PCX
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 98/54161
`(51) International Patent Classification 6 ;
`C07D 263/20, 417/12, 413/10, 413/04,
`A61K 31/42, C07D 261/04, 307/32,
`471/10 //
`(C07D 471/10, 235:00, 221:00)
`
`isi
`
`(11) International Publication Number:
`
`A1
`
`(43) International Publication Date:
`
`3 December 1998 (03.12.98)
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
`GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ,
`LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
`MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,
`TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO
`patent (GH, GM, KE, LS, MW,
`SD,
`SZ,
`patent (AM, AZ, BY, KG, KZ, MD, RU,
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG).
`
`UG,
`TJ,
`
`TM),
`
`Published
`With international search report.
`
`(21) International Application Number:
`
`PCT/US98/09889
`
`(22) International Filing Date:
`
`18 May 1998 (18.05.98)
`
`(30) Priority Data:
`60/048,342
`
`30 May 1997 (30.05.97)
`
`US
`
`(71) Applicant
`except US): PHARMACIA
`
`States
`(for all designated
`& UPJOHN COMPANY [US/US]; 301 Henrietta Street,
`Kalamazoo, MI 49001 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): HESTER, Jackson, B.,
`Jr. [US/US]; 9219 East ML Avenue, Galesburg, MI 49053
`(US). NIDY, Eldon, George [US/US]; 3103 Morgan Street,
`Kalamazoo, MI 49001 (US). PERRICONE, Salvatore,
`Charles [US/US]; 7011 Division Avenue, Delton, MI 49046
`(US). POEL, Toni-Jo [US/US]; 304 Anderson, Wayland,
`MI 49348 (US).
`
`(74) Agent: YANG, Lucy, X.; Pharmacia & Upjohn Company,
`Intellectual Property Legal Services, 301 Henrietta Street,
`Kalamazoo, MI 49001 (US).
`
`(54) Title: OXAZOLIDINONE ANTIBACTERIAL AGENTS HAVING A THIOCARBONYL FUNCTIONALITY
`
`A
`
`s
`W
`C-R
`1
`
`% H
`
`(I)
`
`(57) Abstract
`
`The present invention provides compounds of Formula (I) or pharmaceutical acceptable salts thereof wherein A, G and Ri are as
`defined in the claims which are antibacterial agents.
`
`MYLAN - EXHIBIT 1033
`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CU
`CZ
`DE
`DK
`EE
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`C&te d'lvoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`OXAZOLIDINONE ANTIBACTERIAL AGENTS HAVING A THIOCARBONYL
`FUNCTIONALITY
`
`10
`
`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(0)-R is converted to a thiocarbonyl functionality,
`such as a thiourea -NH-C(S)-NH2, an alkyl thiourea -NH-C(S)-NH-(C^ ^ alkyl),
`alkyl) or -NH-C(S)-H.
`thioamide -NH-C(S)-(C
`1-4
`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
`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
`infection in persons with AIDS.
`
`15
`
`20
`
`SUMMARY OF THE INVENTION
`In one aspect the subject invention is a compound of the Formula I
`
`25
`
`30
`
`35
`
`A
`^3
`
`S
`W
`c —R 1
`
`N
`
`H
`
`I
`or pharmaceutical acceptable salts thereof wherein:
`Gis
`
`O 1 N
`
`0
`
`0
`
`N
`
`O
`
`

`
`WO 98/54161
`
`Ri is
`1
`
`PCT/U S98/09889
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`A is
`
`a)
`b)
`c)
`d)
`e)
`f)
`g)
`h)
`i)
`j)
`
`a)
`
`b)
`
`c)
`
`H,
`NH 2'
`NH-Cm alkyl,
`C1.4 alkyl,
`-OC1.4 alkyl,
`-S C1.4 alkyl,
`C-^ 4 alkyl substituted with 1-3 F, 1-2 CI, CN or -COOC^ 4 alkyl,
`C3-6 cycloalkyl,
`N(CI_4 alkyl)2 or
`@H2)M;
`
`R2
`
`R3
`
`R23
`
`Q
`
`v ^
`
`R24
`
`R43
`
`R46
`
`// \\
`
`R45
`
`R44
`
`d)
`
`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
`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 48'
`
`2
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`5
`
`10
`
`15
`
`20
`
`25
`
`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)
`
`a P-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring,
`optionally substituted with one to three Rgg,
`
`g)
`
`h)
`
`*74
`
`^75
`
`.Rye
`
`, or
`
`R73
`
`K
`
`R 77
`
`R8 0
`
`N
`
`T
`
`^75 ^76
`
`t
`
`R 7 7
`
`F,
`
`wherein R2 is
`a)
`H
`b)
`c)
`d)
`e)
`f)
`g)
`
`CI,
`Br,
`C^.3 alkyl,
`NO2, or
`R2 and Rg taken together are -0-(CH2)J1-0-;
`
`30 Rg is
`
`35
`
`a)
`b)
`c)
`d)
`e)
`f)
`
`-S(=0)i R4,
`-S(=0)2-N=S(0)jR5R6,
`-SC(=0)R
`7'
`-C(=0)R8,
`-C(=0)R9,
`-C(=0)NR
`R
`10"11>
`
`-3-
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`g)
`h)
`i)
`j)
`k)
`1)
`m)
`n)
`o)
`P)
`q)
`
`-C(=NR12)R
`8'
`-C(R8)(R11)-OR
`13'
`-C(R9)(R11)-OR13,
`-C(R8)(R11)-0C(=0)R
`13'
`-C(R9)(R11)-0C(=0)R13,
`-NRioRii,
`-N(R10)-C(=O)R
`7'
`-N(R10)-S(=O)iR7,
`-C(OR14)(OR15)R
`8'
`-C(Rg)(R^0)-NR^QR^^, or
`c
`alkyl substituted with one or more =0 other than at alpha
`1-8
`position, -S(=0)IR17, -NR-^QR-Q, Cg.g alkenyl, or C2.5 alkynyl;
`
`R4 is
`
`a)
`
`alkyl optionally substituted with one or more halos, OH, CN,
`C 1-4
`NR-^QR-Q, or -CO2R13,
`b)
`alkenyl,
`C 2-4
`c)
`-NR16R18,
`d)
`-N 3'
`-NHC(=0)R
`e)
`7'
`-NR20C(=O)R
`f)
`7'
`-N(R19)2,
`g)
`-NR16R19, or
`h)
`-NR19R20,
`i)
`Rg and Rg at each occurrence are the same or different and are
`a)
`^ i-2 alkyl> or
`b)
`Rg and Rg taken together are
`alkyl optionally substituted with one or more halos;
`
`Ry is
`Ro is
`8
`
`Rg is
`
`a)
`b)
`
`a)
`b)
`c)
`
`d)
`
`H, or
`C1_g alkyl optionally substituted with one or more halos, or Cg_g
`cycloalkyl;
`alkyl substituted with one or more
`-S(=0)R
`17'
`-OR
`13'
`-0C(=0)R
`13'
`or
`"NRio^ll'
`
`-4-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`e)
`R10 and
`a)
`b)
`c)
`
`Rl2 is
`
`C^_g alkenyl optionally substituted with CHO;
`at each occurrence are the same or different and are
`H,
`C-^ alkyl, or
`Cg_g cycloalkyl;
`
`-NR^QR-J^,
`-ORio! or
`-NHC(=O)R10;
`
`a)
`b)
`c)
`R-^g is
`H, or
`a)
`C
`b)
`alkyl;
`1-4
`Rj^ and R-^g at each occurrence are the same or different and are
`a)
`C1.4 alkyl, or
`b)
`R-^ and R-^g taken together are -(CH)j-;
`
`5
`
`10
`
`15
`
`R16 is
`
`H,
`a)
`b) C^ alkyl, or
`c)
`Cg g cycloalkyl;
`
`20 R^y IS
`
`R18 18
`
`25
`
`30 R^g is
`
`a)
`b)
`
`a)
`b)
`c)
`d)
`e)
`f)
`
`^ alkyl, or
`Cg_g cycloalkyl;
`
`H,
`C1.4 alkyl,
`C2.4 alkenyl,
`C3_4 cycloalkyl,
`"OR^g or
`
`-NR21R22;
`
`CI,
`a)
`Br, or
`b)
`I;
`c)
`R20 is a physiologically acceptable cation;
`35 R2J and R22 at each occurrence are the same or different and are
`a)
`H,
`
`-5-
`
`

`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`e)
`
`WO 98/54161
`
`PCT/US98/09889
`
`alkyl, or
`b)
`-NR22R22 ^a^-en together are -(CH2)m-;
`c)
`wherein R23 and R24 at each occurrence are the same or different and are
`a)
`H
`b)
`F,
`c)
`CI
`d)
`Cj.g alkyl,
`e)
`CN
`f)
`OH,
`g)
`g alkoxy,
`h)
`nitro, or
`i)
`amino;
`
`Q is
`
`a)
`
`b)
`
`c)
`
`d)
`
`Y-
`
`x
`
`W
`
`'/ N
`
`X
`
`Y
`
`X
`
`w
`
`Y.
`
`z
`
`N
`
`Y.
`
`x
`
`N
`M
`
`Y.
`
`X
`
`N
`
`Z
`
`-6-
`
`

`
`WO 98/54161
`WO 98/54161
`
`PCT/US98/09889
`PCT/US98/09889
`
`f)
`D
`
`N
`
`X
`
`N
`M
`
`N
`
`5
`
`g)
`
`10
`
`h)
`
`15
`
`20
`
`25
`
`30
`
`35
`
`i)
`
`j)
`
`k)
`
`1)
`
`N
`M
`
`x
`
`Y
`
`N
`M
`
`w
`<N
`N
`
`x
`
`Y
`
`OR 30
`
`o
`
`(CH2)n
`
`R 38
`
`^ (C H2 ) p
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`m)
`n)
`o)
`P)
`q)
`
`a diazinyl group optionally substituted with X and Y,
`a triazinyl group optionally substituted with X and Y,
`a quinolinyl group optionally substituted with X and Y,
`a quinoxalinyl group optionally substituted with X and Y,
`a naphthyridinyl group optionally substituted with X and Y,
`
`r)
`
`s)
`
`t)
`
`u)
`
`A
`
`A2
`
`Z1
`
`(CH2)n
`
`N
`A"
`
`Z2
`
`( C H2)m >C
`
`3 ^ -
`z
`
`R1 0 7
`N
`
`N X
`
`V
`
`-8-
`
`

`
`WO 98/54161
`WO 98/54161
`
`9889N89mTCD;
`PCT/US98/09889
`
`v)
`
`w)
`
`5
`
`10
`
`X)
`
`15
`
`y)
`
`z)
`
`20
`
`25
`
`aa)
`
`y.
`
`N —
`
`x
`
`N
`N —
`
`Y
`
`X
`
`Y
`N
`
`N
`
`X
`
`N
`
`* iC'N
`
`Y
`
`I
`
`Y
`N
`\\ I N
`X
`
`X
`
`/N
`
`Y
`
`bb)
`
`or,
`
`//i\\
`Y'
`
`N
`
`30
`
`35
`
`-9-
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`Q and R24 taken together are
`
`106 R \ f N
`
`wherein Z^ is
`a)
`-CH 2''
`b)
`-CH(R104)-CH
`c)
`-C(O)-, or
`d)
`-CH2CH2CH2-;
`
`2"'
`
`2
`is
`wherein Z
`-02S-,
`a)
`-O
`b)
`-N(R107)
`c)
`-OS-, or
`d)
`-S-;
`e)
`wherein Z3 is
`a)
`-02S-,
`b)
`-O
`c)
`-OS-, or
`d)
`-S-;
`wherein
`is
`a)
`H-, or
`b)
`CHo:
`3'
`9
`wherein A
`i is
`a)
`H
`b)
`HO
`c)
`CH 3"'
`d)
`CH3O-,
`e)
`R102O-CH2-C(O)-NH-
`f)
`R103O-C(O)-NH
`g)
`(C1-C2)alkyl-0-C(0)
`h)
`HO-CH
`i)
`CH3O-NH-,
`j)
`(CjL-CgJalkyl-OgC-
`
`2"'
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`-10-
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`k)
`1)
`
`m)
`
`n)
`
`CHg-CCO)
`CH3-C(0)-CH
`
`2"'
`
`o o
`\_y
`
`o
`
`.o
`
`, or
`
`2
`1
`A and A taken together are:
`a)
`
`R112
`
`o
`
`0"^
`
`b)
`
`c)
`
`o=
`
`, or
`
`1 1 4
`
`R \
`
`N =
`
`5
`
`10
`
`15
`
`20
`
`25
`
`102
`wherein R
`is
`a)
`H
`b)
`CH
`3"'
`c)
`phenyl-CH2-, or
`d)
`CHgCCO)-;
`103 •
`wherein R
`is
`a)
`(C-L-Cgjalkyl-, or
`b)
`phenyl-;
`104
`wherein R
`is
`a)
`H-, or
`b)
`HO-;
`105
`35 wherein R
`is
`a)
`H
`
`30
`
`- 1 1 -
`
`

`
`WO 98/54161
`WO 98/54161
`
`PCT/US98/09889
`PCT/US98/09889
`
`(Ci-CgJalkyl-,
`b)
`b)
`(C1-C3)a1ky1-,
`c)
`CH2 = CH-CH2-, or
`c)
`CH2 = CH-CH2-, or
`d)
`CH3-0-(CH2)2-;
`d)
`CH3—O—(CH2)2-;
`106
`is
`wherein R
`wherein R106 is
`CHg-CtO)
`a)
`a)
`CH3-C(O)-,
`H-C(O)
`b)
`H—C(O)-,
`c)
`C12CH-C(0)-,
`C12CH-C(O)-,
`d)
`H0CH2-C(0)
`HOCH2—C(O)-,
`CHgSOg-,
`e)
`CH3SO2-,
`^lirc(o)
`R115
`S
`Vmcwr
`
`f)
`
`g)
`h)
`
`i)
`j)
`
`k)
`
`F2CHC(0)
`F2CHC(O)-,
`N^N-CP)-
`N4‘N—c(o)-
`\=J
`\:/
`
`HgC-CCO-O-CHg-CCO)-,
`H-C(0)-0-CH2-C(0)-,
`H—C(O)-O-CH2-C(O)-,
`
`^rc(o)
`
`1)
`HC=C-CH20-CH2-C(0)
`or
`1)
`HCsC—CH2O-CH2—C(O)-, or
`m)
`phenyl-CH2-0-CH2-C(0)-;
`m)
`phenyl-CH2-O—CH2-C(O)-;
`107
`wherein R
`is
`wherein R107 is
`a)
`R102O-C(R110)(Rm)-C(O)
`a)
`R1020-C(R110)(R111)-C(O)—
`b)
`R103O-C(O)
`R1°3o—c<o>-,
`b>
`R108-C(O)-,
`R108-C(O)—,
`
`c)
`
`c) ok
`
`d)
`
`€54
`u H
`OH
`
`O
`
`e)
`
`f)
`g)
`
`0^ u H
`o¢QH$<
`H3C-C(0)-(CH2)2-C(0)-,
`H30-C(O)-(CH2)2-C(O)—,
`R109-SO
`13109-302-,
`
`2"'
`
`-12-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`
`WO 98/54161
`
`h)
`
`o
`
`o
`<
`o
`
`PCT/U S98/09889
`
`2"'
`
`-13-
`
`5
`
`15
`
`20
`
`30
`
`35
`
`i)
`H0-CH2-C(0)-,
`j)
`R116-(CH2)2-,
`k)
`R113-C(0)-0-CH2-C(0)
`(CH3)2N-CH2-C(0)-NH-,
`1)
`NC-CH2-, or
`m)
`n)
`F2-CH-CH2-;
`108
`10 wherein R
`is
`a)
`H
`b)
`(CrC4)alkyl,
`c)
`aryl -(CH9)
`2 P'
`CIH2C
`d)
`CI2HC
`e)
`FH2C-,
`f)
`F2HC-, or
`g)
`(Cs-Ce^ycloalkyl;
`h)
`109
`is
`wherein R
`a)
`-CH
`3'
`-CH2CI
`b)
`-CH2CH=CH2,
`c)
`d)
`aryl, or
`e)
`-CH2CN;
`25 wherein R^® and R"'""'""'" are independently
`a)
`H
`b)
`CHg-; or
`112 •
`wherein R
`is
`a)
`H
`b)
`CHgO-CHgO-CHg-, or
`c)
`HOCH2-;
`113
`wherein R
`is
`a)
`CH 3"'
`b)
`HOCH
`(CHg)2N-phenyl, or
`c)
`(CHg^N-CHg-;
`d)
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`5
`
`10
`
`is
`
`114
`wherein R
`is
`HO
`a)
`CHgO
`b)
`c)
`HaN-,
`d)
`CH30-C(0)-0
`e)
`CH3-C(0)-0-CH2-C(0)-0
`phenyl-CH2-0-CH2-C(0)-0-,
`f)
`H0-(CH2)2-0
`g)
`h)
`CH30-CH2-0-(CH2)2-0-, or
`i)
`CH30-CH2-0-;wherein
`CH 3"'
`a)
`HOCH2-,
`b)
`(CHg)2N-phenyl, or
`c)
`(CHg)2N-CH2-;
`d)
`115 •
`15 wherein R
`is
`a)
`H-, or
`b)
`CI-;
`116
`wherein R
`is
`a)
`HO-
`CHgO-, or
`b)
`c)
`F;
`B is an unsaturated 4-atom linker having one nitrogen and three carbons;
`M is
`
`20
`
`25
`
`Z is
`
`30
`
`W i s
`
`35
`
`a)
`b)
`c)
`d)
`e)
`
`a)
`b)
`c)
`
`a)
`b)
`c)
`
`H,
`C 1-8
`alkyl,
`C 3-8
`cycloalkyl,
`-(CH2)mOR
`or
`-(CH2)h-NR21R22;
`
`O
`S, or
`NM;
`
`CH
`N, or
`S or O when Z is NM;
`
`-14-
`
`

`
`WO 98/54161
`
`Y is
`
`PCT/US98/09889
`
`a)
`b)
`c)
`d)
`e)
`f)
`
`H,
`F,
`CI,
`Br,
`C1.3 alkyl, or
`NOo:
`2'
`
`X is
`
`a)
`b)
`c)
`d)
`e)
`f)
`
`H
`-CN,
`OR
`27-
`halo,
`NO
`2'
`tetrazoyl,
`-SH,
`-S(=0)iR
`i 4'
`-S(=0)2-N=S(0)jR5R6,
`-SC(=0)R
`7'
`-C(=0)R
`25'
`-C(=0)NRoaR
`27 28'
`-C(=NR29)R
`25'
`-C(R25)(R28)-0R
`13'
`-C(R25)(R28)-0C(=0)R
`13'
`-C(R28)(OR13)-(CH0)1,-NR
`R
`27h"i,,lt27il28'
`-NR27R28,
`-N(R27)C(=0)R
`7'
`-N(R27)-S(=0)iR
`i 7'
`-C(0R14)(0R15)R
`28'
`-C(R25)(Ri6)-NR27R26, or
`alkyl substituted with one or more halos, OH, =0 other than at
`C 1-8
`alpha position, -S(=0)iR17, -NR27R2g, C2_5 alkenyl, C2_5 alkynyl, or
`C 3-8
`cycloalkyl;
`R^, Rg, Rg, Ry, R^g, R-^^, R-^g, R-^g, and R-^y are the same as defined above;
`R
`is
`25
`
`g)
`h)
`i)
`j)
`k)
`1)
`m)
`n)
`o)
`P)
`q)
`r)
`s)
`t)
`u)
`v)
`
`a)
`b)
`
`H,
`C-^ g alkyl optionally substituted with one or more halos, Cg g
`
`-15-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`
`WO 98/54161
`
`c)
`
`Rge is
`
`PCT7US98/09889
`
`cycloalkyl,
`^ alkyl substituted with one or more of -SOO)-R17,
`or 0C(=0)R
`-OR
`^^27^28' or
`13'
`13'
`C2.5 alkenyl optionally substituted with CHO, or CO2R-L3;
`
`5
`
`10
`
`a)
`R
`or
`28'
`NRgyNgg;
`b)
`R27 and R2g at each occurrence are the same or different and are
`H,
`a)
`b)
`C^g alkyl,
`c)
`Cg.g cycloalkyl,
`d)
`-(CH2)mOR13,
`e)
`-(CH2)h-NR21R22' or
`f)
`R2'7 and R2g taken together are
`or -(CH2)2N(CH2)2(R7);
`
`-(CH2)J1CH(CORY)-,
`
`15
`
`1R>29
`
`a)
`-NR27R28,
`b)
`-OR
`or
`27,
`-NHC(=0)R2g;
`c)
`wherein RgQ is
`a)
`H
`b)
`C-^ g alkyl optionally substituted with one or more halos, or
`c)
`C-^.g alkyl optionally substituted with one or more OH, or C-^ g alkoxy;
`wherein E is
`a)
`b)
`c)
`
`NR 39'
`-S(=0)i, or
`O;
`
`Rgg IS
`
`R39 is
`
`a)
`b)
`c)
`d)
`
`a)
`b)
`c)
`d)
`
`H,
`Cj.g alkyl,
`-(CH2)q-aryl, or
`halo;
`
`H,
`C
`alkyl optionally substituted with one or more OH, halo, or -CN,
`1-6
`-(CH2)q-aryl,
`
`-CO2R40,
`
`-16-
`
`20
`
`25
`
`30
`
`35
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`5
`
`10
`
`R40 is
`
`R41 is
`
`15 R42 is
`
`e)
`f)
`g)
`h)
`i)
`
`a)
`b)
`c)
`d)
`
`a)
`b)
`c)
`
`a)
`b)
`c)
`d)
`
`-COR
`41'
`-C(=0)-(CH2) -C(=0)R
`40'
`-S(=0)2-C^ 0 alkyl,
`-S(=0)2-(CH2)q-aryl, or
`-(C=0)--Het;
`J
`
`H
`Cj g alkyl optionally substituted with one or more OH, halo, or -CN,
`-(CH2)q-aryl, or
`-(CH2)q-OR42;
`
`C
`alkyl optionally substituted with one or more OH, halo, or -CN,
`1-6
`-(CHgJq-aryl, or
`-(CH2)q-OR42;
`
`H,
`C^g alkyl,
`-(CH2)q-aryl, or
`-C(=0)-C1 6 alkyl;
`
`20
`
`25
`
`30
`
`35
`
`aryl is
`
`a)
`b)
`c)
`
`phenyl,
`pyridyl, or
`napthyl; a to c optionally substituted with one or more halo, -CN, OH,
`SH, Cj g alkyl, C-^ alkoxy, or C-^g alkylthio;
`wherein R^g is
`a)
`H
`b)
`alkyl,
`C
`1-2
`c)
`F, or
`d)
`OH;
`
`R44 is
`
`a)
`b)
`c)
`d)
`e)
`
`H,
`CF 3'
`C
`alkyl optionally substituted with one or more halo,
`1-3
`phenyl optionally substituted with one or more halo,
`R44 and R^g taken together are a 5-, 6-, or 7-membered ring of the
`
`-17-
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`formula,
`
`or
`
`5
`
`H> = C \
`o =c
`(C H2 ) h
`Vu
`
`f)
`
`when R^g is an electron-
`
`taken together are
`and
`withdrawing group;
`10 R^g and R^g at each occurrence are the same or different and are
`a)
`an electron-withdrawing group,
`b)
`H,
`c)
`CF 3'
`d)
`g alkyl optionally substituted with one halo,
`e)
`phenyl, provided at least one of R^g or R^g is an electron-withdrawing
`group,or
`R45 and R^g taken together are a 5-, 6-, 7-membered ring of the
`
`15
`
`f)
`formula
`
`20
`
`U is
`
`25
`
`a)
`b)
`c)
`d)
`
`CH 2'
`O,
`S, or
`NR47;
`
`R47 is
`
`30
`
`35
`
`a)
`H, or
`b)
`C
`alkyl;
`1-5
`wherein R^g is
`a)
`carboxyl,
`b)
`halo,
`c)
`-CN,
`d)
`mercapto,
`
`o
`11 ^
`c - c ^
`(C H 2 )r
`
`U
`
`-18-
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`e)
`f)
`g)
`h)
`i)
`j)
`k)
`1)
`m)
`
`n)
`
`0)
`
`P )
`
`q)
`
`formyl,
`
`CFg,
`-NO2,
`Ci g alkoxy,
`C1_g alkoxycarbonyl,
`C-^g alkythio,
`Ci.g acyl,
`-NR
`49 R50>
`C^ g alkyl optionally substituted with OH, C-^ g alkoxy, C-^ g acyl, or
`
`-NR49R50,
`C2.8 alkenylphenyl optionally substituted with one or two Rg^,
`phenyl optionally substituted with one or two R
`51'
`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 Rg^, or
`o
`>
`(CHa),
`
`R^g and RgQ at each occurrence are the same or different and are
`H,
`a)
`b)
`C l-4 alkyl,
`c)
`Cg g cycloalkyl, or
`d)
`R^g and RgQ 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-^ 3 alkyl, or C-^.g acyl;
`
`Rgl is
`
`a)
`b)
`c)
`d)
`e)
`f)
`g)
`h)
`
`carboxyl,
`halo,
`-CN,
`mercapto,
`formyl,
`
`CF3,
`-NO2,
`C
`alkoxy,
`1-6
`
`-19-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`i)
`j)
`k)
`1)
`
`m)
`n)
`
`0)
`
`C1_g alkoxycarbonyl,
`Cj.g alkythio,
`Ci.g acyl,
`C-^ g alkyl optionally substituted with OH, C-^ alkoxy, C^_g acyl, or
`-NR49R50,
`phenyl,
`-C(=0)NR52 R 5 3 ,
`-NR49R50,
`"N(R52)(-SO2r64),
`P)
`q)
`" S O 2 - N R 5 2 R 5 3 , or
`-S(=0)IR54;
`r)
`R g 2 and R 5 3 at each occurrence are the same or different and are
`H,
`a)
`b)
`Cj.g alkyl, or
`c)
`phenyl;
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`R 5 4 is
`
`alkyl;
`
`C1.4 alkyl, or
`a)
`phenyl optionally substituted with
`b)
`wherein Rgg is
`a)
`carboxyl,
`b)
`halo,
`c)
`-CN,
`d)
`mercapto,
`e)
`for my 1,
`f)
`CFg,
`g)
`-NO 2'
`h)
`alkoxy,
`C 1-6
`i)
`alkoxycarbonyl,
`C 1-6
`j)
`alkythio
`C 1-6
`k)
`acyl,
`C 1-6
`
`R -NR 56 57'
`1)
`m)
`C-^ g alkyl optionally substituted with OH, C-^ 5 alkoxy, C-^ g acyl, or
`
`"NR56R57'
`Cg.g alkenylphenyl optionally substituted with one or two R5g,
`phenyl optionally substituted with one or two Rgg,
`a 5- or 6-membered (un)saturated heterocyclic moiety having one to
`
`n)
`o)
`P)
`
`-20-
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`three atoms selected from the group consisting of S, N, and O,
`optionally substituted with one or two R^g, or
`
`5
`
`10
`
`15
`
`q)
`
`o
`>
`(CH2)i
`
`y
`
`Rgg and Rgy at each occurrence are the same or different and are
`H,
`a)
`b)
`formyl,
`c)
`C1A alkyl,
`d)
`cl-4 acyl,
`e)
`phenyl,
`f)
`C3-6 cycloalkyl or
`g)
`Rg0 and Rg^ 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, phenyl, pyrimidyl, Cj 3 alkyl, or
`g acyl;
`
`Rgg IS
`
`20
`
`25
`
`30
`
`35
`
`a)
`b)
`c)
`d)
`e)
`f)
`g)
`h)
`i)
`j)
`k)
`1)
`m)
`
`carboxyl,
`halo,
`-CN,
`mercapto,
`formyl,
`CF3,
`-NO2,
`C-L.g alkoxy,
`g alkoxycarbonyl,
`C-^ g alkythio,
`Cx.0 acyl,
`phenyl,
`0-^ 0 alkyl optionally substituted with OH, azido, C-^ g alkoxy, Cj_g
`acyl, -NR65R66, -BRg^, -O-SO2R0g, or
`
`// \\
`
`NH-CO-O-
`
`R69'
`
`-21-
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`n)
`o)
`
`-C(=0)NR59 R
`59 60'
`"NR,56^57'
`-WRggX-SOaR^),
`P)
`-SO2-NR59R60,
`q)
`-S(=0)iR
`r)
`i 54'
`-CH=N-R
`s)
`or
`61'
`t)
`-CH(0H)-S03R64;
`Rg^ is the same as defined above;
`Rgg and R0Q at each occurrence are the same or different and are
`a)
`H,
`b)
`Ci_6 alkyl,
`c)
`phenyl, or
`d)
`tolyl;
`
`5
`
`10
`
`Rgi is
`
`15
`
`OH,
`a)
`b)
`benzyloxy,
`-NH-C(=0)-NH
`c)
`2'
`-NH-C(=S)-NH2, or
`d)
`-NH-C(=NH)-NR62R63;
`e)
`20 Rg2 and Rgg at each occurrence are the same or different and are
`a)
`H, or
`b)
`C 1-4
`alkyl optionally substituted with phenyl or pyridyl;
`
`R64 is
`
`25
`
`30
`
`35
`
`a)
`H, or
`b)
`a sodium ion;
`Rgg and Rgg at each occurrence are the same or different and are
`a)
`H,
`b)
`formyl,
`c)
`C1A alkyl,
`d)
`acyl,
`e)
`phenyl,
`f)
`C3-6 cydoalkyl,
`g)
`Rgg and Rgg 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
`
`-22-
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`atom, phenyl, pyrimidyl, C-^g alkyl, or C-^ g acyl,
`-P(O)(OR70)(OR71), or
`-S02-RY2;
`
`h)
`i)
`
`N - N
`N .
`I
`C H 3
`
`N - N
`
`( C H a J a C
`
`CX
`
`I
`C H 3
`
`or
`
`r—N c ^ N
`
`I
`C H 3
`
`Rg7 is
`
`5
`
`10
`
`15
`
`R68 is Ci-3 afcy1;
`is
`R
`69
`
`C-^ g alkoxycarbonyl, or
`a)
`carboxyl;
`b)
`R^Q and Ry^ at each occurrence are the same or different and are
`a)
`H, or
`b)
`C
`alkyl;
`1-3
`
`20
`
`R72
`
`methyl,
`phenyl, or
`tolyl;
`
`a)
`b)
`c)
`25 wherein K is
`O, or
`a)
`S;
`b)
`R^g, and R77 at each occurrence are the same or different and are
`R73' R74> "75' R
`a)
`H
`b)
`carboxyl,
`c)
`halo,
`d)
`-CN,
`e)
`mercapto,
`f)
`formyl,
`g)
`CF 3'
`h)
`-NO 2'
`
`30
`
`35
`
`-23-
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`i)
`j)
`k)
`1)
`m)
`n)
`
`o)
`P)
`q)
`
`5
`
`10
`
`alkoxy,
`C-^g alkoxycarbonyl,
`Cj.g alkythio,
`Ci.g acyl,
`-NR R
`78 79'
`02,0 alkyl optionally substituted with OH, C-^g alkoxy, C^g acyl,
`-NR78R79, -N(phenyl)(CH2-CH2-OH), -0-CH(CH3)(0CH2CH3), or
`-O-phenyl- [para-NHC(=0)CH3],
`C2.8 alkenylphenyl optionally substituted with Rg-^,
`phenyl optionally substituted with Rgj, or
`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 Rg^;
`Rg! is the same as defined above;
`15 Ryg and Ryg at each occurrence are the same or different and are
`H,
`a)
`b)
`0^4 alkyl,
`c)
`phenyl, or
`d)
`R7g and R7g 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-^ g alkyl, or
`acyl;
`
`20
`
`25
`
`30
`
`35
`
`wherein T is
`O
`a)
`S, or
`b)
`S02;
`c)
`R7g, Ryg; and R77 are the same as defined above;
`is
`R
`80
`
`a)
`b)
`c)
`d)
`e)
`f)
`
`H,
`formyl,
`carboxyl,
`C-^ g alkoxycarbonyl,
`alkyl,
`C2_8 alkenyl,
`wherein the substituents (e) and (f) can be optionally substituted with
`
`-24-
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`OH, halo, C1.6 alkoxy, C^.g acyl, C1.g alkylthio or C-^g
`alkoxycarbonyl, or phenyl optionally substituted with halo,
`an aromatic moiety having 6 to 10 carbon atoms optionally substituted
`with carboxyl, halo, -CN, formyl, CFg, -NC^, C-^g alkyl, C-^ g alkoxy,
`C^g acyl, Cj.g alkylthio, or C16 alkoxycarbonyl;
`-NR81R82>
`-OR 90'
`-S(—0)j-Rgj,
`-S02-N(R92)(R93), or
`a radical of the following formulas:
`
`g)
`
`h)
`i)
`j)
`k)
`1)
`
`R81 and Rg2 at each occurrence are the same or different and are
`a)
`H,
`b)
`Cg g cycloalkyl,
`c)
`phenyl,
`d)
`Ci.g acyl,
`e)
`C^.g alkyl optionally substituted with OH, C^_g alkoxy which can be
`substituted with OH, a 5-, or 6-membered aromatic heterocyclic
`moiety having one to three atoms selected from the group consisting of
`S, N, and O, phenyl optionally substituted with OH, CFg, halo, -NO2,
`C1.4 alkoxy, -NRggR^, or
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`<::o
`
`o
`V-
`R85
`R
`I
`86—CH—
`
`, or
`
`r~\.
`N
`V
`
`(CH2)t
`
`'
`
`O,
`CHg, or
`
`-25-
`
`f)
`
`g)
`
`a)
`b)
`
`V i s
`
`35
`
`

`
`WO 98/54161
`
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`
`c)
`NRgyJ
`Rgg and Rg^ at each occurrence are the same or different and are
`a)
`H, or
`b) C1_ 4 alkyl;
`
`5 Rgg is
`
`a)
`b)
`c)
`Rgg is
`a)
`b)
`
`10
`
`15 Rgy is
`
`OH,
`
`alkoxy, or
`-NR 88 R89'
`
`H, or
`Cj rj alkyl optionally substituted with indolyl, OH, mercaptyl,
`imidazoly, methylthio, amino, phenyl optionally substituted with OH,
`-C(=0)-NH2, -C02H, or -C(=NH)-NH2;
`
`a)
`H,
`b)
`phenyl, or
`c)
`C
`alkyl optionally substituted by OH;
`1-6
`Rgg and Rgg at each occurrence are the same or different and are
`a)
`H,
`b)
`alkyl
`C
`1-5
`c)
`cycloalky, or
`C
`3-6
`d)
`phenyl;
`
`20
`
`R90 is
`
`25
`
`a)
`
`Cj_g alkyl optionally substituted with C-^ g alkoxy or Cj_g hydroxy,
`Cg g 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 -NO2, CFg, halo, -CN, OH, C-^ 5
`alkyl,
`g alkoxy, or C-^ g acyl;
`
`30
`
`35
`
`Rgi is
`
`b)
`
`c)
`d)
`
`/-~\ N
`V
`
`(CH2)t
`
`phenyl, or
`pyridyl;
`
`-26-
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`a)
`b)
`
`c)
`d)
`
`ci-i6 alky1»
`c2-i6 alkeny1
`wherein the substituents (a) and (b) can be optionally substituted with
`C-^ g 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,
`an aromatic moiety having 6 to 10 carbon atoms, or
`a 5-, 6-, 7-membered aromatic heterocyclic moiety having one to three
`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, CFg, -NO2, C-^ alkyl, C-j^ alkoxy, Cj g
`acyl, Cj g alkylthio, or
`Q alkoxycarbonyl;
`Rg2 and Rgg at each occurrence are the same or different and are
`a)
`H,
`b)
`phenyl,
`c)
`alkyl, or
`C
`1-6
`d)
`benzyl;
`Rg4 and Rg5 at each occurrence are the same or different and are
`a)
`H,
`b)
`OH
`c)
`Cj.0 alkyl optionally substituted with -NRgg Rg4, or
`d)
`Rg^ and Rgg taken together are =0;
`
`Rgg IS
`
`a)
`b)
`
`c)
`d)
`e)
`f)
`g)
`
`an aromatic moiety having 6 to 10 carbon atoms,
`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
`with one or three -NOg, CFg, halo, -CN, OH, phenyl, C-^g alkyl, C-^ g
`alkoxy, or C^g acyl,
`morpholinyl,
`OH,
`C^g alkoxy,
`
`"NR83R84'
`-C(=0)-Rg7, or
`
`-27-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`
`WO 98/54161
`
`h)
`
`O
`<
`O
`
`Rgy IS
`
`PCT/US98/09889
`
`morpholinyl
`OH, or
`alkoxy;
`
`5
`
`15
`
`a)
`b)
`c)
`h is 1, 2, or 3;
`i is 0, 1, or 2;
`j is 0 or 1;
`10 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;
`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, or 6;
`u is 1 or 2.
`
`20
`
`25
`
`30
`
`35
`
`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
`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
`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, W094/01110;
`PCT/US94/08904, WO95/07271; PCT/US95/02972, WO95/25106; PCT/US95/10992,
`WO96/13502; PCT/US96/05202, W096/35691; PCT/US96/12766; PCT/US96/13726;
`
`-28-
`
`

`
`WO 98/54161
`
`PCT/US98/09889
`
`10
`
`15
`
`20
`
`PCT/US96/14135; PCTA;S96/17120; PCT/US96/19149; PCTAJS97/01970;
`PCT/US95/12751, WO96/15130; and PCT/US96/00718, W096/23788.
`Chemical conversion techniques for converting various intermediates having
`a CH2NH2 on the oxazolidinone ring to CH^NH-CXS^CHg is disclosed by Hartke, K.,
`5 Barrmeyer, S., J. prakt. Chem. 1996, 338, 251-6. Similarly, conversion of
`CH2NHC(=0)CH3 to CH2NHC(S)NHCH3 is reported by Cava, M.P.; Levinson, M.L,
`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
`and maximum number of carbon atoms in the moiety, i.e., the prefix C— 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^ alkyl", "C^g alkyl", "C^ alkyl", "C^g alkyl", "C^g alkyl",
`"C
`alkyl", and "C
`alkyl" refer to an alkyl group having one to two, one to
`1-16
`1-8
`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.
`alkenyl" and
`The terms "C2.4 alkenyl", "C2_g alkenyl", "C2_g alkenyl",
`alkenyl" refer to at least one double bond alkenyl group having two to four,
`"C 2-16
`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,
`nonatrienyl, undecenyl, undecdienyl, dodecenyl, tridecenyl, tetradecenyl and their
`isomeric forms thereof.
`alkynyl" refer to at least
`The terms "C2.5 alkynyl", "C2_g alkynyl", and
`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 "Cg_4 cycloalkyl", "Cg_g cycloalkyl", "C5 g cycloalkyl", and "Cg g
`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,
`cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms thereof.
`The terms "C-^ alkoxy", "C^_g alkoxy", and "C^_g alkoxy" refer to an alkyl
`
`25
`
`35
`
`-29-
`
`

`
`WO 98/54161
`
`PCT/U S98/09889
`
`5
`
`10
`
`15
`
`group 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
`alkylamino", and "C
`alkylamino" refer to an alkyl group
`1-6
`1-8
`having one to six, or one to eight carbon atoms respectively attached to an amino
`moiety such as, for example, methylamino, ethylamino, propylamine, butylamino,
`pentylamino, hexylamino, heptylamino, or octoylamino and their isomeric forms
`thereof.
`The terms "C-^ g dialkylamino", and "C^_g dialkylamino" refer to two alkyl
`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.
`The terms "C-^ acyl", "C^ acyl", "C^g acyl", "C1.6 acyl", "C^g acyl", and
`"C2_g 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-^ 4 alkoxycarbonyl", "C^g alkoxycarbonyl", and "C
`1-8
`20 alkoxycarbon