WO 98/54161
`
`pct/us98/09889
`
`A mixture of 5815 (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
`5 purification in the next reaction: ''"H NMR (300 MHz, CDCI3) d 2.16 (broad s), 3.02
`(m, 8H), 3.73 (d,d, J = 3.9, 12.6 Hz, 1H), 3.96 (m, 3H), 4.72 (m, 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) mlz 296 (M+H+).
`
`2
`
`10
`
`hn
`
`o
`u-TS-
`n o
`y=z/ \ (,.-H
`OH
`
`PhCH2OCH2COCI
`
`NaHCOa
`(CH3)2C0/H20
`
`59
`
`o
`BZOCH2-C-N
`
`o
`N—ft y=j W...-h
`F
`(
`oh
`
`60
`
`15
`
`A stirred, ice cold mixture of 59 (2.67 g from the previous reaction), acetone (190
`mL) and saturated NaHCOg (70 mL) was treated, dropwise during 2-3 min with a
`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 NaCl, dried and
`concentrated. Chromatography of the residue on silica gel with 30% acetone-C^C^
`20 gave 2.64 g of 60: 1H NMR (300 MHz, CDCI3) d 2.28 (broad s, 1H), 3.00 (m, 4H),
`3.66 (m, 2H), 3.77 (m, 3H), 3.96 (m, 3H), 4.22 (s, 2H), 4.61 (s, 2H), 4.74 (m, 1H), 6.88
`(t, J = 9.2 Hz, 1H), 7.12 (m, 1H), 7.35 (s, 5H), 7.46 (d,d, J = 2.6, 14.2 Hz, 1H); IR
`(mull) 3406, 1748, 1647 cm
`; HRMS(EI) calcd for C^HggFNgOg (M+) 443.1856,
`found 443.1842.
`
`25
`
`3.
`
`30
`
`o
`BzOCHj-C—N
`
`o
`
`F
`
`60
`
`OH
`
`i
`NO2
`
`S02CI
`
`Et3N
`
`CH2CI2
`
`BzOCHj-C-N
`
`0
`M^O
`}=/ \
`(..-H
`N-^—V"
`F
`ONos
`
`77
`
`A stirred, ice cold mixture of 60 (2.64 g, 6.00 mmol) and triethylamine (1.14 mL,
`8.16 mmol) in CH2CI2 (200 mL), under nitrogen, was treated with 3-
`nitrobenzenesulfonyl chloride (1.78 g, 8.04 mmol), warmed to ambient temperature
`35 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
`
`-67-
`
`1396
`
`MYLAN - EXHIBIT 1004 Part 4 of 10
`
`

`

`WO 98/54161
`
`PCT/US98/09889
`
`temperature for 18 h, diluted with CELgC^ and washed with water and dilute NaCl,
`dried (Na2SO^) and concentrated. Chromatography of the residue on silica gel with
`NMR (300 MHz, CDClg) d 3.02 (broad
`40-60% acetone-hexane gave 3.36 g of 77:
`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,
`5 J =9.2 Hz, 1H), 4.22 (s, 2H), 4.41 (m, 2H), 4.61 (s, 2H), 4.84 (m, 1H), 6.88 (t, J = 9.1
`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+).
`
`10
`
`15
`
`20
`
`o
`/—\
`BZOCH2-C-N
`
`o
`N-^V-N^O
`F'
`77
`
`ONos
`
`NH40H
`
`o
`II
`BZOCH2-C-N
`
`o
`>=/ \
`N O
`F
`
`IMH2
`>— f
`
`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 "C
`for 18 h, treated with additional ammonium hydroxide (30 mL), warmed at 40-45 0C
`for 8 h, treated with additional ammonium hydroxide (25 mL) and warmed at 45 0C
`for 18 h. It was then mixed with water and extracted with CH2CI2. The extract
`was washed with dilute NaCl, dried (Na2S04) and concentrated. Chromatography
`of the residue on silica gel with 5% MeOH-O.5% NH^OH-CHClg gave 2.44 g of 61:
`1H NMR (300 MHz, CDClg) d 1.50 (broad s), 3.04 (m, 6H), 3.65 (broad s, 2H), 3.81
`(m, 3H), 3.99 (t, 1H), 4.21 (s, 2H), 4.61 (s, 2H), 4.66 (m, 1H), 6.88 (t, 1H), 7.12 (m,
`1H), 7.33 (m, 5H), 7.47 (d,d, 1H); MS(ES) m/z 443 (M+H+).
`
`25 5.
`
`o
`BZOCH2-C-N
`
`N—
`
`F'
`61
`
`0
`
`\
`
`Hz, 5% Pd / C
`
`NH2
`
`EtOH
`HCI
`
`o
`HOCHj—C—N
`
`o
`
`A
`
`•HCI
`NH2
`r
`
`>=/
`F
`
`29
`
`30 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
`initial pressure of 54 psi for 20 h 15 min. Additional 1.0 N HCI (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
`35 with concentrated NH4OH, filtered and concentrated in vacuo to give 1.18 g of 29:
`1H NMR [300 MHz, (CDg^SO] d 2.94 (broad s, 4H), 3.19 (m, 2H), 3.48 (broad s, 2H),
`
`-68-
`
`1397
`
`

`

`WO 98/54161
`
`PCT/US98/09889
`
`3.60 (broad s, 2H), 3.84 (m, 1H), 4.14 (m, 3H), 4.66 (broad s, 1H), 4.93 (m, 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"1; MS(ES) mlz 353 (M+H+). Anal, calcd for C16H22C1FN404:
`C, 49.42; H, 5.70; CI, 9.12; N, 14.41. Found: C, 48.16; H, 5.82; CI, 10.00; N, 14.28.
`
`5
`
`6.
`
`10
`
`o
`HOCH2-C-N
`
`o
`N—
`N O
`' >=/ \
`(.-"'H
`F
`r
`NH2
`
`•HQ
`
`29
`
`s
`CH3—C—SEt
`
`KOH, NaF
`
`o
`HOCH2-C-N
`
`0
`
`'"£>'6; g
`
`F
`
`30
`
`N-NH-C-CH3
`
`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 CHClg, washed with water and
`15 dilute NaCl, dried (Na2SO(j) and concentrated. Chromatography of the residue on
`silica gel with 5% MeOH-O.5% NH4OH-CHCI3 and crystallization of the resulting
`product from absolute EtOH gave 0.238 mg (44.9%) 30: mp 163-165 "C; ^H NMR
`(300 MHz, CDClg) d 2.60 (s, 3H), 3.06 (m, 4H), 3.45 (m, 2H), 3.61 (m, 1H), 3.82 (m,
`3H), 4.07 (m, 2H), 4.25 (m, 3H), 4.97 (m, 1H), 6.91 (t, 1H), 7.07 (m, 1H), 7.45 (d,d,
`1H), 7.91 (broad s, 1H); MS(FAB) mlz (relative intensity) 411 (M+H+, 100), 410 (M+,
`66.5), 266 (3.1); IR 3292, 1733, 1653 cm"1. Anal, calcd for C18H23FN404S: C, 52.67;
`H, 5.65; N, 13.65. Found: C, 52.76; H, 5.58; N, 13.64.
`
`20
`
`(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-
`25 EXAMPLE 26:
`oxazolidinyl]methyl]thio-acetamide (32).
`
`30
`
`35
`
`o
`3 N-^V-
`N O
`\ /
`\=/ \ L..-H
`N-r
`F
`NH2
`
`31
`
`s
`CH3—C—SEt
`
`EtgN
`
`0
`
`A
`S^N-nfY
`S
`/
`\=/ \ L.."H
`S
`I!
`F
`NH—C-CH3
`
`32
`
`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 CH2CI2 was washed with
`
`-69-
`
`1398
`
`

`

`WO 98/54161
`
`PCT/US98/09889
`
`saturated NaHCOg, water and brine, dried (MgS04) and concentrated.
`Crystallization of the residue from EtOAc-hexane gave 0.355 g of 32: mp 155-156
`0C; MS(ES) mlz 370 (M+H+), 392 (M+Na+); IR (DRIFT) 3206, 3042, 1759, 1738 cm"
`1; 41 NMR (300 MHz, CDClg) d 2.60 (s, 3H), 2.95 (s, 4H), 3.43 (m, 4H), 3.82 (d, d,
`5 1H), 4.08 (m, 2H), 4.27 (m, 1H), 4.98 (m, 1H), 7.06 (m, 1H), 7.33 (broad s, 1H), 7.51
`(d, 1H), 8.03 (broad s, 1H). Anal, calcd for 0^112(^^0282: C, 52.01; H, 5.46; N,
`11.37. Found: C, 51.86; H, 5.43; N, 11.20.
`
`(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-
`EXAMPLE 27:
`10 oxazolidinyl]methyl]thio-acetamide, thiomorpholine S-oxide (34).
`
`15
`
`20
`
`25
`
`30
`
`35
`
`•A
`S^N-fV
`\ (
`y=j \ /..."H
`N_f
`OH
`
`O
`
`F
`
`Nal04
`
`MeOH / H2O
`
`0=S
`
`M-^V-y=J
`
`F
`
`O
`
`A
`
`N—c
`OH
`
`62
`
`63
`An ice cold, stirred mixture of sodium metaperiodate (1.08 g, 5.05 mmol) and water
`(12 mL), under nitrogen, was treated with 6216 (1.5 g, 4.8 mmol) and MeOH (17 mL)
`and kept at 6 0C for 18 h and at 4 °C for 3 h. It was then treated with additional
`sodium metaperiodate (0.1 g), kept at 4QC for 3 h and extracted with CHClg. The
`extract was dried (MgS04) and concntrated to give 1.4 g of 63: *H NMR [300 MHz,
`(CDg^SO] d 2.84 (m, 2H), 3.01 (m, 2H), 3.16 (m, 2H), 3.50 (m, 3H), 3.65 (m, 1H),
`3.77 (d,d, 1H), 4.03 (t, 1H), 4.66 (m, 1H), 5.18 (t, 1H), 7.16 (m, 2H), 7.52 (m, 1H);
`MS(ES) mlz 329 (M+H+), 351 (M+Na+).
`
`2
`
`o=s
`
`N_^V
`
`O
`N O
`
`F
`
`63
`
`NO2
`// \\
`
`so2ci
`
`OH
`
`EtgN
`CH2CI2
`
`0=8
`
`0
`
`N—^"VN^O
`
`\
`
`/..-H
`ONos
`X— (
`
`F'
`
`78
`
`An ice cold, stirred mixture of 63 (1.27 g , 3.87 mmol) and triethylamine (0.732 ml.,
`5 . 2 5 m m o l ) i n C H 2 C I 2 ( 1 3 0 m L ) , u n d e r n i t r o g e n , w a s t r e a t e d w i t h m -
`nitrobenzenesulfonyl chloride (1.15 g, 5.19 mmol) and kept at ambient temperature
`for about 24 h. It was diluted with CH2CI2, washed with water and brine, dried
`(Na2S04) and concentrated to give 78 which was used in the next reaction without
`
`-70-
`
`1399
`
`

`

`WO 98/54161
`
`purification.
`
`3.
`
`o=S
`
`5
`
`PCX/U S98/09889
`
`O
`N O
`y=/ V_X..-H
`ONos
`t
`
`F
`
`78
`
`NH4OH
`
`*•
`
`CH3CN
`(CH3)2CHOH
`
`o=s
`
`O
`
`A
`N- f V
`> = / Y L .-H
`V_r
`F
`NH2
`
`33
`
`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
`10 mL, 29.9% NHg) and kept at 40 0C for 2 h, at ambient temperature for 18 h and at
`40-45 0C for 4 h; it was concentrated to about 50 mL, diluted with water and
`extracted with CH^C^. The extracts were washed with water and brine, dried
`(MgSO^) and concentrated. Chromatography of the residue on silica gel with 5%
`MeOH-CHClg gave 0.58 g of 33: MS(ES) m / z 328 (M+H+), 350 (M+Na+); % NMR
`[300 MHz, (CDg^SO] d 2.81 (m, 4H), 3.01 (m, 2H), 3.16 (m, 2H), 3.30 (broad s), 3.49
`(m, 2H), 3.80 (d,d, 1H), 4.01 (t, 1H), 4.58 (m, 1H), 7.19 (m, 2H), 7.51 (m, 1H).
`
`15
`
`20
`
`25
`
`30
`
`35
`
`o=s
`
`0
`
`N-^V-N^O
`\
`(..•••H
`F'
`NH2
`
`33
`
`S
`
`CHg-C-SEt
`
`EtgN
`
`o=s
`
`o
`
`N-QH
`F/
`
`•H
`S
`II
`-NH-C-CH3
`
`34
`
`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
`concentrated and the residue crystallized from acetonitrile to give 3.61 g of 34: mp
`176-177 0C ; ^ NMR [300 MHz, (CDg^SO] d 2.42 (s, 3H), 2.85 (m, 2H), 3.01 (m,
`2H), 3.18 (m, 3H), 3.50 (m, 2H), 3.78 (d,d, 1H), 3.89 (broad s, 2H), 4.12 (t, 1H), 4.92
`(m, 1H), 7.18 (m, 2H), 7.49 (m, 1H), 10.33 (s, 1H); IR (DRIFT) 3186, 3102, 1741 cm"
`1; MS(ES) m/z 386 (M+H+), 408 (M+Na+). Anal, calcd for C^H^FNgOgS^O.S
`H20: C, 48.71; H, 5.37; N, 10.65; S, 16.26; H20, 2.38. Found: C, 48.75; H, 5.17; N,
`10.72; S, 16.07; H20, 1.72.
`
`EXAMPLE 28:
`
`(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-
`
`-71-
`
`1400
`
`

`

`WO 98/54161
`
`PCT/US98/09889
`
`oxazolidinyl]methyl]thio-acetamide, thiomorpholine S, S-dioxide (36).
`
`5
`
`S/
`\
`
`VN—(f-V-
`/ V=/
`F
`
`o
`NA0
`\
`
`H
`OH
`
`62
`
`OSO4
`NMO
`(CH3)2CO / H2O
`
`O2-S
`
`0
`N- f y
`N O
`\_X."H
`>=/
`F
`V_r
`OH
`
`64
`
`A stirred mixture of 62*® (0.399 g, 0.00128 mol) in 25% water/acetone (12 mL),
`10 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 £er£-butanol. It was kept at
`ambient temperature for 18 h, mixed with saturated NaHSOg (50 mL) and extracted
`with CH2CI2. The extract was washed with saturated NaHSOg and brine, dried
`(Na2SO<j) and concentrated. The residue was mixed with 3.5% MeOH-CH^C^ and
`filtered; the solid was dissolved in 15% MeOH-CH^C^ and concentrated to give 0.29
`g of 64. The filtrate was chromatographed on silica gel with 3.5% MeOH-CE^Clg to
`give 0.1 of additional 64: MS(ES) mlz 345 (M+H+), 367 (M+Na+); % NMR [300
`MHz, (CDg^SO] d 3.26 (m, 4H), 3.44 (m, 4H), 3.60 (m, 2H), 3.80 (d,d, 1H), 4.05 (t,
`1H), 4.69 (m, 1H), 7.22 (m, 2H), 7.54 (d, 1H).
`
`15
`
`20
`
`2
`
`/—\
`02=S
`
`o
`N—^VN^O
`\
`(..•"H
`OH
`
`F
`
`25
`
`64
`
`Q-S02CI
`
`O2N
`
`EtsN
`2. NH4OH
`
`o
`N—^"V-N^O
`
`o2=s
`
`F
`
`35
`
`•H
`NH2
`
`A stirred mixture of 64 (0.39 g, 0.00113 mol) and triethylamine (0.214 mL, 0.00154
`mol) in CH2CI2 (37 mL) was cooled, under nitrogen, in an ice bath and treated,
`30 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% NH4OH (25
`mL), warmed at 50-55 0C for 6 h and kept at ambient temperature for 48 h. It was
`concentrated to remove the organic solvents, diluted with water and extracted with
`CH2CI2. The extract was washed with water and brine, dried (MgSO^) and
`
`35
`
`-72-
`
`1401
`
`

`

`WO 98/54161
`
`PCT/US98/09889
`
`concentrated. Flash chromatography of the residue on silica gel with 6% MeOH-
`0.4% NH4OH-CHClg gave 0.29 g of 35: 1H NMR [300 MHz, (CDg^SO] d 1.59
`(broad s, 2H), 2.78 (m, 2H), 3.24 (m, 4H), 3.43 (m, 4H), 3.81 (d,d, 1H), 4.01 (t, 1H),
`4.57 (m, 1H), 7.18 (m, 2H), 7.52 (m, 1H); MS(ES) mlz 344 (M+H+), 366 (M+Na+).
`
`5
`
`3.
`
`o
`
`A
`/—\ H-TS-
`
`©2=3
`
`F
`
`V_r
`NH2
`
`10
`
`15
`
`25
`
`s
`CH3—C—SEt
`
`EtsN
`
`02-s,
`
`o
`
`S
`MrH
`n
`NH—C—CHg
`
`F'
`
`36
`
`35
`A stirred, ice cold suspension of 35 (0.28 g, 0.85 mmol) in a mixture of EtgN (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
`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 CHgClg (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
`ambient temperature for 5 d and concentrated in vacuo. The residue was mixed
`20 with EtOAc, washed with saturated NaHCOg, water and brine, dried (MgS04) and
`concentrated. Crystallization of the residue from MeOH-EtOAc gave 0.209 g of 36:
`mp 197-198 0C; % NMR [300 MHz, (CDg^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"1; MS(ES) mlz 424
`(M+Na+). Anal, calcd for C^HgoFNgC^Sg: C, 47.87; H, 5.02; N, 10.47. Found: C,
`47.84; H, 5.23; N, 10.28.
`
`(S) -N- [ [3- [3,5-Difluoro-4- [4- (hydroxy acetyl) -1 -
`EXAMPLE 29:
`piperazinyl]ph.enyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (38).
`
`30
`
`35
`
`F
`
`O
`
`Boc-N
`
`N — N ^ O
`\
`
`F'
`
`NHAc
`
`65
`
`NH2OH • HCI
`
`Py / EtOH
`
`Boc—N
`
`F
`
`F
`
`O
`
`V-N^O
`
`66
`
`•H
`NH2
`
`-73-
`
`1402
`
`

`

`WO 98/54161
`
`PCT/US98/09889
`
`A stirred mixture of 6517'*8 (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 ambient temperature for 18 h and at reflux for 4 h. It was concentrated in vacuo
`5 and the residue was mixed with water, adjusted to pH 11 with saturated NaHCOg
`and extracted with EtgO. The extracts were washed with brine, dried (Na2S04) and
`concentrated. Chromatography of the residue on silica gel with 5% MeOH-O.35%
`NH^OH-CHClg gave 0.75 g of recovered 65 and 0.72 g of 66:
`NMR [300 MHz,
`(CD3)2SO] 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+).
`
`10
`
`2
`
`15
`
`Boc—N
`
`F
`
`O
`n-^Vn^q
`' >=/
`\_^-H
`nh2
`
`PhCH2OCOCI
`
`EtaN/THF
`
`F
`N-^^-N^O
`
`O
`
`Boc—N
`
`F
`
`67
`
`•H
`NHCbz
`
`66
`An ice cold, stirred mixture of 66 (0.75 g, 0.0018 mol) and triethylamine (0.315 mL,
`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
`temperature for 2 h and concentrated in vacuo. The residue was mixed with CH2CI2
`and washed with saturated NaHCOg, water and brine, dried (NagSO^) and
`concentrated. This residue was mixed with Et20 and filtered to give 0.939 g of 67:
`mp 116-118 0C; % NMR (300 MHz, CDClg) d 1.48 (s, 9H), 3.08 (m, 4H), 3.53 (m,
`4H), 3.60 (m, 2H), 3.73 (m, 1H), 3.96 (t, 1H), 4.76 (m, 1H), 5.10 (s, 2H), 5.21 (m,
`1H),7.07 (d, 2H), 7.31 (s, 5H); MS(ES) m/z 547 (M+H+), 569 (M+Na+).
`
`3.
`
`F
`
`o
`N-P V-N^O
`Boc-N
`v_y
`
`F
`
`67
`
`1. TFA
`
`2. NaHCOg
`
`HN
`
`..H
`NHCbz
`
`F
`
`O
`
`NJ^VA
`
`•H
`NHCbz
`
`f'
`
`68
`
`20
`
`25
`
`30
`
`Compound 67 (0.805 g, 0.00147 mol) was added with stirring, portionwise during 5
`35 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.
`
`-74-
`
`1403
`
`

`

`WO 98/54161
`
`PCT/US98/09889
`
`The residue was mixed with ice and saturated NaHCOg and extracted with CH2CI2;
`the extract was washed with water and brine, dried (NagSC^) and concentrated to
`give 0.63 g of product. The combined aqueous layer was reextracted with EtOAc;
`the extracts were washed with water and brine, dried (NagSC^) and concntrated to
`5 give additional product. The combined product amounted to 0.68 g of 68 which was
`used in the next reaction without further purification.
`
`10
`
`HN
`
`F
`
`o
`N-^VN^O
`
`F
`
`68
`
`H
`NHCbz
`
`PhCHzOCH2COCI
`
`NaHCOa
`(CHgkCO / H20
`
`O
`
`F
`
`0
`
`BZOCH2-C-N
`
`N—{ M^Q
`' >=/
`
`NHCbz
`
`69
`
`An ice cold, stirred mixture of 68 (0.68 g, 0.00152 mol), saturated NaHCOg (15.2
`15 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: MS(ES) m / z 395 (M+H+), 617 (M+Na+); % NMR (300 MHz, CDCI3) d 3.12 (m,
`4H), 3.59 (m, 4H), 3.74 (m, 3H), 3.96 (t, 1H), 4.22 (s, 2H), 4.62 (s, 2H), 4.75 (broad s,
`1H), 5.10 (s, 2H), 5.22 (m, 1H), 7.08 (d, 2H), 7.33 (m, 10H).
`
`20
`
`5.
`
`25
`
`30
`
`35
`
`0
`/—\
`II
`N-fV-N^O
`BZOCH2-C-N
`' 7>=/ M;""
`
`F
`
`0
`
`NHCbz
`
`69
`
`H2 / Pd
`
`HCII MeOH
`
`o
`II
`/
`HOCH2—C-N
`\
`
`F
`
`0
`
`V
`NHfVNA0
`^=/ \_^-H
`(
`NHZ
`
`37
`
`A mixture of 69 (0.72 g, 0.0012 mol), MeOH and 5% palladium-on-carbon catalyst
`(0.4 g) was hydrogenated at an initial pressure of 45 psi for 4 h. By TLC (8%
`MeOH-O.5% NH4OH-CHCI3) 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
`concentrated to give 0.40 g of 37: MS(ES) m/z 371 (M+H+), 393 (M+Na+); % NMR
`[300 MHz, (CDgXjSO] d 3.02 (s, 4H), 3.20 (m, 2H), 3.43 (s, 2H), 3.56 (s, 2H), 3.84 (m.
`
`-75-
`
`1404
`
`

`

`WO 98/54161
`
`PCT/U S98/09889
`
`1H), 3.84 (broad s), 4.10 (s, 2H), 4.14 (t, 1H), 4.96 (m, 1H), 7.26 (d, 2H), 8.41 (broad
`s, 3H).
`
`6.
`
`5
`
`II
`HOCH2—C-N
`
`F
`
`0
`
`N-^^-N^O
`
`NH2
`
`• x HCI
`
`37
`
`CHg-C-SEt
`EtaN
`
`HOCH2—C-N
`\
`
`N-^V-N^O
`/
`
`...H
`NH-C-CH3
`
`38
`
`10
`
`15
`
`20
`
`A stirred suspension of 37 (0.38 g) in a solution of EtgN (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^OH-CHClg). Additional ethyl dithioacetate (2 drops) was added after 24 h;
`after 30 h CH2CI2 (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 NaHCOg an extracted with
`CH2CI2. The extract was washed with water and brine, dried (MgS04) and
`concentrated. The residue was chromatographed on silica gel with 2.5% MeOH-
`CH2CI2 and the product was crystallized from MeOH to give 0.182 g of 38: mp 110­
`111 0C (dec); MS(ES) mlz 429 (M+H+), 451 (M+Na+); HRMS (FAB) calcd for
`C18H23F2N404S (m+h+) 429.1408, found 429.1415; IR (DRIFT) 1760, 1652, 1639
`[a24D 8° (MeOH).
`cm
`
`(S)-N-[[3- [4-[ 1 -[ 1,2,4]Triazolyl]phenyl]-2-oxo-5-
`EXAMPLE 30:
`25 oxazolidinyl]methyl]thiourea (44).
`
`pN
`
`N^N
`
`30
`
`26
`
`o
`N O
`
`»•••
`
`..H
`NH2
`
`+
`
`V
`
`O S O
`
`rzN
`
`CN-^NAO
`
`o
`II
`
`F
`
`79
`
`•H
`N=C=S
`
`A solution of 26 (0.190 g, 0.685 mmol) in CH2CI2 (20 mL) was added, dropwise
`during 20 min, under nitrogen, to an ice cold, stirred solution of 1,1^-thiocarbonyldi-
`35 2(lH)-pyridone (0.193 g, 0.831 mmol) in CH2CI2 (7 mL). The mixture was kept in
`the ice bath for 20 min and at ambient temperature for 2 h, diluted with CH2CI2,
`
`-76-
`
`1405
`
`

`

`WO 98/54161
`
`PCT/U S98/09889
`
`washed with water and brine, dried (MgS04) and concentrated. Chromatography of
`the residue on silica gel with 10-15% CH3CN-CH2CI2 gave 0.11 g of 79 which was
`used in the next reaction without further purification: MS(ES) mlz 320 (M+H+),
`342 (M+Na+).
`
`5
`
`2
`
`10
`
`15
`
`20
`
`25
`
`o
`
`NH3
`thf
`
`•h
`n=c=s
`
`f
`
`79
`
`o
`
`44
`
`•h
`s ii
`-nh-c-nh2
`
`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
`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 0C; % NMR [300 MHz, (CDg^SO] d 3.82 (m, 3H), 4.18 (t, 1H), 4.89
`(broad s, 1H), 7.20 (broad s, 2H), 7.50 (d, 1H), 7.79 (m, 2H), 7.93 (t, 1H), 8.26 (s, 1H),
`8.97 (s, 1H); MS(ES) mlz 337 (M+H+), 359 (M+Na+). Anal, calcd for
`C13H13FN602S: C' 46-42; H> 3-90; N> 24"- Found: C, 46.22; H, 3.98; N, 24.55.
`
`EXAMPLE 31:
`(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-l-
`piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]thiourea (45).
`
`o
`/—\
`HOCH2-C—N
`N—
`\ I
`
`F'
`
`o
`
`H
`NH2
`
`I V
`
`S O
`
`O
`
`EtjN / CH2CI2
`
`•HCI
`
`29
`
`o
`ii
`HOCH2-C—N
`
`o
`N—(^VN^D
`
`F'
`
`80
`
`N=C=S
`
`30 An ice cold, stirred solution of l,l<2-thiocarbonyl-2(lH)-dipyridone (0.123 g, 0.530
`mmol) in CH2CI2 (5 mL), under nitrogen, was treated with a suspension of 29 (0.17
`g, 0.4 mmol) in CH2CI2 (20 mL) and then during 10 min with a solution of
`triethylamine (0.111 mL, 0.8 mmol) in CH2CI2 (10 mL). It was kept in the ice bath
`for 30 min, at ambient temperature for 2 h and at < 0 0C for 18 h. It was then
`diluted with CH2CI2, washed with water and brine, dried (MgSO^) and
`concentrated. The residue (80) was used without further purification in the next
`
`35
`
`-77-
`
`1406
`
`

`

`WO 98/54161
`
`PCT/US98/09889
`
`reaction. A sample of 80 that was purified by flash chromatography on silica gel
`with 10-20% acetonitrile-CH2Cl2 had: % NMR (300 MHz, CDClg) d 1.60 (broad s),
`3.07 (m, 4H), 3.45 (m, 2H), 3.85 (m, 4H), 3.97 (d,d, 1H), 4.16 (t, 1H), 4.21 (s, 2H),
`4.82 (m, 1H), 6.95 (t, 1H), 7.13 (d,d, 1H), 7.47 (d,d, 1H); MS m l z 395 (M+H+); 417
`(M+Na+).
`
`2
`
`o
`II
`HOCH2-C—N
`
`o
`
`N—^""V-N^O
`
`..H
`N=C=S
`
`80
`
`NH3
`
`o
`HOCH2-C—N
`
`o
`c
`N — N ^ O
`MrH
`M
`F'
`NH-C
`C-NH2
`
`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
`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^OH-CHClg and the product
`was crystallized from acetonitrile to give 0.0544 g of 45: mp 209-210 0C;
`NMR
`[300 MHz, (003)280] 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 (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"1; HRMS (FAB)
`calcd for C17H23FN504S (M+H+) 412.1454, found 412.1447. Anal, calcd for
`C17H22FN504S: C> 49.63; H, 5.39; N, 17.02. Found: C, 49.63; H, 5.48; N, 16.99.
`
`5
`
`10
`
`15
`
`20
`
`(S)-N-[[3-[l - (Hydroxy acetyl) -5-indolinyl] -2-oxo-5-
`25 EXAMPLE 32:
`oxazolidiny 1]methyl]thiourea (46).
`
`HOCH2—c=o
`
`\ COX
`
`•HCI
`
`..H
`NH2
`
`27
`
`30
`
`35
`
`O
`
`A
`
`..H
`N=C=S
`
`HOCH2-C=O
`N
`
`O s O
`
`EtgN
`
`81
`
`-78-
`
`1407
`
`

`

`WO 98/54161
`
`PCX/US98/09889
`
`An ice cold, stirred solution of l,l0-thiocarbonyldi-2(lH)-pyridone (0.096 g, 0.41
`mmol) in CH^C^ (5 mL) was treated with a suspension of 27 (0.10 g, 0.34 mmol) in
`CH2CI2 (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 CH2CI2,
`5 washed with water and brine, dried (MgS04) and concentrated. Chromatography
`ofthe residue on silica gel with 20-40% CHgCN-CHgC^ gave 0.04 g of 81.
`2 HOCHs-C-O
`\
`N
`I A
`
`10
`
`0
`
`NH3
`
`-H
`N-C=S
`
`81
`
`HOCHa-C'O
`\
`
`COA
`
`S
`-H
`-NH-C-NH2
`
`1 1
`
`46
`
`15
`
`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
`under a stream of nitrogen. The residue was crystallized from CHgCN to give
`0.0151 g of 46: mp 214-215 0C (dec); MS (FAB) m / z 351 (M+H+), 350 (M+), 319,
`304, 147; HRMS (FAB) calcd for C15H19N404S (M+H+) 351.1127, found 351.1130;
`IR (DRIFT) 3329, 3296, 3196, 1746, 1655, 1626 cm"1.
`
`20
`
`(S)-N- [ [3-[3-Fluoro-4- (4-thiomorpholiny Dphenyl] -2-oxo-5-
`EXAMPLE 33:
`oxazolidinyl]methyl]thiourea, thiomorpholine S-oxide (47).
`
`25
`
`30
`
`35
`
`n-^V-n^o
`
`t—\
`os
`\
`/
`
`F
`
`33
`
`o
`
`'..'h
`nh2
`
`I ir-Yv
`
`o s o
`ch2Cl2
`
`OS
`
`o
`
`n-^V-n^o
`
`F'
`
`82
`
`: h
`ncs
`
`A suspension of 33 (0.30 g, 0.92 mmol) in CHgC^ (7 mL) was added, during 20 min,
`to an ice cold, stirred mixture of l,l<z-thiocarbonyldi-2(lH)-pyridone (0.258 g, 1.11
`mmol) and CH2CI2 (20 mL). The mixture was kept in the ice bath for 20 min and at
`ambient temperature for 2 h, mixed with CH2CI2 (50 mL), washed with water and
`brine, dried (MgS04) and concentrated. Chromatography of the product on silica gel
`with 20-50% CH3CN-CH2CI2 gave 0.27 g of 82 which was used in the next reaction:
`MS(ES) m/z 370 (M+H+), 392 (M+Na+).
`
`-79-
`
`1408
`
`

`

`wo 98/54161
`
`2
`
`OS
`\
`
`o
`n^Vna0
`/
`
`f'
`
`h
`N=C=S
`
`82
`
`NHg
`
`THF
`
`os
`
`y=J
`
`pct/us98/09889
`
`o
`NA0
`s
`\_^h
`nh-c-nh2
`
`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
`concentrated; crystallization of the residue from MeOH gave 0.175 g of 47; mp 212-
`213 °C; % NMR [300 MHz, (CD3)2SO] 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) mlz 409 (M+Na+); IR (mull) 3335,
`3284, 3211, 3175, 3097, 1750, 1630 cm"\ Anal, calcd for C15H19FN403S2: C, 46.62;
`H, 4.95; N, 14.50. Found: C, 46.50; H, 4.95; N, 14.40.
`
`(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-
`EXAMPLE 34:
`oxazolidinyl]methyl-S-methyldithiocarbamate (48).
`cQN-fVA
`
`O
`O ^N-^A-NI^O
`.h
`ll•,,
`f'
`NH2
`
`39
`
`1. CSj/EtaN
`
`2. Mel
`
`o
`
`S
`•H
`NH-C-SCHg
`
`F'
`
`48
`
`5
`
`10
`
`15
`
`20
`
`25
`
`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
`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
`30 mixture was kept at ambient temperature for 1.5 h and concentrated in vacuo. A
`solution of the residue in EtOAc was washed with saturated NaHCOg, water and
`brine, dried (MgSO^) and concentrated. The residue was chromatographed on silica
`gel with 1.8% MeOH-CH2Cl2 and the product was crystallized from EtOAc to give
`0.197 g of 48: mp 154-155 "C; IR (mull) 3354, 3346, 1726 cm"1. Anal, calcd for
`ci6H2oFN303s2: c> 49-85' H>5-23;N'10-90- Found: c>49-73; H>5-25; N>10-82-
`
`35
`
`-80-
`
`1409
`
`

`

`WO 98/54161
`
`PCT/US98/09889
`
`(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-
`EXAMPLE 35:
`oxazolidinyl]methyl-0-methylthiocarbamate (50).
`
`5
`
`O
`\
`
`N-// \N
`/
`
`F
`
`48
`
`0
`U
`
`N,
`
`P H
`
`S
`
`NaOCHg
`
`MeOH
`
`z-\ •N-//
`
`0
`
`•NH-C-SCHg
`
`F
`
`o
`A
`
`N
`
`O
`' - H
`'—NH-C —OCH3
`
`S
`
`50
`
`15
`
`A stirred mixture of 48 (0.200 g, 0.518 mmol), sodium methoxide (0.003 g, 0.06
`10 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
`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 KHSO4 and saturated NaHCOg and the mixture was extracted with
`CH2CI2. The extract was washed with water and brine, dried (MgS04) and
`concentrated. The residue was chromatographed on silica gel with 5% acetone-
`CH2CI2 and the product was crystallized from EtOAc-hexane to give 0.107 g of 50:
`mp 128-129 °C; MS(ES) mlz 370 (M+H+), 392 (M+Na+); IR (DRIFT) 3282, 3251,
`1753, 1735 cm"1; 1H NMR [300 MHz, (CDg^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 C^gP^oFNgO^S: C, 52.02;
`H, 5.46; N, 11.38. Found: C, 51.97; H, 5.49; N, 11.35.
`
`20
`
`25
`
`-81-
`
`1410
`
`

`

`WO 98/54161
`
`WHAT IS CLAIMED:
`
`A compound of the formula I
`
`PCT/US98/09889
`
`A
`
`S
`W
`C—R 1
`
`N
`\
`H
`
`I
`or pharmaceutical acceptable salts thereof wherein:
`G is
`
`N
`
`o
`
`A
`
`o II
`
`O
`
`is
`
`5
`
`10
`
`15
`
`20
`
`25
`
`a)
`b)
`c)
`d)
`e)
`f)
`g)
`h)
`i)
`j)
`
`a)
`
`H,
`NH
`2'
`NH-C1.4 alkyl,
`Cj.4 alkyl,
`alkyl,
`alkyl,
`^ alkyl substituted with 1-3 F, 1-2 CI, CNor -COOC^ alkyl,
`Cg g cycloalkyl,
`WCj^) alkyl)2 or
`N(CH2)2.5;
`
`-S
`
`P a
`
`R s
`
`-82-
`
`A is
`
`30
`
`1411
`
`

`

`WO 98/54161
`
`PCT/US98/09889
`
`b)
`
`5
`
`^23
`Q
`
`\
`
`^24
`
`10
`
`c)
`
`^43
`
`// \\
`
`R44
`
`R46,
`
`R45'
`
`15
`
`d)
`
`atom,
`
`a 5-membered heteroaromatic moiety having one to three atoms
`selected from the group consisting of S, N, and O,
`wherein the 5-membered heteroaromatic moiety is bonded via a carbon
`
`20
`
`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 to
`
`25
`
`three R 48'
`e)
`
`a 6-membered heteroaromatic moiety having at least one nitrogen atom,
`wherein
`the heteroaromatic moiety
`is bonded via a carbon
`atom,
`wherein the 6-membered heteroaromatic moiety can additionally have a
`fused-on benzene or naphthyl ring,
`wherein the heteroaromatic moiety is optionally substituted with one to
`
`three R 55'
`f)
`
`30
`
`a P-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring,
`optionally substituted with one to three R55,
`
`g)
`
`35
`
`R74
`
`^75
`
`- R y e
`
`R73
`
`K
`
`R 7 7
`
`, or
`
`-83-
`
`1412
`
`

`

`WO 98/54161
`
`PCT/US98/09889
`
`5
`
`10
`
`h)
`
`R 80
`
`N
`
`T
`
`R
`75
`
`R
`76
`
`R 77
`
`wherein R2 is
`a)
`H,
`F,
`b)
`c)
`CI,
`Br,
`d)
`e)
`C
`alkyl,
`1-3
`NO or
`f)
`2'
`g)
`R2 and Rg taken together are -CMCH^h-O-;
`
`15 Rg is
`
`20
`
`25
`
`30
`
`a)
`b)
`c)
`d)
`e)
`f)
`g)
`h)
`i)
`J)
`k)
`1)
`m)
`n)
`
`0 )
`P)
`q)
`
`-S(=0)i R
`4'
`-S(=0)2-N=S(0)JR5R6,
`-SC(=0)R
`7'
`-C(=0)R
`8'
`-C(=0)R
`9'
`-C(=O)NR10Rlll
`-C(=NR12)R8,
`-C(R8)(R11)-OR13,
`-C(R9)(R11)-OR1g,
`-C(R8)(R11)-0C(=0)R
`13'
`-C(R9)(R11)-0C(=0)R13,
`-NR1oR11,
`-N(R10)-C(=O)R
`7-
`-N(R10)-S(=O)iR7,
`-C(OR14)(OR15)R
`8'
`-C(Rq)(RIC)-NR
`R
`or
`16
`10xvll'
`alkyl substituted with one or more =0 other than at alpha
`C 1-8
`position, -S(=0)IR17, -NR-j^R^, €2.5 alkenyl, or C2.5 alkynyl;
`
`R4 is
`
`35
`
`a)
`
`alkyl optionally substituted with one or more halos, OH, CN
`C 1-4
`NR-^QR-J^, or -C02R1g,
`
`-84-
`
`1413
`
`

`

`WO 98/54161
`
`PCT/US98/09889
`
`C2.4 alkenyl
`-NR16R18,
`-N 3'
`-NHC(=0)R
`7'
`-NR20C(=O)R
`7'
`
`or
`
`b)
`c)
`d)
`e)
`f)
`g)
`-NR16R19,
`h)
`i)
`-NR19R20>
`Rg and Rg at each occurrence are the same or different and are
`a)
`C-^ 2 alkyl, or
`b)
`Rg and Rg taken together are -(CH^k-;
`alkyl optionally substituted with one or more halos;
`
`Ry is
`Ro is
`8
`
`Rg is
`
`a)
`b)
`
`H, or
`C
`alkyl optionally