AU1705399A - Oxazolidinone antibacterial agents having a thiocarbonyl functionality - Google Patents

Description

WO 00/32599 PCT/US98/25308 OXAZOLIDINONE ANTIBACTERIAL AGENTS HAVING A THIOCARBONYL FUNCTIONALITY 5 BACKGROUND OF THE INVENTION The present invention relates to new and useful oxazolidinone compounds and their preparations, and more particularly to oxazolidinone compounds in which the carbonyl functionality of -NH-C(O)-R is converted to a thiocarbonyl functionality, such as a thiourea -NH-C(S)-NH.,, an alkyl thiourea -NH-C(S)-NH-(C,.

4 alkyl), 10 thioamide -NH-C(S)-(C,.

4 alkyl) or -NH-C(S)-H. Replacement of the oxygen atom with a sulfur atom has unexpectedly improved the antimicrobial properties of the compounds. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including Gram-positive aerobic bacteria such as multiply-resistant 15 staphylococci and streptococci, Gram-negative organisms such as H. influenzae and M. catarrahlis as well as anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium. The compounds are particularly useful because they are effective against the latter organisms which are known to be responsible for 20 infection in persons with AIDS. SUMMARY OF THE INVENTION In one aspect the subject invention is a compound of the Formula I 25 S A \

C-R

1 N/ \~ H I 30 or pharmaceutical acceptable salts thereof wherein: G is o o -N ~ N"0 - 0 35 -1- WO 00/32599 PCT/US98/25308 R, is a) H, b)

NH

2 , c) NH-C 1 4 alkyl, 5 d) C 1 4 alkyl, e) -OC,.

4 alkyl, f) -S C 1

.

4 alkyl, g) C, 4 alkyl substituted with 1-3 F, 1-2 Cl, CN or -COOC 14 alkyl, h) C 3 6 cycloalkyl, 10 i) N(C 1

-

4 alkyl) 2 or j) N(CH 2

)

2

-

5 ; A is a) R 15 R 23 20 b) R24

R

43 25 c) R 46 / 25R45 R44 d) a 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of S, N, and O, 30 wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom, wherein the 5-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one 35 to three R 4 s , -2- WO 00/32599 PCT/US98/25308 e) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the heteroaromatic moiety is bonded via a carbon atom, 5 wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three

R

55 ss , f) a 3-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, 10 optionally substituted with one to three R.

55 , g) R74 R 7 5

R

7 6 , or R 73"" K"" R7

R

7 7 15 h) R 7 5

R

7 6 N R 80 NT' 20

R

77 wherein R 2 is a) H, b) F, 25 c) Cl, d) Br, e) C 1

.

3 alkyl, f) NO 2 , or g) R., and R 3 taken together are -O-(CH2)h-O-; 30 R 3 is a) -S(=O)i R 4 , b) -S(=O),-N=S(O)jR 5

R

6 , C) -SC(=O)R 7 , d) -C=O)R8, 35 e) -C(=O)I, f -C(=O)NRIoR 11 , -3- WO 00/32599 PCT/US98/25308 g) -C(=NR 1 2)R 8 , h) -C(R 8

)(RI,)-OR,

13 , i) -C(Rg)(R, 1 1

)-OR

1 3 , j) -C(Rs)(R, 1

)-OC(=O)R

13 , 5 k) -C(R)(RI

)-OC(=O)RI

3 , 1) -NRioRID m) -N(R 1 o)-C(=O)R 7 , n) -N(Ro)-S(=O)iR 7 , o)

-C(OR

1 4)(ORs 5 )Rs, 10 p) -C(R 8

)(R

16 )-NRIoR 11 , or q) C 1

-

s alkyl substituted with one or more =0 other than at alpha position, -S(=O)R 17 , -NRIoRi, C2-5 alkenyl, or C 2

.

5 alkynyl;

R

4 is a) C.

4 alkyl optionally substituted with one or more halos, OH, CN, 15

NRIO

0

R

1 , or -COR,3, b) C 2

-

4 alkenyl, c)

-NR

1

,

6

R

1 8 , d)

-N

3 , e) -NHC(=O)R 7 , 20 f) -NR 20

C(=O)R

7 , g) -N(R,9)2, h) -NR 16

R,

9 , or i)

-NRR

2 0 ,o

R

5 and R 6 at each occurrence are the same or different and are 25 a) C 1

.

2 alkyl, or b) R s and R 6 taken together are -(CH2)k-; R, is C 1

.

4 alkyl optionally substituted with one or more halos;

R

8 is a) H, or 30 b) C,.

s alkyl optionally substituted with one or more halos, or C 3

.

8 , cycloalkyl;

R

9 is C, 1 4 alkyl substituted with one or more a)

-S(=O)R

7 , b)

-OR

1 3 , 35 c) -OC(=O)R 3 , d) -NRIoR,1, or -4- WO 00/32599 PCT/US98/25308 e) C, 5 alkenyl optionally substituted with CHO; RIo and RI, at each occurrence are the same or different and are a) H, b) C 1

.

4 alkyl, or 5 c) C 3

.

8 cycloalkyl;

R

12 is a) -NRIoRII b) -ORIo; or c) -NHC(=O)RIo; 10 R 13 is a) H, or b) C1- 4 alkyl;

R

14 and R 15 at each occurrence are the same or different and are a) C.

4 alkyl, or 15 b) R, 14 and R 15 taken together are -(CH)-r;

R,

6 is a) H, b) C 1

-

4 alkyl, or c) C3.

8 cycloalkyl; 20 R 17 is a) C 1

-

4 alkyl, or b) C 3 , cycloalkyl; R,, is a) H, 25 b) C,- 4 alkyl, c) C 2 4 alkenyl, d) C 3

-

4 cycloalkyl, e) -OR 13 or f) -NR21R22 30 R 1 9 is a) Cl, b) Br, or c) I;

R.

2 0 is a physiologically acceptable cation; 35 R, and R., at each occurrence are the same or different and are a) H, -5- WO 00/32599 PCT/US98/25308 b) C- 1 4 alkyl, or c) -NR,,R.

2 taken together are -(CH2)m-; wherein R, 3 and I, 2 4 at each occurrence are the same or different and are a) H, 5 b) F, c) C1, d) C, 2 alkyl, e) CN f) OH, 10 g) C 1

.

2 alkoxy, h) nitro, or i) amino; Qis a) Y 15 Xx b) N? y 20 x c) W x 25 d) I M 30 e) -6- WO 00/32599 PCTIUS98/25308 X NN N I M 5 g)x N N I M 10 h) x N l Y M 15 w X 20 j) 25 k)

OR

30 0 1) 30~ - (CH 2 )

,R

38 35 E (CH2) p -7- WO 00/32599 PCT/US98/25308 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, 5 q) a naphthyridinyl group optionally substituted with X and Y, r) A 2

A

1

(CH

2 )n

Z

I

-

N 10 s) z2 15 (CH 2) t) 20 N u) R 107 25 N v) 30 X 35 Y N x W) -8 35 Y NP x -8- WO 00/32599 PCT/US98/25308 x) y N N x 5 y) N x N yf 10 z) y /4N N I \ N X x 15 aa) X

N

Y 20 bb) x or, N 25 Q and R 24 taken together are

R

06 30 wherein Z 1 is a) -CH, 35 b) -CH(R 4)-CH2-, c) -C(O)-, or -9- WO 00/32599 PCT/US98/25308 d) -CH,CHCH,,-; wherein Z 2 is a) -02S- , 5 b) -0-, c) -N(R7)-, d) -OS-, or e) -S-; wherein Z 3 is 10 a) -O2S-, b) -0-, c) -OS-, or d) -S-; wherein A 1 is 15 a) H-, or b)

CH

3 ; wherein A 2 is a) H-, b) HO-, 20 c) CH 3 -, d) CH 3 O-, e) R10 2 0-CH 2

-C(O)-NH

f) R 10 3 0-C(O)-NH-, g) (C 1

-C

2 )alkyl-O-C(O)-, 25 h) HO-CH 2 -, i) CH30-NH-, j) (C-C 3 )alkyl-O 2

C

k) CH 3 -C(O)-, 1) CH:,-C(O)-CH,-, 30 m) ,or 0 0 35 -10- WO 00/32599 PCT/US98/25308 n) o 0 5 A' and A ' taken together are: a) R112 010 10 b) o= ,or R114 15 c) N wherein R 0 2 is a) H-, b) CHR,-, 20 c) phenyl-CH 2 -, or d) CH 3 C(O)-; wherein R'" 3 is a) (CI-C,)alkyl-, or b) phenyl-; 25 wherein R 04 is a) H-, or b) HO-; wherein R' l " is a) H-, 30 b) (Cl-C,)alkyl-, c) CH, = CH-CH,-, or d) CH 3

-O-(CH,)

2 -; wherein R' 6 is a) CH.-C(O)-, 35 b) H-C(O)-, c) Cl,,CH-C(O)-, -11- WO 00/32599 PCT/US98/25308 d) HOGH 2 ,-C(O)-, e) CH 3

SO

2 -, R115 0/(0) 5 g) F 2 CHC(O)-, h) N- () \-Ij i) H 3

C-C(O)-O-CH

2 -C(O)>, 10 j) H-C(O)-O-CH2-C(Oy-, k) C\J (0 1) HGC=-CCH 9 ,O-CH-C(Oy, or 15 M) phenyl-GH 2

-O-CH

2 -C(O)*; wherein R" 0 is a) R 10 2 OC(RllO)(R11)C(Oy-, b) Rl' 3 -C(O)-, C) R18co 200 H e) 25 H f) H 3 G-C(O)-(CH29 2 -C(o)-, g) R0-O 0 30 h) 03 D) HO-OH.-C(0)-, j) R" 6

-(CH

2

)

2 -, 35 k) R' 13 -C(O )-O-CH-C(O> -12- WO 00/32599 PCT/US98/25308 m) NC-CH,-, n) F 2 -CH-CH,-, or o)

R

15

°R'

51 NS0 2 wherein R 1 8 is 5 a) H-, b) (C 1

-C

4 )alkyl, c) aryl -(CH,,)p, d)

CIH

2 C-, e) C1 2 HC-, 10 f) FH 2 C-, g) F 2 HC-, h) (C 3

-C

6 )cycloalkyl, or i)

CNCH

2 -. wherein R' 09 is 15 a) alkylCI-C 4 , b) -CH2C1 c) -CH 2

CH=CH

2 , d) aryl, or e) -CH 2 CN; 20 wherein R" ' and R 1 '" are independently a) H-, b) CH3-; or wherein R 11 2 is a) H-, 25 b) CH:O-CH20-CH 2 -, or c)

HOCH

2 -; wherein R' 1 3 is a) CH:-, b)

HOCH

2 -, 30 c) (CH,),N-phenyl, or d) (CH 3

)

2 N-CH.,-; wherein R' 14 is a) HO-, b) CH:0-, 35 c) H,N-, d) CH:,O-C(O)-O-, -13- WO 00/32599 PCT/US98/25308 e) CH 3 -C(O)-O-CH,-C(O)-O-, f) phenyl-CH,-O-CH 2 -C(O)-O-, g) HO-(CH,) 2 -O-, h) CH30-CH,,-O-(CH,) 2 -O-, or 5 i) CH30-CH,-O-;wherein

R"

1 13 is a)

CH

3 -, b) HOCH 2 -, c) (CH 3

)

2 N-phenyl, or d) (CH 3

)

2

N-CH

2 -; 10 wherein R" 5 is a) H-, or b) Cl-; wherein R" ' 1 6 is a) HO 15 b) CH 3 O-, or c) F; wherein R' 150 and R"' are each H or alkyl C 1

-C

4 or R 150 and R 151 taken together with the nitrogen atom to which each is attached form a monocyclic heterocyclic ring having from 3 to 6 carbon atoms; 20 B is an unsaturated 4-atom linker having one nitrogen and three carbons; M is a) H, b) C,.

8 alkyl, c) C,. cycloalkyl, 25 d) -(CH 2 )mORi 3 , or e) -(CH 2 )h-NR 2 1

R

22 ; Z is a) O, b) S, or 30 c) NM; W is a) CH, b) N, or c) S or O when Z is NM; 35 Y is a) H, -14- WO 00/32599 PCT/US98/25308 b) F, c) Cl, d) Br, e) C 1

_

3 alkyl, or 5 f) NO 2 ; X is a) H, b) -CN, c)

OR

27 , 10 d) halo, e)

NO

2 , f) tetrazoyl, g) -SH, h) -S(=O)iR 4 , 15 i) -S(=O) 2 -N=S(O)jRsR 6 , j) -SC(=O)R 7 , k) -C(=O)R 2 1 5 , 1) -C(=O)NR.,7R 2 8 , m) -C(=NR 29 )0R 25 , 20 n) -C(R25)(R )-OR 1 3 , o) -C(R 25

)(R

28

)-OC(=O)R,

13 , p) -C(R 28

)(OR

1 3 )-(CH,)h-NR 2 7

R

2 8 , q) -NR7R28, r) -N(R27)C(=O)R, 25 s) -N(R27)-S(=O)iR7, t) -C(OR 1 4

)(OR

5

)R

2 8 s , u) -C(R 25

)(R

16

)-NR

7

R

2 ., or v) C, 8 alkyl substituted with one or more halos, OH, =0 other than at alpha position, -S(=O),Rl 7 , -NR,, 7 R2s 8 , C,- 5 alkenyl, C 2

-

5 alkynyl, or 30 C 3 8 cycloalkyl;

R

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

R

25 is a) H, b) C 18 - alkyl optionally substituted with one or more halos, C 3 8 35 cycloalkyl, C 14 alkyl substituted with one or more of -S(=O)iR, 7 , -OR,,, or OC(=O)Ris, NR 7

R

2 8, or -15- WO 00/32599 PCT/US98/25308 c) C 2

.

s alkenyl optionally substituted with CHO, or CO2,Ri;

R

26 is a) R2s, or b) NR2 7

N

28 s; 5 R, 7 and R 2 , at each occurrence are the same or different and are a) H, b) C 1

,

s alkyl, c) C 3 , cycloalkyl, d) -(CH 2 )mOR, 3 , 10 e) -(CH2)h-NR 2 1

R

22 , or f) R 2 7 and R 28 taken together are -(CH2) 2 0(CH2) 2 -, -(CH2)hCH(COR 7 )-, or -(CH2)2N(CH,)2(R); R2 9 is a) -NR1 7

R

2 8 s , 15 b) -OR 27 , or c) -NHC(=O)R 28 ; wherein R 30 is a) H, b) CIs alkyl optionally substituted with one or more halos, or 20 c) C 1 , alkyl optionally substituted with one or more OH, or C.

6 alkoxy; wherein E is a)

NR

39 , b) -S(=O) i , or c) O; 25 R 38 is a) H, b) C 1

.

6 alkyl, c) -(CH 2 )q-aryl, or d) halo; 30 R 1 9 is a) H, b) C 1

.

6 alkyl optionally substituted with one or more OH, halo, or -CN, c) -(CH 2 )q-aryl, d) -C02R40 , 35 e) -COR 4 1 , f) -C(=O)-(CH,)q-C(=O)R 4 0 , -16- WO 00/32599 PCT/US98/25308 g) -S(=O).-C,_ 6 alkyl, h) -S(=O) 2

-(CH

2 )q-aryl, or i) -(C=O)j-Het;

R

4 0 is 5 a) H, b) C 1

,

6 alkyl optionally substituted with one or more OH, halo, or -CN, c) -(CH 2 ).-aryl, or d) -(CH2),-OR,2;

R

4 , is 10 a) C,- 6 alkyl optionally substituted with one or more OH, halo, or -CN, b) -(CH 2 )q-aryl, or c) -(CH 2 )q-OR 4 2 ;

R

42 is a) H, 15 b) C 1

.

6 alkyl, c) -(CH 2 )q-aryl, or d) -C(=O)-C,.

6 alkyl; aryl is 20 a) phenyl, b) pyridyl, or c) napthyl; a to c optionally substituted with one or more halo, -CN, OH, SH, C , 6 alkyl, C 6 alkoxy, or C 1

_

6 alkylthio; wherein

R

4 3 is 25 a) H, b) C1- 2 alkyl, c) F, or d) OH;

R

44 is 30 a) H, b)

CF

3 , c) C.

3 alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) R 44 and R 45 taken together are a 5-, 6-, or 7-membered ring of the 35 formula, -17- WO 00/32599 PCT/US98/25308 or H O (C 2)h U 5 f) R 44 and R 45 taken together are -(CH,)k-, when R 46 is an electron withdrawing group;

R

45 and R 4 6 at each occurrence are the same or different and are a) an electron-withdrawing group, 10 b) H, c)

CF

3 , d) C,- alkyl optionally substituted with one halo, e) phenyl, provided at least one of R4, or R 4 6 is an electron-withdrawing group, or 15 f) R 45 and R 46 taken together are a 5-, 6-, 7-membered ring of the formula O C-C ,~ CI (C H 2)r 20 U is a)

CH

2 , b) O, c) S, or 25 d) NR 4 7 ; R47 is a) H, or b) CI,5 alkyl; wherein R 4 . is 30 a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, 35 f) CF 3 , g) -NO, -18- WO 00/32599 PCT/US98/25308 h) C,.

6 alkoxy, i) C 1

.

6 alkoxycarbonyl, j) CI- 6 alkythio, k) C 1

.

6 acyl, 5 1) -NR 49 Rs 5 0 , m) C 1

.

6 alkyl optionally substituted with OH, C 1

_

5 alkoxy, C,.

5 acyl, or

-NR

4 9

R

5 o, n) C 2

-

8 alkenylphenyl optionally substituted with one or two R 51 , o) phenyl optionally substituted with one or two R 51 , 10 p) a 5-, or 6-membered (un)saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two Rs 51 , or 0 q) (CH2) 1 15

R

4 9 and R 5 so at each occurrence are the same or different and are a) H, b) C 1

-

4 alkyl, c) C 56 cycloalkyl, or 20 d) R 49 and R 5 0 taken together with the nitrogen atom is a 5-, 6 membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C 1

.

3 alkyl, or C 1 3 acyl; 25 Rs 5 , is a) carboxyl, b) halo, c) -CN, d) mercapto, 30 e) formyl, f) CF, g) -NO

,

, h) C 1

.

6 alkoxy, i) C 1

.

6 alkoxycarbonyl, 35 j) C,_ 6 alkythio, k) C 1

-

6 acyl, -19- WO 00/32599 PCT/US98/25308 1) C., alkyl optionally substituted with OH, C- 5 alkoxy, C 1 . acyl, or

-NR

49 Ro, m) phenyl, n) -C(=O)NR 52

R

53 , 5 o) -NR49Rs , p) -N(R 5 2)(-SO,R 54 ), q) -SO,-NR 52

R

3 , or r) -S(=O),R54;

R.

2 and R 53 at each occurrence are the same or different and are 10 a) H, b) C,_ 6 alkyl, or c) phenyl;

R

54 is a) C, 4 alkyl, or 15 b) phenyl optionally substituted with C 1

.

4 alkyl; wherein R 5 , is a) carboxyl, b) halo, c) -CN, 20 d) mercapto, e) formyl, f)

CF

3 , g) -NO 2 , h) C 1 6 alkoxy, 25 i) C, 6 alkoxycarbonyl, j) C, 6 alkythio k) C, acyl, 1) -NR 56

R

57 , m) C, 6 alkyl optionally substituted with OH, C 1 5 alkoxy, C 1

_

5 acyl, or 30

-NR

6

R

5 7 , n) C 2 8 alkenylphenyl optionally substituted with one or two R 58 s , o) phenyl optionally substituted with one or two R 5 s, p) a 5- or 6-membered (un)saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, 35 optionally substituted with one or two Rs, or -20- WO 00/32599 PCT/US98/25308 q) o (C H2D, Rs 5 6 and R, 57 at each occurrence are the same or different and are 5 a) H, b) formyl, c) C 1 4 alkyl, d) C 1 4 acyl, e) phenyl, 10 f) C 3 6 cycloalkyl, or g) R 56 and R 57 taken together with the nitrogen atom is a 5-, 6 membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the 15 further nitrogen atom, phenyl, pyrimidyl, CI-a alkyl, or C,.

3 acyl;

R

58 is a) carboxyl, b) halo, c) -CN, 20 d) mercapto, e) formyl, f) CF3, g)

-NO

2 , h) CI- 6 alkoxy, 25 i) C.

6 alkoxycarbonyl, j) C 1

-

6 alkythio, k) CI_ 6 acyl, 1) phenyl, m) C 1

-

6 alkyl optionally substituted with OH, azido, C 1 5 alkoxy, CI.

s 30 acyl, -NR 6 5

R,

66 , -SR67 ,

-O-SOR

6 8 , or R69--

NH-CO-O

n) -C(=O)NR 59

R

60 , 35 o) -NRs 6

R

57 , p) -N(R 5 9

)(-SO,R

54 ), -21- WO 00/32599 PCT/US98/25308 q) -SO,-NR 5 9

R

60 o, r) -S(=O)iR54 , s) -CH=N-R 6, or t) -CH(OH)-SO 3

R

4 ; 5 R 54 is the same as defined above; Rs 9 and R 6 0 at each occurrence are the same or different and are a) H, b) CI.

6 alkyl, c) phenyl, or 10 d) tolyl;

R

61 is a) OH, b) benzyloxy, c) -NH-C(=O)-NH 2 , 15 d) -NH-C(=S)-NH, 2 , or e) -NH-C(=NH)-NR 62 R6;

R

62 and R 63 at each occurrence are the same or different and are a) H, or b) C 1

-

4 alkyl optionally substituted with phenyl or pyridyl; 20 R 64 is a) H, or b) a sodium ion;

R

65 and R 6 6 at each occurrence are the same or different and are a) H, 25 b) formyl, c) C1-4 alkyl, d) C, 4 acyl, e) phenyl, f) C 3

_

6 cycloalkyl, 30 g) R 6 5 and R 66 taken together are a 5-, 6-membered saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyl, CI- 3 alkyl, or CI- 3 acyl, h) -P(O)(ORo)(OR7,), or 35 i) -SO2-R72; -22- WO 00/32599 PCT/US98/25308

R

67 is N -N N -N N (C H 3

)

3 C S

CH

3 5 N>- N Sor N

CH

3

CH

3 10

R

68 is CI-3 alkyl; 15 R 69 is a) C 1

.

6 alkoxycarbonyl, or b) carboxyl; R7 0 and R, at each occurrence are the same or different and are a) H, or 20 b) C,- 3 alkyl;

R

72 is a) methyl, b) phenyl, or 25 c) tolyl; wherein K is a) O, or b) S;

R

7 3 , R 7 4 , R 75 , R 7 6 , and R 77 at each occurrence are the same or different and are 30 a) H, b) carboxyl, c) halo, d) -CN, e) mercapto, 35 f) formyl, g) CF,, -23- WO 00/32599 PCT/US98/25308 h) -NO,, i) C 1 .6 alkoxy, j) C,.

6 alkoxycarbonyl, k) C 16 alkythio, 5 1) C,- 6 acyl, m)

-NR

78 R79, n) C 16 alkyl optionally substituted with OH, C 1

.-

5 alkoxy, C- 1

.

5 acyl,

-NR

8

R

79 , -N(phenyl)(CH 2 -CH,-OH), -O-CH(CH: 3

)(OCH

2

CH

3 ), or -O-phenyl- [para-NHC(=O)CH 3 ], 10 o) C 2

.

8 alkenylphenyl optionally substituted with R 51 , p) phenyl optionally substituted with R 51 , or q) a 5-, or 6-membered (un)saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with R 51 ,; 15 R51 is the same as defined above;

R

78 and R 79 at each occurrence are the same or different and are a) H, b)

C

1

.

4 alkyl, c) phenyl, or 20 d) R 78 and R 7 9 taken together with the nitrogen atom is a 5-, 6 membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C 1 _: alkyl, or CI_ 3 acyl; 25 wherein T is a) O, b) S, or c)

SO

2 ; R7s, R 76 , and R 7 7 are the same as defined above; 30 R 80 is a) H, b) formyl, c) carboxyl, d) C, 6 alkoxycarbonyl, 35 e) C,.

8 alkyl, f) C 2

.

8 alkenyl, -24- WO 00/32599 PCT/US98/25308 wherein the substituents (e) and (f) can be optionally substituted with OH, halo, C-6 alkoxy, C 1

.

6 acyl, C 1

-

6 alkylthio or C,.

6 alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted 5 with carboxyl, halo, -CN, formyl, CF 3 , -NO, C 1 ., alkyl, CI.

6 alkoxy,

C

1 6 acyl, C 1 6 alkylthio, or C 1

.

6 alkoxycarbonyl; h) -NRs 1

R

82 , i) -ORo , j) -S(=O)i-Rgl , 10 k) -SO,-N(R 92

)(R

3 ), or 1) a radical of the following formulas: Rs, and R 8 2 at each occurrence are the same or different and are a) H, 15 b) C 3

.

6 cycloalkyl, c) phenyl, d) C,.

6 acyl, e) C 1

.

6 alkyl optionally substituted with OH, C 1

-

6 alkoxy which can be substituted with OH, a 5-, or 6-membered aromatic heterocyclic 20 moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF 3 , halo, -NO 2 ,

C

1

.

4 alkoxy, -NR, 3

R

8 4 , or 25 0 f) 85 , or 30 R86 HC g) V .__N-(CH2)t 35 V is a) O, -25- WO 00/32599 PCT/US98/25308 b) CH,, or c) NR, 7 ; Rs 3 and Rs 4 at each occurrence are the same or different and are a) H, or 5 b) C 1

-

4 alkyl; R, is a) OH, b) Cl.

4 alkoxy, or c) -NR 88

R

8 9 ; 10 R 8 6 is a) H, or b) C 1 7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C(=O)-NHe, -CO,,H, or -C(=NH)-NH 2 ; 15 Rs 87 is a) H, b) phenyl, or c) C 1

-

6 alkyl optionally substituted by OH; 20 R 8 . and R 8 9 at each occurrence are the same or different and are a) H, b) C 15 alkyl c) C: 3

.

6 cycloalky, or d) phenyl; 25 R 90 is a) C, 1 8 alkyl optionally substituted with C,- 6 alkoxy or C 1 6 hydroxy,

C.

1 6 cycloalkyl, a 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three nitrogen atoms, which can in turn be substituted with one or two -NO 2 , CF:,, halo, -CN, OH, C ., 30 alkyl, C 1

.

5 alkoxy, or C 1

-

5 acyl; b) V

N-(CH

2 )t 35 c) phenyl, or d) pyridyl; -26- WO 00/32599 PCT/US98/25308 R,, is a) C 116 alkyl, b) C2_1 6 alkenyl, wherein the substituents (a) and (b) can be optionally substituted with 5

CI.

6 alkoxycarbonyl, or a 5-, 6-, 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, c) an aromatic moiety having 6 to 10 carbon atoms, or d) a 5-, 6-, 7-membered aromatic heterocyclic moiety having one to three 10 atoms selected from the group consisting of S, N, and O, wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, -CN, formyl, CF 3 , -NO, C 1 , alkyl, C,.

6 alkoxy, C 1

.

6 acyl, C,,, alkylthio, or Cl., alkoxycarbonyl;

R

9 2 and R,: at each occurrence are the same or different and are 15 a) H, b) phenyl, c) CI- 6 alkyl, or d) benzyl; R94 and R95 at each occurrence are the same or different and are 20 a) H, b) OH, c) C,.

6 alkyl optionally substituted with -NR 3

R

84 , or d) R,9 4 and R,5 taken together are =0;

R

96 is 25 a) an aromatic moiety having 6 to 10 carbon atoms, b) a 5-, or 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the substituents (a) and (b) which can in turn be substituted 30 with one or three -NO 2 , CF:,, halo, -CN, OH, phenyl, C, 5 alkyl, C 1 5 alkoxy, or C 1

,

5 acyl, c) morpholinyl, d) OH, e) C,.

6 alkoxy, 35 f) -NR 3

R

8 4 , g) -C(=O)-R 7 , or -27- WO 00/32599 PCT/US98/25308 h) 0 R, is 5 a) morpholinyl, b) OH, or c) C 1 6 alkoxy; his 1, 2, or 3; iis 0, 1, or 2; 10 jis 0 or 1; k is 3, 4, or 5; 1 is 2 or 3; m is 4 or 5; n is 0, 1, 2, 3, 4, or 5; 15 p is 0, 1, 2, 3, 4, or 5; with the proviso that n and p together are 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, or6; u is 1 or 2; 20 wis0, 1,2, or3. DETAILED DESCRIPTION OF THE INVENTION The new compounds of the invention can be prepared using known compounds and intermediates of oxzolidinones, isoxazolines and butyolactones as 25 intermediates and synthetic methods known in the art. Thioamides of the invention can typically be prepared by the reaction of the corresponding amide with Lawesson's reagent. Compounds disclosed in the following publications are suitable intermediates for preparation of the compounds of this invention and are hereby incorporated by 30 reference for their disclosure of suitable compounds that can be converted to the subject thiocarbonyl derivatives. U.S. Patents 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 publications PCT/US93/04850, WO94/01110; 35 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; -28- WO 00/32599 PCT/US98/25308 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 a CH.,NH, on the oxazolidinone ring to CH,NH-C(S)-CH:, is disclosed by Hartke, K., 5 Barrmeyer, S., J. prakt. Chem. 1996, 338, 251-6. Similarly, conversion of CH,NHC(=0)CH:, to CHNHC(S)NHCH: 3 is reported by Cava, M.P.; Levinson, M.I., Thionation Reactions of Lawesson's Reagents, Tetrahedron 1985, 41, 5061-87. For the purpose of the present invention, the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum 10 and maximum number of carbon atoms in the moiety, i.e., the prefix Cj defines the number of carbon atoms present from the integer "i" to the integer "j", inclusive. Thus, C 1

_

4 alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof. The terms "C 1

.

2 alkyl", "CI.

3 alkyl", "C 1

_

4 alkyl", "C,_ alkyl", "C.

6 alkyl", "C 1

_

8 15 alkyl", and "C 1 .,6 alkyl" refer to an alkyl group having one to two, one to three, one to four, one to five, one to six, one to eight, or one to sixteen carbon atoms respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and their isomeric forms thereof. 20 The terms "C2- 4 alkenyl", "C 2 -5 alkenyl", "C 2

-

8 alkenyl", "C 2

.

1 4 alkenyl" and "C 2

.-

16 alkenyl" refer to at least one double bond alkenyl group having two to four, two to five, two to eight, two to fourteen, or two to sixteen carbon atoms, respectively such as, for example, ethenyl, propenyl, butenyl, pentenyl, pentdienyl, hexenyl, hexdienyl, heptenyl, heptdienyl, octenyl, octdienyl, octatrienyl, nonenyl, nonedienyl, 25 nonatrienyl, undecenyl, undecdienyl, dodecenyl, tridecenyl, tetradecenyl and their isomeric forms thereof. The terms "C., 5 alkynyl", "C 28 alkynyl", and "C 2

.

1 o alkynyl" refer to at least one triple bond alkynyl group having two to five, two to eight, or two to ten carbon atoms respectively such as, for example, ethynyl, propynyl, butynyl, pentynyl, 30 pentdiynyl, hexynyl, hexdiynyl, heptynyl, heptdiynyl, octynyl, octdiynyl, octatriynyl, nonynyl, nonediynyl, nonatriynyl and their isomeric forms thereof. The terms "C.

4 cycloalkyl", "C 36 cycloalkyl", "C 5

.

6 cycloalkyl", and "C,.

8 cycloalkyl" refer to a cycloalkyl having three to four, three to six, five to six, or three to eight carbon atoms respectively such as, for example, cyclopropyl, cyclobutyl, 35 cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms thereof. The terms "C, 4 alkoxy", "C 1

.

6 alkoxy", and "C,- alkoxy" refer to an alkyl group -29- WO 00/32599 PCT/US98/25308 having one to four, one to six, or one to eight carbon atoms respectively attached to an oxygen atom such as, for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and their isomeric forms thereof. The terms "C, 6 alkylamino", and "C 1 ,- alkylamino" refer to an alkyl group 5 having one to six, or one to eight carbon atoms respectively attached to an amino moiety such as, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, or octoylamino and their isomeric forms thereof. The terms "C,- 6 dialkylamino", and "C.

8 dialkylamino" refer to two alkyl 10 groups having one to six, or one to eight carbon atoms respectively attached to an amino moiety such as, for example, dimethylamino, methylethylamino, diethylamino, dipropylamino, methypropylamino, ethylpropylamino, dibutylamino, dipentylamino, dihexylamino, methylhecylamino, diheptylamino, or dioctoylamino and their isomeric forms thereof 15 The terms "C 1

.

3 acyl", "C 1 4 acyl", "C1.5 acyl", "C- 1

.

6 acyl", "C, 18 acyl", and

"C

2 -8 acyl" refer to a carbonyl group having an alkyl group of one to three, one to four, one to five, one to six, one to eight, or two to eight carbon atoms. The terms "C 1

.

4 alkoxycarbonyl", "Cl.

6 alkoxycarbonyl", and "C, 8 alkoxycarbonyl" refer to an ester group having an alkyl group of one to four, one to 20 six, or one to eight carbon atoms. The term "C- 1

.

8 alkyl phenyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one phenyl radical. The term "C 2

,

- alkenyl phenyl" refers to a at least one double bond alkenyl 25 group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one phenyl radical. The term "C,-, alkyl pyridyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one pyridyl radical. 30 The term "C,., hydroxyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a hydroxy group. The term "Cl _ alkylsulfonyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a SO 2 moiety. The term "C 1 6 alkylthio" refers to an alkyl group having one to six carbon 35 atoms and isomeric forms thereof attached to a sulfur atom. The term "Het" refers to 5 to 10 membered saturated, unsaturated or -30- WO 00/32599 PCT/US98/25308 aromatic heterocyclic rings containing one or more oxygen, nitrogen, and sulfur forming such groups as, for example, pyridine, thiophene, furan, pyrazoline, pyrimi dine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3 pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3 5 isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1 phthalazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2 oxazolyl, 5-oxazolyl, 4,5,-dihydrooxazole, 1,2,3-oxathiole, 1,2,3-oxadiazole, 1,2,4 oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3 10 isothiazole, 4-isothiazole, 5-isothiazole, 2-indolyl, 3-indolyl, 3-indazolyl, 2 benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole, benzisoxazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3,-oxathiazole- 1-oxide, 1,2,4 oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 15 1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4 thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1 pyrrolyl, 1-pyrazolyl, 1,2,3-triazol-1l-yl, 1,2,4-triazol-1l-yl, 1-tetrazolyl, 1-indolyl, 1 indazolyl, 2-isoindolyl, 7-oxo-2-isoindolyl,l1-purinyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadiazol-2-yl, 20 thiazoledione, 1,2,3,4-thiatriazole, 1,2,4-dithiazolone. Each of these moieties may be substituted as appropriate. The term halo refers to fluoro, chloro, bromo, or iodo. The compounds of the present invention can be converted to their salts, where appropriate, according to conventional methods. 25 The term "pharmaceutically acceptable salts" refers to acid addition salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate and the like. These salts may be in hydrated form. 30 When Q is the structure of E (CH2n 39 , (CH2) p the dotted line in the heterocyclic ring means that this bond can be either single or 35 double. In the case where the dotted line is a double bond, the R,, 9 group will not be present. -31- WO 00/32599 PCT/US98/25308 The compounds of Formula I of this invention contain a chiral center at C5 of the isoxazoline ring, and as such there exist two enantiomers or a racemic mixture of both. This invention relates to both the enantiomers, as well as mixtures containing both the isomers. In addition, depending on substituents, additional 5 chiral centers and other isomeric forms may be present in any of A or R, group, and this invention embraces all possible stereoisomers and geometric forms in these groups. The compounds of this invention are useful for treatment of microbial infections in humans and other warm blooded animals, under both parenteral and 10 oral administration. The pharmaceutical compositions of this invention may be prepared by combining the compounds of this invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Solid form composi 15 tions include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, 20 starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring 25 agents, stabilizers and thickening agents. Preferably, the pharmaceutical composition is provided employing conventional techniques in unit dosage form containing effective or appropriate amounts of the active component, that is, the compound according to this invention. The quantity of active component, that is the compound according to this 30 invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the potency of the particular compound, the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition. In therapeutic use for treating, or combatting, bacterial infections in warm 35 blooded animals, the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and/or topically at a dosage to obtain and maintain -32- WO 00/32599 PCT/US98/25308 a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective. Generally, such antibacterially effective amount of dosage of active component will be in the range of about 0.1 to about 100, more preferably about 3.0 to about 50 mg/kg of body 5 weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the bacterial infection being treated, and the particular compound being used. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the 10 optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., 2-4 four times per day. When the compounds according to this invention are administered parenterally, i.e., by injection, for example, by intravenous injection or by other 15 parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound or a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a 20 pH of about 3.5-6. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine to name but a few representative buffering agents. The compound of this invention generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 25 1 mg/mL to about 400 mg/mL of solution. The resulting liquid pharmaceutical composition will be administered so as to obtain the above-mentioned antibacterially effective amount of dosage. The compounds according to this invention are advantageously administered orally in solid and liquid dosage forms. As a topical treatment an effective amount of Formula I is admixed in a 30 pharmaceutically acceptable gel or cream vehicle that can be applied to the patient's skin at the area of treatment. Preparation of such creams and gels is well known in the art and can include penetration enhancers. MIC Test Method The in vitro MICs of test compounds were determined by a standard agar 35 dilution method. A stock drug solution of each analog is prepared in the preferred solvent, usually DMSO:H.,O (1:3). Serial 2-fold dilutions of each sample are made -33- WO 00/32599 PCT/US98/25308 using 1.0 ml aliquots of sterile distilled water. To each 1.0 ml aliquot of drug is added 9 ml of molten Mueller Hinton agar medium. The drug-supplemented agar is mixed, poured into 15 x 100 mm petri dishes, and allowed to solidify and dry prior to inoculation. 5 Vials of each of the test organisms are maintained frozen in the vapor phase of a liquid nitrogen freezer. Test cultures are grown overnight at 35 0 C on the medium appropriate for the organism. Colonies are harvested with a sterile swab, and cell suspensions are prepared in Trypticase Soy broth (TSB) to equal the turbidity of a 0.5 McFarland standard. A 1:20 dilution of each suspension is made in 10 TSB. The plates containing the drug supplemented agar are inoculated with a 0.001 ml drop of the cell suspension using a Steers replicator, yielding approximately 104 to 10 5 cells per spot. The plates are incubated overnight at 35 0 C. Following incubation the Minimum Inhibitory Concentration (MIC pg/ml), the lowest concentration of drug that inhibits visible growth of the organism, is read and 15 recorded. The data is shown in Tables I and II. -34- WO 00/32599 PCT/US98/25308 0 ot 0=0 0 0 z E 0 A0 0 00 -35- WO 00/32599 PCT/US98/25308 Z o OL N N C//2 O O O o, O=0 -- Z zC4 aII zzzz o 000 -36 00 ? aq z mO"4o< 0 0 00 00 0:-36- WO 00/32599 PCTIUS98/25308 0 Ceq 0 V V-4 03 00 00 ID z cn cnw cnrn r -37- WO 00/32599 PCT/US98/25308 - A co M M e4 N N N c - r -- ~ r4e z ~~r e4q*'

F

z qN4 (4V N~4 %n0 - 0 i0-0-00-0- ce - - 00 4n eqW%4 CC4 -38- WO 00/32599 PCTIUS98/25308 u~. QIn - u ~ N ( u1 7. VV ) ~e u 00 0 0- 0 5

----------------

eq0r ei Wi ci .!2 .! ou oo - ( < E4 N W) C6 ci C 39- WO 00/32599 PCT/US98/25308 As shown in Scheme 1, the intermediates II for the compounds of this invention are also intermediates disclosed in the oxazolidinone patents and published applications hereinabove incorporated by reference. The intermediates IV for this invention are final products (Examples) from the oxazolidinone patents 5 and published applications hereinabove incorporated by reference. As shown in Scheme 1, Step 1, and illustrated in Example 5, the isothiocyanates III can be conveniently prepared by allowing the amine intermediates (II) to react with l,l'-thiocarbonyldi-2(1H)-pyridone in solvents such as methylene chloride at 0 to 25 0 C. The thioureas (la, R' = H, alkyll.

4 ) can then be 10 prepared as shown in Step 2 by the reaction of III with ammonia or the appropriate primary amines in solvents such as 1,4-dioxane or tetrahydrofuran at 0-50 0 C. Alternatively, as illustrated in Example 6 and shown in Step 3, the thioureas can be prepared by allowing II to react with an appropriate isothiocyanate (R' - N = C = S) in solvents such as tetrahydrofuran at 0-50'C. Thioamides (Ib, R" = H, alkyll.

4 ) are 15 prepared by allowing II to react with an appropriate dithioester (R'" S-C(=S)-R", Step 4 as illustrated in Example 4. This reaction is carried out in aqueous-alcoholic solvents at 0-50 0 C in the presence of an equivalent of an alkali metal hydroxide. This reaction, especially when R" is methyl or ethyl, can be catalyzed by an alkali metal fluoride. 20 The reaction of II with R"'-S-C(S)-R'" (R'"=CH 3 , C2H.) to give Ib (Step 4) can also be carried out in the presence of a tertiary amine base such as triethylamine in solvents such as THF, dioxane or methylene chloride at 10-50 0 C for 3-48 hr. When the reaction conditions are tolerated by the substituents on R (see, for example, Examples 1-3) the thioamides (Ib, R" - H, alkyl, 4 ) can also be conveniently 25 prepared (Step 5) by allowing the appropriate amide intermediates (IV) to react with reagents such as 2,4-bis(p-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide (Lawesson's Reagent) in 1,4-dioxane, benzene, toluene or tetrahydrofuran at 60 110 0 C; phosphorus decasulfide and sodium carbonate in tetrahydrofuran at 20-50'C [Brillon, D., Synthetic Communications, 20, 3085 (1990)] or phosphorus decasulfide 30 and sodium fluoride in 1,2-dimethoxyethane at 20-50 0 C [Hartke, K., Gerber, H.-D., J. Prakt. Chem., 338, 763 (1996)]. Compounds Ic are prepared (Step 6) by allowing II to react first with carbon disulfide and a tertiary amine base such as triethylamine in solvent mixtures containing water and methanol, ethanol or isopropanol at 10-50 0 C for 5-24 hours. 35 The resulting intermediate is treated with an alkylating agent (R".... X where X represents bromo, iodo, alkylsulfonyloxy or arylsulfonyloxy) at 0-30 0 C to give -40- WO 00/32599 PCT/US98/25308 compounds Ic. In Step 7, compounds Ic are allowed to react with alkali metal alkoxide such as sodium methoxide or potassium ethoxide in the corresponding alkanol as solvent. This reaction is conveniently carried out at the reflux temperature of the alkanol for 1-24 hr. 5 -41- WO 00/32599 PCT/US98/25308 SCHEME 1 5 N N S

R-NH

2 S R-N C=S STEP 1 11 III 10 S I1

R'-NH

2 R-NH-C-NH-R' (R'= H, alkyll- 4 ) STEP 2 la i R'-N=-C=S la (R'= H, alkyll- 4 ) 15 STEP 3 S S II 11 SR"'-S-C-R" R-NH-C -R" (R"= H, alkyll- 4 ) STEP 4 Ib (R"'= OH 3 , C 2 H5, HOOC-CH2) 20 O II R-NH-C-R" lb (R"= H, alkyll- 4 ) IV STEP 5 S 25 11 1) CS 2 /Et 3 N II (R.""...= C1-.4 alkyl, X=Br, I, 2)R X RNH-C-SR.."".. OSO 2 alkyl, OSO 2 aryl) 2)R"" X STEP 6 Ic Ic MOR.."".. S 30 HOR.."".. RNH-C-OR.."".. (M=Li,+ Na,+K+) STEP 7 Id 35 In order to more fully illustrate the nature of the invention and the manner of practicing the same, the following experimental examples are presented. -42- WO 00/32599 PCT/US98/25308 EXAMPLE 1: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]- 2 -oxo-5 oxazolidinyl]methyl]thioacetamide (I) S 5 0 Meo / oc 0 As 11\ 0 /N-1 \ N0 s-- 0 -\N Y N0 0= N N S - H- H 1,4-dioxane O N-',H 1

NH-C-CH

3 F \-NH-C-CH 3 3--NH-C-CH 3

C,

6

H

20

FN

3 0 3 S I 10 A stirred mixture of II (PCT/US94/08904, 3.37 g, 10.0 mmol) in dry dioxane (100 mL), under nitrogen was treated with Lawesson's Reagent ( 4

.

0 4g, 10.0 mml), warmed to reflux during 1 h and refluxed for 1.5 h. The reaction was complete by TLC on silica gel with 10% MeOH-CHCIa. It was kept at ambient temperature for 18 h and concentrated in vacuo. Chromatography of the residue on silica gel with 15 mixtures of acetone-methylene chloride containing 10-15% acetone gave the product which was crystallized from acetone-hexane to give 1: mp 157.5-158.5 C; HRMS theory for C 16

H

20

FN

3 0 3 S (M'): 353.1209; found: 353.1212. Anal. calcd for

C

16

H

20

FN

3 0 3 S: 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. 20 EXAMPLE 2: (S)-N- [[3- [3-Fluoro-4- [4-(5-methyl-1,3,4-thiadiazol-2-yl)- 1 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (2) S 25 Me \Po N-N-rLH-- N-N / S NHAc NH-C---h 21 C 2 30 According to Example 1, for the preparation of 1, 21 (PCT/US97/01970) was allowed to react with Lawesson's Reagent in refluxing dioxane to give 2: mp 222-223 oC; HRMS theory for C 1

,H

2 4 FNOS, (M+H'): 451.1386; found 451.1381. 35 EXAMPLE 3: (S)-N-[[3- [3-Fluoro-4- [2',5'-dioxospiro[piperidine-4,4' -imidazolidine] 1-yll phenyl] -2-oxo-5-oxazolidinyll methyl] thioacetamide (3). -43- WO 00/32599 PCT/US98/25308 STEP A: (S)-N- [[3- [3-Fluoro-4- [2',5'-dioxospiro[piperidine-4,4'-imidazolidine] 1-yl] phenyll- 2 -oxo-5-oxazolidinyl methyl] acetamide (32). 5 0 0 0 KCN"N / \'JH H (NFj) OH H=1 I - INHAc NHAc 31 C12R 32 10 A stirred suspension of 31 (WO95/25106, 0.349 g, 1.00 mmol) in 1:1 EtOH:H, 2 0 (5 mL), under nitrogen, was treated with potassium cyanide (0.130 g, 2.00 mmol) and ammonium carbonate (0.701 g, 7.30 mmol), warmed at 55-60 oC for 5 h 15 min and kept at ambient temperature for 17 h 15 min. It was then chromatographed on 15 silica gel with mixtures of MeOH-NH 4 OH-CHC13 containing 5-20% MeOH and 0.5%

NH

4 OH to give 0.280 g of 32: HRMS calcd for C 19

H

22

FN

5 0,: 419.1605 (M'); found 419.1613; Anal. calcd for C 1 9

H

22

FN

5 0 5 s - 1 HO20: C, 52.17; H, 5.53; N, 16.01. Found: C, 52.44; H, 5.30; N, 16.11. 20 STEP B: (S)-N-[[3-[3-Fluoro-4-[2',5'-dioxospiro[piperidine-4,4'-imidazolidine] 1-yl]phenyll- 2 -oxo-5-oxazolidinyl] methyl] thioacetamide (3). S 0e 0 \---j SI'S\ 0 0 /OO PA S H-OMe O 0 j G N N HHO S O N H A 25 H F -ccNHAc H F -LNHCCH 32

C

9

H

2 2

FN

5 0 4 S 3 A stirred suspension of 32 (0.210 g, 0.500 mmol) in dioxane (5.0 mL), under nitrogen 30 was treated with Lawesson's Reagent (0.202 g, 0.500 mmol), refluxed for 4 h and concentrated in vacuo. The residue was chromatographed on silica gel with mixtures of MeOH-NH 4 OH-CHCI:, containing 1-10% MeOH and 0.1-0.5% NH 4 OH and the resulting product was crystallized from MeOH-CHCl,-EtOAc to give 0.0491 g of 3: mp 218.5 oC; HR FAB MS theory for C, 9 H.,2FNsO4S (M-): 435.1376; found 35 435.1370. Anal. calcd for CgH.,FN 5 0 4 S - 0.5 H.,O: C, 51.34; H, 5.21; N, 15.76. Found: C, 51.69; H, 5.00; N, 15.25. -44- WO 00/32599 PCT/US98/25308 EXAMPLE 4: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyll-2-oxo-5 oxazolidinyllmethyl]thioacetamide (4). S o II o 5 o Q NA H0 CI-C-SEt o N N A0 F 'k ,,H KOH / NaF ,H k S F LL1F \-tl 1 NH2 NH-C-CH 41

C

16

H

20

FN

3 0 3 S 4 10 A solution of 41 (148 mg, 0.500 mmol) and 0.97 M KOH (0.515 mL) in absolute EtOH (5 mL) was added to a solution of ethyl dithioacetate (57 p[L, 0.50 mmol) and sodium fluoride (20 mg, 0.47 mmol) in absolute EtOH (5 mL) and the mixture was kept at ambient temperature for 3 h 40 min. Additional ethyl dithioacetate (5 tpL) was added after I h 55 min and additional 0.97 M KOH (40 mL) and sodium fluoride (6 mg) were 15 added to the mixture after 3h 5 min. The reaction was followed by TLC on silica gel with 10% MeOH-CHCl 3 and 30% acetone-CH,Cl,. The major product had an Rf on TLC that was the same as that of 4. EXAMPLE 5: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5 20 oxazolidinyl]methyl]thiourea (5). STEP A: S II 25 oo/N N A 0 0 r- HA \- '--,,H

>F

=

=/ 1--1H F -NH, F N=C=S 51 C 1 5

H

1 6

FN

3 0 3 S A solution of 51 (PCT/US94/08904, 2.07 g, 7.00 mmol) in CHC1. was added, dropwise during 30 min, under nitrogen to an ice cold, stirred solution of 1,1'-thiocarbonyldi 30 2(1H)-pyridone (1.95 g, 8.40 mmol) in CH,C1, (70 mL). The mixture was warmed slowly to ambient temperature and kept for 18 h. It was then diluted with CH,Cl, washed with water and aqueous NaCL, dried (Na,SO,) and concentrated. Chromatography of the residue on silica gel with 10% acetonitrile-CH,Cl gave 1.60g of the isothiocvanate: HRMS theory for C.,H, 6 FN.,OS (M'): 337.0896: found -45- WO 00/32599 PCT/US98/25308 337.0888. STEP B: 0 0 O/ N .. NH3 O N N O N ~ c =HNH-C-NH 2

C

15

H

1 gFN 4 0 3 S 5 10 Anhydrous ammonia was bubbled for 7 min through a stirred solution of the product from Step I (1.00 g, 2.96 mmol) in THF (10 mL) and the mixture was kept at ambient temperature for 3 h 25 min and concentrated in vacuo. Crystallization of the residue from acetone-hexane gave 0.861 g of 5: mp 199-199.5 oC: MS n/z 354 (M+). Anal. 15 calcd for C 15

H,

9

FN

4 03S: C, 50.84; H, 5.40; N, 15.81. Found: C, 50.87; H, 5.39; N, 15.72. EXAMPLE 6: (S)-N-[[ 3

-[

3 -Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-N'-methylthiourea (6). 20 O 0 O /--N ' N HNO CH 3 NCS O/ N ' N AO 61 -NH 2

-NH-C-NHCH

3 61

C

16

H

2 1

FN

4 0 3 S 6 25 A stirred solution of methyl isothiocyanate (93 mg, 1.27 mmol) in THF, was treated with 61 (295 mg, 1.00 mmol), kept at ambient temperature for 18 h and concentrated in vacuo. The residue was recrystallized from EtOAc-hexane to give 246 mg of 6: mp 30 158-160 'C: MS nm/cz 368 (M'). Anal. calcd for C 6

H_,FN

4 0S: C, 52.16; H, 5.74; N, 15.21. Found: C, 52.20: H. 5.85; N. 15.17. -46- WO 00/32599 PCT/US98/25308 EXAMPLE 7 (S)-cis-N-[[3-[3-Fluoro-4-(tetrahydro- 1-oxido-2H-thiopyran-4 yl)phenyl]- 2 -oxo-5-oxazolidinyl}methyl]ethanethioamide 5 Step 1: A mixture of (S)-(-)-N-[[3-[ 3 -fluoro-4-(3,6-dihydro-2H-thiopyran-4.

yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide S-oxide (4.50 g, can be obtained 10 according to the procedures disclosed in International Publication No. WO 97/09328) and platinum oxide (697 mg) in methanol (164 mL) is shaken on the Parr apparatus under a hydrogen atmosphere at 40 psi for 18 hours. The catalyst is then removed by filtration through Celite, and the filtrate is concentrated under reduced pressure and the residue chromatographed on silica gel (230 - 400 mesh, 350 g), eluting with 15 a gradient of methanol/methylene chloride (3/97 - 7/93). Pooling and concentration of those fractions with an R, = 0.44 by TLC (methanol/chloroform, 10/90) gives (S) cis-(-)-N-[[3-[ 3 -Fluoro-4-(tetrahydro -1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]acetamide, mp 203 - 204oC. 20 Step 2: A mixture of the compound prepared in Step 1 (2.50 g) and hydroxylamine hydrochloride (2.36 g) in pyridine (30.6 mL) and ethanol (3.4 mL) is stirred in a screw-cap vial at 100oC for 22 hrs and at ambient temperature for 16 hrs, during which additional hydroxylamine hydrochloride (944 mg) and pyridine (4 mL) is added. The reaction mixture is then concentrated under reduced pressure, 25 diluted with saturated aqueous sodium bicarbonate (100 mL) and saline (50 mL), adjusted to pH 11 with solid sodium carbonate and extracted with methanol/methylene chloride (10/90, 5 x 100 mL). The combined organic phase is concentrated under reduced pressure, and the crude product is chromatographed on silica gel (230 - 400 mesh, 150 g), eluting with a gradient of methanol/methylene 30 chloride (6/94 - 10/90). Pooling and concentration of those fractions with an Rf = 0.14 by TLC (methanol/chloroform, 10/90) gives (S)-cis- 3 -[3-fluoro-4-(tetrahydro-1 oxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone, mp 159 - 161oC. Step 3: A solution of ethyl dithioacetate (105 mL, 0.919 mmol) and sodium 35 fluoride (39 mg, 0.919 mmol) in ethanol (9.2 mL) under a nitrogen atmosphere was treated with a mixture of (S)-cis-3-1[3-fluoro-4-(tetrahydro-l1-oxido-2H-thiopyran-4 -47- WO 00/32599 PCT/US98/25308 yl)phenyll-5-aminomethyl-2-oxazolidinone, as prepared in Step 2,(300 mg, 0.919 mmol) and aqueous potassium hydroxide (UM, 0.92 mL) in ethanol (46 mL). The resulting solution was stirred at ambient temperature for 4 hours and was then diluted with methylene chloride (150 mL) and washed with water (50 mL), aqueous 5 potassium hydrogen sulfate (1M, 50 mL) and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo, and the crude product was triturated with methylene chloride/diethyl ether and filtered to give the title compound, mp 176 - 177 0 C (dec.). 10 EXAMPLE 8 (S)-cis- [[3- [3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4 yl)phenyl]- 2 -oxo-5-oxazolidinyl]methyl]thiourea O ~s. 15 Step 1: A solution of 1,1'-thiocarbonyldi-2(1H)-pyridone (235 mg, 1.01 20 mmol) in anhydrous methylene chloride (10 mL) at 0oC under a nitrogen atmosphere was treated with a solution of (S)-cis-3-[ 3 -fluoro-4-(tetrahydro-l-oxido 2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone, as prepared in Example 7, Step 2, (275 mg, 0.843 mmol) in anhydrous methylene chloride (34 mL) over 30 minutes. The resulting mixture was stirred at 0 0 C for 30 minutes and at ambient 25 temperature for 1 hour and was then diluted with methylene chloride (40 mL), washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (70 - 230 mesh, 20 g), eluting with acetonitrile/methylene chloride (40/60), and those fractions with an R, = 0.07 by TLC (acetonitrile/methylene chloride, 30/70) were 30 pooled and concentrated to give (S)-cis-3-[3-Fluoro-4-(tetrahydro-l-oxido-2H thiopyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone, mp 187 - 190 0 C (dec.). Step 2: A solution of (S)-cis-3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4 35 yl)phenyll-5-isothiocyanatomethyl-2-oxazolidinone (Step 1, 290 mg, 0.787 mmol) in anhydrous tetrahydrofuran (39 mL) at 00C under a nitrogen atmosphere was treated -48- WO 00/32599 PCT/US98/25308 (bubbled) with a stream of ammonia gas for 5 minutes. The reaction pot was sealed, and the resulting mixture was stirred at 0OC for 1 hour. The excess ammonia was then removed under a stream of nitrogen, and the reaction mixture was concentrated in vacuo to give the crude product. Recrystallization from 5 methanol/methylene chloride/diethyl ether gave the title compound, mp 206 - 208 0 C (dec.). EXAMPLE 9 (S)-trans-N-[[3-[ 3 -Fluoro-4-(tetrahydro- 1-oxido-2H-thiopyran-4 10 yl)phenyl]- 2 -oxo-5-oxazolidinyl]methyl]ethanethioamide o,,0 15 Z'S. Step 1: (S)-(-)-N-[[3-[ 3 -fluoro-4-(3,6-dihydro-2H-thiopyran-4-yl)phenyll-2-oxo 5-ox azolidinyl]methyl]acetamide S-oxide (disclosed in International Publication No. 20 WO 97/09328) may be reduced to the corresponding cis- and trans-sulfoxides by catalytic hydrogenation in the presence of a catalyst and solvent. Alternatively, the sulfide by product of this reduction reaction can be oxidized with an oxidizing agent such NaIO 4 or meta-chloroperoxybenzoic acid in solvent to provide the cis- and trans-sulfoxides. Alternatively, the sulfide byproduct acn be oxidized selectively to 25 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 the trans-sulfoxide, mp 211 - 212oC (dec.). A mixture of the trans-sulfoxide, (S)-trans-(-)-N-[[3-[3-fluoro-4-(tetrahydro-1-oxido 2H-thiopyran-4-yl)phenyll- 2 -oxo-5-oxazolidinyl methyl] acetamide, (0.90 g) and 30 hydroxylamine hydrochloride (0.85 g) in pyridine (11.0 mL) and ethanol (1.2 mL) is stirred in a screw-cap vial at 100'C for 23 hrs and at ambient temperature for 19 hrs, during which additional hydroxylamine hydrochloride (340 mg) and pyridine (1 mL) is added. The reaction mixture is then concentrated under reduced pressure, diluted with saturated aqueous sodium carbonate (50 mL) and saline (50 mL) and 35 extracted with methanol/methylene chloride (10/90, 6 x 100 mL). The combined organic phase is concentrated under reduced pressure, and the crude product is -49- WO 00/32599 PCT/US98/25308 chromatographed on silica gel (230 - 400 mesh, 45 g), eluting with a gradient of methanol/methylene chloride (7.5/92.5 - 10/90). Pooling and concentration of those fractions with an Rf = 0.14 by TLC (methanol/chloroform, 10/90) gives (S)-trans-3-[3 fluoro-4-(tetrahydro- 1-oxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2 5 oxazolidinone, mp 138 - 140 0 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) under a nitrogen atmosphere was treated with a mixture of (S)-trans-3-[3-fluoro-4-(tetrahydro-1l-oxido-2H-thiopyran-4 10 yl)phenyl}-5-aminomethyl-2-oxazolidinone, as prepare in Step 1, (300 mg, 0.919 mmol) and aqueous potassium hydroxide (IM, 0.92 mL) in ethanol (46 mL). The resulting solution was stirred at ambient temperature for 17 hours and was 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 15 product was chromatographed on silica gel (230 - 400 mesh, 35 g), eluting with methanol/methylene chloride (3/97), and those fractions with an Rf = 0.56 by TLC (methanol/chloroform, 10/90) were pooled and concentrated and the residue recrystallized from methylene chloride/diethyl ether to give the title compound, mp 193 - 194oC (dec.). 20 EXAMPLE10 (S)-trans-[[3-[ 3 -Fluoro-4-(tetrahydro- 1-oxido-2H thiopyran-4-yl)phenyl]- 2 -oxo-5-oxazolidinyl]methyll thiourea 25 "'s F N O II WOC INH2 H 30 Step 1: A solution of 1,1'-thiocarbonyldi-2(1H)-pyridone (192 mg, 0.827 mmol) in anhydrous methylene chloride (8.3 mL) at 00C under a nitrogen atmosphere was treated with a solution of (S)-trans-3-[3-fluoro-4-(tetrahydro-1-oxido 2H-thiopyran-4-yl)phenyll-5-aminomethyl-2-oxazolidinone, as prepared in Example 9, Step 1, (225 mg, 0.689 mmol) in anhydrous methylene chloride (28 mL) over 30 35 minutes. The resulting mixture was stirred at 00C for 30 minutes and at ambient temperature for 40 minutes and was then diluted with methylene chloride (20 mL), -50- WO 00/32599 PCT/US98/25308 washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (32 - 63 mm, 40 g), eluting with a gradient of acetonitrile/methylene chloride (30/70 60/40) under 15 psi N 2 , and those fractions with an Rf= 0.12 by TLC 5 (acetonitrile/methylene chloride, 30/70) were pooled and concentrated to give (S) trans-3-[3-Fluoro-4-(tetrahydro- 1-oxido-2H-thiopyran-4- yl)phenyl]-5 isothiocyanatomethyl-2-oxazolidinone, mp 165 - 167oC. Step 2: A solution of (S)-trans-3-[3-fluoro-4-(tetrahydro-l1-oxido-2H 10 thiopyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone (Step 1, 230 mg, 0.624 mmol) in anhydrous tetrahydrofuran (31.2 mL) at 00oC under a nitrogen atmosphere was treated (bubbled) with a stream of ammonia gas for 5 minutes. The reaction pot was sealed, and the resulting mixture was stirred at 00C for 1 hour. The excess ammonia was then removed under a stream of nitrogen, and the reaction mixture 15 was concentrated in vacuo to give the crude product. Trituration with methanol/methylene chloride/diethyl ether gave the title compound, mp 209 - 2100C (dec.). 20 EXAMPLE 11 (S)-N-[[3-[ 3 -Fluoro-4-(tetrahydro-1,1-dioxido-2H thiopyran-4-yl)phenyl]- 2 -oxo-5-oxazolidinyllmethyl]ethanethioamide 02 25 0 Step 1: Starting with (S)-cis-(-)-N-[[3- [3-Fluoro-4-(tetrahydro- 1-oxido 2H-thiopyran-4-yl)phenyl]- 2 -oxo-5-oxazolidinyllmethyl]acetamide as prepared in 30 Example 7, Step 1, and following the general procedure of Step 2, and making non critical variations by substituting (S)-(-)-N-[[ 3 -[3-fluoro-4-(tetrahydro-2H-thiopyran-4 yl)phenyl]- 2 -oxo-5-oxazolidinyl]lmethyllacetamide S,S-dioxide (disclosed in International Publication No. WO 97/09328) for (S)-cis-(-)-N-[[3-[3-fluoro-4 (tetrahydro- 1-oxido-2H-thiopyran-4-yl)phenyl]

-

2 -oxo-5-oxazolidinyl] methyl]acetamide, 35 the product (S)-(-)-3-[ 3 -Fluoro-4-(tetrahydro-1,1l-dioxido-2H-thiopyran-4-yl)phenyl]-.5.

aminomethyl-2-oxazolidinone is obtained, mp 1940C (dec.). -51- WO 00/32599 PCT/US98/25308 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) under a nitrogen atmosphere was treated with a mixture of (S)-(-)-3-[ 3 -fluoro-4-(tetrahydro-1,1l-dioxido-2H-thiopyran-4 yl)phenyll-5-aminomethyl-2-oxazolidinone, as prepared in Step 1, (300 mg, 0.876 5 mmol) and aqueous potassium hydroxide (1M, 0.88 mL) in ethanol (43.8 mL). The resulting mixture was stirred at ambient temperature for 26 hours, during which additional ethyl dithioacetate (50 mL, 0.438 mmol), sodium fluoride (19 mg, 0.438 mmol), aqueous potassium hydroxide (IM, 0.44 mL) and ethanol (3.0 mL) was added, and was then diluted with methylene chloride (150 mL), washed with water 10 (50 mL), aqueous potassium hydrogen sulfate (IM, 50 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was recrystallized from methylene chloride/diethyl ether to give the title compound, mp 186 - 187 0 C (dec.). 15 EXAMPLE12 (S)-N- [[3-[ 3 -Fluoro-4-(tetrahydro-1,1-dioxido-2H thiopyran-4-yl)phenyll

-

2 -oxo-5-oxazolidinyll methyl] thiourea

O

2 S 20 0 F N o II N

NH

2 H 25 Step 1: A solution of 1,1'-thiocarbonyldi-2(1H)-pyridone (304 mg, 1.31 mmol) in anhydrous methylene chloride (13 mL) at 0oC under a nitrogen atmosphere was treated with a solution of (S)-(-)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4 yl)phenyl]-5-aminomethyl-2-oxazolidinone, as prepared in Example 11, Step 1, (375 mg, 1.09 mmol) in anhydrous methylene chloride (88 mL) over 30 minutes. The 30 resulting mixture was stirred at 0OC for 30 minutes and at ambient temperature for 30 minutes and was then diluted with methylene chloride (40 mL), washed with water (25 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, 45 g), eluting with acetonitrile/methylene chloride (7.5/92.5), and those 35 fractions with an R,= 0.64 by TLC (acetonitrile/methylene chloride, 20/80) were pooled and concentrated to give (S)-3-[ 3 -fluoro-4-(tetrahydro- 1,1-dioxido-2H -52- WO 00/32599 PCT/US98/25308 thiopyran-4-yl)phenyll-5-isothiocyanatomethyl-2-oxazolidinone, mp 158 - 162o C (dec.). Step 2: A solution of (S)- 3 -[3-fluoro-4-(tetrahydro-1,1-dioxido-2H 5 thiopyran-4-yl)phenyl-5-isothiocyanatomethyl-2-oxazolidinone (Step 1, 380 mg, 0.988 mmol) in anhydrous tetrahydrofuran (49 mL) at 00C under a nitrogen atmosphere was treated (bubbled) with a stream of ammonia gas for 5 minutes. The reaction pot was sealed, and the resulting mixture was stirred at OOC for 1 hour. The excess ammonia was then removed under a stream of nitrogen, and the reaction mixture 10 was concentrated in vacuo to give the crude product. Recrystallization from methanol/methylene chloride/diethyl ether gave the title compound, mp 196 - 198 0 C (dec.). EXAMPLE 13: (S)-N-[[ 3

-[

3 -Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5 15 oxazolidinyl]methyl]-thioformamide (7). 0 0 1. O/N ~ NO HCOOH /--N N F- _Q H AcO \jF Q H 20NH 2 "NHCHO 20 39 6 A stirred mixture of acetic anhydride (0.23 mL, 0.0024 mol) and 95-97% formic acid (0.10 mL, 0.0027 mL) was warmed, under nitrogen at 50-55 oC for 2 h, cooled to 25 ambient temperature and treated, portionwise during 2 min, with 398 (0.45 g, 0.0015 mol). The suspension was kept at ambient temperature for 4 h and the resulting solution was treated with Et 2 0 (1 mL) and kept at ambient temperature for 18 h. The mixture was diluted with additional Et 2 O (10 mL) and the solid was collected by filtration, washed with EtO and dried to give 0.38 g of 69: MS (ES) m/z 324 30 (M+H*), 346 (M+Na+); 'H NMR (300 mHz, CDC:) d 3.08 (m, 4H), 3.72 (min, 2H), 3.77 (d,d, 1H), 3.89 (min, 4H), 4.04 (t, 1H), 4.80 (min, 1H), 6.33 (s, 1H), 7.05 (min, 2H), 7.45 (d,d, 1H), 8.27 (s, 1H). 35 -53- WO 00/32599 PCT/US98/25308 2. s OCHO , .OCHO 0 S"1 F NHCHO dioxane NNH-CHS NH-CHS 5 6 7 A stirred mixture of 6 (0.38 g, 0.00118 mol) in dioxane (20 mL), under nitrogen was treated with 4 (0.51 g, 0.00126 mol), warmed to reflux during 30 min and kept at 10 this temperature for 90 min. It was then evaporated under a stream of nitrogen. The residue was chromatographed on silica gel with 1.25% MeOH-CH 2 C1 2 and the slightly impure product was rechromatographed on silica gel with 25% EtOAc

CH

2 C1 2 . The resulting product was crystallized from EtOAc-methyl tert-butyl ether to give 0.114 g of 7: mp 150-155 'C (dec); IR (DRIFT) 3322, 1752 cm- 1 ; MS(ES) m/z 15 340 (M+H'), 362 (M+Na'); 'HNMR [300 MHz, (CD 3

)

2

SO

] d 2.94 (min, 4H), 3.72 (m, 4H), 3.77 (d,d, 1H), 3.94 (t, 2H), 4.12 (t, 1H), 4.93 (min, 1H), 7.05 (t, 1H), 7.16 (d,d, 1H), 7.47 (d,d, 1H), 9.33 (d, 1H), 10.59 (s, 1H). Anal. calcd for C 5

H

18 sFN 3 0 3 S: C, 53.08; H, 5.35; N, 12.38. Found: C, 53.02; H, 5.44; N, 12.36. 20 EXAMPLE 14: (S)-N-[[ 3

-[

3 -Fluoro-4-(4-morpholinyl)phenyl]-.2.-oxo-5 oxazolidinyl]methyl]thiopropion-amide (9). 1. 0 0

CH

3

CH

2 COCI O N NO 0O N NO 25 F H Et 3 N F H

NH

2

NH-C-CCH

3 CH 39 An ice cold, stirred solution of 39 (0.395 g, 0.00134 mol) and triethyl amine (0.186 mL, 0.0027 mol) in CH 2 C1 2 (20 mL), under nitrogen was treated, dropwise during 2 30 min, with a solution of propionyl chloride (0.128 mL, 0.00147 mol) in CH2C1 2 (3 mL). The mixture was kept in the ice bath for 20 min and at ambient temperature for 1 h. It was then diluted with CH 2 C1 2 , washed with saturated NaHCO 3 , water and brine, dried (MgSO 4 ) and concentrated. The residue (8) was used without further purification in the next reaction. 35 -54- WO 00/32599 PCT/US98/25308 2. S 0" 1- 1F

-

a °c 0 &l NA 0 ' S ---- 0NO k./ ,H 0 "-/H S 1--' 11C H F I , 1 5N+c-xa-pt r"+C--1 2 a-1 3 8 9 A stirred mixture of the product (8) from the previous reaction and dioxane (20 mL), under nitrogen, was treated, portionwise during 1 min, with Lawesson's reagent (0.58 g, 0.0014 mol) and refluxed for 2 h; it was then concentrated. The residue was chromatographed on silica gel with 2% MeOH-CHC13 and the product was 10 crystallized from methyl tert-butyl ether to give 0.259 g of 9: mp 138-139 'C; MS(ES) m/z 368 (M+H'), 390 (M+Na+); IR (DRIFT) 3284, 3266, 1748, 1744 cm'; [a] 24 D +200 (MeOH); 1H NMR[300 MHz, (CD 3

)

2

SO

] d 1.12 (t, 3H), 2.56 (q, 2H), 2.94 (min, 4H), 3.72 (min, 4H), 3.78 (d,d, 1H), 3.90 (t, 2H), 4.11 (t, 1H), 4.93 (min, 1H), 7.05 (t, 1H), 7.16 (d,d, 1H), 7.47 (d,d, 1H), 10.30 (broad s, 1H). Anal. calcd for 15 C 17

H

22

FN

3 0 3 S: C, 55.57; H, 6.03; N, 11.44. Found: C, 55.68; H, 6.21; N, 11.37. EXAMPLE 15: (S)-N- [ [ 3

-[

3 -Fluoro-4-(4-morpholinyl)phenyl]-.2.-oxo-.5. oxazolidinyl]methyl]-2-chlorothioacetamide (11). 20 1. 0 0 r--\

ACICH

2 COC 0 ON! \NO aON' N \ F -H Et 3 N *H

NH

2

"NH-C-CH

2 Cl 39 10 25 A stirred solution of 39 (1.54 g, 5.2 mmol) and triethylamine (750 mg, 7.5 mmol) in

CH

2 C1 2 (50 mL), under nitrogen, was treated, dropwise, during 15 min with a solution of chloroacetyl chloride (465 mL, 5.8 mmol) in CH 2 C1 2 (30 mL) and kept at ambient temperature for 18 h. It was then washed with saturated NaHCO 3 and dilute NaC1, dried (Na 2

SO

4 ) and concentrated. The residue was flash 30 chromatographed on silica gel with 20-30% acetone-CH 2 C1 2 to give 1.49 g of 109 which was used in the next reaction without further purification. -55- WO 00/32599 PCT/US98/25308 2. S 2. O3 HO S a O \ H 50 C a p- 0 ,, 0\+-± N-J+CN-Q 0N- vp 10 11 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 for 2 h and concentrated under reduced pressure. The residue was chromatographed on silica gel with 3-10% 10 acetone-CH 2 C1 2 to give 0.143 g of 11: MS (CI) m/z 388 (M+H+); 'H NMR (300 MHz,

CDCI

3 ) d 3.07 (min, 4H), 3.77 (d,d, 1H), 3.88 (min, 4H), 4.04 (min, 1H), 4.12 (t, 1H), 4.35 (min, 1H), 4.61 (s, 2H), 4.98 (min, 1H), 6.96 (t, 1H), 7.08 (d,d, 1H), 7.44 (d,d, 1H), 8.69 (s, 1H). Anal. calcd for C,,H,,CIFN 1 OS: C, 49.55; H, 4.94; N, 10.83. Found: C, 49.38; H, 5.20; N, 10.27. 15 EXAMPLE 16: (S)-N-[[3-[3-Fluoro-4-(4-moropholinyl)phenyl].-2-oxo-.5.

oxazolidinyl]methyll- ,a,-trifluorothioacetamide (13). 1. 20 O O

(CF

3

CO)

2 0 0 O N NO 0O N NO F HEt 3 N F H I

NH

2 F-NH-C-CF 3 39 12 25 An ice cold stirred solution of 39 (0.590 g, 2.0 mmol) and triethylamine (640 mL, 4.6 mmol) in CH2C1 2 (10 mL) was treated with trifluoroacetic anhydride (325 mL, 2.3 mmol) and kept in the ice bath for 10 min and then at ambient temperature. The reaction was followed by TLC on silica gel with 30% acetone-CH 2

CL

2 . Additional trifluoroacetic anhydride and triethylamine were added after 3 d (64 mL / 125 mL), 30 4 d (100 mL / 220 mL) and 6 d (325 mL / 1.0 mL). The reaction was complete 1 h after the last addition; it was mixed with CHCI, washed with water and dilute NaCl, dried (Na.,SO 4 ) and concentrated. The solid residue was recrystallized from acetone-heptane to give 0.566 g of 12: mp 161-164 oC (dec); MS(EI) m/z 391 (M'). Anal. calcd for C16H, 7

F

4

N

3 0 4 : C, 49.11; H, 4.38; N, 10.74. Found: C, 48.99; H, 4.56; 35 N, 10.73. -56- WO 00/32599 PCT/US98/25308 S 2. O o OC OH S HS 5 1 J+C-GF 3 13 N+ C- CF 3 12 13 A stirred mixture of 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 for 2 h, cooled slowly to ambient temperature and concentrated in vacuo. The residue was flash 10 chromatographed on silica gel with 5-15% acetone-CH.,C1, and the product was crystallized from acetone-heptane to give 0.249 g of 13: mp 151-152 oC; MS(EI) m/z 407 (M-), 363, 209, 151, 95; 1 H NMR (300 MHz, CDC1 3 ) d 3.05 (min, 4H), 3.75 (d,d, 1H), 3.87 (m, 4H), 3.95 (m, 1H), 4.14 (t, 1H), 4.32 (min, 1H), 5.01 (min, 1H), 6.92 (t, 1H), 7.05 (d,d, 1H), 7.38 (d,d, 1H), 9.03 (s, 1H). Anal. calcd for C,H, 1 7

F

4 N.0 3 S: C, 47.17; 15 H, 4.21; N, 10.31. Found: C, 47.09; H, 4.35; N, 10.27. EXAMPLE 17: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2.-oxo-.5.

oxazolidinyl]methyl]-o-fluorothioacetamide (15). O O 20 1. ON /--- FCH 2 COC /--NO N NO 0 N N F H Et 3 N F 0

FNH

2

NH-C-CH

2 F 39 14 A stirred, ice cold solution of 39 (0.590 g, 2.0 mmol) and triethylamine (611 mL, 4.4 25 mmol) in CHIC1 2 (10 mL), under nitrogen, was treated, dropwise, with a solution of fluoroacetyl chloride (220 mL, 2.2 mmol) in CH 2 C1 2 (5 mL), kept in the ice bath for 10 min and at ambient temperature for 2 h. It was then diluted with CH 2 C1 2 , washed with water and dilute NaC1, dried (Na,SO 4 ) and concentrated. The residue was chromatographed on silica gel with 10-30% acetone-CH,Cl, to give 0.180 g of 14: 30 MS(ES) m/z 356 (M+H'), 378 (M+Na'). 2. s 0 CH3O--. - .. \-OCH 3 0_ N S 0 N0 s N N S \N N * H 0 N N O S 35 14 NH--CHF

NH-C-CH

2 F -57-15 -57- WO 00/32599 PCT/US98/25308 A solution of 14 (0.180 g, 0.507 mmol) in dioxane, under nitrogen, was treated with Lawesson's reagent (0.206 g, 0.51 mmol), warmed at 90-100 oC for 1 h and concentrated in vacuo. The residue was chromatographed on silica gel with 15% acetone-CHCl1 2 to give 0.161 g of 15: MS(EI) m/z 371 (M'); 'H NMR (300 MHz, 5 CDCI: 1 ) d 3.05 (m, 4H), 3.78 (d,d, 1H), 3.87 (m, 4H), 4.03 (min, 1H), 4.11 (t, 1H), 4.38 (m, 1H), 4.98 (min, 1H), 5.07 (s, 1H), 5.23 (s, 1H), 6.93 (t, 1H), 7.08 (dd, 1H), 7.42 (d,d, 1H), 8.42 (s, 1H). Anal. calcd for C, 6

H,

9

F.N

3 0 3 S: C, 51.74; H, 5.16; N, 11.31. Found: C, 51.79; H, 5.31; N, 11.02. 10 EXAMPLE 18: (S)-N-[[ 3

-[

3 -Fluoro-4-(4-morpholinyl)phenyl]-.2.-oxo-5 oxazolidinyl]methyl]-t,o*x-difluorothioacetamide (17). 1. O O / 1OEDC-HCI A O N- N O + F2CHCOOH 0 O N-Y N O 15 F H oo HOBT LoF H 39

NH

2

NH-C-CHF

2 39 16 A stirred, ice cold mixture of 39 (0.590 g, 2.0 mmol), difluroacetic acid (190 mL, 2.0 mmol), and 1-hydroxybenzotriazole (0.297 g, 2.2 mmol) in DMF (5 mL) under 20 nitrogen, was treated with 1-( 3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.843 g, 4.4 mmol) and kept at ambient temperature for 18 h. It was diluted with CH,CI 2 , washed with water and dilute NaC1, dried (Na 2

SO

4 ) and concentrated. The solid residue was crystallized form EtOAc-heptane to give 0.617 g of 16: mp 149-150 oC; 1H NMR (300 MHz, CDC13) d 3.05 (m, 4H), 3.66 (min, 2H), 25 3.85 (min, 5H), 4.08 (t, 1H), 4.80 (m, 1H), 5.93 (t, J = 53.9 Hz, 1H), 6.92 (t, 1H), 7.06 (min, 2H), 7.39 (d,d, 1H); MS(EI) m/z 373 (M'). Anal. calcd for C 1 6 H,FN:,0 4 : C, 51.48; H, 4.86; N, 11.26. Found: C, 51.59; H, 4.91; N, 11.29. 2. 30 O O 0 N NO 4 0 N N H S F 0HHFS -- NH-C-CHF 2 F-NH-C-CHF 2 16 17 35 A stirred solution of 16 (0.373 g, 1.00 mmol) in dioxane (10 mL), under nitrogen was treated with Lawesson's reagent (0.404 g, 1.00 mmol), warmed at about 95 'C for 1 -58- WO 00/32599 PCT/US98/25308 h and concentrated in vacuo. Chromatography of the residue on silica gel with 10% acetone-CHC, and cyrstallization of the product from EtOAc-heptane gave 0.276 g of 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 MHz, CDCl1 3 ) d 3.05 (min, 4H), 3.76 (d,d, 1H), 3.86 (m, 4H), 4.01 5 (m, 1H), 4.12 (t, 1H), 4.30 (m, 1H), 4.99 (m, 1H), 6.20 (t, J = 55.9 Hz, 1H), 6.92 (t, 1H), 7.06 (d,d, 1H), 7.38 (d,d, 1H), 8.78 (broad s, 1H). Anal. calcd for C 16

H

1 aF 3

N

3 0 3 S: C, 49.35; H, 4.66; N, 10.79. Found: C, 49.37; H, 4.71; N, 10.83. EXAMPLE 19: (S)-N-[[ 3 -[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5. 10 oxazolidinyl]methyl]-ca-cyanothioacetamide (19). 1. 0 o 0 N N O + N=CCH 2 COOH EDCH N N -t-0 NOB \ / H 0 15 F F HOT 15

NH

2 NH-C-CH 2 CN 39 18 An ice cold, stirred mixture of 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), under 20 nitrogen, was treated with 1-( 3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.997 g, 5.2 mmol) and kept at ambient temperature for 24 h. It was diluted with CH2C1 2 , washed with water and dilute NaC1, dried (Na 2

SO

4 ) and concentrated. The solid residue was crystallized from EtOAc-heptane to give 0.546 g of 18: mp 172-174 °C: IR (DRIFT) 3316, 2256, 1754, 1684 cm '; MS(EI) m/z 362 25 (M*). Anal. calcd for C 1 7

H

1 qFN 4 04: C, 56.35; H, 5.28; N, 15.46. Found: C, 56.33; H, 5.30; N, 15.36. 2. 8 30 0 cxs Q IP ' A S 0 N- -')-No0D F F ",C -C-I4CN A stirred solution of 18 (0.453 mg, 1.25 mmol) in dioxane (10 mL), under nitrogen, 35 was treated with Lawesson's reagent (0.505 g, 1.25 mmol) and warmed at about 100 oC. When the reaction was over (TLC with 30% acetone-CH,Cl,) the mixture was -59- WO 00/32599 PCT/US98/25308 cooled and concentrated in vacuo. Chromatography of the residue on silica gel with 10-20% acetone-CHCl, and crystallization of the product from EtOAc-heptane gave 0.110 g of 19: mp 186-187 'C (dec); MS(ES) m/z 379 (M+H*), 401 (M+Na'); 'H NMR (300 MHz, CDCI 3 ) d 3.05 (min, 4H), 3.81 (d,d, 1H), 3.86 (min, 4H), 3.89 (s, 2H), 4.09 (t, 5 1H), 4.14 (min, 2H), 5.01 (min, 1H), 6.92 (t, 1H), 7.05 (d,d, 1H), 7.34 (d,d, 1H), 9.15 (s, 1H); IR (DRIFT) 3244, 2260, 1754 cm'. Anal. calcd for C1 7 H19FN 4 0 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 10 oxazolidinyl]methyl]-cx,-dichlorothioacetamide (21). 1. 0 0 (Cl 2

CHCO)

2 0 A ON NO sON NO 15 H Et 3 N F 39

NH

2 20

NH-C-CHC

2 39 A stirred, ice cold solution of 39 (0.885 g, 3.00 mmol) and triethylamine (975 mL, 7 mmol) in CH 2

CI

2 (15 mL), under nitrogen was treated, dropwise with a solution of 20 dichloroacetic anhydride (555 mL, 3.5 mmol) in CH 2 C1 2 (5 mL) and kept in the ice bath for 15 min and at ambient temperature for 18 h. It was diluted with CH 2

CI

2 , washed with water, saturated NaHCO 3 and dilute NaC1, dried (Na 2

SO

4 ) and concentrated. Chromatography of the residue on silica gel with 10% acetone-CH 2 C12 and crystallization of the product from acetone-heptane gave 0.463 g of 20: mp 197 25 198 oC (dec); MS(ES) m/z 406 (M+H'), 428 (M+Na); 'H NMR (300 MHz, CDC1 3 ) d 3.05 (min, 4H), 3.75 (min, 3H), 3.86 (min, 4H), 4.07 (t, 1H), 4.83 (min, 1H), 5.94 (s, 1H), 6.92 (t, 1H), 7.06 (min, 2H), 7.41 (d,d, 1H). 2. o o 30 o N\ N O 0 N N O 0 H0 F F t N--H2 NH-C-CHC 2 21 NH-C-CHCI 2 20 21 A stirred solution of 20 (0.

3 05g, 0.75 mmol) in dioxane (5 ml), under nitrogen, was treated with Lawesson's reagent (0.

2 02g, 0.5 mmol), warmed at about 90'C for 1 35 hour, cooled and concentrated in vacuo. Chromatography of the residue on silica gel first with 30% acetone-heptane and then with 10% acetone-methylene chloride and -60- WO 00/32599 PCT/US98/25308 crystallization of rh product form methylene chloride - heptane gave 0.203g with 21: mp 143-144°cd.; HR17S (EI) calculated for C,6H 1 8 cl F N 3 03 S(M) 421.0431. Anal. calcd for C16H, 8 cl F N 3 03 S, C, 45.51; H, 4.30; N, 9.95. Found: C, 45.47; H, 4.24; H, 9.88. 5 EXAMPLE 21: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-(-(methoxycarbonyl)thioacetamide (23). 1. o o 10 ON oN CH 3

OCH

2 COC ON N F \QEtNF 01 39 "NH 2 22 NH-C-CH 2

COOCH

3 A stirred solution of 39 (0.955 g, 3.2 mmol) and triethylamine (650 mL, 4.5 mmol) in 15 CH 2 C1 2 (50 mL), under nitrogen, was treated, dropwise during 15-20 min with a solution of methyl malonyl chloride (475 mL, 4.3 mmol) in CH 2 C1 2 (10 mL) and kept at ambient temperature for 3 days. It was then washed with water and dilute NaC1, dried and concentrated. The residue was flash chromatographed on silica gel with 15-30% acetone-CH 2 C1 2 and the product was crystallized form acetone-hexane to give 20 0.873 g of 22: mp 150-151 oC; 'H NMR (300 MHz, CDC13) d 3.03 (m, 4H), 3.34 (s, 2H), 3.67 (s, 3H), 3.69 (m, 2H), 3.76 (d,d, 1H), 3.85 (m, 4H), 4.00 (t, 1H), 4.78 (m, 1H), 6.90 (t, 1H), 7.06 (d,d, 1H), 7.41 (d,d, 1H), 7.57 (t, 1H); MS(ES) m/z 396 (M+H*), 418 (M+Na'); HRMS (FAB) calcd for CH 23 FN:,0 6 (M+H*) 396.1571, found 396.1579. Anal. calcd for Cs, 8

H

22

FN

3 0 6 : C, 54.68; H, 5.61; N, 10.63. Found: C, 25 54.69; H, 5.68; N, 10.58. 2. s CH30--o -P S / / \-OC H 3 0 S s II - 0 30 30 F~' \--t 1 F 22 NH-C-CH 2

COOCH

3 23 NH-C-CH2COOCH3 A stirred solution of 22 (0.395 g, 1.0 mmol) in dioxane (10 mL), under nitrogen, was treated with Lawesson's reagent (0.202 g, 0.5 mmol) and kept at ambient 35 temperature for 4 h 10 min and at 80-90 oC for 1.5 h. The reaction was followed by TLC on silica gel with 10% MeOH-CHC1,. At this time a new, less polar product -61- WO 00/32599 PCT/US98/25308 had begun to form. It was kept at ambient temperature for 18 h and at 80 oC for 2 h; additional Laewsson's reagent (40 mg, 0.099 mmol) was added and warming at 80 °C was continued for 2 h; some starting material still remained. The mixture was concentrated and the residue was chromatographed on silica gel with 15% acetone 5 CH 2 C1, to give 0.348 g of 23: 'H NMR (300 MHz, CDC13) d 3.05 (m, 4H), 3.71 (s, 3H), 3.81 (d,d, 1H), 3.86 (min, 4H), 3.88 (s, 2H), 4.07 (t, 1H), 4.19 (m, 2H), 4.99 (inm, 1H), 6.91 (t, 1H), 7.07 (d,d, 1H), 7.42 (d,d, 1H), 9.52 (s, 1H); IR (DRIFT) 3269, 1743 cm'1; MS(EI) m/z 411 (M*). Anal. calcd for CisH 2 2

FN:

3 0 5 S: C, 52.54; H, 5.39; N, 10.21. Found: C, 52.58; H, 5.43; N, 10.14. 10 EXAMPLE 22: (S)-N-[[3-[4-[ 1-[1, 2 ,4]Triazolyl]phenyl-2-oxo-.5.

oxazolidinyl]methyl]thioacetamide (25). O s O N:N / \ N O + MeO --------- OMe N N / O S N =/ \ / I' s 'N' H S 15

NHCOCH

3 F NH-C-CH 24 25 3 A stirred mixture of 24 (0.150 g, 0.470 mmol) and dioxane (12.5 mL), under nitrogen, was treated with Lawesson's reagent (0.20 g, 0.50 mmol), refluxed for 1.5 h, kept at ambient temperature for 18 h and concentrated in vacuo. Flash 20 chromatography of the residue on silica gel with 5% MeOH-CHC13 gave the product which was crystallized from MeOH to give 0.100 g (63.4%) of 25: mp 161-163 oC; 'H NMR [300 MHz, (CD 3

)

2

SO

] d 2.43 (s, 3H), 3.87 (min, 3H), 4.22 (t, 1H), 4.99 (min, 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'; MS(ES) m/z 336 (M+H'), 358 (M+Na'). Anal. calcd for 25 C, 4

H,

4 FNO,,S: 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 (25). S 30 0 O I N N00 N N Oz / KOH/NaF NN S H EtOH/H 2 0 1 S F

NH

2 F 335.36

NH-C-CH

3 277.27 35 26

C

1 4

H

14

FN

5 0 2 S 25 -62-35 26 25 -62- WO 00/32599 PCT/US98/25308 A stirred mixture of 26 (0.26 g, 0.938 mmol), ethyl dithioacetate (0.12 g, 0.998 mmol), sodium fluoride (0.040 g, 0.953 mmol) and absolute EtOH (10 mL), under nitrogen, was treated during 5 min with a solution of 0.97 M KOH (1.03 mL) in EtOH and kept at ambient temperature for 2 h. It was then diluted with CH 2

CL

2 5 (75mL), washed with water, IM KHSO 4 , water and brine and evaporated. The residue was flash chromatographed on silica gel with 5% MeOH-CHC13 and the product was crystallized from MeOH to give 0.118 g, mp 164-165 0 C (dec) and 0.026 g, mp 162-163oC (dec) of 25. 10 EXAMPLE 24: (S)-N-[[3-[1-(Hydroxyacetyl)-5-indolinyll-2-oxo5 oxazolidinyl]methyl]thioacetamide (28). 1. Boc 15 \N 1. TFA N NHCbz 1CH2C2 NHCbz 2. NaHCO 3 52 53 A stirred, ice cold solution of 52 (8.80 g, 0.0240 mol) in CH 2 C1 2 (25 mL) was treated 20 during 20 min with a solution of trifluoroacetic acid (25 mL) in CH 2 C1 2 (10 mL). The mixture was kept in the ice bath for 2 h 15 min and concentrated under reduced pressure. A solution of the residue in CH 2 C1 2 was washed with saturated NaHCO 3 and dilute NaC1, dried (NaSO 4 ) and concentrated. The residue was used in the next reaction without further purification. A sample of this material (53) had: 1 H NMR 25 (300 MHz, CDCI:) d 3.00 (t, 2H), 3.54 (t, 2H), 3.85 (broad s, 1H), 5.17 (s, 2H), 6.59 (d, 1H), 6.66 (broad s, 1H), 6.91 (d, 1H), 7.23 (s, 1H), 7.36 (min, 5H); MS m/z 269 (M+H'). 2. BzO-CH 2 -C=O 30 H N BzOCH 2 COCI N NaHCO 3 NHCbz (CH 3

)

2

CO/H

2 0 NHCbz 268.22 416.48 C16H16N202 0 25

H

2 4

N

2 0 4 53 54 -63- WO 00/32599 PCT/US98/25308 An ice cold, stirred mixture of 53 (crude product from the previous reaction), acetone (200 mL), saturated NaHCO 3 (200 mL) and water (30 mL) was treated, dropwise during 20 min, with a solution of benzyloxyacetyl chloride (4.70 mL, 0.030 mol) in acetone (55 mL), warmed slowly to ambient temperature and kept for 18 h. 5 Additional benzyloxytacetyl chloride (1.0 mL) in acetone 35 mL) was added dropwise and the mixture was kept at ambient temperature for an additional 3 h and diluted with EtOAc and water. A 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 5.36 g of additional crude product. Crystallization of the product from EtOAc gave a 10 total of 6.35 g of 5414, mp 157-159.5oC. The analytical sample had: mp 158-159.5 0 C; 'H NMR (300 MHz, CDCI 3 ) 5 3,16 (t,2H), 4.01(t,2H), 4.21 (s, 2H), 4.69 (s, 2H), 5.19 (s, 2H), 6.67 (s, 1H), 6.97 (d, 1H), 7.36 (min, 10H), 7.50 (braod s, 1H), 8.15 (d, 1H); MS(EI) m/z (relative intensity) 416 (M, 9), 310 (8), 202 (10), 133 (8), 92 (8), 91 (99), 79 (7), 77 (9), 65 (12), 51 (6); IR (mull) 2381, 1722, 1659, 1608, 1558 cm'. Anal. 15 calcd for CH 2 ,4N 2 0 4 : C, 72.10; H, 5.81; N, 6.73. Found: C, 72.05; H, 5.86; N, 6.68. 3. BzO-CH 2 -C=O BzO-CH 2 -C=O 1 1. nBuLi 20 N 5 N 0 20NHCbz 2. -N 416.48 OC 382.42 H 54 "H 021H 2 2

N

2 0 5 OH 55 25 A stirred suspension of 54 (1.16 g, 2.78 mmol) in THF (42 mL) was cooled, under nitrogen, to -78oC and treated, dropwise, during 5 min with 1.6 M n-BuLi in hexane (1.83 mL). It was kept at -78 0 C for 50 min, treated, dropwise, during 5 min with a solution of (R)-(-)-glycidyl butyrate (0.500 g, 3.47 mmol) in THF (2 mL), allowed to warm to ambient temperature during 3 h and kpet for 18 h. It was then diluted 30 with EtOAc, washed with saturated NH 4 C1, water and brine, dried (MgSO 4 ) and concentrated. Chromatography of the residue on silica gel with 3% MeOH-0.2%

NH

4 OH-CHC:l 3 gave 0.60 g (56%) of 5514: 'H NMR [300 MHz, (CD:3),SO] 6 3.14 (t, 2H), 3.59 (min, 2H), 3.79 (d,d, 1H), 4.03 (min, 3H), 4.29 (s, 2H), 4.58 (s, 2H), 4.65 (inm, 1H), 5.20 (t, 1H), 7.31 (min, 6H), 7.55 (s, 1H), 8.03 (d, 1H); MS(ES) m/z 383 (M+H'), 35 405 (M+Na'). -64- WO 00/32599 PCT/US98/25308 4. NO2 BzO-CH 2 -C=0 N0 2 BzO-CH 2 -C=O I I N 0 SO 2 CI 5 N 0 H Et 3 N S2N 0H 5HOH 56 -- O-Nos 55 An ice cold, stirred mixture of 55 (0.60 g, 1.57 mmol), triethylamine (2.2 mL), and CHC1 2 (12 mL), under nitrogen, was treated with 3-nitrobenzenesulfonyl chloride (0.44 g, 1.99 mmol) and kept in the ice bath for 30 min and at ambient temperature 10 for 60 min. It was then diluted with CHC12, washed with water and brine, dried (NaSO 4 ) and concentrated. Chromatography of the residue on silica gel with 15%

CH

3

CN-CH

2 C1 2 gave 0.70 g of 56: 'H NMR (300 MHz, CDCI 3 ) d 3.19 (t, J = 8.3 Hz, 2H), 3.88 (d,d, 1H), 4.04 (t, J = 8.4 Hz, 2H), 4.14 (t, 1H), 4.23 (s, 2H), 4.42 (m, 2H), 4.70 (s, 2H), 4.84 (min, 1H), 6.97 (m, 1H), 7.34 (m, 5H), 7.58 (s, 1H), 7.81 (t, 1H), 8.22 15 (m, 2H), 8.53 (m, 1H), 8.73 (m, 1H); MS(ES) m/z 568 (M+H ), 590 (M+Na'). 5. BzO-CH 2 -C=O BzO-CH 2 -C=O I I 20 NHO N NO 20 N A,0 H H3 A 0 56 -ONos 57 NH 2 A stirred mixture of 56 (crude product from 0.00314 mol of 55), acetonitride (70 mL), isopropanol (70 mL) and 29% ammonium hydroxide (70 mL) was warmed at 40-44 25 oC for 7h and kept at ambient temperature for 18 h. It was concentrated in vacuo to an aqueous residue with was extracted with CH 2 C1 2 . The extract was washed with water and brine, dried (Na 2

SO

4 ) and concentrated. Chromatography of the residue on silica gel with 8% MeOH-0.5% NH 4 OH-CHCl 3 gave 1.05 g of 57: 'H NMR [300 MHz, (CD 3

)

2 SO] d 2.78 (m, 2H), 3.13 (t, 2H), 3.82 (d,d, 1H), 4.01 (m, 3H), 4.29 (s, 30 2H), 4.58 (s, 2H), 4.58 (m, 1H), 7.31 (m, 6H), 7.54 (broad s, 1H), 8.03 (d, 1H); MS(ES) m/z 382 (M+H'), 404 (M+Na'). -65- WO 00/32599 PCT/US98/25308 6. HO CH 2 -C=0 BzO-CH 2 -C=O O O HO HCI N 0H2/Pd N 5;HO1 5 MeOH/HCI CN 0 N 0O 381.42 327.77 57 NH 2

C

14

H

1 8

CIN

3 0 4

NH

2 27 10 A mixture of 57 (0.46 g, 1.21 mmol), MeOH (150 mL), 1 M HCI (1.2 mL) and 5% palladium-on-carbon catalyst (250 mg) was hydrogenated at an initial pressure of 49 psi for 5 h. Additional 1M HC1 (0.5 mL) and catalyst (100 mg) were added and hydrogenation was continued for 18 h. The catalyst was removed by filtration and 15 the filtrate was concentrated to give 0.34 g of 27: 'H NMR [300 MHz, (CD 3

)

2 SO] 8 3.15 (t, 2H), 3.22 (broad s, 2H), 3.84 (d,d, 1H), 4.00 (t, 2H), 4.15 (s, 2H), 4.15 (m, 1H), 4.92 (min, 1H), 7.24 (q, 1H), 7.50 (d, 1H), 8.03 (d, 1H), 8.37 (broad s, 3H); MS(ES) m/z 2.92 (M+H*). 20 7. HO CH 2 -C=O S HO CH 2 -C=O I SI C CH 3 -C -SEt N O N 0 HNaF, KOH N 0 s 27 NH2 28 H-\INH -C-CH 3 25 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 added, under nitrogen to a stirred mixture of ethyl dithioacetate (0.0412 g, 0.343 mmol) and sodium fluoride (0.0137 g, 0.326 mmol) in EtOH (5 mL) 30 and the mixture was kept at ambient temperature for 2h 15 min. 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, mixed with CH,C1, (150 mL), washed with water, 1M KHSO 4 and brine, dried (Na,,SO4) and concentrated. The residue was crystallized from acetone to give 0.0404 g of 28: mp 175-176 oC (dec); MS (FAB) 35 m/z 350 (M+H'), 349 (M), 331, 316, 205, 73; HR MS (FAB) calcd for C 16

H

20 N:,04S (M+H*) 350.1174, found 350.1183; 'H NMR [300 MHz, (CD:,),SO] d 2.42 (s, 3H), 3.14 -66- WO 00/32599 PCT/US98/25308 (t, 2H), 3.79 (d,d, 1H), 3.89 (t, 2H), 4.00 (t, 2H), 4.12 (m, 3H), 4.83 (t, 1H), 4.90 (inm, 1H), 7.25 (d, 1H), 7.50 (s, 1H), 8.03 (d, 1H), 10.35 (s, 1H); IR (DRIFT) 3255, 3223, 3068, 1747, 1639, 1614 cm -1 . 5 EXAMPLE 25: (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(hydroxyacetyl)-.1 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (30). 1. 0 0 10 Cbz-N N -- O N HO H 2 /Pd H N 1 - N N O ..- 1H Et H__HF... F OH F OH 58 59 15 A mixture of 58 (3.00 g, 7.00 mmol), THF (60 mL), absolute EtOH (100 mL) and 10% palladium-on-carbon catalyst (415 mg) was hydrogenated at an initial pressure of 58 psi for 2 h 50 min. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 2.67 g of 59 which was used without further purification in the next reaction: 'H NMR (300 MHz, CDC1 3 ) d 2.16 (broad s), 3.02 20 (min, 8H), 3.73 (d,d, J = 3.9, 12.6 Hz, 1H), 3.96 (min, 3H), 4.72 (min, 1H), 6.92 (t, J = 9.2 Hz, 1H), 7.11 (m, 1H), 7.43 (d,d, J = 2.6, 14.3 Hz, 1H); MS(ES) m/z 296 (M+H+). 2. o 0 /--\ A PhCH20CH2COCl -\ HNN / N O HHC3C BzOCH 2 -C-N N/ \N 25p OH NaHCO3 FH 25 F - H (CH3)2CO / H 2 0 F 60 59 60 A stirred, ice cold mixture of 59 (2.67 g from the previous reaction), acetone (190 mL) and saturated NaHCO, (70 mL) was treated, dropwise during 2-3 min with a 30 solution of benzyloxyacetyl chloride (1.34 mL, 8.61 mmol) in acetone (25 mL), kept in the ice bath for 1 h and diluted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic solution was washed with dilute NaC1, dried and concentrated. Chromatography of the residue on silica gel with 30% acetone-CHC1 2 gave 2.64 g of 60: 'H NMR (300 MHz, CDCI.

3 ) d 2.28 (broad s, 1H), 3.00 (min, 4H), 35 3.66 (min, 2H11), 3.77 (min, 3H), 3.96 (min, 3H), 4.22 (s, 2H), 4.61 (s, 2H), 4.74 (m, 1H), 6.88 (t, J = 9.2 Hz, 1H), 7.12 (min, 1H), 7.35 (s, 5H), 7.46 (d,d, J = 2.6, 14.2 Hz, 1H); IR -67- WO 00/32599 PCT/US98/25308 (mull) 3406, 1748, 1647 cm'; HRMS(EI) calcd for C,:H 26

FN:,O

5 (M-) 443.1856, found 443.1842. 3. 5 oo o 0 II S/--\N A'_ <SOCI Et 3 N 11 /\ BzOCH 2 -C-N N \ N O + . BzOCH 2 -C-N N N 0 - \ . CH 2 C1 2 F -OH CH22 -ONos 60 NO2 77 10 A stirred, ice cold mixture of 60 (2.64 g, 6.00 mmol) and triethylamine (1.14 mL, 8.16 mmol) in CH 2 C1 (200 mL), under nitrogen, was treated with 3 nitrobenzenesulfonyl chloride (1.78 g, 8.04 mmol), warmed to ambient temperature and kept for 5 h 20 min. Additional 3-nitrobenzenesulfonyl chlroide (180 mg) and triethylamine (0.20 mL) were added and the mixture was kept at ambient 15 temperature for 18 h, diluted with CH 2 C1 2 and washed with water and dilute NaCl, dried (Na 2

SO

4 ) and concentrated. Chromatography of the residue on silica gel with 40-60% acetone-hexane gave 3.36 g of 77: 'H NMR (300 MHz, CDC1 3 ) d 3.02 (broad s, 4H), 3.66 (broad s, 2H), 3.78 (broad s, 2H), 3.87 (d,d, J = 5.9, 9.1 Hz, 1H), 4.09 (t, J = 9.2 Hz, 1H), 4.22 (s, 2H), 4.41 (m, 2H), 4.61 (s, 2H), 4.84 (min, 1H), 6.88 (t, J = 9.1 20 Hz, 1H), 7.02 (m, 1H), 7.35 (m, 6H), 7.82 (t, J = 8.0 Hz, 1H), 8.23 (m, 1H), 8.53 (m, 1H), 8.73 (m, 1H); MS(ES) m/z 629 (M+H*). 4. 0 0 0 0 O O O O 11 /-\ NH 4 0H I /- 25 BzOCH 2 -C-N N N O0 - BzOCH 2 -C-N N N 0 =/H - _H F H'-ONos F -NH 2 77 61 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 at 40-45 oC 30 for 18 h, treated with additional ammonium hydroxide (30 mL), warmed at 40-45 oC for 8 h, treated with additional ammonium hydroxide (25 mL) and warmed at 45 oC for 18 h. It was then mixed with water and extracted with CH.,Cl. The extract was washed with dilute NaC1, dried (Na.,SO 4 ) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-0.5% NH 4 OH-CHCI:, gave 2.44 g of 61: 'H NMR 35 (300 MHz, CDCI,) d 1.50 (broad s), 3.04 (m, 6H), 3.65 (broad s, 2H), 3.81 (min, 3H), 3.99 (t, 1H), 4.21 (s, 2H), 4.61 (s, 2H), 4.66 (min. 1H), 6.88 (t, 1H), 7.12 (m, 1H), 7.33 -68- WO 00/32599 PCT/US98/25308 (min, 5H), 7.47 (d,d, 1H); MS(ES) m/z 443 (M+H'). 5. S0 H 2 ,5% Pd / C 00 II -H\ II /---\ A BzOCH-C--NNHC 5 BzOCH 2 -C-N N NO - HOCH 2 -C-N N-/ \NO HCI H EtOH H F

NH

2 HCI F

NH

2 61 29 A solution of 61 (1.45 g, 3.3 mmol) and 1.0 N HCI (3.65 mL) in 95% EtOH (150 mL) was treated with 5% palladium-on-carbon catalyst (500 mg) and hydrogenated at an 10 initial pressure of 54 psi for 20 h 15 min. Additional 1.0 N HC1 (0.5 mL) and catalyst (100 mg) were added and hydrogenation was continued for 20 h 30 min at an initial pressure of 60 psi. The reaction was compete by TLC; it was neutralized with concentrated

NH

4 OH, filtered and concentrated in vacuo to give 1.18 g of 29: 'H NMR [300 MHz, (CD 3 ),SOI d 2.94 (broad s, 4H), 3.19 (min, 2H), 3.48 (broad s, 2H), 15 3.60 (broad s, 2H), 3.84 (min, 1H), 4.14 (min, 3H), 4.66 (broad s, 1H), 4.93 (min, 1H), 7.07 (t, 1H), 7.16 (d,d, 1H), 7.48 (d,d, 1H), 8.04 (broad s); IR (mull) 3420, 3099, 3040, 3008, 1755, 1641 cm'; MS(ES) m/z 353 (M+H*). Anal. calcd for C16H 2 2 ClFN 4 0 4 : 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. 20 6. 0 0 AI UCH 3 -C-SEt INI/-\Q HOCH,-C-N N- \)-N 0 HCI CHO -- SEt IHOCH2--N Ho-HHOCHN-N/--NNNO-- N \

,,

H KOH. NaF H - N S F

NH

2 F NH-G-CH 29 30 25 A stirred mixture of ethyl dithioacetate (180 mL, 1.56 mmol), sodium fluoride (72 mg, 1.7 mmol), 29 (500 mg, 1.29 mmol) and EtOH (70 mL) under nitrogen, was treated with 0.97M KOH (1.46 mL, 1.42 mmol) and the resulting solution was kept at ambient temperature for 3 h 35 min, diluted with CHCI:,, washed with water and dilute NaC1, dried (Na.,SO 4 ) and concentrated. Chromatography of the residue on 30 silica gel with 5% MeOH-0.5%

NH

4 OH-CHC1: 3 and crystallization of the resulting product from absolute EtOH gave 0.238 mg (44.9%) 30: mp 163-165 oC; 'H NMR (300 MHz, CDCI: 3 ) d 2.60 (s, 3H), 3.06 (min, 4H), 3.45 (min, 2H), 3.61 (min, 1H), 3.82 (inm, 3H), 4.07 (m, 2H), 4.25 (min, 3H), 4.97 (min, 1H), 6.91 (t, 1H), 7.07 (min, 1H), 7.45 (d,d, 1H), 7.91 (broad s, 1H); MS(FAB) m/z (relative intensity) 411 (M+H', 100), 410 (M+, 35 66.5), 266 (3.1); IR 3292, 1733, 1653 cm-'. Anal. calcd for ClsH 2 3

FN

4 0 4 S: C, 52.67; H, 5.65; N, 13.65. Found: C, 52.76; H, 5.58; N, 13.64. -69- WO 00/32599 PCT/US98/25308 EXAMPLE 26: (S)-N-[[ 3

-[

3 -Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-.5.

oxazolidinyl]methyl]thio-acetamide (32). 5 S 0 II 0 S N N AO CH 3 -C-SEt S/N N 0 F H Et3N H S F 31 -- HNH 2 F -NH-C-CH 3 31 32 10 An ice cold, stirred mixture of 31 (0.38 g, 0.0012 mol) and triethylamine (0.38 mL, 0.0027 mol) in THF (12 mL), under nitrogen, was treated with ethyl dithioacetate (0.16 mL, 0.0014 mol) and then kept at ambient temperature for 24.5 h and concentrated in vacuo. A solution of the residue in CH,Cl 2 was washed with saturated NaHCO,, water and brine, dried (MgSO 4 ) and concentrated. 15 Crystallization of the residue from EtOAc-hexane gave 0.355 g of 32: mp 155-156 'C; MS(ES) m/z 370 (M+H'), 392 (M+Na'); IR (DRIFT) 3206, 3042, 1759, 1738 cm ; 'H NMR (300 MHz, CDC1 3 ) d 2.60 (s, 3H), 2.95 (s, 4H), 3.43 (min, 4H), 3.82 (d, d, 1H), 4.08 (min, 2H), 4.27 (min, 1H), 4.98 (min, 1H), 7.06 (min, 1H), 7.33 (broad s, 1H), 7.51 (d, 1H), 8.03 (broad s, 1H). Anal. calcd for C, 6

H

20

FN

3 0 2

S

2 : C, 52.01; H, 5.46; N, 11.37. 20 Found: C, 51.86; H, 5.43; N, 11.20. EXAMPLE 27: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyll-2-oxo-5. oxazolidinyllmethyl]thio-acetamide, thiomorpholine S-oxide (34). 25 1. O O SN / 1--\ NalO 4 S N N O0o o=S N N o F HO MeOH / H 2 0 0=5 HO F OH F - -OH 62 63 30 An ice cold, stirred mixture of sodium metaperiodate (1.08 g, 5.05 mmol) and water (12 mL), under nitrogen, was treated with 62 (1.5 g, 4.8 mmol) and MeOH (17 mL) and kept at 6 oC for 18 h and at 4 oC for 3 h. It was then treated with additional sodium metaperiodate (0.1 g), kept at 4oC for 3 h and extracted with CHCI: 3 . The extract was dried (MgSO 4 ) and concntrated to give 1.4 g of 63: 'H NMR [300 MHz, 35 (CD,),,SO] d 2.84 (min, 2H), 3.01 (min, 2H), 3.16 (min, 2H), 3.50 (min, 3H), 3.65 (min, 1H), 3.77 (dd, 1H), 4.03 (t, 1H), 4.66 (min, 1H), 5.18 (t, 1H), 7.16 (min, 2H), 7.52 (min, 1H); -70- WO 00/32599 PCT/US98/25308 MS(ES) m/z 329 (M+H ), 351 (M+Na*).

NO

2 2. o so 2 O=S/--/N ! NAO H O=S N - N AO OH.. Et 3 NQ I- 1I

SCH

2 01 2 F ONos 63 78 An ice cold, stirred mixture of 63 (1.27 g, 3.87 mmol) and triethylamine (0.732 mL, 10 5.25 mmol) in CH 2 C1 2 (130 mL), under nitrogen, was treated with m nitrobenzenesulfonyl chloride (1.15 g, 5.19 mmol) and kept at ambient temperature for about 24 h. It was diluted with CH 2 C1 2 , washed with water and brine, dried (Na 2 SO,) and concentrated to give 78 which was used in the next reaction without purification. 15 0 o 3. O=S /--N \ N O

NH

4 OH O=S NN AO F _H CH 3 CN H F ONos (CH 3

)

2 CHOH F NH 2 78 33 20 A stirred mixture of the product (78) from the previous reaction, acetonitrile (70 mL) and isopropanol (70 mL) was treated with concentrated ammonium hydroxide (70 mL, 29.9% NH,) and kept at 40 oC for 2 h, at ambient temperature for 18 h and at 40-45 oC for 4 h; it was concentrated to about 50 mL, diluted with water and 25 extracted with CH 2 ,C1 2 . The extracts were washed with water and brine, dried (MgSO 4 ) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-CHC13 gave 0.58 g of 33: MS(ES) m/z 328 (M+H*), 350 (M+Na'); 'H NMR [300 MHz, (CD3) 2 SO] d 2.81 (min, 4H), 3.01 (min, 2H), 3.16 (min, 2H), 3.30 (broad s), 3.49 (min, 2H), 3.80 (d,d, 1H), 4.01 (t, 1H), 4.58 (min, 1H), 7.19 (min, 2H), 7.51 (min, 1H). 30 4. s 0 II 0 -- \ CH 3 -C-SEt O=S N N CH3-C-SEt O=S N N O S - ,H Et 3 N _ \/. ,,H S F HNH2 F

NH-C-CH

3 33 34 35 -71- WO 00/32599 PCT/US98/25308 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, under nitrogen, treated, dropwise during 2 min, with a solution of ethyl dithioacetate (1.47 mL, 0.0128 mol) in THF (2 mL) and kept at ambient temperature for 22 h. The resulting solution was 5 concentrated and the residue crystallized from acetonitrile to give 3.61 g of 34: mp 176-177 OC ; 'H NMR [300 MHz, (CD,) 2

SO

] d 2.42 (s, 3H), 2.85 (min, 2H), 3.01 (m, 2H), 3.18 (min, 3H), 3.50 (min, 2H), 3.78 (d,d, 1H), 3.89 (broad s, 2H), 4.12 (t, 1H), 4.92 (min, 1H), 7.18 (min, 2H), 7.49 (m, 1H), 10.33 (s, 1H); IR (DRIFT) 3186, 3102, 1741 cm1; MS(ES) m/z 386 (M+H'), 408 (M+Na'). Anal. calcd for Ci 6

H

2 0 FNO3 3

S

2 o0.5 H 2 0: C, 10 48.71; H, 5.37; N, 10.65; S, 16.26; H 2 0, 2.38. Found: C, 48.75; H, 5.17; N, 10.72; S, 16.07; H 2 0, 1.72. EXAMPLE 28: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]thio-acetamide, thiomorpholine S, S-dioxide (36). 15 1. O O SN -- N NA Os0 4 0 2 S N N OH \/ - -,,H NMO QH F -OH (CH 3

)

2 CO / H 2 0 F OH 20 62 64 A stirred mixture of 62 (0.399 g, 0.00128 mol) in 25% water/acetone (12 mL), under nitrogen was treated with N-methylmorpholine, N-oxide (0.45 g, 0.00384 mol) and 0.1 mL of a 2.5 wt% solution of osmium tetroxide in tert-butanol. It was kept at 25 ambient temperature for 18 h, mixed with saturated NaHSO, (50 mL) and extracted with CH 2 CI.,. The extract was washed with saturated NaHSO 3 and brine, dried (Na 2

SO

4 ) and concentrated. The residue was mixed with 3.5% MeOH-CHC1 2 and filtered; the solid was dissolved in 15% MeOH-CH 2 C1 2 and concentrated to give 0.29 g of 64. The filtrate was chromatographed on silica gel with 3.5% MeOH-CH 2 Cl12 to 30 give 0.1 of additional 64: MS(ES) m/z 345 (M+H+), 367 (M+Na'); 'H NMR [300 MHz, (CD 3

),SO

] d 3.26 (min, 4H), 3.44 (min, 4H), 3.60 (min, 2H), 3.80 (d,d, 1H), 4.05 (t, 1H), 4.69 (min, 1H), 7.22 (min, 2H), 7.54 (d, 1H). -72- WO 00/32599 PCT/US98/25308 2. O 1. S o 2 C O 0 2 N 0 2 =S N NO N 2N S N N 0 - \,.H Et 3 N O 2 =S\ - 'I H F ~O H 30 F HNH 2. NH 4 OH F

NH

2 5 64 35 A stirred mixture of 64 (0.39 g, 0.00113 mol) and triethylamine (0.214 mL, 0.00154 mol) in CHC1 2 (37 mL) was cooled, under nitrogen, in an ice bath and treated, 10 portionwise during 5 min, with 3-nitrobenzenesulfonyl chloride (0.335 g, 0.00151 mol). The mixture was kept in the ice bath for 20 min and at ambient temperature for 18 h and concentrated in vacuo. A stirred solution of the residue in 2-propanol (25 mL) and acetonitrile (25 mL), under nitrogen, was treated with 30% NH40H (25 mL), warmed at 50-55 oC for 6 h and kept at ambient temperature for 48 h. It was 15 concentrated to remove the organic solvents, diluted with water and extracted with

CH

2

CI

2 . The extract was washed with water and brine, dried (MgSO 4 ) and concentrated. Flash chromatography of the residue on silica gel with 6% MeOH 0.4% NH 4 OH-CHC13 gave 0.29 g of 35: 'H NMR [300 MHz, (CD3) 2 SO] d 1.59 (broad s, 2H), 2.78 (min, 2H), 3.24 (m, 4H), 3.43 (min, 4H), 3.81 (d,d, 1H), 4.01 (t, 1H), 4.57 (m, 20 1H), 7.18 (m, 2H), 7.52 (min, 1H); MS(ES) m/z 344 (M+H*), 366 (M+Na*). 3. s 0 II 0 0 2 =S N " N O CH 3 -C-SEt O 2 =S N O NAO S -j w..H Et 3 N F2=S H F -- NH 2 F

NH-C-CH

3 25 35 36 A stirred, ice cold suspension of 35 (0.28 g, 0.85 mmol) in a mixture of Et, 3 N (0.26 mL, 1.9 mmmol) and THF (10 mL) was treated with ethyl dithioacetate (0.11 mL, about 6 drops) and kept in the ice bath for 20 min and then at ambient temperature; the reaction was followed by TLC. After 20 h there was still a suspension and only 30 partial reaction; additional THF (10 mL) and ethyl dithioacetate (3 drops) were added. After an additional 48 h the reaction was still incomplete; the suspension was treated with CHC1 2 (10 mL) and kept for 72 h. At this time almost complete solution and an almost complete conversion to product had been obtained. An additional drop of ethyl dithioacetate was added and the mixture was kept at 35 ambient temperature for 5 d and concentrated in vacuo. The residue was mixed with EtOAc, washed with saturated NaHCO 3 , water and brine, dried (MgSO 4 ) and -73- WO 00/32599 PCT/US98/25308 concentrated. Crystallization of the residue from MeOH-EtOAc gave 0.209 g of 36: mp 197-198 'C; 'H NMR [300 MHz, (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, 1H), 4.92 (m, 1H), 7.18 (m, 2H), 7.50 (m, 1H), 10.37 (broad s, 1H); IR (mull) 3300, 3267, 1743 cm'; MS(ES) m/z 424 (M+Na'). 5 Anal. called for C6H20OFN,:30 4 S2: C, 47.87; H, 5.02; N, 10.47. Found: C, 47.84; H, 5.23; N, 10.28. EXAMPLE 29: (S)-N-[[ 3 -1[3,5-Difluoro-4-[4-(hydroxyacetyl)-1. piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (38). 10 1. F 0 F 0 _.\NFO

NH

2 OH " HCI F _ Boc-N/--" N O 0 Boc-N N NO0 F -NHAc Py / EtOH F H Fo \-- ~ --. NH 2 15 65 66 A stirred mixture of 65 (1.8 g, 0.00396 mol), pyridine (30 mL) and absolute EtOH (3 mL), under nitrogen, was treated with hydroxylamine hydrochloride (1.44 g, 0.0207 mol), warmed to the reflux temperature during 2 h, refluxed for 3.5 h, kept at 20 ambient temperature for 18 h and at reflux for 4 h. It was concentrated in vacuo and the residue was mixed with water, adjusted to pH 11 with saturated NaHCO 3 and extracted with Et 2 0. The extracts were washed with brine, dried (Na 2

SO

4 ) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-0.35%

NH

4 OH-CHC1 3 gave 0.75 g of recovered 65 and 0.72 g of 66: 'H NMR [300 MHz, 25 (CD 3

)

2 SO] d 1.40 (s, 9H), 1.72 (broad s, 2H), 2.78 (m, 2H), 2.97 (m, 4H), 3.40 (m, 4H), 3.80 (d,d, 1H), 4.00 (t, 1H), 4.59 (m, 1H), 7.27 (d, 2H); MS(ES) m/z 413 (M+H+), 435 (M+Na+). 2. 30 30F 0 F 0 /- PhCH 2 0COCI Boc-N N / N'A0 Boc-N N -"N NJJ O PhHOC C Boc-N/'--N NO F H- Et 3 N / THF F NHCbz \il...i~F NHCbz

NH

2 67 66 An ice cold, stirred mixture of 66 (0.75 g, 0.0018 mol) and triethylamine (0.315 mL, 35 0.00225 mol) in THF (12 mL), under nitrogen, was treated, dropwise with benzyl chloroformate (0.29 mL, 0.0020 mol), kept in the ice bath for 15 min and at ambient -74- WO 00/32599 PCT/US98/25308 temperature for 2 h and concentrated in vacuo. The residue was mixed with CH,C1 2 and washed with saturated NaHCO 3 , water and brine, dried (Na 2

SO

4 ) and concentrated. This residue was mixed with Et.,O and filtered to give 0.939 g of 67: mp 116-118 oC; 'H NMR (300 MHz, CDC13) d 1.48 (s, 9H), 3.08 (min, 4H), 3.53 (m, 5 4H), 3.60 (min, 2H), 3.73 (min, 1H), 3.96 (t, 1H), 4.76 (min, 1H), 5.10 (s, 2H), 5.21 (inm, 1H),7.07 (d, 2H), 7.31 (s, 5H); MS(ES) m/z 547 (M+H*), 569 (M+Na). 3. F 0 F 0 10 Boc-N \ N-/\NAO 1. TFA 0HNN / \ -H 2. NaHCO 3 H N ,,H F -- NHCbz F NH--FNHCbz 67 68 Compound 67 (0.805 g, 0.00147 mol) was added with stirring, portionwise during 5 15 min, under nitrogen, to ice cold trifluoroacetic acid (9 mL). The resulting solution was kept in the ice bath for 1 h and then concentrated under a stream of nitrogen. The residue was mixed with ice and saturated NaHCO 3 and extracted with CH 2 C1 2 ; the extract was washed with water and brine, dried (Na 2

SO

4 ) and concentrated to give 0.63 g of product. The combined aqueous layer was reextracted with EtOAc; 20 the extracts were washed with water and brine, dried (Na 2

SO

4 ) and concntrated to give additional product. The combined product amounted to 0.68 g of 68 which was used in the next reaction without further purification. 4. 25 25 F O O F O HNN/-1 /N N PhCH 2

OCH

2 COCI I- /--NN \ O H N N-- Y NAO a BzOCH2-C-N \- .,H NaHCO 3 F NHCbz F NHCbz (CH 3

)

2 C00 / H 2 0 NHCbz 68 69 30 An ice cold, stirred mixture of 68 (0.68 g, 0.00152 mol), saturated NaHCO 3 (15.2 mL) and acetone (40 mL), under nitrogen was treated, dropwise during 15 min, with a solution of benzyloxyacetyl chloride (0.29 mL, 0.0019 mol) in acetone (5 mL), kept at ambient temperature for 6 h, diluted with EtOAc and washed with water and brine. The extract was dried (MgSO,) and concentrated in vacuo to give 0.72 g of 69: 35 MS(ES) m/z 395 (M+H+), 617 (M+Na'); 'H NMR (300 MHz, CDC1 3 ) d 3.12 (min, 4H), 3.59 (min, 4H), 3.74 (min, 3H), 3.96 (t, 1H), 4.22 (s, 2H), 4.62 (s, 2H), 4.75 (broad s, 1H), -75- WO 00/32599 PCT/US98/25308 5.10 (s, 2H), 5.22 (min, 1H), 7.08 (d, 2H), 7.33 (min, 10H). 5. 0 F 0 0 F 0 11N / \ A.

H

2 /Pd Il ,--\ A 5 zoc2- N N- N - HOCH 2 -C-N N/ \N 0 - NHb HCI / MeOH - F NHCbz F -NH 2 69 37 A mixture of 69 (0.72 g, 0.0012 mol), MeOH and 5% palladium-on-carbon catalyst 10 (0.4 g) was hydrogenated at an initial pressure of 45 psi for 4 h. By TLC (8% MeOH-0.5% NH 4 OH-CHC1 3 ) the starting material had been reduced and two products formed. 1M Hydrochloric acid (1.34 mL) was added and hydrogenation was continued at an initial pressure of 40 psi for 21 h. By TLC only the more polar product remained. The catalyst was removed by filtration and the filtrate was 15 concentrated to give 0.40 g of 37: MS(ES) m/z 371 (M+H*), 393 (M+Na'); 'H NMR [300 MHz, (CD 3

)

2 SOJ d 3.02 (s, 4H), 3.20 (min, 2H), 3.43 (s, 2H), 3.56 (s, 2H), 3.84 (inm, 1H), 3.84 (broad s), 4.10 (s, 2H), 4.14 (t, 1H), 4.96 (min, 1H), 7.26 (d, 2H), 8.41 (broad s, 3H). 20 6. 0 F 0 , F IICH,-c-sEt rI H O C H 2 -2 - S t H O C H 2 - C - N N- / \ N -. j / L_ ,,, Et 3 N \.--/ .__ ,,H I F XNH 2 F .- NH-C-CH 3 x HCI 38 37 25 A stirred suspension of 37 (0.38 g) in a solution of EtN (0.31 mL) and THF (10 mL), under nitrogen, was treated with ethyl dithioacetate (0.13 mL, about 7 drops) and kept at ambient temperature for 7 d; the reaction was followed by TLC (8% MeOH 0.5% NH 4 OH-CHCls). Additional ethyl dithioacetate (2 drops) was added after 24 h; 30 after 30 h CHCI 2 (10 mL) and ethyl dithioacetate (3 drops) were added; after 48 h additional triethylamine (0.3 mL) was added. The mixture was concentrated in vacuo and the residue was mixed with ice and saturated NaHCO 3 an extracted with CHC1 2 . The extract was washed with water and brine, dried (MgSO 4 ) and concentrated. The residue was chromatographed on silica gel with 2.5% MeOH 35 CHC1, and the product was crystallized from MeOH to give 0.182 g of 38: mp 110 111 oC (dec); MS(ES) m/z 429 (M+H'), 451 (M+Na'); HRMS (FAB) calcd for -76- WO 00/32599 PCT/US98/25308

C

8 H,FjN 4 0 4 S (M+H ) 429.1408, found 429.1415; IR (DRIFT) 1760, 1652, 1639 cm-; [a 24 D 8 (MeOH). EXAMPLE 30: (S)-N-[[34-[- 1-[1,2,4]Triazolyl]phenyl]-2-oxo.5. 5 oxazolidinyl]methyl]thiourea (44). 1. 0 0 r-N 'N- 1I'J 0 Jr N \N' NN-Z NAOH + Nt 10 F "NH 2 O0S O N=C=S 26 79 A solution of 26 (0.190 g, 0.685 mmol) in CH 2

CI

2 (20 mL) was added, dropwise during 20 min, under nitrogen, to an ice cold, stirred solution of 1,10-thiocarbonyldi 15 2 (1H)-pyridone (0.193 g, 0.831 mmol) in CH 2 C1 2 (7 mL). The mixture was kept in the ice bath for 20 min and at ambient temperature for 2 h, diluted with CH 2 C1 2 , washed with water and brine, dried (MgSO 4 ) and concentrated. Chromatography of the residue on silica gel with 10-15% CH 3

CN-CH

2 C1 2 gave 0.11 g of 79 which was used in the next reaction without further purification: MS(ES) m/z 320 (M+H'), 342 20 (M+Na+). 2. 0 0 N NHN~/ NZN '' N, 0 25N .,,,H THF - /'-- x ..H I 25 N=C=S NF - NH-c-NH 2 79 44 A stirred, ice cold solution of 79 (0.10 g, 0.31 mmol) in THF (15 mL) was treated with excess anhydrous ammonia and kept in the ice bath for 90 min. It was then 30 evaporated under a stream of nitrogen to a volume of about 5 mL to give a solid which was collected by filtration and washed with cold THF to give 0.105 g of 44: mp 214-215 oC; 'H NMR [300 MHz, (CD3),SO d 3.82 (min, 3H), 4.18 (t, 1H), 4.89 (broad s, 1H), 7.20 (broad s, 2H), 7.50 (d, 1H), 7.79 (min, 2H), 7.93 (t, 1H), 8.26 (s, 1H), 8.97 (s, 1H); MS(ES) m/z 337 (M+H'), 359 (M+Na'). Anal. calcd for C 13

H,

3

FN

6 0S: 35 C, 46.42; H, 3.90; N, 24.99. Found: C, 46.22; H, 3.98; N, 24.55. -77- WO 00/32599 PCT/US98/25308 EXAMPLE 31: (S)-N-[ [ 3 -[3-Fluoro-4-[4-(hydroxyacetyl)-.

piperazinyl]phenyl]- 2 -oxo-5-oxazolidinyl]-methyl]thiourea (45). 1. 5 1. o 0 Q 0 0

HOCH

2 - - NN S N O S 0 HOCH2 C- N N N N=CO _-/ / ' ,,,, et 3 N / CH2CI2 \..._/ - ,,,,,H F %-NH 2 22 F N=C=S -HCI 29 80 29 s 10 An ice cold, stirred solution of 1,10-thiocarbonyl-2(1H)-dipyridone (0.123 g, 0.530 mmol) in CH 2 C1 2 (5 mL), under nitrogen, was treated with a suspension of 29 (0.17 g, 0.4 mmol) in CH 2 C 2 (20 mL) and then during 10 min with a solution of triethylamine (0.111 mL, 0.8 mmol) in CH,C1 2 (10 mL). It was kept in the ice bath for 30 min, at ambient temperature for 2 h and at < 0 oC for 18 h. It was then 15 diluted with CH 2 C1 2 , washed with water and brine, dried (MgSO 4 ) and concentrated. The residue (80) was used without further purification in the next reaction. A sample of 80 that was purified by flash chromatography on silica gel with 10-20% acetonitrile-CH 2 C1 2 had: 'H NMR (300 MHz, CDC1 3 ) d 1.60 (broad s), 3.07 (min, 4H), 3.45 (min, 2H), 3.85 (min, 4H), 3.97 (d,d, 1H), 4.16 (t, 1H), 4.21 (s, 2H), 4.82 (m, 1H), 20 6.95 (t, 1H), 7.13 (d,d, 1H), 7.47 (d,d, 1H); MS m/z 395 (M+H ); 417 (M+Na'). 2. 0 0 0 0 II / _

NH

3 II /-\ HOCH2--C- N NNO - HOCH 2 -C-N N--/ \ N O0 FH H 25 F -N=C=S F NH-C-NH 2 80 45 Excess anhydrous ammonia was bubbled into a stirred, ice cold solution of 80 (crude product from the previous reaction) in THF (25 mL) and the mixture was kept in the 30 ice bath for 90 min and concentrated under a stream of nitrogen. The residue was chromatographed on silica gel with 5% MeOH-0.4% NH 4 OH-CHC1 3 and the product was crystallized from acetonitrile to give 0.0544 g of 45: mp 209-210 oC; 'H NMR [300 MHz, (CD,),SO ] d 294 (broad s, 4H), 3.47 (broad s, 2H), 3.60 (broad s, 2H), 3.78 (broad s, 3H), 4.07 (t, 1H), 4.10 (d, J = 5.5 Hz, 2H), 4.63 (t, J = 5.5 Hz, 1H), 4.81 35 (broad s, 1H), 7.05 (t, 1H), 7.16 (d,d, 1H), 7.15 (broad s, 2H), 7.49 (d,d, 1H), 7.91 (t, 1H); IR (mull) 3443, 3403, 3321, 3202, 3081, 1753, 1655, 1648 cm'; HRMS (FAB) -78- WO 00/32599 PCT/US98/25308 called for C 17

H

2 3

FN

5 0 4 S (M+H') 412.1454, found 412.1447. Anal. calcd for

C,

7 H,2FN 5 0 4 S: C, 49.63; H, 5.39; N, 17.02. Found: C, 49.63; H, 5.48; N, 16.99. EXAMPLE 32: (S)-N-[ [3-[ 1-(Hydroxyacetyl)-5-indolinyl]-2-oxo-5 5 oxazolidinyl]methyl]thiourea (46). 1.

HOCH

2 -C=0 QN N HOCH-C=0 N0 0 N 0 10 N 0 cl Et 3 N N 0O

NH

2 81 N--C=S 27 15 An ice cold, stirred solution of 1,1¢-thiocarbonyldi-2(1H)-pyridone (0.096 g, 0.41 mmol) in CH 2 C1 2 (5 mL) was treated with a suspension of 27 (0.10 g, 0.34 mmol) in

CH

2

C

2 (15 mL) and then with 0.05 mL (0.36 mmol) of triethylamine. It was kept in the ice bath for 30 min and at ambient temperature for 2 h, diluted with CH 2 C1 2 , 20 washed with water and brine, dried (MgSO 4 ) and concentrated. Chromatography ofthe residue on silica gel with 20-40% CH 3

CN-CH

2 Cl 2 gave 0.04 g of 81. 2.

HOCH

2 -C-0 HOCH 2 -C--O NO NH 3 N 0. 25 N "0 K 0 N-,H C SC k ' N=C6 NH-C-NH2 81 46 Excess anhydrous ammonia was bubbled into an ice cold solution of 81 (0.04 g) in THF (30 mL) and the mixture was kept in the ice bath for 80 min and concentrated 30 under a stream of nitrogen. The residue was crystallized from CH 3 CN to give 0.0151 g of 46: mp 214-215 'C (dec); MS (FAB) m/z 351 (M+H*), 350 (M+), 319, 304, 147; HRMS (FAB) calcd for C 1 5

H

19

N

4 0 4 S (M+H ) 351.1127, found 351.1130; IR (DRIFT) 3329, 3296, 3196, 1746, 1655, 1626 cm 1. 35 EXAMPLE 33: (S)-N-[[3-1[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 -79- WO 00/32599 PCT/US98/25308 oxazolidinyl]methyl]thiourea, thiomorpholine S-oxide (47). 1. 5 Os N F NNH O S ,C 0 - OS N NNCS

HCH

2

CI

2 H F N2F 33 82 A suspension of 33 (0.30 g, 0.92 mmol) in CH 2 Cl 2 (7 mL) was added, during 20 min, 10 to an ice cold, stirred mixture of 1,1l-thiocarbonyldi-2(1H)-pyridone (0.258 g, 1.11 mmol) and CH 2 C1 2 (20 mL). The mixture was kept in the ice bath for 20 min and at ambient temperature for 2 h, mixed with CH2C12 (50 mL), washed with water and brine, dried (MgSO 4 ) and concentrated. Chromatography of the product on silica gel with 20-50% CH 3 CN-CHC1 2 gave 0.27 g of 82 which was used in the next reaction: 15 MS(ES) m/z 370 (M+H*), 392 (M+Na'). 2. 0 0 OS-N-\ N "O NH3 OS /--\ N- NA 0 H 20 F os--- N=C=S NF N NH--NH 2 82 47 A stirred, ice cold solution of 82 (0.27g, 0.73 mmol) in THF (15 mL), under nitrogen, was treated with excess anhydrous ammonia, kept in the ice bath for 1 h and 25 concentrated; crystallization of the residue from MeOH gave 0.175 g of 47; mp 212 213 'C; 'H NMR [300 MHz, (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, 1H), 4.80 (broad s, 1H), 7.17 (m, 2H), 7.17 (broad s, 2H), 7.50 (d, 1H), 7.90 (t, 1H); MS(ES) m/z 409 (M+Na'); IR (mull) 3335, 3284, 3211, 3175, 3097, 1750, 1630 cm'. Anal. calcd for C, 5

H,

9

FN

4 0 3

S

2 : C, 46.62; H, 30 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-S-methyldithiocarbamate (48). O O 35 0 -- ' O 1. CS 2 /Et 3 N O /--\ P NAO0 ,/0 - H 2. Mel \. ,H II F

NH

2 F -- NH-C-SCH 3 48 39 -80- WO 00/32599 PCT/US98/25308 An ice cold, stirred mixture of 39 (0.59 g, 0.0020 mol), EtOH (1.5 mL), water (2 drops) and triethylamine (0.613 mL, 0.00440 mol), under nitrogen, was treated with carbon disulfide (0.066 mL, 0.0011 mol) and kept in the ice bath for 2 h and at 5 ambient temperature for 18 h. (A solution was obtained after the addition of carbon disulfide; a white precipitate began to form soon after the mixture was warmed to ambient temperature.) The thick suspension was treated, dropwise during 2 min, with a solution of methyl iodide (0.137 mL, 0.00220 mol) in EtOH (2 mL) and the mixture was kept at ambient temperature for 1.5 h and concentrated in vacuo. A 10 solution of the residue in EtOAc was washed with saturated NaHCO 3 , water and brine, dried (MgSO 4 ) and concentrated. The residue was chromatographed on silica gel with 1.8% MeOH-CH 2 C1 2 and the product was crystallized from EtOAc to give 0.197 g of 48: mp 154-155 oC; IR (mull) 3354, 3346, 1726 cm -1 . Anal. calcd for

C

16

H

20

FN,

3 0 3

S

9 : C, 49.85; H, 5.23; N, 10.90. Found: C, 49.73; H, 5.25; N, 10.82. 15 EXAMPLE 35: (S)-N-[[3-[ 3 -Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl-O-methylthiocarbamate (50). O NaOCH 3 O 20 /-N N OH MeOH /-- N N /kOH S F NH-C-SCH 3 F NH-C -OCH 3 48 50 48 s A stirred mixture of 48 (0.200 g, 0.518 mmol), sodium methoxide (0.003 g, 0.06 25 mmol) and MeOH (5 mL), under nitrogen, was refluxed for 4 h and kept at ambient temperature for 18 h. It was found that the starting material and product had similar mobilities on TLC. the reaction was therefore followed by MS(ES). Starting material was still present. The mixture was refluxed for 3 h, additional sodium methoxide (0.005 g) was added and reflux was continued for 2 h. It was kept at 30 ambient temperature for 18 h, refluxed for 1 h, kept at ambient temperature 1.5 h and concentrated in vacuo. The residue was mixed with ice, the pH was adjusted to 9-10 with 1M KHSO 4 and saturated NaHCO, and the mixture was extracted with

CH

2 C1. The extract was washed with water and brine, dried (MgSO 4 ) and concentrated. The residue was chromatographed on silica gel with 5% acetone 35 CH 2 C12 and the product was crystallized from EtOAc-hexane to give 0.107 g of 50: mp 128-129 oC; MS(ES) m/z 370 (M+H+), 392 (M+Na+); IR (DRIFT) 3282, 3251, -81- WO 00/32599 PCT/US98/25308 1753, 1735 cm-'; 'H NMR [300 MHz, (CD 3

)

2 SO] d 2.94 (m, 4H), 3.47, 374 (m,m, 7H), 3.86, 3.91 (s,s, 3H), 4.10 (m, 1H), 4.73, 4.86 (m,m, 1H), 7.05 (t, 1H), 7.16 (d,d, 1H), 7.47 (d,d, 1H), 9.41, 9.50 (s,s, 1H). Anal. calcd for C16H 20

FN

3 0 4 S: C, 52.02; H, 5.46; N, 11.38. Found: C, 51.97; H, 5.49; N, 11.35. 5 -82- WO 00/32599 PCT/US98/25308 When in the procedure of Example 35 an appropriate amount of sodium ethoxide was substituted for sodium methoxide, the compound of Example 36 below in Table A was obtained. When in the procedure of Example 1 an appropriate amount of (S)-N-[[3-[3-fluoro 5 4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]isopropylcarboxamide, (S)-N-[[3-[3 fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropylcarboxamide, or (S)-N-[[3-[3,5-difluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide was substituted for (S)-N-[[3-[3-fluoro- 4

-(

4 -morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]acetamide (Compound 11) and the general procedures of Example I was followed, 10 the compounds of Examples 37, 38 and 39 respectively as set forth below in Table A were obtained. The isopropylcarboxamide and the cyclopropylcarboxamide are obtained by following the procedure in Example 5 of U.S. Patent No. 5,688,792 only substituting isobutyric anhydride and cyclopropane carbonyl chloride respectively for acetic anhydride in step 7. The acetamide is obtained as described in U.S. Patent No. 5,688,792 at Example 15 4. When in the procedure of Example 5, step B, an excess amount of dimethylamine in THF is substituted for anhydrous ammonia, the compound of Example 40 set forth below in Table A is obtained. TABLE A 20 R O ON NAO F -NH-C-R' Example No. Compound R 36 (S)-N-[[ 3 -[3-Fluoro-4-(4-morpholinyl)- R = H, R'= OC 2

H

5 phenyl]-2-oxo-5- oxazolidinyl]methyl]-O ethylthiocarbamate; mp 120 oC. MS(ES) m/z 384 (M+H+). Anal. calcd for

C

17

H

22

FN

3 0 4 S: C. 53.25: H, 5.78; N, 10.96. Found: C, 53.23; H, 5.82; N, 10.92. - 83 - WO 00/32599 PCT/US98/25308 Example No. Compound R. R' 37 (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)- R = H. R' = CH(CH 3 )2 phenyl]- 2 -oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide: mp 152-153 oC (dec.): Anal. called for CisH 24 FN303S: C, 56.67; H, 6.34: N, 11.02. Found: C, 56.58: H, 6.41: N, 10.81 38 (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)- R = H, R'= phenyl]- 2 -oxo-5-oxazolidinyl]methyl] cyclopropane-carbothioamide: mp 155-156 'C; Anal. called for CI 8

H

2 2FN30 3 S: 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)- R = F, R' = CH 3 phenyl]-2-oxo-5-oxazolidinyl]methyl] thioacetamide 40 (S)-N-[[ 3 -[3-Fluoro-4-(4-morpholinyl)- R = H. R' = N(CH 3

)

2 phenyl]- 2 -oxo-5-oxazolidinyl]methyl]-N'

N'

dimethylthiourea PREPARATION Z Methyl Dithiopropionate 1) CH 3

CH

2 MgBr S

CS

2 CH 3

CH

2

-C-SCH

3 2) CH31i (a) 5 A stirred mixture of magnesium turnings ( 12 .6 g, 0.520 g atom) and THF (100 mL) under nitrogen is treated with a crystal of iodine and about 5% of a solution of bromoethane (30.0 mL. 0.40 mol) in THF (200 mL). When the reaction starts, the remainder of the bromoethane solution is added. dropwise at a rate sufficient to maintain a gentle reflux. 10 After the addition. stirring is continued for 1 hour: the resulting solution is cooled to -20 'C and treated, during 10 minutes with carbon disulfide (24.0 mL, 0.40 mol). The mixture is warmed to 15 oC, treated with methyl iodide (28.0 mL, 0.45 mol) and kept at 60 oC for I hour. It is then cooled in an ice bath, treated with ice and extracted with Et2O. The extract is washed with brine, dried (MgSO 4 ) and concentrated. Distillation of the residue gives 15 34.0 g of the titled product, bp 48-52 'C (12 mmHg). - 84 - WO 00/32599 PCT/US98/25308 The following methyl dithio compounds were obtained when the appropriate alkyl magnesium bromide was substituted for ethyl magnesium bromide in the above procedure: TABLE B 5 S 11 Rs-C-SCH 3 Rs = (b)

(CH

3

)

2 CH- (h) (c) (i) (d)

CH

3

CH

2

CH

2 - (j) (e)

OH

3 (k)

CH

2

CH

3

CH-CH

2 (f)

CH

3 (1) /\ M1 CH2

CH

3

CH

2 CH-0

H

2 (g) (CH 3

)

3 C-CH2- (m) CH2 Z C H 2 When following the general procedure of Example 27, step 4, an appropriate 10 amount of the amine listed below is reacted with the dithio compound listed below the respective compounds, Examples 41 to 61 of Table C are obtained. When following the general procedure of Example 25, step 6, an appropriate amount of the amine listed below is reacted with the dithio compound listed below, the respective compounds, Examples 62 to 67, of Table C are obtained. - 85 - WO 00/32599 PCT/US98/25308 TABLE C Example Compound Amine Dithio Compound No. (from Preparation Z) 41 (S)-N-[[3-[3-Fluoro-4- o Z (a) (4-thiomorpholinyl)- O=S N N 0 phenyl]-2-oxo-5- F --- H oxazolidinyl]methylj- NH propanethioamide, thiomorpholine S-oxide: mp 196-197°C; Anal. calcd for

CI

7 H-22FN 3 0 3 S2: 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 42 S)-N-[[3-[3-Fluoro-4-(4- Same as above Z (b) thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethio amide, thiomorpholine S-oxide; mp 195-196 0 C; Anal. called for

C

1 8

H

24

FN

3 0 3 S2: 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 43 (S)-N-[[3-[3-Fluoro-4- Same as above Z (c) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide, thiomorpholine S-oxide: mp 109-1 10oIC: Anal. calcd for

C

18

H

22

FN

3 0 3 S2: 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 - 86- WO 00/32599 PCT/US98/25308 Example Compound Amine Dithio Compound No. (from Preparation Z) 44 (S)-N-[[3-[3-Fluoro-4- Same as above Z (d) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] butanethioamide, thiomorpholine S-oxide 45 (S)-N-[[3-[3-Fluoro-4- Same as above Z (e) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-3 methylbutanethioamide, thiomorpholine S-oxide 46 (S)-N-[[3-[3-Fluoro-4- Same as above Z (f) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylbutanethioamide, thiomorpholine S-oxide 47 (S)-N-[[3-[3-Fluoro-4- Same as above Z (g) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] 3,3-dimethylbutanethio amide, thiomorpholine S-oxide 48 (S)-N-[[3-[3-Fluoro-4- Same as above Z (h) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclobutanecarbothio amide, thiomorpholine S-oxide 49 (S)-N-[[3-[3-Fluoro-4- Same as above Z (i) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]- 1 cyclopentanecarbothio amide. thiomorpholine S-oxide - 87 - WO 00/32599 PCT/US98/25308 Example Compound Amine Dithio Compound No. (from Preparation Z) 50 (S)-N-[[3-[3-Fluoro-4- Same as above Z (j) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclohexanecarbothio amide, thiomorpholine S-oxide 51 (S)-N-[[3-[3-Fluoro-4- Same as above Z (k) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 cyclopropylethanethio amide, thiomorpholine S-oxide 52 (S)-N-[[3-[3-Fluoro-4- Same as above Z (1) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 cyclobutylethanethio amide, thiomorpholine S-oxide 53 (S)-N-[[3-[3-Fluoro-4- Same as above Z (m) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 cyclopentylethanethio amide, thiomorpholine S-oxide 54 (S)-N-[[3-[3,5-Difluoro- F Ethyl dithioacetate 4 -(4-thiomorpholinyl)- o=s N / E\ NO phenyl]-2-oxo-5- - -H oxazolidinyl]methyl]- F

NH

2 thioacetamide, thiomorpholine S-oxide 55 (S)-N-[[3-[3.5-Difluoro- Same as above Z (a) 4 -(4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] propanethioamide, thiomorpholine S-oxide - 88 - WO 00/32599 PCT/US98/25308 Example Compound Amine Dithio Compound No. (from Preparation Z) 56 (S)-N-[[3-[3.5-Difluoro- Same as above Z (b) 4 -(4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethio amide, thiomorpholine S-oxide 57 (S)-N-[[3-[3,5-Difluoro- Same as above Z (c) 4-(4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide, thiomorpholine S-oxide 58 (S)-N-[[3-[4-(4- o Ethyl dithioacetate thiomorpholinyl)- o=s.N / \ N 0 phenyl]-2-oxo-5- - ---- H oxazolidinyl]methyl]-

NH

2 thioacetamide, thiomorpholine S-oxide 59 (S)-N-[[3-[4-(4- Same as above Z (a) thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] propanethioamide, thiomorpholine S-oxide 60 (S)-N-[[3-[4-(4- Same as above Z (b) thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethio amide, thiomorpholine S-oxide 61 (S)-N-[[3-[4-(4- Same as above Z (c) thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide, thiomorpholine S-oxide - 89- WO 00/32599 PCT/US98/25308 Example Compound Amine Dithio Compound No. (from Preparation Z) 62 (S)-N-[[3-[3,5-Difluoro- o F 0 Z (a) 4-(4-hydroxyacetyl)-1- HOCH 2 -C -N N N OH piperazinyl]phenyl]-2- F oxo-5-oxazolidinyl]- 2 methyl]propanethio amide 63 (S)-N-[[3-[3,5-Difluoro- Same as above Z (b) 4-(4-hydroxyacetyl)- 1 piperazinyl]phenyl]-2 oxo-5-oxazolidinyl] methyl]-2-methyl propanethioamide 64 (S)-N-[[3-[3,5-Difluoro- Same as above Z (c) 4 -(4-hydroxyacetyl)- I piperazinyl]phenyl]-2 oxo-5-oxazolidinyl] methyl]cyclopropane thioamide 65 (S)-N-[[3-[3-[4- 0 0 Z (a) (hydroxyacetyl)- 1 - HOCH2-C-N \ N~ N O piperazinyl]phenyl]-2- -LN-H oxo-5-oxazolidinyl] methyl]propanethio amide 66 (S)-N-[[3-[3-[4- Same as above Z (b) (hydroxyacetyl)- 1 piperazinyl]phenyl]-2 oxo-5-oxazolidinyl] methyl]-2-methyl propanethioamide 67 (S)-N-[[3-[3-[4- Same as above Z (c) (hydroxyacetyl)- 1 piperazinyl]phenyl]-2 oxo-5-oxazolidinyl] methyl]cyclopropane carbothioamide When following the procedure of Example 28. step 3, an appropriate amount of the amine listed below is reacted with the dithio compound listed below, the respective compounds. Examples 68 to 78 of Table D are obtained. - 90- WO 00/32599 PCT/US98/25308 TABLE D Example Compound Amine Dithio Compound No. (see Preparation Z) 68 (S)-N-[[3-[3-Fluoro-4- o Z (a) (4-thiomorpholinyl)- o 2 S -- N/ N lO phenyl]-2-oxo-5- .. _ - ---- H oxazolidinyl]methyl]- F

.NH

2 propanethioamide, thiomorpholine S.S dioxide 69 (S)-N-[[3-[3-Fluoro-4- Same as above Z (b) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methylJ-2 methylpropanethio amide, thiomorpholine S,S-dioxide 70 (S)-N-[[3-[3-Fluoro-4- Same as above Z (c) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide, thiomorpholine S,S-dioxide 71 (S)-N-[[3-[3,5- Difluoro- F 0 Ethyl dithioacetate 4 -(4-thiomorpholinyl)-

O

2 S \/N N O phenyl]-2-oxo-5- - - H...

H oxazolidinyl]- F

.NH

2 methyl]thioacetamide, thiomorpholine S,S dioxide 72 (S)-N-[[3-[3,5- Difluoro- Same as above Z (a) 4 -(4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] propanethioamide, thiomorpholine S,S dioxide -91- WO 00/32599 PCT/US98/25308 Example Compound Amine Dithio Compound No. (see Preparation Z) 73 (S)-N-[[3-[3.5- Difluoro- Same as above Z (b) 4-(4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethio amide, thiomorpholine S,S-dioxide 74 (S)-N-[[3-[3,5- Difluoro- Same as above Z (c) 4-(4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide. thiomorpholine S,S-dioxide 75 (S)-N-[[3-[4-(4-thio- o Ethyl dithioacetate morpholinyl)phenyl]-2-

O

2 SFN /\ NO oxo-5-oxazolidinyl]- - ---H methyl]thioacetamide, 2 -- N 2 thiomorpholine S,S dioxide 76 (S)-N-[[3-[4-(4-thio- Same as above Z (a) morpholinyl)phenyl]-2 oxo-5-oxazolidinyl] methyl]propanethio amide, thiomorpholine SS-dioxide 77 (S)-N-[[3-[4-(4-thio- Same as above Z (b) morpholinyl)phenyl]-2 oxo-5-oxazolidinyl] methyl]-2-methyl propanethioamide, thiomorpholine S,S dioxide 78 (S)-N-[[3-[4-(4-thio- Same as above Z (c) morpholinyl)phenyl]-2 oxo-5-oxazolidinyl] methyl]cyclopropane carbothioamide, thiomorpholine S.S dioxide - 92 - WO 00/32599 PCT/US98/25308 When following the procedure of Example 26. an appropriate amount of the amine listed below is reacted with the dithio compound listed below the respective compounds. Examples 79 to 99 of Table E are obtained. 5 TABLEE Example Compound Amine Dithio Compound No. (See Preparation Z) 79 (S)-N-[[3-[3-Fluoro-4- 0 Z (a) (4-thiomorpholinyl)- S N / N 0 phenyl]-2-oxo-5- .- H oxazolidinyl]methyl]- F--NH2 propanethioamide

NH

2 80 (S)-N-[[3-[3-Fluoro-4- Same as above Z (b) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethioamide 81 (S)-N-[[3-[3-Fluoro-4- Same as above Z (c) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide 82 (S)-N-[[3-[3-Fluoro-4- Same as above Z (d) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] butanethioamide 83 (S)-N-[[3-[3-Fluoro-4- Same as above Z (e) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-3 methylbutanethioamide 84 (S)-N-[[3-[3-Fluoro-4- Same as above Z (f) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylbutanethioamide - 93 - WO 00/32599 PCT/US98/25308 Example Compound Amine Dithio Compound No. (See Preparation Z) 85 (S)-N-[[3-[3-Fluoro-4- Same as above Z (g) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] 3

.

3 -dimethylbutanethio amide 86 (S)-N-[[3-[3-Fluoro-4- Same as above Z (h) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclobutanecarbothio amide 87 (S)-N-[[3-[3-Fluoro-4- Same as above Z (i) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopentanecarbothio amide 88 (S)-N-[[3-[3-Fluoro-4- Same as above Z (j)

(

4 -thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclohexanecarbothio amide 89 (S)-N-[[3-[3-5 Fluoro-4- Same as above Z (k)

(

4 -thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 cyclopropylethanethio amide 90 (S)-N-[[3-[3-Fluoro-4- Same as above Z (1) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 cyclobutylethanethio amide - 94 - WO 00/32599 PCT/US98/25308 Example Compound Amine Dithio Compound No. (See Preparation Z) 91 (S)-N-[[3-[3-Fluoro-4- Same as above Z (m) (4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 cyclopentylethanethio amide 92 (S)-N-[[3-[3,5-Difluoro- F 0 Ethyl dithioacetate 4-(4-thiomorpholinyl)- SN / 0 phenyl]-2-oxo-5- S ... H oxazolidinyl]methyl]- F -H thioacetamide NH 2 93 (S)-N-[[3-[3,5-Difluoro- Same as above Z (a) 4-(4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] propanethioamide 94 (S)-N-[[3-[3,5-Difluoro- Same as above Z (b) 4-(4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethioamide 95 (S)-N-[[3-[3,5-Difluoro- Same as above Z (c) 4-(4-thiomorpholinyl) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide 96 (S)-N-[[3-[4-(4-thio- 0 Ethyl dithioacetate morpholinyl)phenyl]-2- S N / N 0 oxo-5-oxazolidinyl]- L./ -- H methyl]thioacetamide

NH

2 NH, 97 (S)-N-[[3-[4-(4-thio- Same as above Z (a) morpholinyl)phenyl]-2 oxo-5-oxazolidinyl] methyl]propanethio amide - 95 - WO 00/32599 PCT/US98/25308 Example Compound Amine Dithio Compound No. (See Preparation Z) 98 (S)-N-[[3-[4-(4-thio- Same as above Z (b) morpholinyl)phenyl]-2 oxo-5-oxazolidinyl] methyl]-2-methyl propanethioamide 99 (S)-N-[[3-[4-(4-thio- Same as above Z (c) morpholinyl)phenyl]-2 oxo-5-oxazolidinyl] methylicyclopropane carbothioamide The amine utilized in Examples 41 to 53 is prepared as described in Example 27, step 3. The amine utilized in Examples 54 to 57 is prepared by the procedure of Example 27, steps 1 to 3 by substituting the appropriate (S)-N-[[3-[3.5-difluoro-4-(4-thio 5 morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methanol for compound 62 in step 1 of Example 27. The amine utilized in Examples 58 to 61 is prepared by the procedure of Example 27, steps 1 to 3 by substituting the appropriate (S)-N-[[3-[4-(4-thiomorpholinyl)phenyl]-2 oxo-5-oxazolidinyl]methanol for compound 62 in Example 27, step 1. The appropriate o10 oxazolidinyl methanol compound is obtained by following the procedure of Example 1 in U.S. Patent 5.688,792, steps 1 through 3. only substituting 4-fluoronitrobenzene for 3,4 difluoronitrobenzene in step 1 thereof. The amine utilized in Examples 62 to 64 is prepared as compound 37 in Example 29 from the amide, 65, which is prepared as described in Example 32 of U.S. Patent No. 15 5,700,799. The amine utilized in Examples 65 to 67 is prepared by the general procedure of Example 29 from the following amide, the preparation of which is decribed in Example 3 of U.S. Patent 5.700,799: O Boc -N N N 1 O -- NHAc - 96 - WO 00/32599 PCT/US98/25308 The amine utilized in Examples 68 to 70 is prepared as described in step 2 of Example 28 above. The amine utilized in Examples 71 to 74 is prepared as described in Example 28 by substituting (S)-N-[[ 3 -[3.5-difluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 5 oxazolidinyl]methanol for compound 62 in step 1 and following the procedure of steps 1 and 2. The appropriate oxazolidinyl methanol compound is prepared by following the general procedure of Example 4 of U.S. Patent No. 5,688.792, steps I through 4, only substituting thiomorpholine for morpholine in step I thereof. The amine utilized in Examples 75 to 78 is prepared as described in Example 28, 10 step 1, above by substituting (S)-N-[ 3

-[

4 -(4-thiomorpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methanol for compound 62 in step 1. The appropriate oxazolidinyl methanol is obtained by following the procedure of Example 1 in U.S. Patent No. 5,688,792, steps 1 through 3, only substituting 4 -fluoronitrobenzene for 3,4-difluoronitrobenzene in step 1 thereof. 15 The amine utilized in Examples 79 to 91 is prepared as described in Example 1, step 4, of U.S. Patent No. 5,688,792. The amine utilized in Examples 92 to 95 is prepared as described in Example 4 of U.S. Patent No. 5,688,792 only substituting thiomorpholine for morpholine in step 1 thereof. The amine utilized in Examples 96 to 99 is prepared by the procedure of Example 1 of U.S. Patent No. 5,688,792, only substituting 4-fluoronitro 20 benzene for 3 ,4-difluoronitrobenzene in step I thereof. EXAMPLE 100 (S)-N-[[ 3

-[

3 -Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate, thiomorpholine S-oxide O O= S/---N N A O S---HS F II F __NHC-OCH 3 A solution of 201 mg (0.554 mmol) of (S)-N-[[3-[3-fluoro-4-(4-thiomorpholinyl) 25 phenyl]- 2 -oxo-5-oxazolidinyl]methyl]isothiocyanate, thiomorpholine s-oxide compound 82 from Example 33. step 1, in methanol (10 mL) is refluxed, under nitrogen for 18 hours and cooled. The solid is collected by filtration to give 0.138 g of the titled product. m.p. 208 209 0 C: Anal. called for CI 6 H2oFNO30 4

S

2 : C, 47.87: H, 5.02: N. 10.47. Found: C, 47.81; H, 5.04: N, 10.49. - 97 - WO 00/32599 PCT/US98/25308 When in the procedure of Example 100 the thioisocyanate listed below is substituted for compound 82 the products listed below as Examples 101 to 109 are obtained. TABLE F Isothiocyanate Ra O Rc N N O Rb H 5 N= 0= S Rc Ra Rb Example Compound No. OS F F 101 (S)-N-[[3-[3.5-Difluoro-4-(4 thiomorpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthio carbamate, thiomorpholine S-oxide OS H H 102 (S)-N-[[3-[4-(4-thiomorpholinyl)phenyl]-2 oxo-5-oxazolidinyl]methyl]-O-methylthio carbamate, thiomorpholine S-oxide

O

2 S H F 103 (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl) phenyl]-2-oxo-5-oxazolidinyl]methyl]-O methylthiocarbamate, 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]-O-methylthio carbamate, thiomorpholine S,S-dioxide

O

2 S H H 105 (S)-N-[[3-[4-(4-thiomorpholinyl)phenyl]-2 oxo-5-oxazolidinyl]methyl]-O-methylthio carbamate, thiomorpholine S,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-thiomorph olinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate - 98 - WO 00/32599 PCT/US98/25308 Rc Ra Rb Example Compound No. S H H 108 (S)-N-[[3-[4-(4-thiomorpholinyl)phenyl]-2 oxo-5-oxazolidinyl]methyl]-O-methylthio carbamate 0 H H 109 (S)-N-[[3-[3-Fluoro-4-(4-(hydroxvacetyl)-1

HOCH

2 CN piperazinyl]phenyl]- 2 -oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate When in the procedure of Example 100 an appropriate amount of ethanol and isopropyl alcohol were substituted for methanol, the following respective compounds were obtained: 5 EXAMPLE 110: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-ethylthiocarbamate, thiomorpholine S-oxide. m.p. 198-199 0 C; Anal. calcd for C 7

H

22

FN

3 0 4 S2: 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 10 oxazolidinyl]methyl]-O-isopropylthiocarbamate, thiomorpholine S-oxide. m.p. 180-181 C; Anal. calcd for Cs 18

H

24

FN

3 0 4

S

2 : C, 50.33; H, 5.63: N, 9.78. Found: C, 50.29; H, 5.69; N, 9.82. When in the procedure of Example 114 an appropriate amount of (S)-N-[[3-[3 fluoro-4-( 4 -thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]isothiocyanate is substituted for 15 compound 82 and ethanol or isopropyl alcohol is substituted for methanol, the following respective products are obtained: EXAMPLE 112: (S)-N-[[ 3 -[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-ethylthiocarbamate; EXAMPLE 113: (S)-N-[[ 3 -[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 20 oxazolidinyl]methyl]-O-iso-propylthiocarbamate; EXAMPLE 114: (S)-N-[[ 3 -[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-N-methylthiourea, thiomorpholine S-oxide. A stirred suspension of 240 mg (0.650 mmol) of compound 82 from Example 33, step 1 in THF (5 mL) at 0 'C is treated with a 2M solution of methylamine in THF (0.42 25 mL, 0.845 mmol) and kept at ambient temperature for 18 hours. The solid is collected by filtration to give 0.221 g of the titled product. - 99 - WO 00/32599 PCT/US98/25308 Following the procedure of Example 114, only substituting an appropriate amount of dimethylamine and azetidine for methylamine, the following compounds are obtained: EXAMPLE 115: (S)-N-[[3-[ 3 -Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-N',.N'-dimethylthiourea, thiomorpholine S-oxide; Anal. Called for 5 C 17

H

23

FN

4 0 3

S

2 , C, 49.26: H, 5.59: N, 13.52. Found C, 49.11; H, 5.57: N, 13.40; mp 180 182 0 C. EXAMPLE 116: (S)-N-[[ 3

-[

3 -Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]- I -azetidinecarbothioamide, thiomorpholine S-oxide: Anal. Calcd for

C

18

H

23

FN

4 0 3

S

2 , C, 50.69; H. 5.43; N, 13.14. Found: C, 50.79; H, 5.45; N, 12.82; mp 213 10 214 0 C. When in the procedure of Example 114 an appropriate amount of (S)-N-[[3-[3 fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]isothiocyanate is substituted for compound 82. the following compound is obtained: EXAMPLE 117: (S)-N-[[ 3

-[

3 -Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 15 oxazolidinyl]methyl]methyl-N'-methylthiourea. When in the procedure of Example 117 an appropriate amount of dimethylamine and azetidine are substituted for methylamine, the following respective products are obtained: EXAMPLE 118: (S)-N-[[3-[ 3 -Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 20 oxazolidinyl]methyl]-N',N'-dimethylthiourea; EXAMPLE 119: (S)-N-[[ 3

-[

3 -Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]- I -azetidinecarbothioamide. When in the procedure of Example 33 an appropriate amount of compound 31 from Example 26 is substituted for compound 33 and the general procedure of steps 1 and 2 of 25 Example 33 are followed, the following compound is obtained. EXAMPLE 120: (S)-N-[[ 3

-[

3 -Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]thiourea. EXAMPLE 121: (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(hydroxyacetyl)- 1-piperazinyl]phenyl-2 30 oxo-5-oxazolidinyl]methyl]propanethioamide - 100- WO 00/32599 PCT/US98/25308 S II

CH

3

CH

2

CSCH

3 O IILEt3N I II 'u HOCH2/ O HOCH 2 N N/ \

-

2 CN N / \-/ N 0 -= L ,.--H H _ s F NH 2 F NH-C 29 CH 2

CH

3 A stirred mixture of 200 mg (0.514 mmol) of 29 methyl dithiopropionate (247 mg, 2.06 mmol), triethylamine (0.58 mL, 4.11 mmol), THF (5.4 mL) and methylene chloride (5.4 mL) is kept, under nitrogen, for 3 days, diluted with water and extracted with 5 methylene chloride. The extracts are dried (MgSO 4 ) and concentrated. Chromatography of the residue on silica gel and crystallization of the product from methanol gives 0.132 g of the titled product. m.p. 190-191'C: Anal. calcd for C 19

H

25

FN

4 0 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. Following the procedure of Example 121 only substituting dithio compounds Z (b) 10 to Z (m) from Preparation Z above for methyl dithiopropionate, the following compounds are obtained. TABLE G O O

HOCH

2 CN N N O F H IF' F .NH-C-R 15 Example No. Compound 122 (S)-N-[[3-[3-Fluoro-4-[4-(hydroxy- R = CH(CH 3

)

2 acetyl)- 1 -piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-2-methylpropane thioamide: Anal. calcd for

C

2 0H2 7

FN

4 04S: C, 54.78; H, 6.21: N, 12.78: S, 7.31. Found: C, 54.67; H, 6.34; N, 12.41: S, 7.15 - 101 - WO 00/32599 PCT/US98/25308 Example No. Compound 123 (S)-N-[[3-[3-Fluoro-4-[4-(hydroxy- R acetyl)- I-piperazinyllphenyl]-2-oxo-.. oxazolidinyllmethyllcyclopropane carbothioamide, mp 179-181'C; Anal. called for C,2OH- 5

FN

4 0 4 S: C, 55.03; H, 5.77; N, 12.84, S, 7.34. Found: C, 55.15; H, 5.72; N, 12.76: S, 7.09 124 (S)-N- [[3- [ 3 -Fluoro-4-[4-(hydroxy- R = CH,-CH,-CH 3 acetyl)- 1 -piperazinyljphenylj-2-oxo-5 oxazolidinyl]methyl]butanethioamide 125 (S)-N-[[3- [ 3 -Fluoro-4-[4-(hydroxy- C H 3 acetyl)- I-piperazinyl]phenyl].3.oxo-5- R CH 2

-CH-CH

3 oxazolidinyl]methyll-3-methylbutane. thioamide 126 (S)-N-[[3-[3-Fluoro-4- [4-(hydroxy-

OH

3 acetyl)- 1 -pipe razi nyIlphenyl ]-2-oxo.5 - R OH -CH 2

-CH

3 oxazolidlinyl ]methyl1]-2 methy Ibutane thioamide 127 (S)-N-[[3-[3-Fluoro-4-[4-(hydroxy- R =CH- 2

-C(CH

3

)

3 acetyl)- I -piperazinyllphenyl]-2-oxo.5 oxazolidinyllmethyl]-3 ,3-dimethyl butanethioamide 128 (S)-N-[[3-[3-Fluoro-4-[4-(hydroxy. R acetyl )- 1 -piperazinyllphenyl ]-2-oxo-5 oxazolidinyl]methyllcyclobutane. carbothioamidce 129 (S)-N-[[3- [3-Fluoro-4- [4-( hydroxy- R acetyl )- 1 -piperazinyllphenyl]-2-oxo.5 oxazoildinyl]methyllcyclopentane carbothioamide 130 (S)-N-[[3- [3-Fluoro-4- [4-( hydroxy- R -0 acetyl)- I -piperazinyllphenyl]-2-oxo-5 oxazolidinyl]methy] ]cyclohexane carbothioamide 131 (S)-N-[[3-[3-Fluoro-4-[4(hvdroxy- R H acetyl)- 1 -piperazinyllphenyl]-2-oxo-5 oxazolidinyl]methyl]-2-cyclopropyl ethanethioamide - 102 - WO 00/32599 PCT/US98/25308 Example No. Compound 132 (S)-N-[[3-[3-Fluoro-4-[4-(hydroxy- R = CH2 acetyl)- 1-piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-2-cyclobutyl ethanethioamide 133 (S)-N-[[3-[3-Fluoro-4-[4-(hydroxy- R = CH 2 acetyl)- 1 -piperazinyllphenyl]-2-oxo-5 oxazolidinyl]methyl]-2-cyclopentyl ethanethioamide When in the procedure of Example 100 an appropriate amount of compound 80 from Example 31 is substituted for compound 82, and ethanol or isopropyl alcohol is substituted for methanol, the following respective compounds are obtained: 5 EXAMPLE 134: (S)-N-[[3-[3-Fluoro-4-[ 4 -(hydroxyacetyl)- I -piperazinyl]phenyl]-2 oxo-5-oxazolidinyl]methyl]-O-ethylthiocarbamate; EXAMPLE 135: (S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)- 1 -piperazinyl]phenyl]-2 oxo-5-oxazolidinyl]methyl]-O-iso-propylthiocarbamate; EXAMPLE 136: (S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)- 1-piperazinyl]phenyl]-2 10 oxo-5-oxazolidinyl]methyl]-N'-methylthiourea. When in the procedure of Example 114 an appropriate amount of compound 80 from Example 31 is substituted for compound 82, the title compound is obtained. Following the procedure of Example 114 only substituting an appropriate amount of compound 80 from Example 31 for compund 82 and substituting an appropriate amount of 15 dimethylamine and azetidine for methylamine, the following compounds, Examples 137 and 138, are obtained: EXAMPLE 137: (S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)- I -piperazinyl]phenyl]-2 oxo-5-oxazolidinyl]methyl]-N'.N'-dimethylthiourea: EXAMPLE 138: (S)-N-[[ 3 -[3-Fluoro-4-[4-(hydroxyacetyl)- l-piperazinyl]phenyl]-2 20 oxo-5-oxazolidinyl]methyl]- 1-azetidinecarbothioamide. EXAMPLE 139: (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(hydroxyacetyl)- I -piperazinyl]phenyl] 2 -oxo-5-oxazolidinyl]methyl]-O-methylthiocarbamate. Part A: Following the procedure of Example 33, step 1, only substituting an 25 appropriate amount of compound 37 from Example 29. step 5, for compound 33. (S)-N - 103- WO 00/32599 PCT/US98/25308

[[

3

,

5

-[

3 -difluoro-4-[4-(hydroxyacetyl)- I -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]isothiocyanate is obtained. Part B: Upon substitution of an appropriate amount of (S)-N-[[3-[3,5-difluoro-4-[4 (hydroxyacetyl)- 1-piperazinyl]phenyl]- 2 -oxo-5-oxazolidinyl]methyllisothiocyanate for 5 compound 82 in the general procedure of Example 100, the title compound is obtained. EXAMPLE 140: (S)-N-[[3-[4-[4-(hydroxyacetyl)- I -piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate Part A: Following the procedure of Example 33, step 1, only substituting an 10 appropriate amount of (S)-N-[[3-[4-[4-(hydroxyacetyl)- 1-piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]amine for compound 33, (S)-N-[[3-[ 4 -[4-(hydroxyacetyl)-1 piperazinyl]phenyl]- 2 -oxo- 5 -oxazolidinyl]methyl]isothiocyanate is obtained. - 104- WO 00/32599 PCT/US98/25308 Part B: Upon substituting an appropriate amount of (S)-N-[[3-[4-[4-(hydroxy acetyl)- I -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]isothiocyanate for compound 82 in the general procedure of Example 100. the title compound is obtained. 5 EXAMPLE 141: (S)-N-[[3-Fluoro-4-(4-acetyl- 1-piperazinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]thioacetamide Step 1 NO2 0 0 0 II > S0 2 O S02CI PhCH 2 0C N N NO H Cbz-N N- N 0 F OH Et 3 F ONos 58 85 10 An ice cold, stirred solution of 30.4 g (70.8 mmol) of starting material 58 from Example 25, step 1), and triethylamine (15.4 mL, 110 mmol) in methylene chloride (2570 mL) is treated with m-nitrobenzenesulfonyl chloride (18.8 g, 84.9 mmol) and kept, under nitrogen, at ambient temperature (24 'C) for 24 hours. Additional m-nitrobenzenesulfonyl chloride (1.88 g) and triethylamine (1.54 mL) are added and the mixture is kept for one 15 additional day at ambient temperature, washed with water, saturated sodium bicarbonate and brine, dried (Na 2

SO

4 ) and concentrated to give an oily product, 85. The alcohol, 58 is prepared according to the procedures of Brickner (J. Med. Chem. 1996, 39, 673-679), see compound 5a therein. Step 2 O O 0 0 CbZ N"-N ./ , N O NH 4 OH Cbz N /- N- N O F ONos F NH 2 20 85 86 20 A stirred mixture of 85, acetonitrile (1270 mL), isopropanol (1270 mL) and ammonium hydroxide (1270 mL) is kept at ambient temperature for 3 days and concentrated in vacuo. Chromatography of the residue on silica gel with 0.5% NHOH- 1% 25 MeOH-CHCI 2 l gives 22.4 g of the amine. 86. Step 3 - 105- WO 00/32599 PCT/US98/25308 0 O Cbzd' ABoc 2 O Cbz N N N B020 Cbz-N N NA o F HC F - '-NHBoc 86 87 An ice cold, stirred solution of the amine 86 in THF (650 mL) is treated, during 20 mintues with a solution of di-tert-butyl dicarbonate (12.0 g, 55.2 mmol) in THF (90 mL). The mixture is kept at ambient temperature for 18 hours and concentrated in vacuo. The 5 residue, dissolved in methylene chloride, is washed with dilute sodium bicarbonate, dried (MgSO4) and concentrated. Crystallization of the residue from methanol-ethyl acetate gives 20.0 g of the Boc protected amine. Additional product (4.1 g) is obtained by chromatographing the mother liquors on silica gel with 1-2% methanol-methylene chloride. Step 4 0 0 Cbz N N / N H c H0 HN N N H \_j ~ H Pd /C - ... H F NHBoc F NHBoc 0 87 88 10 A solution of the protected amine, 87, (5.00 g, 9.46 mmol) in ethanol (150 mL) is treated with 10% palladium-on-carbon catalyst (1.0 g) and hydrogenated at an initial pressure of 30 psi for 3 hours. The catalyst is removed by filtration through Celite and the filtrate was concentrated to give 3.66 g of compound 88. 15 Step 5 0 0 0 O O O 0 - CH 3 CN F_ .. '~kHB Py F -_ \_'-NHBoc HF N HBoc A 2CH N NNH o 88 89 A stirred solution of compound 88 (1.10 g, 2.79 mmol) in pyridine (10 mL) is treated with acetic anhydride (289 pL. 3.07 mmol), kept at ambient temperature for 2 hours and concentrated in vacuo. A solution of the residue in methylene chloride is washed with 20 dilute hydrochloric acid, dried (MgSO 4 ) and concentrated to give 1.23 gof compound 89: MS nm/z 436 (M'). Step 6 - 106- WO 00/32599 PCT/US98/25308 O O

CH

3 N N--/ \N O HCI O 0H 3 8 N\__N-/ _ N 0~ OH1 C N N\ A~ L H dioxane CH3CN -N N N0 H F NHBoc._j F \ H 2 89 P-90 -HCI An ice cold, stirred 4N solution of HCI in dioxane (10 mL) is treated with compound 89 ( 1 .10 g, 2.52 mmol). The mixture is kept in the ice bath for 30 minutes and at ambient temperature for 1 hour. It was then mixed with methylene chloride and 5 concentrated. The residue is triturated with methylene chloride to give 1.03 g of the amine hydrochloride. Step 7 O O S 1H 3 CN-N / N,-\O

CH

3 CSEt CI I N N CH N N N H C NS* CH 3 N N / 1 N H - - ... H Et 3 N H-1 F -HCI H 2 F

NH-C-CH

3 P-90 A stirred mixture of compound P-90 (250 mg), triethylamine (0.75 mL, 5.36 mmol), 10 ethyl dithioacetate (307 gL, 2.68 mmol), methylene chloride (7.4 mL) and THF (7.4 mnL) is kept at ambient temperature for 1 day, concentrated and chromatographed on silica gel with mixtures of methanol-methylene chloride containing 1-2% methanol. Crystallization of the product from ethyl acetate-heptane gives 0.160 g of the titled product: Anal. calcd for CisH 2 3 FN40 3 S: C, 54.81: H, 5.88: N, 14.20; S, 8.13. Found: C, 54.92: H, 5.95; N, 14.08: 15 S, 7.94: mp 158oC. When in the general procedure of Example 141 an appropriate amount of 0 0 o 0 PhCH 2 0 N N/ -N O PhH 2 0 N N / NO 20C J N F\- / -- H or PhCH2OC.N / F - - -OH Y s--OH x y is substituted for compound 58 and the procedure of steps I through 6 are followed, the respective amine compounds P-91 and P-92 listed below are obtained: - 107- WO 00/32599 PCT/US98/25308 O F O 1H1N //- ' N CH3CN \--

/

N \-N O - ..H P-91 F L

NH

2 O O

CH

3 C-N N N O ..- H P-92

NH

2 The alcohols above designated as x and y are prepared according to the procedures of Brickner (J. Med. Chem., 1996, 39, 673-679), by substituting an appropriate amount of 2,6-difluoro-4-nitrobenzene (trifluoromethane) sulfonate and 4-fluoronitrobenzene 5 respectively for 3,4-difluoronitrobenzene in the preparation of 2a therein. When in the procedure of Example 141 an appropriate amount of x or y is substituted for compound 58 and the procedures of steps 1 through 4 are followed, the following Boc protected compounds listed below are obtained. F O HN N N \ N' 0 x-b HN N N O x -b - ~ ---- H F NHBoc O HN N /\N O - ----H y-b --NHBoc 10 When in the procedure of Example 141, step 5, an appropriate amount of compound 88, compound x-b or compound y-b is treated with the reagent listed below and the general procedures of step 5 and step 6 are followed, the amines listed below as Preparation P-93 through P-128 are obtained. The amine compound set forth below as P- 129 is obtained by refluxing for 6 days a 15 solution of compound 8 8 (1.00 g, 2.54 mmol), sulfamide (305 mg, 3.18 mmol) and 1,2 dimethyoxyethane (6 mL). The solid which precipitates is collected by filtration and chromatographed on silica gel with 5% methanol-methylene chloride. Crystallization of the product from methanol-methylene chloride gives 0.551 g of the sulfamoyl derivative, which is used in step 6 of Example 141 to give P-129. When compounds x-b and y-b are - 108- WO 00/32599 PCT/US98/25308 substituted for compound 88 and this general procedure is followed. Preparations P-130 and P-131 respectively set forth below are obtained. Following the general procedures of steps 5 and 6 of Example 141 only in step 5 substituting chloroacetonitrile or 2-fluoroethyl bromide respectively for acetic anhydride 5 and using potassium carbonate in acetonitrile, and using either compound 88, compound x b or compound y-b, the respective amines set forth below as Preparations P-132 to P-137 are obtained. The amine compound set forth below as Preparation P-138 is obtained by combining compound 88 (1.10 g, 2.75 mmol) set forth in step 5 of Example 141 with N 10 formylbenzotriazole (493 mg, 3.35 mmol) in THF (30 mL) and the mixture is kept at ambient temperature for 18 hours. The mixture is concentrated and the residue in methylene chloride is washed with IN sodium hydroxide and dilute sodium chloride, dried (MgSO 4 ), concentrated, and chromatographed on silica gel with mixtures of methanol and methylene chloride containing 1-2% methanol to give 1.09 g of the N-formyl derivative 15 which is utilized in the general procedure of step 6 of Example 141 to give Preparation P 138. When in this foregoing procedure compound x-b or compound y-b is substituted for compound 88, Preparations P-139 and and P-140 as set forth below are obtained. R" O R-N N N N O ---- H R'

NH

2 20 Reagent Boc R R" R Preparation Compound No. methoxyacetylchloride 88 O H F P-93 x-b ii x-b CH 3 0H 2 F F P-94 y-b H H P-95 cyanoacetyl chloride 88 O H F P-96 x-b NCCH2__ F F P-97 y-b

NCCH

2 C H H P-98 acetoxyacetyl chloride 88 O O H F P-99 x-b II II F F P-O x-b CH 3

C-O-CH

2 C- F F P-100 y-b H H P-101 - 109- WO 00/32599 PCT/US98/25308 Reagent Boc R R- R Preparation Compound No. benzyloxyacetyl chloride 88 O H F P-102 x-b PhCH 2 0CH 2 c F F P-103 y-b H H P-104 methyl chloroformate 88 O H F P-105 x-b II x-b CH 3 0 - F F P-106 y-b H H P-107 methanesulfonyl chloride 88 CH 3 SO2- H F P-108 x-b F F P-109 y-b H H P-110 ethanesulfonyl chloride 88 H F P-111 x-b CH 3 CH2SO 2 - F F P-112 y-b H H P-113 chloromethanesulfonyl 88 H F P- 114 chloride x-b CICH2SO 2 - F F P-115 y-b H H P-116 cyanomethanesulfonyl 88 H F P- 117 chloride x-b NCCH2SO2- F F P- 118 y-b H H P-119 N-methylsulfamoyl 88 H F P-120 chloride x-b CH 3

NHSO

2 - F F P-121 y-b H H P-122 N,N-dimethylsulfamoyl 88 H F P-123 chloride x-b (CH 3

)

2 NSO2- F F P-124 y-b H H P-125 ethyl chloroformate 88 O H F P-126 x-b

CH

3

CH

2 0- F F P-127 y-b H H P-128 sulfamide 88 H F P-129 x-b HzNSO 2 - F F P-130 y-b H H P-131 chloroacetonitrile 88 H F P-132 x-b NCCH 2 - F F P-133 y-b H H P-134 -110- WO 00/32599 PCT/US98/25308 Reagent Boc R R'" R Preparation Compound No. 2-fluoroethyl bromide 88 H F P-135 x-b FCH2CH,- F F P-136 y-b H H P-137 N-formylbenzotriazole 88 O H F P-138 I I x-b HC- F F P-139 y-b H H P-140 EXAMPLES 142-161: When following the general procedures of Example 141, step 7, an appropriate amount of the amine listed below and the dithio compound from Preparation Z listed below are utilized, the respective products designated as Examples 142 to 400 in Table H are 5 obtained. TABLE H Example Dithio No. Product Amine Compound 142 (S)-N-[[3-[3-Fluoro-4-(4-acetyl- 1-piperazinyl)phenyl]- P-90 Z (a) 2-oxo-5-oxazolidinyl]methyl]propanethioamide; mp 161-162oC; Anal. calcd for Cl 9

H

25

FN

4 0 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, 7.71 143 (S)-N-[[3-[3-Fluoro-4-(4-acetyl- 1-piperazinyl)phenyl]- P-90 Z (b) 2-oxo-5-oxazolidinyl]methyl]-2-methylpropane thioamide 144 (S)-N-[[3-[3-Fluoro-4-(4-acetyl- 1-piperazinyl)phenyl]- P-90 Z (c) 2-oxo-5-oxazolidinyl]methyl]cyclopropanecarbo thioamide; mp 159-160'C; Anal. calcd for

C

2 0

H

25

FN

4 0 3 S: 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. 145 (S)-N-[[3-[3-Fluoro-4-(4-acetyl- 1-piperazinyl)phenyl]- P-90 Z (d) 2-oxo-5-oxazolidinyl]methyl]butanethioamide 146 (S)-N-[[3-[3-Fluoro-4-(4-acetyl- 1 -piperazinyl)phenyl]- P-90 Z (e) 2-oxo-5-oxazolidinyl]methyl]-3-methylbutane thioamide - Ill - WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 147 (S)-N-[[3-13-Fluoro-4-(4-acetyl- 1 -piperazinvl)phenyl]- P-90 Z (f) 2 -oxo-.-oxzolidinyl]methylp2methylbutane thioamide 148 (S)-N-[[3-[3-Fluoro-4-(4-acety[. 1 -piperazinvl)phenyl]- P-90 Z (g) 2 -oxo-5-oxazolidinyl]methyl]y3,3-dimethylbutane thioamide 149 (S)-N-[[3- [3-Fluoro-4-(4-acetyl- 1 -piperazinyl )phenyl]- P-90 Z (h) 2 -oxo-5-oxazolidinyl~methyl]cyclobutanecarbo thioamide 150 (S)-N-[[3-[3-Fluoro-4-(4-acetyl- I -piperazinyl )phenyl]- P-90 Z (i) 2 -oxo-5-oxazolidinyllmethyljcyclopentanecarbo thioamide 151 (S)-N-iI[3-[3-Fluoro-4-(4-acetyl- I -piperazinyl )phenyl]- P-90 Z() 2 -oxo-5-oxazolidinyllmethyl]cyclohexanecarbo thioamide 152 (S)-N-[[3-[3-Fluoro-4-(4-acetyl- I -piperazinyl)phenyl]- P-90 Z (k) 2 -oxo-5-oxazolidinyl]methyl]-2-cyclopropylethane thioamide 153 (S)-N-[[3-[3-Fluoro-4-(4-acetyl. 1 -piperazinyl )phenyl]- P-90 Z (1) 2 -oxo-5-oxazolidinyl]methyl]-2-cyclobutylethane thioamide 154 (S)-N-II[3-13-Fluoro-4-(4-acetyl- 1 -piperazinvl)phenyl]- P-90 Z (in) 2 -oxo-5-oxazolidinyl]methyly2-cyclopentylethane thioamide 155 (S)-N-[13-[35-Difluoro-4-(4-acetyl- I -piperazinyl)- P-9 1 Ethyl phenyl]- 2 -oxo-5-oxazolidinyl]methyllthioacetamide dithio acetate 156 (S)-N-[[3- [3.5-Difluoro4(4-acety[. I -piperazinyl)- P-91I Z (a) phenyl ]- 2 -oxo-5-oxazolidinyl]methyl ]propane thioamide 157 (S)-N-I[3-[3.5-Difluoro-4-(4-acety[- 1 -piperazinyl)- P-91I Z (b) phenyl]1- 2 -oxo-5-oxazolidinyl]methylp2-methyl propanethioamide WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 158 (S)-N-[[3-[3.5-Difluoro-4-(4-acetyl- 1 -piperazinyl)- P-9 1 Z (c) phenyl]- 2 -oxo-5-oxazolicdinyljmethyl]cyclopropane carbothioamide 159 (S)-N-113-4-(4-Acetyl- I -piperazinyl)phenyl]-2-oxo-5- P-92 Ethyl oxazolidinyl] methyl]thioacetamide dithio acetate 160 (S)-N-[jI3-[4-(4-Acetyl- I -piperazinyl)phenyl]-2-oxo-5- P-92 Z (a) oxazol idi nylI] methy I Ipropane thioarnide 161 (S)-N-II[3-[4-(4-Acetyl- I -piperazinyl)phenyl]-2-oxo-5- P-92 Z (b) oxazolidinyl]methyl]-2-methylpropanethioamide 162 (S)-N-[[3-[4-(4-Acetyl- Il-piperazinvl)phenyl]-2-oxo-5- P-92 Z (c) oxazolidinylimethyl ]cyclopropanecarbothioamide 163 (S)-N-[[3- [ 3 -Fluoro-4-[4-(methoxyacetyly I1- P-93 Ethyl piperazinyllphenyl]-2-oxo5oxazolidinyllmethyly- dithio thioacetamide acetate 164 (S)-N-[[ 3 -[3-Fluoro-4-[4-(methoxyacetyl) I1- P-93 Z (a) piperazinyllphenyl]-2-oxo-5-oxazolidinyl]methyl]. propane thioamide 165 (S)-N-[[3- [ 3 -Fluoro-4-[4-(methoxyacetyl)> I - P-93 Z (b) piperazinyllphenyl]-2-oxo-5-oxazolidinylmethyl.2 methylIpropane thiloamide 166 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)- I P-93 Z (c) piperazinyllphenyl]-2-oxo-5oxazoidinyljmthylI cyclopropanecarbothioan-ude 167 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)- Il P-93 Z (d) piperazinyllphenyl]-2-oxo-5-oxazolidiny]methy1> butanethioamide 168 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)1 P-93 Z (e) piperazinyllphenyl]-2-oxo-5-oxazolidinyl]methyl]-3 methylIbutane th ioamide 169 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)- 1- P-93 Z (f) piperazinyljphenyl]-2-oxo-5-oxazoldinyllmethyl].2 methylbutanethioamide -113 - WO 00/32599 PCTIUS98/25308 Example Dithio No. Product Amine Compound 170 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)>1I. P-93 Z (g) piperazinyllphenyl]-2-oxo-5-oxazoldinyl]methyly3.3 dimethylbutanethioamide 171 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyly I1- P-93 Z (h) piperazinyljphenyl

]-

2 -oxo-5-oxazolidinyl]methyl]p cyclobutanecarbothioamide 172 (S)-N-[[3- [ 3 -Fluoro-4-[4-(methoxyacetyl)- I1- P-93 Z (i) piperazinyl]phenyl

]-

2 -oxo-5-oxazolidinyllmethylj cyclopentanecarbothioamide 173 (S)-N-[[3- [3-Fluoro-4- [4-(methoxyacetyl)- I1- P-93 Z() piperazinyllphenyl]-2-oxo-5-oxazolidinyllmethyly cyclohexanecarbothioamide 174 (S)-N-[[3- [3-Fluoro-4- [4-(methoxyacetyl)-1- P-93 Z (k) piperazinyljphenyl]-2-oxo-5-oxazolidinyljmethyl]-2 cyclopropylethanethioamide 175 (S)-N-[[3- [3-Fluoro-4- [4-(methoxyacetyl)- 1 - P-93 Z (1) piperazinyl ]phenyl ]- 2 -oxo-5-oxazolidinyllmethyl]-2 cyclobutylethanethioamide 176 (S)-N-[[3- [3-Fiuoro-4- [4-(methoxyacetyl)- I1- P-93 Z (in) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl-2 cyclopentylethanethioamide 177 (S)-N-[[3-[3,5-Difluoro.j4-[4-(methoxyacetyl)- 1- P-94 Ethyl piperazinyllphenyl]-2-oxo-5oxazolidinyl]methyl]- dithio thioacetamide acetate 178 (S)-N-[[3-[3,5-Difluoro4-44(methoxyacetyl)- 1- P-94 Z (a) piperazinyl Iphenyl I- 2 -oxo-5-oxazolidinyljmethyl] propane thioamide 179 (S)-N-[[ 3 -[3.5-.Difluoro-[4-[4-(methoxyacetyl). I - P-94 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyllmethyl-2 methy Ipropane thi oamide 180 (S)-N-[[ 3 -[3,5-Difluoro-[4-[4-(methoxvacety1- I1- P-94 Z (c) piperazinyllphenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 181 (S)-N-[[3-[4-[4-(methoxyacetyl)- 1-piperazinyl]phenyl]- P-95 Ethyl 2-oxo-5-oxazolidinyl]methyl]thioacetamide dithio acetate 182 (S)-N-[[3-[4-[4-(methoxyacetyl)- 1 -piperazinyl]phenyl]- P-95 Z (a) 2-oxo-5-oxazolidinyl]methyl]propanethioamide 183 (S)-N-[[3-[4-[4-(methoxyacetyl)- 1-piperazinyl]phenyl]- P-95 Z (b) 2 -oxo-5-oxazolidinyl]methyl]-2-methylpropane thioamide 184 (S)-N-[[3-[4-[4-(methoxyacetyl)- I -piperazinyl]phenyl]- P-95 Z (c) 2-oxo-5 oxazolidinyl]methyl]cyclopropanecarbothioamide 185 (S)-N-[[ 3 -[3-Fluoro-4-[4-(cyanoacetyl)- 1 -piperazinyl]- P-96 Ethyl phenyl]- 2 -oxo-5-oxazolidinyl]methyl]thioacetamide dithio acetate 186 (S)-N-[[3-[ 3 -Fluoro-4-[4-(cyanoacetyl)- I -piperazinyl]- P-96 Z (a) phenyl]- 2 -oxo-5-oxazolidinyl]methyl]propanethio amide 187 (S)-N-[[3-[ 3 -Fluoro-4-[4-(cyanoacetyl)- 1 -piperazinyl]- P-96 Z (b) phenyl]- 2 -oxo-5-oxazolidinyl]methyl]-2-methyl propanethioamide 188 (S)-N-[[ 3 -[3-Fluoro-4-[4-(cyanoacetyl)- I -piperazinyl]- P-96 Z (c) phenyl]- 2 -oxo-5-oxazolidinyl]methyl]cyclopropane carbothioamide 189 (S)-N-[[3-[3,5-Difluoro-4-[4-(cyanoacetyl)- 1- P-97 Ethyl piperazinyllphenyl]-2-oxo-5-oxazolidinyl]- dithio methyl]thioacetamide acetate 190 (S)-N-[[ 3

-[

3 .5-Difluoro-4-[4-(cyanoacetyl)- 1- P-97 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]propanethioamide 191 (S)-N-[[3-[3,5-Difluoro-4-[4-(cyanoacetyl)- 1- P-97 Z (b) piperazinyl]phenyl]- 2 -oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 192 (S)-N-[[3-[3.5-Difluoro-4-[4-(cyanoacetyl)- 1- P-97 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]cyclopropanecarbothioamide -115- WO 00/32599 PCTIUS98/25308 Example Dithio No. Product Amine Compound 193 (S)-N-[[3-[4-[4-(Cyanoacetyl). I -piperazinyl]phenyl]-2- P-98 Ethyl oxo-5 -oxazol idinyl I]methyl Jthioacetamid e dithio acetate 194 (S)-N-[13-[4-[4-(Cyanoacetyl)y 1 -piperazinyllphenyl]-2- P-98 Z (a) oxo-5-oxazoildinyl] methyllpropanethioamide 195 (S)-N-[[3-[4-14-(Cyanoacetyl)> I -piperazinyllphenyl]-2- P-98 Z (b) oxo-5-oxazolidinyl] methyl ]- 2 -methylpropanethioamide 196 (S)-N-[[3-[4-[4-(Cyanoacetyl)y 1 -piperazinyllphenyl]-2- P-98 Z (c) oxo-5-oxazolidinyl] methllcycopropanecarbothio amide 197 (S)-N-[[ 3 -[3-Fluoro-4-[4-(acetoxyacetyl)- I1- P-99 Ethyl piperazinyllphenylj-2oxo-5oxazolidinyllmethyll- dithio thioacetamide acetate 198 (S)-N- [[3 -[3 -Fl uoro-4- [ 4 -(ace toxyacetyl)- 1 - P-99 Z (a) piperazinyl]phenyl]-2-oxo..5-.oxazolidinyljmethylp propanethioamide 199 (S)-N-II[ 3

-[

3 -Fluoro-4-[4-(acetoxyacetyl)-I P-99 Z (b) piperazinyl]phenylI-2-oxo5-oxazolidinyllmethyll-2 methylIpropane thi oamide 200 (S)-N-[[3- [3-Fluoro-4- E 4 -(acetoxyacetyl)- I1- P-99 Z (c) piperazinyllphenvl]-2-oxo5oxazoldinyl]methylp cyclopropanecarbothioan-Lde 201 (S)-N-II[3- [ 3 -Fluoro-4-[4-(acetoxyacetyl). 1- P-99 Z (d) piperazinyliphenvl]-2-oxo5oxazolidinyljmethyly. butanethioamide 202 (S)-N-[[ 3

-[

3 -Fluoro-4-[4(acetoxyacetyl)l P-99 Z (e) piperazinyllphenyI1-2-oxo-5-oxazolidinyl]methylp-3 methylbutanethioamide 203 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(acetoxyacetyl).Ij P-99 Z (f) piperazinyllphenvl 1- 2 -oxo-5-oxazolidinyllmethyl-2-. methylbutanethioamide 204 (S)-N-[ [3- [3-Fluoro-4-[14-( acetoxyacetyl)- I1- P-99 Z (g) piperazinyljphenvl]-2-oxo5oxazolidinyl]methyly.3,3 dimethylbutanethioamide - 116- WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 205 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyvacetyl)>I1 P-99 Z (h) piperazinyl]phenyl]-2-oxo-5oxazoldinljmethyl] cyclobutanecarbothioamide 206 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl).I1 P-99 Z (i) piperazinyllphenyl]-2-oxo-5-oxazolidinyl~methyl]p cyc lope ntanec arboth ioami de 207 (S)-N-[[3- [ 3 -Fluoro-4-[4-(acetoxyacetyl)- 1- P-99 Z() piperazinyllphenyl]-2-oxo-5oxazolidinyllmethyl].. cyclohexanecarbothioamide 208 (S)-N-[[3- [ 3 -Fluoro-4-[4-(acetoxyacetyl)- 1- P-99 Z (k) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 cyclopropylethanethioamide 209 (S)-N-[[3-[3-Fluoro-4-

[

4 -(acetoxyacetyl)- 1 - P-99 Z (1) piperazinyllphenyll-2-oxo-5-oxazolidinyl]methyl]y2. cyclobutylethanethioamide 210 (S)-N-[[3- [3-Fluoro-4- [4-(acetoxyacetyl)- 1 - P-99 Z (in) piperazinyljphenyl]-2-oxo-5-oxazolidinylimethyl-2 cyclopentylethanethioamide 211 (S)-N-[[3- [3 ,-Difluoro-4-[4-(acetoxyacetyI 1- P-I100 Ethyl piperazinyllphenyl]-2-oxo-5-oxazolidinyllmethyl]. dithio thioacetamide acetate 22 (S)-N-[[3-[3,5-Difluoro-4-[4(aeoyct1I- P- 100 Z(a piperazinyllphenyl]-2-oxo-5-oxazoidinyl]methy] propane thioamide 213 (S)-N-[[3-[3,5-Difluoro-4-[4-(acetoxyacetyl)- I - P- 100 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyllmethyl-2 methylpropanethioamide 214 (S)-N-[[ 3 -[3.5-Difluoro-4-[4-(acetoxvacetyl)> 1- P- 100 Z (c) piperazinyl~phenyl]-2-oxo-5-oxazolidinyljmethyl]p cyc lo pro pan ec arboth io amide 215 (S)-N-[[3-[4-[4-(Acetoxyacetyl>- 1 -piperazinyl]phenyl]- P-I101 Ethyl 2-oxo-5-oxazolidiny llmethyl]thioacetamide dithio acetate 216 (S)-N-[[3-[4-[4-(Acetoxyacetyl)- I -piperazinyl]phenyl]- P-i101 Z (a) 2-oxo-5-oxazolidlinyil]methvllpropanethioamide - 117 - WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 217 (S)-N-[[ 3 -[4-[4-(Acetoxyacetyl)- I -piperazinyl]phenyl]- P-101 Z (b) 2 -oxo-5-oxazolidinyl]methyl]- 2 -methylpropane thioamide 218 (S)-N-[[3-[4-[4-(Acetoxyacetyl)- I -piperazinyl]phenyl]- P-101 Z (c) 2 -oxo-5-oxazolidinyl]methyl]cyclopropanecarbo thioamide 219 (S)-N-[[3-[3-Fluoro-4-[4-(benzyloxyacetyl)- 1- P-102 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methylj- dithio thioacetamide acetate 220 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(benzyloxyacetyl) I - P-102 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]j propanethioamide 221 (S)-N-[[3-[ 3 -Fluoro- 4 -[4-(benzyloxyacetyl)- 1- P-102 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 222 (S)-N-[[3-[ 3 -Fluoro-4-[4-(benzyloxyacetyl)- 1- P- 102 Z (c) piperazinyl]phenyl]- 2 -oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 223 (S)-N-[[ 3 -[3,5-Difluoro-4-[4-(benzyloxyacetyl)- I1- P-103 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 224 (S)-N-[[ 3

-[

3 .5-Difluoro-4-[4-(benzyloxyacetyl)- I - P-103 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 225 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(benzyloxyacetyl)- 1 - P-103 Z (b) piperazinyl]phenyl]- 2 -oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 226 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(benzyloxyacetyl)- 1- P-103 Z (c) piperazinyllphenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 227 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(methoxycarbonyl)- I - P-105 Ethyl piperazinyl]phenyl]-2-oxo-5- dithio oxazolidinyljmethyl]thioacetamide acetate -118- WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 228 (S)-N-[[ 3 -[3-Fluoro-4-[4-(methoxycarbonyl)- I - P-I105 Z (a) piperazinyl]phenyl]-2-oxo-5oxazoldinvljmethyl]j propane thioarmde 229 (S)-N-[[ 3- [3-Fluoro-4- [4-(methoxvcarbonyi )- 1 - P-I105 Z (b) piperazinyllphenyl]-2-oxo-5-oxazolidinyllmethylj2-? methylpropanethioamide 230 (S)-N- [[3- [ 3 -Fluoro-4-[4-(methoxycarbonyl )- 1 - P-l05 Z (C) piperazinyllphenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 23 1 (S)-N-[[ 3 -[3-Fluoro-4-[4-(methoxycarbonyl). 1 - P-105 Z (d) piperazinyllphenyl]-2-oxo-5-oxazolldinyljmethvlj.. butanethioamide 232 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(methoxycarbonyl..I1 P-105 Z (e) piperazinyljphenyl]-2-oxo-5-oxazolidinyl]methyl-3 methylbutanethioamide 233 (S)-N- [13- [3-Fluoro-4- [4-(methoxycarbonyl)- I - P-105 Z (f) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl~methyl-2 methylbutanethioamide 234 (S)-N-[[3- [3-Fluoro-4- [4-(methoxycarbonyl)- 1 - P-105 Z (g) piperazinyliphenyllj-2-oxo-5-oxazolidinyllmethyl]-3,3. dime thylbutane thi oamide 235 (S)-N-[[3-[3-Fluoro-4-[4-(methoxvcarbonyl)- 1- P-l05 Z (h) piperazinyllphenyl]-2-oxo-5-oxazolidinyljmeth1I]. cyclobutanecarbothioamide 236 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl) 1 - P-lO5 Z (i) piperazinyl ]phenyl]- 2 -oxo-5-oxazolidinvl]methylj cyclopentanecarbothioamjdce 237 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)y 1- P-105 Z(j piperazinyl]phenyl]-2-oxo-5-oxazolidinyljmethyly cyclohexanecarbothioamide 238 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl) I - P-105 Z (k) piperazinyllphenyl]-2-oxo-5oxazoldinyl]methyl]-2 cyclopropylethanethioamjdice WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 239 (S)-N-[[ 3 -[3-Fluoro-4-[4-(methoxycarbonyl)- 1- P-105 Z (1) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 cyclobutylethanethioamide 240 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)- I1- P-105 Z (m) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 cyclopentylethanethioamide 241 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(methoxycarbonyl)- 1- P-106 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 242 (S)-N-[[ 3

-[

3 .5-Difluoro-4-[4-(methoxycarbonyl)- 1- P-106 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 243 (S)-N-[[ 3 -[3,5-Difluoro-4-[4-(methoxycarbonyl)- 1 - P-106 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 244 (S)-N-[[3-[3,5-Difluoro-4-[4-(methoxycarbonyl)- 1- P-106 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioanmide 245 (S)-N-[[ 3

-[

4 -[4-(methoxycarbonyl)- 1- P-107 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 246 (S)-N-[[ 3 -[4-[4-(methoxycarbonyl)- 1- P-107 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 247 (S)-N-[[3-[4-[4-(methoxycarbonyl)- 1- P-107 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 248 (S)-N-[[3-[4-[4-(methoxycarbonyl)-

-

P-107 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]inethyl] cyclopropanecarbothioamide 249 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(methanesulfonyl)- 1- P-108 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide: mp 197-198 0 C: Anal. calcd for acetate

C

17 H2 3

FN

4 0 4 S2: 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. - 120- WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 250 (S)-N-[[3-[3-Fluoro-4-[4-(methanesulfonyl)- 1- P-108 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide: mp 207-208 0 C: Anal. calcd for Ci 8 H25FN 4 04S 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. 251 (S)-N-[[ 3 -[3-Fluoro-4-[4-(methanesulfonyl)- 1 - P-108 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide; mp 204-206'C; Anal. calcd for CI 9

H

27

FN

4 0 4 S2: 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. 252 (S)-N-[[3-[ 3 -Fluoro-4-[4-(methanesulfonyl)- 1 - P-108 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide; Anal. called for

C

1 gH 2 5

FN

4 0 4

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. 253 (S)-N-[[3-[3,5-Difluoro-4-[4-(methanesulfonyl)- 1- P-109 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 254 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(methanesulfonyl)- 1- P- 109 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 255 (S)-N-[[ 3 -[3,5-Difluoro-4-[4-(methanesulfonyl)- 1- P-109 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 256 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(methanesulfonyl)- 1- P-109 Z (c) piperazinyl]phenyl]- 2 -oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioanmide 257 (S)-N-[[3-[4-[4-(methanesulfonyl)-1- P- 110 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 258 (S)-N-[[3-[4-[4-(methanesulfonyl)- 1- P-110 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 259 (S)-N-[[3-[4-[4-(methanesulfonyl)- 1- P-110 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]j-2 methylpropanethioamide - 121 - WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 260 (S)-N-[[3-[4-[4-(methanesulfonyl)-1- P-110 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 261 (S)-N-[[3-[3-Fluoro-4-[4-(ethanesulfonyl)- 1- P-111 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 262 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(ethanesulfonyl)-1- P-111 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 263 (S)-N-[[ 3 -[3-Fluoro-4-[4-(ethanesulfonyl)-1- P-111 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 264 (S)-N-[[ 3 -[3-Fluoro-4-[4-(ethanesulfonyl)-1- P-111 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 265 (S)-N-[[ 3 -[3,5-Difluoro-4-[4-(ethanesulfonyl)- 1- P-112 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinylmethyl]- dithio thioacetamide acetate 266 (S)-N-[[3-[ 3 ,5-Difluoro-4-[4-(ethanesulfonyl)- I - P-112 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 267 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(ethanesulfonyl)- 1- P-112 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 268 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(ethanesulfonyl)- 1- P-112 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 269 (S)-N-[[3-[4-[4-(ethanesulfonyl)- 1 -piperazinyl]phenyl]- P-l 3 Ethyl 2 -oxo-5-oxazolidinyl]methyl]thioacetamide dithio acetate 270 (S)-N-[[3-[4-[4-(ethanesulfonyl)- I -piperazinyl]phenyl]- P-113 Z (a) 2-oxo-5-oxazolidinyl]methyl]propanethioamide 271 (S)-N-[[3-[4-[4-(ethanesulfonyl)- I -piperazinyl]phenyl]- P-113 Z (b) 2-oxo-5-oxazolidiny l]methyl]-2-methylpropane thioamide - 122- WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 272 (S)-N-[[3-[4-[4-(ethanesulfonyl)- 1-piperazinyl]phenyl]- P- 113 Z (c) 2 -oxo-5-oxazolidinyl]methyl]cyclopropanecarbothio amide 273 (S)-N-[[3-[3-Fluoro-4-[ 4 -(chloromethanesulfonyl)- 1- P-114 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 274 (S)-N-[[3-[3-Fluoro-4-[4-(chloromethanesulfonyl)- 1- P-114 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 275 (S)-N-[[3-[ 3 -Fluoro-4-[4-(chloromethanesulfonyl)- 1- P-114 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 276 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(chloromethanesulfonyl)- 1- P-114 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 277 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(chloromethanesulfonyl)- P- 115 Ethyl 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyll- dithio thioacetamide acetate 278 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(chloromethanesulfonyl)- P-115 Z (a) 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 279 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(chloromethanesulfonyl)- P-115 Z (b) 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 280 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(chloromethanesulfonyl)- P-115 Z (c) 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 281 (S)-N-[[3-[4-[4-(chloromethanesulfonyl)- I- P-116 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 282 (S)-N-[[3-[4-[4-(chloromethanesulfonyl)- 1 - P-116 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide - 123- WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 283 (S)-N-[[3-[4-[4-(chloromethanesulfonyl)- 1- P-116 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 284 (S)-N-[[3-[4-[4-(chloromethanesulfonyl)- 1- P-116 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 285 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(cyanomethane-sulfonyl)- 1- P-117 Ethyl piperazinyl]phenyl]-2-oxo-5- dithio oxazolidinyl]methyl]thioacetamide acetate 286 (S)-N-[[3-[3-Fluoro-4-[ 4 -(cyanomethane-sulfonyl)- 1- P-117 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 287 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(cyanomethane-sulfonyl)- I- P- 117 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 288 (S)-N-[[3-[ 3 -Fluoro-4-[4-(cyanomethane-sulfonyl)- 1- P-117 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamnide 289 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(cyanomethane-sulfonyl)- P- 118 Ethyl 1-piperazinyl]phenyl]-2-oxo-5- dithio oxazolidinyl]methyl]thioacetamide acetate 290 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(cyanomethane-sulfonyl)- P- 118 Z (a) 1 -piperazinyl]phenyl]- 2 -oxo-5-oxazolidinyl] methyl]propanethioamide 291 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(cyanomethane-sulfonyl)- P-118 Z (b) 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 292 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(cyanomethane-sulfonyl)- P-118 Z (c) 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 293 (S)-N-[[ 3 -[4-[4-(Cyanomethanesulfonyl)- 1- P-119 Ethyl piperazinyl]phenyl]-2-oxo-5- dithio oxazolidinyl]methyl]thioacetamide acetate - 124- WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 294 (S)-N-[[3-[4-[4-(Cyanomethanesulfonyl)- 1- P-119 Z (a) piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]propanethioamide 295 (S)-N-[[3-[4-[4-(Cyanomethanesulfonyl)- 1- P-119 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 296 (S)-N-[[3-[4-[4-(Cyanomethanesulfonyl)- 1- P-119 Z (c) piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]cyclopropanecarbothioamide 297 (S)-N-[[3-[ 3 -Fluoro-4-[4-(N-methylsulfamoyl)- 1- P-120 Ethyl piperazinyl]phenyl]-2-oxo-5- dithio oxazolidinyl]methyl]thioacetamide acetate 298 (S)-N-[[ 3 -[3-Fluoro-4-[4-(N-methylsulfamoyl)- I- P-120 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 299 (S)-N-[[3-[3-Fluoro-4-[4-(N-methylsulfamoyl)- 1- P- 120 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 300 (S)-N-[[3-[ 3 -Fluoro-4-[4-(N-methylsulfamoyl)- 1- P- 120 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 301 (S)-N-[[3-[3,5-Difluoro-4-[4-(N-methylsulfamoyl)- I - P-121 Ethyl piperazinyl]phenyl]-2-oxo-5- dithio oxazolidinyl]methyl]thioacetamide acetate 302 (S)-N-[[3-[3,5-Difluoro-4-[4-(N-methylsulfamoyl)- 1- P-121 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 303 (S)-N-[[3-[3,5-Difluoro-4-[4-(N-methylsulfamoyl)- I - P-121 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 304 (S)-N-[[3-[3.5-Difluoro-4-[4-(N-methylsulfamoyl)- I - P-121 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide - 125 - WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 305 (S)-N-[[3-[4-[4-(N-methylsulfamoyl)-

-

P-122 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 306 (S)-N-[[3-[4-[4-(N-methylsulfamoyl)- 1- P-122 Z (a) piperazinyl]phenyl]- 2 -oxo-5-oxazolidinyl]methyl] propanethioamide 307 (S)-N-[[3-[4-[4-(N-methylsulfamoyl)- I - P-122 Z (b) piperazinyl]phenyl]- 2 -oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 308 (S)-N-[[3-[4-[4-(N-methylsulfamoyl)- 1- P-122 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyll cyclopropanecarbothioamide 309 (S)-N-[[3-[ 3 -Fluoro-4-[4-(N,N-dimethylsulfamoyl)- 1- P-123 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 310 (S)-N-[[3-[3-Fluoro-4-[ 4 -(N,N-dimethylsulfamoyl)- I - P-123 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 311 (S)-N-[[3-[ 3 -Fluoro-4-[4-(N,N-dimethylsulfamoyl)- 1- P-123 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 312 (S)-N-[[3-[3-Fluoro-4-[4-(N,N-dimethylsulfamoyl)- 1- P-123 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 313 (S)-N-[[3-[3,5-Difluoro-4-[4-(N,N-dimethylsulfamoyl)- P-124 Ethyl l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 314 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(N,N-dimethylsulfamoyl)- P-124 Z (a) 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 315 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(N,N-dimethylsulfamoyl)- P-124 Z (b) I -piperazinylJphenyl]-2-oxo-5-oxazolidinyl]methyll-2 methylpropanethioamide -126- WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 316 (S)-N-[[3-[3,5-Difluoro-4-[4-(N.N-dimethylsulfamoyl)- P-124 Z (c) 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 317 (S)-N-[[3-[4-[4-(N,N-dimethylsulfamoyl)- 1 - P-125 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 318 (S)-N-[[3-[4-[4-(N,N-dimethylsulfamoyl)-1- P-125 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 319 (S)-N-[[3-[4-[4-(N,N-dimethylsulfamoyl)- 1- P-125 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 320 (S)-N-[[3-[4-[4-(N,N-dimethylsulfamoyl)-1- P-125 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 321 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)- 1- P-126 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio thioacetamide acetate 322 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)- 1- P-126 Z (a) piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 323 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1 - P-126 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 324 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)- 1- P-126 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 325 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)- 1- P-126 Z (d) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] butanethioamide 326 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)- 1- P-126 Z (e) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-3 methylbutanethioamide - 127- WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 327 (S)-N- [[3- [3-Fluoro-4-[4-(ethoxycarbonyl)- 1 - P-i126 Z (f) piperaziny11phenyI]-2-oxo-5-oxazolidinyI~methyI]l methyl butane thioamide 328 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1I- P-126 Z (g) piperazinyllphenyl]-2-oxo-5-oxazoldinyllmethyl]-3,3 dime thy lbu tanethi oamide 329 (S)-N- [[3- [3-Fluoro-4-[4-(ethoxycarbonyl)- 1 - P-i126 Z (h) piperazinyl]phenylll-2-oxo-5-oxazolidinyl] methyl] cyclobutanecarbothioamide 330 (S)-N-[[3- [3-Fluoro-4- [4-(ethoxycarbonyl)- 1- P-I126 Z (i) piperazinyl]phenyl]-2-oxo-5-oxazolidinyllmethyl] cyclopentanecarbothioamide 331 (S)-N-[[3- [3-Fluoro-4-[4-(ethoxycarbonyl)- I - P-I126 Z j piperazinyl]phenyl]-2-oxo-5-oxazoildinyllmethyl]y cyclohexanecarbothioamide 332 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl) 1- P-i126 Z (k) piperazinyllphenyl]-2-oxo-5-oxazolidinyllmethyll cyclopropylethanethioamnide, 333 (S)-N-[[3- [3-Fluoro-4-[4-(ethoxycarbonyl)- 1 - P-i126 Z (1) piperazinylllphenyl]-2-oxo-5-oxazolidinyllmethyll-2 cyclobutylethanethioamiude 334 (S)-N- [[ 3 -[3-Fluoro-4-[4-(ethoxycarbonyl)- I1- P-i126 Z (in) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 cyc lope nty le thane thioamide 335 (S)-N-[[3-[3,5-Difiuoro-4-[4-(ethoxycarbonyl)- 1- P- 127 Ethyl piperazinyllphenyl]-2-oxo-5-oxazolidinyllmethyly- dithio thioacetmide acetate 336 (S)-N-[[3-[3.5-Difluoro-4-[4-(ethoxycarbonyl)- I P-127 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyi> propane th i oamide 337 (S)-N-[[3-[3.5-Difluoro-4-[4-(ethoxycarbonyl)- I - P-i127 Z (b) piperazinvl~phenyl]-2-oxo-5-oxazolidinyljmethyl]-2) methyl propane thi oam ide - 128 - WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 338 (S)-N-[[3-[3,5-Difluoro-4-[4-(ethoxycarbonyl)- 1- P-127 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 339 (S)-N-[[3-[4-[4-(ethoxycarbonyl)- 1-piperazinyl]- P-128 Ethyl phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide dithio acetate 340 (S)-N-[[3-[4-[4-(ethoxycarbonyl)- 1-piperazinyl]- P-128 Z (a) phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 341 (S)-N-[[3-[4-[4-(ethoxycarbonyl)- 1-piperazinyl]- P-128 Z (b) phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 342 (S)-N-[[ 3

-[

4 -[4-(ethoxycarbonyl)- 1-piperazinyl]- P-128 Z (c) phenyl]- 2 -oxo-5-oxazolidinyl]methyl]cyclopropane carbothioamide 343 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- 1 -piperazinyl)- P-129 Ethyl phenyl]- 2 -oxo-5-oxazolidinyl]methyl]thioacetamide dithio acetate 344 (S)-N-[[3-[ 3 -Fluoro-4-(4-sulfamoyl- 1 -piperazinyl)- P-129 Z (a) phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 345 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- -piperazinyl)- P-129 Z (b) phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 346 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- 1 -piperazinyl)- P-129 Z (c) phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 347 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- 1 - P-129 Z (d) piperazinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]butanethioamide 348 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- - P-129 Z (e) piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-3 methylbutanethioamide - 129- WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 349 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1 I- P-129 Z (f) piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylbutanethioamide 350 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- 1- P-129 Z (g) piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-3,3 dimethylbutanethioamide 351 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- 1- P-129 Z (h) piperazinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]cyclobutanecarbothioamide 352 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- 1- P-129 Z (i) piperazinyl)phenyl]-2-oxo-5 oxazolidinyl] methyl]cyclopentanecarbothioamide 353 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1- P-129 Z (j) piperazinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]cyclohexanecarbothioamide 354 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- 1- P-129 Z (k) piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 cyclopropylethanethioamide 355 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- 1- P-129 Z (1) piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 cyclobutylethanethioamide 356 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1 I- P-129 Z (m) piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 cyclopentylethanethioamide 357 (S)-N-[[3- [3.5-Difluoro-4-(4-sulfamoyl- I - P-130 Ethyl piperazinyl)phenyl]-2-oxo-5- dithio oxazolidinyl]methyl]thioacetamide acetate 358 (S)-N-[[3-[3.5-Difluoro-4-(4-sulfamoyl- 1- P-130 Z (a) piperazinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]propanethioamide 359 (S)-N-[[3-[3.5-Difluoro-4-(4-sulfamoyl-1- P-130 Z (b) piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide -130- WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 360 (S)-N-[[3-[3.5-Difluoro-4-(4-sulfamoyl- I1- P-130 Z (c) piperazinyl)phenyl]-2-oxo-5 oxazolidinyl]methyllcyclopropanecarbothioamide 361 (S)-N-[[3-[4-(4-sulfamoyl- I -piperazinyl)phenyl]-2-oxo- P-131 Ethyl 5-oxazolidinyl]methyl]thioacetamide dithio acetate 362 (S)-N-[[3-[4-(4-sulfamoyl- I -piperazinyl)phenyl]-2-oxo- P-131 Z (a) 5-oxazolidinyl]methyl]propanethioamide 363 (S)-N-[[3-[4-(4-sulfamoyl- I -piperazinyl)phenyl]-2-oxo- P-131 Z (b) 5-oxazolidinyl]methyl]-2-methylpropanethioamide 364 (S)-N-[[3-[4-(4-sulfamoyl- 1 -piperazinyl)phenyl]-2-oxo- P-131 Z (c) 5-oxazolidinyl]methyl]cyclopropanecarbothioamide 365 (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethyl)- 1- P-132 Ethyl piperazinyl]phenyl]-2-oxo-5- dithio oxazolidinyl]methyl]thioacetamide acetate 366 (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethyl)- 1- P-132 Z (a) piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]propanethioamide 367 (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethyl)- 1- P-132 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 368 (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethyl)- 1- P-132 Z (c) piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]cyclopropanecarbothioamide 369 (S)-N-[[3-[3,5-Difluoro-4-[4-( cyanomethyl)- 1- P-133 Ethyl piperazinyl]phenyl]-2-oxo-5- dithio oxazolidinyl]methyl]thioacetamide acetate 370 (S)-N-[[3-[3,5-Difluoro-4-[4-( cyanomethyl)-1 - P-133 Z (a) piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]propanethioamide 371 (S)-N-[[3-[3,5-Difluoro-4-[4 cyanomethyl)-l- P-133 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide - 131 - WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 372 (S)-N-[[ 3

-[

3 ,5-Difluoro-4-[4-(cyanomethyl)-Il P- 33 Z (c) piperazinyllphenyl]-2oxo-5oxaolidinyl~meth1]. cyclopropanecarbothioamide 373 (S)-N-[[3-[4-[4-(cyanomethyl). 1 -piperazinyl]phenyl]-2- P-I 134 Ethyl oxo-5-oxazolidinyl] methyllthioacetamide dithio acetate 374 (S)-N-[[3- [4-[4-(cyanomethyl)y 1 -piperazinyl]phenyl]-2- P-I 134 Z (a) oxo-5-oxazolidinyllmethyl]propanethioamide 375 (S)-N-[[3-[4-[1 4 -(cyanomethyl)- I -piperazinyllphenyl]-2- P-I134 Z (b) oxo-5 -oxazol idinyllImethyl J 2 me thyl propane th Ioamide 376 (S)-N-[[3-[4-[4-( cyanomethyl)- 1 -piperazinyl]phenyl]- P-i 134 Z (c) 2 -oxo-5-oxazoildinyllmethyl Icyclopropane carbothioamide 377 (S)-N-[I[ 3

-[

3 -Fluoro-4-[4-(2-fluoroethyl)y I - P-i135 Ethyl piperazinyl]phenyl]-2-oxo-5- dithio oxazolidinyl]methyl]thioacetamide acetate 378 (S)-N-[[3-[3-Fluoro-4-[4-(2-fIuoroethyl)yIl P- 135 Z (a) piperazinyllphenyl]-2-oxo-5 oxazolidinyl]methyl]propanethioamide 379 (S)-N-[13-[3-Fluoro-4-[4-(2-fluoroethyl).I.- P- 135 Z (b) plperazinyllphenyl]-2-oxo-5oxazolidinyl ]methyl]-2 methylIpropane thi oamide 380 (S)-N-[[ 3 -[3-Fluoro-4-[4(2-fluoroethyl)- 1- P- 135 Z (c) piperazinyl]phenyl]-2-oxo-5-oxaolidinyllmethyI] cyclopropanecarbothioamide 381 (S)-N-[[3-[3,5-Difluoro-4-[4-(2-fluoroethyl). I - P-i136 Ethyl piperazinyl ]phenyl]-2-oxo-5-oxazolhdinyllimethyl]

-

dithio thioacetamide acetate 382 (S)-N-[[3-[3.5-Difluoro-4-[4-(2-fluoroethyl). I - P- 136 Z (a) plperazinyllphenyl]-2-oxo5oxazoldinyllmethyl]p propane thioamide 383 (S)-N-[[3-[3.5-Difluoro-4-[4-(2..fuoroethyl)> 1- P- 136 Z (b) piperazinyllphenyl

I-

2 -oxo-5-oxazolidiny I]methyl]-2 methylIpropane thi1oamide - 132- WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 384 (S)-N-[[3-[3,5-Difluoro-4-[4-(2-fluoroethyl)- 1- P-136 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropanecarbothioamide 385 (S)-N-[[3-[4-[4-(2-fluoroethyl)- 1 -piperazinyl]phenyl]- P-137 Ethyl 2-oxo-5-oxazolidinyl]methyl]thioacetamide dithio acetate 386 (S)-N-[[3-[4-[4-(2-fluoroethyl)- I -piperazinyl]phenyl]- P-137 Z (a) 2-oxo-5-oxazolidinyl]methyl]propanethioamide 387 (S)-N-[[3-[4-[4-(2-fluoroethyl)- 1-piperazinyl]phenyl]- P-137 Z (b) 2 -oxo-5-oxazolidinyl]methyl]-2 methylpropanethioamide 388 (S)-N-[[3-[4-[4-(2-fluoroethyl)- 1-piperazinyl]phenyl]- P-137 Z (c) 2 -oxo-5-oxazolidinyl]methyl]cyclopropane carbothioamide 389 (S)-N-[[3-[3-Fluoro-4-(4-formyl- 1-piperazinyl)phenyl]- P-138 Ethyl 2 -oxo-5-oxazolidinyl]methyl]thioacetamide; Anal calcd dithio for C 17

H

2 1

FN

4 0 3 S: C, 53.67; H, 5.56; N, 14.73; S, acetate 8.43. Found: C, 53.14; H, 5.42; N, 14.25; S, 8.18. 390 (S)-N-[[3-[3-Fluoro-4-(4-formyl- I -piperazinyl)phenyl]- P-138 Z (a) 2 -oxo-5-oxazolidinyl]methyl]propanethioamide; mp 166-167°C; Anal. calcd for C 18 H2 3

FN

4 0 3 S: 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. 391 (S)-N-[[3-[3-Fluoro-4-(4-formyl- 1-piperazinyl)phenyl]- P-138 Z (b) 2 -oxo-5-oxazolidinyl]methyl]-2-methylpropane thioamide: mp 157-158 0 C: Anal. calcd for Cl 9

H

2 5

FN

4 03S: 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. 392 (S)-N-[[3-[3-Fluoro-4-(4-formyl- 1-piperazinyl)phenyl]- P-138 Z (c) 2 -oxo-5-oxazolidinyl]methyl]cyclopropane carbothioamide; mp 178-179 0 C; Anal. calcd for Cl 9

H

2 3 FNaO 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. 393 (S)-N-[[3-[3,5-Difluro-4-(4-formyl- 1-piperazinyl)- P-139 Ethyl phenyl]- 2 -oxo-5-oxazolidinyl]methyl]thioacetamide dithio acetate - 133- WO 00/32599 PCT/US98/25308 Example Dithio No. Product Amine Compound 394 (S)-N-[[3-[3,5-Difluro-4-(4-formyl- 1 -piperazinyl)- P-139 Z (a) phenyl]-2-oxo-5-oxazolidinyl]methyl] propanethioamide 395 (S)-N-[[ 3

-[

3 ,5-Difluro-4-(4-formyl- 1-piperazinyl)- P-139 Z (b) phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methyl propanethioamide 396 (S)-N-[[3-[3,5-Difluro-4-(4-formyl- 1-piperazinyl)- P-139 Z (c) phenyl]- 2 -oxo-5-oxazolidinyl]methyl]cyclo propanecarbothioamide 397 (S)-N-[[3-[4-(4-formyl- I -piperazinyl)phenyl]-2-oxo-5- P- 140 Ethyl oxazolidinyl]methyl]thioacetamide dithio acetate 398 (S)-N-[[3-[4-(4-formyl- I -piperazinyl)phenyl]-2-oxo-5- P- 140 Z (a) oxazolidinyl]methyl]propanethioamide 399 (S)-N-[[3-[4-(4-formyl- I -piperazinyl)phenyl]-2-oxo-5- P-140 Z (b) oxazolidinyl]methyl]-2-methylpropanethioamide 400 (S)-N-[[3-[4-(4-formyl- 1-piperazinyl)phenyl]-2-oxo-5- P- 140 Z (c) oxazolidinyl]methyl]cyclopropane-carbothioamide When in the general procedure of Example 31, step 1, an appropriate amount of the amine listed below is substituted for compound 33, the isothiocyanate corresponding to the amines P-90, P-93, P-99, P-105, P-126 and P-129 are obtained. 5 When in the general procedure of Example 114 an appropriate amount of the isothiocyanate and the amine listed below are substituted for compound 82 and methylamine, the respective products listed below are obtained. TABLE I Isothiocyanate Example Corresponding No. Product to Amine No. Amine 401 (S)-N-[[ 3 -[3-Fluoro-4-(4-acetyl- 1- P-90 methylamine piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] I-N'-methylthiourea -134- WO 00/32599 PCT/US98/25308 Isothiocyanate Example Corresponding No. Product to Amine No. Amine 402 (S)-N-[[3-[3-Fluoro-4-(4-acetyl- 1- P-90 dimethylamine piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-N',N'-dimethylthiourea 403 (S)-N-[[3-[3-Fluoro-4-(4-acetyl- 1- P-90 azetidine piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]- 1 -azetidinecarbothioamide 404 (S)-N-[[ 3

-[

3 -Fluoro-4-(4-thiomorpholinyl)- P-90 anhydrous phenyl]- 2 -oxo-5-oxazolidinyl]methyl]- ammonia thiourea 405 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(methoxyacetyl)- 1- P-93 methylamine piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-N'-methylthiourea 406 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(methoxyacetyl)- I1- P-93 dimethylamine piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-N',N'-dimethylthiourea 407 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(methoxyacetyl)- 1- P-93 azetidine piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]- 1 azetidinecarbothioamide 408 (S)-N-[[3-[ 3 -Fluoro-4-[4-(acetoxyacetyl)- I - P-99 methylamine piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-N'-methylthiourea 409 (S)-N-[[ 3

-[

3 -Fluoro-4-[4-(acetoxyacetyl)- 1- P-99 dimethylamine piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-N',N'-dimethylthiourea 410 (S)-N-[[3-[ 3 -Fluoro- 4 -[4-(acetoxyacetyl)- 1- P-99 azetidine piperazinyl]phenylj-2-oxo-5-oxazolidinyl] methyl]- I -azetidinecarbothioanmide 411 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)- P-105 methylamine 1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-N'-methylthiourea 412 (S)-N-[[3-[ 3 -Fluoro-4-[4-(methoxycarbonyl)- P-105 dimethylamine I -piperazinyl]phenyl]- 2 -oxo-5-oxazolidinyl] methyl]-N',N'-dimethylthiourea - 135- WO 00/32599 PCT/US98/25308 Isothiocyanate Example Corresponding No. Product to Amine No. Amine 413 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)- P-105 azetidine 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]- 1-azetidinecarbothioamide 414 (S)-N-[[3-[ 3 -Fluoro-4-[4-(ethoxycarbonyl)- 1- P-126 methylamine piperazinyl]phenyl]- 2 -oxo-5-oxazolidinyl] methyl]-N'-methylthiourea 415 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)- 1- P-126 dimethylamine piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-N'.N'-dimethylthiourea 416 (S)-N-[[3-[ 3 -Fluoro-4-[4-(ethoxycarbonyl)- I - P-126 azetidine piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]- 1 -azetidinecarbothioamide 417 (S)-N-[[3-[ 3 -Fluoro-4-(4-sulfamoyl- 1- P-129 methylamine piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-N'-methylthiourea 418 (S)-N-[[3-[ 3 -Fluoro-4-(4-sulfamoyl- 1- P-129 dimethylamine piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-N',N'-dimethylthiourea 419 (S)-N-[[3-[ 3 -Fluoro-4-(4-sulfamoyl- 1- P-129 azetidine piperazinyl)phenyl]- 2 -oxo-5-oxazolidinyl] methyl]- I -azetidinecarbothioamide When in the general procedure of Example 100 an appropriate amount of the isothiocyanate and alcohol listed below are utilized in the same manner as Compound 82 and methanol are utilized, the respective products listed below are obtained. 5 TABLE J Isothiocyanate Example Corresponding No. Product to Amine No. Amine 420 (S)-N-[[ 3

-[

3 -Fluoro-4-(4-acetyl- 1- P-90 methanol piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate -136- WO 00/32599 PCT/US98/25308 Isothiocyanate Example Corresponding No. Product to Amine No. Amine 421 (S)-N-[[3-[3-Fluoro-4-(4-acetyl- 1- P-90 ethanol piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-ethylthiocarbamate 422 (S)-N-[[3-[3-Fluoro-4-(4-acetyl- 1- P-90 isopropyl piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]- alcohol methyl]-O-iso-propylthiocarbamate 423 (S)-N-[[3-[3,5-Difluoro-4-(4-acetyl- 1- P-91 methanol piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 424 (S)-N-[[3-[4-(4-Acetyl- I - P-92 methanol piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 425 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)- 1- P-93 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 426 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)- 1- P-93 ethanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-ethylthiocarbamate 427 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)- 1- P-93 isopropyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]- alcohol methyl]-O-iso-propylthiocarbamate 428 (S)-N-[[3-[3,5-Difluoro-[4-[4-(methoxy- P-94 methylaminel acetyl)- 1 -piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 429 (S)-N-[[ 3 -[4-[4-(methoxyacetyl)- 1- P-95 methylamine piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 430 (S)-N-[3-[3-Fluoro-4-[4-(cyanoacetyl)- 1- P-96 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 431 (S)-N-[[3-[3,5-Difluoro-4-[4-(cyanoacetyl)- P-97 methanol 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate - 137- WO 00/32599 PCT/US98/25308 Isothiocyanate Example Corresponding No. Product to Amine No. Amine 432 (S)-N-[[3-[4-[4-(Cyanoacetyl)-l1- P-98 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 433 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)- 1- P-99 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 434 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)- 1- P-99 ethanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-ethylthiocarbamate 435 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)- 1- P-99 isopropyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]- alcohol methyl]-O-iso-propylthiocarbamate 436 (S)-N-[[3-[3,5-Difluoro-4-[4-(acetoxyacetyl)- P-100 methanol 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 437 (S)-N-[[3-[4-[4-(Acetoxyacetyl)- 1- P-101 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 438 (S)-N-[[3-[3-Fluoro-4-[4-(benzyloxyacetyl)- P- 102 methanol 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 439 (S)-N-[[3-[3.5-Difluoro-4-[4-(benzyloxy- P-103 methanol acetyl)- 1-piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 440 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)- P-105 methanol 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 441 (S)-N-[[3-[ 3 -Fluoro-4-[4-(methoxycarbonyl)- P-105 ethanol 1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-ethylthiocarbamate 442 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)- P-105 isopropyl I -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]- alcohol methyl]-O-iso-propylthiocarbamate - 138- WO 00/32599 PCT/US98/25308 Isothiocyanate Example Corresponding No. Product to Amine No. Amine 443 (S)-N-[[3-[3,5-Difluoro-4-[4-(methoxy- P-106 methanol carbonyl)- 1-piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 444 (S)-N-[[3-[4-[4-(methoxycarbonyl)- 1- P-107 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 445 (S)-N-[[3-[3-Fluoro-4-[4-(methanesulfonyl)- P-108 methanol 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 446 (S)-N-[[3-[3,5-Difluoro-4-[4-(methane- P-109 methanol sulfonyl)- 1-piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 447 (S)-N-[[3-[4-[4-(methanesulfonyl)- 1- P-110 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 448 (S)-N-[[3-[3-Fluoro-4-[4-(ethanesulfonyl)- 1- P-111 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 449 (S)-N-[[3-[3,5-Difluoro-4-[4-(ethane- P- 112 methanol sulfonyl)- I -piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]cyclopropane carbothioamide 450 (S)-N-[[3-[4-[4-(ethanesulfonyl)- 1- P-113 methanol piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 451 (S)-N-[[3-[3-Fluoro-4-[4-(chloromethane- P-l 4 methanol sulfonyl)- 1 -piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 452 (S)-N-[[3-[3,5-Difluoro-4-[4-(chloro- P-115 methanol methanesulfonyl)- 1-piperazinyl]phenyl]-2 oxo-5-oxazolidinyl]methyl]-O-methyl thiocarbamate 453 (S)-N-[[3-[4-[4-(chloromethanesulfonyl)- I - P-116 methanol piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate - 139- WO 00/32599 PCT/US98/25308 Isothiocyanate Example Corresponding No. Product to Amine No. Amine 454 (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethane- P- 117 methanol sulfonyl)- 1-piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 455 (S)-N-[[3-[3,5-Difluoro-4-[4-(cyanomethane- P-118 methanol sulfonyl)- 1-piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 456 (S)-N-[[3-[4-[4-(Cyanomethanesulfonyl)- I - P-119 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 457 (S)-N-[[3-[3-Fluoro-4-[4-(N-methyl- P-120 methanol sulfamoyl)- I -piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 458 (S)-N-[[3-[3,5-Difluoro-4-[4-(N-methyl- P-121 methanol sulfamoyl)- 1 -piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 459 (S)-N-[[3-[4-[4-(N-methylsulfamoyl)- 1- P-122 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 460 (S)-N-[[3- [3-Fluoro-4-[4-(N,N-dimethyl- P-123 methanol sulfamoyl)- 1-piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 461 (S)-N-[[3-[3,5-Difluoro-4-[4-(N,N-dimethyl- P-124 methanol sulfamoyl)- 1-piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 462 (S)-N-[[3-[4-[4-(N,N-dimethylsulfamoyl)- 1 - P-125 methanol piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 463 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)- 1- P-126 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 464 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)- 1- P-126 ethanol piperazinyljphenyl]-2-oxo-5-oxazolidinyl] methyl]-O-ethylthiocarbamate - 140- WO 00/32599 PCT/US98/25308 Isothiocyanate Example Corresponding No. Product to Amine No. Amine 465 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)- 1- P-126 isopropyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]- alcohol methyl]-O-iso-propylthiocarbamate 466 (S)-N-[[3-[3,5-Difluoro-4-[4-(ethoxy- P-127 methanol carbonyl)- I -piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 467 (S)-N-[[3-[4-[4-(ethoxycarbonyl)- 1- P-128 methanol piperazinyl]phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 468 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- 1- P-129 methanol piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate, 469 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- 1- P-129 ethanol piperazinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-ethylthiocarbamate 470 (S)-N-[[3-[ 3 -Fluoro-4-(4-sulfamoyl- 1- P-129 isopropyl piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]- alcohol methyl]-O-iso-propylthiocarbamate 471 (S)-N-[[3-[ 3 ,5-Difluoro-4-(4-sulfamoyl- I - P-130 methanol piperazinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O-methylthiocarbamate 472 (S)-N-[[3-[4-(4-sulfamoyl- I -piperazinyl)- P-131 methanol phenyl]-2-oxo-5-oxazolidinyl]methyl]-O methylthiocarbamate 473 (S)-N-[[3-[ 3 -Fluoro-4-[4-(cyanomethyl)- 1- P-132 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 474 (S)-N-[[3-[3,5-Difluoro-4-[4-(cyanomethyl)- P-133 methanol 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 475 (S)-N-[[3-[4-[4-( cyanomethyl)- 1- P-134 methanoll piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate - 141 - WO 00/32599 PCT/US98/25308 Isothiocvanate Example Corresponding No. Product to Amine No. Amine 476 (S)-N-[[3-[3-Fluoro-4-[4-(2-fluoroethyl)- 1- P-135 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 477 (S)-N-[[3-[ 3 ,5-Difluoro-4-[4-(2-fluoroethyl)- P-136 methanol 1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 478 (S)-N-[[3-[4-[4-(2-fluoroethyl)- I - P-137 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 479 (S)-N-[[3-[3-Fluoro-4-(4-formyl- I - P-138 methanol piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 480 (S)-N-[[3-[3,5-Difluro-4-(4-formyl- 1- P-139 methanol piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methylthiocarbamate 481 (S)-N-[[3-[4-(4-formyl- 1-piperazinyl)- P- 140 methanol phenyl]-2-oxo-5-oxazolidinyl]methyl]-O methylthiocarbamate - 142 - WO 00/32599 PCT/US98/25308 EXAMPLE 482. (5S)-N-[[3-[3-Fluoro-4-(tetrahydro- 1.4-thiazepin-4(5H) yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide. thiazepine S-oxide N H H N CH3 S 5 Step 1. Hexahydro-5-oxo-1,4-thiazepine is prepared according to the procedure described by Gallego (J. Org. Chem. 1993, 58, 3905-3911). Step 2. Lithium aluminum hydride (5.5 mL of a I M solution in THF) is added dropwise to a stirred solution of hexahydro-5-oxo- 1,4-thiazepine (721.5 mg) in dry THF 10 (21 mL) cooled to 0 'C. The reaction mixture is stirred at 0 oC for 10 min, then at room temperature for 4 h. The reaction mixture is quenched by careful successive addition of water (0.2 mL), 5 N aqueous NaOH (0.2 mL) and water (0.74 mL). The reaction mixture becomes very thick and gel-like. The reaction mixture is diluted with ether (50 mL) and filtered through a pad of celite. The filter cake is washed with ether (100 mL). 15 The filtrate is concentrated to afford 616.6 mg of 1,4-hexahydrothiazepine which is used immediately in the next step. Step 3. To a stirred solution of 1,4-hexahydrothiazepine (596.0 mg) and 3,4 difluoronitrobenzene (0.51 mL) in acetonitrile (14 mL) is added diisopropylethylamine (1.0 mL). The yellow solution is heated at reflux for 18 h, then cooled and concentrated. 20 The residue is diluted with CHCl., (100 mL) and washed with saturated aqueous NH Cl (35 mL). The phases are separated and the organics are dried (MgSO4), filtered and concentrated. The residue is purified by flash chromatography using 20% EtOAc in hexane as the eluent to afford 830.2 mg of the nitrobenzene. Mp 115-116 oC: Anal. Calcd for C I H3FN,202,S: C, 51.55: H, 5.11: N, 10.93: S, 12.51. Found: C, 51.47: H, 25 5.12: N, 10.79: S, 12.42. Step 4. To a stirred suspension of the nitrobenzene prepared in Step 3 (5.5 g) in EtOH (260 mL) is added a solution of 2 M aqueous CuSO 4 (11.9 mL). The mixture is cooled to 0 'C and NaBH (4.1 g) is added in portions. The reaction mixture turns very - 143- WO 00/32599 PCT/US98/25308 dark and is stirred at 0 oC for 10 min. at room temperature for 30 min, and then heated at reflux for 3 h. The cooled reaction mixture is diluted with EtOAc (500 ml) and washed with water (200 mL). The aqueous mixture is extracted with EtOAc (3 x 200 mL). The combined organics are dried (MgSO 4 ). filtered and concentrated to afford the aniline 5 intermediate. Step 5. The dark residue from Step 4 is dissolved in 2:1 acetone/water (255 mL) and cooled to 0 oC. To this stirred mixture is added solid NaHCO (5.4 g) followed by benzylchloroformate (7.7 mL). The reaction mixture is stirred at 0 'C for 10 min, then at room temperature for 24 h. The reaction mixture is quenched with 10% aqueous 10 NaHSO 4 (200 mL) and then poured into EtOAc (300 mL). The phases are separated and the aqueous phase is extracted with EtOAc (2 x 250 mL). The combined organics are dried (MgSO,) filtered and concentrated. The residue is purified by MPLC using 20% EtOAc in hexane to afford 6.03 g of the benzylcarbamate as a yellow solid. mp 72-74 °C; Anal. Calcd for C 1 9 H, FNOS: C, 63.31; H, 5.87: N, 7.77; S, 8.89. Found: C, 15 63.31; H, 5.97; N, 7.69; S, 8.79. Step 6. To a stirred solution of the carbamate from Step 5 (3.0 g) in dry THF (33 mL) under N, cooled to -78 oC, is added dropwise via syringe a 1.6 M solution of nBuLi in hexane (5.4 mL). The reaction mixture was stirred at -78 oC for 35 min, then R glycidyl butyrate (1.2 mL) is added. The reaction mixture is stirred at -78 oC for 30 min, 20 then at room temperature overnight during which time a precipitate forms. The reaction mixture is quenched with saturated aqueous NH 4 CI (33 mL) and poured into EtOAc (100 mL). The phases are separated. The organic phase is washed with saturated aqueous NaHCO (50 mL), brine ( 50 mL), dried (MgSO 4 ), filtered and concentrated. The residue is purified by flash chromatography using EtOAc as the eluent to afford 2.5 25 g of a hydroxymethyl oxazolidinone. Mp 100-102 oC. Anal. Calcd for CH 9

FN

2 0 3 ,O S: 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,C1, (35 mL) cooled to 0 oC, is added triethylamine (1.1 mL) followed by methanesulfonyl chloride (0.5 mL). The reaction mixture is stirred at 0 oC for 10 min. then at room 30 temperature for I h. The reaction mixture is treated with water (35 mL). The phases are separated and the aqueous phase is extracted with CH,CI, (35 mL). The combined - 144 - WO 00/32599 PCT/US98/25308 organic phases are dried (MgSO 4 ), filtered and concentrated. The residue is purified by flash chromatography using 80% EtOAc in hexane as the eluent to afford 2.1 g of the mesylate. Mp 132-142 'C. Anal. Calcd for C 1 6

H

2 1

FN

2 ,O 5

S

2 : 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. 5 Step 8. Ammonia gas is bubbled into a stirred suspension of the mesylate prepared in Step 7 (941.7 mg) in 1:1 THF/CH 3 OH (40 mL) until saturated (approx. 5 min). The reaction mixture is heated in a sealed tube at 100 'C for 72 h. The cooled reaction mixture is concentrated to give the crude amine, which is immediately suspended in CH 2 Cl 2 (35 mL) and cooled to 0 oC. To this stirred suspension is added 10 triethylamine (0.97 mL, 6.9 mmol) followed by di-tert-butyl dicarbonate (759.5 mg, 3.5 mmol). The reaction mixture becomes homogeneous and is stirred at RT for 18 h. The reaction mixture is poured into CH 2 Cl 2 (75 mL) and washed with HO 2 0 (1 x 50 mL). The organic phase is dried (MgSO 4 ), filtered and concentrated. The resulting residue is purified on a Biotage 40 S column using 30-35 % ethyl acetate in CH 3 OH as the eluent 15 to afford 867.4 mg of the protected amine. mp 74-75 'C. Anal Cald: C, 56.45; H, 6.63; N, 9.88. Found: C, 56.95; H, 6.85; N, 9.55. Step 9. To a stirred suspension of the protected amine prepared in Step 8 (205.2 mg) in 1:1 CH 3

OH/H

2 0 (6 mL) cooled to 0OC is added sodium meta periodate (113.5 mg). The resulting suspension is stirred at RT for 18 h. The reaction mixture is filtered 20 and the solid is washed with CHaCl (2 x 20 mL). The filtrate is extracted with H 2 0 (1 x 10 mL). The phases are separated. The aqueous phase is extracted with CH 2 Cl 2 (1 x 25 mL). The combined organic phases are dried (MgSO 4 ), filtered and concentrated. The white solid residue is purified on a Biotage 12 M column using 5% CH 3 OH in

CH

2 Cl 2 as the eluent to afford 187.3 mg of the sulfoxide. mp 78-81 oC. 25 Step 10. Dry HCI gas is passed over the surface of a stirred solution of the sulfoxide prepared in Step 9 (179.3 mg) in CH 3 OH (2 mL) cooled to 0 'C for 1 minute. The reaction mixture is stirred at 0 oC for 10 min, then at room temperature for 15 min, then concentrated. The resulting yellow residue is suspended in THF (5 mL) and

CH

2 CI, (5 mL) and cooled to 0OC. To this stirred suspension is added triethylamine 30 (0.46 mL) followed by ethyldithioacetate (0.18 mL). The dark reaction mixture is stirred at RT overnight then concentrated. The dark residue is diluted with CH 2

CI

2 (30 mL) and washed with HO 2 0 (2 x 15 mL). The organic phases are dried (MgSO 4 ), filtered and - 145- WO 00/32599 PCT/US98/25308 concentrated. The dark residue is purified on a Biotage 12 M column using 5% CH30H in CH2Cl, as the eluent to afford 71.5 mg of the title compound as a tan solid. mp 85-89 oC. Following the general procedure outlined in Step 10 of Example 482. but 5 substituting the dithioesters listed below, the compounds of Examples 483 to 495 of Table K can be obtained. TABLE K Example Compound Amine Dithioester No. (from Preparation Z) 483 (5S)-N-[[3-[3-Fluoro-4- 0 Z (a) (tetrahydro- 1,4 thiazepin-4(5H)-yl))- N 0 phenyl]-2-oxo-5- 0 oxazolidinyl]methyl]- N O propanethioamide, NH2 thiazepine S-oxide 484 S)-N-[[3-[3-Fluoro-4- Same as above Z (b) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethio amide, thiazepine S oxide. 485 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (c) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide, thiazepine S oxide. - 146- WO 00/32599 PCT/US98/25308 Example Compound Amine Dithioester No. (from Preparation Z) 486 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (d) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] butanethioamide, thiazepine S-oxide 487 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (e) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-3 methylbutanethioamide, thiazepine S-oxide 488 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (f) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylbutanethioamide, thiazepine S-oxide 489 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (g) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] 3.3-dimethylbutanethio amide, thiazepine S oxide 490 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (h) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclobutanecarbothio amide, thiazepine S oxide - 147- WO 00/32599 PCT/US98/25308 Example Compound Amine Dithioester No. (from Preparation Z) 491 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (i) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]- 1 cyclopentanecarbothio amide, thiazepine S oxide 492 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (j) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclohexanecarbothio amide, thiazepine S oxide 493 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (k) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 cyclopropylethanethio amide, thiazepine S oxide 494 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (1) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 cyclobutylethanethio amide, thiazepine S oxide - 148- WO 00/32599 PCT/US98/25308 Example Compound Amine Dithioester No. (from Preparation Z) 495 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (m) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 cyclopentylethanethio amide, thiazepine S oxide Example 496. (5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H) yl)phenyl]- 2 -oxo-5-oxazolidinyl]methyl]thioacetamide, thiazepine S-oxide 0 F N N 0 0 F NOA H '{ N CH 3 5 S The title compound can be prepared by the procedure of Example 482, by substituting an appropriate quantity of 2,6-difluoro-4-nitrobenzene (trifluoromethane) sulfonate for 3,4-difluoronitrobenzene in Step 1. 10 Utilizing the amine prepared in Example 496, but substituting the dithioester listed below for ethyl dithioacetate in the final step, the compounds of Examples 497 to 499 of Table L are obtained. -149- WO 00/32599 PCT/US98/25308 TABLE L Example Compound Amine Dithioester No. (from Preparation Z) 497 (5S)-N-[[3-[3,5- 0 Z (a) Difluoro-4-(tetrahydro- S F 1,4-thiazepin-4(5H)-yl))- N phenyl]-2-oxo-5 oxazolidinyl]methyl]- F No propanethioamide,

-NH

2 thiazepine S-oxide 498 (5S)-N-[[3-[3,5- Same as above Z (b) Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethio amide, thiazepine S oxide 499 (5S)-N-[[3-[3,5- Same as above Z (c) Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide, thiazepine S oxide 5 Example 500. (5S)-N-[[3-[4-(Tetrahydro-1, 4 -thiazepin-4(5H)-yl)phenylJ-2-oxo-.5.

oxazolidinyl]methyl]thioacetamide, thiazepine S-oxide. N 0 NO H -N

CH

3 S - 150- WO 00/32599 PCT/US98/25308 The title compound can be prepared by the procedure of Example 482. by substituting an appropriate quantity of 4 -fluoronitrobenzene for 3,4-difluoronitro benzene in Step 1. Utilizing the amine prepared in Example 500. but substituting the dithioester 5 listed below for ethyl dithioacetate in the final step, the compounds of Examples 501 to 503 of Table M are obtained TABLE M 10 Example Compound Amine Dithioester No. (from Preparation Z) 501 (5S)-N-[[3-[4- 0 Z (a) (Tetrahydro- 1,4- s thiazepin-4(5H)-yl))- N phenyl]-2-oxo-5 oxazolidinyl]methyl]- No propanethioamide,

-NH

2 thiazepine S-oxide 502 (5S)-N-[[3-[4- Same as above Z (b) (Tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethio amide. thiazepine S oxide 503 (5S)-N-[[3-[4- Same as above Z (c) (Tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide, thiazepine S oxide Example 504. (5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1, 4 -thiazepin-4(5H)-yl)phenyl].-2.

oxo-5-oxazolidinyl]methyl]thioacetamide, thiazepine S,S-dioxide -151- WO 00/32599 PCT/US98/25308 0 O H -kN

CH

3 S Step 1. To a stirred solution of the thiazepine prepared in Step 8 of Example 482 (243.7 mg) in 25 % H20/acetone (8 mL) is added 4-methylmorpholine N-oxide (201.5 5 mg) followed by a solution of osmium tetroxide in 2 -methyl-2-propanol (2.5 wt %, 30 gL). The reaction mixture is stirred at room temperature for 18 h. The reaction mixture is treated with saturated sodium bisulfate (8 mL), then poured into CHzCl, (50 mL). The phases are separated. The aqueous phase is extracted with CH 2 Cl 2 (2 x 25 mL). The combined organic phases are washed with brine (I x 25 mL), dried (MgSO 4 ), 10 filtered and concentrated. The residue is purified on a Biotage 40 S column using 1 %

CH

3 OH in CH 2

CI

2 as the eluent to afford 216.1 mg (0.47 mmol, 83%) of the thiazepine S,S-dioxide as a white solid. mp 144-146 oC. Step 2. Dry HCI gas is passed over the surface of a stirred solution of the thiazepine S,S-dioxide prepared in Step 1 (108.2 mg) in CH 3 OH(3 mL) at O'C for 1 15 minute. The reaction mixture is stirred at 0 oC for 10 min and then at room temperature for 15 min. The reaction is concentrated and the yellow residue is suspended in CH 2

CI

2 (2 mL) and THF (2 mL). This stirred suspension is cooled to O'C and triethylamine (0.27 mL) is added followed by a solution of ethyldithioacetate (0.11 mL) in THF (0.5 mL) with 0.25 mL rinse. The yellowish-green solution is stirred at (PC for 10 min then 20 at room temperature for 18 h. The reaction mixture is poured into CH

-

CI

2 (20 mL) and washed with H 2 0 (2 x 10 mL). The organic phase was dried (MgSO4), filtered and concentrated. The residue is purified on a Biotage 12 M column using 2 % CH3OH in

CH

2 Cl as the eluent to afford 77.3 mg of the title compound as a white solid. mp 88-90 oC. 25 Following the general procedure outlined in Step 2 of Example 504, but substituting the dithioester listed below for ethyl dithioacetate, the compounds of Examples 505 to 507 of Table N are obtained. - 152 - WO 00/32599 PCT/US98/25308 TABLE N Example Compound Amine Dithioester No. (from Preparation Z) 505 (5S)-N-[[3-[3-Fluoro-4- o Z (a) (4-thiomorpholinyl]- 0-S phenyl]-2-oxo-5- N oxazolidinyl]methyl] propanethioamide, F N 0O thiazepine S,S-dioxide VNH2 506 (5S)-N-[[3-[3-FIuoro-4- Same as above Z (b) (4-thiomorpholinyl] phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethio amide, thiazepine S,S dioxide 507 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (c) (4-thiomorpholinyl] phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide. thiazepine S,S dioxide 5 Example 508. (5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide, thiazepine S,S-dioxide 0 O S -S F N0 F NO H N CH 3 S - 153- WO 00/32599 PCT/US98/25308 The title compound can be prepared by the procedures of Examples 504 and 482. by substituting an appropriate quantity of 2.6-difluoro-4-nitrobenzene (trifluoromethane) sulfonate for 3,4-difluoronitrobenzene in Step 1 of Example 482. Utilizing the amine prepared in Example 508, but substituting the dithioester 5 listed below for ethyl dithioacetate in the final step, the compounds of Examples 509 to 511 of Table O are obtained. TABLE O Example Compound Amine Dithioester No. (from Preparation Z) 509 (5S)-N-[[3-[3,5- o Z (a) Difluoro-4-(4- o--F thiomorpholinyl]- N F phenyl]-2-oxo-5- 0 oxazolidinyl]methyl]- F N 0O propanethioamide, vNH2 thiazepine S,S-dioxide 510 (5S)-N-[[3-[3,5- Same as above Z (b) Difluoro-4-(4 thiomorpholinyl] phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethio amide, thiazepine S,S dioxide 511 (5S)-N-[[3-[3,5- Same as above Z (c) Difluoro-4-(4 thiomorpholinyl] phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide, thiazepine S.S dioxide 10 Example 512. (5S)-N-[[3-[4-(Tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]thioacetamide, thiazepine S,S-dioxide - 154- WO 00/32599 PCT/US98/25308 0 OZ==S N H I-JN CH 3 S The title compound can be prepared by the procedure of Examples 504 and 482, by substituting an appropriate quantity of 4-fluoronitrobenzene for 3,4-difluoronitro 5 benzene in Step 1 of Example 482. Utilizing the amine prepared in Example 512, but substituting the dithioester listed below for ethyl dithioacetate in the final step, the compounds of Examples 513 to 515 of Table P are obtained. TABLE P 10 Example Compound Amine Dithioester No. (From Preparation Z) 513 (5S)-N-[[3-[4- o Z (a) (tetrahydro- 1,4- O..Sthiazepin-4(5H)- N yl))phenyl]-2-oxo-5 oxazolidinyl]-" N 0 methyl]propanethio-

NH

2 amide, thiazepine S.S dioxide 514 (5S)-N-[[3-[4- Same as above Z (b) (tetrahydro- 1,4 thiazepin-4(5H) yl))phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethio amide, thiazepine S.S dioxide - 155 - WO 00/32599 PCT/US98/25308 Example Compound Amine Dithioester No. (From Preparation Z) 515 (5S)-N-[[3-[4- Same as above Z (c) (tetrahydro- 1,4 thiazepin-4(5H) yl))phenyl]-2-oxo-5 oxazolidinyl] methyl]cyclopropane carbothioamide, thiazepine S.S-dioxide EXAMPLE 516. (5S)-N-[[3-[3-Fluoro-4-(tetrahydro- 1,4-thiazepin-4(5H) yl)phenyl]- 2 -oxo-5-oxazolidinyl]methyl]thioacetamide. NO H N CH3 5 S This compound is prepared according to the procedure of Step 8 in Example 482, but stubstituting an appropriate quantity of ethyl dithioacetate for di-tert-butyl dicarbonate: mp 129-131 C. 10 Utilizing the amine prepared in Step 8 of Example 482. but substituting an appropriate quantity of the dithioester listed below for di-tert-butyl dicarbonate, the compounds of Examples 517 to 529 of Table Q are obtained. TABLE Q 15 Example Compound Amine Dithioester No. (From Preparation Z) 517 (5S)-N-[[3-[3-Fluoro-4- s Z (a) (tetrahydro- 1,4- No thiazepin-4(5H)-yl))- 0 phenyl]-2-oxo-5- F N O oxazolidinyl]methyl]- -- NH 2 propanethioamide - 156- WO 00/32599 PCT/US98/25308 Example Compound Amine Dithioester No. (From Preparation Z) 518 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (b) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethioamide 519 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (c) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide 520 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (d) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] butanethioamide 521 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (e) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-3 methylbutanethioamide 522 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (f) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylbutanethioamide 523 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (g) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] 3.3-dimethylbutanethio amide - 157- WO 00/32599 PCT/US98/25308 Example Compound Amine Dithioester No. (From Preparation Z) 524 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (h) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclobutanecarbothioami de 525 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (i) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopentanecarbothio amide 526 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (j) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclohexanecarbothio amide 527 (5S)-N-[[3-[3-5 Fluoro- Same as above Z (k) 4-(tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 cyclopropylethanethio amide 528 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (1) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 cyclobutylethanethio amide - 158- WO 00/32599 PCT/US98/25308 Example Compound Amine Dithioester No. (From Preparation Z) 529 (5S)-N-[[3-[3-Fluoro-4- Same as above Z (m) (tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 cyclopentylethanethioam ide EXAMPLE 530. (5S)-N-[[ 3 -[3,5-Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H) yl)phenyl]- 2 -oxo-5-oxazolidinyl]methyl]thioacetamide. S F N/ O 0 F NO 1-KN

CH

3 5 S This compound can be prepared according to the procedures of Example 482 and Example 516, but substituting an appropriate quantity of 2,6-difluoro-4-nitrophenyl trifluoromethane sulfonate for 3

,

4 -difluoronitrobenzene in Step 1 of Example 482. 10 Utilizing the amine prepared in Example 530, but substituting an appropriate quantity of the dithioester listed below for di-tert-butyl dicarbonate, the compounds of Examples 531 to 533 of Table R can be prepared. TABLE R 15 Example Compound Amine Dithio Compound No. (from Preparation Z) 531 (5S)-N-[[3-[3.5- S F Z (a) Difluoro-4-(tetrahydro- N 1,4-thiazepin-4(5H)-yl)) phenyl]-2-oxo-5- F N 0 oxazolidinyl]methyl]- -- NH 2 propanethioamide - 159- WO 00/32599 PCT/US98/25308 Example Compound Amine Dithio Compound No. (from Preparation Z) 532 (5S)-N-[[3-[3.5- Same as above Z (b) Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethioamide 533 (5S)-N-[[3-[3,5- Same as above Z (c) Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl] cyclopropanecarbothio amide EXAMPLE 534. (5S)-N-[[3-[4-(Tetrahydro-1, 4 -thiazepin-4(5H)-yl)phenyl]-2.-oxo-5 oxazolidinyl]methyl]thioacetamide; mp 129-131oC N CH 3 5 S This compound can be prepared according to the procedures of Example 482 and Example 516, but substituting an appropriate quantity of 4-fluoronitrobenzene for 3,4 difluoronitrobenzene in Step 1 of Example 482. 10 Utilizing the amine prepared in Example 534, but substituting an appropriate quantity of the dithioester listed below for di-tert-butyl dicarbonate, the compounds of Examples 535 to 537 of Table S can be prepared. - 160- WO 00/32599 PCT/US98/25308 TABLE S Example Compound Amine Dithio Compound No. (from Preparation Z) 535 (5S)-N-[[3-[4- S- Z (a) (Tetrahydro- 1.4- N thiazepin-4(5H)-yl))- " phenyl]-2-oxo-5- NO oxazolidinyl]-

NH

2 methyl]propanethio amide 536 (5S)-N-[[3-[4- Same as above Z (b) (Tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl]methyl]-2 methylpropanethioamide 537 (5S)-N-[[3-[4- Same as above Z (c) (Tetrahydro- 1,4 thiazepin-4(5H)-yl)) phenyl]-2-oxo-5 oxazolidinyl] methyl]cyclopropane carbothioamide EXAMPLE 538. (5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5H) 5 yl)phenyl]- 2 -oxo-5-oxazolidinyl]methyl]thiourea, thiazepine S-oxide ON NO H N 'N

NH

2 S This compound can be prepared by the procedure described in Example 33. but 10 substituting the amine prepared in Example 482 for the amine 33. By reaction of the isothiocyanate prepared in Example 538 with the amines and alcohols listed in Table T. the compounds of Examples 539 to 544 can be prepared. - 161 - WO 00/32599 PCT/US98/25308 TABLE T Example Compound Isothiocvanate Amine or No. Alcohol 539 (5S)-N-[[3-[3-Fluoro-4- 0

CH

3 NH2 (tetrahydro- 1,4- S thiazepin-4(5H)- N yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-N'- F N O methylthiourea, -IV.N=C=S thiazepine S-oxide 540 (5S)-N-[[3-[3-Fluoro-4- Same as above

(CH

3

)

2 NH (tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl] N',N'-dimethylthiourea, thiazepine S-oxide 541 (5S)-N-[[3-[3-Fluoro-4- Same as above Azetidine (tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]- 1 azetidinecarbothioamide, thiazepine S-oxide 542 (5S)-N-[[3-[3-Fluoro-4- Same as above

CH

3 OH (tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O methylthiocarbamate. thiazepine S-oxide 543 (5S)-N-[[3-[3-Fluoro-4- Same as above

CH

3

CH

2 OH (tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O ethylthiocarbamate, thiazepine S-oxide - 162- WO 00/32599 PCT/US98/25308 Example Compound Isothiocvanate Amine or No. Alcohol 544 (5S)-N-[[3-[3-Fluoro-4-

(CH

3

)

2 CHOH (tetrahydro-1,4- Same as above thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O isopropylthiocarbamate, Sthiazepine S-oxide EXAMPLE 545.(5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thiourea, thiazepine S-oxide 0 F NNO 0 , 0 F NOA H -VN -NH 2 5 S This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 496 for the amine 33. By reaction of the isothiocyanate prepared in Example 545 with the amines and 10 alcohols listed in Table U, the compounds of Examples 546 to 551 can be prepared. TABLE U Example Compound Isothiocyanate Amine or No. Alcohol 546 (5S)-N-[[3-[3,5- o\

CH

3

NH

2 Difluoro-4-(tetrahydro- S F 1.4-thiazepin-4(5H)- N yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-N'- F N O methylthiourea. N:C=S thiazepine S-oxide - 163- WO 00/32599 PCT/US98/25308 Example Compound Isothiocvanate Amine or No. Alcohol 547 (5S)-N-[[3-[3,5- Same as above (CH 3

)

2 NH Difluoro-4-(tetrahydro 1.4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl] N'.N'-dimethylthiourea, thiazepine S-oxide 548 (5S)-N-[[3-[3,5- Same as above Azetidine Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]- 1 azetidinecarbothioamide. thiazepine S-oxide 549 (5S)-N-[[3-[3,5- Same as above CH 3 OH Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O methylthiocarbamate, thiazepine S-oxide 550 (5S)-N-[[3-[3,5- Same as above CH 3

CH

2 OH Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O ethylthiocarbamate, thiazepine S-oxide 551 (5S)-N-[[3-[3,5-

(CH

3 )2CHOH Difluoro-4-(tetrahydro- Same as above 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O isopropylthiocarbamate, thiazepine S-oxide EXAMPLE 552. (5S)-N-[[3-[4-(Tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl-2-oxo.5 oxazolidinyl]methyl]thiourea, thiazepine S-oxide -164- WO 00/32599 PCT/US98/25308 N 0 NO H N NH 2 S This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 500 for the amine 33. 5 By reaction of the isothiocyanate prepared in Example 552 with the amines and alcohols listed in Table V, the compounds of Examples 553 to 558 can be prepared. TABLE V Example Compound Isothiocyanate Amine or No. Alcohol 553 (5S)-N-[[3-[4- 0o\

CH

3

NH

2 (Tetrahydro- 1,4- S thiazepin-4(5H)- N yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-N'- N 0 methylthiourea, N=C=S thiazepine S-oxide 554 (5S)-N-[[3-[4- Same as above

(CH

3

)

2 NH (Tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl] N',N'-dimethylthiourea, thiazepine S-oxide 555 (5S)-N-[[3-[4- Same as above Azetidine (Tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]- 1 azetidinecarbothioamide, thiazepine S-oxide - 165- WO 00/32599 PCT/US98/25308 Example Compound Isothiocvanate Amine or No. Alcohol 556 (5S)-N-[[3-[4- Same as above CH 3 OH (Tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O methylthiocarbamate, thiazepine S-oxide 557 (5S)-N-[[3-[4- Same as above CH 3

CH

2 OH (Tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O ethylthiocarbamate, thiazepine S-oxide 558 (5S)-N-[[3-[4-

(CH

3

)

2 CHOH (Tetrahydro-1,4- Same as above thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O isopropylthiocarbamate, Sthiazepine S-oxide EXAMPLE 559. (5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thiourea, thiazepine S,S-dioxide 0 O F, NO0 H - N NH 2 5 S This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 504 for the amine 33. By reaction of the isothiocyanate prepared in Example 559 with the amines and 10 alcohols listed in Table W. the compounds of Examples 560 to 565 can be prepared. - 166- WO 00/32599 PCT/US98/25308 TABLE W Example Compound Isothiocyanate Amine or No. Alcohol 560 (5S)-N-[[3-[3-Fluoro-4- 0

CH

3 NH2 (tetrahydro- 1,4- O=S thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-N'- F N 0 methylthiourea, \ .N=C=S thiazepine S,S-dioxide 561 (5S)-N-[[3-[3-Fluoro-4- Same as above

(CH

3

)

2 NH (tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl] N',N'-dimethylthiourea, thiazepine S,S-dioxide 562 (5S)-N-[[3-[3-Fluoro-4- Same as above Azetidine (tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]- 1 azetidinecarbothioamide, thiazepine S,S-dioxide 563 (5S)-N-[[3-[3-Fluoro-4- Same as above

CH

3 OH (tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O methylthiocarbamate, thiazepine S,S-dioxide 564 (5S)-N-[[3-[3-Fluoro-4- Same as above

CH

3 CH20H (tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O ethylthiocarbamate. thiazepine S.S-dioxide - 167- WO 00/32599 PCT/US98/25308 Example Compound Isothiocyanate Amine or No. Alcohol 565 (5S)-N-[[3-[3-Fluoro-4-

(CH

3

)

2 CHOH (tetrahydro- 1,4- Same as above thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O isopropylthiocarbamate, thiazepine S.S-dioxide EXAMPLE 566. (5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5H) yl)phenyl]- 2 -oxo-5-oxazolidinyl]methyl]thiourea, thiazepine S,S-dioxide 0 F NO ~{N NH 2 5 S This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 508 for the amine 33. By reaction of the isothiocyanate prepared in Example 566 with the amines and 10 alcohols listed in Table X, the compounds of Examples 561 to 572 can be prepared. TABLE X Example Compound Isothiocyanate Amine or No. Alcohol 567 (5S)-N-[[3-[3,5- 0

CH

3

NH

2 Difluoro-4-(tetrahydro- os F 1,4-thiazepin-4(5H)- N yl)phenyl]-2-oxo-5- o oxazolidinyl]methyl]-N'- F N 0 methylthiourea, N=C=S thiazepine S,S-dioxide - 168- WO 00/32599 PCT/US98/25308 Example Compound Isothiocvanate Amine or No. Alcohol 568 (5S)-N-[[3-[3,5- Same as above (CH 3

)

2 NH Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl] N',N'-dimethylthiourea, thiazepine S.S-dioxide 569 (5S)-N-[[3-[3,5- Same as above Azetidine Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]- 1 azetidinecarbothioamide, thiazepine S.S-dioxide 570 (5S)-N-[[3-[3,5- Same as above CH 3 OH Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O methylthiocarbamate, thiazepine S,S-dioxide 571 (5S)-N-[[3-[3,5- Same as above CH 3

CH

2 OH Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O ethylthiocarbamate, thiazepine S.S-dioxide 572 (5S)-N-[[3-[3,5- (CH3)2CHOH Difluoro-4-(tetrahydro- Same as above 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O isopropylthiocarbamate, thiazepine S.S-dioxide EXAMPLE 573. (5S)-N-[[3-[4-(Tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]thiourea, thiazepine S,S-dioxide - 169 - WO 00/32599 PCT/US98/25308 0 0 O Na NO H ,-'VN NH 2 S This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 512 for the amine 33. 5 By reaction of the isothiocyanate prepared in Example 573 with the amines and alcohols listed in Table Y, the compounds of Examples 574 to 579 can be prepared. TABLE Y Example Compound lsothiocvanate Amine or No. Alcohol 574 (5S)-N-[[3-[4- 0

CH

3

NH

2 (Tetrahydro- 1,4- Othiazepin-4(5H)- N yl)phenyl]-2-oxo-5- o oxazolidinyl]methyl]-N'- N Ao methylthiourea, _ NC=S thiazepine S,S-dioxide 575 (5S)-N-[[3-[4- Same as above

(CH

3 )2NH (Tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl] N',N'-dimethylthiourea, thiazepine S,S-dioxide 576 (5S)-N-[[3-[4- Same as above Azetidine (Tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]- 1 azetidinecarbothioamide, thiazepine S,S-dioxide -170- WO 00/32599 PCT/US98/25308 Example Compound Isothiocvanate Amine or No. Alcohol 577 (5S)-N-[[3-[4- Same as above

CH

3 OH (Tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O methylthiocarbamate, thiazepine S,S-dioxide 578 (5S)-N-[[3-[4- Same as above CH 3

CH

2 OH (Tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O ethylthiocarbamate, thiazepine S.S-dioxide 579 (5S)-N-[[3-[4-

(CH

3

)

2 CHOH (Tetrahydro-1,4- Same as above thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O isopropylthiocarbamate, thiazepine S.S-dioxide EXAMPLE 580. (5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thiourea S NO H N NH2 5 S This compound can be prepared by the procedure described in Example 33. but substituting the amine prepared in Step 8 of Example 482 for the amine 33. By reaction of the isothiocyanate prepared in Example 580 with the amines and 10 alcohols listed in Table Z, the compounds of Examples 581 to 586 can be prepared. - 171 - WO 00/32599 PCT/US98/25308 TABLE Z Example Compound Isothiocvanate Amine or No. Alcohol 581 (5S)-N-[[3-[3-Fluoro-4- s

CH

3

NH

2 (tetrahydro- 1,4-N thiazepin-4(5H) yl)phenyl]-2-oxo-5- F N O oxazolidinyl]methyl]-N'-

I-N=C=

s methylthiourea 582 (5S)-N-[[3-[3-Fluoro-4- Same as above

(CH

3

)

2 NH (tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl] N',N'-dimethylthiourea 583 (5S)-N-[[3-[3-Fluoro-4- Same as above Azetidine (tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]- 1 azetidinecarbothioamide 584 (5S)-N-[[3-[3-Fluoro-4- Same as above

CH

3 OH (tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O methylthiocarbamate 585 (5S)-N-[[3-[3-Fluoro-4- Same as above CH 3 CH20H (tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O ethylthiocarbamate 586 (5S)-N-[[3-[3-Fluoro-4-

(CH

3

)

2 CHOH (tetrahydro-1,4- Same as above thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O isopropylthiocarbamate -172- WO 00/32599 PCT/US98/25308 EXAMPLE 587. (SS)-N-[[3-[3,5-Difluoro-4-(tetrahydro- 1.4-thiazepin-4(5H) yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thiourea s F NNO 0 F N A o H ,-k N NH 2 S 5 This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 530 for the amine 33. By reaction of the isothiocyanate prepared in Example 587 with the amines and alcohols listed in Table AA, the compounds of Examples 588 to 593 can be prepared. 10 TABLE AA Example Compound Isothiocyanate Amine or No. Alcohol 588 (5S)-N-[[3-[3,5- s F

CH

3

NH

2 Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5- F N o oxazolidinyl]methyl]-N'- - N=C=S methylthiourea 589 (5S)-N-[[3-[3,5- Same as above (CH 3

)

2 NH Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl] N',N'-dimethylthiourea 590 (5S)-N-[[3-[3,5- Same as above Azetidine Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]- 1 azetidinecarbothioamide - 173- WO 00/32599 PCT/US98/25308 Example Compound Isothiocvanate Amine or No. Alcohol 591 (5S)-N-[[3-[3.5- Same as above CH 3 OH Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O methylthiocarbamate 592 (5S)-N-[[3-[3,5- Same as above CH 3

CH

2 OH Difluoro-4-(tetrahydro 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O ethylthiocarbamate 593 (5S)-N-[[3-[3,5-

(CH

3

)

2 CHOH Difluoro-4-(tetrahydro- Same as above 1,4-thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O isopropylthiocarbamate EXAMPLE 594. ( 5 S)-N-[[3-[4-(Tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-.2.-oxo-.5. oxazolidinyl]methyl]thiourea Sm N 1 H LK Nr NH 2 5 S This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 534 for the amine 33. By reaction of the isothiocyanate prepared in Example 594 with the amines and 10 alcohols listed in Table BB, the compounds of Examples 595 to 600 can be prepared. - 174 - WO 00/32599 PCT/US98/25308 TABLE BB Example Compound Isothiocyanate Amine or No. Alcohol 595 (5S)-N-[[3-[4- S

CH

3

NH

2 (Tetrahydro- 1,4- N thiazepin-4(5H) yl)phenyl]-2-oxo-5- N 0 oxazolidinyl]methyl]-N'- VN=C=S methylthiourea 596 (5S)-N-[[3-[4- Same as above

(CH

3 )2NH (Tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl] N',N'-dimethylthiourea 597 (5S)-N-[[3-[4- Same as above Azetidine (Tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]- 1 azetidinecarbothioamide 598 (5S)-N-[[3-[4- Same as above

CH

3 OH (Tetrahydro- 1,4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O methylthiocarbamate 599 (5S)-N-[[3-[4- Same as above

CH

3

CH

2 OH (Tetrahydro- 1.4 thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O ethylthiocarbamate 600 (5S)-N-[[3-[4-

(CH

3 )2CHOH (Tetrahydro-1,4- Same as above thiazepin-4(5H) yl)phenyl]-2-oxo-5 oxazolidinyl]methyl]-O isopropylthiocarbamate - 175-

Claims (11)

1. A compound of the formula R 2 3 5Z 2 N N O R 24 NHC-R1 wherein Z, is -0,S-, -0-, -N(R 1 0 7 )-, -OS-, or -S-; wis0, 1,2, or3; 10 R 23 and R 24 are the same or different and can be H or F; and R 1 is H, NH, 2 , NHalkylC-C 4 ; N(alkylC-C 4 ) 2 ; alkylC 1 -C 4 ; OalkylC 1 -C 4 ; SalkylC-C 4 ; alkylC 1 -C 4 substituted with 1-3F, 1-2C1, 15 CN, or -COOalkylC 1 -C 4 , or cycloalkylC,-C 6 , wherein in each occurence of the alkyl group may be straight or branched; and R 1 07 is a) R1020-C(RO)(R"')-C(O)-, b) R 103 0-C(O)-, 20 c) Rio8-C(O)-, d) R' 0 9 -SO2-, e) NC-CH 2 -, f) FCHCH 2 -, or g) Rs 15 0 Ri 15 NS0 2 ; 25 wherein R 1 o 2 is H, CH-, phenyl-CH 2 -, or CH 3 C(O); each of R 11 0 and R 111 is selected from H or CH 3 ; R'o 3 is alkylC-C: 3 or phenyl; Ro s is H, alkylCl-C 4 , aryl(CH 2 )0-5, CNCH 2 -, CICH,-, C1 2 HC-, FH 2 C-, F 2 HC-, or cycloalkylC. 3 -C 6 ; R 1 5 o and R1 5 T are the same or different and are selected from H, alkylC-C 4 , or R 1 50 and R' 5 1 taken together with the nitrogen to which each is attached forms a monocyclic heterocyclic ring 30 having from 3 to 6 carbon atoms.

2. A compound of claim 1 wherein Z" is -0.,S-.

3. A compound of claim 2 which is (5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4 35 thiazepin-4(5H)-yl)phenyll- 2 -oxo-5-oxazolidinyllmethyllthioacetamide, thiazepine S,S-dioxide. -176- WO 00/32599 PCT/US98/25308

4. A compound of claim 1 wherein Z 2 is -OS-.

5. A compound of claim 4 which is (S)-N-[[3-[ 3 -Fluoro-4-(4-thiomorpholinyl)phenyl] -2-oxo-5-oxazolidinyl] methyl] 5 propanethioamide, thiomorpholine S-oxide; (S)-N-[[3-[ 3 -Fluoro-4-(4-thiomorpholinyl)phenyl] - 2 -oxo-5-oxazolidinyl] methyl] 2 -methylpropanethioamide, thiomorpholine S-oxide; (S)-N-[[3- [ 3 -Fluoro-4-(4-thiomorpholinyl)phenyl- 2 -oxo-5-oxazolidinyl]methyl] cyclopropanecarbothio-amide, thiomorpholine S-oxide; 10 (S)-N-[[3- [ 3 -Fluoro-4-(4-thiomorpholinyl)phenyll - 2 -oxo-5-oxazolidinyl] methyl] O-methylthiocarbamate, 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] 15 O-isopropylthiocarbamate, thiomorpholine S-oxide; (5S)-N-[[3- [3-Fluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)-yl)phenyl] -2-oxo-5 oxazolidinyl]methyl]thioacetamide, thiazepine S-oxide; (S)-N-[[3-[ 3 -Fluoro-4-(4-thiomorpholinyl)phenyll- 2 -oxo-5-oxazolidinyl]methyl] N',N'-dimethylthiourea, thiomorpholine S-oxide; or 20 (S)-N- [[3-[ 3 -Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] 1-azetidinecarbothioamide, thiomorpholine S-oxide.

6. A compound of claim 1 wherein Z 2 is O. 25

7. A compound of claim 6 which is (S)-N-[[3- [ 3 -Fluoro-4-(4-morpholinyl)phenyl]l-2-oxo-5- oxazolidinyl] methyll-O ethylthiocarbamate; (S)-N-[[3- [ 3 -Fluoro-4-(4-morpholinyl)phenyl] -2-oxo-5-oxazolidinyl] methyl] -2 methylpropanethioamide; 30 (S)-N-[[3-[ 3 -Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] cyclopropane-carbothioamide

8. A compound of claim 1 wherein Z 2 is -S-. 35

9. A compound of claim 8 which is (5S)-N-[[ 3 -[4-(tetrahydro-1,4-thiazepine 4(5H)-yl)phenyll-2-oxo-5-oxazolidinyl] methyl]-thioacetamide. -177- WO 00/32599 PCT/US98/25308

10. A compound of claim 1 wherein Z 2 is -N(Ri 7 )-.

11. A compound of claim 10 which is 5 (S)-N- [[3- [3-Fluoro-4- [4-(hydroxyacetyl)- 1-piperazinyl] phenyl-2-oxo-5 oxazolidinyl] methyl] propanethiomide; (S)-N- [[3- [3-Fluoro-4- [4-(hydroxyacetyl)- 1-piperazinyl] phenyl]-2-oxo-5 oxazolidinyl]methyl]- 2 -methylpropanethioamide; (S)-N- [[3- [3-Fluoro-4- [4-(hydroxyacetyl)- 1-piperazinyl]phenyl]l-2-oxo-5 10 oxazolidinyl] methyl] cyclopropanecarbothioamide; (S)-N-[[ 3 -Fluoro-4-(4-acetyl-l-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; 15 (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]methyl]- 2 -methylpropanethioamide; (S)-N-[[3-[3-Fluoro-4-[4-(methanesulfonyl)- 1-piperazinyl]phenyl] -2-oxo-5 20 oxazolidinyl] methyl]cyclopropanecarbothioamide; (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-l-piperazinyl)phenyl]l-2-oxo-5 oxazolidinyl] methyl] propanethioamide; 25 (S)-N-[[3-[3-Fluoro-4-(4-formyl-l-piperazinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl]- 2 -methylpropanethioamide; (S)-N-[[3-[3-Fluoro-4-(4-formyl- 1-piperazinyl)phenyl]l -2-oxo-5 oxazolidinyl] methyl] cyclopropanecarbothioamide; or (S)-N-[[3-Fluoro-4-(4-acetyl-l-piperazinyl)phenyl]-2-oxo-5 30 oxazolidinyl]methyl]thioacetamide. -178-