C (O) -NH,

i) (C ₁ -C ₂ ) alkyl-OC (O) —, or

j) HO-CH ₂ ; or

A ₁ and A ₂ taken together

a) or

b) O =;

R ₆₄ 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 is 0, 1, 2, 3, 4 or 5;

w is 1, 2 or 3;

q is 1, 2, 3 or 4;

Z is 0 or 1;

R ₆₅ is

a) R ₇₄ OC (R ₇₅ ) (R ₇₆ ) -C (O)-,

b) R ₇₇ OC (O)-,

c) R ₇₈ (O)-,

d) R ₇₉ -SO _2- , or

e) R ₈₀ -NH-C (O)-;

R ₇₀ is H or (C ₁ -C ₃ ) alkyl;

R ₇₁ is

a) R ₇₄ OC (R ₇₅ ) (R ₇₆ ) -C (O)-,

b) R ₇₇ OC (O)-,

c) R ₇₈ -C (O)-,

d) ,

e) ,

f) H ₃ CC (O)-(CH ₂ ) ₂ -C (O)-,

g) R ₇₉ -SO _2- ,

h) ,

i) R ₈₀ -NH-C (O)-;

R ₇₂ is

a) H,

b) CH ₃ ,

c) phenyl-CH _2- , 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)-;

R ₇₅ and R ₇₆ are each independently H or CH ₃ or R ₇₅ and R ₇₆ taken together are —CH ₂ CH ₂ —;

R ₇₇ is (C ₁ -C ₃ ) alkyl or phenyl;

R ₇₈ is H, (C ₁ -C ₄ ) alkyl, aryl- (CH ₂ ) _{n 1} , ClH ₂ C, Cl ₂ HC, FH ₂ C-, F ₂ HC- or (C ₃ -C ₆ ) cycloalkyl ;

R ₇₉ is CH ₃ , —CH ₂ Cl, —CH ₂ CH═CH ₂ , aryl or —CH ₂ CN;

R ₈₀ is — (CH ₂ ) _n1 -aryl, wherein n ¹ is 0 or 1;

R ₈₁ is

a) H,

b) C _1-6 alkyl optionally substituted with one or more OH, halo or CN,

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

d)-(CH ₂ ) _q -OR ₈₃ where q is as described above;

R ₈₂ is

a) C _1-6 alkyl optionally substituted with one or more OH, halo, or CN,

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

c)-(CH ₂ ) -OR ₈₃ wherein q is as described above;

R ₈₃ is

a) H,

b) C _1-6 alkyl,

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

d) —C (═O) C _1-6 alkyl; And

Aryl is phenyl, pyridyl or naphthyl, wherein the phenyl, pyridyl or naphthyl group may be optionally substituted with one or more halo, —CN, OH, SH, C _1-6 alkoxy or C _1-6 alkylthio.

Another preferred embodiment of the present invention consists of a compound having formula (IA) or a pharmaceutically acceptable salt thereof,

[Formula IA]

Wherein R ₁ is H, C _1-8 alkyl optionally substituted with one or more F, Cl, OH, C _1-8 alkoxy or C _1-8 acyloxy, C _3-8 cycloalkyl, or C _1-8 An alkoxy group;

R ₂ and R ₃ are each independently H or F; Or R ₂ and R ₃ taken together represent the formula:

;

Q is

a) hydrogen,

b) halo,

c) NO ₂ ,

d) N ₃ ,

e) C ₁ -C ₆ alkylthio,

f) ,

g) ,

h) C ₁ -C ₆ alkyl,

i) C ₁ -C ₆ alkoxy,

j) formyl,

k) ,

l) ,

m) ,

n) (C ₁ -C ₆ alkoxy) ₂ N-,

o) 5- or 6-membered heterocyclic groups comprising 1-3 O, N, or S, and bonded with a phenyl substituent via carbon or nitrogen, wherein the heterocyclic group is optionally substituted with R ₉₆ ,

p) ,

q) phenyl optionally substituted with R ₉₆ , or

r) 5- or 6-membered saturated or unsaturated heterocyclic groups containing 1-3 O, N, or S, and bonded with a phenyl substituent via carbon or nitrogen, wherein the heterocyclic group is optionally R ₉₆ Substituted with; And

R ₉₆ is

a) C ₁ -C ₆ alkyl-OH,

b) ,

c) ,

d) cyano,

e) formyl,

f) ,

g) ,

h) (Wherein R ₉₉ , R ₁₀₀ and R ₁₀₁ are each independently C _1-6 alkyl),

i) ,

j) ,

k) (Wherein phenyl may be optionally substituted with halo),

l) ,

m) (C ₁ -C ₆ alkyl) ₂ N-,

n) C ₁ -C ₆ alkyl-NH—,

o) amino,

p) ,

q) , or

r) Wherein R ₉₈ comprises 1-3 O, N, or S, and 5- or 6-membered heteroaryl, or 1-4 O, N or S, bonded to a phenyl group via a ring carbon atom And 5- or 6-membered saturated or unsaturated heterocyclic bonded to a phenyl substituent via a ring carbon atom.

Some of the specific preferred examples of the present invention are shown in Table 1 below.

Compounds of the present invention can be prepared by methods as outlined below.

Those skilled in the art will appreciate that the method as described herein is in fact representative and that other methods may be used.

Isoxazoline 5 of the present invention is preferably prepared via a process as shown in Scheme 1 below. Aryl acetic acid 1 can be prepared using, but not limited to, any of the known methods disclosed in many chemical literatures, including those commercially available or as shown in Schemes 2 or 3 below. Ixoxazolinone 3 is Marcheshi [J. ORg. Chem., 1984, 49, p. 4287-4290. 2 is prepared through the reaction of 1 with sodium hydride and ethyl formate, which is reacted with hydroxyamine to give 3. 3 was treated with a mild base, preferably potassium carbonate, in a suitable solvent, preferably in the presence of dichloromethane or N, N-dimethylformamide, followed by 4 (as disclosed by Barnes et al. In US Pat. No. 5,284,863). Prepared according to the method) to prepare isooxazolinone 5.

Another method for preparing the aryl acetic acid ester 1 of the present invention is shown in the following scheme 2. Triflate 6 (prepared from methyl 4-hydroxyphenyl acetate by known methods known to those skilled in the art) was prepared by Buchwald [Tet. Lett., 1997, 38, p. The ester compound represented by 7 is prepared by treating with N, N-dialkylamine according to the method as disclosed in 6363-6366. Aryl-bromide, -iodide compound, and -chloride are also suitable for replacing triflate 6 in the following scheme 2. The N, N-dialkylamines used in Scheme 2 can be synthesized using commercially available or by methods known in the literature. Known methods for preparing a number of cyclic N, N-dialkylamines are described in detail in Gadwood (WO 97/10223), and various other methods are well known to those skilled in the art.

Another alternative method for preparing the aryl acetic acid ester 1 of the present invention is shown in Scheme 3 below. 8 is treated in a suitable solvent, preferably in the presence of acetonitrile or N, N-dimethylformamide with a mild base, preferably potassium carbonate and primary or secondary amines or thiolates, between about 25 ° C. to 100 ° C. 9 To prepare. The compound 8 can also use a commercial item. Compound 9 is converted to 11 or 12 according to the method disclosed by Gravestock (International Patent 97/14690). This process is also known to those skilled in the art as Willgerodt reactions. In addition, the reaction of converting 11 to 12 can be accomplished by various known methods known in the chemical literature, including, but not limited to, acid treatment in hot-alcohol and the like.

Sulfoxides and sulfones 14 and l16 are described by Barbachyn [J. Med. Chem., 1996, 39, 680-685 and prepared by reacting sulfides 13 and 15 with an oxidizing agent such as m-chloroperoxybenzoic acid or osmium tetraoxide, respectively, according to methods well known to those skilled in the art. .

Another method of preparing compound 18 of the present invention is as shown in Scheme 5 below. 18 is prepared by reacting 17 with an appropriate organotin compound. This method is known to the person skilled in the art as Stille cross-coupling reaction.

The preparation methods of 21, 22, 23 and 24 of the present invention are as shown in Scheme 6 below. 19 is reacted with trifluoroacetic acid to produce 20. Compound 20 is reacted with acid chloride, chloroformate, sulfonyl halide, or isocyanate in the presence of triethylamine according to methods well known in the chemical literature to produce 21, 22, 23 and 24, respectively.

Triazole-substituted compounds 27 and 28 are prepared by cycling the azide 25 with acetylene 26 (Scheme 7). This is a standard 3 + 2 cycling reaction well described in the chemical literature. Acetylene 26 can be purchased commercially or prepared according to literature methods. For example, cyanoacetylene is described in Murahashi [J. Chem. Soc. Jap., 1956, 77, 1689. This cycling reaction was usually carried out at temperatures between 25 ° C. and 80 ° C., under suitable solvents such as DMF. In addition, suitable solvents include, but are not limited to, DMSO, NMP, and DMA. Two cycling reaction adducts 27 and 28 were isolated using preparative HPLC or triturating with a suitable solvent such as ethylene acetate. Suitable solvents for mastication include, but are not limited to, methanol, ethanol, diethyl ether and acetone.

Azidophenylisoxazolinone 25 was reacted with aminophenylisooxazolinone through one of a number of methods well known in the chemical literature, including reaction with tin chloride in a suitable solvent such as a 2: 1 combination of ethyl acetate and methanol. It is not limited to this method. Aminophenylisooxalinone 29 is reacted with 2,5-dimethoxytetrahydrofuran 30 under acetic acid to give pyrrole-substituted isoxoxazolinone 31 (Scheme 8). Subsequent conversion reactions of the pyrroles are also possible, for example by preparing the corresponding oximes under reflux with 50% aqueous hydroxylamine solution in methanol.

N-thioacetate 33 can be prepared from the corresponding N-acetate 32 using a number of known literature methods, for example by refluxing under benzene with Lawesson reagent. Other solvents such as toluene and xylene are also suitable.

It is well known to those skilled in the art that when the substituents used in the reactions include certain reaction-sensitive functional groups that may cause undesirable side reactions, such substituents may be substituted with conventional protecting groups. Suitable protecting groups and thus deprotecting reactions are disclosed, for example, in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons, 1991). Such "protective group substituted" intermediates and end-products may be considered to be within the scope of the description and claims of the present invention.

Some of the preferred end-products of Formula (I) above include amines. In such cases, the final product can be recovered in the form of a pharmaceutically acceptable acid addition salt, for example by adding a suitable acid such as HCl, HI, or methane-sulfonic acid to the amine.

It will be appreciated that certain products falling within the scope of Formula I may have substituents capable of forming optical isomers. The invention can be said to include all such optical isomers and epimer mixtures thereof, ie R- or S- or racemic forms, in their scope.

The compounds of the present invention are particularly useful for having pharmacological activity in animals, including mammals and, more particularly, humans. The novel isooxazolinone derivatives of formula (I), or pharmaceutically acceptable salts or prodrugs thereof, have effective antibiotic activity against Gram-positive bacteria. These include, for example, animal feed additives that promote growth, as food preservatives, for example in aqueous paints and as bactericides for industrial use in the foaming water of paper mills to inhibit the growth of harmful bacteria, and for medical devices and While they may be used as fungicides to inhibit or destroy the growth of harmful bacteria on dental tools, they are particularly useful for treating bacterial infections in humans and other animals caused by Gram-positive bacteria sensitive to new derivatives. The pharmaceutically active compound of the present invention may be used alone or in combination as a pharmaceutical composition containing a pharmaceutically acceptable carrier or excipient in addition to the active isoxazolinone component. These compounds can be administered in a variety of ways, such as by oral administration, topical administration or parenteral administration (intravenous or intramuscular injection) and the like. The pharmaceutical composition may be in solid form, such as capsules, tablets, powders, etc., or in liquid form, such as solutions, suspensions, or emulsions. Injectable compositions may be prepared in unit dosage form, in ampoules or in multidose dosage forms, and may include additives such as suspensions, stabilizers and dispersants. The compositions may be in powder form or instant-use form, which may be remixed at the time of administration with a suitable excipient such as sterile water.

Thus, another feature of the present invention is that it provides a method for treating bacterial infections comprising administering a therapeutically effective amount of the compound to a host, in particular a mammalian host and more particularly to a human patient. Also provided is the use of the compound of the invention as a medicament and the use of the compound of the invention in the manufacture of a medicament for the treatment of bacterial infections.

Dosage depends greatly on the specific compound employed, the specific composition formulated, the route of administration, the nature and condition of the host, and the organism and specific location to be treated. Thus, the choice of specific preferred dosage and route of application is at the discretion of the physician or veterinarian. Generally, however, the compounds of the present invention can be administered orally or parenterally to mammalian hosts in an amount of about 25 mg / day to 2 g / day.

The preparation method of the pyrazole substituted compound is outlined in Scheme 10 below. Following diazotization of compound 29, reduction is via one of a number of methods well known in the chemical literature, including reaction with tin chloride and sodium nitrile to form hydrazine hydrochloride 34, but is not limited to this method. . 34 is ethoxycarbonylmalondialdehyde, cyanomalondialdehyde [Bertz, S.H., Dabbagh, G and Cotte, P. J. Org. Chem., 1982, 47, p. 2216], or malondialdehyde [Martinez, A.M., Cushmac, G.E., Rocek, J. J. Amer. Chem. Soc., 1975, 97, p.6502] in the presence of sodium bicarbonate at room temperature to give compound 35.

In vitro activity

From the sample of compounds prepared in Examples 1-97 following dissolution in water and diluted in Nutrient Broth, the following range of minimum inhibition against the described microorganisms, as determined by tube dilution: It was found that the concentration (MIC) appeared. This MIC was measured using a broth micro dilution assay as recommended by the National Council for Clinical Trial Standards (NCCLS) in the United States. Mueller-Hinton medium was used except for Streptococci tested on Todd Hewitt broth. The final bacterial inoculation contained about 5 × 10 ⁵ cfu / mL and the plates were incubated for 18 hours at 35 ° C. in air (streptococcus under 5% CO ₂ ). MIC refers to the optimal drug concentration that inhibits visible growth.

microbe MIC value (µg / mL) Streptococcus pneumoniae A9585 ≤ 8 Fecal enterococci A20688 ≤ 16 Staphylococcus aureus A15090, penicillinase positive ≤ 16

Representative Example

The following examples are intended to illustrate the invention and are not intended to limit the invention thereto. Abbreviations used in the examples are common abbreviations well known to those skilled in the art. Some of the abbreviations are as follows:

In the following examples, all temperatures are brow seed temperatures. The melting point was measured on the heating device and was not calibrated. Proton and carbon-13 nuclear magnetic resonance ( ¹ H and ¹³ C) spectra were measured with Bruker AM-300 or Varian Gemini 300 spectrometers. All spectra were measured under CDCl ₃ , DMSO-d ₆ , CD ₃ OD or D ₂ O unless otherwise noted. Chemical shifts were measured in units of delta relative to tetramethylsilane (TMS) or reference solution peaks, and interproton coupling constants were expressed in hertz (Hz). The splitting pattern is shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad peak; dd, doublet of doublets; doublet of dt triplets; And app d, apparent doublet, etc. The infrared spectrum was measured in the range of 4000 cm ^-1 to 400 cm ^-1 using a Perkin-Elmer 1800 FT-IR spectrometer and calibrated to 1601 cm ^-1 absorption of polystyrene film, expressed in inverse centimeters (cm ^-1 ). It was. Mass spectra were measured using direct chemical ionization (DCI, isobutene), rapid atomic flame ionization (FAB), or electron ion spray (ESI) with a Kratos MS-50 or Finnegan 4500 device. Ultraviolet spectra were measured with a Hewlett Packward 8452 diode stack photometer under the indicated solvent.

Analytical thin layer chromatography (TLC) was measured on silica gel plates (60F-254) and visualized using dyeing by heating with UV light, iodine vapor, and / or methanolic phosphomolybdic acid. Column chromatography, described by flash chromatography, was also performed in glass columns using silica gel finely divided under a pressure above some atmospheric pressure with the solvent indicated. Reversed phase analytical thin layer chromatography was performed on precoated reversed phase plates and visualized using UV light and iodine vapor.

<Example 1>

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

A. Ethyl 4-methylthiophenylacetate

A catalytic amount of concentrated sulfuric acid was slowly added dropwise to a solution of 4-methylthiophenylacetic acid (1.0 g, 5.48 mmol) in 55 mL of ethanol. The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was partitioned between methylene chloride and sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 1.1 g of a colorless oil (96%).

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

A suspension of NaH (0.84 g, 20.8 mmol) was added to a solution of ethyl 4-methylthiophenylacetate (1.1 g, 5.2 mmol) in ethyl formate (20 mL) at room temperature. After stirring the mixture to room temperature for 1 hour, cold 0.5 N HCl (20 mL) was added slowly dropwise. Thereafter, the crude reactant was extracted with ether, the organic layer was washed with sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated to give 1.2 g of ethyl 4-methylthio-α-formyl-phenylacetate as colorless oil. It was produced on a daily basis and used in the next step without further purification.

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

To a solution of 4-methylthio-α-formyl-phenylacetate in 20 mL of methanol and 1 mL of water, hydroxylamine hydrochloride (0.54 g, 7.8 mmol) was added. The mixture was refluxed for 1 hour. After evaporation of the solvent, the residue was triturated with water to give a precipitate, followed by further etherification to yield 0.48 g of a pale yellow solid (two steps, 44%).

D. N-[[4- (4-methylthiophenyl) -5-oxo-2-isooxazolinyl] methyl] acetamide

To a solution of 4- (4-methylthio) -phenylisoxazolin-5-one (0.2 g, 0.97 mmol) in 10 mL of methylene chloride, potassium carbonate (0.67 g, 4.85 mmol) and N- (hydroxymethyl) Acetamide acetate (0.64 g, 4.85 mmol) was added. The mixture was stirred at rt for 18 h. Then poured into 10 mL of 1N HCl and extracted three times with chloroform. Thereafter, the organic layer was washed with sodium bicarbonate, brine, dried over magnesium sulfate and concentrated after filtration to give a dark coppery solid which was then recrystallized from hexane / chloroform. The resulting solid was further triturated with ether to give 0.186 g (69%) of a dark coppery solid.

<Example 2>

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

N-{[4- (3-fluoro-4-morpholin-4-ylphenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (200 mg, 0.60 in 50 mL of methanol) mmol) was added magnesium monoperoxyphthalate (300 mg, 0.60 mmol). After 2 hours at room temperature, the white precipitate was filtered off and the filtrate was concentrated. The resulting residue was pressurized through a basic alumina layer with dichloromethane. The eluate was concentrated and recrystallized from dichloromethane / hexanes to give 162 mg (44%) of the title compound as a brown solid.

<Example 3>

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

To N-({4- [4- (methylsulfinyl) phenyl] -5-oxo-2-hydroisoxazol-2-yl} methyl) acetamide (1.0 g, 3.6 mmol) in 50 mL of chloroform at 0 ° C. , M-CPBA (1.12 g, 3.6 mmol) in 30 mL of chloroform was added via syringe pump for 2 hours. Saturated sodium bicarbonate was added and the reaction mixture was vigorously stirred for 10 minutes, at which time it was poured into saturated sodium bicarbonate and 4: 1 chloroform: methanol. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was triturated with ether to give 800 mg (79%) of the desired compound as a colorless solid.

<Example 4>

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

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

Example 5

N-({4- [4- (1,1-dioxo (1,4-thiazaperhydroin-4-yl))-3-fluorophenyl] -5-oxo-2-hydroisoxazole-2 -Yl} methyl) acetamide

N-{[4- (3-fluoro-4- (1,4thiazaperhydroin-4-yl) phenyl) -5-oxo-2-hydroisoxazole- in 2 mL of water and 8 mL of acetone. After addition of N-methylmorpholine N-oxide (98 mg, 0.85 mmol) to 2-yl] methyl} acetamide (100 mg, 0.29 mmol), osmium tetraoxide (2.5 wt% isopropanol solution; 7 μL; 0.07 mmol) was added. 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 concentrated to give 85 mg (77%) of the title compound as a colorless solid.

<Example 6>

4- (3-fluoro-4-morpholin-4-ylphenyl) -2 {[(thiooxoethyl) amino] methyl} -2-hydroisoxazol-5-one

N-{[4- (3-fluoro-4-morpholinylphenyl-5-oxo-2-isooxazolinyl] methyl} acetamide (0.25 g, 0.75 mmol) in a 10 mL solvent of benzene and Lowesson reagent (Lawesson's reagent: 0.4 g, 1.0 mmol) was heated to reflux for 3 hours, after which the mixture was concentrated under reduced pressure, the residue was eluted with methylene chloride and ethyl acetate and purified by silica gel chromatography. A colorless solid was produced.

<Example 7>

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

N-{[4-phenyl-5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (3.0 g, 12.9 mmol) and aluminum (III) chloride (13.8) under 150 mL of 1,2-dichloroethane. acetyl chloride (7.3 mL, 103.4 mol) was added dropwise over 10 minutes. The resulting red mixture was heated to 80 ° C. for 3 hours, cooled to room temperature and placed in a rapid stirred mixture of 20% methanol / chloroform and 1N hydrochloric acid in an ice bath for 10 minutes. The mixture was poured into a separatory funnel and the layers separated. The water layer was extracted twice with 20% methanol / chloroform and the combined organic layers were washed with 1N aqueous sodium hydroxide solution, saturated sodium bicarbonate and brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated to afford an amorphous yellow solid, which was dissolved in 20% methanol / chloroform. Ether was added and the mixture was left at 0 ° C. for 18 hours. The resulting precipitate was filtered to give 2.48 g (70%) of the title compound as a pale pink solid.

<Example 8>

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

N-{[4- (4-acetylphenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (2.0 g, 7.3 mmol) and 50% hydroxylamine (1.0 mL, 14.6 mmol ) Was heated to reflux for 1.5 hours, concentrated to near dryness and redissolved in 20% methanol / chloroform. Hexane was added until the solution was cloudy and the mixture was left at 0 ° C. for 3 hours. The precipitate was filtered off to give 1.42 g (67%) of the title compound as a pale yellow solid.

Example 9

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

N-{[4- (4-iodinephenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (300 mg, 0.84 mmol) under 5 mL DMF, 2-tributyltinfuran ( 0.26 mL, 0.84 mmol), tris (dibenzylideneacetone) dipalladium (0) (77 mg, 0.08 mmol), triphenylarcin (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) Nitrogen was bubbled into the mixture. The reaction mixture was capped and stirred at room temperature for 8 hours, diluted with 20% methanol / chloroform, filtered through celite and concentrated. The residue is suspended in chloroform, passed through frit, loaded onto a Biotage Flash 40i Chromatography Module (12M), eluted with 50% hexanes / ethylacetate and the resulting solid is triturated with chloroform / ether. 132 mg (53%) of the title compound were obtained as a colorless solid.

<Example 10>

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

N-{[4- (4-iodinephenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (300 mg, 0.84 mmol) under 5 mL DMF, 2-tributyltinthiophene (0.27 mL, 0.84 mmol), tris (dibenzylideneacetone) dipalladium (0) (77 mg, 0.08 mmol), triphenylarcin (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) Nitrogen was bubbled into the mixture. The reaction mixture was capped and stirred at room temperature for 8 hours, diluted with 20% methanol / chloroform, filtered through celite and concentrated. The residue was suspended in chloroform, loaded on a Biotage Flash 40i Chromatography Module via frit, eluted with 15% acetone / chloroform and the resulting solid was triturated with chloroform / ether to give 165 mg (63%) of the desired compound. ) Was obtained as a colorless solid.

<Example 11>

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

N-{[4- (4-iodinephenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (300 mg, 0.84 mmol) under 2-mL DMF, 2- (tributyltin) -5,6-dihydro- [1,4] -dioxine (346 mg, 0.92 mmol), tris (dibenzylideneacetone) dipalladium (0) (77 mg, 0.08 mmol), triphenylarcin (51 mg, 0.17 mmol), and a mixture of lithium chloride (106 mg, 2.51 mmol) were bubbled with nitrogen. The reaction mixture was capped and stirred at room temperature for 16 hours, diluted with 20% methanol / chloroform and 10% aqueous potassium fluoride solution was added and the mixture was stirred vigorously for 1 hour. The reaction mixture was filtered through celite and concentrated. The resulting black oil phase was dissolved in 20% methanol / chloroform and adsorbed onto silica gel and loaded into the Biotage Flash 40i Chromatography Module SIM. Chromatography was performed by eluting with 20% acetone / chloroform using a 12M silica gel cartridge, and the resulting brownish oily phase was triturated with ether to give 115 mg (44%) of the target compound as a dark coppery solid.

<Example 12>

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

N-{[4- (4-iodinephenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (300 mg, 0.84 mmol) under 2-mL DMF, 2- (tributyltin) Pyrazine (340 mg, 0.92 mmol), tris (dibenzylideneacetone) dipalladium (0) (77 mg, 0.08 mmol), triphenylarcin (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol Nitrogen was bubbled through a mixture of The reaction mixture was cappped and stirred at room temperature for 16 hours, diluted with 20% methanol / chloroform, 10% potassium fluoride was added and the mixture was vigorously stirred for 1 hour. The reaction mixture was filtered through celite and concentrated. The resulting black oil phase was dissolved in 20% methanol / chloroform and adsorbed onto silica gel and loaded into the Biotage Flash 40i Chromatography Module SIM. Chromatography was performed by eluting with 25% acetone / chloroform using a 12M silica gel cartridge, and the resulting brownish oily phase was triturated with ether to give 52 mg (44%) of the title compound as a colorless solid.

Example 13

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

N-{[5-oxo-4- (piperazinylphenyl) -2-hydroisooxazol-2-yl] methyl} acetamide trifluoroacetate salt under 2 mL of dimethylformamide and 10 mL of dichloromethane (0.43 g) , 1.0 mmol) was added triethylamine (0.7 mL, 0.5 mmol), followed by (t-butyldimethylsiloxy) acetyl chloride (1.0 g, 4.8 mmol). The resulting mixture was stirred at room temperature for 1.5 hours, then partitioned between dichloromethane and water. The organic layer was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated. The residue was triturated with ether to yield 0.24 g (49%) of the target compound.

<Example 14>

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

N-{[5-oxo-4- (4- {4- [2- (1,1,2,2-tetramethyl-1-silapropoxy) acetyl] piperazinyl} phenyl under 4 mL of dichloromethane 4 mL of trifluoroacetic acid was added to -2-hydroisooxazol-2-yl] methyl} acetamide (0.3 g, 0.6 mmol). After 1 hour, the reaction was concentrated and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was triturated with ether to give 92 mg (40%) of the target compound.

<Example 15>

N-{[4- (4-azidophenyl) -2-hydroisooxazol-2-yl] methyl} acetamide

Prepared from ethyl 4-azidophenylacetate according to the general route as shown in Scheme 1 above. Starting material was prepared as follows.

Ethyl 4-azidophenyl acetate

According to the general method of Marchesini (J. Org. Chem., 49, p.4287-4290, 1984), sodium nitrile (38 g, 0.56 mol) was added ethyl 4-aminophenylacetate (25 g, 0.14) under 700 mL TFA. mol) was added to the cold stirring mixture. After completion of the dropwise, the reaction was stirred for an additional 0.5 hour at 0 ° C., and then sodium azide (27 g, 0.42 mol) was slowly added dropwise over 0.5 hour. The mixture was stirred for additional 2 h at 0 ° C., then quenched with ice water and the product extracted with EtOAc. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated to give 26.5 g (90%) of the title compound as a white solid.

<Example 16>

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

N-{[4- (4-azidophenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (80 mg, 0.29 mmol) under 3 mL DMF and propazyl alcohol (0.1 mL , 1.71 mmol) was heated to 100 ° C for 10 h. Thereafter, the reaction mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel: EtOAc, eluted sequentially with 10% MeOH / EtOAc) to give 62 mg of a yellow solid. ¹ H NMR spectra showed that this crude product was a mixture of two triazole isomers. These isomers were separated by preparative HPLC (H ₂ O / MeOH) to give 10 mg (10%) of the title compound as a white solid.

<Example 17>

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

N-{[4- (4-azidophenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (80 mg, 0.29 mmol) and methyl propionate (0.05 under 3 mL of DMF) mL, 0.58 mmol) was heated to 54 ° C for 24 h. Thereafter, the reaction mixture was concentrated under reduced pressure and triturated with EtOAc to yield 25 mg (24%) of the target compound as a yellow solid (another more reliable method was to carry out the reaction for 10 days at room temperature, then as described above). Same purification process).

Example 18

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

N-{[4- (4-azidophenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (100 mg, 0.36 mmol) and 3-butyn-2- under 3 mL DMF. Warm (0.035 mL, 0.72 mmol) was heated to 50 ° C. for 24 h. The reaction mixture was then concentrated under reduced pressure and triturated with EtOAc to give 60 mg (49%) of the title compound as a yellow solid.

Example 19

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

N-{[4- (4-azidophenyl) -5-oxo-2-hydroisooxazol-2-yl] methyl} acetamide (500 mg, 1.83 mmol) and 5 mL cyanoacetylene under 5 mL DMF. Murahaxhi, S .; Takizawa, T .; Kurioka, S .; Maekawa, S .; J. Chem. Soc. Jap., 77, p. 1689, prepared as disclosed in 1956, was heated to 50 ° C. for 48 hours. After cooling, the precipitated solids were collected by filtration and washed with DMF to give 375 mg (63%) of the title compound as a white solid.

Example 20

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

SnCl _{2 in} N-{[4- (4-azidophenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide (3 g, 10.98 mmol) under 40 mL of EtOAc and 20 mL of MeOH. 2H ₂ O (12.5 g, 54.9 mmol) was added. After all the solids had dissolved, the reaction mixture was concentrated under reduced pressure and neutralized with a saturated aqueous solution of sodium bicarbonate. The mixture was concentrated under reduced pressure again and the residue was dissolved in a mixture of 4: 1 CHCl ₃ / MeOH. The resulting solution was filtered through celite and the insoluble material was discarded. The filtrate was then concentrated under reduced pressure to give 3 g (100%) of the title compound as a yellow solid.

Example 21

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

2,5-dimethoxy in N-{[4- (4-azidophenyl) -5-oxo-2-hydroisooxazol-2-yl] methyl} acetamide (200 mg, 0.81 mmol) under 3 mL of acetic acid. 3-tetrahydrofurancarboaldehyde (184 mg, 1.27 mmol) was added. The mixture was refluxed for 0.5 h and then concentrated under reduced pressure to afford the crude product. Purification by silica gel chromatography (EtOAc, eluting sequentially with 8% MeOH in EtOAc) gave 240 mg (91%) of the title compound as a yellow solid.

<Example 22>

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

The compound is 2,5-dimethoxy-3-tetrahydrofurancarbo from N-{[4- (4-aminophenyl) -5-oxo-2-hydroisoxazol-2-yl] methyl} acetamide N-({4- [4- (3-formylpyrrolyl) phenyl] -5-oxo-2-hydroisoxazole, except that 2,5-dimethoxy-3-tetrahydrofuran was used instead of aldehyde. 2-yl} methyl) acetamide was prepared as described above.

<Example 23>

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

N-({4- [4- (3-formylpyrrolyl) phenyl] -5-oxo-2-hydroisoxazol-2-yl} methyl) acetamide (100 mg, 0.30 mmol) under 50 mL MeOH and 50 A mixture of aqueous solution of% NH ₂ OH (40 mg, 0.60 mmol) was heated to reflux for 2 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, and the residue was triturated with ether to give 96 mg (94) of the target compound as a yellow solid.

<Example 24>

t-butyl 4- (4- {2-[(acetylamino) methyl] -5-oxo-2-hydroisooxazol-4-yl} phenyl) piperazine carboxylate

N- (hydroxymethyl) in t-butyl 4- [4- (5-oxo-2-hydroisooxazol-4-yl) phenyl] piperazinecarboxylate (1.5 g, 4.3 mmol) under 35 mL of dimethylformamide. Acetamide acetate (2.9 g, 22.0 mmol) was added followed by potassium carbonate (3.0 g, 22.0 mmol). After 5 hours, the reaction mixture was poured into ice water. After 18 hours had elapsed, the precipitate was filtered and dried under reduced pressure to obtain 1.4 g (77%) of the title compound.

Starting materials were prepared as follows:

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

The flask filled with cesium carbonate (4.6 g, 14.0 mmol), palladium (II) acetate (0.07 g, 0.3 mmol), and (S) -BINAP (0.28 g, 4.5 mmol) was depressurized and flushed with dry nitrogen. ) Methyl 2- {4-[(trifluoromethyl) sulfonyloxy] phenyl} acetate (3.0 g, 10.0 mmol) and t-butyl-1-piperazinecarboxylate (2.3 g, 12.0 mmol) under 20 mL of toluene. Was added in a syringe, and the resulting mixture was stirred at room temperature for 30 minutes and at 80 ° C. for 16 hours. The heating bath was removed from the reaction mixture, concentrated and chromatographed (0-30% ethyl acetate / hexane) on silica gel to give 1.7 g (50%) of the title compound.

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

Dissolve 60% in sodium hydride (mineral oil) in methyl 2- (4- {4-[(t-butyl) oxycarbonyl] piperazinyl} phenyl) acetate (0.67 g, 2.0 mmol) in 8 mL of ethyl formate. Water) (0.32 g, 8.0 mmol) was added in portions. After 1.5 hours had elapsed, 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. This crude product was used directly in the next step without further purification.

t-butyl 4- [4- (5-oxo-2-hydroisoxazol-4-yl) phenyl] piperazincarboxylate

Hydroxyl in ethyl 2- (4- {4-[(t-butyl) oxycarbonyl] piperazinyl} phenyl) -3-oxopropanoate (7.8 g, 20.7 mmol) in 140 mL methanol and 40 mL water. Amine (50% aqueous solution, 3.0 mL, 49.0 mmol) was added. The reaction mixture was heated to reflux for 3 hours, cooled and concentrated. The residue was triturated with water, the precipitate was filtered, dried and washed with ether to give 4.3 g of the desired compound. The aqueous solution was frozen to further obtain 1.5 g of the target compound.

<Example 25>

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

T-butyl 4- (4- {2-[(acetylamino) methyl] -5-oxo-2-hydroisoxazol-4-yl} phenyl) piperazine carboxylate (0.3 g, 0.7 in 5 mL of dichloromethane) mmol) was added 2 mL of trifluoroacetic acid. After 30 minutes, the reaction mixture was concentrated and triturated with ether to give 0.3 g (97%) of the title compound.

Example 26

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

Prepared according to the general procedure as shown in Schemes 1, 3 and 6. Starting materials were prepared as follows:

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

To the 4- [2-fluoro-4- (2-morpholin-4-yl-2-thiooxoethyl) phenyl] piperazinecarboxylate (4.2 g, 10 mmol), 22 mL of concentrated hydrochloric acid was added at 0 ° C. It was. The resulting mixture was heated to reflux for 1.5 hours, cooled to 0 ° C., and the pH was adjusted to 14 by addition of 23 mL of 10N sodium hydroxide. Then 50 mL of water was added and di-t-butyl dicarbonate (5.6 g, 26.0 mmol) in 5 mL was added. The resulting mixture was stirred at 0 ° C. for 30 minutes, at room temperature for 1 hour, and diluted with 200 mL of water. Thereafter, 5 mL of sodium hydroxide was added to bring the pH to 14, and the reaction mixture was extracted with ether. The water layer was acidified to pH 3 with careful addition of 6N hydrochloric acid and then extracted three times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The resulting residue was dissolved in dichloromethane and hexane and hexane was added to form a precipitate which was collected by filtration to give 3.0 g (89%) of the title compound.

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

Trimethylsilyldiazo in 2- (4- {4-[(t-butyl) oxycarbonyl] piperazinyl} -3-fluorophenyl) acetic acid (0.3 g, 1.0 mmol) in 2 mL methanol and 7 mL benzene. Methane (0.65 mL, 1.30 mmol) was added. After stirring for 1 hour at room temperature, the reaction mixture was concentrated to give 0.36 g (99%) of the title compound.

Example 27

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

Prepared according to the general procedure as shown in Schemes 1 and 2. Starting materials were prepared as follows:

Methyl-4- (trifluoromethylsulfonyloxy) phenyl acetate

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

Methyl-4-morpholinophenyl acetate

Methyl-4- (trifluoromethylsulfonyloxy) phenyl acetate (1.0 g, 3.35 mmol) in 8 mL toluene, cesium carbonate (1.6 g, 4.69 mmol), palladium (II) acetate (22 mg, 0.10 mmol), Nitrogen was bubbled into a mixture of (S) -BINAP (93 mg, 0.15 mmol), and morpholine (0.35 mL, 4.02 mmol) and the reaction mixture was heated to 80 ° C for 6 h. Thereafter, the reaction was cooled and celite was added to concentrate the mixture. On the Biotage Flash 40i Chromatography Module, the SIM was loaded with dry celite and eluted with 20% ethyl acetate / hexanes (40S cartridge) to perform chromatography and 250 mg (37%) of the desired compound as a yellow oil phase. .

<Example 28>

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

Prepared according to the general procedure as shown in Schemes 1 and 3. Starting materials were prepared as follows:

4-thiomorpholinoacetophenone

To 4-fluoroacetophenone (20 g, 145 mmol) in 100 mL of dimethylformamide was added potassium carbonate (39 g, 580 mmol) and thiomorpholine (87 mL, 870 mmol). The reaction mixture was heated to reflux and after 24 hours, cooled to room temperature and partitioned into water and dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in ether and precipitated with hexanes to give 31 g (96%) of the title compound as a yellow solid.

4-thiomorpholinophenylthioacetomorpholide

A mixture of 4-thiomorpholinoacetophenone (30 g, 136 mmol), morpholine (16 mL, 180 mmol) and sulfur (6 g, 180 mmol) was heated to reflux for 6 hours, cooled to 50 ° C and , 100 mL of 1: 1 hexanes: ethyl acetate was added. The reaction mixture was again refluxed for 30 minutes and cooled to recover the resulting orange precipitate through filtration. This precipitate was washed with additional 1: 1 ether / hexanes to afford 31 g (73%) of the desired compound as an yellow-orange solid.

Ethyl-4-thiomorpholinophenyl acetate

1: 1 ethanol: A solution of 4-thiomorpholinophenylthioacetomorpholide (30 g, 93.2 mmol) in 70 mL of sulfuric acid was heated to reflux for 18 hours and cooled to room temperature to give solid sodium bicarbonate Slowly added to the reaction until reaching 7. The reaction mixture was extracted with chloroform, the organic layer washed with brine, dried over magnesium sulfate, filtered and concentrated to give a yellow residue. This residue is then dissolved in chloroform, loaded onto a Biotage Flash 40i Chromatography Module (40M cartridge) and chromatographed with 10% ethyl acetate / hexanes to give 12 g (51%) of the desired compound as yellow. Obtained as an oil phase.

<Example 29>

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

Prepared according to the general procedure as shown in Schemes 1 and 3. Starting materials were prepared as follows:

3-fluoro-4-methylthioacetophenone

To 3,4-difluoroacetophenone (30 g, 192 mmol) in 200 mL of dimethylsulfoxide was added sodium thiomethoxide (15 g, 211 mmol). The reaction mixture was heated to 150 ° C. for 2 hours and then partitioned between ethyl acetate and sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate and precipitated with hexanes. The precipitate was recovered by filtration 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 to reflux for 4 hours, and 50 ° C. Was cooled down and 1: 1 hexanes: ethyl acetate was added. The reaction mixture was again refluxed for 30 minutes, cooled to room temperature and the resulting orange precipitate was recovered by filtration. This precipitate was washed with additional 1: 1 hexanes / ether to give 10.1 g (73%) of the desired compound as a yellow-orange solid.

3-fluoro-4-methylthiophenylacetic acid

500 mL of 10% potassium hydroxide was added to 3-fluoro-4-methylthiophenylthioacetomorpholide (2.6 g, 90.9 mmol). The reaction mixture was heated to reflux for 3 hours, cooled to room temperature and adjusted to pH 4 by careful addition of 2N hydrochloric acid. After the aqueous solution was extracted with dichloromethane, the organic layer was extracted with 200 mL of 10% potassium hydroxide. Thereafter, 2N hydrochloric acid was slowly added to the aqueous layer to pH 4 and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 10.0 g (55%) of the title compound as a brown oil.

<Example 30>

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

It was prepared according to the general procedure as shown in Scheme 1 above. Starting materials were prepared as follows:

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

To ethyl- (3-fluoro-4-hydroxy) phenyl acetate (2.5 g, 8.9 mmol) in 20 mL of acetone was added potassium carbonate (3.4 g, 24.2 mmol) and methane iodide (1.5 mL, 24.2 mmol). The reaction mixture was heated to reflux for 2 hours, cooled and partitioned between saturated sodium bicarbonate and ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 2.3 g (88%) of the title compound as a yellow oil.

<Example 31>

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

N-[(4- {4- [3-((hydroxyimido)] methyl) pyrrolyl] phenyl} 5-oxo-2-hydroisoxazole-2- in 3 mL of CH ₃ CN and 1 mL of CCl ₄ . To the mixture of I) methyl] acetamide (100 mg, 0.29 mmol) was added polymer-bound triphenylphosphine (400 mg, 1.2 mmol), and the mixture was heated to reflux for 8 hours. Thereafter, it was dissolved in ethyl acetate, filtered and concentrated to give a yellow solid. This solid was then triturated with ether to give 30 mg (32%) of the title compound as a yellow solid.

<Example 32>

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

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

<Example 33>

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

N-({4- [4- (3-formylpyrrolyl) phenyl] -5-oxo-2-hydroisoxazol-2-yl} methyl] acetamide (100 mg, 0.30 mmol) in 3 mL of EtOH A mixture of tic hydrazide (28 mg, 0.38 mmol) was heated to reflux for 1 hour The reaction was cooled to room temperature and the yellow solid was recovered by filtration to give 80 mg (36%) of the desired compound: (M ⁺ H ⁺ ) = 382.

<Example 34>

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

Sodium carbonate (150 mg, 0.5 mmol) in N-{[4- (4-hydrazinylphenyl) -5-oxo-2-hydroisooxazol-2-yl} methyl] acetamide hydrochloride (150 mg, 0.5 mmol) in 3 mL methanol. 50 mg, 0.6 mmol) and ethoxycarbonylmalondialdehyde (75 mg, 0.52 mmol) were added. The mixture was stirred at rt overnight. After recovering the solid through filtration, it was washed with water and dried to give 140 mg of a purple solid. The crude product was purified by silica gel chromatography (eluted sequentially with ethyl acetate, 55 methanol / ethyl acetate) to give 123 mg (66%) of the title compound as a yellow solid.

The starting material, N-{[4- (4-hydrazinylphenyl) -5-oxo-2-hydroisooxazol-2-yl} methyl] acetamide hydrochloride, was prepared as follows. Sodium nitrile (112 mg, 1.6 mmol) in 2 mL water was diluted with N-{[4- (4-aminophenyl) -5-oxo-2-hydroisoxazol-2-yl} methyl] acet in concentrated hydrochloric acid at 0 ° C. To a solution of amide (400 mg, 1.6 mmol) was added over 5 minutes. The reaction was stirred for an additional 10 minutes at 0 ° C., then SnCl ₂ · 2H ₂ O (720 mg, 3.2 mmol) in 2 mL concentrated hydrochloric acid was added. The mixture was stirred at rt for 3 h. After that, the reaction mixture was filtered to recover as a yellow solid, washed with 3 mL of water and dried to give 260 mg (55%) of the title compound.

<Example 35>

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

To a mixture of N-{[4- (4-hydrazinylphenyl) -5-oxo-2-hydroisooxazol-2-yl] methyl} acetamide hydrochloride (50 mg, 0.17 mmol) in 2 mL methanol 20 mg (0.24 mmol) of carbonate and cyanomalondialdehyde (30 mg, 0.3 mmol) were added. This mixture was stirred overnight at room temperature. Thereafter, the mixture was concentrated and washed with water and then with methanol to give 42 mg (76%) of the title compound as a yellow solid.

Method for preparing cyanomalon dialdehyde. To the dried flask was added sodium hydride (0.82 mg, suspended in 50% mineral oil, 17 mmol). After washing this sodium hydride three times with 15 mL of ether, 15 mg of ether was added to this flask. It was. After cooling the slurry to 0 ° C., ethyl formate (10.4 g, 140 mmol) was added. To this mixture was added 3,3-diethoxypropionitrile (2 g, 14 mmol) in 10 mL of ether over 2 hours (using a syringe pump). The mixture was stirred at rt for 20 h and then poured into 100 mL of ice water. After this solution was extracted three times with ether, the extract was discarded. The water layer was acidified to pH 3 with concentrated hydrochloric acid and extracted with dichloromethane. The organic layer was dried over MgSO ₄ , filtered and concentrated to give 0.3 g of cyanomalondialdehyde as a yellow solid. Additional product was recovered from the water layer at pH 3: The water layer was concentrated to dryness and then dissolved in 5 mL of methanol. The inorganic salts were removed via filtration and the filtrate was concentrated to give 1 g of cyanomalondialdehyde as a yellow solid.

<Example 36>

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

To a mixture of N-{[4- (4-hydrazinylphenyl) -5-oxo-2-hydroisooxazol-2-yl] methyl} acetamide hydrochloride (100 mg, 0.33 mmol) in 3 mL methanol Carbonate (28 mg, 0.33 mmol) and cyanomalondialdehyde (50 mg, 0.35 mmol) were added. This mixture was stirred overnight at room temperature. Thereafter, the mixture was concentrated to give 120 mg of a yellow oil, which was then purified by silica gel chromatography (eluted with ethyl acetate) to give 30 mg (30%) of the title compound as a yellow solid.

The chemical structures, properties (MS data) of some of the representative compounds of the present invention, including the compounds of Examples 1-36 as described above, and methods for their preparation are shown in Table 2 below.

Claims (7)

Compounds having Formula I and pharmaceutically acceptable salts thereof [Formula I] Wherein R ₁ is a) H, b) C _1-8 alkyl, C _1-8 alkoxy or C _1-8 acyloxy, optionally substituted with one or more F, Cl, OH, c) C _3-8 cycloalkyl, or d) a C _1-8 alkoxy group; L is oxygen or sulfur; A is a) b) c) 1 to 3 heteroatoms selected from the group consisting of S, N and O, optionally substituted with 1 to 3 R ₈ groups, which may additionally have a benzene or naphthyl ring fused and bonded via a carbon atom 5-membered heteroaromatic group having, d) a 6-membered heteroaromatic group having one or more nitrogen atoms, optionally substituted with 1 to 3 R ₉ groups, which may additionally have a fused or benzene or naphthyl ring, and is bonded via a carbon atom, e) indolinyl or β-carbolin-3-yl, optionally substituted with one to three R ₉ groups, and bonded through a six-membered ring, f) , or g) ego; Wherein R ₂ and R ₃ are each independently, a) H, b) F, c) Cl, d) Br, e) C _1-6 alkyl, f) NO ₂ , g) I, h) C _1-6 alkoxy, i) OH, j) amino, k) cyano, or l) R ₂ and R ₃ taken together are —O (CH ₂ ) _h —O; Where R ₄ is a) H, b) C _1-2 alkyl, c) F, or d) OH; R ₅ is a) H, b) CF ₃ , c) C _1-3 alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) R ₅ and R ₆ taken together are a 5-, 6- or 7-membered ring having the formula: , f) , Wherein D is S, O or NR ₈₆ , wherein R ₈₆ is H or C _1-6 alkyl, or g) when R ₇ is an electron-withdrawing group, R ₅ and R ₆ taken together are — (CH ₂ ) _k —; R ₆ and R ₇ are the same or different at each position, a) e-trailer, b) H, c) CF ₃ , d) C _1-3 alkyl optionally substituted with one halo, e) if at least one of R ₆ and R ₇ is an electron-drawing group, phenyl, or f) R ₆ and R ₇ taken together are a 5-, 6- or 7-membered ring having the formula: ; U is a) CH ₂ , b) O, c) S, or d) NR ₁₆ ; R ₁₆ is a) H or b) C _1-5 alkyl; Wherein R ₁₈ is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF ₃ , g) NO ₂ , h) C _1-6 alkoxy, i) C _1-6 alkoxycarbonyl, j) C _1-6 alkylthio, k) C _1-6 acyl, l) -NR ₁₇ R ₁₈ , m) Wherein R ₈₇ is H or C _1-6 alkyl n) C _1-6 alkyl, sulfamoyl, C _1-5 alkoxy, —C _1-5 acyl, or NR ₁₇ R ₁₈ , optionally substituted with OH, o) C _2-8 alkyl optionally substituted with one or two R ₁₉ , p) phenyl optionally substituted with one or two R ₁₉ , q) Or a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 3 atoms selected from the group consisting of S, N and O, optionally substituted with one or two R ₁₉ ; At each position R ₁₇ and R ₁₈ are the same or different, a) H, b) C _1-4 alkyl, c) C _5-6 cycloalkyl, or d) R ₁₇ and R ₁₈ taken together with a nitrogen atom are 5- or 6-membered saturated or unsaturated heterocyclic groups having additional heteroatoms optionally selected from the group consisting of S, N, O, and then optionally further nitrogen atoms Including C _1-3 alkyl, formyl, 5- or 6-membered heteroatom containing 1-3 O, N or S, Wherein R ₈₈ and R ₈₉ are each independently hydrogen or C _1-6 alkyl, SO ₂ R ₉₀ (wherein R ₉₀ is H or C _1-6 alkyl), or optionally one or more F, Cl or Optionally substituted with C _1-3 acyl optionally substituted with OH; R ₁₉ is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF ₃ , g) NO ₂ , 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, sulfamoyl, C _1-5 alkoxy, —C _1-5 acyl, or NR ₁₇ R ₁₈ optionally substituted with OH, m) phenyl, n) -C (= 0) NR ₂₀ R ₂₁ , o) -NR ₁₇ R ₁₈ , p) -N (R ₂₀ ) (-SO ₂ R ₂₂ ), q) -SO ₂ -NR ₂₀ R ₂₁ , or r) -S (= 0) iR ₂₂ ; At each position R ₂₀ and R ₂₁ are the same or different, a) H, b) C _1-6 alkyl, or c) phenyl; R ₂₂ is a) C _1-4 alkyl, or b) phenyl optionally substituted with C _1-4 alkyl; Wherein R ₉ is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF ₃ , g) NO ₂ , h) C _1-6 alkoxy, i) C _1-6 alkoxycarbonyl, j) C _1-6 alkylthio, k) C _1-6 acyl, l) -NR ₁₇ R ₁₈ , m) C _1-6 alkyl, sulfamoyl, C _1-5 alkoxy, —C _1-5 acyl, or NR ₁₇ R ₁₈ , optionally substituted with OH, n) C _2-8 alkenylphenyl 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 having 1 to 3 atoms selected from the group consisting of S, N and O, optionally substituted with one or two R ₂₅ , or q) ego; At each position R ₂₃ and R ₂₄ are the same or different, a) H, b) formyl, c) C _1-4 alkyl, d) C _1-4 acyl, e) phenyl, f) C _3-6 cycloalkyl, or d) R ₂₃ and R ₂₄ taken together with a nitrogen atom are 5- or 6-membered saturated or unsaturated heterocyclic groups having additional hetero atoms optionally selected from the group consisting of S, N, O, and then optionally further nitrogen Atoms may be substituted with phenyl, pyrimidyl, C _1-3 alkyl, or C _1-3 acyl; R ₂₅ is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF ₃ , g) NO ₂ , 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, azido, C _1-5 alkoxy, C _1-5 acyl, —NR ₃₂ R ₃₃ , —SR ₃₄ , —O—SO ₂ R ₃₅ , optionally substituted with OH or , n) -C (= 0) 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) iR ₂₂ , s) -CH = NR ₂₈ , or t) -CH (OH) -SO ₃ R ₃₁ ; R ₂₂ is as described above; At each position R ₂₆ and R ₂₇ are the same or different, a) H, b) C _1-6 alkyl, or c) phenyl, or d) tolyl; R ₂₈ is a) OH, b) benzyloxy, c) -NH-C (= 0) -NH ₂ , d) -NH-C (= S) -NH ₂ , or e) -NH-C (= NH) -NR ₂₉ R ₃₀ ; At each position R ₂₉ and R ₃₀ are the same or different, a) H, or b) C _1-4 alkyl optionally substituted with phenyl or pyridyl; R ₃₁ is a) H, or b) sodium ions; At each position R ₃₂ and R ₃₃ are the same or different, a) H, b) formyl, c) C _1-4 alkyl, d) C _1-4 acyl, e) phenyl, f) C _3-6 cycloalkyl, g) R ₃₂ and R ₃₃ taken together are a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 3 atoms, optionally selected from the group consisting of S, N, O, and optionally comprising further nitrogen atoms May be substituted with phenyl, pyrimidyl, C _1-3 alkyl, or C _1-3 acyl, h) -P (O) (OR ₃₇ ) (OR ₃₈ ), or i) -SO ₂ -R ₃₉ ; R ₃₄ ego; R ₃₅ is C _1-3 alkyl; R ₃₆ is a) C _1-6 alkoxycarbonyl, or b) carboxyl; At each position R ₃₇ and R ₃₈ are the same or different, a) H, or b) C _1-3 alkyl; R ₃₉ is a) methyl, b) phenyl, or c) tolyl; Where K is a) O, 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 ₃₈ ) Or -SO-R ₃₉ , wherein R ₃₇ , R ₃₈ and R ₃₉ are as described above); At each position R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are the same or different, a) H, b) formyl, c) carboxyl, d) C _1-6 alkoxycarbonyl, e) C _1-8 alkyl, f) C _2-8 alkenyl, Wherein the substituents (e) and (f) are optionally OH, halo, C _1-6 alkoxy, C _1-6 acyl, C _1-6 alkylthio or C _1-6 alkoxycarbonyl, or phenyl optionally substituted with halo May be substituted with), g) optionally carboxyl, halo, -CN, formyl, CF ₃ , NO ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 alkylthio or C _1-6 alkoxy Aromatic groups having 6 to 10 carbon atoms substituted with carbonyl; h) -NR ₄₂ R ₄₃ , i) OR ₄₄ , j) -S (= O) _i -R ₄₅ , k) -SO ₂ -N (R ₄₆ ) (R ₄₇ ), or l) a substituent having the formula: ; R ₁₉ is as described above; T a) O, b) S, or c) SO ₂ ; At each position R ₄₂ and R ₄₃ are the same or different, a) H, b) C _3-6 cycloalkyl, c) phenyl, d) C _1-6 acyl, e) 5- or 6-membered aromatic heteroaryl having 1 to 3 atoms selected from the group consisting of C _1-8 alkyl optionally substituted with OH, C _1-6 alkoxy which may be substituted with OH, S, N and O Phenyl, phenyl optionally substituted with OH, CF ₃ , halo, —NO ₂ , C _1-4 alkoxy, —NR ₄₈ R ₄₉ or , f) , or g) ego; V is a) O, b) CH ₂ , or c) NR ₅₆ ; At each position R ₄₈ and R ₄₉ are the same or different, a) H, or b) C _1-4 alkyl; R ₅₄ is a) OH, b) C _1-4 alkoxy, or d) -NR ₅₇ R ₅₈ ; R ₅₅ is a) H, or b) C _1-7 alkyl, mercaptyl, imidazolyl, methylthio, amino, optionally substituted with OH, phenyl optionally substituted with OH, -C (= 0) -NH ₂ , -CO ₂ H, or -C (= NH) -NH ₂ ; R ₅₆ is a) H, b) phenyl, or c) optionally OH substituted C _1-6 alkyl; At each position R ₅₇ and R ₅₈ are the same or different, a) H, b) C _1-5 alkyl, c) C _1-3 cycloalkyl, or d) phenyl; R ₄₄ is a) C _1-8 alkyl, C _3-6 cycloalkyl, 6-membered aromatic optionally benzo-fused with 1 to 3 nitrogen atoms, optionally substituted with C _1-6 alkoxy or C _1-6 hydroxy Heterocyclic group, which may be further substituted with one or two —NO ₂ , CF ₃ , halo, —CN, OH, C _1-5 alkyl, C _1-5 alkoxy or C _1-5 acyl , b) , c) phenyl, or d) pyridyl; R ₄₅ is a) C _1-16 alkyl, b) C _2-16 alkenyl, Wherein the substituents (a) and (b) are optionally C _1-6 alkoxycarbonyl, or 5-, 6- or 7-membered aromatic hetero having 1 to 3 atoms selected from the group consisting of S, N and O Cyclic group), c) aromatic groups having 6 to 10 carbon atoms, or d) 5-, 6- or 7-membered aromatic heterocyclic groups having 1 to 3 atoms selected from the group consisting of S, N and O, wherein substituents (c) and (d) are optionally carboxyl, To be substituted with halo, -CN, formyl, CF ₃ , -NO ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 alkylthio or C _1-6 alkoxycarbonyl Can be); At each position R ₄₆ and R ₄₇ are the same or different, a) H, b) phenyl, c) C _1-6 alkyl or d) benzyl; At each position R ₅₀ and R ₅₁ are the same or different, a) H, b) OH, c) C _1-6 alkyl optionally substituted with NR ₄₈ R ₄₉ , wherein R ₄₈ and R ₄₉ are as described above, d) R ₅₀ and R ₅₁ taken together are ═O; R ₅₂ is a) an aromatic group having 6 to 10 carbon atoms, b) 5-, or 6-membered aromatic optionally benzo-fused heterocyclic groups having 1 to 3 atoms selected from the group consisting of S, N and O, wherein substituents (a) and (b) are further optionally may be substituted with one to three -NO _2, CF _3, halo, -CN, OH, phenyl, C _1-5 alkyl, C _1- 5 alkoxy, or C _1-5 acyl) by, c) morpholinyl, d) OH, e) C _1-6 alkoxy, f) -NR ₄₈ R ₄₉ , wherein R ₄₈ and R ₄₉ are as described above, g) -C (= 0) -R ₅₉ , or h) ego; R ₅₃ is a) H, b) formyl, c) C _1-4 alkyl, d) C _1-4 acyl, e) phenyl, f) C _3-6 cycloalkyl, g) -P (O) (OR ₃₇ ) (OR ₃₈ ), or h) -SO ₂ R ₃₉ , wherein R ₃₇ , R ₃₈ and R ₃₉ are as described above; R ₅₉ is a) morpholinyl, b) OH, or 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; Q is a) hydrogen, b) halo, c) NO ₂ , d) N ₃ , e) C ₁ -C ₆ alkylthio, f) , g) , h) C ₁ -C ₆ alkyl, i) C ₁ -C ₆ alkoxy, j) formyl, k) , l) , m) sulfamoyl (H ₂ NSO _2- ), n) -NHOH, o) , p) Wherein heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S), q) , r) amino, s) C ₁ -C ₆ alkylamino-, t) di (C ₁ -C ₆ alkyl) amino-, u) (Wherein R ₆₀ and R ₆₁ are each independently hydrogen or C ₁ -C ₆ alkyl), v) OH, w) cyano, x) hydroxy (C ₁ -C ₆ alkyl), y) , z) (Where r is 1-6), aa) , bb) , cc) Wherein R ₈₄ is hydrogen or C _1-6 alkyl dd) Wherein R ₈₅ is hydrogen, C _1-8 alkyl, C _1-8 alkoxy or C _1-8 acyoxy, C _3-6 cycloalkyl or C _1-8 alkoxy, optionally substituted with one or more F, Cl, OH being), ee) Wherein R ₈₄ is hydrogen or C _1-6 alkyl ff) substituted or unsubstituted C ₆ -C ₁₀ aryl group, gg) heterocy, having 1-3 atoms selected from O, N or S, substituted or unsubstituted monocyclic or bicyclic, saturated or unsaturated, in which the ring is bonded to a phenyl substituent via a ring carbon or nitrogen; Clicker, hh) heteroatoms having 1-3 atoms selected from O, N or S, in which the ring is bonded to the phenyl substituent via ring carbon or nitrogen and the heteroatoms can be added to the benzene or naphthalene ring fused; Is a substituted or unsubstituted monocyclic or bicyclic group; Substituents for such groups p, q, ff, gg and hh are selected from one or two of the following: 1) halo, 2) C _1-6 alkyl, 3) NO ₂ , 4) N ₃ , 5) , 6) , 7) formyl, 8) , 9) , 10) Wherein heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 heteroatoms selected from O, N or S, 11) , 12) (Wherein R ₆₀ and R ₆₁ are each independently hydrogen or C ₁ -C ₆ alkyl), 13) OH, 14) hydroxy (C ₁ -C ₆ alkyl), 15) , 16) (Where r is 1-6), 17) , 18) -CH ₂ -R ₈₀ , wherein R ₈₀ is a) -OR ₃₂ (where R ₃₂ is as described above), b) -SR ₃₂ (where R ₃₂ is as described above), c) -NR ₃₂ R ₃₃ , wherein R ₃₂ and R ₃₃ are as described above, or d) 5- or 6-membered heteroaromatic groups having 1-4 O, S or N atoms, 19) (Wherein R ₈₄ is as described above), 20) cyano, 21) carboxyl, 22) CF ₃ , 23) , 24) Wherein the phenyl group may be optionally substituted with halo or (C ₁ -C ₆ ) alkyl), 25) (Wherein R ₆₀ and R ₆₁ are as described above), 26) Wherein R ₉₁ is a 5- or 6-membered aromatic heterocyclic group having 1-3 O, N or S, 27) , 28) (Wherein R ₈₅ is as described above), 29) Wherein R ₉₉ , R ₁₀₀ and R ₁₀₁ are each independently C _1-6 alkyl; or Q and _one of R ₁ and R ₂ together form —O—CH ₂ —O. A compound according to claim 1 wherein A has the formula: Wherein Q, R ₂ and R ₃ are as described above in claim 1. Compounds having the general formula (IA) 닢 pharmaceutically acceptable salts thereof [Formula IA] Wherein R ₁ is H, C _1-8 alkyl optionally substituted with one or more F, Cl, OH, C _1-8 alkoxy or C _1-8 acyloxy, C _3-8 cycloalkyl, or C _1-8 An alkoxy group; R ₂ and R ₃ are each independently, a) H, b) F, c) Cl, d) Br, e) C _1-6 alkyl, f) NO ₂ , g) I, h) C _1-6 alkoxy, i) OH, j) amino, or k) cyano; And Q is a) hydrogen, b) halo, c) NO ₂ , d) N ₃ , e) C ₁ -C ₆ alkylthio, f) , g) , h) C ₁ -C ₆ alkyl, i) C ₁ -C ₆ alkoxy, j) formyl, k) , l) , m) , n) Wherein heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S), o) , p) amino, q) C ₁ -C ₆ alkylamino-, r) di (C ₁ -C ₆ alkyl) amino-, s) (Wherein R ₆₀ and R ₆₁ are each independently hydrogen or C ₁ -C ₆ alkyl), t) OH, u) cyano, v) hydroxy (C ₁ -C ₆ alkyl), w) , x) (Where r is 1-6), y) , z) , aa) Wherein R ₈₄ is hydrogen or C _1-6 alkyl bb) Wherein R ₈₅ is hydrogen, C _1-8 alkyl, C _1-8 alkoxy or C _1-8 acyoxy, C _3-6 cycloalkyl or C _1-8 alkoxy, optionally substituted with one or more F, Cl, OH being), cc) (Wherein R ₈₄ is as described above), dd) , ee) , ff) , gg) , hh) , ii) , jj) , kk) , ll) , mm) , nn) , oo) Wherein R ₉₂ is H or C _1-6 alkyl pp) , qq) , rr) , ss) , tt) , uu) , vv) , ww) , xx) , yy) , zz) , aaa) a diazinyl group, optionally substituted with X and Y, bbb) triazinyl groups, optionally substituted with X and Y, ccc) a quinolinyl group, optionally substituted with X and Y, ddd) a quinooxalinyl group, optionally substituted with X and Y, eee) a naphthyridinyl group, optionally substituted with X and Y, fff) , ggg) , hhh) , or iii) ego; B is an unsaturated four-membered linker having one nitrogen atom and three carbons; M is a) H, b) C _1-8 alkyl, c) C _3-8 cycloalkyl, d)-(CH ₂ ) _m OR ₆₆ , or e)-(CH ₂ ) _n NR ₆₇ R ₆₈ ; Z is a) O, b) S or c) NM; W is a) CH, b) N or c) O or S when Z is NM; X and Y are each independently a) hydrogen, b) halo, c) NO ₂ , d) N ₃ , e) C _1-6 alkylthio, f) , g) , h) C ₁ -C ₆ alkyl, i) C ₁ -C ₆ alkoxy, j) formyl, k) , l) , m) Wherein heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S), n) , o) amino, p) C ₁ -C ₆ alkylamino-, q) di (C ₁ -C ₆ alkyl) amino-, r) (Wherein R ₆₀ and R ₆₁ are each independently hydrogen or C ₁ -C ₆ alkyl), s) OH, t) hydroxy (C ₁ -C ₆ alkyl), u) , v) (Where r is 1-6), w) , x) , y) (Wherein R ₈₄ is as described above), z) cyano, aa) carboxyl, bb) CF ₃ , cc) mercapto, dd) , ee) Wherein the phenyl group may be optionally substituted with halo or C ₁ -C ₆ alkyl ff) , gg) Where R ₈₅ is as described above, or hh) Wherein R ₉₉ , R ₁₀₀ and R ₁₀₁ are each independently C _1-6 alkyl; or One of Q and R ₁ and R ₂ together form —O—CH ₂ —O, R ₆₂ is a) H, b) C _1-8 alkyl optionally substituted with one or more halo, or c) C _1-8 alkyl, or C _1-8 alkoxy, optionally substituted with one or more OH; E is a) NR ₆₉ , b) -S (= O) _i , where i is 0, 1 or 2, or c) O; R ₆₃ is a) H, b) C _1-6 alkyl, c)-(CH ₂ ) _q -aryl, or d) halo; R ₆₆ is H or C _1-4 alkyl; R ₆₇ and R ₆₈ are each independently H or C _1-4 alkyl, or NR ₆₇ R ₆₈ taken together is — (CH ₂ ) _m —; R ₆₉ is a) H, b) C _1-6 alkyl, c)-(CH ₂ ) _q -aryl, d) -CO ₂ R ₈₁ , e) COR ₈₂ , f) -C (= O)-(CH ₂ ) _q -C (= O) R ₈₁ , g) -S (= 0) _Z- C _1-6 alkyl, h) -S (= 0) _Z- (CH ₂ ) _q -aryl, or i)-(C = O) _j -Het, where j is 0 or 1; Z ₁ is a) -CH _2- , or b) -CH (R ₇₀ ) -CH _2- ; Z is a) -O ₂ S-, b) -O-, c) -S-, d) -SO-, or e) -N (R ₇₁ )-; Z ₃ is a) S, b) SO, c) SO ₂ , or d) O; A ₁ is H or CH ₃ ; A ₂ is a) H, b) OH-, c) CH ₃ CO _2- , d) CH _3- , e) CH ₃ O-, f) R ₇₂ O-CH ₂ -C (O) -NH-, g) R ₇₃ OC (O) -NH-, h) R ₇₃ -C (O) -NH, i) (C ₁ -C ₂ ) alkyl-OC (O) —, or j) HO-CH ₂ ; or A ₁ and A ₂ taken together a) or b) O =; R ₆₄ 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 is 0, 1, 2, 3, 4 or 5; w is 1, 2 or 3; q is 1, 2, 3 or 4; Z is 0 or 1; R ₆₅ is a) R ₇₄ OC (R ₇₅ ) (R ₇₆ ) -C (O)-, b) R ₇₇ OC (O)-, c) R ₇₈ (O)-, d) R ₇₉ -SO _2- , or e) R ₈₀ -NH-C (O)-; R ₇₀ is H or (C ₁ -C ₃ ) alkyl; R ₇₁ is a) R ₇₄ OC (R ₇₅ ) (R ₇₆ ) -C (O)-, b) R ₇₇ OC (O)-, c) R ₇₈ -C (O)-, d) , e) , f) H ₃ CC (O)-(CH ₂ ) ₂ -C (O)-, g) R ₇₉ -SO _2- , h) , i) R ₈₀ -NH-C (O)-; R ₇₂ is a) H, b) CH ₃ , c) phenyl-CH _2- , 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)-; R ₇₅ and R ₇₆ are each independently H or CH ₃ or R ₇₅ and R ₇₆ taken together are —CH ₂ CH ₂ —; R ₇₇ is (C ₁ -C ₃ ) alkyl or phenyl; R ₇₈ is H, (C ₁ -C ₄ ) alkyl, aryl- (CH ₂ ) _{n 1} , ClH ₂ C, Cl ₂ HC, FH ₂ C-, F ₂ HC- or (C ₃ -C ₆ ) cycloalkyl ; R ₇₉ is CH ₃ , —CH ₂ Cl, —CH ₂ CH═CH ₂ , aryl or —CH ₂ CN; R ₈₀ is — (CH ₂ ) _n1 -aryl, wherein n ¹ is 0 or 1; R ₈₁ is a) H, b) C _1-6 alkyl optionally substituted with one or more OH, halo or CN, c)-(CH ₂ ) _q -aryl, wherein q is as described above, or d)-(CH ₂ ) _q -OR ₈₃ where q is as described above; R ₈₂ is a) C _1-6 alkyl optionally substituted with one or more OH, halo, or CN, b)-(CH ₂ ) _q -aryl, wherein q is as described above, or c)-(CH ₂ ) -OR ₈₃ wherein q is as described above; R ₈₃ is a) H, b) C _1-6 alkyl, c)-(CH ₂ ) _q -aryl, wherein q is as described above, or d) —C (═O) C _1-6 alkyl; And Aryl is phenyl, pyridyl or naphthyl, wherein the phenyl, pyridyl or naphthyl group may be optionally substituted with one or more halo, —CN, OH, SH, C _1-6 alkoxy or C _1-6 alkylthio. Compounds having Formula (IA) and pharmaceutically acceptable salts thereof: [Formula IA] Wherein R ₁ is H, C _1-8 alkyl optionally substituted with one or more F, Cl, OH, C _1-8 alkoxy or C _1-8 acyloxy, C _3-8 cycloalkyl, or C _1-8 An alkoxy group; R ₂ and R ₃ are each independently H or F; Or R ₂ and R ₃ taken together represent the formula: ; Q is a) hydrogen, b) halo, c) NO ₂ , d) N ₃ , e) C ₁ -C ₆ alkylthio, f) , g) , h) C ₁ -C ₆ alkyl, i) C ₁ -C ₆ alkoxy, j) formyl, k) , l) , m) , n) (C ₁ -C ₆ alkoxy) ₂ N-, o) 5- or 6-membered heterocyclic groups comprising 1-3 O, N, or S, and bonded with a phenyl substituent via carbon or nitrogen, wherein the heterocyclic group is optionally substituted with R ₉₆ , p) , q) phenyl optionally substituted with R ₉₆ , or r) 5- or 6-membered saturated or unsaturated heterocyclic groups containing 1-3 O, N, or S, and bonded with a phenyl substituent via carbon or nitrogen, wherein the heterocyclic group is optionally R ₉₆ Substituted with; And R ₉₆ is a) C ₁ -C ₆ alkyl-OH, b) , c) , d) cyano, e) formyl, f) , g) , h) (Wherein R ₉₉ , R ₁₀₀ and R ₁₀₁ are each independently C _1-6 alkyl), i) , j) , k) (Wherein phenyl may be optionally substituted with halo), l) , m) (C ₁ -C ₆ alkyl) ₂ N-, n) C ₁ -C ₆ alkyl-NH—, o) amino, p) , q) , or r) Wherein R ₉₈ comprises 1-3 O, N, or S, and 5- or 6-membered heteroaryl, or 1-4 O, N or S, bonded to a phenyl group via a ring carbon atom And 5- or 6-membered saturated or unsaturated heterocyclic bonded to a phenyl substituent via a ring carbon atom. A compound selected from the group consisting of the compounds of Examples 1-97 described in the detailed description of the invention. A pharmaceutical composition comprising a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. A method for treating a bacterial infection in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1.