KR20010107987A - Oxazolidinone Antibacterial Agents Having a Thiocarbonyl Functionality - Google Patents

Abstract

The present invention provides a compound of the following formula, or an antimicrobial agent, or a pharmaceutically acceptable salt thereof.

≪

Wherein A, G and R < ₁ > are as defined in the claims.

Description

Oxazolidinone Antibacterial Agents Having a Thiocarbonyl Functionality with a Thiocarbonyl Function [

Substitution of oxygen atoms with sulfur atoms improves the antimicrobial properties of the compounds unexpectedly. The present compounds are useful antimicrobial agents, including Gram-positive aerobic bacteria such as multidrug resistant staphylococci and streptococci; Gram-negative organisms such as HEC. H. influenzae and M. < RTI ID = 0.0 > In addition to M. catarrahis , anaerobic organisms such as bacteroid and clostridia species and acid-resistant organisms such as Mycobacterium tuberculosis and Mycobacterium tuberculosis , It is effective against many human and animal pathogens including Mycobacterium avium . This compound is particularly useful because it is effective against the latter organisms known to cause infections and the like in AIDS patients.

The present invention relates to novel and useful oxazolidinone compounds and their preparation, and more specifically, -NH-C (O) is a carbonyl functional group -R thiourea _{-NH-C (S) -NH 2} , alkyl thiourea - A thiocarbonyl functional group such as NH-C (S) -NH- (C _1-4 alkyl), thioamide -NH-C (S) - (C _1-4 alkyl) or -NH-C (S) ≪ / RTI >

In one aspect, the invention relates to a compound of formula I:

In this formula,

G ego,

R ₁ is a) H,

b) NH ₂ ,

c) NH-C _1-4 alkyl,

d) C _1-4 alkyl,

e) -OC _1-4 alkyl,

f) -SC _1-4 alkyl,

g) 1-3 F, 1-2 Cl, CN or -COOC _1-4 alkyl substituted with C _1-4 alkyl,

h) C _3-6 cycloalkyl,

i) N (C _1-4 alkyl) ₂ or

j) N (CH _{2) 2-5,} and;

A is a) ,

b) ,

c) ,

d) a 5-membered heteroaromatic moiety having 1 to 3 atoms selected from the group consisting of S, N and O, wherein said 5-membered heteroaromatic moiety is bonded through a carbon atom, The aromatic moiety can additionally have a fused benzene or naphthyl ring, said heteroaromatic moiety being optionally substituted with 1 to 3 R < ₄₈ >),

e) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein said heteroaromatic moiety is bonded via a carbon atom and said 6-membered heteroaromatic moiety has an additional fused benzene or naphthyl ring And said heteroaromatic moiety is optionally substituted with 1 to 3 R < ₅₈ >),

f)? -carboline-3-yl or indolizinyl, optionally interrupted by 6-membered ring and optionally substituted by 1 to 3 R ₅₅ ,

g) , or

h) ;

R ₂ is a) H,

b) F,

c) Cl,

d) Br,

e) C _1-3 alkyl,

f) NO ₂ , or

g) R ₂ and R ₃ together form -O- (CH ₂ ) _h -O-;

R ₃ is _{a) -S (= O) i} R 4,

_{b) -S (= O) 2} -N = S (O) j R 5 R 6,

c) -SC (= O) R ₇ ,

d) -C (= O) R ₈ ,

e) -C (= O) R ₉ ,

f) -C (= O) NR 10 R 11,

_{g) -C (= NR 12)} R 8,

_{h) -C (R 8) (} R 11) -OR 13,

_{i) -C (R 9) (} R 11) -OR 13,

_{j) -C (R 8) (} R 11) -OC (= O) R 13,

_{k) -C (R 9) (} R 11) -OC (= O) R 13,

l) -NR ₁₀ R _11,

_{m) -N (R 10) -C} (= O) R 7,

_{n) -N (R 10) -S} (= O) i R 7,

_{o) -C (OR 14) (} OR 15) R 8,

_{p) -C (R 8) (} R 16) -NR 10 R 11, or

q) C _1-8 alkyl substituted with one or more = O other than the alpha position, -S (= O) _i R ₁₇ , -NR ₁₀ R ₁₁ , C _2-5 alkenyl or C _2-5 alkynyl;

R ₄ is a) C _1-4 alkyl optionally substituted with one or more halogens, OH, CN, NR ₁₀ R ₁₁ or -CO ₂ R ₁₃ ,

b) C _2-4 alkenyl,

c) -NR ₁₆ R ₁₈ ,

d) -N _3,

e) -NHC (= O) R ₇ ,

f) -NR ₂₀ C (= O) R ₇ ,

_{g) -N (R 19) 2} ,

h) -NR ₁₆ R ₁₉ , or

i) -NR ₁₉ R ₂₀ ;

R ₅ and R ₆ are the same or different from each other,

a) C _1-2 alkyl, or

b) R ₅ and R ₆ together form - (CH ₂ ) _k -;

R ₇ is C _1-4 alkyl optionally substituted with one or more halogens;

R ₈ is a) H, or

b) C _1-8 alkyl optionally substituted by one or more halogens or C _3-8 cycloalkyl;

R < ₉ >

a) -S (= O) R < ₁₇ >

b) -OR ₁₃ ,

c) -OC (= O) R 13,

d) -NR < ₁₀ > R < ₁₁ &

e) C _1-5 alkenyl optionally substituted with CHO

&_Lt; / RTI >

R ₁₀ and R ₁₁ are the same or different from each other,

a) H,

b) C _1-4 alkyl, or

c) _C3-8 cycloalkyl;

R ₁₂ is a) -NR ₁₀ R ₁₁ ,

b) -OR ₁₀ ; or

c) -NHC (= O) R < _{10 &} gt ;;

R < ₁₃ > is a) H, or

b) C _1-4 alkyl;

R ₁₄ and R ₁₅ are the same or different from each other,

a) C _1-4 alkyl, or

b) R ₁₄ and R ₁₅ together form - (CH) _l -;

R < ₁₆ > is a) H,

b) C _1-4 alkyl, or

c) C _3-8 cycloalkyl;

R ₁₇ is a) C _1-4 alkyl, or

b) C _3-8 cycloalkyl;

R < ₁₈ > is a) H,

b) C _1-4 alkyl,

c) _C2-4 alkenyl,

d) C _3-4 cycloalkyl,

e) -OR ₁₃ , or

f) -NR ₂₁ R ₂₂ ;

R < ₁₉ > is a) Cl,

b) Br, or

c) I;

R < ₂₀ > is a physiologically acceptable cation;

R ₂₁ and R ₂₂ are the same or different from each other,

a) H,

b) C _1-4 alkyl, or

c) -NR ₂₁ R ₂₂ together form - (CH ₂ ) _m -

R ₂₃ and R ₂₄ are the same or different from each other,

a) H,

b) F,

c) Cl,

d) C _1-2 alkyl,

e) CN,

f) OH,

g) C _1-2 alkoxy,

h) nitro, or

i) amino;

Q is a) ,

b) ,

c) ,

d) ,

e) ,

f) ,

g) ,

h) ,

i) ,

j) ,

k) ,

l) ,

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

n) a triazinyl group optionally substituted with X and Y,

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

p) a quinoxalinyl group optionally substituted with X and Y,

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

Lt; / RTI >

Q and R < ₂₄ > Lt; / RTI >

Z ¹ is a) -CH ₂ -,

b) -CH (R ¹⁰⁴ ) -CH ₂ -,

c) -C (O) -, or

_{d) -CH 2 CH 2 CH 2} - , and;

Z ² is a) -O ₂ S-,

b) -O-,

c) -N (R ¹⁰⁷ ) -,

d) -OS-, or

e) -S-;

Z ³ is a) -O ₂ S-,

b) -O-,

c) -OS-, or

d) -S-;

A ¹ is a) H-, or

b) CH _3, and;

A ² is a) H-,

b) HO-,

c) CH ₃ -,

d) CH ₃ O-,

_{^{e) R 102 O-CH 2}} -C (O) -NH-,

f) R ^{103 is} OC (O) -NH-,

g) (C ₁ -C ₂ ) alkyl-OC (O) -,

h) HO-CH ₂ -,

i) CH ₃ O-NH-,

j) (C ₁ -C ₃ ) alkyl-O ₂ C-,

_{k) CH 3 -C (O)} -,

_{l) CH 3 -C (O)} -CH 2 -,

m) , or

n) ;

A ¹ and A ² together

a) ,

b) O =, or

c) ≪ / RTI >

R ¹⁰² is a) H-,

b) CH ₃ -,

c) phenyl -CH ₂ -, or

_{d) CH 3 C (O)} - and;

R ¹⁰³ is a) (C ₁ -C ₃ ) alkyl-, or

b) phenyl-;

R ¹⁰⁴ is a) H-, or

b) HO-;

R ¹⁰⁵ is a) H-,

b) (C ₁ -C ₃₎ alkyl-,

_{c) CH 2 = CH-CH} 2 -, or

_{d) CH 3 -O- (CH 2} ) 2 - and;

R ¹⁰⁶ is a) CH ₃ -C (O) -,

b) H-C (O) -,

_{c) Cl 2 CH-C (} O) -,

d) HOCH ₂ -C (O) -,

e) CH ₃ SO ₂ -,

f) ,

g) F ₂ CHC (O) -,

h) ,

i) H ₃ CC (O) -O-CH ₂ -C (O) -,

j) HC (O) -O- CH 2 -C (O) -,

k) ,

1) HC≡C-CH ₂ O-CH ₂ -C (O) -, or

m) phenyl _{-CH 2 -O-CH 2 -C (} O) - and;

R ¹⁰⁷ is a) R ¹⁰² OC (R ¹¹⁰ ) (R ¹¹¹ ) -C (O) -,

b) R @ ^{103 is} OC (O) -,

c) R < ^{108 > is} -C (O) -,

d) ,

e) ,

f) H ₃ CC (O) - (CH ₂ ) ₂ -C (O) -,

g) R ¹⁰⁹ -SO ₂ -,

h) ,

_{i) HO-CH 2 -C (} O) -,

_{^{j) R 116 - (CH 2}} ) 2 -,

k) R ¹¹³ -C (O) -O-CH ₂ -C (O) -,

_{l) (CH 3) 2 N} -CH 2 -C (O) -NH-,

m) NC-CH ₂ -,

_{n) F 2 -CH-CH 2} -, or

o) R ¹⁵⁰ R ¹⁵¹ NSO _2, and

R ^{< 108 >} is a) H-,

b) (C ₁ -C ₄₎ alkyl,

c) aryl - (CH _{2) p,}

d) ClH ₂ C-,

e) Cl ₂ HC-,

f) FH ₂ C-,

g) F ₂ HC-,

h) (C ₃ -C ₆₎ cycloalkyl, or

i) CNCH ₂ -.

R ¹⁰⁹ is a) alkyl C ₁ -C _4,

b) -CH ₂ Cl,

_{c) -CH 2 CH = CH 2} ,

d) aryl, or

e) -CH ₂ CN, and;

R < ¹¹⁰ > and R < ¹¹¹ &

a) H-, or

b) CH ₃ -, and;

R ¹¹² is a) H-,

b) CH ₃ O-CH ₂ O-CH ₂ -, or

c) HOCH ₂ -;

R ¹¹³ is a) CH ₃ -,

b) HOCH ₂ -,

c) (CH _{3) 2} N-, phenyl, or

_{d) (CH 3) 2 N} -CH 2 - , and;

R < ¹¹⁴ > is a) HO-,

b) CH ₃ O-,

c) H ₂ N-,

_{d) CH 3 OC (O)} -O-,

_{e) CH 3 -C (O)} -O-CH 2 -C (O) -O-,

f) phenyl _{-CH 2 -O-CH 2 -C (} O) -O-,

_{g) HO- (CH 2) 2} -O-,

h) CH ₃ O-CH ₂ -O- (CH ₂ ) ₂ -O-, or

_{i) CH 3 O-CH 2} -O- , and;

R ¹¹⁵ is a) H-, or

b) Cl-;

R < ¹¹⁶ > is a) HO-,

b) CH ₃ O-, or

c) F;

R ¹⁵⁰ and R ¹⁵¹ are each H or alkyl C ₁ -C ₄ , or R ¹⁵⁰ and R ¹⁵¹ together with the nitrogen atom to which they are attached form a monocyclic heterocyclic ring having 3 to 6 carbon atoms;

B is an unsaturated 4-atom linker having one nitrogen atom and three carbon atoms;

M is a) H,

b) C _1-8 alkyl,

c) _C3-8 cycloalkyl,

_{d) - (CH 2) m} OR 13, or

_{e) - (CH 2) h} -NR 21 R 22 a;

Z is a) O,

b) S, or

c) NM;

W is a) CH,

b) N, or

c) S or O when Z is NM;

Y is a) H,

b) F,

c) Cl,

d) Br,

e) C _1-3 alkyl, or

f) NO _2, and;

X is a) H,

b) -CN,

c) OR ₂₇ ,

d) halo,

e) NO ₂ ,

f) tetraoyl,

g) -SH,

_{h) -S (= O) i} R 4,

_{i) -S (= O) 2} -N = S (O) j R 5 R 6,

j) -SC (= O) R ₇ ,

k) -C (= O) R ₂₅ ,

l) -C (= O) NR 27 R 28,

_{m) -C (= NR 29)} R 25,

_{n) -C (R 25) (} R 28) -OR 13,

_{o) -C (R 25) (} R 28) -OC (= O) R 13,

p) -C (R ₂₈ ) (OR ₁₃ ) - (CH ₂ ) _h -NR ₂₇ R ₂₈ ,

q) -NR ₂₇ R _28,

r) -N (R ₂₇ ) C (= O) R ₇ ,

_{s) -N (R 27) -S} (= O) i R 7,

_{t) -C (OR 14) (} OR 15) R 28,

_{u) -C (R 25) (} R 16) -NR 27 R 26, or

v) one or more halogen, OH, at position other than alpha = O, -S (= O) i R 17, -NR 27 R 28, C 2-5 alkenyl, C _2-5 alkynyl or C _3-8 cycloalkyl C _1-8 alkyl substituted with alkyl;

R ₄ , R ₅ , R ₆ , R ₇ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ are as defined above;

R < ₂₅ > is a) H,

b) C _1-4 alkyl substituted with one or more halogens, C _3-8 cycloalkyl, one or more -S (═O) _i R ₁₇ , -OR ₁₃ or OC (═O) R ₁₃ , NR ₂₇ R ₂₈ Optionally substituted C _1-8 alkyl, or

c) C _2-5 alkenyl optionally substituted with CHO or CO ₂ R ₁₃ ;

R < ₂₆ > is a) R < ₂₈ &

b) NR ₂₇ R ₂₈ and;

R ₂₇ and R ₂₈ are the same or different from each other,

a) H,

b) C _1-8 alkyl,

c) _C3-8 cycloalkyl,

_{d) - (CH 2) m} OR 13,

e) - (CH ₂ ) _h -NR ₂₁ R ₂₂ , or

f) R ₂₇ and R ₂₈ are together _{- (CH 2) 2 O (} CH 2) 2 -, - (CH 2) h CH (COR 7) - or _{- (CH 2) 2 N (} CH 2) 2 (R ₇ );

R ₂₉ is a) -NR ₂₇ R ₂₈ ,

b) -OR ₂₇ , or

c) -NHC (= O) R < _{28 &} gt ;;

R < ₃₀ > is a) H,

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

c) C _1-8 alkyl optionally substituted with one or more OH or C _1-6 alkoxy;

E is a) NR ₃₉ ,

b) -S (= O) _i , or

c) O;

R < ₃₈ > is a) H,

b) _C1-6 alkyl,

_{c) - (CH 2) q} - aryl, or

d) halo;

R ₃₉ is a) H,

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

_{c) - (CH 2) q} - aryl,

d) -CO ₂ R ₄₀ ,

e) -COR ₄₁ ,

f) -C (= O) - (CH ₂ ) _q -C (= O) R ₄₀ ,

g) -S (= O) _2- C _1-6 alkyl,

_{h) -S (= O) 2} - (CH 2) q - aryl, or

i) - (C = O) _j -Het;

R < ₄₀ > is a) H,

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

_{c) - (CH 2) q} - aryl, or

_{d) - (CH 2) q} -OR 42 , and;

R ₄₁ is a) C _1-6 alkyl optionally substituted with one or more OH, halo or -CN,

_{b) - (CH 2) q} - aryl, or

c) - (CH ₂ ) _q -OR ₄₂ ;

R ₄₂ is a) H,

b) _C1-6 alkyl,

_{c) - (CH 2) q} - aryl, or

d) -C (= O) -C 1-6 alkyl;

Aryl is a) phenyl,

b) pyridyl, or

c) naphthyl wherein a) to c) are optionally substituted with one or more halo, -CN, OH, SH, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkylthio;

R ₄₃ is a) H,

b) C _1-2 alkyl,

c) F, or

d) OH;

R < ₄₄ > is a) H,

b) CF _3,

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

d) phenyl optionally substituted with one or more halogens,

e) R ₄₄ and R ₄₅ of the formula with Membered < / RTI > 5-, 6- or 7-membered ring,

f) when R ₄₆ is an electron-withdrawing group, R ₄₄ and R ₄₅ together form - (CH ₂ ) _k -;

R ₄₅ and R ₄₆ are the same or different from each other,

a) an electron withdrawing device,

b) H,

c) CF _3,

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

e) phenyl, if at least one of R ₄₅ or R ₄₆ is an electron withdrawing group, or

f) R ₄₅ and R ₄₆ of the formula with Of a 5-, 6- or 7-membered ring;

U is a) CH _2,

b) O,

c) S, or

d) NR ₄₇ ;

R < ₄₇ > is a) H, or

b) _C1-5 alkyl;

R < ₄₈ > is a)

b) halo,

c) -CN,

d) mercapto,

e) formyl,

f) CF _3,

g) -NO ₂ ,

h) _C1-6 alkoxy,

i) C _1-6 alkoxycarbonyl,

j) C _1-6 alkylthio,

k) _C1-6 acyl,

l) -NR ₄₉ R _50,

m) OH, C _1-5 alkoxy, C _1-5 acyl or C _1-6 alkyl optionally substituted with -NR ₄₉ R ₅₀ ,

n) C _{2-8 alkenylphenyl} optionally substituted with one or two R < ₅₁ >

o) phenyl optionally substituted with one or two R < ₅₁ >

p) a 5- or 6-membered saturated or unsaturated heterocyclic residue optionally substituted with 1 or 2 R < ₅₁ > and having 1 to 3 atoms selected from the group consisting of S, N and O, or

q) ego;

R ₄₉ and R ₅₀ are the same or different from each other,

a) H,

b) C _1-4 alkyl,

c) _C5-6 cycloalkyl, or

d) R ₄₉ and R ₅₀ together with the nitrogen atom form a 5- or 6-membered saturated heterocyclic residue, said residue optionally having an additional heteroatom selected from the group consisting of S, N and O, Optionally substituted on the nitrogen atom, including C _1-3 alkyl or C _1-3 acyl;

R < ₅₁ > is a) carboxyl,

b) halo,

c) -CN,

d) mercapto,

e) formyl,

f) CF _3,

g) -NO ₂ ,

h) _C1-6 alkoxy,

i) C _1-6 alkoxycarbonyl,

j) C _1-6 alkylthio,

k) _C1-6 acyl,

l) OH, C _1-5 alkoxy, C _1-5 acyl or C _1-6 alkyl optionally substituted with -NR ₄₉ R ₅₀ ,

m) phenyl,

n) -C (= O) NR ₅₂ R ₅₃ ,

o) -NR ₄₉ R ₅₀ ,

p) -N (R ₅₂ ) (-SO ₂ R ₅₄ ),

_{q) -SO 2 -NR 52 R 53} , or

_{r) -S (= O) i} R 54 a;

R ₅₂ and R ₅₃ are the same or different from each other,

a) H,

b) _C1-6 alkyl, or

c) phenyl;

R ₅₄ is a) C _1-4 alkyl, or

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

R ₅₅ is a) carboxyl,

b) halo,

c) -CN,

d) mercapto,

e) formyl,

f) CF _3,

g) -NO ₂ ,

h) _C1-6 alkoxy,

i) C _1-6 alkoxycarbonyl,

j) C _1-6 alkylthio,

k) _C1-6 acyl,

1) -NR ₅₆ R ₅₇ ,

m) OH, C _1-5 alkoxy, C _1-5 acyl or C _1-6 alkyl optionally substituted with -NR ₅₆ R ₅₇ ,

n) C _{2-8 alkenylphenyl} optionally substituted with one or two R ₅₈ ,

o) phenyl optionally substituted with one or two R < ₅₈ >

p) a 5- or 6-membered saturated or unsaturated heterocyclic residue optionally substituted with 1 or 2 R < ₅₈ > and having 1 to 3 atoms selected from the group consisting of S, N and O, or

q) ego;

R ₅₆ and R ₅₇ are the same or different from each other,

a) H,

b) formyl,

c) C _1-4 alkyl,

d) C _1-4 acyl,

e) phenyl,

f) C _3-6 cycloalkyl, or

g) R ₅₆ and R ₅₇ together with the nitrogen atom form a 5- or 6-membered saturated heterocyclic residue optionally having an additional heteroatom selected from the group consisting of S, N and O, Optionally substituted on the nitrogen atom, including phenyl, pyrimidyl, C _1-3 alkyl or C _1-3 acyl;

R ₅₈ is a) carboxyl,

b) halo,

c) -CN,

d) mercapto,

e) formyl,

f) CF _3,

g) -NO ₂ ,

h) _C1-6 alkoxy,

i) C _1-6 alkoxycarbonyl,

j) C _1-6 alkylthio,

k) _C1-6 acyl,

l) phenyl,

m) OH, azido, C _1-5 alkoxy, C _1-5 acyl, -NR ₆₅ R ₆₆ , -SR ₆₇ , -O-SO ₂ R ₆₈ or _Lt; RTI ID = 0.0 > Cl 6alkyl, < / RTI &

n) -C (= O) NR ₅₉ R ₆₀ ,

o) -NR ₅₆ R ₅₇ ,

p) -N (R ₅₉ ) (-SO ₂ R ₅₄ ),

q) -SO ₂ -NR ₅₉ R ₆₀ ,

_{r) -S (= O) i} R 54,

s) -CH = NR < ₆₁ >, or

_{t) -CH (OH) -SO 3} R 64 a;

R ₅₄ is as defined above;

R ₅₉ and R ₆₀ are the same or different from each other,

a) H,

b) _C1-6 alkyl,

c) phenyl, or

d) tolyl;

R < ₆₁ > is a) OH,

b) benzyloxy,

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

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

e) -NH-C (= NH) -NR < ₆₂ > R < _{63 &} gt ;;

R ₆₂ and R ₆₃ are the same or different from each other,

a) H, or

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

R ₆₄ is a) H, or

b) a sodium ion;

R ₆₅ and R ₆₆ are the same or different from each other,

a) H,

b) formyl,

c) C _1-4 alkyl,

d) C _1-4 acyl,

e) phenyl,

f) C _3-6 cycloalkyl,

g) R ₆₅ and R ₆₆ together are phenyl, pyrimidyl, C _1-3 alkyl or C ₁ -3 alkyl optionally substituted on the nitrogen atom, having 1 to 3 atoms selected from the group consisting of S, N and O, It achieved a 5-or 6-membered saturated heterocyclic moiety which optionally substituted with acyl, or _-3,

h) -P (O) (OR ₇₀ ) (OR ₇₁ ), or

i) -SO ₂ -R _72, and;

R ₆₇ is ;

R ₆₈ is C _1-3 alkyl;

R ₆₉ is a) C _1-6 alkoxycarbonyl, or

b) carboxyl;

R ₇₀ and R ₇₁ are the same or different from each other,

a) H, or

b) C _1-3 alkyl;

R ₇₂ is a) methyl,

b) phenyl, or

c) tolyl;

K is a) O, or

b) S;

R ₇₃ , R ₇₄ , R ₇₅ , R ₇₆ and R ₇₇ are the same or different from each other,

a) H,

b) carboxyl,

c) halo,

d) -CN,

e) mercapto,

f) formyl,

g) CF _3,

h) -NO ₂ ,

i) C _1-6 alkoxy,

j) C _1-6 alkoxycarbonyl,

k) _C1-6 alkylthio,

l) _C1-6 acyl,

m) -NR ₇₈ R ₇₉ ,

n) OH, C _1-5 alkoxy, C _1-5 acyl, -NR ₇₈ R _79, -N _{(phenyl) (CH 2 -CH 2 -OH)} , -O-CH (CH 3) (OCH 2 CH 3 ) -O- or phenyl- [para -NHC (= O) CH _3], optionally substituted C _1-6 alkyl,

o) C _{2-8 alkenylphenyl} optionally substituted with R ₅₁ ,

p) phenyl optionally substituted with R < _{51 &} gt ;, or

q) a 5- or 6-membered saturated or unsaturated heterocyclic residue optionally substituted with R ₅₁ and having 1 to 3 atoms selected from the group consisting of S, N and O;

R ₅₁ is as defined above;

R ₇₈ and R ₇₉ are the same or different from each other,

a) H,

b) C _1-4 alkyl,

c) phenyl, or

d) R ₇₈ and R ₇₉ together with the nitrogen atom form a 5- or 6-membered saturated heterocyclic residue, said residue optionally having an additional heteroatom selected from the group consisting of S, N and O, Optionally substituted on the nitrogen atom, including C _1-3 alkyl or C _1-3 acyl;

T is a) O,

b) S, or

c) SO ₂ ;

R ₇₅ , R ₇₆ and R ₇₇ are as defined above;

R < _{80 &} gt _; is a) H,

b) formyl,

c) carboxyl,

d) C _1-6 alkoxycarbonyl,

e) _C1-8 alkyl,

f) C _2-8 alkenyl wherein the substituents (e) and (f) are OH, halo, C _1-6 alkoxy, C _1-6 acyl, C _1-6 alkylthio or C _1-6 alkoxycarbonyl , Or phenyl optionally substituted with halogen),

g) 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 An aromatic moiety of 6 to 10 carbon atoms optionally substituted with carbonyl,

h) -NR ₈₁ R ₈₂ ,

i) -OR ₉₀ ,

j) -S (= O) _i- R ₉₁ ,

_{k) -SO 2 -N (R 92} ) (R 93), or

l) a radical of the formula:

R ₈₁ and R ₈₂ are the same or different from each other

a) H,

b) C _3-6 cycloalkyl,

c) phenyl,

d) C _1-6 acyl,

e) C _1-6 alkoxy which may be substituted by OH, OH, 5- or 6-membered aromatic heterocyclic residue having 1 to 3 atoms selected from the group consisting of S, N and O, OH, CF ₃ , Halo, -NO ₂ , C _1-4 alkoxy, -NR ₈₃ R ₈₄ or / RTI > optionally substituted < RTI ID = 0.0 > C _1-8 alkyl,

f) , or

g) ;

V is a) O,

b) CH ₂ , or

c) NR ₈₇ ;

R ₈₃ and R ₈₄ are the same or different from each other,

a) H, or

b) C _1-4 alkyl;

R ₈₅ is a) OH,

b) C _1-4 alkoxy, or

c) -NR ₈₈ R ₈₉ ;

R ₈₆ is a) H, or

b) indolyl, OH, MER kaptil, imidazolyl, methylthio, amino, phenyl, -C (= O optionally substituted with OH) -NH _2, -CO ₂ H, or -C (= NH) -NH _{2 Lt} ; / RTI >alkyl;

R ₈₇ is a) H,

b) phenyl, or

c) C _1-6 alkyl optionally substituted with OH;

R ₈₈ and R ₈₉ are the same or different from each other,

a) H,

b) _C1-5 alkyl,

c) C _3-6 cycloalkyl, or

d) phenyl;

R ₉₀ is selected from a) C _1-6 alkoxy or C _1-6 hydroxy, C _3-6 cycloalkyl, 1 to 3 nitrogen atoms and also 1 or 2 --NO ₂ , CF ₃ , halo, -CN , C _1-8 alkyl optionally substituted with a benzo-fused heterocyclic residue of a six-membered aromatic which may be substituted with OH, C _1-5 alkyl, C _1-5 alkoxy or C _1-5 acyl,

b) ,

c) phenyl, or

d) pyridyl;

R ₉₁ is a) C _1-16 alkyl,

b) C _2-16 alkenyl, wherein said substituents (a) and (b) are selected from C _1-6 alkoxycarbonyl, or C _1-6 alkoxycarbonyl having 5 to 5 atoms having 1 to 3 atoms selected from the group consisting of S, -, 6- or 7-membered aromatic heterocyclic residue), < RTI ID = 0.0 >

c) an aromatic moiety having 6 to 10 carbon atoms,

d) a 5-, 6- or 7-membered aromatic heterocyclic residue having 1 to 3 atoms selected from the group consisting of S, N and O, wherein said substituents (c) and (d) , 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 Lt; / RTI >

R ₉₂ and R ₉₃ are the same or different from each other,

a) H,

b) phenyl,

c) _C1-6 alkyl, or

d) benzyl;

R ₉₄ and R ₉₅ are the same or different from each other,

a) H,

b) OH,

c) C _1-6 alkyl optionally substituted by -NR ₈₃ R ₈₄ , or

d) R ₉₄ and R ₉₅ together form = O;

R ₉₆ is a) an aromatic moiety having 6 to 10 carbon atoms,

b) optionally benzo-fused heterocyclic residue of 5- or 6-membered aromatic having 1 to 3 atoms selected from the group consisting of S, N and O, wherein said substituents (a) and (b) Which may be further substituted with 1-3 of -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) _C1-6 alkoxy,

f) -NR ₈₃ R ₈₄ ,

g) -C (= O) -R < _{97 &} gt ;, or

h) ego;

R ₉₇ 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;

l is 2 or 3;

m is 4 or 5;

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

p is 0, 1, 2, 3, 4 or 5, provided that the sum of n and p is 1, 2, 3, 4 or 5;

q is 1, 2, 3 or 4;

r is 2, 3 or 4;

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

u is 1 or 2;

w is 0, 1, 2 or 3;

The novel compounds of the present invention can be prepared by synthetic methods known in the art using known compounds and intermediates of oxazolidinones, isoxazolines and butyolactones as intermediates. Typically, the thioamide of the present invention can be prepared by reacting the corresponding amide with Lawesson's reagent.

The compounds disclosed in the following publications are suitable intermediates for the preparation of the compounds of the present invention and are herein incorporated by reference for the disclosures of suitable compounds which can be converted into thiocarbonyl derivatives of the invention.

U.S. Patent No. 5,225,565; 5,182,403; 5,164,510; 5,247,090; 5,231, 188; 5,565,571; 5,547,950; And 5,523,403.

PCT Application and Disclosure Publication PCT / US93 / 04850, WO94 / 01110; PCT / US94 / 08904, WO95 / 07271; PCT / US95 / 02972, WO95 / 25106; PCT / US95 / 10992, WO96 / 13502; PCT / US96 / 05202, WO96 / 35691; PCT / US96 / 12766; PCT / US96 / 13726; PCT / US96 / 14135; PCT / US96 / 17120; PCT / US96 / 19149; PCT / US97 / 01970; PCT / US95 / 12751, WO96 / 15130; And PCT / US96 / 00718, WO96 / 23788.

Chemical conversion techniques for converting various intermediates having CH ₂ NH ₂ on the oxazolidinone ring to CH ₂ NH-C (S) -CH ₃ are described by Hartke, K., Barrmeyer, S.), J. prakt. Chem. 1996, 338, 251-6. Similarly, CH ₂ NHC (= O) is described by Cava (Cava, MP) for converting the CH ₃ to CH ₂ NHC (S) NHCH ₃ In this; Levinson, MI, Thionation Reactions of Lawesson ' s Reagents, Tetrahedron 1985, 41, 5061-87.

For purposes of the present invention, the carbon content of the various hydrocarbon containing moieties is denoted by a prefix indicating the minimum and maximum number of carbon atoms in the residue, i. E., The prefix C _{ij is a} number from "i" to "j" And the presence of a carbon atom in the molecule. Thus, C _1-4 alkyl means alkyl of 1 to 4 carbon atoms, i.e. methyl, ethyl, propyl, butyl and isomeric forms thereof.

"C _1-2 alkyl", "C _1-3 alkyl", "C _1-4 alkyl", "C _1-5 alkyl", "C _1-6 alkyl", "C _1-8 alkyl" and "C _1-16 alkyl "are each carbon atoms of 1 to 2, 1-3, 1-4, 1-5, 1-6, 1 to 8 stands for, or an alkyl group of 1 to 16, for example, methyl, ethyl, propyl , Butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and isomeric forms thereof.

"C _2-4 alkenyl", "C _2-5 alkenyl", "C _2-8 alkenyl", "C _2-14 alkenyl" and "C _2-16 alkenyl" are each carbon atoms of 2 to Refers to an alkenyl group having at least one double bond of 4, 2 to 5, 2 to 8, 2 to 14, or 2 to 16 carbon atoms, for example, ethenyl, propenyl, butenyl, pentenyl, pentadienyl, hexenyl , Hexadienyl, heptenyl, heptadienyl, octenyl, octadienyl, octadienyl, nonenyl, nonadienyl, nonadienyl, undecenyl, undecenyl, undecenyl, tridecenyl , Tetradecenyl, and isomeric forms thereof.

&Quot; C _2-5 alkynyl "," C _2-8 alkynyl ", and " C _2-10 alkynyl " mean an alkynyl group having at least two triple bonds each having 2 to 5, 2 to 8, And examples thereof include ethynyl, propynyl, butynyl, pentynyl, pentynyl, hexynyl, hexynyl, heptynyl, heptynyl, octynyl, octynyl, octanthryl, nonynyl, Nonadienyl, nonadienyl, and isomeric forms thereof.

The terms "C _3-4 cycloalkyl", "C _3-6 cycloalkyl", "C _5-6 cycloalkyl" and "C _3-8 cycloalkyl" , Or a cycloalkyl group having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms.

"C _1-4 alkoxy", "C _1-6 alkoxy", and "C _1-8 alkoxy" refer to an alkyl group of 1-4 carbon atoms, For example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy or octyloxy, and isomeric forms thereof.

&Quot; C _1-6 alkylamino " and " C _1-8 alkylamino " mean alkyl groups of 1 to 6 carbon atoms or 1 to 8 carbon atoms, respectively, bonded to the amino moiety and include, for example, , Butylamino, pentylamino, hexylamino, heptylamino or octylamino, and isomeric forms thereof.

&Quot; C _1-6 dialkylamino " and " C _1-8 dialkylamino " mean two alkyl groups each having 1 to 6 carbon atoms or 1 to 8 carbon atoms bonded to an amino residue, for example, dimethylamino, methyl Ethylamino, diethylamino, dipropylamino, methylpropylamino, ethylpropylamino, dibutylamino, dipentylamino, dihexylamino, methylhexylamino, diheptylamino or dioctylamino and isomeric forms thereof.

"C _1-3 acyl", "C _1-4 acyl", "C _1-5 acyl", "C _1-6 acyl", "C _1-8 acyl" and "C _2-8 acyl" Means a carbonyl group having an alkyl group of 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 8, or 2 to 8 in embroidery.

The "C _1-4 alkoxycarbonyl", "C _1-6 alkoxycarbonyl" and "C _1-8 alkoxycarbonyl" are each an ester having an alkyl group having 1 to 4, 1 to 6, or 1 to 8 carbon atoms It means the period.

"C _1-8 alkylphenyl" refers to an alkyl group of 1 to 8 carbon atoms and isomeric forms thereof, substituted with one or more phenyl radicals.

"C _2-8 alkenylphenyl" means an alkenyl group having 1 to 8 carbon atoms, at least one double bond, and isomeric forms thereof, substituted with one or more phenyl radicals.

"C _1-8 alkylpyridyl" refers to an alkyl group of 1 to 8 carbon atoms and isomeric forms thereof, substituted with one or more pyridyl radicals.

&Quot; C _1-8 hydroxyl " refers to an alkyl group of 1 to 8 carbon atoms and isomers thereof, bonded to a hydroxyl group.

&Quot; C _1-8 alkylsulfonyl " means an alkyl group of 1 to 8 carbon atoms bonded to the SO ₂ moiety and isomers thereof.

"C _1-6 alkylthio" means an alkyl group having 1 to 6 carbon atoms bonded to a sulfur atom and isomers thereof.

&Quot; Het " includes, for example, pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3- pyridyl, 4- pyridyl, 2- pyrimidinyl, 4- pyrimidinyl, 2-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinolyl, Imidazolyl, 4-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-quinazolinyl, 2- quinazolinyl, 4-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, , 4,5-dihydrooxazole, 1,2,3-oxathiol, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1 , 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2- 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzo Thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isohexyl, 2-thienyl, Pyridyl, pyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3-oxathiazole-1-oxide, 1,2,4-oxadiazol- Oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazole-5 Thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, Triazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1, Pyrrolyl, 1-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1 -tetrazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-oxadiazole, 4-isothiazolyl, 4-isothiazolyl, Oxo-2-thiazolinyl or 5-methyl-1,3,4-thiadiazol-2-yl, thiazolidone, 1,2,3,4-thiatriazole, A 5-10-membered saturated, unsaturated or aromatic heterocyclic ring containing one or more oxygen, nitrogen and sulfur atoms which forms a group such as 2,4-diethylazone. These residues may each be appropriately substituted.

&Quot; Halo " means fluoro, chloro, bromo or iodo.

The compounds of the present invention can be converted into their salts, if appropriate, in the customary manner.

&Quot; Pharmaceutically acceptable salts " refer to acid addition salts useful in the administration of the compounds of the present invention, including those derived from hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, acetates, propionates, lactates, mesylates, Acid salts, malic acid salts, succinic acid salts, tartaric acid salts, citric acid salts, 2-hydroxyethylsulfonic acid salts, fumaric acid salts and the like. These salts may exist in the form of hydrates.

When Q has the structure of the following formula, the dotted line in the heterocyclic ring means that the bond may be a single bond or a double bond. If the dotted line is a double bond, then the R ₃₉ group will not be present.

The compounds of formula (I) of the present invention contain a chiral center at C5 of the isoxazoline ring and thus both enantiomers or racemic mixtures thereof are present in all. The present invention relates to both mixtures comprising both enantiomers and both isomers. Further, depending on the substituent, there may be additional chiral centers and other isomeric forms at every A or R ₁ group, and the present invention includes all possible stereoisomeric and geometric forms of these groups.

The compounds of the present invention are useful for the treatment of microbial infections in humans and other warm-blooded animals by parenteral and oral administration.

The pharmaceutical compositions of the present invention may be prepared by admixing the compounds of the present invention with pharmaceutically acceptable solid or liquid carriers using standard and conventional techniques, optionally with pharmaceutically acceptable adjuvants and excipients therein. Solid form compositions include powders, tablets, dispersible granules, capsules, cachets, and suppositories. The solid carrier may be one or more substances which may also function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, tablet disintegrating agents and encapsulating agents. Examples of the inert solid carrier include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulose-based material, low melting point wax, cocoa butter and the like. The liquid composition includes a solution, a suspension, and an emulsion. For example, solutions of the compounds of the present invention in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional colorants, flavors, stabilizers and thickeners, may be provided.

Preferably, the pharmaceutical compositions are provided in unit dosage form containing an effective amount or an appropriate amount of the active compound, i.e., a compound according to the present invention, using conventional techniques.

The amount of the active compound, i.e., the compound according to the present invention, in the pharmaceutical composition and its unit dosage form can vary or be varied widely depending on the particular application, the potency of the particular compound, and the desired concentration. Generally, the amount of active compound will range from 0.5 to 90% by weight of the composition.

In therapeutic applications for treating or defeating bacterial infections in warm-blooded animals, the compounds of the present invention or pharmaceutical compositions thereof may be used to obtain and maintain an antimicrobially effective concentration, i.e., a positive or blood level, of an active ingredient in an animal undergoing treatment Orally, parenterally and / or topically to the patient for a predetermined period of time. In general, the dosage as such an antibacterially effective amount of active ingredient will range from about 0.1 to about 100 mg per kg of body weight per day, more preferably from about 3.0 to about 50 mg per day. It is understood that the dosage will vary depending upon the requirements of the patient, the severity of the bacterial infection to be treated and the particular compound being employed. In addition, the initial dose may be increased above the upper limit to achieve the desired blood level quickly, or the initial dose may be made smaller than the optimal value, and the daily dose Can be gradually increased. If desired, the daily dose may be divided into a plurality of doses for administration, for example, two to four times daily.

The compounds according to the invention are administered parenterally, i. E. By injection, for example by intravenous injection or other parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally comprise a pharmaceutically acceptable liquid carrier such as, for example, water for injection, and a pharmaceutical agent dissolved in a buffer to provide, for example, a suitably buffered isotonic solution having a pH of about 3.5 to 6 Acceptable amount of the compound or a soluble salt (acid addition salt or base salt). Suitable buffers include, for example, sodium orthosontin, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) - lysine and L (+) - arginine and many other representative buffers. The compounds of the present invention will generally be dissolved in a carrier in an amount sufficient to provide a pharmaceutically acceptable, injectable concentration in the range of about 1 mg / ml to about 400 mg / ml in solution. The resulting liquid pharmaceutical composition will be administered to obtain an antimicrobially effective dose as described above. The compounds according to the invention are conveniently orally administered in solid and liquid dosage forms.

An effective amount of a compound of formula I as topical treatment is incorporated into a pharmaceutically acceptable gel or cream vehicle that is capable of being applied to the treatment site of the patient's skin. Such creams and gels are well known in the art and may include penetration enhancers.

MIC Test Method

The in vitro MIC of test compounds was determined by standard agar dilution method. A crude stock solution of each analogue was prepared using the desired solvent, generally DMSO: H ₂ O (1: 3). A 1.0-ml aliquot of sterile distilled water was used to prepare a two-fold serial dilution of each sample. To each 1.0 ml aliquot of the drug was added 9 ml of molten Mueller Hinton agar medium. Agents - supplemented agar were mixed and poured into 15 x 100 mm Petri dishes, solidified and dried and then inoculated.

Each vial containing test organisms was kept frozen on the vapor of a liquid nitrogen freezer. Test cultures were grown overnight at 35 ° C on a medium suitable for organisms. Colonies were collected with a sterile swab and the cell suspension was prepared in Trypticase Soy broth (TSB) to equal the turbidity of the 0.5 McFarland standard. A 1: 20 dilution of each suspension was prepared in TSB. A plate containing the drug-supplemented agar was inoculated with 0.001 ml of the cell suspension using a Steers replicator to a concentration of about 10 ⁴ to 10 ⁵ cells per spot. Plates were incubated overnight at < RTI ID = 0.0 > 35 C. < / RTI >

After incubation, the minimum inhibitory concentration (MIC / / ml), the minimum concentration of drug that inhibits the visible growth of the organism, is read and recorded. The data are shown in Tables I and II below.

rescue Oxazolidinone MIC value (Gram +) < RTI ID = 0.0 > SAUR 9213 SEPI 12084 EFAE 9217 SPNE 9912 SPYO 152 Comparative Example * 16 4 8 .5 One Example 3 4 One 2 .25 .5 * Not a compound of the present invention.

rescue Oxazolidinone MIC value (Gram +) &lt; RTI ID = 0.0 &gt; SAUR 9213 SEPI 12084 EFAE 9217 SPNE 9912 SPYO 152 Comparative Example * 2 One 2 .5 One Example 1 One .25 .5 .13 .13 Example 5 One .25 .5 <.125 .25 Example 6 2 One 2 .5 One Comparative Example * .5 .25 One .13 .25 Example 2 8 2 4 2 4 SAUR: S. aureus (Stability Philo nose kusu aureus (S. aureus)) SEPI: Staphylococcus epidermidis (Stability Philo nose kusu epi der US display (S. epidermidis)) EFAE: Enterococcus faecalis kusu nose (E. faecalis ) SPNE: Streptococcus pneumoniae (Streptococcus pneumoniae ) SPYO: Purulent streptococcus (Streptococcus pyogenes ) * Not a compound of the present invention.

Example No. SAUR 9213MIC SEPI 30593 MIC EFAE 12712 MIC SPNE 9912MIC SYPO152MIC HINF 30063 MIC MCAT 30610 MIC EFAE9217MIC One One 0.25 0.5 <0.125 <0.125 8 One 0.5 2 8 4 8 2 4 > 16 > 16 4 3 4 One One 0.25 0.5 16 4 2 5 One 0.5 0.5 <0.125 0.25 4 2 0.5 6 2 2 2 0.5 One 16 8 2 7 0.5 0.25 0.5 <0.125 0.25 4 One 0.5 8 2 One 0.5 <0.125 0.25 4 2 One 9 0.5 0.25 0.25 <0.125 <0.125 2 0.5 0.25 10 2 One 0.5 <0.125 0.25 2 One One 11 0.25 0.25 0.25 <0.125 0.25 2 One 0.25 12 One 0.5 0.25 <0.125 <0.125 One 0.5 0.5 13 One One 2 0.5 One > 16 8 2 14 One 0.5 One 0.25 0.5 8 One One 15 32 16 32 4 8 > 64 64 32 16 8 8 16 2 8 > 64 32 16 17 2 2 4 One 2 64 16 4 18 2 One 2 <0.5 One 32 4 2 19 32 16 32 16 16 64 32 32 21 4 4 8 2 4 64 16 8 22, 23 0.5 0.5 One <0.125 0.25 4 2 One 24 One 0.25 0.5 <0.125 0.25 4 2 0.5 25 0.5 0.25 0.5 <0.125 <0.125 2 2 0.5 26 One 0.5 One 0.25 0.5 16 2 One 27 0.5 0.5 0.5 <0.125 0.25 4 2 One 28 0.5 0.25 0.5 0.25 0.25 2 One 0.5 29 0.25 0.25 0.25 <0.125 <0.125 2 0.5 0.25 30 4 One 0.5 <0.125 0.25 8 2 One 31 2 One One <0.125 0.25 4 One One 32 16 2 2 0.25 0.25 8 2 4 33 4 2 One 0.25 0.25 4 2 4 34 2 One 2 0.5 One > 16 4 2 35 One 0.5 One 0.25 0.5 16 2 One Key: SAUR 9213: Staphylococcus aureus (S. aureus) SEPI 30593: Staphylococcus epidermidis (S. epidermidis) EFAE 12712: a. Passive help (E. Faecium) SPNE 9912: Streptococcus pneumoniae (S. pneumoniae) SPYO 152: suppurative streptococcus (S. pyogenes) HINF 30063: Haemophilus influenzae (Haemophilus influenza) MCAT 30610: morak Cellar Qatar LAL-less (Moraxella catarrhalis) EFAE 9217: Enterococcus faecalis ( Enterococcus faecalis)

As shown in Reaction Scheme 1, Intermediate II for the compounds of the present invention is also an intermediate which is also disclosed in the oxazolidinone patents and published applications cited therein. Intermediate IV of the present invention is the final product (example) of the oxazolidinone patents and published applications cited above.

Isothiocyanate III can be prepared by reacting the amine intermediate II with 1, 1 ' -thiocarbonyldi-2 &lt; RTI ID = 0.0 &gt; (1H) -pyridone. &Lt; / RTI &gt; The thiourea (Ia, R '= H, alkyl _1-4 ) can then be reacted with ammonia or a suitable tertiary amine, such as ammonia, in a solvent such as 1,4-dioxane or tetrahydrofuran at 0-50 & Amine in the presence of a base. Alternatively, as illustrated in Example 6 and shown in Step 3, thiourea can be prepared by reacting Compound II with the appropriate isothiocyanate (R'-N = C = S) and a suitable isothiocyanate in a solvent such as tetrahydrofuran at 0-50 & Followed by reaction. Thioamide (Ib, R "= H, alkyl _1-4) is illustrated in Example 4 and as shown in step 4, the appropriate dithio ester of the compound Ⅱ (R"'SC (= S) -R ") and The reaction is carried out in the presence of an alkali metal hydroxide equivalent in an aqueous-alcoholic solvent at 0 to 50 ° C. The reaction can be catalyzed by an alkali metal fluoride, especially when R "'is methyl or ethyl have.

The reaction of compound II with R "'- SC (S) - R"' (R "'= CH ₃ , C ₂ H ₅ ) to give compound Ib (step 4) In the presence of a tertiary amine base such as triethylamine in a solvent such as THF, dioxane or methylene chloride for 48 hours.

(Ib, R " = H, alkyl _1-4 ) is reacted with an appropriate amide intermediate (IV) in a ratio of 60 to 110 2,4-bis (p-methoxyphenyl) -1,3-dithiadiposphane-2,4-disulfide (Lawess reagent) in 1,4-dioxane, benzene, toluene or tetrahydrofuran at 0- (Brillon, D., Synthetic Communications, 20 , 3085 (1990)) in phosphorus pentachloride and sodium carbonate in tetrahydrofuran at 20 to 50 &lt; 0 &gt; C, or in 10 to 1,2-dimethoxyethane Can conveniently be prepared by reacting with reactants such as phosphorus sulphide and sodium fluoride (Hartke, K., Gerber, HD, J. Prakt. Chem., 338 , 763 (1996) (Step 5).

Compound Ic is prepared by first reacting compound II with a tertiary amine base such as triethylamine and carbon disulfide in a solvent mixture containing water and methanol, ethanol or isopropanol at 10 to 50 &lt; 0 &gt; C for 5 to 24 hours ). The resulting intermediate is treated with an alkylating agent (R &quot; 'X, wherein X is bromo, iodo, alkylsulfonyloxy or arylsulfonyloxy) at 0-30 ° C to give compound Ic. In step 7, compound Ic is reacted with an alkali metal alkoxide such as sodium methoxide or potassium ethoxide in a corresponding alkanol as solvent. This reaction can conveniently be carried out at the reflux temperature of the alkanol for 1 to 24 hours.

In order to further illustrate the features of the present invention and its implementation, the following embodiments are presented.

Example 1: Synthesis of (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide .

A stirred mixture of compound II (PCT / US94 / 08904, 3.37 g, 10.0 mmol) in anhydrous dioxane (100 mL) was treated with Lawesson's reagent (4.04 g, 10.0 mmol) under nitrogen atmosphere and heated at reflux for 1.5 h Lt; / RTI &gt; To 10% MeOH-CHCl ₃ was confirmed completion of the reaction by TLC on silica gel using. This was kept at ambient temperature for 18 hours and concentrated in vacuo. The residue on silica gel was chromatographed with an acetone-methylene chloride mixture containing 10-15% acetone to give the product which was crystallized from acetone-hexane to give compound 1: mp 157.5-158.5 C; HRMS theory for C ₁₆ H ₂₀ FN ₃ O ₃ S (M ⁺ ): 353.1209; Found: 353.1212. Elemental analysis for C ₁₆ H ₂₀ FN ₃ O ₃ S Calculated: C, 54.38; H, 5.38; N, 11.89; S, 9.07. Found: C, 54.21; H, 5.58; N, 11.78; S, 8.93.

Example 2: Synthesis of (S) -N- [[3- [3-fluoro-4- [4- (5-methyl-1,3,4-thiadiazol-2-yl) ] Phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide (2).

Compound 21 (PCT / US97 / 01970) was reacted with a Lawess reagent in refluxing dioxane according to Example 1 for the preparation of compound 1 to give compound 2: mp 222-223 [deg.] C; _{C 19 H 24 FN 6 O 2} S 2 (M + H +) HRMS Calcd for: 451.1386, Found: 451.1381.

Example 3: Synthesis of (S) -N- [[3- [3-fluoro-4- [2 ', 5'-dioxospiro [piperidine-4,4'-imidazolidine] Phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide (3).

Step A: (S) -N- [[3- [3-Fluoro-4- [2 ', 5'-dioxospiro [piperidine-4,4'-imidazolidin] ] Phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (32).

A stirred suspension of 31 (WO 95/25106, 0.349 g, 1.00 mmol) in EtOH: H ₂ O 1: 1 (5 mL) was treated with potassium cyanide (0.130 g, 2.00 mmol) and ammonium carbonate (0.701 g, 7.30 mmol), warmed to 55-60 &lt; 0 &gt; C for 5 h 15 min and maintained at ambient temperature for 17 h 15 min. This was then chromatographed on silica gel with a MeOH-NH ₄ OH-CHCl ₃ mixture containing 5-20% MeOH and 0.5% NH ₄ OH to give 0.280 g of compound 32. HRMS calculated for C ₁₉ H ₂₂ FN ₅ O ₅ : 419.1605 (M ⁺ ); Found: 419.1613; Elemental analysis for C ₁₉ H ₂₂ FN ₅ O ₅ .1H ₂ O Calculated: C, 52.17; H, 5.53; N, 16.01. Found: C, 52.44; H, 5.30; N, 16.11.

Step B: (S) -N- [[3- [3-Fluoro-4- [2 ', 5'-dioxospiro [piperidine- ] Phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide (3)

A stirred suspension of 32 (0.210 g, 0.500 mmol) in dioxane (5.0 mL) was treated with Lawesson's reagent (0.202 g, 0.500 mmol) under nitrogen atmosphere and refluxed for 4 h and concentrated in vacuo. Chromatography of the residue with 1-10% MeOH and the MeOH-NH ₄ OH-CHCl ₃ mixture, containing 0.1-0.5% NH ₄ OH on silica gel and crystallization the resulting product from MeOH-CHCl ₃ -EtOAc Compound 3 0.0491 g: melting point 218.5 DEG C; HR FAB MS theoretical value for C ₁₉ H ₂₂ FN ₅ O ₄ S (M ⁺ ): 435.1376; Found: 435.1370. Elemental analysis for C ₁₉ H ₂₂ FN ₅ O ₄ S .0.5H ₂ O Calculated: C, 51.34; H, 5.21; N, 15.76. Found: C, 51.69; H, 5.00; N, 15.25.

Example 4: Synthesis of (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide .

A solution of 41 (148 mg, 0.500 mmol) and 0.97 M KOH (0.515 mL) in dry EtOH (5 mL) was treated with ethyl dithioacetate (57 L, 0.50 mmol) and sodium fluoride 20 mg, 0.47 mmol) and the mixture was kept at ambient temperature for 3 hours and 40 minutes. After 1 hour and 55 minutes, ethyl dithioacetate (5 μl) was further added and after 3 hours and 5 minutes 0.97 M KOH (40 ml) and sodium fluoride (6 mg) were added to the mixture. The reaction was followed by TLC on silica gel with 10% MeOH-CHCl ₃ and 30% acetone-CH ₂ Cl ₂ . The main product had the same R _f value as compound 4 on TLC.

Example 5: (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thiourea (5).

Step A:

Under a nitrogen atmosphere CH ₂ Cl ₂ and the solution of compound 51 (PCT / US94 / 08904, 2.07 g, 7.00 mmol) CH 2 Cl 2 1,1'- carbonyldiimidazole thio -2 in (70 ㎖) (1H) - Pyridone (1.95 g, 8.40 mmol) in an ice-cooled stirred solution over 30 min. The mixture was slowly warmed to ambient temperature and held for 18 hours. It was then diluted with CH ₂ Cl ₂ , washed with water and aqueous NaCl solution, then dried (Na ₂ SO ₄ ) and concentrated. By chromatography of the residue on silica gel with 10% acetonitrile -CH ₂ Cl ₂ to give the isothiocyanate 1.60 g; _{C 15 H 16 FN 3 O 3} HRMS Calcd for S (M ^+): 337.0896; Found: 337.0888.

Step B:

Anhydrous ammonia was bubbled through the stirred solution of the product from Step I (1.00 g, 2.96 mmol) in THF (10 mL) for 7 min and the mixture was kept at ambient temperature for 3 h 25 min and then concentrated in vacuo. The residue was crystallized from acetone-hexane to give 0.861 g of compound 5: mp 199-199.5 C; MS m / z 354 (M ^&lt; ^{+ &} gt ^; ). Elemental analysis for C ₁₅ H ₁₉ FN ₄ O ₃ S Calculated: C, 50.84; H, 5.40; N, 15.81. Found: C, 50.87; H, 5.39; N, 15.72.

Example 6: Synthesis of (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Urea (6).

A stirred solution of methyl isothiocyanate (93 mg, 1.27 mmol) in THF was treated with 61 (295 mg, 1.00 mmol) and kept at ambient temperature for 18 hours and then concentrated in vacuo. The residue was recrystallized from EtOAc-hexane to give 246 mg of compound 6: mp 158-160 &lt; 0 &gt;C; MS m / z 368 (M ^&lt; ^{+ &} gt ^; ). Elemental analysis for C ₁₆ H ₂₁ FN ₄ O ₃ S Calculated: C, 52.16; H, 5.74; N, 15.21. Found: C, 52.20; H, 5.85; N, 15.17.

Example 7: Synthesis of (S) -cis-N - [[3- [3-fluoro-4- (tetrahydro-1-oxido-2H-thiopyran- - &lt; / RTI &gt; oxazolidinyl] methyl] ethanethioamide.

Step 1: To a solution of (S) - (-) - N - [[3- [3-fluoro-4- (3,6-dihydro-2H-thiopyran- (4.50 g, obtainable according to the procedure described in WO97 / 09328) and platinum oxide (697 mg) was dissolved in 18 Lt; / RTI &gt; under a hydrogen atmosphere at 40 psi pressure for a period of time. The catalyst was then removed by filtration through celite and the filtrate was concentrated under reduced pressure and then the residue was eluted with a methanol / methylene chloride gradient (3 / 97-7 / 93) on silica gel (230-400 mesh, 350 g) &Lt; / RTI &gt; The fractions with R _f = 0.44 were collected by TLC (methanol / chloroform, 10/90) and concentrated to give (S) -cis- (-) - N - [[3- [3-fluoro- Yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide, melting point 203-204 占 폚.

Step 2: To a mixture of the compound obtained in step 1 (2.50 g) and hydroxylamine hydrochloride (2.36 g) in pyridine (30.6 mL) and ethanol (3.4 mL) at 100 &lt; 0 &gt; C for 22 h and at ambient temperature for 16 h Was stirred in a screw-cap vial during which time additional hydroxylamine hydrochloride (944 mg) and pyridine (4 mL) were added. The reaction mixture was then concentrated under reduced pressure, diluted with a saturated aqueous sodium bicarbonate solution (100 ml) and brine (50 ml), adjusted to pH 11 with solid sodium carbonate and then washed with methanol / methylene chloride (10/90, 5 x 100 ml) . The combined organic phases were concentrated under reduced pressure and the crude product was chromatographed on silica gel (230-400 mesh, 150 g) eluting with a methanol / methylene chloride gradient (6 / 94-10 / 90). The fractions with R _f = 0.14 were collected by TLC (methanol / chloroform, 10/90) and concentrated to give (S) -cis-3- [3-fluoro-4- (tetrahydro- Pyran-4-yl) phenyl] -5-aminomethyl-2-oxazolidinone, melting point 159-161 DEG C.

Step 3: A solution of ethyl dithioacetate (105 mL, 0.919 mmol) and sodium fluoride (39 mg, 0.919 mmol) in ethanol (9.2 mL) was added dropwise to a solution of (S) 4-yl) phenyl] -5-aminomethyl-2-oxazolidinone (300 mg, 0.919 mmol, ) And aqueous potassium hydroxide solution (1 M, 0.92 mL). The resulting solution was stirred at ambient temperature for 4 hours then diluted with methylene chloride (150 mL), washed with water (50 mL), aqueous potassium hydrogen sulfate (1 M, 50 mL) and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo, then the crude product was triturated with methylene chloride / diethyl ether and filtered to give the title compound, mp 176-177 C (decomp.).

Example 8: Preparation of (S) -cis- [[3- [3-fluoro-4- (tetrahydro-1-oxido-2H-thiopyran- Methyl] thiourea. &Lt; / RTI &gt;

Step 1: A solution of 1,1'-thiocarbonyldi-2 (1H) -pyridone (235 mg, 1.01 mmol) in anhydrous methylene chloride (10 mL) was treated at 0 <0> C under an atmosphere of nitrogen with anhydrous methylene chloride Cis-3- [3-fluoro-4- (tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -5- And treated with a solution of aminomethyl-2-oxazolidinone (275 mg, 0.843 mmol) for 30 min. The resulting mixture was stirred at 0 &lt; 0 &gt; C for 30 minutes and at ambient temperature for 1 hour, then diluted with methylene chloride (40 mL), washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, &Lt; / RTI &gt; The crude product was chromatographed on silica gel (70-230 mesh, 20 g) eluting with acetonitrile / methylene chloride (40/60) and purified by TLC (acetonitrile / methylene chloride, 30/70) to give _Rf = The fractions were collected and concentrated to give (S) -cis-3- [3-fluoro-4- (tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -5-isothiocyanatomethyl- 2-oxazolidinone, melting point 187-190 DEG C (decomposition).

Step 2: To a solution of (S) -cis-3- [3-fluoro-4- (tetrahydro-1-oxido-2H-thiopyran- -Isothiocyanatomethyl-2-oxazolidinone (step 1, 290 mg, 0.787 mmol) was treated (bubbled) at 0 &lt; 0 &gt; C for 5 minutes with an ammonia gas stream under a nitrogen atmosphere. The reaction pot was sealed and the resulting mixture was stirred at 0 &lt; 0 &gt; C for 1 hour. The excess ammonia was then removed under a stream of nitrogen and the reaction mixture was concentrated in vacuo to give a crude product. Recrystallization from methanol / methylene chloride / diethyl ether gave the title compound, mp 206-208 C (decomposition).

Example 9: Synthesis of (S) -trans-N - [[3- [3-fluoro-4- (tetrahydro-1-oxido-2H-thiopyran- - &lt; / RTI &gt; oxazolidinyl] methyl] ethanethioamide.

Step 1: (S) - (-) - N - [[3- [3-Fluoro-4- (3,6-dihydro-2H-thiopyran- -Oxazolidinyl] methyl] acetamide S-oxide (disclosed in WO 97/09328) can be reduced to the corresponding cis- and trans-sulfoxide by catalytic hydrogenation in the presence of a catalyst and a solvent have. Alternatively, the sulphide, which is a by-product of the reduction reaction, can be oxidized with an oxidizing agent such as NaIO ₄ or meta-chloroperoxybenzoic acid in a solvent to provide cis- and trans-sulfoxide. Alternatively, the sulfide byproduct can be selectively oxidized to the trans isomer using t-butyl hydroperoxide and a catalyst such as Ti (OiPr) ₄ and D-diisopropyl tartrate in a suitable solvent. The isomeric mixture can then be separated by chromatography to isolate trans-sulfoxide (melting point 211-212 占 폚 (decomposition)). (-) - N - [[3- [3-fluoro-4- (tetrahydro-1-oxo- Methyl] acetamide (0.90 g) and hydroxylamine hydrochloride (0.85 g) was stirred at 100 ° C for 23 hours, and Was stirred in a screw-cap vial for 19 hours at ambient temperature during which time additional hydroxylamine hydrochloride (340 mg) and pyridine (1 mL) were added. The reaction mixture was then concentrated under reduced pressure, diluted with a saturated aqueous sodium carbonate solution (50 mL) and brine (50 mL), and extracted with methanol / methylene chloride (10/90, 6 x 100 mL). The combined organic phases were concentrated under reduced pressure and the crude product was chromatographed over silica gel (230-400 mesh, 45 g) eluting with a methanol / methylene chloride gradient (7.5 / 92.5-10 / 90). The fractions with R _f = 0.14 were collected by TLC (methanol / chloroform, 10/90) and concentrated to give (S) -trans-3- [3-fluoro-4- (tetrahydro- Pyran-4-yl) phenyl] -5-aminomethyl-2-oxazolidinone, mp 138-140 &lt; 0 &gt; C.

Step 2: A solution of ethyl dithioacetate (105 mL, 0.919 mmol) and sodium fluoride (39 mg, 0.919 mmol) in ethanol (9.2 mL) was added dropwise to a solution of (S) Phenyl] -5-aminomethyl-2-oxazolidinone (300 mg, 0.919 mmol) was added dropwise to a solution of 3-fluoro-4- (tetrahydro- ) And potassium hydroxide aqueous solution (1 M, 0.92 mL). The resulting solution was stirred at ambient temperature for 17 hours then diluted with methylene chloride (150 mL), washed with water (2 x 50 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (230-400 mesh, 35 g) eluting with methanol / methylene chloride (3/97) and the fractions with R _f = 0.56 were collected by TLC (methanol / chloroform, 10/90) The residue was then recrystallized from methylene chloride / diethyl ether to give the title compound, mp 193-194 占 (decomposition).

Example 10: Synthesis of (S) -trans- [[3- [3-fluoro-4- (tetrahydro-1 -oxido-2H-thiopyran- Methyl] thiourea. &Lt; / RTI &gt;

Step 1: A solution of 1,1'-thiocarbonyldi-2 (1H) -pyridone (192 mg, 0.827 mmol) in anhydrous methylene chloride (8.3 mL) was treated at 0 ° C. with anhydrous methylene chloride (S) -trans-3- [3-fluoro-4- (tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -5- Was treated with a solution of aminomethyl-2-oxazolidinone (225 mg, 0.689 mmol) for 30 min. The resulting mixture was stirred at 0 &lt; 0 &gt; C for 30 min, and at ambient temperature for 40 min, then diluted with methylene chloride (20 mL), washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, &Lt; / RTI &gt; The crude product was chromatographed on silica gel (32-63 mm, 40 g) eluting with an acetonitrile / methylene gradient (30 / 70-60 / 40) with a gradient of 15 psi nitrogen and eluted with TLC (acetonitrile / methylene chloride, 30 to collect the fraction R _f = 0.12 by / 70) enriched (S) - trans-3- [4- (tetrahydro-1-oxido -2H- thiopyran-4-yl) 3-fluorophenyl ] -5-isothiocyanato-2-oxazolidinone, melting point 165-167 [deg.] C.

Step 2: To a solution of (S) -trans-3- [3-fluoro-4- (tetrahydro-1-oxo-2H-thiopyran- -Isothiocyanatomethyl-2-oxazolidinone (step 1, 230 mg, 0.624 mmol) was treated (bubbled) at 0 &lt; 0 &gt; C under an atmosphere of nitrogen for 5 minutes with an ammonia gas stream. The reaction pot was sealed and the resulting mixture was stirred at 0 &lt; 0 &gt; C for 1 hour. The excess ammonia was then removed under a stream of nitrogen and the reaction mixture was concentrated in vacuo to give a crude product. Trituration with methanol / methylene chloride / diethyl ether gave the title compound, melting point; 209-210 占 폚 (decomposition).

Example 11: Synthesis of (S) -N- [[3- [3-fluoro-4- (tetrahydro-1,1-dioxido-2H-thiopyran- 5-oxazolidinyl] methyl] ethanethioamide. &Lt; / RTI &gt;

Step 1: (S) -cis- (-) - N - [[3- [3-Fluoro-4- (tetrahydro-1-oxido-2H-thiopyran- Cis- (-) - N- (4-methylpiperidin-4-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a starting material following the general procedure of Step 2, Phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide was reacted with (S (3-fluoro-4- ) - (-) - N - [[3- [3-fluoro-4- (S) - (-) - 3- [3-fluoro-4- (tetrahydro-1, 1 -dioxine) Thiopyran-4-yl) phenyl] -5-aminomethyl-2-oxazolidinone, melting point 194 DEG C (decomposition).

Step 2: A solution of ethyl dithioacetate (100 mL, 0.876 mmol) and sodium fluoride (37 mg, 0.876 mmol) in ethanol (8.8 mL) was added to a solution of (S) - (-) - 3- [3-fluoro-4- (tetrahydro-1,1-dioxido-2H-thiopyran-4- yl) phenyl] -5-aminomethyl-2-oxazolidinone 300 mg, 0.876 mmol) and potassium hydroxide aqueous solution (1 M, 0.88 mL). The resulting mixture was stirred at ambient temperature for 26 h and treated with additional ethyl dithioacetate (50 mL, 0.438 mmol), sodium fluoride (19 mg, 0.438 mmol), potassium hydroxide aqueous solution (1 M, 0.44 mL) (50 ml), aqueous potassium hydrogen sulfate solution (1 M, 50 ml) and brine (25 ml), and anhydrous sodium sulfate Lt; / RTI &gt; and concentrated in vacuo. The crude product was recrystallized from methylene chloride / diethyl ether to give the title compound, mp 186-187 C (decomposition).

Example 12: Synthesis of (S) -N- [[3- [3-fluoro-4- (tetrahydro-1,1-dioxido-2H-thiopyran- 5-oxazolidinyl] methyl] thiourea.

Step 1: A solution of 1,1'-thiocarbonyldi-2 (1H) -pyridone (304 mg, 1.31 mmol) in anhydrous methylene chloride (13 mL) was treated at 0 ° C. with anhydrous methylene chloride (S) - (-) - 3- [3-fluoro-4- (tetrahydro-1,1-dioxido-2H-thiopyran- Phenyl] -5-aminomethyl-2-oxazolidinone (375 mg, 1.09 mmol) in DMF (2 mL). The resulting mixture was stirred at 0 &lt; 0 &gt; C for 30 min and at ambient temperature for 30 min, then diluted with methylene chloride (40 mL), washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, &Lt; / RTI &gt; The crude product was chromatographed on silica gel (230-400 mesh, 45 g) eluting with acetonitrile / methylene chloride (7.5 / 92.5) and purified by TLC (acetonitrile / methylene chloride, 20/80) to give _Rf = 0.64 The fractions were collected and concentrated to give (S) -3- [3-fluoro-4- (tetrahydro-1,1-dioxido-2H-thiopyran-4-yl) phenyl] -5-isothiocyanato methyl -2-oxazolidinone, melting point 158-162 DEG C (decomposition).

Step 2: To a solution of (S) -3- [3-fluoro-4- (tetrahydro-1,1-dioxido-2H-thiopyran- A solution of 5-isothiocyanatomethyl-2-oxazolidinone (step 1, 380 mg, 0.988 mmol) was treated (bubbled) at 0 &lt; 0 &gt; C for 5 minutes with an ammonia gas stream under a nitrogen atmosphere. The reaction pot was sealed and the resulting mixture was stirred at 0 &lt; 0 &gt; C for 1 hour. The excess ammonia was then removed under a stream of nitrogen and the reaction mixture was concentrated in vacuo to give a crude product. Recrystallization from methanol / methylene chloride / diethyl ether gave the title compound, melting point 196-198 DEG C (decomposition).

Example 13: Preparation of (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -thioformamide ).

Acetic anhydride (0.23 ㎖, 0.0024 mol) and 95-97% formic acid was allowed to warm and stirring a mixture of (0.10 ㎖, 0.0027 mol) in 50-55 ℃ for 2 hours under a nitrogen atmosphere during, and after cooling to ambient temperature, and then 2 minutes compound 39 ⁸ (0.45 g, 0.0015 mol) in portions. Process the maintenance and the resulting solution and the suspension to ambient temperature for 4 hours with Et ₂ O (1 ㎖) and it was maintained at ambient temperature for 18 hours. The mixture was diluted with additional Et ₂ O (10 ㎖) and was collected by filtration and the solid washed with Et ₂ O and dried to give the compound ^{6 9 0.38 g: MS (ES} ) m / z 324 (M + H +) , 346 (M + Na &lt; ⁺ &gt;); ^{1 H NMR (300 ㎒, CDCl} 3) d 3.08 (m, 4H), 3.72 (m, 2H), 3.77 (d, d, 1H), 3.89 (m, 4H), 4.04 (t, 1H), 4.80 ( 1H), 6.33 (s, 1H), 7.05 (m, 2H), 7.45 (d,

A stirred mixture of compound 6 (0.38 g, 0.00118 mol) in dioxane (20 mL) was treated with compound 4 (0.51 g, 0.00126 mol) under nitrogen atmosphere and heated at reflux temperature for 30 minutes and held at this temperature for 90 minutes. It was then evaporated under a stream of nitrogen. The residue was chromatographed on silica gel with 1.25% MeOH-CH ₂ Cl ₂ and the slightly impure product was rechromatographed on silica gel with 25% EtOAc-CH ₂ Cl ₂ . The product was crystallized from EtOAc-methyl t-butyl ether to give 0.114 g of compound 7 : mp 150-155 DEG C (decomposition); IR (DRIFT) 3322, 1752 cm &lt; ^{-1 &} gt ;; MS (ES) m / z 340 (M + H @ ⁺ ), 362 (M + Na @ ⁺ ); ^{1 H NMR [300 ㎒, (} CD 3) 2 SO] d 2.94 (m, 4H), 3.72 (m, 4H), 3.77 (d, d, 1H), 3.94 (t, 2H), 4.12 (t, 1H ), 4.93 (m, 1H), 7.05 (t, 1H), 7.16 (d, d, 1H), 7.47 (d, d, 1H), 9.33 (d, 1H), 10.59 Elemental analysis for C ₁₅ H ₁₈ FN ₃ O ₃ S Calculated: C, 53.08; H, 5.35; N, 12.38. Found: C, 53.02; H, 5.44; N, 12.36.

Example 14: Preparation of (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thiopropionamide 9 ).

CH ₂ Cl ₂ (20 ㎖) propionyl chloride in the solution of compound 39 (0.395 g, 0.00134 mol) and triethylamine and CH ₂ Cl ₂ (3 ㎖) to which was added ice-cooled in (0.186 ㎖, 0.0027 mol) under a nitrogen atmosphere (0.128 mL, 0.00147 mol) was added dropwise over 2 min. The mixture was kept in an ice bath for 20 minutes, and at ambient temperature for 1 hour. It was then diluted with CH ₂ Cl ₂ , washed with saturated NaHCO ₃ solution, water and brine, dried (MgSO ₄ ) and concentrated. The residue ( 8 ) was used in the next reaction without further purification.

A stirred mixture of the product ( 8 ) and dioxane (20 ml) obtained in the previous step was treated portionwise with Rosen reagent (0.58 g, 0.0014 mol) for 1 minute under nitrogen atmosphere, refluxed for 2 hours and concentrated. The residue was chromatographed on silica gel with 2% MeOH-CHCl ₃ and the product crystallized from methyl t-butyl ether to give 0.259 g of compound 9 : mp 138-139 ° C; MS (ES) m / z 368 (M + H @ ⁺ ), 390 (M + Na @ ⁺ ); IR (DRIFT) 3284, 3266, 1748, 1744 cm &lt; ^{-1 &} gt ;; [[alpha]] ²⁴ _D + 20 [deg.] (MeOH); ^{1 H NMR [300 ㎒, (} CD 3) 2 SO] d 1.12 (t, 3H), 2.56 (q, 2H), 2.94 (m, 4H), 3.72 (m, 4H), 3.78 (d, d, 1H ), 3.90 (t, 2H), 4.11 (t, IH), 4.93 (m, IH), 7.05 broad s, 1 H). C ₁₇ H ₂₂ FN ₃ O elemental analysis calculated for ₃ S: C, 55.57; H, 6.03; N, 11.44. Found: C, 55.68; H, 6.21; N, 11.37.

Example 15: Preparation of (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Amide (11).

A stirred solution of 39 (1.54 g, 5.2 mmol) and triethylamine (750 mg, 7.5 mmol) in CH ₂ Cl ₂ (50 mL) was treated with chloroacetyl chloride (30 mL) in CH ₂ Cl ₂ (465 mL, 5.8 mmol) was treated dropwise and maintained at ambient temperature for 18 hours. It was then washed with saturated NaHCO ₃ solution and diluted NaCl solution, dried (Na ₂ SO ₄ ) and concentrated. The residue was flash chromatographed on silica gel with 20-30% acetone-CH ₂ Cl ₂ to give 1.49 g of compound 10 ⁹ which was used in the next reaction without further purification.

A stirred mixture of 10 (0.371 g, 1.0 mmol) and Lawesson's reagent (0.420 mg, 1.04 mmol) in dioxane (10 mL) was refluxed under nitrogen atmosphere for 2 hours and concentrated under reduced pressure. The residue was chromatographed on silica gel with 3-10% acetone-CH ₂ Cl ₂ to give 0.143 g of 11 : MS (CI) m / z 388 (M + H ⁺ ); ^{1 H NMR (300 ㎒, CDCl} 3) d 3.07 (m, 4H), 3.77 (d, d, 1H), 3.88 (m, 4H), 4.04 (m, 1H), 4.12 (t, 1H), 4.35 ( (d, IH), 7.46 (d, IH), 7.69 (m, IH) . Elemental analysis for C ₁₆ H ₁₉ ClFN ₃ O ₃ S Calculated: C, 49.55; H, 4.94; N, 10.83. Found: C, 49.38; H, 5.20; N, 10.27.

Example 16: Preparation of (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -Trifluorothioacetamide (13).

A cold, stirred solution of 39 (0.590 g, 2.0 mmol) and triethylamine (640 mL, 4.6 mmol) in CH ₂ Cl ₂ (10 mL) was treated with trifluoroacetic anhydride (325 mL, 2.3 mmol) Kept in an ice bath for 10 minutes and then kept at ambient temperature. The reaction was followed by TLC on silica gel using 30% acetone-CH ₂ Cl ₂ . Additional trifluoroacetic anhydride and triethylamine were added after 3 days (64 ml / 125 ml), after 4 days (100 ml / 220 ml) and after 6 days (325 ml / 1.0 ml). The reaction was complete one hour after the last addition; It was mixed with CH ₂ Cl ₂ , mixed, washed with water and diluted NaCl solution, dried (Na ₂ SO ₄ ) and concentrated. The solid residue was recrystallized from acetone-heptane to give 0.566 g of compound 12 : mp 161-164 DEG C (decomposition); MS (EI) m / z 391 (M ^&lt; ^{+ &} gt ^; ). _{C 16 H 17 F 4 N 3} O 4 Elemental Analysis for Calculated: C, 49.11; H, 4.38; N, 10.74. Found: C, 48.99; H, 4.56; N, 10.73.

A stirred mixture of compound 12 (0.391 g, 1.0 mmol) and Lawesson's reagent (0.422 g, 1.1 mmol) in dioxane (10 mL) was refluxed under nitrogen atmosphere for 2 h, cooled slowly to ambient temperature and then concentrated in vacuo . The residue was flash chromatographed on silica gel with 5-15% acetone-CH ₂ Cl ₂ and the product crystallized from acetone-heptane to give 0.249 g of compound 13 : mp 151-152 ° C; MS (EI) m / z 407 (M @ ⁺ ), 363, 209, 151, 95; ^{1 H NMR (300 ㎒, CDCl} 3) d 3.05 (m, 4H), 3.75 (d, d, 1H), 3.87 (m, 4H), 3.95 (m, 1H), 4.14 (t, 1H), 4.32 ( (d, IH), 7.08 (d, IH), 7.08 (d, Elemental analysis for C ₁₆ H ₁₇ F ₄ N ₃ O ₃ S Calculated: C, 47.17; H, 4.21; N, 10.31. Found: C, 47.09; H, 4.35; N, 10.27.

Example 17: Synthesis of (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Acetamide (15).

CH ₂ Cl ₂ (10 ㎖) acetyl fluoroalkyl of of compound 39 (0.590 g, 2.0 mmol) and triethylamine and CH ₂ Cl ₂ (5 ㎖) to which an ice-cooled stirring solution under a nitrogen atmosphere (611 ㎖, 4.4 mmol) A solution of chloride (220 mL, 2.2 mmol) was added dropwise, maintained and maintained in an ice bath for 10 minutes, and at ambient temperature for 2 hours. It was then diluted with CH ₂ Cl ₂ , washed with water and diluted NaCl solution, dried (Na ₂ SO ₄ ) and concentrated. The residue was chromatographed on silica gel with 10-30% acetone-CH ₂ Cl ₂ to give 0.180 g of 14 : MS (ES) m / z 356 (M + H ⁺ ), 378 (M + Na ⁺ ).

A solution of compound 14 (0.180 g, 0.507 mmol) in dioxane was treated with Lawesson's reagent (0.206 g, 0.51 mmol) under nitrogen atmosphere, heated to 90-100 &lt; 0 &gt; C for 1 hour and concentrated in vacuo. The residue was chromatographed on silica gel with 15% acetone-CH ₂ Cl ₂ to give 0.161 g of compound 15 : MS (EI) m / z 371 (M ⁺ ); ¹ H NMR (300 MHz, CDCl ₃ ) d 3.05 (m, 4H), 3.78 (d, 1H), 7.08 (d, IH), 7.42 (d, IH), 5.07 (s, , 8.42 (s, 1 H). Elemental analysis for C ₁₆ H ₁₉ F ₂ N ₃ O ₃ S Calculated: C, 51.74; H, 5.16; N, 11.31. Found: C, 51.79; H, 5.31; N, 11.02.

Example 18: Synthesis of (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Fluorothioacetamide (17).

The ice-cooled stirred mixture of compound 39 (0.590 g, 2.0 mmol), difluoroacetic acid (190 mL, 2.0 mmol) and 1-hydroxybenzotriazole (0.297 g, 2.2 mmol) in DMF (5 mL) Was treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.843 g, 4.4 mmol) and kept at ambient temperature for 18 hours. Diluted with CH ₂ Cl ₂ , washed with water and diluted NaCl solution, dried (Na ₂ SO ₄ ) and concentrated. The solid residue was crystallized from EtOAc-heptane to give 0.617 g of compound 16 : mp 149-150 &lt; 0 &gt;C; ^{1 H NMR (300 ㎒, CDCl} 3) d 3.05 (m, 4H), 3.66 (m, 2H), 3.85 (m, 5H), 4.08 (t, 1H), 4.80 (m, 1H), 5.93 (t, J = 53.9 Hz, 1 H), 6.92 (t, 1 H), 7.06 (m, 2 H), 7.39 (d, d, 1 H); MS (EI) m / z 373 (M ^&lt; ^{+ &} gt ^; ). Elemental analysis for C ₁₆ H ₁₈ F ₃ N ₃ O ₄ Calcd .: C, 51.48; H, 4.86; N, 11.26. Found: C, 51.59; H, 4.91; N, 11.29.

A stirred solution of 16 (0.373 g, 1.00 mmol) in dioxane (10 mL) was treated with Lawesson's reagent (0.404 g, 1.00 mmol) under nitrogen atmosphere, heated to about 95 C for 1 hour and concentrated in vacuo. The residue was chromatographed on silica gel with 10% acetone-CH ₂ Cl ₂ and the product crystallized from EtOAc-heptane to give 0.276 g of compound 17 : mp 125-127 ° C; MS (EI) m / z 389 (M @ ⁺ ), 345, 305, 247, 209, 195, 151, 138, 123, 109, 95; ^{1 H NMR (300 ㎒, CDCl} 3) d 3.05 (m, 4H), 3.76 (d, d, 1H), 3.86 (m, 4H), 4.01 (m, 1H), 4.12 (t, 1H), 4.30 ( d, 1H), 7.38 (d, IH), 8.78 (d, IH) (broad s, 1 H). Elemental analysis for C ₁₆ H ₁₈ F ₃ N ₃ O ₃ S Calculated: C, 49.35; H, 4.66; N, 10.79. Found: C, 49.37; H, 4.71; N, 10.83.

Example 19: Synthesis of (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -a-cyanothio Set amide (19).

The ice-cooled stirred mixture of compound 39 (0.646 g, 2.19 mmol), cyanoacetic acid (0.179 g, 2.1 mmol) and 1-hydroxybenzotriazole (0.351 g, 2.6 mmol) in DMF (5 mL) Was treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.997 g, 5.2 mmol) and kept at ambient temperature for 24 hours. Diluted with CH ₂ Cl ₂ , washed with water and diluted NaCl solution, dried (Na ₂ SO ₄ ) and concentrated. The solid residue was crystallized from EtOAc-heptane to give 0.546 g of compound 18 : mp 172-174 DEG C: IR (DRIFT) 3316, 2256, 1754, 1684 cm- ¹ ; MS (EI) m / z 362 (M ^&lt; ^{+ &} gt ^; ). C ₁₇ H ₁₉ FN Elemental analysis calculated for ₄ O _4: C, 56.35; H, 5.28; N, 15.46. Found: C, 56.33; H, 5.30; N, 15.36.

A stirred solution of 18 (0.453 mg, 1.25 mmol) in dioxane (10 mL) was treated with Lawesson's reagent (0.505 g, 1.25 mmol) under nitrogen atmosphere and warmed to about 100 &lt; 0 &gt; C. When the reaction was complete (as confirmed by TLC using 30% acetone-CH ₂ Cl ₂ ), the mixture was cooled and concentrated in vacuo. The residue was chromatographed on silica gel with 10-20% acetone-CH ₂ Cl ₂ and the product crystallized from EtOAc-heptane to give 0.110 g of compound 19 : mp 186-187 ° C (dec); MS (ES) m / z 379 (M + H @ ⁺ ), 401 (M + Na @ ⁺ ); ^{1 H NMR (300 ㎒, CDCl} 3) d 3.05 (m, 4H), 3.81 (d, d, 1H), 3.86 (m, 4H), 3.89 (s, 2H), 4.09 (t, 1H), 4.14 ( (m, 2H), 5.01 (m, 1H), 6.92 (t, 1H), 7.05 (d, d, 1H), 7.34 (d, d, 1H), 9.15 IR (DRIFT) 3244, 2260, 1754 cm &lt; ^{-1 &} gt ;. C ₁₇ H ₁₉ FN ₄ O elemental analysis calculated for ₃ S: C, 53.96; H, 5.06; N, 14.81. Found: C, 53.88; H, 5.39; N, 14.61.

Example 20: (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thioacetamide (21).

Dichloro acetic acid anhydride in CH ₂ Cl ₂ (15 ㎖) of compound 39 (0.885 g, 3.00 mmol) and triethylamine and CH ₂ Cl ₂ (5 ㎖) to which an ice-cooled stirring solution under a nitrogen atmosphere (975 ㎖, 7 mmol) (555 mL, 3.5 mmol) was treated dropwise and maintained in an ice bath for 15 minutes, and at ambient temperature for 18 hours. It was then diluted with CH ₂ Cl ₂ , washed with water, saturated NaHCO ₃ solution and diluted NaCl solution, dried (Na ₂ SO ₄ ) and concentrated. The residue was chromatographed on silica gel with 10% acetone-CH ₂ Cl ₂ and the product crystallized from acetone-heptane to give 0.463 g of compound 20 : mp 197-198 ° C (dec.); MS (ES) m / z 406 (M + H @ ⁺ ), 428 (M + Na @ ⁺ ); ^{1 H NMR (300 ㎒, CDCl} 3) d 3.05 (m, 4H), 3.75 (m, 3H), 3.86 (m, 4H), 4.07 (t, 1H), 4.83 (m, 1H), 5.94 (s, 1H), 6.92 (t, IH), 7.06 (m, 2H), 7.41 (d, d, IH).

A stirred solution of compound 20 (0.305 g, 0.75 mmol) in dioxane (5 mL) was treated with Lawesson's reagent (0.202 g, 0.5 mmol) under nitrogen atmosphere and heated to about 90 C for 1 hour, Lt; / RTI &gt; The residue was chromatographed on silica gel, first with 30% acetone-heptane, then with 10% acetone-methylene chloride, and the product crystallized from methylene chloride-heptane to give 0.203 g of compound 21 : mp 143-144 DEG C; HR ₁₇ S (EI) calculated for C ₁₆ H ₁₈ Cl ₂ FN ₃ O ₃ S (M) 421.0431. Elemental analysis for C ₁₆ H ₁₈ Cl ₂ FN ₃ O ₃ S Calculated: C, 45.51; H, 4.30; N, 9.95. Found: C, 45.47; H, 4.24; N, 9.88.

Example 21: Synthesis of (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbonyl) thioacetamide (23).

Methyl malonyl chloride in CH ₂ Cl ₂ (50 ㎖) of compound 39 (0.955 g, 3.2 mmol) and triethylamine to a stirred solution of (650 ㎖, 4.5 mmol) under a nitrogen atmosphere, _{CH 2 Cl 2 (10 ㎖)} ( 475 mL, 4.3 mmol) was added dropwise over 15-20 minutes and maintained at ambient temperature for 3 days. It was then washed with water and diluted NaCl solution, dried and concentrated. The residue was flash chromatographed on silica gel with 15-30% acetone-CH ₂ Cl ₂ and the product crystallized from acetone-hexane to give 0.873 g of compound 22 : mp 150-151 ° C; ^{1 H NMR (300 ㎒, CDCl} 3) d 3.03 (m, 4H), 3.34 (s, 2H), 3.67 (s, 3H), 3.69 (m, 2H), 3.76 (d, d, 1H), 3.85 ( d, 1H), 7.57 (t, IH), 7.08 (d, IH) ; MS (ES) m / z 396 (M + H @ ⁺ ), 418 (M + Na @ ⁺ ); _{C 18 H 23 FN 3 O 6} (M + H +) HRMS (FAB) Calcd for: 396.1571, Found: 396.1579. Elemental analysis for C ₁₈ H ₂₂ FN ₃ O ₆ Calculated: C, 54.68; H, 5.61; N, 10.63. Found: C, 54.69; H, 5.68; N, 10.58.

A stirred solution of compound 22 (0.395 g, 1.0 mmol) in dioxane (10 mL) was treated with Lawesson's reagent (0.202 g, 0.5 mmol) under nitrogen atmosphere at ambient temperature for 4 hours 10 minutes and 1.5 Hour. The reaction was tracked by TLC on silica gel, using 10% MeOH-CHCl _3. At this point a new less polar product began to form. This was maintained at ambient temperature for 18 hours and at 80 &lt; 0 &gt; C for 2 hours; Additional Lawess reagent (40 mg, 0.099 mmol) was added and warmed to 80 &lt; 0 &gt; C continued for 2 h; Some starting material still remained. The mixture was concentrated and the residue was chromatographed on silica gel with 15% acetone-CH ₂ Cl ₂ to give 0.348 g of compound 23 : ¹ H NMR (300 MHz, CDCl ₃ ) d 3.05 (m, 4H), 3.71 2H), 4.99 (m, 1H), 6.91 (d, 1H), 3.81 (d, , 7.07 (d, d, 1 H), 7.42 (d, d, 1 H), 9.52 (s, 1 H); IR (DRIFT) 3269, 1743 cm &lt; ^{-1 &} gt ;; MS (EI) m / z 411 (M ^&lt; ^{+ &} gt ^; ). C ₁₈ H ₂₂ FN ₃ O elemental analysis calculated for ₅ S: C, 52.54; H, 5.39; N, 10.21. Found: C, 52.58; H, 5.43; N, 10.14.

Example 22: Synthesis of (S) -N- [[3- [4- [1- [1,2,4] triazolyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide ).

A stirred mixture of compound 24 (0.150 g, 0.470 mmol) and dioxane (12.5 mL) was treated with Lawesson's reagent (0.20 g, 0.50 mmol) under nitrogen atmosphere, refluxed for 1.5 hours and maintained at ambient temperature for 18 hours, &Lt; / RTI &gt; The residue was flash chromatographed on silica gel with 5% MeOH-CHCl ₃ to give the product which was crystallized from MeOH to yield 0.100 g (63.4%) of compound 25 : mp 161-163 ° C; ^{1 H NMR (300 ㎒, (} CD 3) 2 SO) d 2.43 (s, 3H), 3.87 (m, 3H), 4.22 (t, 1H), 4.99 (m, 1H), 7.51 (d, 1H), 7.77 (m, 2H), 8.26 (s, 1H), 8.97 (d, 1H), 10.35 (broad s, 1H); IR (mull) 3259, 3226, 3044, 1752 cm &lt; ^{-1 &} gt ;; MS (ES) m / z 336 (M + H @ ⁺ ), 358 (M + Na @ ⁺ ). Elemental analysis for C ₁₄ H ₁₄ FN ₅ O ₂ S Calculated: C, 50.14; H, 4.21; N, 20.88. Found: C, 50.18; H, 4.26; N, 20.94.

Example 23: (S) -N- [[3- [4- [1- [1,2,4] triazolyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide ).

A stirred mixture of compound 26 (0.26 g, 0.938 mmol), ethyl dithioacetate (0.12 g, 0.998 mmol), sodium fluoride (0.040 g, 0.953 mmol) and anhydrous EtOH (10 mL) Was treated with a solution of KOH (1.03 mL) for 5 minutes and maintained at ambient temperature for 2 hours. It was then diluted with CH ₂ Cl ₂ (75 mL), washed with water, 1 M KHSO ₄ , water and brine and evaporated. The residue was flash chromatographed on silica gel with 5% MeOH-CHCl ₃ and the product crystallized from MeOH to afford 0.118 g of compound 25 (melting point 164-165 DEG C (decomposition)) and 0.026 g (melting point 162-163 DEG C .

Example 24: (S) -N- [[3- [1- (hydroxyacetyl) -5-indolinyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide (28).

CH ₂ Cl ₂ (25 ㎖) was for 20 minutes with a solution of compound 52 in which the ice-cooling was added CH ₂ Cl ₂ (10 ㎖) acetate (25 ㎖) trifluoroacetate in a (8.80 g, 0.0240 mol). The mixture was kept in an ice bath for 2 hours and 15 minutes and concentrated under reduced pressure. A solution of the residue in CH ₂ Cl ₂ was washed with saturated NaHCO ₃ solution and diluted NaCl solution, dried (Na ₂ SO ₄ ) and concentrated. The residue was used in the next reaction without further purification. The analytical results of this material 53 are as follows: ¹ H NMR (300 MHz, CDCl ₃ ) d 3.00 (t, 2H), 3.54 (t, 2H), 3.85 (broad s, 1H), 5.17 (s, 2H), 6.59 (d, 1H), 6.66 (s, 1H), 6.91 (d, 1H), 7.23 MS m / z 269 (M + H ^& lt ^{; +} & gt ^; ).

The ice-cooled stirred mixture of compound 53 (crude product from previous reaction), acetone (200 mL), saturated NaHCO ₃ solution (200 mL) and water (30 mL) was added to a solution of benzyloxyacetyl chloride , 0.030 mol) in water for 20 minutes, slowly warmed to ambient temperature and held for 18 hours. Benzyloxyacetyl chloride (1.0 mL) in acetone (35 mL) was further added dropwise and the mixture was kept at ambient temperature for a further 3 hours and then diluted with EtOAc and water. The solid was collected by filtration and dried to give 4.00 g of crude product. The EtOAc solution was dried (Na ₂ SO ₄₎ and concentrated to give an additional 5.36 g of crude product. Crystallization of the product from EtOAc to give the compound 54 ¹⁴ (melting point 157-159.5 ℃) total 6.35 g. Analytical sample: melting point 158-159.5 DEG C; ^{1 H NMR (300 ㎒, CDCl} 3) δ3.16 (t, 2H), 4.01 (t, 2H), 4.21 (s, 2H), 4.69 (s, 2H), 5.19 (s, 2H), 6.67 (s (D, 1H), 6.97 (d, 1H), 7.36 (m, 10H), 7.50 (broad s, 1H), 8.15 MS (EI) m / z (relative intensity) 416 (M ⁺ , 9), 310 (8), 202 (10), 133 (8), 92 (8), 91 (99), 79 (9), 65 (12), 51 (6); IR (mull) 2381, 1722, 1659, 1608, 1558 cm &lt; ^-1 &gt;. Elemental analysis calculated for _{C 25 H 24 N 2 O 4} : C, 72.10; H, 5.81; N, 6.73. Found: C, 72.05; H, 5.86; N, 6.68.

A stirred suspension of 54 (1.16 g, 2.78 mmol) in THF (42 mL) was cooled to -78 <0> C under nitrogen atmosphere and treated dropwise with 1.6 M n-BuLi in hexanes (1.83 mL) for 5 min. This was kept at -78 ° C for 50 minutes and treated dropwise with a solution of (R) - (-) - glycidyl butyrate (0.500 g, 3.47 mmol) in THF (2 mL) for 5 minutes Warmed and maintained for 18 hours. It was then diluted with EtOAc and washed with a saturated solution of NH ₄ Cl, water and brine, then dried (MgSO ₄ ) and concentrated. The residue was chromatographed on silica gel with 3% MeOH-0.2% NH ₄ OH-CHCl ₃ to give 0.60 g (56%) of the compound 55 ¹⁴ : ¹ H NMR (300 MHz, (CD ₃ ) ₂ SO) 2H), 3.59 (m, 2H), 3.79 (d, IH), 4.03 (m, 3H), 4.29 5.20 (t, 1 H), 7.31 (m, 6 H), 7.55 (s, 1 H), 8.03 (d, 1 H); MS (ES) m / z 383 (M + H @ ⁺ ), 405 (M + Na @ ⁺ ).

The ice-cooled stirred mixture of compound 55 (0.60 g, 1.57 mmol), triethylamine (2.2 mL) and CH ₂ Cl ₂ (12 mL) was treated with 3-nitrobenzenesulfonyl chloride (0.44 g, 1.99 mmol) And maintained in an ice bath for 30 minutes and at ambient temperature for 60 minutes. It was then diluted with CH ₂ Cl ₂ , washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was chromatographed on silica gel with 15% CH ₃ CN-CH ₂ Cl ₂ to give 0.70 g of compound 56 : ¹ H NMR (300 MHz, CDCl ₃ ) d 3.19 (t, J = 8.3 Hz, 2H), 3.88 2H), 4.70 (s, 2H), 4.84 (m, 2H), 4.04 (t, 1H), 8.73 (m, 2H), 8.53 (m, 1H), 8.73 (m, , 1H); MS (ES) m / z 568 (M + H @ ⁺ ), 590 (M + Na @ ⁺ ).

A stirred mixture of compound 56 (the crude product from 0.00314 mol of compound 55 ), acetonitrile (70 mL), isopropanol (70 mL) and 29% ammonium hydroxide (70 mL) was warmed to 40-44 [ &Lt; / RTI &gt; for a period of time. Concentration in vacuo afforded an aqueous residue which was extracted with CH ₂ Cl ₂ . The extract was washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was chromatographed on silica gel with 8% MeOH-0.5% NH ₄ OH-CHCl ₃ to give 1.05 g of compound 57 : ¹ H NMR [300 MHz, (CD ₃ ) ₂ SO] d 2.78 (m, 2H), 4.58 (m, 1H), 7.31 (m, 6H), 3.18 (d, , 7.54 (broad s, 1 H), 8.03 (d, 1 H); MS (ES) m / z 382 (M + H @ ⁺ ), 404 (M + Na @ ⁺ ).

A mixture of 57 (0.46 g, 1.21 mmol), MeOH (150 mL), 1 M HCl (1.2 mL) and 5% palladium on carbon catalyst (250 mg) was hydrogenated at an initial pressure of 49 psi for 5 hours. Additional 1 M HCl (0.5 mL) and catalyst (100 mg) were added and hydrogenated for 18 h. The catalyst was removed by filtration and the filtrate was concentrated to obtain 0.34 g of Compound 27 : ¹ H NMR [300 MHz, (CD ₃ ) ₂ SO]? 3.15 (t, 2H), 3.22 (broad s, 2H), 3.84 2H), 4.15 (s, 2H), 4.15 (m, IH), 4.92 (m, IH), 7.24 (d, 1 H), 8.37 (broad s, 3H); MS (ES) m / z 2.92 (M + H ^& lt ^{; +} & gt ^; ).

A suspension of 27 (0.10 g, 0.34 mmol) in a mixture of EtOH (15 mL) and 0.97 M KOH (0.7 mL) was treated with ethyl dithioacetate (0.0412 g, 0.343 mmol) in EtOH (5 mL) Was added to a stirred mixture of sodium hydroxide (0.0137 g, 0.326 mmol) and the mixture was maintained at ambient temperature for 2 hours and 15 minutes. An additional 0.97 M KOH (0.2 mL), sodium iodide (6 mg) and ethyl dithioacetate (20 mg) were added and the mixture was stirred for 2 h before being mixed with CH ₂ Cl ₂ (150 mL) 1 M KHSO ₄ and washed with brine, dried (Na ₂ SO ₄₎ and concentrated. The residue was crystallized from acetone to give 0.0404 g of compound 28 : mp 175-176 &lt; 0 &gt; C (decomposition); MS (FAB) m / z 350 (M + H @ ⁺ ), 349 (M @ ⁺ ), 331, 316, 205, 73; _{C 16 H 20 N 3 O 4} HRMS (FAB) to S (M + H ⁺⁾ Calcd: 350.1174, Found: 350.1183; ^{1 H NMR [300 ㎒, (} CD 3) 2 SO] d 2.42 (s, 3H), 3.14 (t, 2H), 3.79 (d, d, 1H), 3.89 (t, 2H), 4.00 (t, 2H 1H), 7.50 (s, 1H), 8.03 (d, 1H), 10.35 (s, 1H) ; IR (DRIFT) 3255, 3223, 3068, 1747, 1639, 1614 cm &lt; ^{-1 &} gt ;.

Example 25: Synthesis of (S) -N- [[3- [3-fluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] thioacetamide (30).

A mixture of 58 (3.00 g, 7.00 mmol), THF (60 mL), anhydrous EtOH (100 mL) and 10% palladium on carbon catalyst (415 mg) was hydrogenated at 58 psi for 2 h 50 min . Filtration removed the catalyst and the filtrate was concentrated in vacuo to give 2.67 g of compound 59 which was used in the following reaction without further purification: ¹ H NMR (300 MHz, CDCl ₃ ) d 2.16 (broad s), 3.02 (m, 2H), 3.73 (d, J = 3.9, 12.6 Hz, 1H), 3.96 , 1 H), 7.43 (d, d, J = 2.6, 14.3 Hz, 1 H); MS (ES) m / z 296 (M + H ^& lt ^{; +} & gt ^; ).

The ice-cooled stirred mixture of compound 59 (obtained in the previous reaction, 2.67 g), acetone (190 mL) and saturated NaHCO ₃ (70 mL) was added to a solution of benzyloxyacetyl chloride (1.34 mL, 8.61 mmol) Solution for 2-3 min, kept in an ice bath for 1 h and diluted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with NaCl diluted solution, dried and concentrated. The residue was chromatographed on silica gel with 30% acetone-CH ₂ Cl ₂ to give 2.64 g of compound 60 : ¹ H NMR (300 MHz, CDCl ₃ ) d 2.28 (broad s, 1H), 3.00 2H), 4.74 (m, 1H), 6.88 (t, J = 9.2 Hz), 3.76 (m, 2H) , 7.12 (m, 1H), 7.35 (s, 5H), 7.46 (d, d, J = 2.6, 14.2 Hz, 1H); IR (mull) 3406, 1748, 1647 cm &lt; ^{-1 &} gt ;; HRMS (EI) calcd for C ₂₃ H ₂₆ FN ₃ O ₅ (M ⁺ ): 443.1856, found 443.1842.

The ice-cooled stirred mixture of 60 (2.64 g, 6.00 mmol) and triethylamine (1.14 mL, 8.16 mmol) in CH ₂ Cl ₂ (200 mL) was treated with 3-nitrobenzenesulfonyl chloride (1.78 g, 8.04 mmol), warmed to ambient temperature and maintained for 5 h 20 min. Further, 3-nitrobenzenesulfonyl chloride (180 mg) and triethylamine (0.20 ml) were added and the mixture was kept at ambient temperature for 18 hours, then diluted with CH ₂ Cl ₂ , washed with water and diluted NaCl solution and dried (Na ₂ SO ₄₎ and concentrated. The residue was chromatographed on silica gel with 40-60% acetone-hexanes to give 3.36 g of compound 77 : ¹ H NMR (300 MHz, CDCl ₃ ) d 3.02 (broad s, 4H), 3.66 (T, J = 9.2 Hz, 1H), 4.22 (s, 2H), 4.41 (m, 2H), 3.78 (d, J = 8.0 Hz, 1H), 7.02 (m, 2H), 4.84 (m, 2H), 4.84 ), 8.23 (m, 1 H), 8.53 (m, 1 H), 8.73 (m, 1 H); MS (ES) m / z 629 (M + H ^& lt ^{; +} & gt ^; ).

A solution of 77 (3.36 g, 5.34 mmol) in a mixture of acetonitrile (90 mL), isopropanol (90 mL) and concentrated ammonium hydroxide (90 mL) was warmed to 40-45 [deg.] C for 18 h, (30 mL), warmed to 40-45 [deg.] C for 8 hours, treated again with additional ammonium hydroxide (25 mL) and warmed to 45 [deg.] C for 18 hours. It was then mixed with water and extracted with CH ₂ Cl ₂ . The extract was washed with NaCl diluted solution, dried (Na ₂ SO ₄ ) and concentrated. The residue was chromatographed on silica gel with 5% MeOH-0.5% NH ₄ OH-CHCl ₃ to give 2.44 g of compound 61 : ¹ H NMR (300 MHz, CDCl ₃ ) d 1.50 (broad s), 3.04 ), 3.65 (s, 2H), 4.66 (m, 1H), 3.88 (s, 2H) ), 7.12 (m, 1 H), 7.33 (m, 5 H), 7.47 (d, d, 1 H); MS (ES) m / z 443 (M + H ^& lt ^{; +} & gt ^; ).

A solution of 61 (1.45 g, 3.3 mmol) and 1.0 N HCl (3.65 mL) in 95% EtOH (150 mL) was treated with 5% palladium on carbon catalyst (500 mg) psi. &lt; / RTI &gt; Additional 1.0 N HCl (0.5 mL) and catalyst (100 mg) were added and continued hydrogenation at 60 psi initial pressure for 20 h 30 min. The reaction was terminated by TLC; This was neutralized with concentrated NH ₄ OH, filtered and concentrated in vacuo to give 1.18 g of compound 29 : ¹ H NMR [300 MHz, (CD ₃ ) ₂ SO] d 2.94 (broad s, 4H), 3.19 2H), 3.84 (m, 2H), 3.84 (m, 3H), 4.64 (broad s, 1H), 7.16 (d, d, 1 H), 7.48 (d, d, 1 H), 8.04 (broad s); IR (mull) 3420, 3099, 3040, 3008, 1755, 1641 cm ^-1 ; MS (ES) m / z 353 (M + H ^& lt ^{; +} & gt ^; ). Elemental analysis for C ₁₆ H ₂₂ ClFN ₄ O ₄ Calculated: C, 49.42; H, 5.70; Cl, 9.12; N, 14.41. Found: C, 48.16; H, 5.82; Cl, 10.00; N, 14.28.

A stirred mixture of ethyl dithioacetate (180 mL, 1.56 mmol), sodium fluoride (72 mg, 1.7 mmol), compound 29 (500 mg, 1.29 mmol) and EtOH (70 mL) was treated with 0.97 M KOH ML, 1.42 mmol) and the resulting solution was kept at ambient temperature for 3 h 35 min, diluted with CHCl _3, then washed with water and diluted NaCl solution, dried (Na ₂ SO ₄ ) and concentrated. The residue was chromatographed on silica gel with 5% MeOH-0.5% NH ₄ OH-CHCl ₃ and the resulting product was crystallized from absolute EtOH to afford 0.238 mg (44.9%) of compound 30 : mp 163-165 ° C; ^{1 H NMR (300 ㎒, CDCl} 3) d 2.60 (s, 3H), 3.06 (m, 4H), 3.45 (m, 2H), 3.61 (m, 1H), 3.82 (m, 3H), 4.07 (m, 2H), 4.25 (m, 3H), 4.97 (m, IH), 6.91 (t, IH), 7.07 (m, IH), 7.45 (d, MS (FAB) m / z (relative intensity) 411 (M + H ⁺ , 100), 410 (M ⁺ , 66.5), 266 (3.1); IR 3292, 1733, 1653 cm &lt; ^{-1 &} gt ;. C ₁₈ H ₂₃ FN ₄ O elemental analysis calculated for ₄ S: C, 52.67; H, 5.65; N, 13.65. Found: C, 52.76; H, 5.58; N, 13.64.

Example 26: Preparation of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide 32).

The ice-cooled stirred mixture of 31 (0.38 g, 0.0012 mol) and triethylamine (0.38 ml, 0.0027 mol) in THF (12 ml) was treated with ethyl dithioacetate (0.16 ml, 0.0014 mol) Held at temperature for 24.5 hours and then concentrated in vacuo. A solution of the residue in CH ₂ Cl ₂ was washed with saturated NaHCO ₃ solution, water and brine, dried (MgSO ₄ ) and concentrated. The residue was crystallized from EtOAc-hexane to give 0.355 g of compound 32 : mp 155-156 &lt; 0 &gt;C; MS (ES) m / z 370 (M + H @ ⁺ ), 392 (M + Na @ ⁺ ); IR (DRIFT) 3206, 3042, 1759, 1738 cm &lt; ^{-1 &} gt ;; ^{1 H NMR (300 ㎒, CDCl} 3) d 2.60 (s, 3H), 2.95 (s, 4H), 3.43 (m, 4H), 3.82 (d, d, 1H), 4.08 (m, 2H), 4.27 ( (m, 1H), 4.98 (m, IH), 7.06 (m, IH), 7.33 (broad s, IH), 7.51 (d, C ₁₆ H ₂₀ FN ₃ O _2. Elemental analysis calculated for S _2: C, 52.01; H, 5.46; N, 11.37. Found: C, 51.86; H, 5.43; N, 11.20.

Example 27: Synthesis of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide, Thiomorpholine S-oxide (34).

The ice-cooled stirred mixture of sodium meta-sodium iodate (1.08 g, 5.50 mmol) and water (12 mL) was treated with 62 (1.5 g, 4.8 mmol) and MeOH (17 mL) under nitrogen atmosphere and 18 C , And 4 &lt; 0 &gt; C for 3 hours. Then process them with additional sodium metaperiodate (0.1 g) in, and maintained at 4 ℃ for 3 hours and extracted with CHCl _3. The extract was dried (MgSO ₄ ) and concentrated to give 1.4 g of compound 63 : ¹ H NMR [300 MHz, (CD ₃ ) ₂ SO] d 2.84 (m, 2H), 3.01 2H), 3.50 (m, 3H), 3.65 (m, IH), 3.77 (d, , &Lt; / RTI &gt; 2H), 7.52 (m, 1H); MS (ES) m / z 329 (M + H @ ⁺ ), 351 (M + Na @ ⁺ ).

CH ₂ Cl ₂ (130 ㎖) of compound 63 (1.27 g, 3.87 mmol) and triethylamine m- nitrobenzene sulfonyl chloride (1.15 g, 5.19 a stirred ice-cooled mixture of (0.732 ㎖, 5.25 mmol) under a nitrogen atmosphere mmol) and maintained at ambient temperature for about 24 hours. This was diluted with CH ₂ Cl ₂ , washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated to afford 78 , which was used in the next reaction without purification.

The compound obtained in the previous reaction (78), acetonitrile (70 ㎖) and isopropanol (70 ㎖) stirred mixture of concentrated ammonium hydroxide _{(70 ㎖, 29.9% NH 3} ) as a treatment and in 2 hours, ambient temperature is from 40 ℃ 18 of Hour, and at 40-45 &lt; 0 &gt; C for 4 hours; Concentrated to about 50 mL, diluted with water and extracted with CH ₂ Cl ₂ . The extract was washed with water and brine, dried (MgSO ₄₎ and concentrated. By chromatography of the residue with 5% MeOH-CHCl ₃ on silica gel to give 0.58 g of compound 33: MS (ES) m / z 328 (M + H +), 350 (M + Na +); ^{1 H NMR [300 ㎒, (} CD 3) 2 SO] d 2.81 (m, 4H), 3.01 (m, 2H), 3.16 (m, 2H), 3.30 (broad s), 3.49 (m, 2H), 3.80 (d, IH), 4.01 (t, IH), 4.58 (m, IH), 7.19 (m, 2H), 7.51 (m, IH).

A stirred suspension of 33 (3.7 g, 0.011 mol) and triethylamine (3.5 mL, 0.025 mol) in THF (120 mL) was cooled in an ice bath and treated with ethyl dithioacetate in THF (2 mL) 1.47 mL, 0.0128 mol) for 2 minutes and maintained at ambient temperature for 22 hours. The resulting solution was concentrated and the residue was crystallized from acetonitrile to give 3.61 g of compound 34 : mp 176-177 [deg.] C; ^{1 H NMR [300 ㎒, (} CD 3) 2 SO] d 2.42 (s, 3H), 2.85 (m, 2H), 3.01 (m, 2H), 3.18 (m, 3H), 3.50 (m, 2H), 1H), 7.18 (m, 2H), 7.49 (m, 1H), 10.33 (s, 1H) ); IR (DRIFT) 3186, 3102, 1741 cm &lt; ^{-1 &} gt ;; MS (ES) m / z 386 (M + H @ ⁺ ), 408 (M + Na @ ⁺ ). Elemental analysis for C ₁₆ H ₂₀ FN ₃ O ₃ S ₂ .0.5H ₂ O Calculated: C, 48.71; H, 5.37; N, 10.65; S, 16.26; H ₂ O, 2.38. Found: C, 48.75; H, 5.17; N, 10.72; S, 16.07; H ₂ O, 1.72.

Example 28: Synthesis of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thio- Thiomorpholine S, S-dioxide (36).

A stirred mixture of 62 (0.399 g, 0.00128 mol) in 25% water / acetone (12 mL) was treated with N-methylmorpholine, N-oxide (0.45 g, 0.00384 mol) and osmium tetroxide And treated with 0.1 ml of a 2.5 wt% solution. This was kept at ambient temperature for 18 h, mixed with a saturated solution of NaHSO ₃ (50 mL) and extracted with CH ₂ Cl ₂ . The extract was washed with saturated NaHSO ₃ solution and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was mixed with 3.5% MeOH-CH ₂ Cl ₂ and filtered; The solid was dissolved in 15% MeOH-CH ₂ Cl ₂ and concentrated to give 0.29 g of compound 64 . The filtrate was chromatographed on silica gel with 3.5% MeOH-CH ₂ Cl ₂ to afford 0.1 g of 64 : MS (ES) m / z 345 (M + H ⁺ ), 367 (M + Na ⁺ ); ^{1 H NMR [300 ㎒, (} CD 3) 2 SO] d 3.26 (m, 4H), 3.44 (m, 4H), 3.60 (m, 2H), 3.80 (d, d, 1H), 4.05 (t, 1H ), 4.69 (m, 1 H), 7.22 (m, 2 H), 7.54 (d, 1 H).

A stirred mixture of compound 64 (0.39 g, 0.00113 mol) and triethylamine (0.214 mL, 0.00154 mol) in CH ₂ Cl ₂ (37 mL) was cooled in an ice bath under a nitrogen atmosphere and 3-nitrobenzenesulfonyl chloride (0.335 g, 0.00151 mol) in portions for 5 minutes. The mixture was kept in an ice bath for 20 minutes and at ambient temperature for 18 hours and then concentrated in vacuo. 2-propanol (25 ㎖), and acetonitrile (25㎖) 48 hours of stirring in a solution of the residue in 30% NH ₄ OH treated with a (25 ㎖) and allowed to warm to 50-55 ℃ for 6 hours and ambient temperature in a nitrogen atmosphere Respectively. It was concentrated to remove the organic solvent, diluted with water and extracted with CH ₂ Cl ₂ . The extract was washed with water and brine, dried (MgSO ₄₎ and concentrated. The residue was flash chromatographed on silica gel with 6% MeOH-0.4% NH ₄ OH-CHCl ₃ to give 0.29 g of compound 35 : ¹ H NMR [300 MHz, (CD ₃ ) ₂ SO] d 1.59 (broad s, 2H 1H), 2.78 (m, 2H), 3.24 (m, 4H), 3.43 (m, 4H), 3.81 (d, 2H), 7.52 (m, 1 H); MS (ES) m / z 344 (M + H @ ⁺ ), 366 (M + Na @ ⁺ ).

A cold stirred suspension of 35 (0.28 g, 0.85 mmol) in a mixture of Et ₃ N (0.26 mL, 1.9 mmol) and THF (10 mL) was treated with ethyl dithioacetate (0.11 mL, Maintained in a bath for 20 minutes, then at ambient temperature; The reaction was monitored by TLC. After 20 hours, it was still in suspension and the reaction proceeded in part; Additional THF (10 mL) and ethyl dithioacetate (3 drops) were added. The reaction was still not terminated after an additional 48 hours; The suspension was treated with CH ₂ Cl ₂ (10 mL) and held for 72 hours. This time it was almost completely dissolved and almost completely converted to the product. Ethyldithioacetate was further added and the mixture was kept at ambient temperature for 5 days and then concentrated in vacuo. The residue was mixed with EtOAc saturated NaHCO ₃ solution, washed with water and brine, dried (MgSO ₄₎ and concentrated. The residue was crystallized from MeOH-EtOAc to give 0.209 g of compound 36 : mp 197-198 [deg.] C; ^{1 H NMR [300 ㎒, (} CD 3) 2 SO] d 2.42 (s, 3H), 3.24 (m, 4H), 3.43 (m, 4H), 3.78 (d, d, 1H), 3.88 (m, 2H ), 4.12 (t, IH), 4.92 (m, IH), 7.18 (m, 2H), 7.50 (m, IH), 10.37 (broad s, IH); IR (mull) 3300, 3267, 1743 cm &lt; ^{-1 &} gt ;; MS (ES) m / z 424 (M + Na &lt; ⁺ &gt;). Elemental analysis for C ₁₆ H ₂₀ FN ₃ O ₄ S ₂ Calculated: C, 47.87; H, 5.02; N, 10.47. Found: C, 47.84; H, 5.23; N, 10.28.

Example 29: (S) -N- [[3- [3,5-Difluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] &Lt; / RTI &gt; zolydinyl] methyl] thioacetamide (38).

A stirred mixture of compound 65 (1.8 g, 0.00396 mol), pyridine (30 mL) and anhydrous EtOH (3 mL) was treated with hydroxylamine hydrochloride (1.44 g, 0.0207 mol) under nitrogen atmosphere and heated to reflux for 2 hours , Refluxed for 3.5 hours, then maintained at ambient temperature for 18 hours, and at reflux temperature for 4 hours. This was concentrated under vacuum and the residue was mixed with water, adjusted to pH 11 with a saturated solution of NaHCO ₃ and extracted with Et ₂ O. The extract was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was chromatographed on silica gel with 5% MeOH-0.35% NH ₄ OH-CHCl ₃ to recover 0.75 g of compound 65 to give 0.72 g of compound 66 : ¹ H NMR [300 MHz, (CD ₃ ) ₂ SO] d 2H), 2.78 (m, 2H), 2.97 (m, 4H), 3.40 (m, 4H), 3.80 (d, ), 4.59 (m, 1 H), 7.27 (d, 2 H); MS (ES) m / z 413 (M + H @ ⁺ ), 435 (M + Na @ ⁺ ).

The ice-cooled stirred mixture of compound 66 (0.75 g, 0.0018 mol) and triethylamine (0.315 mL, 0.00225 mol) in THF (12 mL) was treated dropwise with benzyl chloroformate (0.29 mL, 0.0020 mol) , Held in an ice bath for 15 minutes, and at ambient temperature for 2 hours and then concentrated in vacuo. The residue was mixed with CH ₂ Cl ₂ , washed with saturated NaHCO ₃ solution, water and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was mixed with Et ₂ O and filtered to give 0.939 g of compound 67 : mp 116-118 ° C; ^{1 H NMR (300 ㎒, CDCl} 3) d 1.48 (s, 9H), 3.08 (m, 4H), 3.53 (m, 4H), 3.60 (m, 2H), 3.73 (m, 1H), 3.96 (t, 1H), 4.76 (m, IH), 5.10 (s, 2H), 5.21 (m, IH), 7.07 (d, 2H), 7.31 (s, 5H); MS (ES) m / z 547 (M + H @ ⁺ ), 569 (M + Na @ ⁺ ).

Compound 67 (0.805 g, 0.00147 mol) was added portion-wise to trifluoroacetic acid (9 mL) which was ice-cooled for 5 minutes under nitrogen atmosphere with stirring. The resulting solution was kept in an ice bath for 1 hour and then concentrated under a nitrogen stream. The residue was mixed with ice and saturated NaHCO ₃ solution and extracted with CH ₂ Cl ₂ ; The extract was washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated to give 0.63 g of product. The aqueous layers were combined and extracted again with EtOAc; The extract was washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated to obtain additional product. The resulting products were combined (0.68 g of compound 68 ) and used in the next reaction without further purification.

Compound 68 (0.68 g, 0.00152 mol) , NaHCO 3 saturated solution (15.2 ㎖) and acetone and benzyloxy acetyl chloride (0.29 ㎖, 0.0019 mol) in acetone (5 ㎖) the stirred mixture in a nitrogen atmosphere while cooling on ice in (40 ㎖) For 15 min, maintained at ambient temperature for 6 h, then diluted with EtOAc and washed with water and brine. The extract was dried (MgSO ₄₎ and concentrated in vacuo to 0.72 g compound 69: MS (ES) m / z 395 (M + H +), 617 (M + Na +); ^{1 H NMR (300 ㎒, CDCl} 3) d 3.12 (m, 4H), 3.59 (m, 4H), 3.74 (m, 3H), 3.96 (t, 1H), 4.22 (s, 2H), 4.62 (s, 2H), 4.75 (broad s, 1H), 5.10 (s, 2H), 5.22 (m, 1H), 7.08 (d, 2H), 7.33 (m, 10H).

A mixture of 69 (0.72 g, 0.0012 mol), MeOH and 5% palladium on carbon catalyst (0.4 g) was hydrogenated at an initial pressure of 45 psi for 4 hours. The starting material was reduced by TLC (8% MeOH-0.5% NH ₄ OH-CHCl ₃ ) and two products were formed. 1 M hydrochloric acid (1.34 mL) was added and hydrogenation was continued for 21 hours at an initial pressure of 40 psi. TLC showed that only the product with the greater polarity remained. The catalyst was filtered off and the filtrate was concentrated to give 0.40 g of compound 37 : MS (ES) m / z 371 (M + H ⁺ ), 393 (M + Na ⁺ ); ^{1 H NMR [300 ㎒, (} CD 3) 2 SO] d 3.02 (s, 4H), 3.20 (m, 2H), 3.43 (s, 2H), 3.56 (s, 2H), 3.84 (m, 1H), 3.84 (broad s), 4.10 (s, 2H), 4.14 (t, IH), 4.96 (m, IH), 7.26 (d, 2H), 8.41 (broad s, 3H).

A stirred suspension of 37 (0.38 g) in Et ₃ N (0.31 mL) and THF (10 mL) was treated with ethyl dithioacetate (0.13 mL, approximately 7 drops) under nitrogen atmosphere and maintained at ambient temperature for 7 days ; The reaction was followed by TLC (8% MeOH-0.5% NH ₄ OH-CHCl ₃ ). After 24 h ethyldithioacetate (2 drops) was further added; After 30 hours, CH ₂ Cl ₂ (10 mL) and ethyl dithioacetate (3 drops) were added; After 48 hours, triethylamine (0.3 ml) was further added. The mixture was concentrated under vacuum and mixed with ice and NaHCO ₃ saturated solution and the residue extracted with CH ₂ Cl _2. The extract was washed with water and brine, dried and concentrated (MgSO _4). The residue was chromatographed on silica gel with 2.5% MeOH-CH ₂ Cl ₂ and crystallized from MeOH to yield 0.182 g of compound 38 : mp 110-111 ° C (dec); MS (ES) m / z 429 (M + H @ ⁺ ), 451 (M + Na @ ⁺ ); _{C 18 H 23 F 2 N 4} O 4 HRMS (FAB) to S (M + H ⁺⁾ Calcd: 429.1408, Found: 429.1415; IR (DRIFT) 1760, 1652, 1639 cm &lt; ^{-1 &} gt ;; [[alpha] ²⁴ _D ] 8 [deg.] (MeOH).

Example 30: Synthesis of (S) -N- [[3- [4- [1- [1,2,4] triazolyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thiourea (44) .

A solution of 26 (0.190 g, 0.685 mmol) in CH ₂ Cl ₂ (20 mL) was added to a solution of 1,1'-thiocarbonyldi-2 (1H) -pyridon in CH ₂ Cl ₂ (7 mL) (0.193 g, 0.831 mmol) in an ice-cooled stirred solution over 20 min. The mixture was kept in an ice bath for 20 min, and at ambient temperature for 2 h, then diluted with CH ₂ Cl ₂ , washed with water and brine then dried (MgSO ₄ ) and concentrated. By chromatography of the residue with _{10-15% CH 3 CN-CH 2} Cl 2 on silica gel to obtain 0.11 g of the compound 79 without purification longer was used in the next reaction: MS (ES) m / z 320 (M + H ^& lt ^{; +} & gt ^; ), 342 (M + Na &lt; ⁺ &gt;).

An ice cold stirred solution of 79 (0.10 g, 0.31 mmol) in THF (15 mL) was treated with excess anhydrous ammonia and held in an ice bath for 90 minutes. It was then evaporated to a volume of about 5 mL under a nitrogen stream to give a solid which was collected by filtration and washed with cold THF to give 0.105 g of compound 44 : mp 214-215 [deg.] C; ^{1 H NMR [300 ㎒, (} CD 3) 2 SO] d 3.82 (m, 3H), 4.18 (t, 1H), 4.89 (broad s, 1H), 7.20 (broad s, 2H), 7.50 (d, 1H ), 7.79 (m, 2H), 7.93 (t, IH), 8.26 (s, IH), 8.97 (s, IH); MS (ES) m / z 337 (M + H @ ⁺ ), 359 (M + Na @ ⁺ ). Elemental analysis for C ₁₃ H ₁₃ FN ₆ O ₂ S Calculated: C, 46.42; H, 3.90; N, 24.99. Found: C, 46.22; H, 3.98; N, 24.55.

Example 31: Synthesis of (S) -N- [[3- [3-fluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] thiourea (45).

The ice-cooled stirred solution of 1,1-thiocarbonyl-2 (1H) -dipyridone (0.123 g, 0.530 mmol) in CH ₂ Cl ₂ (5 mL) was added to CH ₂ Cl ₂ (20 mL) Was treated with a suspension of compound 29 (0.17 g, 0.4 mmol) in THF (10 mL) and treated with a solution of triethylamine (0.111 mL, 0.8 mmol) in CH ₂ Cl ₂ (10 mL) for 10 min. It was kept in an ice bath for 30 minutes, at ambient temperature for 2 hours, at less than 0 ° C for 18 hours. It was then diluted with CH ₂ Cl ₂ , washed with water and brine, dried (MgSO ₄ ) and concentrated. The residue ( 80 ) was used in the next reaction without further purification. The analytical results of a sample of Compound 80 purified by flash chromatography on silica gel with 10-20% acetonitrile-CH ₂ Cl ₂ are as follows: ¹ H NMR (300 MHz, CDCl ₃ ) d 1.60 (broad s), 3.07 (m, 2H), 3.85 (m, 2H), 3.85 (m, 2H) 6.95 (t, 1 H), 7.13 (d, d, 1 H), 7.47 (d, d, 1 H); MS m / z 395 (M + H ^& lt ^{; +} & gt ^; ), 417 (M + Na &lt; ⁺ &gt;).

An excess of anhydrous ammonia was bubbled through an ice cold stirred solution of compound 80 (crude product from previous step) in THF (25 mL) and the mixture was held in an ice bath for 90 minutes and then concentrated under a nitrogen stream. The residue was chromatographed on silica gel with 5% MeOH-0.4% NH ₄ OH-CHCl ₃ and the product crystallized from acetonitrile to afford 0.0544 g of 45 : Melting point 209-210 ° C; ^{1 H NMR [300 ㎒, (} CD 3) 2 SO] d 2.94 (broad s, 4H), 3.47 (broad s, 2H), 3.60 (broad s, 2H), 3.78 (broad s, 3H), 4.07 (t 1H), 7.15 (d, J = 5.5 Hz, 2H), 4.63 (t, J = 5.5 Hz, 1H), 4.81 (broad s, ), 7.15 (broad s, 2H), 7.49 (d, d, 1 H), 7.91 (t, 1 H); IR (mull) 3443, 3403, 3321, 3202, 3081, 1753, 1655, 1648 cm ^-1 ; _{C 17 H 23 FN 5 O 4} HRMS (FAB) to S (M + H ⁺⁾ Calcd: 412.1454, Found: 412.1447. Elemental analysis for C ₁₇ H ₂₂ FN ₅ O ₄ S Calculated: C, 49.63; H, 5.39; N, 17.02. Results: C, 49.63; H, 5.48; N, 16.99.

Example 32: (S) -N- [[3- [1- (hydroxyacetyl) -5-indolinyl] -2-oxo-5-oxazolidinyl] methyl] thiourea (46).

CH ₂ Cl ₂ (5 ㎖) of 1,1 ¢ - thio carbonyldiimidazole -2 (1H) - a stirring solution of ice-cooled-pyridone (0.096 g, 0.41 mmol) CH 2 Cl 2 of the compound 27 (15 ㎖) (0.10 g, 0.34 mmol) and treated with 0.05 ml (0.36 mmol) of triethylamine. It was stored in an ice bath for 30 min, and at ambient temperature for 2 h, diluted with CH ₂ Cl ₂ , then washed with water and brine, dried (MgSO ₄ ) and concentrated. The residual 20-40% of water on silica gel with CH ₃ CN-CH ₂ Cl ₂ to chromatography to obtain 0.04 g of compound 81.

An excess of anhydrous ammonia was bubbled through an ice-cooled solution of compound 81 (0.04 g) in THF (30 mL) and the mixture was kept in an ice bath for 80 minutes and then concentrated under a nitrogen stream. Crystallization of the residue from CH ₃ CN to give the compound 46 0.0151 g: melting point 214-215 ℃ (decomposition); MS (FAB) m / z 351 (M + H @ ⁺ ), 350 (M @ ⁺ ), 319, 304, 147; _{C 15 H 19 N 4 O 4} HRMS (FAB) to S (M + H ⁺⁾ Calcd: 351.1127, Found: 351.1130; IR (DRIFT) 3329, 3296, 3196, 1746, 1655, 1626 cm &lt; ^{-1 &} gt ;.

Example 33: (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thiourea, Palline S-oxide (47).

_{CH 2 Cl 2 (7 ㎖)} 1,1 A suspension of compound 33 (0.30 g, 0.92 mmol) ¢ - thio carbonyldiimidazole -2 (1H) - pyridone (0.258 g, 1.11 mmol) and CH ₂ Cl ₂ (20 ml) in an ice-cooled stirred mixture for 20 minutes. The mixture was kept in an ice bath for 20 minutes and at ambient temperature for 2 hours, mixed with CH ₂ Cl ₂ (50 mL), washed with water and brine, dried (MgSO ₄ ) and concentrated. By chromatography of the product in _{20-50% CH 3 CN-CH 2} Cl 2 on silica gel to obtain 0.27 g compound 82 was used in this next reaction: MS (ES) m / z 370 (M + H +), 392 ( M + Na &lt; ⁺ &gt;).

An ice cold stirred solution of 82 (0.27 g, 0.73 mmol) in THF (15 mL) was treated with excess anhydrous ammonia under a nitrogen atmosphere, held in an ice bath for 1 hour and then concentrated; The residue was crystallized from MeOH to give 0.175 g of compound 47 ; Mp 212-213 [deg.] C; ^{1 H NMR [300 ㎒, (} CD 3) 2 SO] d 2.83 (m, 2H), 3.01 (m, 2H), 3.17 (m, 2H), 3.50 (t, 2H), 3.78 (broad s, 3H) , 4.08 (t, IH), 4.80 (broad s, IH), 7.17 (m, 2H), 7.17 (broad s, 2H), 7.50 (d, IH), 7.90 MS (ES) m / z 409 (M + Na &lt; ⁺ &gt;); IR (mull) 3335, 3284, 3211, 3175, 3097, 1750, 1630 cm &lt; ^{-1 &} gt ;. Elemental analysis for C ₁₅ H ₁₉ FN ₄ O ₃ S ₂ Calculated: C, 46.62; H, 4.95; N, 14.50. Found: C, 46.50; H, 4.95; N, 14.40.

Example 34: (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl- The bar mate (48).

The ice-cooled stirred mixture of compound 39 (0.59 g, 0.0020 mol), EtOH (1.5 mL), water (2 drops) and triethylamine (0.613 mL, 0.00440 mol) was treated with carbon disulfide (0.066 mL, 0.0011 mol) , Maintained in an ice bath for 2 hours, and at ambient temperature for 18 hours (after addition of carbon disulfide, a solution was obtained; a white precipitate soon began to form after the mixture was warmed to ambient temperature). The tilted suspension was treated dropwise with a solution of methyl iodide (0.137 mL, 0.00220 mol) in EtOH (2 mL) for 2 min and the mixture was held at ambient temperature for 1.5 h then concentrated in vacuo. Washing the solution of the residue in EtOAc with a saturated NaHCO ₃ solution, water and brine, dried (MgSO ₄₎ and concentrated. The residue was chromatographed on silica gel with 1.8% MeOH-CH ₂ Cl ₂ and the product crystallized from EtOAc to yield 0.197 g of 48 : Melting point 154-155 ° C; IR (mull) 3354, 3346, 1726 cm &lt; ^{-1 &} gt ;. Elemental analysis for C ₁₆ H ₂₀ FN ₃ O ₃ S ₂ Calculated: C, 49.85; H, 5.23; N, 10.90. Found: C, 49.73; H, 5.25; N, 10.82.

Example 35: Synthesis of (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl- Mate (50).

A stirred mixture of 48 (0.200 g, 0.518 mmol), sodium methoxide (0.003 g, 0.06 mmol) and MeOH (5 mL) was refluxed under nitrogen atmosphere for 4 hours and maintained at ambient temperature for 18 hours. The starting material and the product were found to have similar mobility on TLC. Therefore, the reaction was traced by MS (ES). The starting material was still present. The mixture was refluxed for 3 hours and additional sodium methoxide (0.005 g) was added and reflux continued for 2 hours. It was held at ambient temperature for 18 hours, refluxed for 1 hour, again held at ambient temperature for 1.5 hours and concentrated in vacuo. The residue was mixed with ice, the pH was adjusted to 9-10 with a saturated solution of 1 M KHSO ₄ and NaHCO ₃ and the mixture was extracted with CH ₂ Cl ₂ . The extract was washed with water and brine, dried (MgSO ₄₎ and concentrated. The residue was chromatographed on silica gel with 5% acetone-CH ₂ Cl ₂ and the product crystallized from EtOAc-hexane to give 0.107 g of compound 50 : mp 128-129 ° C; MS (ES) m / z 370 (M + H @ ⁺ ), 392 (M + Na @ ⁺ ); IR (DRIFT) 3282, 3251, 1753, 1735 cm &lt; ^{-1 &} gt ;; ^{1 H NMR [300 ㎒, (} CD 3) 2 SO] d 2.94 (m, 4H), 3.47, 3.74 (m, m, 7H), 3.86, 3.91 (s, s, 3H), 4.10 (m, 1H) , 4.73, 4.86 (m, 1 H), 7.05 (t, 1H), 7.16 (d, d, 1H), 7.47 (d, d, 1H), 9.41, 9.50 (s, Elemental analysis for C ₁₆ H ₂₀ FN ₃ O ₄ S Calculated: C, 52.02; H, 5.46; N, 11.38. Found: C, 51.97; H, 5.49; N, 11.35.

In the method of Example 35, sodium methoxide was replaced by an appropriate amount of sodium ethoxide to give the compound of Example 36, Table A below.

(3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (Compound 11) was dissolved in an appropriate amount of (S) -N- [[3- [3-fluoro-4-morpholinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] isopropylcarboxamide, Methyl] cyclopropylcarboxamide or (S) -N - [[3-fluoro-4-morpholinyl] phenyl] -2-oxo-5-oxazolidinyl] Phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide in accordance with the general method of example 1 and substituting The compounds of the same Examples 37, 38 and 39 were obtained, respectively. Isopropylcarboxamide and cyclopropylcarboxamide were obtained according to the method of Example 5 of U.S. Patent No. 5,688,792 only by replacing acetic anhydride of Step 7 with isobutyric anhydride and cyclopropanecarbonyl chloride, respectively. Acetamide was obtained as described in Example 4 of U.S. Patent No. 5,688,792.

In the method of Example 5, Step B, the ammonia anhydride was replaced with an excess of dimethylamine in THF to give the compound of Example 40 shown in Table A below.

Example No. compound R, R ' 36 (S) -N - [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-ethylthiocarbamate; MS (ES) m / z 384 (M + H ^& lt ^{; +} & gt ^; ). C ₁₇ H ₂₂ FN ₃ O elemental analysis calculated for ₄ S: C, 53.25; H, 5.78; N, 10.96. Found: C, 53.23; H, 5.82; N, 10.92. R = H, R '= OC 2 H 5 37 (S) -N - [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanethioamide; Mp 152-153 &lt; 0 &gt; C (decomposition); Elemental analysis calculated for _{C 18 H 24 FN 3 O 3} S: C, 56.67; H, 6.34; N, 11.02. Found: C, 56.58; H, 6.41; N, 10.81. R = H, R '= CH (CH 3) 2 38 (S) -N - [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane-carbothioamide; Mp 155-156 C; Elemental analysis for C ₁₈ H ₂₂ FN ₃ O ₃ S Calculated: C, 56.98; H, 5.84; N, 11.07. Found: C, 56.98; H, 5.85; N, 10.97. 39 (S) -N- [[3- [3,5-difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide R = F, R '= CH 3 40 (3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -N ', N'-dimethylthiourea R = H, R '= N (CH 3) 2

Preparation Z: Methyl dithiophosphonate

A stirred mixture of magnesium debris (12.6 g, 0.520 g atoms) and THF (100 mL) was treated with iodine crystals and a solution of about 5% bromoethane in THF (200 mL) (30.0 mL, 0.40 mol) under nitrogen atmosphere. When the reaction started, the remaining bromoethane solution was added dropwise at a rate sufficient to maintain a gentle reflux. After the addition, stirring is continued for 1 hour; The resulting solution was cooled to -20 &lt; 0 &gt; C and treated with carbon disulfide (24.0 mL, 0.40 mol) for 10 min. The mixture was warmed to 15 &lt; 0 &gt; C and treated with methyl iodide (28.0 ml, 0.45 mol) and held at 60 [deg.] C for 1 hour. Then it was cooled in an ice bath and treated with ice and extracted with Et ₂ O. The extract was washed with brine, dried (MgSO ₄₎ and concentrated. The residue was distilled to obtain 34.0 g of the title product (boiling point 48-52 占 폚, 12 mmHg).

In this process magnesium ethyl bromide was replaced by the appropriate magnesium alkyl bromide to give the following methyl dithio compound:

According to the general method of Step 4 of Example 27, an appropriate amount of the amine described below was reacted with the dithio compound described below to give each compound of Examples 41 to 61 in Table C. [

Following the general method of example 6 step 6, the appropriate amounts of the amine described below were reacted with the dithiocarbamates described below to give each compound of examples 62-67 of table C.

Example No. compound Amine The dithio compound (preparation method Z) 41 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide, thiomorpholine S- Oxide; Melting point 196-197 DEG C; Elemental analysis for C ₁₇ H ₂₂ FN ₃ O ₃ S ₂ Calculated: C, 51.11; H, 5.55; N, 10.52; S, 16.05. Found: C, 50.99; H, 5.60; N, 10.55; S, 15.75 Z (a) 42 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide, Morpholine S-oxide; Melting point 195-196 DEG C; Elemental analysis calculated for _{C 18 H 24 FN 3 O 3} S 2: C, 52.28; H, 5.85; N, 10.16; S, 15.51. Found: C, 52.24; H, 5.97; N, 10.16; S, 15.28 Same as above Z (b) 43 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide, Folin S-oxide; Mp 109-110 [deg.] C; C ₁₈ H ₂₂ FN ₃ O ₃ Elemental analysis calculated for S _2: C, 52.54; H, 5.39; N, 10.21; S, 15.58. Found: C, 52.48; H, 5.51; N, 10.28; S, 15.29 Same as above Z (c)

Example No. compound Amine The dithio compound (preparation method Z) 44 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] butane thioamide, thiomorpholine S- Oxide Same as above Z (d) 45 (3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -3-methylbutanethioamide, thio Morpholine S-oxide Same as above Z (e) 46 (3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylbutanethioamide, thio Morpholine S-oxide Same as above Z (f) 47 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -3,3-dimethylbutanethioamide , Thiomorpholine S-oxide Same as above Z (g) 48 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclobutanecarbothioamide, Pauline S-oxide Same as above Z (h) 49 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -1-cyclopentanecarbothioamide , Thiomorpholine S-oxide Same as above Z (i)

Example No. compound Amine The dithio compound (preparation method Z) 50 (3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclohexanecarbothioamide, thiomal Pauline S-oxide Same as above Z (j) 51 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- cyclopropylethanethioamide, Thiomorpholine S-oxide Same as above Z (k) 52 (S) -N - [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- cyclobutylethanethioamide, Thiomorpholine S-oxide Same as above Z (1) 53 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- cyclopentylethanethioamide, Thiomorpholine S-oxide Same as above Z (m) 54 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide, Pauline S-oxide Ethyl dithioacetate 55 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide, Pauline S-oxide Same as above Z (a)

Example No. compound Amine The dithio compound (preparation method Z) 56 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Amide, thiomorpholine S-oxide Same as above Z (b) 57 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide , Thiomorpholine S-oxide Same as above Z (c) 58 (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide, thiomorpholine S- Ethyl dithioacetate 59 (S) -N - [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide, thiomorpholine S- Same as above Z (a) 60 (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide, thiomorpholine S- Same as above Z (b) 61 (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide, thiomorpholine S- Same as above Z (c)

Example No. compound Amine The dithio compound (preparation method Z) 62 (S) -N- [[3- [3,5-difluoro-4- (4-hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Propanethioamide Z (a) 63 (S) -N- [[3- [3,5-difluoro-4- (4-hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanethioamide Same as above Z (b) 64 (S) -N- [[3- [3,5-difluoro-4- (4-hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Cyclopropanethioamide Same as above Z (c) 65 (S) -N- [[3- [3- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide Z (a) 66 (S) -N- [[3- [3- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide Same as above Z (b) 67 (S) -N - [[3- [3- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide Same as above Z (c)

Following the procedure of Step 3 of Example 28, the appropriate amounts of the amine described below were reacted with the dithiocarbide compounds described below to give each compound of Examples 68-78 in Table D.

Example No. compound Amine The dithio compound (preparation method Z) 68 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide, thiomorpholine S, S-dioxide Z (a) 69 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide, Morpholine S, S-dioxide Same as above Z (b) 70 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide, Pauline S, S-Dioxide Same as above Z (c) 71 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide, Pauline S, S-Dioxide Ethyl dithioacetate 72 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide, Pauline S, S-Dioxide Same as above Z (a)

Example No. compound Amine The dithio compound (preparation method Z) 73 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Amide, thiomorpholine S, S-dioxide Same as above Z (b) 74 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide , Thiomorpholine S, S-dioxide Same as above Z (c) 75 (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide, thiomorpholine S, S- Ethyl dithioacetate 76 (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide, thiomorpholine S, S- Same as above Z (a) 77 (S) -N - [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide, thiomorpholine S, S - Dioxide Same as above Z (b) 78 (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide, thiomorpholine S, S- Dioxide Same as above Z (c)

According to the method of Example 26, an appropriate amount of the amine described below was reacted with the dithio compound described below to give each compound of Examples 79 to 99 in Table E.

Example No. compound Amine The dithio compound (preparation method Z) 79 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide Z (a) 80 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide Same as above Z (b) 81 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide Same as above Z (c) 82 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] butane thioamide Same as above Z (d) 83 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -3-methylbutanethioamide Same as above Z (e) 84 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylbutanethioamide Same as above Z (f)

Example No. compound Amine The dithio compound (preparation method Z) 85 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -3,3-dimethylbutanethioamide Same as above Z (g) 86 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclobutanecarbothioamide Same as above Z (h) 87 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopentanecarbothioamide Same as above Z (i) 88 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclohexanecarbothioamide Same as above Z (j) 89 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- cyclopropylethanethioamide Same as above Z (k) 90 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- cyclobutylethanethioamide Same as above Z (1)

Example No. compound Amine The dithio compound (preparation method Z) 91 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- cyclopentylethanethioamide Same as above Z (m) 92 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide Ethyl dithioacetate 93 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide Same as above Z (a) 94 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- amides Same as above Z (b) 95 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide Same as above Z (c) 96 (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide Ethyl dithioacetate 97 (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide Same as above Z (a) 98 (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methyl-propanethioamide Same as above Z (b) 99 (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide Same as above Z (c)

The amines used in Examples 41-53 were prepared as described in Example 27, step 3. The amine used in Examples 54-57 was prepared by treating compound 62 in Step 1 of Example 27 with the appropriate (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) Phenyl] -2-oxo-5-oxazolidinyl] methanol.

The amine used in Examples 58-61 was prepared by treating compound 62 in Step 1 of Example 27 with the appropriate (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] - &lt; / RTI &gt; oxazolidinyl] methanol. A suitable oxazolidinylmethanol compound was obtained according to the method of steps 1 to 3 of Example 1 of U.S. Patent No. 5,688,792 only in step 1 by replacing 3,4-difluoronitrobenzene with 4-fluoronitrobenzene.

The amines used in Examples 62-64 were prepared from amide 65, prepared according to the method described in Example 32 of U.S. Patent No. 5,700,799, as in Example 37, The amines used in Examples 65-67 were prepared from the following amides by the general method of Example 29, the preparation of which is described in Example 3 of U.S. Patent 5,700,799:

The amines used in Examples 68-70 were prepared as described in step 2 of Example 28 above.

The amine used in Examples 71-74 is prepared by reacting Compound 62 of Step 1 with (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) Oxo-5-oxazolidinyl] methanol and following the method of steps 1 and 2, as described for example 28. &lt; 1 &gt; Suitable oxazolidinylmethanol compounds were prepared according to the general method of Example 4 of US Pat. No. 5,688,792, Steps 1 to 4, only by replacing the porphorin of Step 1 with thiomorpholine.

The amines used in Examples 75-78 can be prepared by reacting Compound 62 of Step 1 with (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] Methanol as described in step 1 of Example 28 above. Suitable oxazolidinylmethanol was obtained according to steps 1-3 of the method of Example 1 of US 5,688,792 only by replacing the 3,4-difluoronitrobenzene of step 1 with 4-fluoronitrobenzene.

The amines used in Examples 79-91 were prepared as described in Step 4 of Example 1 of U.S. Patent No. 5,688,792. The amines used in Examples 92-95 were prepared as described in Example 4 of U.S. Patent No. 5,688,792 only in Step 1 by replacing morpholine with thiomorpholine. The amines used in Examples 96-99 were prepared by the method of Example 1 of U.S. Patent No. 5,688,792 only in Step 1, replacing 3,4-difluoronitrobenzene with 4-fluoronitrobenzene.

Example 100: Synthesis of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbamate, thiomorpholine S-oxide

To a solution of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo- Methyl] isothiocyanate, thiomorpholine s-oxide compound 82 (20 mg, 0.554 mmol) was refluxed under nitrogen atmosphere for 18 hours and cooled. The solid was collected by filtration to give 0.138 g of the title product. Mp 208-209 C; Elemental analysis for C ₁₆ H ₂₀ FN ₃ O ₄ S ₂ Calculated: C, 47.87; H, 5.02; N, 10.47. Found: C, 47.81; H, 5.04; N, 10.49.

In the method of Example 100, Compound 82 was replaced with the thioisocyanate described below to give the product described below as Examples 101-109.

Isothiocyanate Rc Ra Rb Example No. compound OS F F 101 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Benzoate, thiomorpholine S-oxide OS H H 102 (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5- oxazolidinyl] methyl] -O- methylthiocarbamate, thiomorpholine S- Oxide O ₂ S H F 103 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thiomorpholine S, S-dioxide O ₂ S F F 104 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Benzoate, thiomorpholine S, S-dioxide O ₂ S H H 105 (S) -N - [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] S-dioxide S H F 106 (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate S F F 107 (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Barmate S H H 108 (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate H H 109 (3-fluoro-4- (4-hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O- Methyl thiocarbamate

In the method of Example 100, methanol was replaced by an appropriate amount of ethanol and isopropyl alcohol to give each of the following compounds:

Example 110: Synthesis of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbamate, thiomorpholine S-oxide. Melting point 198-199 DEG C; Elemental analysis for C ₁₇ H ₂₂ FN ₃ O ₄ S ₂ Calculated: C, 49.14; H, 5.34; N, 10.11. Found: C, 49.06; H, 5.27; N, 10.10.

Example 111: (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thiocarbamate, thiomorpholine S-oxide. Melting point 180-181 DEG C; Elemental analysis calculated for _{C 18 H 24 FN 3 O 4} S 2: C, 50.33; H, 5.63; N, 9.78. Found: C, 50.29; H, 5.69; N, 9.82.

Compound 82 was reacted with an appropriate amount of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] Was replaced with isothiocyanate and methanol was replaced by ethanol or isopropyl alcohol to give each of the following products:

Example 112: Preparation of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbamates ;

Example 113: (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Propyl thiocarbamate ;

Example 114: (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Urea, thiomorpholine S-oxide.

A stirred suspension of 240 mg (0.650 mmol) of 82 from step 1 of Example 33 in THF (5 mL) was treated with a 2 M solution of methylamine (0.42 mL, 0.845 mmol) in THF at 0 & Hour. The solid was collected by filtration to give 0.221 g of the title product.

According to the method of Example 114, substituting methylamine only with an appropriate amount of dimethylamine and azetidine gave the following compounds:

Example 115: (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] '-Dimethylthiourea, thiomorpholine S-oxide ; C ₁₇ H ₂₃ FN ₄ O ₃ Elemental analysis calculated for S _2: C, 49.26; H, 5.59; N, 13.52. Found: C, 49.11; H, 5.57; N, 13.40; Melting point 180-182 占 폚.

Example 116: (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbothioamide, thiomorpholine S-oxide ; C ₁₈ H ₂₃ FN ₄ O ₃ Elemental analysis calculated for S _2: C, 50.69; H, 5.43; N, 13.14. Found: C, 50.79; H, 5.45; N, 12.82; Melting point 213-214 [deg.] C.

Compound 82 was reacted with an appropriate amount of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] Methyl] isothiocyanate, the following compounds were obtained: &lt; RTI ID = 0.0 &gt;

Example 117: (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Methyl thiourea.

In the method of Example 117, methylamine was replaced with an appropriate amount of dimethylamine and azetidine to give each of the following products:

Example 118: Preparation of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] - dimethylthiourea ;

Example 119: (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbothioamide.

In the method of Example 33, Compound 33 was replaced with an appropriate amount of Compound 31 from Example 26 and according to the general procedure of Steps 1 and 2 of Example 33, the following compounds were obtained.

Example 120: (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thiourea.

Example 121: Synthesis of (S) -N- [[3- [3-fluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] propanethioamide

A stirred mixture of 200 mg (0.514 mmol) of compound 29 methyl dithiophosphonate (247 mg, 2.06 mmol), triethylamine (0.58 mL, 4.11 mmol), THF (5.4 mL) and methylene chloride (5.4 mL) It was maintained under a nitrogen atmosphere for 3 days, diluted with water and extracted with methylene chloride. The extract was dried (MgSO ₄ ) and concentrated. The residue was chromatographed on silica gel and the product crystallized from methanol to give 0.132 g of the title product. Melting point 190-191 占 폚; C ₁₉ H ₂₅ FN Elemental analysis calculated for _{4 O 4 S: C, 53.76} ; H, 5.94; N, 13.20; S, 7.55. Found: C, 53.66; H, 5.94; N, 13.20; S, 7.37.

According to the method of Example 121, only methyl dithiophosphonate was replaced with the dithio compounds Z (b) to Z (m) from the above preparation method Z to obtain the following compounds.

In the method of Example 100, compound 82 was replaced by the appropriate amount of compound 80 from Example 31, and methanol was replaced by ethanol or isopropyl alcohol to give each of the following compounds:

Example 134: Preparation of (S) -N- [[3- [3-fluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] -O-ethylthiocarbamate ;

Example 135: Preparation of (S) -N- [[3- [3-fluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] -O-iso-propylthiocarbamate ;

Example 136: Synthesis of (S) -N- [[3- [3-fluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] -N'-methylthiourea.

Compound 82 in the method of Example 114 was substituted with the appropriate amount of Compound 80 from Example 31 to give the title compound.

According to the method of Example 114, only compound 82 was replaced by the appropriate amount of compound 80 from Example 31 and methylamine was replaced by an appropriate amount of dimethylamine and azetidine to give the following compound, Examples 137 and 138:

Example 137: Preparation of (S) -N- [[3- [3-fluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] -N ', N'-dimethylthiourea ;

Example 138: Preparation of (S) -N- [[3- [3-fluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] -1-azetidinecarbothioamide.

Example 139: (S) -N- [[3- [3,5-Difluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2- Methyl] -O-methylthiocarbamate. &Lt; / RTI &gt;

Part A: According to the procedure of Step 1 of Example 33, substituting the appropriate amount of Compound 37 from Step 5 of Example 29 with only compound 33 gave (S) -N- [[3,5- [3-difluoro -4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] isothiocyanate.

Part B: In the general method of Example 100, Compound 82 is dissolved in an appropriate amount of (S) -N - [[3- [3,5-difluoro-4- [4- (hydroxyacetyl) ] Phenyl] -2-oxo-5-oxazolidinyl] methyl] isothiocyanate gave the title compound.

Example 140: Synthesis of (S) -N- [[3- [4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Methyl thiocarbamate

Part A: According to the procedure of Step 1 of Example 33, Compound 33 was reacted with an appropriate amount of (S) -N- [[3- [4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] (S) -N - [[3- [4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo- -5-oxazolidinyl] methyl] isothiocyanate.

Part B: In the general method of Example 100, Compound 82 is dissolved in an appropriate amount of (S) -N - [[3- [4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] 5-oxazolidinyl] methyl] isothiocyanate to give the title compound.

Example 141: Synthesis of (S) -N- [[3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide

Step 1

An ice-cooled stirred solution of 30.4 g (70.8 mmol) of the starting material 58 from step 1 of Example 25 and 15.4 mL (110 mmol) of triethylamine in methylene chloride (2570 mL) was treated with m-nitrobenzenesulfonyl chloride g, 84.9 mmol) and kept at ambient temperature (24 &lt; 0 &gt; C) for 24 hours under a nitrogen atmosphere. Additional m-nitrobenzenesulfonyl chloride (1.88 g) and triethylamine (1.54 mL) were added and the mixture was kept at ambient temperature for one more day, washed with water, saturated sodium bicarbonate solution and brine, dried (Na ₂ SO ₄ ) and concentrated to give an oily product 85. Alcohol 58 was prepared following the method of Brickner (J. Med. Chem. 1996, 39 , 673-679, reference 5a).

Step 2

A stirred mixture of 85, acetonitrile (1270 mL), isopropanol (1270 mL) and ammonium hydroxide (1270 mL) was kept at ambient temperature for 3 days and concentrated in vacuo. The residue was chromatographed on silica gel with 0.5% NH ₄ OH-1% MeOH-CH ₂ Cl ₂ to give 22.4 g of amine 86.

Step 3

An ice cold stirred solution of amine 86 in THF (650 mL) was treated with a solution of di-tert-butyl dicarbonate (12.0 g, 55.2 mmol) in THF (90 mL) for 20 min. &Lt; / RTI &gt; and concentrated in vacuo. Washing the residue dissolved in methylene chloride with sodium bicarbonate diluted solution and dried (MgSO ₄₎ and concentrated. The residue was crystallized from methanol-ethyl acetate to give 20.0 g of Boc protected amine. The mother liquor was chromatographed on silica gel with 1-2% methanol-methylene chloride to give an additional product (4.1 g).

Step 4

A solution of protected amine 87 (5.00 g, 9.46 mmol) in ethanol (150 mL) was treated with 10% palladium on carbon catalyst (1.0 g) and hydrogenated at 30 psi initial pressure for 3 h. The catalyst was removed by filtration through Celite, and the filtrate was concentrated to obtain 3.66 g of Compound 88.

Step 5

A stirred solution of 88 (1.10 g, 2.79 mmol) in pyridine (10 mL) was treated with acetic anhydride (289 L, 3.07 mmol), held at ambient temperature for 2 hours and concentrated in vacuo. The solution of the residue in methylene chloride was washed with hydrochloric acid diluted solution, dried (MgSO ₄ ) and concentrated to give 1.23 g of 89: MS m / z 436 (M ⁺ ).

Step 6

An ice-cold 4 N stirred solution of HCl in dioxane (10 mL) was treated with 89 (1.10 g, 2.52 mmol). The mixture was kept in an ice bath for 30 minutes and at ambient temperature for 1 hour. It was then mixed with methylene chloride and concentrated. The residue was triturated with methylene chloride to obtain 1.03 g of an amine hydrochloride.

Step 7

A stirred mixture of compound P-90 (250 mg), triethylamine (0.75 mL, 5.36 mmol), ethyl dithioacetate (307 L, 2.68 mmol), methylene chloride (7.4 mL) and THF (7.4 mL) For one day, concentrated and chromatographed on a silica gel with a mixture of methanol-methylene chloride containing 1-2% methanol. Ethyl acetate-crystallization of the product from heptane to give the title product _{0.160 g: C 18 H 23 FN} 4 O elemental analysis calculated for ₃ S: C, 54.81; H, 5.88; N, 14.20; S, 8.13. Found: C, 54.92; H, 5.95; N, 14.08; S, 7.94; Melting point 158 캜.

In the general method of Example 141, Compound 58 was replaced with an appropriate amount of Compound (x, y) of the formula: and the respective amine compounds P-91 and P-92 described below were obtained according to the methods of Steps 1-6:

The above-mentioned alcohol-called x and y is 2,6-difluoro-nitrobenzene respectively, in an appropriate amount of 3,4-difluoro in the preparation of compound 2a -4- nitrobenzene (trifluoromethane) sulfonate and 4- (J. Med. Chem., 1996, 39 , 673-679) in place of fluoronitrobenzene.

In the method of Example 141, compound 58 was replaced by an appropriate amount of x or y and following the procedure of steps 1-4, the Boc protected compound described below was obtained.

In the process of Step 5 of Example 141, an appropriate amount of Compound 88, compound xb or compound yb is treated with the reagents described below and the amine described in Preparations P-93 to P-128 below according to the general method of Step 5 and Step 6 &Lt; / RTI &gt;

A solution of Compound 88 (1.00 g, 2.54 mmol), sulfamide (305 mg, 3.18 mmol) and 1,2-dimethyloxyethane (6 mL) was refluxed for 6 days to give the amine compound shown below as P-129 . The precipitated solid was collected by filtration and chromatographed on silica gel with 5% methanol-methylene chloride. The product was crystallized from methanol-methylene chloride to give 0.551 g of the sulfamoyl derivative used to provide P-129 in step 6 of Example 141. Compound 88 was substituted for compounds xb and yb , and according to this general method, Preparation Examples P-130 and P-131 shown below were obtained, respectively.

Following the general procedure of steps 5 and 6 of Example 141, except substituting acetic anhydride for chloroacetonitrile or 2-fluoroethyl bromide, respectively, in step 5 and using compound 88, compound xb or compound yb , -132 to P-137 were obtained.

The amine compound shown below in Preparation P-138 was reacted with N-formylbenzotriazole (493 mg, 3.35 mmol) in THF (30 mL) with the compound 88 (1.10 g, 2.75 mmol) And the mixture was maintained at ambient temperature for 18 hours. The mixture was concentrated and was chromatographed with a mixture of methanol and methylene chloride containing 1-2% methanol Photography on washing of the residue in methylene chloride with 1 N sodium hydroxide and sodium chloride diluted solution, dried (MgSO _4), concentrated, and purified by silica gel N -Formyl &lt; / RTI &gt; derivative, which is used in the general method of Example 6 step 6 to provide Preparation P-138. In the above-mentioned method, the compounds xb and yb were used instead of the compound 88 to give the following Production Examples P-139 and P-140.

reagent Boc compound R R &quot; R ' Manufacturing Example No. Methoxyacetyl chloride 88x-by-b HFH FFH P-93P-94P-95 Cyanoacetyl chloride 88x-by-b HFH FFH P-96P-97P-98 Acetoxyacetyl chloride 88x-by-b HFH FFH P-99P-100P-101 Benzyloxyacetyl chloride 88x-by-b HFH FFH P-102P-103P-104 Methyl chloroformate 88x-by-b HFH FFH P-105P-106P-107 Methanesulfonyl chloride 88x-by-b CH ₃ SO ₂ - HFH FFH P-108P-109P-110 Ethanesulfonyl chloride 88x-by-b CH ₃ CH ₂ SO ₂ - HFH FFH P-111P-112P-113 Chloromethanesulfonyl chloride 88x-by-b ClCH ₂ SO ₂ - HFH FFH P-114P-115P-116

reagent Boc compound R R &quot; R ' Manufacturing Example No. Cyanomethanesulfonyl chloride 88x-by-b NCCH ₂ SO ₂ - HFH FFH P-117P-118P-119 N-methylsulfamoyl chloride 88x-by-b CH ₃ NHSO ₂ - HFH FFH P-120P-121P-122 N, N-Dimethylsulfamoyl chloride 88x-by-b (CH ₃ ) ₂ NSO ₂ - HFH FFH P-123P-124P-125 Ethyl chloroformate 88x-by-b HFH FFH P-126P-127P-128 Sulfamide 88x-by-b H ₂ NSO ₂ - HFH FFH P-129P-130P-131 Chloroacetonitrile 88x-by-b NCCH ₂ - HFH FFH P-132P-133P-134 2-fluoroethyl bromide 88x-by-b FCH ₂ CH ₂ - HFH FFH P-135P-136P-137 N-formylbenzotriazole 88x-by-b HFH FFH P-138P-139P-140

Examples 142-161:

According to the general method of Step 7 of Example 141, the respective products named Examples 142 to 400 in Table H were obtained using an appropriate amount of the amine described below and the dithio compound from Preparation Z described below.

Example No. product Amine Dithio compound 142 (S) -N - [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide; Melting point 161-162 DEG C; C ₁₉ H ₂₅ FN ₄ O elemental analysis calculated for ₃ S: C, 55.87; H, 6.17; N, 13.72; S, 7.85. Found: C, 55.79; H, 6.26; N, 13.60; S, 7.71 P-90 Z (a) 143 (S) -N- [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- amides P-90 Z (b) 144 (S) -N- [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide ; Melting point 159-160 DEG C; Elemental analysis for C ₂₀ H ₂₅ FN ₄ O ₃ S Calculated: C, 57.13; H, 5.99; N, 13.32; S, 7.62. Found: C, 57.05; H, 6.01; N, 13.15; S, 7.45 P-90 Z (c) 145 (S) -N- [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] butane thioamide P-90 Z (d) 146 (S) -N - [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] amides P-90 Z (e) 147 (S) -N - [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- amides P-90 Z (f) 148 (S) -N- [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Butanethioamide P-90 Z (g) 149 (S) -N- [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclobutanecarbothioamide P-90 Z (h) 150 (S) -N - [[3- [3-fluoro-4- (4-acetyl- 1 -piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopentanecarbothioamide P-90 Z (i) 151 (S) -N- [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclohexanecarbothioamide P-90 Z (j) 152 (S) -N- [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Thioamide P-90 Z (k) 153 (3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Thioamide P-90 Z (1) 154 (S) -N- [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Thioamide P-90 Z (m) 155 (S) -N- [[3- [3,5-difluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-91 Ethyl dithioacetate 156 (S) -N- [[3- [3,5-difluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-91 Z (a) 157 (S) -N- [[3- [3,5-difluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] Methyl propanethioamide P-91 Z (b) 158 (S) -N- [[3- [3,5-difluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarboxylate Butothioamide P-91 Z (c) 159 (S) -N- [[3- [4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-92 Ethyl dithioacetate 160 (S) -N- [[3- [4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-92 Z (b)

Example No. product Amine Dithio compound 161 (S) -N- [[3- [4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide P-92 Z (b) 162 (S) -N- [[3- [4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide P-92 Z (c) 163 (S) -N- [[3- [3-fluoro-4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetate amides P-93 Ethyl dithioacetate 164 (S) -N- [[3- [3-fluoro-4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethio amides P-93 Z (a) 165 (3-fluoro-4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2 - methylpropanethioamide P-93 Z (b) 166 (S) -N- [[3- [3-fluoro-4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane Carbothioamide P-93 Z (c) 167 (3-fluoro-4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] butane thio amides P-93 Z (d) 168 (3-fluoro-4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -3 - methyl butanethioamide P-93 Z (e) 169 (3-fluoro-4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2 - methyl butanethioamide P-93 Z (f) 170 (3-fluoro-4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -3 , 3-dimethylbutanethioamide P-93 Z (g) 171 (S) -N- [[3- [3-fluoro-4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbothioamide P-93 Z (h) 172 (S) -N- [[3- [3-fluoro-4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopentane Carbothioamide P-93 Z (i) 173 (S) -N- [[3- [3-fluoro-4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclohexane Carbothioamide P-93 Z (j) 174 (3-fluoro-4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2 - cyclopropylethanethioamide P-93 Z (k) 175 (3-fluoro-4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2 - cyclobutylethanethioamide P-93 Z (1) 176 (3-fluoro-4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2 - cyclopentylethanethioamide P-93 Z (m) 177 (S) -N- [[3- [3,5-difluoro- [4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] Methyl] thioacetamide P-94 Ethyl dithioacetate

Example No. product Amine Dithio compound 178 (S) -N- [[3- [3,5-difluoro- [4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] Methyl] propanethioamide P-94 Z (a) 179 (S) -N- [[3- [3,5-difluoro- [4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] Methyl] -2-methylpropanethioamide P-94 Z (b) 180 (S) -N- [[3- [3,5-difluoro- [4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] Methyl] cyclopropanecarbothioamide P-94 Z (c) 181 (S) -N- [[3- [4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-95 Ethyl dithioacetate 182 (S) -N- [[3- [4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-95 Z (a) 183 (S) -N- [[3- [4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide P-95 Z (b) 184 (S) -N- [[3- [4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide P-95 Z (c) 185 (S) -N- [[3- [3-fluoro-4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetate amides P-96 Ethyl dithioacetate 186 (S) -N- [[3- [3-fluoro-4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethio amides P-96 Z (a) 187 (S) -N- [[3- [3-fluoro-4- [4- (cyanoacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] - methylpropanethioamide P-96 Z (b) 188 (S) -N- [[3- [3-fluoro-4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane Carbothioamide P-96 Z (c) 189 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Thioacetamide P-97 Ethyl dithioacetate 190 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Propanethioamide P-97 Z (a) 191 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -2-methylpropanethioamide P-97 Z (b) 192 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Cyclopropanecarbothioamide P-97 Z (c) 193 (S) -N- [[3- [4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-98 Ethyl dithioacetate 194 (S) -N - [[3- [4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-98 Z (a) 195 (S) -N- [[3- [4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide P-98 Z (b) 196 (S) -N - [[3- [4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide P-98 Z (c) 197 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetate amides P-99 Ethyl dithioacetate

Example No. product Amine Dithio compound 198 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethiol amides P-99 Z (a) 199 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] - methylpropanethioamide P-99 Z (b) 200 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane Carbothioamide P-99 Z (c) 201 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] butane thio amides P-99 Z (d) 202 (3-fluoro-4- [4- (acetoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -3 - methyl butanethioamide P-99 Z (e) 203 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] - methyl butanethioamide P-99 Z (f) 204 (3-fluoro-4- [4- (acetoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -3 , 3-dimethylbutanethioamide P-99 Z (g) 205 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbothioamide P-99 Z (h) 206 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopentane Carbothioamide P-99 Z (i) 207 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclohexane Carbothioamide P-99 Z (j) 208 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] - cyclopropylethanethioamide P-99 Z (k) 209 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] - cyclobutylethanethioamide P-99 Z (1) 210 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] - cyclopentylethanethioamide P-99 Z (m) 211 (S) -N- [[3- [3,5-difluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Thioacetamide P-100 Ethyl dithioacetate 212 (S) -N- [[3- [3,5-difluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Propanethioamide P-100 Z (a)

Example No. product Amine Dithio compound 213 (S) -N- [[3- [3,5-difluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -2-methylpropanethioamide P-100 Z (b) 214 (S) -N- [[3- [3,5-difluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Cyclopropanecarbothioamide P-100 Z (c) 215 (S) -N- [[3- [4- [4- (acetoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-101 Ethyl dithioacetate 216 (S) -N - [[3- [4- [4- (acetoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-101 Z (a) 217 (S) -N- [[3- [4- [4- (acetoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide P-101 Z (b) 218 (S) -N - [[3- [4- [4- (acetoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide P-101 Z (c) 219 (3-fluoro-4- [4- (benzyloxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetate amides P-102 Ethyl dithioacetate 220 (S) -N- [[3- [3-fluoro-4- [4- (benzyloxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethiol amides P-102 Z (a) 221 (3-fluoro-4- [4- (benzyloxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2 - methylpropanethioamide P-102 Z (b) 222 (S) -N- [[3- [3-fluoro-4- [4- (benzyloxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane Carbothioamide P-102 Z (c) 223 (S) -N- [[3- [3,5-difluoro-4- [4- (benzyloxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Thioacetamide P-103 Ethyl dithioacetate

Example No. product Amine Dithio compound 224 (S) -N- [[3- [3,5-difluoro-4- [4- (benzyloxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Propanethioamide P-103 Z (a) 225 (S) -N- [[3- [3,5-difluoro-4- [4- (benzyloxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -2-methylpropanethioamide P-103 Z (b) 226 (S) -N- [[3- [3,5-difluoro-4- [4- (benzyloxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Cyclopropanecarbothioamide P-103 Z (c) 227 (S) -N- [[3- [3-fluoro-4- [4- (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thio Acetamide P-105 Ethyl dithioacetate 228 (S) -N- [[3- [3-fluoro-4- [4- (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Thioamide P-105 Z (a) 229 (3-fluoro-4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2-methylpropanethioamide P-105 Z (b) 230 (S) -N- [[3- [3-fluoro-4- [4- (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Propanecarbothioamide P-105 Z (c) 231 (S) -N- [[3- [3-fluoro-4- [4- (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] butane Thioamide P-105 Z (d) 232 (3-fluoro-4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 3-methylbutanethioamide P-105 Z (e) 233 (3-fluoro-4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2-methylbutanethioamide P-105 Z (f) 234 (3-fluoro-4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 3,3-dimethylbutanethioamide P-105 Z (g) 235 (S) -N- [[3- [3-fluoro-4- [4- (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Butane carbothioamide P-105 Z (h) 236 (S) -N- [[3- [3-fluoro-4- [4- (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Pentanecarbothioamide P-105 Z (i) 237 (S) -N- [[3- [3-fluoro-4- [4- (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Hexane carbothioamide P-105 Z (j) 238 (3-fluoro-4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2-Cyclopropylethanethioamide P-105 Z (k)

Example No. product Amine Dithio compound 239 (3-fluoro-4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2-Cyclobutylethanethioamide P-105 Z (1) 240 (3-fluoro-4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2-cyclopentylethanethioamide P-105 Z (m) 241 (S) -N- [[3- [3,5-difluoro-4- [4- (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] thioacetamide P-106 Ethyl dithioacetate 242 (S) -N- [[3- [3,5-difluoro-4- [4- (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] propanethioamide P-106 Z (a) 243 (S) -N- [[3- [3,5-difluoro-4- [4- (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] -2-methylpropanethioamide P-106 Z (b) 244 (S) -N- [[3- [3,5-difluoro-4- [4- (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] cyclopropanecarbothioamide P-106 Z (c) 245 (S) -N- [[3- [4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-107 Ethyl dithioacetate 246 (S) -N- [[3- [4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-107 Z (a) 247 (S) -N - [[3- [4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- amides P-107 Z (b) 248 (S) -N- [[3- [4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide P-107 Z (c) 249 (S) -N- [[3- [3-fluoro-4- [4- (methanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetate amides; Melting point 197-198 DEG C; Elemental analysis for C ₁₇ H ₂₃ FN ₄ O ₃ S ₂ Calculated: C, 47.43; H, 5.39; N, 13.01; S, 14.89. Found: C, 47.25; H, 5.40; N, 12.82; S, 14.56. P-108 Ethyl dithioacetate 250 (S) -N- [[3- [3-fluoro-4- [4- (methanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethio amides; Mp 207-208 [deg.] C; C ₁₈ H ₂₅ FN ₄ O ₄ Elemental analysis calculated for S _2: C, 48.63; H, 5.67; N, 12.60; S, 14.42. Found: C, 48.51; H, 5.59; N, 12.52; S, 14.09. P-108 Z (a) 251 (S) -N- [[3- [3-fluoro-4- [4- (methanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -Methylpropanethioamide; Melting point: 204-206 DEG C; C ₁₉ H ₂₇ FN ₄ O ₄ Elemental analysis calculated for S _2: C, 49.76; H, 5.93; N, 12.22; S, 13.98. Found: C, 49.63; H, 5.92; N, 14.14; S, 13.91. P-108 Z (b) 252 (S) -N- [[3- [3-fluoro-4- [4- (methanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane Carbothioamide; C ₁₉ H ₂₅ FN ₄ O ₄ Elemental analysis calculated for S _2: C, 49.98; H, 5.52; N, 12.27; S, 14.04. Found: C, 49.42; H, 5.50; N, 12.08; S, 13.80. P-108 Z (c)

Example No. product Amine Dithio compound 253 (S) -N- [[3- [3,5-difluoro-4- [4- (methanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Thioacetamide P-109 Ethyl dithioacetate 254 (S) -N- [[3- [3,5-difluoro-4- [4- (methanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Propanethioamide P-109 Z (a) 255 (S) -N- [[3- [3,5-difluoro-4- [4- (methanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -2-methylpropanethioamide P-109 Z (b) 256 (S) -N- [[3- [3,5-difluoro-4- [4- (methanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Cyclopropanecarbothioamide P-109 Z (c) 257 (S) -N- [[3- [4- [4- (methanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-110 Ethyl dithioacetate 258 (S) -N - [[3- [4- [4- (methanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-110 Z (a) 259 (S) -N - [[3- [4- [4- (methanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide P-110 Z (b) 260 (S) -N - [[3- [4- [4- (methanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide P-110 Z (c) 261 (S) -N- [[3- [3-fluoro-4- [4- (ethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetate amides P-111 Ethyl dithioacetate 262 (S) -N- [[3- [3-fluoro-4- [4- (ethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethio amides P-111 Z (a) 263 (S) -N- [[3- [3-fluoro-4- [4- (ethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] - methylpropanethioamide P-111 Z (b) 264 (S) -N- [[3- [3-fluoro-4- [4- (ethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane Carbothioamide P-111 Z (c) 265 (S) -N- [[3- [3,5-difluoro-4- [4- (ethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Thioacetamide P-112 Ethyl dithioacetate 266 (S) -N- [[3- [3,5-difluoro-4- [4- (ethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Propanethioamide P-112 Z (a) 267 (S) -N- [[3- [3,5-difluoro-4- [4- (ethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -2-methylpropanethioamide P-112 Z (b) 268 (S) -N- [[3- [3,5-difluoro-4- [4- (ethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Cyclopropanecarbothioamide P-112 Z (c) 269 (S) -N- [[3- [4- [4- (4-ethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-113 Ethyl dithioacetate

Example No. product Amine Dithio compound 270 (S) -N- [[3- [4- [4- (4-ethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-113 Z (a) 271 Phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanethioamide &lt; / RTI &gt; P-113 Z (b) 272 (S) -N- [[3- [4- [4- (4-ethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide P-113 Z (c) 273 (S) -N- [[3- [3-fluoro-4- [4- (chloromethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thio Acetamide P-114 Ethyl dithioacetate 274 (S) -N- [[3- [3-fluoro-4- [4- (chloromethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Thioamide P-114 Z (a) 275 (S) -N- [[3- [3-fluoro-4- [4- (chloromethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] 2-methylpropanethioamide P-114 Z (b) 276 (S) -N- [[3- [3-fluoro-4- [4- (chloromethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Propanecarbothioamide P-114 Z (c) 277 (S) -N- [[3- [3,5-difluoro-4- [4- (chloromethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] thioacetamide P-115 Ethyl dithioacetate 278 (S) -N- [[3- [3,5-difluoro-4- [4- (chloromethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] propanethioamide P-115 Z (a) 279 (S) -N- [[3- [3,5-difluoro-4- [4- (chloromethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] -2-methylpropanethioamide P-115 Z (b) 280 (S) -N- [[3- [3,5-difluoro-4- [4- (chloromethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] cyclopropanecarbothioamide P-115 Z (c) 281 (S) -N - [[3- [4- [4- (chloromethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-116 Ethyl dithioacetate 282 (S) -N - [[3- [4- [4- (chloromethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-116 Z (a) 283 (S) -N - [[3- [4- [4- (chloromethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- amides P-116 Z (b) 284 (S) -N- [[3- [4- [4- (chloromethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide P-116 Z (c) 285 (S) -N- [[3- [3-fluoro-4- [4- (cyanomethane- sulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Thioacetamide P-117 Ethyl dithioacetate 286 (S) -N- [[3- [3-fluoro-4- [4- (cyanomethane- sulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Propanethioamide P-117 Z (a) 287 (S) -N- [[3- [3-fluoro-4- [4- (cyanomethane- sulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -2-methylpropanethioamide P-117 Z (b) 288 (S) -N- [[3- [3-fluoro-4- [4- (cyanomethane- sulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Cyclopropanecarbothioamide P-117 Z (c) 289 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanomethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5- Decyl] methyl] thioacetamide P-118 Ethyl dithioacetate 290 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanomethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5- Decyl] methyl] propanethioamide P-118 Z (a)

Example No. product Amine Dithio compound 291 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanomethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5- Dynyl] methyl] -2-methylpropanethioamide P-118 Z (b) 292 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanomethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5- Decyl] methyl] cyclopropanecarbothioamide P-118 Z (c) 293 (S) -N- [[3- [4- [4- (Cyanomethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-119 Ethyl dithioacetate 294 (S) -N - [[3- [4- [4- (Cyanomethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-119 Z (a) 295 (S) -N - [[3- [4- [4- (Cyanomethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Thioamide P-119 Z (b) 296 (S) -N - [[3- [4- [4- (Cyanomethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothio amides P-119 Z (c) 297 (3-fluoro-4- [4- (N-methylsulfamoyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Thioacetamide P-120 Ethyl dithioacetate 298 (3-fluoro-4- [4- (N-methylsulfamoyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Propanethioamide P-120 Z (a) 299 (3-fluoro-4- [4- (N-methylsulfamoyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanethioamide P-120 Z (b) 300 (3-fluoro-4- [4- (N-methylsulfamoyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Cyclopropanecarbothioamide P-120 Z (c) 301 (S) -N- [[3- [3,5-difluoro-4- [4- (N-methylsulfamoyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] Methyl] thioacetamide P-121 Ethyl dithioacetate 302 (S) -N- [[3- [3,5-difluoro-4- [4- (N-methylsulfamoyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] Methyl] propanethioamide P-121 Z (a) 303 (S) -N- [[3- [3,5-difluoro-4- [4- (N-methylsulfamoyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] Methyl] -2-methylpropanethioamide &lt; / RTI &gt; P-121 Z (b) 304 (S) -N- [[3- [3,5-difluoro-4- [4- (N-methylsulfamoyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] Methyl] cyclopropanecarbothioamide P-121 Z (c)

Example No. product Amine Dithio compound 305 (S) -N- [[3- [4- [4- (N-methylsulfamoyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-122 Ethyl dithioacetate 306 (S) -N- [[3- [4- [4- (N-methylsulfamoyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-122 Z (a) 307 (S) -N- [[3- [4- [4- (N-methylsulfamoyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Thioamide P-122 Z (b) 308 (S) -N- [[3- [4- [4- (N-methylsulfamoyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothio amides P-122 Z (c) 309 (S) -N- [[3- [3-fluoro-4- [4- (N, N- dimethylsulfamoyl) -1- piperazinyl] phenyl] Methyl] thioacetamide P-123 Ethyl dithioacetate 310 (S) -N- [[3- [3-fluoro-4- [4- (N, N- dimethylsulfamoyl) -1- piperazinyl] phenyl] Methyl] propanethioamide P-123 Z (a) 311 (S) -N- [[3- [3-fluoro-4- [4- (N, N- dimethylsulfamoyl) -1- piperazinyl] phenyl] Methyl] -2-methylpropanethioamide P-123 Z (b) 312 (S) -N- [[3- [3-fluoro-4- [4- (N, N- dimethylsulfamoyl) -1- piperazinyl] phenyl] Methyl] cyclopropanecarbothioamide P-123 Z (c) 313 (S) -N- [[3- [3,5-difluoro-4- [4- (N, N- dimethylsulfamoyl) -1- piperazinyl] phenyl] Zolydinyl] methyl] thioacetamide P-124 Ethyl dithioacetate 314 (S) -N- [[3- [3,5-difluoro-4- [4- (N, N- dimethylsulfamoyl) -1- piperazinyl] phenyl] &Lt; RTI ID = 0.0 &gt; zolydinyl] methyl] propanethioamide P-124 Z (a) 315 (S) -N- [[3- [3,5-difluoro-4- [4- (N, N- dimethylsulfamoyl) -1- piperazinyl] phenyl] &Lt; RTI ID = 0.0 &gt; zolydinyl] methyl] -2-methylpropanethioamide P-124 Z (b) 316 (S) -N- [[3- [3,5-difluoro-4- [4- (N, N- dimethylsulfamoyl) -1- piperazinyl] phenyl] Zolydinyl] methyl] cyclopropanecarbothioamide P-124 Z (c) 317 (S) -N - [[3- [4- [4- (N, N-dimethylsulfamoyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-125 Ethyl dithioacetate 318 (S) -N - [[3- [4- [4- (N, N-dimethylsulfamoyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-125 Z (a) 319 (S) -N - [[3- [4- [4- (N, N-Dimethylsulfamoyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl propanethioamide P-125 Z (b)

Example No. product Amine Dithio compound 320 (S) -N - [[3- [4- [4- (N, N-Dimethylsulfamoyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarboxylate Butothioamide P-125 Z (c) 321 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thio Acetamide P-126 Ethyl dithioacetate 322 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propane Thioamide P-126 Z (a) 323 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] 2-methylpropanethioamide P-126 Z (b) 324 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Propanecarbothioamide P-126 Z (c) 325 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] butane Thioamide P-126 Z (d) 326 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] 3-methylbutanethioamide P-126 Z (e) 327 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] 2-methylbutanethioamide P-126 Z (f) 328 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] 3,3-dimethylbutanethioamide P-126 Z (g) 329 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Butane carbothioamide P-126 Z (h) 330 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Pentanecarbothioamide P-126 Z (i) 331 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Hexane carbothioamide P-126 Z (j) 332 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] 2-Cyclopropylethanethioamide P-126 Z (k) 333 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] 2-Cyclobutylethanethioamide P-126 Z (1) 334 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] 2-cyclopentylethanethioamide P-126 Z (m)

Example No. product Amine Dithio compound 335 (S) -N- [[3- [3,5-difluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] Methyl] thioacetamide P-127 Ethyl dithioacetate 336 (S) -N- [[3- [3,5-difluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] Methyl] propanethioamide P-127 Z (a) 337 (S) -N- [[3- [3,5-difluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] Methyl] -2-methylpropanethioamide P-127 Z (b) 338 (S) -N- [[3- [3,5-difluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] Methyl] cyclopropanecarbothioamide P-127 Z (c) 339 (S) -N- [[3- [4- [4- (ethoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-128 Ethyl dithioacetate 340 (S) -N- [[3- [4- [4- (ethoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-128 Z (a) 341 (S) -N- [[3- [4- [4- (ethoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- amides P-128 Z (b) 342 (S) -N- [[3- [4- [4- (ethoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide P-128 Z (c) 343 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-129 Ethyl dithioacetate 344 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-129 Z (a) 345 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Thioamide P-129 Z (b) 346 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothio amides P-129 Z (c) 347 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] butane thioamide P-129 Z (d) 348 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thioamide P-129 Z (e) 349 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thioamide P-129 Z (f) 350 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Dimethyl butanethioamide P-129 Z (g) 351 (S) -N - [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclobutanecarbothio amides P-129 Z (h) 352 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopentanecarbothio amides P-129 Z (i)

Example No. product Amine Dithio compound 353 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclohexanecarbothio amides P-129 Z (j) 354 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Ethanethioamide P-129 Z (k) 355 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Ethanethioamide P-129 Z (1) 356 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Ethanethioamide P-129 Z (m) 357 (S) -N- [[3- [3,5-difluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetate amides P-130 Ethyl dithioacetate 358 (S) -N- [[3- [3,5-difluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethiol amides P-130 Z (a) 359 (S) -N- [[3- [3,5-difluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] - methylpropanethioamide P-130 Z (b) 360 (S) -N- [[3- [3,5-difluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane Carbothioamide P-130 Z (c) 361 (S) -N- [[3- [4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-131 Ethyl dithioacetate 362 (S) -N- [[3- [4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-131 Z (a) 363 (S) -N- [[3- [4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide P-131 Z (b) 364 (S) -N- [[3- [4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide P-131 Z (c) 365 (S) -N- [[3- [3-fluoro-4- [4- (cyanomethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetate amides P-132 Ethyl dithioacetate 366 (S) -N- [[3- [3-fluoro-4- [4- (cyanomethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethiol amides P-132 Z (a) 367 (S) -N- [[3- [3-fluoro-4- [4- (cyanomethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] - methylpropanethioamide P-132 Z (b) 368 (S) -N- [[3- [3-fluoro-4- [4- (cyanomethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane Carbothioamide P-132 Z (c) 369 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanomethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Thioacetamide P-133 Ethyl dithioacetate

Example No. product Amine Dithio compound 370 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanomethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Propanethioamide P-133 Z (a) 371 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanomethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -2-methylpropanethioamide P-133 Z (b) 372 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanomethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Cyclopropanecarbothioamide P-133 Z (c) 373 (S) -N- [[3- [4- [4- (Cyanomethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-134 Ethyl dithioacetate 374 (S) -N- [[3- [4- [4- (Cyanomethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-134 Z (a) 375 (S) -N - [[3- [4- [4- (cyanomethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide P-134 Z (b) 376 (S) -N - [[3- [4- [4- (Cyanomethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide P-134 Z (c) 377 (S) -N- [[3- [3-fluoro-4- [4- (2- fluoroethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Thioacetamide P-135 Ethyl dithioacetate 378 (S) -N- [[3- [3-fluoro-4- [4- (2- fluoroethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Propanethioamide P-135 Z (a) 379 (S) -N- [[3- [3-fluoro-4- [4- (2- fluoroethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanethioamide P-135 Z (b) 380 (S) -N- [[3- [3-fluoro-4- [4- (2- fluoroethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Cyclopropanecarbothioamide P-135 Z (c) 381 (S) -N- [[3- [3,5-difluoro-4- [4- (2-fluoroethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] Methyl] thioacetamide P-136 Ethyl dithioacetate 382 (S) -N- [[3- [3,5-difluoro-4- [4- (2-fluoroethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] Methyl] propanethioamide P-136 Z (a) 383 (S) -N- [[3- [3,5-difluoro-4- [4- (2-fluoroethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] Methyl] -2-methylpropanethioamide &lt; / RTI &gt; P-136 Z (b) 384 (S) -N- [[3- [3,5-difluoro-4- [4- (2-fluoroethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] Methyl] cyclopropanecarbothioamide P-136 Z (c) 385 (S) -N- [[3- [4- [4- (2-fluoroethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-137 Ethyl dithioacetate 386 (S) -N- [[3- [4- [4- (2-fluoroethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-137 Z (a) 387 (S) -N- [[3- [4- [4- (2-fluoroethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Thioamide P-137 Z (b)

Example No. product Amine Dithio compound 388 (S) -N- [[3- [4- [4- (2-fluoroethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothio amides P-137 Z (c) 389 (S) -N - [[3- [3-fluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide; Elemental analysis calculated for _{C 17 H 21 FN 4 O 3} S: C, 53.67; H, 5.56; N, 14.73; S, 8.43. Found: C, 53.14; H, 5.42; N, 14.25; S, 8.18. P-138 Ethyl dithioacetate 390 (S) -N - [[3- [3-fluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide; Melting point 166-167 DEG C; Elemental analysis for C ₁₈ H ₂₃ FN ₄ O ₃ S Calculated: C, 54.81; H, 5.88; N, 14.20; S, 8.13. Found: C, 54.83; H, 6.00; N, 14.12; S, 7.96. P-138 Z (a) 391 (S) -N - [[3- [3-fluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Thioamide; Mp 157-158 [deg.] C; C ₁₉ H ₂₅ FN ₄ O elemental analysis calculated for ₃ S: C, 55.87; H, 6.17; N, 13.72; S, 7.85. Found: C, 55.67; H, 6.19; N, 13.50; S, 7.70. P-138 Z (b) 392 (S) -N - [[3- [3-fluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothio amides; Melting point 178-179 DEG C; C ₁₉ H ₂₃ FN ₄ O elemental analysis calculated for ₃ S: C, 56.14; H, 5.70; N, 13.78; S, 7.89. Found: C, 56.13; H, 5.64; N, 13.64; S, 7.75. P-138 Z (c) 393 (S) -N - [[3- [3,5-difluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetate amides P-139 Ethyl dithioacetate 394 (S) -N- [[3- [3,5-difluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethio amides P-139 Z (a) 395 (S) -N- [[3- [3,5-difluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] - methylpropanethioamide P-139 Z (b) 396 (S) -N- [[3- [3,5-difluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane Carbothioamide P-139 Z (c) 397 (S) -N- [[3- [4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide P-140 Ethyl dithioacetate 398 (S) -N- [[3- [4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide P-140 Z (a) 399 (S) -N- [[3- [4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide P-140 Z (b) 400 (S) -N - [[3- [4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide P-140 Z (c)

In the general procedure of Step 1 of Example 31, Compound 33 was replaced with an appropriate amount of the appropriate amount of amine described below to give the corresponding amine P-90, P-93, P-99, P-105, P-126 and P- Of isothiocyanate.

In the general method of Example 114, replacing Compound 82 and methylamine with appropriate amounts of isothiocyanates and amines described below, the respective products described below were obtained.

Example No. product The isothiocyanate corresponding to the amine number Amine 415 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] N ', N'-dimethylthiourea P-126 Dimethylamine 416 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] 1-azetidine carbothioamide P-126 Azetidine 417 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thiourea P-129 Methylamine 418 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] '-Dimethylthiourea P-129 Dimethylamine 419 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbothioamide P-129 Azetidine

In the general method of Example 100, the appropriate amounts of the isothiocyanates and alcohols described below were used in the same manner as with the use of Compound 82 and methanol to give each product described below.

Example No. product The isothiocyanate corresponding to the amine number Amine 420 (S) -N- [[3- [3-fluoro-4- (4-acetyl- 1 -piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Barmate P-90 Methanol 421 (S) -N- [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Barmate P-90 ethanol 422 (3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O- Thiocarbamate P-90 Isopropyl alcohol 423 (S) -N- [[3- [3,5-difluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Methyl thiocarbamate P-91 Methanol 424 (S) -N- [[3- [4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate P-92 Methanol 425 (S) -N- [[3- [3-fluoro-4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - methylthiocarbamate P-93 Methanol 426 (S) -N- [[3- [3-fluoro-4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - ethyl thiocarbamate P-93 ethanol 427 (S) -N- [[3- [3-fluoro-4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - iso-propylthiocarbamate P-93 Isopropyl alcohol 428 (S) -N- [[3- [3,5-difluoro- [4- [4- (methoxyacetyl) -1- piperazinyl] phenyl] Methyl] -O-methylthiocarbamate P-94 Methylamine 429 (S) -N- [[3- [4- [4- (methoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarb Mate P-95 Methylamine 430 (S) -N- [[3- [3-fluoro-4- [4- (cyanoacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - ethyl thiocarbamate P-96 Methanol 431 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -O-methylthiocarbamate P-97 Methanol 432 (S) -N- [[3- [4- [4- (cyanoacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarb Mate P-98 Methanol 433 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - methylthiocarbamate P-99 Methanol

Example No. product The isothiocyanate corresponding to the amine number Amine 434 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - ethyl thiocarbamate P-99 ethanol 435 (S) -N- [[3- [3-fluoro-4- [4- (acetoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - iso-propylthiocarbamate P-99 Isopropyl alcohol 436 (S) -N- [[3- [3,5-difluoro-4- [4- (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -O-methylthiocarbamate P-100 Methanol 437 (S) -N- [[3- [4- [4- (acetoxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarb Mate P-101 Methanol 438 (3-fluoro-4- [4- (benzyloxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O - methylthiocarbamate P-102 Methanol 439 (S) -N- [[3- [3,5-difluoro-4- [4- (benzyloxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -O-methylthiocarbamate P-103 Methanol 440 (3-fluoro-4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - O-methylthiocarbamate P-105 Methanol 441 (3-fluoro-4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - O-ethyl thiocarbamate P-105 ethanol 442 (3-fluoro-4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - O-iso-propylthiocarbamate P-105 Isopropyl alcohol 443 (S) -N- [[3- [3,5-difluoro-4- [4- (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] -O-methylthiocarbamate P-106 Methanol 444 (S) -N- [[3- [4- [4- (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Barmate P-107 Methanol 445 (S) -N- [[3- [3-fluoro-4- [4- (methanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - methylthiocarbamate P-108 Methanol 446 (S) -N- [[3- [3,5-difluoro-4- [4- (methanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -O-methylthiocarbamate P-109 Methanol 447 (S) -N- [[3- [4- [4- (methanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarb Mate P-110 Methanol 448 (S) -N- [[3- [3-fluoro-4- [4- (ethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - methylthiocarbamate P-111 Methanol 449 (S) -N- [[3- [3,5-difluoro-4- [4- (ethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] Cyclopropanecarbothioamide P-112 Methanol

Example No. product The isothiocyanate corresponding to the amine number Amine 450 (S) -N- [[3- [4- [4- (4-ethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarb Mate P-113 Methanol 451 (S) -N- [[3- [3-fluoro-4- [4- (chloromethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] O-methylthiocarbamate P-114 Methanol 452 (S) -N- [[3- [3,5-difluoro-4- [4- (chloromethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] -O-methylthiocarbamate P-115 Methanol 453 (S) -N - [[3- [4- [4- (chloromethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Barmate P-116 Methanol 454 (S) -N- [[3- [3-fluoro-4- [4- (cyanomethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate P-117 Methanol 455 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanomethanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] Methyl] -O-methylthiocarbamate P-118 Methanol 456 (S) -N - [[3- [4- [4- (Cyanomethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbamate P-119 Methanol 457 (3-fluoro-4- [4- (N-methylsulfamoyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate P-120 Methanol 458 (S) -N- [[3- [3,5-difluoro-4- [4- (N-methylsulfamoyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] Methyl] -O-methylthiocarbamate P-121 Methanol 459 (S) -N- [[3- [4- [4- (N-methylsulfamoyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbamate P-122 Methanol 460 (S) -N- [[3- [3-fluoro-4- [4- (N, N- dimethylsulfamoyl) -1- piperazinyl] phenyl] Methyl] -O-methylthiocarbamate P-123 Methanol 461 (S) -N- [[3- [3,5-difluoro-4- [4- (N, N- dimethylsulfamoyl) -1- piperazinyl] phenyl] &Lt; RTI ID = 0.0 &gt; zolydinyl] methyl] -O-methylthiocarbamate & P-124 Methanol 462 (S) -N - [[3- [4- [4- (N, N-Dimethylsulfamoyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Methyl thiocarbamate P-125 Methanol 463 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] O-methylthiocarbamate P-126 Methanol 464 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] O-ethyl thiocarbamate P-126 ethanol 465 (S) -N- [[3- [3-fluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] O-iso-propyl carbamate P-126 Isopropyl alcohol

Example No. product The isothiocyanate corresponding to the amine number Amine 466 (S) -N- [[3- [3,5-difluoro-4- [4- (ethoxycarbonyl) -1- piperazinyl] phenyl] Methyl] -O-methylthiocarbamate P-127 Methanol 467 (S) -N- [[3- [4- [4- (ethoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Barmate P-128 Methanol 468 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbamate P-129 Methanol 469 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbamate P-129 ethanol 470 (S) -N- [[3- [3-fluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Propylthiocarbamate P-129 Isopropyl alcohol 471 (S) -N- [[3- [3,5-difluoro-4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] - methylthiocarbamate P-130 Methanol 472 (S) -N- [[3- [4- (4-sulfamoyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate P-131 Methanol 473 (S) -N- [[3- [3-fluoro-4- [4- (cyanomethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - methylthiocarbamate P-132 Methanol 474 (S) -N- [[3- [3,5-difluoro-4- [4- (cyanomethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -O-methylthiocarbamate P-133 Methanol 475 (S) -N- [[3- [4- [4- (Cyanomethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarb Mate P-134 Methanol 476 (S) -N- [[3- [3-fluoro-4- [4- (2- fluoroethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate P-135 Methanol 477 (S) -N- [[3- [3,5-difluoro-4- [4- (2-fluoroethyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] Methyl] -O-methylthiocarbamate P-136 Methanol 478 (S) -N- [[3- [4- [4- (2-fluoroethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbamate P-137 Methanol 479 (S) -N - [[3- [3-fluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Carbamate P-138 Methanol 480 (S) -N- [[3- [3,5-difluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] - methylthiocarbamate P-139 Methanol 481 (S) -N- [[3- [4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate P-140 Methanol

Example 482: (5S) -N- [[3- [3-Fluoro-4- (tetrahydro-1,4-thiazepin- Zolydinyl] methyl] thioacetamide, thiazepine S-oxide.

Step 1. Gallego, J. &lt; RTI ID = 0.0 &gt; J. &lt; / RTI &gt; Org. Chem. 1993, 58, 3905-3911. &Lt; RTI ID = 0.0 &gt; Hexahydro-5-oxo-1,4-thiazepine &lt; / RTI &gt;

Step 2. Aluminum hydride (5.5 mL of a 1 M solution in THF) was added dropwise to a stirred solution of hexahydro-5-oxo-1,4-thiazepine (721.5 mg) in anhydrous THF (21 mL) Respectively. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 10 minutes and then at ambient temperature for 4 hours. The reaction mixture was quenched by careful continuous addition of water (0.2 mL), aqueous 5 N NaOH (0.2 mL) and water (0.74 mL). The reaction mixture became a highly viscous gel. The reaction mixture was diluted with ether (50 mL) and filtered through a pad of celite. The filter cake was washed with ether (100 mL). The filtrate was concentrated to give 616.6 mg of 1,4-hexahydrothiazepine, which was used in the next step.

Step 3. Diisopropylethylamine (1.0 mL) was added to a stirred solution of 1,4-hexahydrothiazepine (596.0 mg) and 3,4-difluoronitrobenzene (0.51 mL) in acetonitrile (14 mL) . The yellow solution was heated at reflux temperature for 18 hours, then cooled and concentrated. The residue was diluted with CH ₂ Cl ₂ (100 mL) and washed with saturated NH ₄ Cl solution (35 mL). The phases were separated and the organic phase was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography using 20% EtOAc in hexanes as the eluent to give 830.2 mg of nitrobenzene. Melting point 115-116 DEG C; Elemental analysis for C ₁₁ H ₁₃ FN ₂ O ₂ S Calculated: C, 51.55; H, 5.11; N, 10.93; S, 12.51. Found: C, 51.47; H, 5.12; N, 10.79; S, 12.42.

Step 4. A one-nitrobenzene To a stirred suspension of (5.5 g) 2 M CuSO ₄ solution (11.9 ㎖) prepared in Step 3 in EtOH (260 ㎖) was added. The mixture was cooled to 0 ℃ and was added to NaBH ₄ (4.1 g) by some. When the reaction mixture turned very dark, it was stirred at 0 ° C for 10 minutes, at ambient temperature for 30 minutes, and then at reflux temperature for 3 hours. The cooled reaction mixture was diluted with EtOAc (500 mL) and washed with water (200 mL). The aqueous mixture was extracted with EtOAc (3 x 200 mL). The combined organic phases were dried (MgSO ₄ ), filtered and concentrated to give the aniline intermediate.

Step 5. The black residue from step 4 was dissolved in 2: 1 acetone / water (255 mL) and cooled to 0 <0> C. To this stirred mixture was added solid NaHCO ₃ (5.4 g) followed by benzyl chloroformate (7.7 mL). The reaction mixture was stirred at 0 &lt; 0 &gt; C for 10 minutes and then at ambient temperature for 24 hours. The reaction mixture was quenched with 10% aqueous NaHSO ₄ (200 mL) and poured into EtOAc (300 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 250 mL). The combined organic phases were dried (MgSO _4), filtered and concentrated. The residue was purified by MPLC using 20% EtOAc in hexanes to give the benzyl carbamate as a yellow solid 6.03 g. Melting point 72-74 DEG C; C ₁₉ H ₂₁ FN ₂ O _2. Elemental analysis calculated for S: C, 63.31; H, 5.87; N, 7.77; S, 8.89. Found: C, 63.31; H, 5.97; N, 7.69; S, 8.79.

Step 6. To a stirred solution of the carbamate of step 5 (3.0 g) in anhydrous THF (33 mL) cooled to -78 C under nitrogen was added dropwise a 1.6 M solution of nBuLi in hexanes (5.4 mL) via syringe. The reaction mixture was stirred at -78 &lt; 0 &gt; C for 35 min, then R-glycidyl butyrate (1.2 ml) was added. The reaction mixture was stirred at -78 &lt; 0 &gt; C for 30 minutes and at ambient temperature overnight, during which time a precipitate formed. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (33 mL) and poured into EtOAc (100 mL). The phases were separated. The organic phase was washed with saturated aqueous NaHCO ₃ (50 mL) and brine (50 mL), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography using EtOAc as the eluent to give 2.5 g of hydroxymethyloxazolidinone. Melting point 100-102 占 폚. Elemental analysis for C ₁₅ H ₁₉ FN ₂ O ₃ S Calculated: C, 55.20; H, 5.87; N, 8.58; S, 9.82. Found: C, 55.09; H, 5.91; N, 8.36; S, 9.57.

Step 7. To a stirred solution of the alcohol prepared in Step 6 (1.7 g) in CH ₂ Cl ₂ (35 mL) cooled to 0 ° C was added triethylamine (1.1 mL) followed by methanesulfonyl chloride (0.5 mL) Was added. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 10 min and at ambient temperature for 1 h. The reaction mixture was treated with water (35 mL). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (35 mL). The combined organic phases were dried (MgSO _4), filtered and concentrated. The residue was purified by flash chromatography using 80% EtOAc in hexanes as the eluent to give 2.1 g of mesylate. Melting point 132-142 占 폚. Elemental analysis for C ₁₆ H ₂₁ FN ₂ O ₅ S ₂ Calculated: C, 47.51; H, 5.23; N, 6.93; S, 15.85. Found: C, 47.18; H, 5.28; N, 6.84; S, 15.60.

Step _{8. 1: 1 THF / CH 3} OH (40 ㎖) was bubbled ammonia gas (about 5 minutes) until saturation to a stirred suspension of mesylate (941.7 ㎎) prepared in Step 7 of. The reaction mixture was heated to 100 &lt; 0 &gt; C in a sealed tube for 72 h. The cooled reaction mixture was concentrated to give the crude amine, which was immediately suspended in CH ₂ Cl ₂ (35 mL) and cooled to 0 ° C. To this stirred suspension was added triethylamine (0.97 mL, 6.9 mmol) followed by di-tert-butyl dicarbonate (759.5 mg, 3.5 mmol). When the reaction mixture became homogeneous, it was stirred at ambient temperature for 18 hours. The reaction mixture was poured into CH ₂ Cl ₂ (75 mL) and washed with H ₂ O (1 × 50 mL). The organic phase was dried (MgSO _4), filtered and concentrated. Purification of the resulting residue on a Biotage 40 S column using 30-35% ethyl acetate in CH ₃ OH as eluent afforded 867.4 mg of the protected amine. Melting point 74-75 캜. Calculated: C, 56.45; H, 6.63; N, 9.88. Found: C, 56.95; H, 6.85; N, 9.55.

Step 9. cooled to 0 ℃ 1: meta and sodium periodate (113.5 ㎎) To a stirred suspension of the protected amine prepared (205.2 ㎎) in step 8 of the _{1 CH 3 OH / H 2 O} (6 ㎖) was added Respectively. The resulting suspension was stirred at ambient temperature for 18 hours. The reaction mixture was filtered and the solid was washed with CH ₂ Cl ₂ ( ₂ x 20 mL). The filtrate was extracted with H ₂ O (1 x 10 mL). The phases were separated. The aqueous phase was extracted with CH ₂ Cl ₂ (1 x 25 mL). The combined organic phases were dried (MgSO _4), filtered and concentrated. The white solid residue was purified on a Biotage 12 M column using 5% CH ₃ OH in CH ₂ Cl ₂ as eluent to give 187.3 mg of sulfoxide. Melting point 78-81 캜.

Step 10. Dry HCl gas was passed through the surface of the stirred solution of the sulfoxide (179.3 mg) prepared in Step 9 in CH ₃ OH (2 mL) cooled to 0 ° C for 1 minute. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 10 min, then stirred at ambient temperature for 15 min and concentrated. The resulting yellow residue was suspended in THF (5 mL) and CH ₂ Cl ₂ (5 mL) and cooled to 0 ° C. To the stirred suspension was added triethylamine (0.46 mL) followed by ethyl dithioacetate (0.18 mL). The black reaction mixture was stirred overnight at ambient temperature and concentrated. The black residue was diluted with CH ₂ Cl ₂ (30 mL) and washed with H ₂ O ( ₂ x 15 mL). The organic phase was dried (MgSO _4), filtered and concentrated. Purification of the black residue on a Biotage 12 M column using 5% CH ₃ OH in CH ₂ Cl ₂ as eluent yielded 71.5 mg of the title product as a tan solid. Melting point 85-89 캜.

Following the general procedure described in step 10 of Example 482, but substituting the dithioester described below, the compounds of Examples 483 to 495 in the following Table K were obtained.

Example No. compound Amine Dithioester (Preparation Example Z) 483 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] Propanethioamide, thiazepine S-oxide Z (a) 484 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -2-methylpropanethioamide, thiazepine S-oxide Same as above Z (b) 485 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] Cyclopropanecarbothioamide, thiazepine S-oxide Same as above Z (c) 486 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] Butanethioamide, thiazepine S-oxide Same as above Z (d) 487 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -3-methylbutanethioamide, thiazepine S-oxide Same as above Z (e) 488 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -2-methylbutanethioamide, thiazepine S-oxide Same as above Z (f) 489 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -3,3-dimethylbutanethioamide, thiazepine S-oxide Same as above Z (g) 490 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] Cyclobutane carbothioamide, thiazepine S-oxide Same as above Z (h) 491 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -1-cyclopentanecarbothioamide, thiazepine S-oxide Same as above Z (i) 492 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] Cyclohexanecarbothioamide, thiazepine S-oxide Same as above Z (j)

Example No. compound Amine Dithioester (preparation method Z) 493 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -2-cyclopropylethanethioamide, thiazepine S-oxide Same as above Z (k) 494 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -2-cyclobutylethanethioamide, thiazepine S-oxide Same as above Z (1) 495 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -2-cyclopentylethanethioamide, thiazepine S-oxide Same as above Z (m)

Example 496: (5S) -N- [[3- [3,5-Difluoro-4- (tetrahydro-1,4-thiazepin- 5-oxazolidinyl] methyl] thioacetamide, thiazepine S-oxide.

The title compound is prepared according to the method of Example 482 substituting 3,4-difluoronitrobenzene of Step 1 with an appropriate amount of 2,6-difluoro-4-nitrobenzene (trifluoromethane) sulfonate .

Using the amine prepared in Example 496, but replacing ethyl dithioacetate in the final step with the dithioester described below, the compounds of Examples 497-499 in Table L below were obtained.

Example No. compound Amine Dithioester (Preparation Example Z) 497 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Dinyl] methyl] propanethioamide, thiazepine S-oxide Z (a) 498 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] -2-methylpropanethioamide, thiazepine S-oxide Same as above Z (b) 499 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] cyclopropanecarbothioamide, thiazepine S-oxide Same as above Z (c)

Example 500: Synthesis of (5S) -N- [[3- [4- (tetrahydro-1,4-thiazepin-4 (5H) Thioacetamide, thiazepine S-oxide.

The title compound can be prepared according to the method of Example 482 substituting the appropriate amount of 4-fluoronitrobenzene for 3,4-difluoronitrobenzene in Step 1.

Using the amine prepared in Example 500 but replacing ethyl dithioacetate in the final step with dithioester described below, the compounds of Examples 501 to 503 in Table M below were obtained.

Example No. compound Amine Dithioester (Preparation Example Z) 501 (5S) -N- [[3- [4- (tetrahydro-1,4-thiazepine-4 (5H) -yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide, Thiazepine S-oxide Z (a) 502 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Propanethioamide, thiazepine S-oxide Same as above Z (b) 503 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepin-4 (5H) -yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbo Thioamide, thiazepine S-oxide Same as above Z (c)

Example 504: (5S) -N- [[3- [3-Fluoro-4- (tetrahydro-1,4-thiazepin- Zolydinyl] methyl] thioacetamide, thiazepine S, S-dioxide.

Step 1. To a stirred solution of thiazepine (243.7 mg) prepared in Step 8 of Example 482 in 25% H ₂ O / acetone (8 mL) was added 4-methylmorpholine N-oxide (201.5 mg) A solution of osmium tetroxide (2.5 wt%, 30 [mu] l) in 2-methyl-2-propanol was added. The reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was treated with saturated sodium bisulfate solution (8 mL) and then poured into CH ₂ Cl ₂ (50 mL). The phases were separated. The aqueous phase was extracted with CH ₂ Cl ₂ ( ₂ x 25 mL). The combined organic phases were washed with brine (1 x 25 mL), dried (MgSO ₄ ), filtered and concentrated. The residue was purified on a Biotage 40 S column using 1% CH ₃ OH in CH ₂ Cl ₂ as eluent to give 216.1 mg (0.47 mmol, 83%) of thiazepine S, S-dioxide as a white solid. Melting point 144-146 [deg.] C.

Step 2. Dry HCl gas was passed through the surface of the stirred solution of thiazepine S, S-dioxide (108.2 mg) prepared in Step 1 in CH ₃ OH (3 mL) at 0 ° C for 1 minute. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 10 min and then at ambient temperature for 15 min. The reaction was concentrated and the yellow residue was suspended in CH ₂ Cl ₂ (2 mL) and THF (2 mL). The stirred suspension was cooled to 0 C and triethylamine (0.27 mL) was added and rinsed with 0.25 mL of a solution of ethyl dithioacetate (0.11 mL) in THF (0.5 mL). The greenish green solution was stirred at 0 &lt; 0 &gt; C for 10 minutes and then at ambient temperature for 18 hours. The reaction mixture was poured into CH ₂ Cl ₂ (20 mL) and washed with H ₂ O (2 x 10 mL). The organic phase was dried (MgSO _4), filtered and concentrated. The residue was purified on a Biotage 12 M column using 2% CH ₃ OH in CH ₂ Cl ₂ as eluent to give 77.3 mg of the title compound as a white solid. Melting point 88-90 캜.

Following the general procedure described in step 2 of Example 504, but replacing ethyl dithioacetate with the dithioester described below, the compounds of Examples 505 to 507 in the following Table N were obtained.

Example No. compound Amine Dithioester (Preparation Example Z) 505 (5S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide, thiazepine S, S - Dioxide Z (a) 506 (5S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide, Zepin S, S-dioxide Same as above Z (b) 507 (5S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide, thiazepine S, S-dioxide Same as above Z (c)

Example 508: (5S) -N- [[3- [3,5-Difluoro-4- (tetrahydro-1,4-thiazepine-4 (5H) 5-oxazolidinyl] methyl] thioacetamide, thiazepine S, S-dioxide.

The title compound was prepared according to the methods of Examples 504 and 482, substituting 3,4-difluoronitrobenzene with an appropriate amount of 2,6-difluoro-4-nitrobenzene (trifluoromethane) sulfonate in step 1 of Example 482 The title compound can be prepared.

The amine prepared in Example 508 was used, but in the final step ethyl dithioacetate was replaced by the dithioester described below to give the compounds of Examples 509 to 511 in Table O below.

Example No. compound Amine Dithioester (Preparation Example Z) 509 (5S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide, S, S-dioxide Z (a) 510 (5S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Amide, thiazepine S, S-dioxide Same as above Z (b) 511 (5S) -N - [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide , Thiazepine S, S-dioxide Same as above Z (c)

Example 512: Synthesis of (5S) -N- [[3- [4- (tetrahydro-1,4-thiazepin-4 (5H) Thioacetamide, thiazepine S, S-dioxide.

The title compound can be prepared according to the methods of Examples 504 and 482, substituting the appropriate amount of 4-fluoronitrobenzene for 3,4-difluoronitrobenzene in step 1 of Example 482.

Using the amine prepared in example 512, but replacing ethyl dithioacetate in the final step with the dithioester described below, the compounds of examples 513-515 in the following Table P were obtained.

Example No. compound Amine Dithioester (Preparation Example Z) 513 (5S) -N- [[3- [4- (tetrahydro-1,4-thiazepine-4 (5H) -yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide, Thiazepine S, S-dioxide Z (a) 514 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Propanethioamide, thiazepine S, S-dioxide Same as above Z (b) 515 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepin-4 (5H) -yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbo Thioamide, thiazepine S, S-dioxide Same as above Z (c)

Example 516: (5S) -N- [[3- [3-Fluoro-4- (tetrahydro-1,4-thiazepin- &Lt; / RTI &gt; zolydinyl] methyl] thioacetamide.

This compound was prepared by following the procedure in step 8 of Example 482, but replacing di-tert-butyl dicarbonate with an appropriate amount of ethyl dithioacetate; Melting point 129-131 [deg.] C.

Using the amine prepared in Step 8 of Example 482, but replacing di-tert-butyl dicarbonate with an appropriate amount of dithioester described below, the compounds of Examples 517 to 529 in Table Q below were obtained.

Number of conduct compound Amine Dithioester (Preparation Example Z) 517 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] Propanethioamide Z (a) 518 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -2-methylpropanethioamide Same as above Z (b) 519 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] Cyclopropanecarbothioamide Same as above Z (c) 520 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] Butanethioamide Same as above Z (d) 521 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -3-methylbutanethioamide Same as above Z (e) 522 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -2-methylbutanethioamide Same as above Z (f) 523 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -3,3-dimethylbutanethioamide Same as above Z (g) 524 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] Cyclobutane Carbothioamide Same as above Z (h) 525 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] Cyclopentanecarbothioamide Same as above Z (i) 526 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] Cyclohexanecarbothioamide Same as above Z (j) 527 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -2-cyclopropylethanethioamide Same as above Z (k) 528 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -2-cyclobutylethanethioamide Same as above Z (1) 529 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -2-cyclopentylethanethioamide Same as above Z (m)

Example 530: (5S) -N- [[3- [3,5-Difluoro-4- (tetrahydro-1,4-thiazepine- 5-oxazolidinyl] methyl] thioacetamide.

This compound follows the procedure of Example 482 and Example 516 but using 3,4-difluoronitrobenzene in Step 1 of Example 482 in an appropriate amount of 2,6-difluoro-4-nitrophenyltrifluoromethanesulfo Nate. &Lt; / RTI &gt;

Using the amine prepared in Example 530, but replacing di-tert-butyl dicarbonate with an appropriate amount of dithioester described below, the compounds of Examples 531 to 533 in Table R below can be prepared.

Example No. compound Amine The dithio compound (Preparation Example Z) 531 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] propanethioamide Z (a) 532 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Dynyl] methyl] -2-methylpropanethioamide Same as above Z (b) 533 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] cyclopropanecarbothioamide Same as above Z (c)

Example 534: (5S) -N- [[3- [4- (Tetrahydro-1,4-thiazepin-4 (5H) -yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thioacetamide; Melting point 129-131 [deg.] C.

This compound follows the procedure of Example 482 and Example 516, but can be prepared by replacing 3,4-difluoronitrobenzene with an appropriate amount of 4-fluoronitrobenzene in Step 1 of Example 482.

Using the amine prepared in Example 534, but replacing di-tert-butyl dicarbonate with an appropriate amount of dithioester described below, the compounds of Examples 535 to 537 in Table S below can be prepared.

Example No. compound Amine The dithio compound (Preparation Example Z) 535 (5S) -N- [[3- [4- (tetrahydro-1,4-thiazepin-4 (5H) -yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide Z (a) 536 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Propanethioamide Same as above Z (b) 537 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepin-4 (5H) -yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbo Thioamide Same as above Z (c)

Example 538: (5S) -N- [[3- [3-Fluoro-4- (tetrahydro-1,4-thiazepin- Zolydinyl] methyl] thiourea, thiazepine S-oxide.

This compound follows the procedure described in Example 33, but can be prepared by replacing amine 33 with the amine prepared in Example 482.

The isothiocyanates prepared in Example 538 can be reacted with the amines and alcohols described in Table T to give the compounds of Examples 539-544.

Example No. compound Isothiocyanate Amine or alcohol 539 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -N'-methylthiourea, thiazepine S-oxide CH ₃ NH ₂ 540 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -N ', N'-dimethylthiourea, thiazepine S-oxide Same as above (CH _{3) 2} NH 541 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -1-azetidinecarbothioamide, thiazepine S-oxide Same as above Azetidine 542 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -O-methylthiocarbamate, thiazepine S-oxide Same as above CH ₃ OH 543 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -O-ethylthiocarbamate, thiazepine S-oxide Same as above CH ₃ CH ₂ OH 544 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -O-isopropylthiocarbamate, thiazepine S-oxide Same as above (CH _{3) 2} CHOH

Example 545: (5S) -N- [[3- [3,5-Difluoro-4- (tetrahydro-1,4-thiazepin- 5-oxazolidinyl] methyl] thiourea, thiazepine S-oxide.

This compound follows the procedure described in Example 33, but can be prepared by replacing amine 33 with the amine prepared in Example 496.

The isothiocyanates prepared in Example 545 can be reacted with the amines and alcohols described in Table U to give the compounds of Examples 546 to 551.

Example No. compound Isothiocyanate Amine or alcohol 546 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Dinyl] methyl] -N'-methylthiourea, thiazepine S-oxide CH ₃ NH ₂ 547 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] -N ', N'-dimethylthiourea, thiazepine S-oxide Same as above (CH _{3) 2} NH 548 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Dinyl] methyl] -1-azetidinecarbothioamide, thiazepine S-oxide Same as above Azetidine 549 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] -O-methylthiocarbamate, thiazepine S-oxide Same as above CH ₃ OH 550 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] -O-ethylthiocarbamate, thiazepine S-oxide Same as above CH ₃ CH ₂ OH 551 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Dinyl] methyl] -O-isopropylthiocarbamate, thiazepine S-oxide Same as above (CH _{3) 2} CHOH

Example 552: (5S) -N- [[3- [4- (Tetrahydro-1,4-thiazepin-4 (5H) -yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thiourea, thiazepine S-oxide.

This compound follows the procedure described in Example 33, but can be prepared by replacing amine 33 with the amine prepared in Example 500.

The isothiocyanates prepared in Example 552 can be reacted with the amines and alcohols described in Table V to prepare the compounds of Examples 553 to 558.

Example No. compound Isothiocyanate Amine or alcohol 553 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Methyl thiourea, thiazepine S-oxide CH ₃ NH ₂ 554 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 N'-dimethylthiourea, thiazepine S-oxide Same as above (CH _{3) 2} NH 555 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Thiazine carbothioamide, thiazepine S-oxide Same as above Azetidine 556 (5S) -N- [[3- [4- (tetrahydro-1,4-thiazepine-4 (5H) -yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thiocarbamate, thiazepine S-oxide Same as above CH ₃ OH 557 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Thiocarbamate, thiazepine S-oxide Same as above CH ₃ CH ₂ OH 558 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Propyl thiocarbamate, thiazepine S-oxide Same as above (CH _{3) 2} CHOH

Example 559: (5S) -N- [[3- [3-Fluoro-4- (tetrahydro-1,4-thiazepin- Zolydinyl] methyl] thiourea, thiazepine S, S-dioxide.

This compound follows the procedure described for Example 33, but can be prepared by replacing amine 33 with the amine prepared in Example 504.

The isothiocyanates prepared in Example 559 can be reacted with the amines and alcohols described in Table W to give the compounds of Examples 560-565.

Example No. compound Isothiocyanate Amine or alcohol 560 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -N'-methylthiourea, thiazepine S, S-dioxide CH ₃ NH ₂ 561 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -N ', N'-dimethylthiourea, thiazepine S, S-dioxide Same as above (CH _{3) 2} NH 562 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -1-azetidinecarbothioamide, thiazepine S, S-dioxide Same as above Azetidine 563 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -O-methylthiocarbamate, thiazepine S, S-dioxide Same as above CH ₃ OH 564 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -O-ethylthiocarbamate, thiazepine S, S-dioxide Same as above CH ₃ CH ₂ OH 565 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -O-isopropylthiocarbamate, thiazepine S, S-dioxide Same as above (CH _{3) 2} CHOH

Example 566: (5S) -N- [[3- [3,5-Difluoro-4- (tetrahydro-1,4-thiazepin- 5-oxazolidinyl] methyl] thiourea, thiazepine S, S-dioxide.

This compound follows the procedure described in Example 33, but can be prepared by replacing amine 33 with the amine prepared in Example 508.

The isothiocyanates prepared in Example 566 can be reacted with the amines and alcohols described in Table X to give the compounds of Examples 561-572.

Example No. compound Isothiocyanate Amine or alcohol 567 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Dinyl] methyl] -N'-methylthiourea, thiazepine S, S-dioxide CH ₃ NH ₂ 568 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Dinyl] methyl] -N ', N'-dimethylthiourea, thiazepine S, S-dioxide Same as above (CH _{3) 2} NH 569 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Dinyl] methyl] -1-azetidinecarbothioamide, thiazepine S, S-dioxide Same as above Azetidine 570 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] -O-methylthiocarbamate, thiazepine S, S-dioxide Same as above CH ₃ OH 571 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] -O-ethylthiocarbamate, thiazepine S, S-dioxide Same as above CH ₃ CH ₂ OH 572 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Dinyl] methyl] -O-isopropylthiocarbamate, thiazepine S, S-dioxide Same as above (CH _{3) 2} CHOH

Example 573: (5S) -N- [[3- [4- (Tetrahydro-1,4-thiazepin-4 (5H) Thiourea, thiazepine S, S-dioxide.

This compound follows the procedure described for Example 33, but can be prepared by replacing amine 33 with the amine prepared in Example 512.

The isothiocyanates prepared in Example 573 can be reacted with the amines and alcohols described in Table Y to give the compounds of Examples 574 to 579.

Example No. compound Isothiocyanate Amine or alcohol 574 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Methyl thiourea, thiazepine S, S-dioxide CH ₃ NH ₂ 575 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 N'-dimethylthiourea, thiazepine S, S-dioxide Same as above (CH _{3) 2} NH 576 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Thiazine carbothioamide, thiazepine S, S-dioxide Same as above Azetidine 577 (5S) -N- [[3- [4- (tetrahydro-1,4-thiazepine-4 (5H) -yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thiocarbamate, thiazepine S, S-dioxide Same as above CH ₃ OH 578 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Thiocarbamate, thiazepine S, S-dioxide Same as above CH ₃ CH ₂ OH 579 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Propyl thiocarbamate, thiazepine S, S-dioxide Same as above (CH _{3) 2} CHOH

Example 580: Synthesis of (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- Methyl] thiourea. &Lt; / RTI &gt;

This compound follows the procedure described for Example 33, but can be prepared by replacing amine 33 with the amine prepared in Step 8 of Example 482.

The isothiocyanates prepared in Example 580 can be reacted with the amines and alcohols described in Table Z to give the compounds of Examples 581 to 586.

Example No. compound Isothiocyanate Amine or alcohol 581 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -N'-methylthiourea CH ₃ NH ₂ 582 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -N ', N'-dimethylthiourea Same as above (CH _{3) 2} NH 583 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -1-azetidinecarbothioamide Same as above Azetidine 584 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -O-methylthiocarbamate Same as above CH ₃ OH 585 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -O-ethylthiocarbamate Same as above CH ₃ CH ₂ OH 586 (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] -O-isopropylthiocarbamate Same as above (CH _{3) 2} CHOH

Example 587: (5S) -N- [[3- [3,5-Difluoro-4- (tetrahydro-1,4-thiazepin- 5-oxazolidinyl] methyl] thiourea.

This compound can be prepared by replacing amine 33 with the amine prepared in Example 530, but according to the method described in Example 33. [

The isothiocyanates prepared in Example 587 can be reacted with the amines and alcohols described in Table AA to give the compounds of Examples 588-593.

Example No. compound Isothiocyanate Amine or alcohol 588 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Yl] methyl] -N'-methylthiourea CH ₃ NH ₂ 589 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] -N ', N'-dimethylthiourea Same as above (CH _{3) 2} NH 590 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] -1-azetidinecarbothioamide Same as above Azetidine 591 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] -O-methylthiocarbamate Same as above CH ₃ OH 592 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] -O-ethylthiocarbamate Same as above CH ₃ CH ₂ OH 593 (5S) -N- [[3- [3,5-difluoro-4- (tetrahydro-1,4-thiazepin- Decyl] methyl] -O-isopropylthiocarbamate Same as above (CH _{3) 2} CHOH

Example 594: (5S) -N- [[3- [4- (Tetrahydro-1,4-thiazepin-4 (5H) -yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thiourea.

This compound follows the procedure described in Example 33 but can be prepared by replacing amine 33 with the amine prepared in Example 534. [

The compounds of Examples 595 to 600 can be prepared by reacting the isothiocyanates prepared in Example 594 with the amines and alcohols described in Table BB.

Example No. compound Isothiocyanate Amine or alcohol 595 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Methyl thiourea CH ₃ NH ₂ 596 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 N'-dimethylthiourea Same as above (CH _{3) 2} NH 597 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Thiazine carbothioamide Same as above Azetidine 598 (5S) -N- [[3- [4- (tetrahydro-1,4-thiazepine-4 (5H) -yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thiocarbamate Same as above CH ₃ OH 599 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Thiocarbamate Same as above CH ₃ CH ₂ OH 600 (5S) -N - [[3- [4- (tetrahydro-1,4-thiazepine-4 Propylthiocarbamate Same as above (CH _{3) 2} CHOH

Claims (11)

&Lt; / RTI &gt; Wherein Z ₂ is -O ₂ S-, -O-, -N (R ¹⁰⁷ ) -, -OS- or -S-; w is 0, 1, 2 or 3; R ²³ and R ²⁴ are the same or different and can be H or F; R ¹ is H, NH _2, NH alkyl C ₁ -C _4; N (alkyl C ₁ -C _{4) 2;} ; Alkyl C ₁ -C _4; O-alkyl C ₁ -C _4; S-alkyl C ₁ -C _4; 1-3 F, 1-2 Cl, CN or -COO-alkyl C ₁ -C ₄ alkyl substituted with C ₁ -C _4, or a cycloalkyl C ₃ -C ₆ (here, groups They may be each straight-chain or branched Lt; / RTI &gt; R ¹⁰⁷ is a) R ¹⁰² OC (R ¹¹⁰ ) (R ¹¹¹ ) -C (O) -, b) R @ ^{103 is} OC (O) -, c) R &lt; ^{108 &gt; is} -C (O) -, d) R ¹⁰⁹ -SO ₂ -, e) NC-CH ₂ -, f) FCHCH ₂ -, or g) R ¹⁵⁰ R ¹⁵¹ NSO ₂ - {wherein R ¹⁰² is H, CH ₃ -, phenyl-CH ₂ - or CH ₃ C (O); R ¹¹⁰ and R ¹¹¹ are each selected from H or CH ₃ ; R ¹⁰³ is alkyl C ₁ -C ₃ or phenyl; R ¹⁰⁸ is selected from H, alkyl C ₁ -C ₄ , aryl (CH ₂ ) _0-5 , CNCH ₂ -, ClCH ₂ -, Cl ₂ HC-, FH ₂ C-, F ₂ HC- or cycloalkyl C ₃ -C ₆ ; R ¹⁵⁰ and R ¹⁵¹ are the same or different and are selected from H and alkyl C ₁ -C ₄ ; or R ¹⁵⁰ and R ¹⁵¹ , together with the nitrogen atom to which they are attached, form a monocyclic heterocycle having 3 to 6 carbon atoms Lt; / RTI &gt; 2. The method of claim 1, wherein Z ² is -O ₂ S- compounds. 3. The compound of claim 2, which is (5S) -N- [[3- [3-fluoro-4- (tetrahydro- -Oxazolidinyl] methyl] thioacetamide, thiazepine S, S-dioxide. 2. The compound according to claim 1, wherein Z &lt; ² &gt; is -OS-. 5. The method of claim 4, (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide, thiomorpholine S- Oxide; (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanethioamide, Morpholine S-oxide; (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide, Morpholine S-oxide; (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] Thiomorpholine S-oxide; (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl ]- O-ethylthiocarbamate, Thiomorpholine S-oxide; (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-isopropylthiocarbamate , Thiomorpholine S-oxide; (5S) -N- [[3- [3-fluoro-4- (tetrahydro-1,4-thiazepin- ] Thioacetamide, thiazepine S-oxide; (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -N ', N'- Urea, thiomorpholine S-oxide; or (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -1- azetidinecarbothioamide , Thiomorpholine S-oxide. 2. The compound according to claim 1, wherein Z &lt; ² &gt; The method according to claim 6, (S) -N - [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-ethylthiocarbamate; (S) -N - [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanethioamide; or (S) -N - [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane-carbothioamide. 2. The compound according to claim 1, wherein Z &lt; ² &gt; is -S-. 9. The compound according to claim 8, which is (5S) -N- [[3- [4- (tetrahydro- 1, 4-thiazepin- Methyl] thioacetamide. &Lt; / RTI &gt; 2. The compound according to claim 1, wherein Z &lt; ² &^gt; is -N (R &lt; ^{107 &gt;} ) -. 11. The method of claim 10, (S) -N- [[3- [3-fluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethiol amides; (S) -N- [[3- [3-fluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -Methylpropanethioamide; (S) -N- [[3- [3-fluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane Carbothioamide; (S) -N - [[3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide; (S) -N - [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide; (S) -N- [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide ; (S) -N- [[3- [3-fluoro-4- [4- (methanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -Methylpropanethioamide; (S) -N- [[3- [3-fluoro-4- [4- (methanesulfonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropane Carbothioamide; (S) -N - [[3- [3-fluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide; (S) -N - [[3- [3-fluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propanethioamide; (S) -N - [[3- [3-fluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Thioamide; (S) -N - [[3- [3-fluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothio amides; or (S) -N - [[3- [3-fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide.