US006057352A United States Patent (19) 11 Patent Number: 6,057,352 Brown et al. (45) Date of Patent: May 2, 2000

54 FUNGICIDAL CYCLIC AMIDES WO 96/17851 6/1996 WIPO ...... CO7F 7/08 WO 96/26.191 8/1996 WIPO ...... CO7D 249/12

75 Inventors: Richard James Brown, Newark, Del.: WO 96/36633 11/1996 WIPO ...... CO7D 405/04 Deborah Ann Frasier, Martinez, Calif.; WO96/36229 11/1996 WIPO ...... A01N 43/653 Michael Henry Howard, Jr., WO 97/02255 1/1997 WIPO m CO7D 261/12 Rockland; Gerard Michael Koether, OTHER PUBLICATIONS Bear, both of Del. Zvilichovsky, G., J. Heterocyclic Chem., 24,465–470, 1987. 73 Assignee: E. I. du Pont de Nemours and Zvilichovsky, G. et al., J. Heterocyclic Chem., 25, Company, Wilmington, Del. 1307-1310, 1988. Davis, M. et al., Australian J. Chem., 30(8), 1815-1818, 21 Appl. No.: 08/952,380 1977. 22 PCT Filed: May 8, 1996 Primary Examiner Mukund J. Shah 86 PCT No.: PCT/US96/06534 Assistant Examiner Deepak R. Rao S371 Date: Nov. 13, 1997 57 ABSTRACT S 102(e) Date: Nov. 13, 1997 Compounds of Formula (I), 87 PCT Pub. No.: WO96/36616 (I) PCT Pub. Date: Nov. 21, 1996 1.Y. Nz Related U.S. Application Data x - W 63 Continuation-in-part of application No. 08/442,433, May NY 17, 1995, abandoned. A-N 60 Provisional application No. 60/004,183, Sep. 22, 1995. Ye 51) Int. Cl." ...... C07D 249/12; CO7D 233/30; AO1N 43/74; AO1N 43/56 and their N-oxides and agriculturally Suitable Salts are 52 U.S. Cl...... 514/384; 514/386; 548/263.4; disclosed which are useful as fungicides, wherein E is 548/264.6; 548/316.7: 548/325.1; 548/325.5; 1.2-phenylene optionally substituted with one of R, R", or 548/263.8 both R and R'; A is O; S; N; NR; or CR'; G is C or N; 58 Field of Search ...... 514/384, 359, provided that when G is C, then A is O, S or NR and the 514/386, 360; 548/263.4, 263.8, 264.6, floating double bond is attached to G, and when G is N, then 316.7, 325.1, 325.5 A is N or CR'' and the floating double bond is attached to A; W is O; S; NH; N(C-C alkyl); or NO(C-C alkyl); X 56) References Cited is OR; S(O).R'; or halogen; R is C-C alkyl; C-C, haloalkyl, C-C alkenyl, C-C haloalkenyl, C-C alky U.S. PATENT DOCUMENTS nyl, C-C haloalkynyl, C-C cycloalkyl, C-C alkylcar 4,098,896 7/1978 Edwards ...... 424/269 bonyl; or C-C alkoxycarbonyl; R is H; C1-C alkyl; 5,108,486 4/1992 Kondo et al...... 71/92 C-Chaloalkyl, C-C alkenyl: C-C haloalkenyl, C-C, 5,416,110 5/1995 Wingert et al...... 514/488 alkynyl, C-C haloalkenyl, C-C cycloalkyl, C-C alky 5,474,974 12/1995 Kruger et al...... 504/236 lcarbonyl: C-alkoxycarbonyl, hydroxy; C1-C alkoxy; or 5,747,516 5/1998 Brown et al...... 514/359 acetyloxy; and Y, Z, R, R", R, R'' and mare as defined in FOREIGN PATENT DOCUMENTS the disclosure. Also disclosed are compositions containing the compounds of Formula (I) and a method for controlling O 508 126 10/1992 European Pat. Off...... CO7D 231/32 plant diseases caused by fungal plant pathogens which O 617 014 9/1994 European Pat. Off. ... CO7C 327/58 44 13 669 1/1995 Germany ...... CO7D 307/94 involves applying an effective amount of a compound of WO 94/11334 5/1994 WIPO ...... CO7C 70/734 Formula (I). WO95/14009 5/1995 WIPO ...... CO7D 249/12 WO95/18789 7/1995 WIPO ...... CO7C 251/60 10 Claims, No Drawings 6,057,352 1 FUNGCIDAL CYCLIC AMIDES ii This application is a national filing under 35 USC 371 of International Application Number PCT/US96/06534 filed May 8, 1996 and claiming priority of U.S. Provisional S Ne Application No. 60/004,183 filed Sep. 22, 1995 which is R2 R3 --(R'), continuation-in-part of U.S. patent application Ser. No. N S 08/442,433 filed May 17, 1995, now abandoned. OR1 O BACKGROUND OF THE INVENTION wherein R" is C-C alkyl; This invention relates to certain cyclic amides, their R’ is OR or NHR; N-oxides, agriculturally Suitable Salts and compositions, and 15 R is C-Cs cycloalkyl; methods of their use as fungicides. R" is, among others, C-Clio alkoxy, C-C, alkoxycarbonyl, halogen, cyano, C-C alkylthio, The control of plant diseases caused by fungal plant C-C alkyl, or C-C haloalkyl, pathogens is extremely important in achieving high crop R and Rare C-C alkyl; and efficiency. Plant disease damage to ornamental, vegetable, n is 0–5. EP-A-656,351, WO 95/18789 and WO 95/21153 also field, cereal, and fruit crops can cause Significant reduction disclose amides and esters Similar to those in the above two in productivity and thereby result in increased costs to the publications as fungicides. consumer. Many products are commercially available for The cyclic amides of the present invention are not dis these purposes, but the need continues for new compounds 25 closed in any of the above publications. which are more effective, leSS costly, leSS toxic, environ J. Heterocyclic Chem., (1987), 24, 465, J. Heterocyclic Chem., (1988), 25, 1307, and Australian J. Chem., (1977), mentally safer or have different modes of action. 30 (8), 1815 disclose 4-nitrophenyl isoxazoles (iii), phenyl pyrazolones (iv), and aryl isothiazolinones (v) respectively. WO 94/11334 discloses certain amides and esters of Formula i as fungicides iii NO

35

r'2 cifC YR3 MeO O YCH 40 X O-N O M Me iv.

45 wherein n is 0-4, CHCHO O X is CHOCH, CHCH, or NOCH: 50 Y is O or NH; N-N R" is, among others, nitro; cyano; halogen; C1-C alkyl; M N H H C-C haloalkyl, C-C alkoxy; C-C haloalkoxy; or w C-C alkylthio; Air R is, among others, nitro, cyano, halogen, C-C alkoxy, 55 C-C alkylcarbonylanrino, or C-C alkoxycarbony MeS 21 O lamino; S-N R is, among others, R-T-C(=Z)- or R-C M (=Z)-; 60 Me Z' is, among others, O or S; However, no utility as fungicides is alleged and the cyclic Z is, among others, O or S; and amides of the present invention are not disclosed therein. T is, among others, O, S, or NR"; and 65 SUMMARY OF THE INVENTION EP-A-617,014 discloses certain amides and esters of This invention is directed to compounds of Formula I Formula ii as fungicides including all geometric and Stereoisomers, N-oxides, and

6,057,352 S 6 ring System containing one or two nonaromatic rings when Yis-CHRN(R')C(=O)N(R)-, the two R' that each include one or two Q as ring members and attached to nitrogen atoms on Said group can be taken one or two ring members independently Selected together as -(CH2)-; or from C(=O) and S(O), and any remaining rings as when Y is –CHRO-N=C(R7)NR'-, R7 and the aromatic carbocyclic rings, each multicyclic ring adjacently attached R' can be taken together as system substituted with Rand optionally substituted CH-(CH), ; -O-(CH)-, -S-(CH)-; with one or more R'; and O v) adamantyl substituted with R and optionally substi -N(C-C alkyl)-(CH)-; with the directionality tuted with one or more R'; of Said linkage defined Such that the moiety depicted each Q is independently Selected from the group on the left side of the linkage is bonded to the carbon CHR-, -NR13-, -O-, and -S(O)-; and the moiety on the right Side of the linkage is R is H; 1-2 halogen; C-C alkyl; C-C haloalkyl; bonded to the nitrogen; C-C alkoxy; C1-C haloalkoxy, C-C alkenyl, R", R7, and Rare each independently H; C1-C alkyl; C-C haloalkenyl, C-C alkynyl, C-C alkylthio; C-C cycloalkyl, or phenyl optionally Substituted with C-Chaloalkylthio; C-C alkylsulfinyl, C-C alkyl 15 halogen, C-C alkyl, C-Chaloalkyl, C-C alkoxy, Sulfonyl, C-C cycloalkyl, C-C alkenyloxy; CO C-C haloalkoxy, nitro or cyano; (C-C alkyl); NH(C-C alkyl); N(C-C alkyl); R. R. R. R. R., and R' are each independently cyano; nitro; SiR'R'R'; or GeR'R'R'; C-C alkyl, C-C alkenyl; C1-C alkoxy, or phenyl, R’ is H; 1-2 halogen; C-C alkyl, C-C haloalkyl; each R is independently C-C alkyl; C-C haloalkyl; C-C alkoxy; C1-C haloalkoxy, C-C alkenyl, C-C alkenyl, C. alkoxy, or phenyl, C-C haloalkenyl, C-C alkynyl, C-C alkylthio; R’ is H; C-C alkyl, C-C cycloalkyl; or phenyl C-Chaloalkylthio; C-C alkylsulfinyl, C-C alkyl optionally Substituted with halogen, C-C alkyl, Sulfonyl, C-C cycloalkyl, C-C alkenyloxy, CO C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, (C-C alkyl); NH(C-C alkyl); N(C-C alkyl); 25 nitro or cyano; –C(R)=NOR7; cyano; nitro; SF; SiR'R'R'; or R7 and Rare each independently C-C alkoxy; C-C, GeR’RR'; or R is phenyl, benzyl, benzoyl, cycloalkyl, formylamino; C-C alkylcarbonylamino; phenoxy, pyridinyl, pyridinyloxy, thienyl, thienyloxy, C-C alkoxycarbonylarnino; NHC(O)NH; (C-C, furanyl, pyrimidinyl, or pyrimidinyloxy each option alkyl)NHC(O)NH; (C-C alkyl)-NC(O)NH; N(C-C, ally substituted with one of R'', R', or both R'' and alkyl); piperidinyl; morpholinyl, cyano; or nitro, R12; R’ is C-C alkoxy; C-C cycloalkyl; formylamino; each R" is independently halogen; C1-C, alkyl, C-C, C-C alkylcarbonylamino; C-C alkoxycarbony haloalkyl, C-C alkoxy, nitro, or cyano, or lamino; NHC(O)NH; (C-C, alkyl)NHC(O)NH; when R and an R' are attached to adjacent atoms on Z. (C-C alkyl)-NC(O)NH; N(C-C alkyl)2; piperidi R” and said adjacently attached R' can be taken 35 nyl; morpholinyl; halogen; cyano, or nitro, together as -OCH-O- or -OCHCH-O-, each R is C-C cycloalkyl; or phenyl optionally substituted CH group of said taken together RandR' optionally with halogen, C-C alkyl, C-C haloalkyl, C-C, Substituted with 1-2 halogen; or alkoxy, C-Chaloalkoxy, nitro or cyano; R is C-C, when Y and an R'' are attached to adjacent atoms on Z alkylthio; C1-C alkylsulfinyl, C-C alkylsulfonyl, and Y is 40 C-C haloalkylthio; C-C haloalkylsulfinyl, C-C, –O-CHCHO-N=C(R)-, -CHRO-C(R) haloalkylsulfonyl; nitro; hydroxy; amino; NH(C-C, =C(R)-, -CH=N-N=C(R)-, alkyl); N(C-C alkyl), or halogen; -CHRSN (RS)-N=C(R7)-, -CHR N R’ is C-C cycloalkyl; (COCH)-N=C(R)- or m, n and p are each independently 0, 1 or 2, —CHRO-N=C(R)-, R7 and said adjacently 45 r is 0 or 1; and attached R' can be taken together as-(CH2)-J- S is 2 or 3; Such that J is attached to Z, provided that J is -CH-, -CHCH-, -OCH-, -CHO-; i) when Y is -CH(OR°)-, -CHR 7–, -SCH-, -CHS-, -N(R')CH-, or -CHRCHR-, -CHRCHR-, -OCHR , -CHN(R')-; each CH group of said J optionally 50 -S(O)CHR- or -(R)C=N-OCH(R)- and substituted with 1 to 2 CH; Z is C-Co alkyl, C-Coalkenyl, or C-Co alkynyl R'' and R'' are each independently halogen; C-C alkyl; each substituted with R and optionally substituted C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, with one or more R', then R is other than H, C-C, nitro; cyano; Si(R); or Ge(R); 55 alkyl, C-C alkenyl, or C-C alkynyl, each R" is independently H; C-C alkyl; C-C, ii) when Y is –CR=CR°– or –CR’=CR- and Z haloalkyl; or phenyl optionally substituted with is C-Co alkyl or C-Coalkenyl each Substituted with halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, R and optionally substituted with one or more R', C-C haloalkoxy, nitro or cyano; then R is other than H, 1-2 halogen, C-C alkyl, R" is H.; halogen; C1-C alkyl, C-C haloalkyl, C-C, 60 C-Chaloalkyl, C-C alkenyl, or C-C haloalkenyl, alkenyl, C-C haloalkenyl, C-C alkynyl, C-C, iii) when Y is -NR'-, R is H or C-C alkyl, and R' haloalkynyl, or C-C cycloalkyl, is SiR'R'R' or GeR'R'R'', then Z is other than each R" is independently H; C-C alkyl; C-C, phenyl or a 5 to 14-membered aromatic heterocyclic cycloalkyl, or phenyl or benzyl, each optionally Sub ring system each substituted with R and optionally Stituted on the phenyl ring with halogen, C-C alkyl, 65 Substituted with one or more R'; C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, iv) when Y is –C(=O)- and R is SiR'R'R' or nitro or cyano; or GeR'R'R'', then Z is other than phenyl or a 5 to 6,057,352 7 8 14-membered aromatic heterocyclic ring System each ii) a 8 to 14-membered multicyclic ring System selected Substituted with R and optionally substituted with one from fused-bicyclic and fused-tricyclic ring Systems or more R'; which are an aromatic carbocyclic ring System, a v) when Yis-CH(OR)-, R is Hor C-C alkyl, and nonaromatic carbocyclic ring System, or a ring Sys R’ is SiR'R'R' or GeR'R'R'', then Z is other tem containing one or two nonaromatic rings that than phenyl or a 5 to 14-membered aromatic hetero each include one or two Q as ring members and one cyclic ring system each Substituted with R and option or two ring members independently Selected from ally substituted with one or more R'; C(=O) and S(O) substituted with Rand optionally vi) when Yis-NR'- and R' is H or C-C alkyl, then substituted with one or more R'; or Z is other than 1O iii) adamantyl substituted with R and optionally sub i) an N-oxide of a 5 to 14-membered aromatic hetero stituted with one or more R', and cyclic ring system substituted with Rand optionally x) when Yis-CH(OR)- and R is H or C-C alkyl, substituted with one or more R'; then Z is other than ii) a 8 to 14-membered multicyclic ring System selected i) an N-oxide of a 5 to 14-membered aromatic hetero from fused-bicyclic and fused-tricyclic ring Systems 15 cyclic ring system substituted with R and optionally which are an aromatic carbocyclic ring System, a substituted with one or more R'; nonaromatic carbocyclic ring System, or a ring Sys ii) a 8 to 14-membered multicyclic ring System selected tem containing one or two nonaromatic rings that from fused-bicyclic and fused-tricyclic ring Systems each include one or two Q as ring members and one which are an aromatic carbocyclic ring System, a or two ring members independently Selected from nonaromatic carbocyclic ring System, or a ring Sys C(=O) and S(O) substituted with Rand optionally tem containing a one or two nonaromatic rings that substituted with one or more R'; or each include one or two Q as ring members and one iii) adamantyl substituted with R and optionally sub or two ring members independently Selected from stituted with one or more R'; C(=O) and S(O) substituted with R and optionally vii) when Y is –CHRO-N=C(R)- or -(R) 25 substituted with one or more R'; or C=N-OCH(R)-, R is Hor C-C, alkyl and R' iii) adamantyl substituted with R and optionally sub is C-C alkylthio, C-C alkylsulfinyl, C-C, stituted with one or more R'. alkylsulfonyl, C-C halo alkylthio, C-C, haloalkylsulfinyl, C-C haloalkylsulfonyl or halogen, DETAILS OF THE INVENTION then Z is other than In the above recitations, the term “alkyl”, used either i) an N-oxide of a 5 to 14-membered aromatic hetero alone or in compound words Such as “alkylthio’ or cyclic ring system substituted with R and optionally "haloalkyl” includes Straight-chain or branched alkyl, Such substituted with one or more R'; as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, ii) a 8 to 14-membered multicyclic ring System selected pentyl or hexyl isomers. The term “1-2 CH” indicates that from fused-bicyclic and fused-tricyclic ring Systems 35 the Substituent can be methyl or, when there is a hydrogen which are an aromatic carbocyclic ring System, a attached to the same atom, the Substituent and Said hydrogen nonaromatic carbocyclic ring System, or a ring Sys can both be methyl. The term “1-2 alkyl” indicates that one tem containing one or two nonaromatic rings that or two of the available positions for that Substituent may be each include one or two Q as ring members and one alkyl which are independently selected. “Alkenyl' includes or two ring members independently Selected from 40 Straight-chain or branched alkenes Such as Vinyl, 1-propenyl, C(=O) and S(O) substituted with R and optionally 2-propenyl, and the different butenyl, pentenyl and hexenyl substituted with one or more R'; or isomers. “Alkenyl also includes polyenes Such as 1,2- iii) adamantyl substituted with R and optionally sub propadienyl and 2,4-hexadienyl. “Alkynyl' includes stituted with one or more R'; Straight-chain or branched alkynes Such as ethynyl, viii) when Y is -C(=O)-, then Z is other than 45 1-propynyl, 2-propynyl and the different butynyl, pentynyl i) an N-oxide of a 5 to 14-membered aromatic hetero and heXynyl isomers. “Alkynyl' can also include moieties cyclic ring system substituted with R and optionally comprised of multiple triple bonds Such as 2.5-hexadiynyl. substituted with one or more R'; “Alkylene' denotes a Straight-chain alkanediyl. Examples of ii) a 8 to 14-membered multicyclic ring System selected “alkylene” include CHCHCH, CHCHCHCH, from fused-bicyclic and fused-tricyclic ring Systems 50 CHCHCHCHCH. “Alkenyle” denotes a straight-chain which are an aromatic carbocyclic ring System, a alkenediyl containing one olefinic bond. Examples of “alk nonaromatic carbocyclic ring System, or a ring Sys enylene” include CH-CH=CH, CHCH-CH=CH, tem containing one or two nonaromatic rings that CH-CH=CHCH and CH-CH=CHCHCH. “Alkoxy” each include one or two Q as ring members and one includes, for example, methoxy, ethoxy, n-propyloxy, iso or two ring members independently Selected from 55 propyloxy and the different butoxy, pentoxy and hexyloxy C(=O) and S(O) substituted with R and optionally isomers. “Alkenyloxy' includes Straight-chain or branched substituted with one or more R'; or alkenyloxy moieties. Examples of “alkenyloxy” include iii) adamantyl substituted with R and optionally sub HC=CHCH, O, (CH), C = CHCH, O, (CH) stituted with one or more R'; CH=CHCH, O, (CH) CH=C(CH) CHO and ix) when Y is –C(R)=N-O- or -O-N=C 60 CH=CHCHCHO. “Alkynyloxy” includes straight-chain (R)- and R is C-C alkylthio, C-C, or branched alkynyloxy moieties. Examples of “alkynyloxy” alkylsulfinyl, C-C alkylsulfonyl, C-C, include HCE CCHO, CH CE CCHO and haloalkylthio, C-C haloalkylsulfinyl, C-C, CHC=CCHCHO. “Alkylthio” includes branched or haloalkylsulfonyl or halogen, then Z is other than Straight-chain alkylthio moieties Such as methylthio, i) an N-oxide of a 5 to 14-membered aromatic hetero 65 ethylthio, and the different propylthio, butylthio, pentylthio cyclic ring system substituted with R and optionally and hexylthio isomers. “Alkylsulfinyl' includes both enan substituted with one or more R'; tiomers of an alkylsulfinyl group. Examples of “alkylsulfi 6,057,352 9 10 nyl” include CHS(O), CHCHS(O), CHCHCHS(O), is taken as hydrogen, it is recognized that this is equivalent (CH4). CHS(O) and the different butylsulfinyl, pentylsulfi to Said group being unsubstituted. nyl and hexylsulfinyl isomers. Examples of “alkylsulfonyl Compounds of this invention can exist as one or more include CHS(O), CHCHS(O), CHCHCHS(O), (CH4)2CHS(O) and the different butylsulfonyl, pentylsul Stereoisomers. The various StereolSomers include fonyl and hexylsulfonyl isomers. “Cycloalkyl” includes, for enantiomers, diastereomers, atropisomers and geometric example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclo isomers. One skilled in the art will appreciate that one hexyl. "Cycloalkenyl' includes groupS Such as cyclopente Stereoisomer may be more active and/or may exhibit ben nyl and cyclohexenyl as well as groups with more than one eficial effects when enriched relative to the other double bond such as 1,3- and 1,4-cyclohexadienyl. The term Stereoisomer(s) or when separated from the other "aromatic carbocyclic ring System” includes fully aromatic Stereoisomer(s). Additionally, the skilled artisan knows how carbocycles and carbocycles in which at least one ring of a to Separate, enrich, and/or to Selectively prepare said Stere polycyclic ring System is aromatic (where aromatic indicates oisomers. Accordingly, the present invention comprises that the Hickel rule is satisfied). The term “nonaromatic compounds Selected from Formula I, N-oxides and agricul carbocyclic ring System' denotes fully Saturated carbocycles turally suitable salts thereof. The compounds of the inven as well as partially or fully unsaturated carbocycles where 15 tion may be present as a mixture of Stereoisomers, individual the Hickel rule is not satisfied by any of the rings in the ring Stereoisomers, or as an optically active form. System. The term “aromatic heterocyclic ring System' The salts of the compounds of the invention include includes fully aromatic heterocycles and heterocycles in acid-addition Salts with inorganic or organic acids Such as which at least one ring of a polycyclic ring System is hydrobromic, hydrochloric, nitric, phosphoric, Sulfuric, aromatic (where aromatic indicates that the Hickel rule is acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, Satisfied). The term “nonaromatic heterocyclic ring System” propionic, Salicylic, tartaric, 4-toluenesulfonic or Valeric denotes fully Saturated heterocycles as well as partially or acids. The Salts of the compounds of the invention also fully unsaturated heterocycles where the Hickel rule is not include those formed with organic bases (e.g., pyridine, Satisfied by any of the rings in the ring System. The hetero ammonia, or triethylamine) or inorganic bases (e.g., cyclic ring Systems can be attached through any available 25 carbon or nitrogen by replacement of a hydrogen on Said hydrides, hydroxides, or carbonates of Sodium, potassium, carbon or nitrogen. One skilled in the art will appreciate that lithium, calcium, magnesium or barium) when the com not all nitrogen containing heterocycles can form N-oxides pound contains an acidic group Such as a phenol. Since the nitrogen requires an available lone pair for Oxida Preferred compounds for reasons of better activity and/or tion to the oxide, one skilled in the art will recognize those ease of Synthesis are: nitrogen containing heterocycles which can form N-oxides. Preferred 1. Compounds of Formula I above, and The term "halogen', either alone or in compound words N-oxides and agriculturally Such as “haloalkyl', includes fluorine, chlorine, bromine or Suitable Salts thereof, wherein: iodine. The term “1-2 halogen indicates that one or two of W is O; the available positions for that Substituent may be halogen 35 R" is C-C alkyl or C-C haloalkyl; which are independently Selected. Further, when used in R’ is H; C-C alkyl; C-C haloalkyl; or C-C, compound words Such as "haloalkyl', Said alkyl may be cycloalkyl, partially or fully Substituted with halogen atoms which may R and R" are each independently halogen; cyano; be the same or different. Examples of “haloalkyl” include nitro, C-C alkyl, C-C haloalkyl, C-C alkoxy, FC, ClCH, CFCH and CFCC1. The terms 40 C-C haloalkoxy; C1-C alkylthio; C-C alkylsul “haloalkenyl', “haloalkynyl', “haloalkoxy”, and the like, fonyl, C-C alkylcarbonyl, C-C alkoxycarbonyl, are defined analogously to the term "haloalkyl”. Examples (C-C alkyl)NHC(O); (C-C alkyl)-NC(O); ben of “haloalkenyl” include (C1)-C=CHCH and Zoyl, or phenylsulfonyl, CFCH-CH=CHCH. Examples of “haloalkynyl” include HC–CCHC1, CFCEC, CC1-C=C and FCHC=CCH. 45 Examples of “haloalkoxy” include CF3O, CC1-CHO, HCFCHCHO and CFCHO. Examples of “haloalky lthio” include CC1S, CFS, CC1, CHS and R’ is H; C1-C alkyl; C1-C, haloalkyl, C-C alkoxy; CICHCHCHS. Examples of “haloalkylsulfinyl' include C14 C alkylthio; C-C alkenyl, C-C alkynyl, CFS(O), CCS(O), CFCHS(O) and CFCFS(O). 50 C-C cycloalkyl, halogen; or cyano; Examples of “haloalkylsulfonyl” include CFS(O), CCIS Z is Selected from the group C-Co alkyl, C-Cs (O), CFCHS(O) and CFCFS(O). cycloalkyl, phenyl, naphthalenyl; anthracenyl, The total number of carbon atoms in a Substituent group phenanthrenyl, 1 H-pyrrolyl; furanyl; thienyl, is indicated by the “C-C," prefix where i and j are numbers 1H-pyrazolyl, 1H-imidazolyl; isoxazolyl, oxazolyl, from 1 to 10. For example, C-C alkylsulfonyl designates 55 isothiazolyl; thiazolyl; 1H-1,2,3-triazolyl; 2H-1,2,3- methylsulfonyl through propylsulfonyl. Examples of “alky triazolyl; 1H-1,2,4-triazolyl; 4H-1,2,4-triazolyl; 1.2, lcarbonyl” include C(O)CH, C(O)CHCHCH and C(O) 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, CH(CH). Examples of “alkoxycarbonyl” include CHOC 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4- (=O), CHCHOC(=O), CHCHCHOC(=O), thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, (CH4)2CHOC(=O) and the different butoxy- or pentoxy 60 1H-tetrazolyl; 2H-tetrazolyl; pyridinyl; pyridazinyl; carbonyl isomers. In the above recitations, when a com pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4- pound of Formula I is comprised of one or more heterocyclic triazinyl; 1,2,4,5-tetrazinyl; 1H-indolyl; benzofura rings, all Substituents are attached to these rings through any nyl; benzob thiophenyl; 1H-indazolyl; available carbon or nitrogen by replacement of a hydrogen 1H-benzimidazolyl; benzoxazolyl; benzothiazolyl; on Said carbon or nitrogen. 65 quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, When a group contains a Substituent which can be quinazolinyl; quinoxalinyl, 1,8-naphthyridinyl, pte hydrogen, for example R or R', then, when this substituent ridinyl; 2,3-dihydro-1H-indenyl; 1,2,3,4-

6,057,352 13 14 —CHROC(=O)N(R)-; embodiments where R7 is H, or basic reagents or other reagents (Scheme 1). Suitable C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C, Solvents are Selected from the group consisting of polar haloalkoxy, C-C alkylthio, C-C alkylsulfinyl, C-C, aprotic Solvents Such as acetonitrile, dimethylformarnide or alkylsulfonyl, C-C halo alkylthio, C - C dimethyl Sulfoxide; etherS Such as tetrahydrofuran, haloalkylsulfinyl, C-C haloalkylsulfonyl, C-C alkenyl, dimethoxyethane, or diethyl ether, ketones Such as acetone C-C haloalkenyl, C-C alkynyl, C-C haloalkynyl, or 2-butanone, hydrocarbons Such as toluene or benzene, C-C C-C alkylcarbonyl, C-C alkoxycarbonyl, and halocarbons Such as dichloromethane or chloroform. halogen, cyano or morpholinyl, embodiments where Z is other than adamantyl substituted with R and optionally Scheme 1 substituted with one or more R'; embodiments where Z is other than C-C cycloalkenyl and adamantyl each Substi E1 Y.N, E1 Y.N, tuted with R and optionally substituted with one or more R"; embodiments where, when Y and an R" are attached to X G W Methods 1-4 X e W adjacent atoms on Z and Y is -CH=N-N=C(R)-, -CHRN(COCH)-N=C(R)- or -CHRO-N=C R- A-N (R)-, R7 and said adjacently attached R' are taken 15 A. N R2 YR2 together as -(CH2), J- such that J is attached to Z, 1. I embodiments where R', R', R', R’, R', and R'' are X = OH or SH X = OR or SR each independently C-C alkyl, C-C alkoxy or phenyl, Method 1: U-CH=N2 (U= H or (CH3)3Si) embodiments where each R is independently C-C alkyl 2 or phenyl; and embodiments where R and R' are each Method 2: u ;Lewis acid independently halogen, cyano, nitro, C-C alkyl, C-C, haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C, Cl3C OR1 alkylsulfonyl, C-C alkylcarbonyl, C-C alkoxycarbonyl, 3 (C-C alkyl)NHC(O), (C-C alkyl)-NC(O), benzoyl or Method 3: (R')O'BF phenylsulfonyl. 25 4 The compounds of Formula I can be prepared by one or Method 4: (R)2SO4. ROSOV; or R-hal; more of the following methods and variations as described optional base in Schemes 1-33. The definitions of E, A, G, W, X, R-R-, (hal = F, Cl, Br, or I) Y, Z", W., A'-A, Z, Q, J, m, n, p, rands in the compounds (V = C1-Clkyl, C1-C, haloalkyl, or 4-CH-CH4) of Formulae 1-58 below are as defined above in the Sum mary of the Invention. Compounds of Formulae Ia-Io are various Subsets of the compounds of Formula I, and all For example, compounds of Formula I can be prepared by Substituents for Formulae Ia-Io are as defined above for the action of diazoalkane reagents of Formula 2 Such as Formula I. diazomethane (U=H) or trimethylsilyldiazomethane (U= One skilled in the art will recognize that Some compounds 35 (CH),Si) on dicarbonyl compounds of Formula I (Method of Formula I can exist in one or more tautomeric forms. For 1). Use of trimethylsilyldiazomethane requires a protic example, a compound of Formula I wherein R is H may coSolvent Such as methanol. For examples of these exist as tautomer Ia or Ib, or both Ia and Ib. The present procedures, see Chem. Pharm. Bull., (1984), 32, 3759. invention comprises all tautomeric forms of compounds of As indicated in Method 2, compounds of Formula I can Formula I. 40 also be prepared by contacting carbonyl compounds of Formula I with alkyl trichloroacetimidates of Formula 3 and a Lewis acid catalyst. Suitable Lewis acids include trimeth Ia ylsilyl triflate and tetrafluoroboric acid. The alkyl trichloro E1 Y.Nz acetimidates can be prepared from the appropriate alcohol 45 and trichloroacetonitrile as described in the literature (J. Dankimaier and H. Honig, Synth. Commun., (1990), 20, sy 203). AN Compounds of Formula I can also be prepared from H compounds of Formula I by treatment with a trialkyloxo b 50 nium tetrafluoroborate (i.e., Meerwein's salt) of Formula 4 E1 Y.Nz (Method 3). The use of trialkyloxonium salts as powerful alkylating agents is well known in the art (see U. Schöllkopf, U. Groth, C. Deng, Angew. Chem., Int. Ed. Engl., (1981), 20, sy-" 798). 55 Other alkylating agents which can convert carbonyl com A-N pounds of Formula I to compounds of Formula I are dialkyl Sulfates Such as dimethyl Sulfate, haloalkyl Sulfonates Such The compounds of Formula I can be prepared as as methyl trifluoromethaneSulfonate, and alkyl halides Such described below in Procedures 1) to 5). Procedures 1) to 4) as iodomethane and propargyl bromide (Method 4). These describe Syntheses involving construction of the amide ring 60 alkylations can be conducted with or without additional after the formation of the aryl moiety (E-Y-Z). Procedure 5) base. Appropriate bases include alkali metal alkoxides Such describes syntheses of the aryl moiety (E-Y-Z) with the as potassium tert-butoxide, inorganic baseS Such as Sodium amide ring already in place. hydride and potassium carbonate, or tertiary amines Such as 1) Alkylation Procedures triethylamine, pyridine, 1,8-diazabicyclo5.4.0]undec-7-ene The compounds of Formula I are prepared by treating 65 (DBU), and triethylenediamine. See R. E. Benson, T. L. compounds of Formula I with an appropriate alkyl transfer Cairns, J. Am. Chem. Soc., (1948), 70, 2115 for alkylation reagent in an inert Solvent with or without additional acidic examples using agents of this type. 6,057,352 15 16 Compounds of Formula 1a (compounds of Formula 1 Esters of Formula 5a can be prepared from copper (I)- wherein G=C, W=O and X=OH) can be prepared by con catalyzed reaction of malonate esters of Formula 7 with densation of malonates or malonate derivatives of Formula substituted aryl halides of Formula 8 according to methods 5 with an ambident nucleophile of Formula 6 (Scheme 2). adapted from A. Osuka, T. Kobayashi and H. Suzuki, The nucleophiles of Formula 6 are N-substituted hydroxy 5 lamines (HO-NHR) and substituted hydrazines (HN Synthesis, (1983), 67 and M. S. Malamas, T. C. Hohman, (R)-NHR). Examples of such nucleophiles are and J. Millen, J. Med. Chem., 1994, 37, 2043–2058, and N-methylhydroxylamine and methylhydrazine. The mal illustrated in Scheme 3. Procedures to prepare compounds of onate esters of Formula 5 can be prepared by methods Formula 8 are described below (see Scheme 32). described hereinafter. The esters of Formula 5 can also be activated by first hydrolyzing the ester to form the corre sponding carboxylic acid, and then converting the acid into Malonate esters of Formula 5a can also be prepared from the acid chloride (T=Cl) using thionyl chloride or oxalyl diester carboxylic acids of Formula 5c after modification of chloride, or into the acyl imidazole (T=1-imidazolyl) by the carboxylic acid functional group to the appropriate Yand treating with 1,1'-carbonyldiirnidazole. Compounds of For 15 Z group. A copper (I)-catalyzed coupling of malonates of mula 1 aa can be prepared by reaction of nitrile esters of Formula 7 with orthobromocarboxylic acids of Formula 8a Formula 5b with ambident nucleophiles of Formula 6. See (see A. Bruggink, A. McKillop, Tetrahedron, (1975), 31, M. Scobie and G. Tennant, J. Chem. Soc., Chem. Comm., 2607) can be used to prepare compounds of Formula 5c as (1994), 2451. Alkylation of 1aa with alkyl halides in the shown in Scheme 3. Methods to prepare compounds of presence of base provides compounds of Formula 1ab. Formula 8a are common in the art (see P. Beak, V. Snieckus, Alternatively, treatment of 1aa with alkylarnines or Acc. Chem. Res., (1982), 15, 306 and Org. React., (1979), alkoxyamines provides compounds of Formula 1ab. 26, 1 and references therein). Scheme 2 Scheme 3 25 1.Y. Nz ROC N1 COR 1.Y. Nz

He7 H I CuI, base 1 O 8 OS-1 N2

OR OR T = O(C1-C4 alkyl), Cl, 1-imidazolyl 5a R = C1-C4 alkyl

35

E -CO2H E -CO2H He-CuBr |-H R2 Br NaH 1 1a 8a ROCN-COR OS 1 N20 40 7 OR OR E 1N, 5c H HA-NHR2 R= C1-C4 alkyl O 1 S.? NCN 45 OR Sb Additionally, the malonate esters of Formula 5a can be Y. prepared by treating aryl acetic acid esters of Formula 9 with 1"Ya, a dialkyl carbonate or alkyl chloroformate in the presence of W 50 a Suitable base Such as, but not limited to, Sodium metal or HO-Na HeC1-C alkyl (Br, Cl, I) sodium hydride (Scheme 4). For example, see J. Am. Chem. Base A-NN R2 O Soc., (1928), 50, 2758. Nitrile esters of Formula 5b can be 1aa H2NCC1-C6 alkyl) prepared similarly from compounds of Formula 10. W = NH O 55 H2NO(C-C alkyl) Scheme 4 Y. 1YN O 1'N, E Z. | 1YS 1CN E Z. W HC RO OR |-H HO-N-4 60 N2O O 1 O OS 1 N2O -N A. YR2 9ÖR | 1ab c11 NoR. OR 5a OR base 65 R = C1-C4 alkyl 6,057,352 17 18 -continued Sodium hydride, is used to generate the corresponding 1YS O alkoxide or thioalkoxide of the compound of Formula 14. E Z. 1YS 1CN E Z. Scheme 7 HC RO OR |-H N O 1. 5 33 2 CN O 1S 1 R Lg-Zor 1YS No CN He15 7 1O C b Lg-CHR30-Z: c1 YOR. Sb HCN2O S. 16 HCN2O base base R= C1-C4 alkyl 1O OR OR 14 9b R = C1-C4 alkyl Esters of Formula 9 can be prepared from acid-catalyzed R3 = OH, SH, CHROH, CHRSH, NHRIs alcoholysis of aryl acetonitriles of Formula 10 or esterifi Y2 = OCHR3, SCHR30, CHRO, CHROS, NRIs cation of aryl acetic acids of Formula 11 as illustrated in Lg = Br, Cl, I, OSOCH3, OSO(4-Me-Ph) Scheme 5 (see Org. Synth., Coll. Vol. I, (1941), 270). 15 Additionally, esters of formula 9 can be prepared by palladium (0)-catalyzed cross coupling reaction of aryl Some esters of Formula 9 (Formula 9e) can also be iodides of Formula 8 with a Reformatsky reagent or an prepared by forming the Y bridge from substituted alkoxy(trialkylstannyl)acetylene followed by hydration hydroxylamine 9d and carbonyl compounds 14a. The (Scheme 5). For example, see T. Sakamoto, A. Yasuhara, Y. 20 hydroxylamine 9d is in turn prepared from esters 9c. This Kondo, H. Yamanaka, Synlett., (1992), 502, and J. F. method has been described in EP-A-600,835 and illustrated Fauvarque, A. Jutard, J. Organometal. Chem., (1977), 132, in Scheme 8. C17. Scheme 8 Scheme 5 25 B Y& 1YS 1YN 1YN E1 1N, 7 ROH 7 ROH Z. H l 1CN H l id acid - N2O Z. R35 "NeO HCYoN acid H. N2 O HC N2 O 14a ? 3O OR OR OR OH 9c. B = CHRBr 9e 1O 9 11 9d B = CHRONH2-HCI BrZnCH2COR or R = C1-C4 alkyl (1) RSnCECOR 35 Y= CHRON=C(R) Pd'cat. R* and Rare RandR, respectively, or (2) H' RandR are Rand R', respectively Y. 1'N, 2) Displacement and Conjugate Addition/Elimination Pro cedures 40 Compounds of Formula I can also be prepared by reaction 8 of Formula 17 compounds with alkali metal alkoxides R = C1-C4 alkyl (ROM") or alkali metal thioalkoxides (RSM) in a suitable solvent (Scheme 9). The leaving group Lg" in the Aryl acetic acid esters of Formula 9a can also be prepared amides of Formula 17 are any group known in the art to by copper (I)-catalyzed condensation of aryl halides of 45 undergo a displacement reaction of this type. Examples of Formula 12 with compounds of Formula 13 as described in Suitable leaving groups include chlorine, bromine, and Sul EP-A-307,103 and illustrated below in Scheme 6. fonyl and Sulfonate groups. Examples of Suitable inert solvents are dimethylformamide or dimethyl sulfoxide. Scheme 6 50 Scheme 9 E -(Cl, Br, I) 1YN1. HY-Z, E Z. Y. Y. Her 1. Nz 1. Nz HC2 O 13 H2 l N2a N2 O Lg' G W R1OM" or RX G W a H- Y 55 OR OR N. Y RSM Y 12 9a A-N A-N

R= C1-C4 alkyl Ye Ye Y= OCHR, SCHR3, O-N=C(R31), NRIs 17 I 60 Lg' = Cl, Br, SOV, or OSOV V = C1-C alkyl, C1-C, haloalkyl, or 4-CH3 CoH4 Some esters of Formula 9 (Formula 9b) can also be prepared by forming the Yf bridge using conventional M = K or Na nucleophilic substitution chemistry (Scheme 7). Displace ment of an appropriate leaving group (Lg) in electrophiles of 65 Compounds of Formula 17a can be prepared from com Formula 15 or 16 with a nucleophilic ester of Formula 14 pounds of Formula 1b (compounds of Formula 1 wherein X affords compounds of Formula 9b. A base, for example is OH) by reaction with halogenating agents Such as thionyl 6,057,352 19 chloride or phosphorus oxybromide to form the correspond ing B-halo-substituted derivatives (Scheme 10). Scheme 12 Alternatively, compounds of Formula 1b can be treated with 1YS 1YS an alkylsulfonyl halide or haloalkylsulfonyl anhydride, such Z. E Z. as methaneSulfonyl chloride, p-toluenesulfonyl chloride, On -NH HN and trifluoromethanesulfonyl anhydride, to form the corre f R36 S O sponding B-alkylsulfonate of Formula 17a. The reaction HN N/ R = C(=S)S(C-C,s . . 4 alkylalkyl) with the Sulfonyl halides may be performed in the presence R2 (O) (hal)2 N Na of a Suitable base (e.g., triethylamine). 19 R2 2O R = C(=S)S(C1-C4 alkyl) or R2 Scheme 10 S(O)(hal)2 Y. Y. R36 = R2 1 Nz 1 Nz COCl. 15 HO G W Lg G W 1 Y.Nz Y. Y Hehalogenating agent N. Y A-N or VSO-hal or A-N Ye VSO-O-OSV Ye 1b 17a "NY" N-N Lg. = Cl, Br, or -OSOV Ye V = C1-C alkyl, C1-C, haloalkyl, or 4-CH3 CoH4 17c hal = Br, Cl, or F hal= C. Br. I 25 The hydrazides of Formula 19 can be prepared as illus trated in Scheme 13. Condensation of the isocyanate of AS illustrated in Scheme 11, Sulfonyl compounds of Formula 21 with the hydrazine of Formula HNNR'R' in Formula 17b can be prepared by oxidation of the corre an inert Solvent Such as tetrahydrofuran affords the sponding thio compound of Formula 18 using well-known hydrazide. methods for the oxidation of Sulfur (see Schrenk, K. In The Chemistry of Sulphones and Sulphoxides; Patai, S. et al., Scheme 13 Eds.; Wiley: New York, 1988). Suitable oxidizing reagents Y. include meta-chloro-peroxybenzoic acid, hydrogen peroxide R36 E1 Nz and Oxone(R) (KHSO). 35 E 1N, HN-N? O t He-Ys 's- R36 Scheme 11 N. al N^ Y. Y. so N 1. N, 1 N, R2 40 21 19 VS G O VSO G O

Y. Y HeOxidizing agent n Y A-N A-N 3) Conjugate Addition/Cyclization Procedures Ye Ye 45 In addition to the methods disclosed above, compounds of Formula I wherein X=SR and G=C (Formula Ic) can be 18 17b prepared by treating a ketenedithioacetal of Formula 22 with V = C1-C alkyl, C1-Chaloalkyl, or 4-CH3 CH4 an ambident nucleophile of Formula 6 (Scheme 14). The nucleophiles of Formula 6 are described above. 50 Scheme 14 Alternatively, halo-compounds of Formula 17c 1.Y. Nz 1 Y.Nz (compounds of Formula 17a wherein A=N, G=N, and W=O) can be prepared from hydrazides of Formula 19 as illustrated R's 2 2w tasti-R's6 W in Scheme 12. When R=C(=S)S(C-C alkyl), the diacyl 55 Y Y 2 compound of Formula 19 is treated with excess thionyl SR OR A-N V halide, for example excess thionyl chloride. The product R2 formed first is the ring-closed compound of Formula 20 R = C1-C4 alka2 Ic which can be isolated or converted in Situ to the compound of Formula 17c, see P. Molina, A. Tarraga, A. Espinosa, 60 Ketene dithioacetals of Formula 22a or 22b can be Synthesis, (1989), 923 for a description of this process. prepared by condensing arylacetic acid esters of Formula 9 or amides of Formula 9a, respectively, with carbon disulfide Alternatively, when R=R as defined above, the in the presence of a suitable base, followed by reaction with hydrazide of Formula 19 is cyclized with phosgene to form two equivalents of an R'-halide, Such as iodomethane or the cyclic urea of Formula 17c wherein hal=Cl. This pro 65 propargyl bromide (Scheme 15). Conversion of 22b to 22c cedure is described in detail in J. Org. Chem., (1989), 54, can be accomplished by reaction with trialkyl tetrafluorobo 1048. rateS. 6,057,352

Scheme 16 Scheme 15 Y. Y. X1 Z 1) CS2, base Z. Y. Ho 1YS 1. n Z. 2) 2 equiv. R-(Br, Cl, I 1. E Z. 1N H:Ceo ) 2 eq ( ) R Snen 2 T1 T2 HN 2W 24 X N W OR SR OR na optional base y HNN- \ \N-N 9 R = C1-C4 alkyl 22a V V Y. R2 R2 1. Nz 1) CS2, base 23 1d He NHT 2) 2 equiv. R-(Br, Cl, I) T and T are independently Cl, OCCls, O(C1-C4 alkyl), 1-imidazolyl, 1, 2,4-triazolyl 15 X = OH or SH O X = O or S 9a T = H, C-C, alkyl, C1-C, alkoxy N-Amino-ureas of Formula 23 can be prepared as illus Y. trated in Scheme 17. Treatment of an arylamine of Formula E 1. Nz 25 with phosgene, thiophosgene, N, N'- carbonyldilimnidazole, or N,N'-thiocarbonyldiimidazole RS NHT RO'BF produces the isocyanate or isothiocyanate of Formula 26. A H base can be added for reactions with phosgene or thiophos gene. Isocyanates of Formula 26 can also be prepared by RS O heating acylazides of Formula 25a in a Solvent Such as 22b 25 toluene or benzene (Curtius rearrangement). The corre sponding acylazides can be prepared using well known Y. methods in the art (see March, J., Advanced Organic Chem 1"N, istry; 3rd Edition, John Wiley: New York, (1985), pp. 428, 637 and also Chem. Pharm. Bull (1977), 25 (7) 1651, and R1S N references therein. Subsequent treatment of the iso(thio) NT4 cyanate with an R-substituted hydrazine produces the R1S OR N-arnrno-urea of Formula 23. Scheme 17 22c CWCl2 or 35 N % N-n %N 1N, 1'nY. Compounds of Formula 1d (compounds of Formula 1 E Z. tional b s wherein A=N, G=N) can be prepared by condensation of NH2 optional base S. 40 N-amino-ureas of Formula 23 with a carbonylating agent of 25 Formula 24 (Scheme 16). The carbonylating agents of Formula 24 are carbonyl or thiocarbonyl transfer reagents Such as phosgene, thiophosgene, diphosgene (ClC(=O) 45 OCC1), triphosgene (C1 COC(=O)CCC1), N,N'- Y. carbonyldiimidazole, N,N'-thiocarbonyldiimidazole, and 1 n Z. 1,1'-carbonyldi(1,2,4-triazole). Alternatively, the com CON pounds of Formula 24 can be alkyl chloroformates or dialkyl 25a carbonates. Some of these carbonylating reactions may 50 require the addition of a base to effect reaction. Appropriate bases include alkali metal alkoxides Such as potassium Compounds of Formula 1e (compounds of Formula 1 tert-butoxide, inorganic baseS Such as Sodium hydride and wherein A=CR, G=N, and X=O) can be prepared by either potassium carbonate, tertiary amines Such as triethylarnine 55 method illustrated in Scheme 18. Ureas of Formula 27 are reacted with activated 2-halocarboxylic acid derivatives and triethylenediaamine, pyridine, or 1,8-diazabicyclo Such as 2-halocarboxylic acid chlorides, 2-halocarboxylic 5.4.0]undec-7-ene (DBU). Suitable solvents include polar acid esters or 2-haloacyl imidazoles. The initial acylation on aprotic Solvents Such as acetonitrile, dimethylformamide, or the arylamino nitrogen is followed by an intramolecular displacement of the 2-halo group to effect cyclization. Base dimethyl Sulfoxide; etherS Such as tetrahydrofuran, 60 may be added to accelerate the acylation and/or the Subse dimethoxyethane, or diethyl ether, ketones Such as acetone quent cyclization. Suitable bases include triethylamine and Sodium hydride. Alternatively, Formula 1e compounds can or 2-butanone; hydrocarbons Such as toluene or benzene, or be prepared by reaction of Formula 26 iso(thio)cyanates or halocarbons Such as dichloromethane or chloroform. The Formula 26a carbodiimides with Formula 28a esters. As reaction temperature can vary between 0° C. and 150° C. described above, base may be added to accelerate the 65 reaction and Subsequent cyclization to Formula 1e com and the reaction time can be from 1 to 72 hours depending pounds. Carbodiimides 26a can be prepared as shown in on the choice of base, Solvent, temperature, and Substrates. Scheme 18, starting with compounds of Formula 26. 6,057,352 24

Scheme 18 E1.Y. Nz E 1YS Z. O| l N ls na W T3 1N CHR-hal Y. Cn 1. 28 Nz W HNN R2 26 27 optional base O W = O, S T = Cl, O (C1-C4 alkyl), or 1-imidazolyl S hal = Cl, Br, or I 5 N 2 TNH W = O, S, NT

1YS Y. RNHCHRC(O)OR E Z. 1'N, E Z. 28a HN NHTS dehydration N optional base Cn R = C1-C4 alkyl W W 26a 23a 5 WNT W = O, S T = C1-C, alkyl, C1-C6 alkoxy

The thioureas or amidines of Formula 27 can be prepared 25 4) Thionation Procedures by either of the methods illustrated in Scheme 19. The arylamine of Formula 25 can be contacted with an isocy anate or isothiocyanate of Formula R'N=C=W as Compounds of Formula Ie, compounds of Formula I described above. Alternatively, an iso(thio)cyanate of For wherein W=S, can be prepared by treating compounds of mula 26 or carbodiimide of Formula 26a can be condensed Formula Id (I wherein W=O) with thionating reagents such with an amine of Formula R’-NH2 to form the urea or as PSs or Lawesson's reagent (2,4-bis(4-methoxyphenyl)- amidine. The arylamine and iso(thio)cyanates of Formulae 1,3-dithia-2,4-diphosphetane-2,4-disulfide) as illustrated in 25 and 26, respectively, are commercially available or prepared by well-known methods. For example, isothiocy Scheme 20 (see Bull. Soc. Chim. Beig, (1978), 87,229; and anates can be prepared by methods described in J. Hetero Tetrahedron Lett., (1983), 24, 3815). cycl. Chem., (1990), 27,407. Isocyanates can be prepared as 35 described in March, J. Advanced Organic Chemistry; 3rd Scheme 20 ed., John Wiley: New York, (1985), pp. 944, 1166 and also Y. Y. in Synthetic Communications, (1993), 23(3), 335 and refer 1. Nz 1 Nz ences therein. For methods describing the preparation of arylamines of Forrnula 25 that are not commercially 40 X G O P2S5 or X G S available, see M. S. Gibson. In The Chemistry of the Amino n Y Lawesson's reagent Y Group; Patai, S., Ed., Interscience Publishers, 1968; p 37 A-N A-N and Tetrahedron Lett. (1982), 23(7), 699 and references therein. Ye Ye 45 Id e Scheme 19 X = OR or SR 1 Y.Nz NH2 N 50 Reaction of compounds of Formula Iea with an alkyl 25 R2NECEW halide in the presence of base provides compounds of 1.Y. Nz Formula Ieb, which can be reacted with compounds of Formula TNH, and then alkylated with R-(Br, Cl, or I) to provide compounds of Formula Iec. HNeW 55 1'N,Y. in Scheme 20a E Z. R2-NH. Y. R Y.Nz N 27 S. 60 X G S R (Br, Cl, I) Sw a He 26: W = O, S neA-N 26a: W = NT V T = C-C, alkyl, C1-C5 alkoxy H 65 Iea R = C1-C4 alkyl 6,057,352 25 26 -continued Some aryl halides of Formula 29 can be prepared by 1.Y. NZ radical halogenation of the corresponding alkyl compound 1) TNH (i.e., H instead of halogen in Formula 29), or by acidic X G S-R Her 2) R-(Br, Cl, I) cleavage of the corresponding methylether (i.e., OMe Yey instead of halogen in Formula 29). Other aryl halides of A-N eb Formula 29 can be prepared from the appropriate alcohols of I T = C1-C, alkyl, C1-C5 alkoxy Formula 30 by well known halogenation methods in the art 1Y. Nz (see Carey, F. A.; Sundberg, R. J. Advanced Organic Chem istry; 3rd ed., Part B, Plenum: New York, (1990), p 122). X NY NTS A-N Compounds of Formula I wherein Y is CR =CR', Ye 15 CR’=CR, CHRCHR or CHRCHR (Formula Ig and Iec Ih, respectively) can be prepared as illustrated in Scheme 22. Treatment of the halides of Formula 29 with triphenylphos 5) Aryl Moiety (E-Y-Z) Synthesis Procedures phine or a trialkylphosphite produces the corresponding Compounds of Formula If (compounds of Formula I wherein Y is CHRO, CHRS, CHRO-N=C(R) or phosphonium salt (Formula 31) or phosphonate (Formula CHRO-N=C(R) can be prepared by contacting halides 32), respectively. Condensation of the phosphorus com of Formula 29 with various nucleophiles (Scheme 21). The pound with a base and a carbonyl compound of Formula appropriate alcohol or thiol is treated with a base, for example Sodium hydride, to form the corresponding alkOX Z(R') C=O affords the olefin of Formula Ig. ide or thioalkoxide which acts as the nucleophile.

Scheme 21 E.1 CHR (C1, Br, or I) 1'Y4 N, HO-Z, or X G YW HO-N=CR38-Z,HS-Z: base or X n G y W A-N A-N Ye Ye 29 If

Y4 = CHR30O. CHRISO-N=CR31, CHR30S, Halogenation CHRO-N=CR7

37 R37 R15 O R30 E-CHROH R38–R7 or R31

X G W A-NYe

55

60

65 6,057,352

Scheme 22 -CHR'(CI,37 Br, or I) -CHR39-D1 P -CR 39-=CR 40 Z.

X G W P(C6H5)3 or X G W O=C(R")Zo 40 X G W g- Y P(OR)s g Y base g- Y

A-NR2 R = C1-C4 alkyl A-N R2 A-N R2 29 31: P = P(C6Hs).halide Ig O Rand Rare Rand R', repectively, or Rand Rare RandR, respectively H 1) Halogenation 2 Catalyst 2) Dehalogenation

-CHR39- CR40- Z. -C=C-ZS E G YW X s G YW A-N A-N VR2 Y.R Ih Ii RandR'' are R and R, repectively, or Rand R' are Rand R, respectively

The olefins of Formula Ig can be converted to the satu which in turn can be condensed with a phosphorus rated compounds of Formula Ih by hydrogenation over a containing nucleophile of Formula 36 or 37 to afford the metal catalyst Such as palladium on carbon as is well-known olefin of Formula Ig. Carbonyl compounds of Formula 35 in the art (Rylander, Catalytic Hydrogenation in Organic 35 can also be prepared by oxidation of halides of Formula 29 Synthesis; Academic: New York, 1979). in Scheme 22 (see Tetrahedron Lett. (1990), 31, 4825 and Formula Ii alkynes can be prepared by halogenation/ Bull. Chem. Soc. Jpn, (1981), 54, 2221 and references dehalogenation of Formula Ig olefins using procedures well therein). Additionally, compounds of Formula 35 can be known in the art (March, J. Advanced Organic Chemistry; 40 prepared by Oxidation of the corresponding alcohols of 3rd ed., John Wiley: New York, (1985), p. 924). Additionally, Formula 30. Formula Ii alkynes can be prepared by well-known reaction of aryl halides with alkyne derivatives in the presence of Vinylhalides of Formula I can be prepared by reacting catalysts Such as nickel or palladium (see J. Organomet. phosphorus reagents of Formulae 37a or 37b with carbonyl Chem., (1975), 93,253–257). 45 compounds of Formula 35 (Scheme 23). The preparations of The olefin of Formula Ig can also be prepared by revers halides of Formula 37a from the appropriate dieth ing the reactivity of the reactants in the Wittig or Horner ylphosphonoacetate are described by McKenna and Khawli Emmons condensation. For example, 2-alkylaryl derivatives in J. Org. Chem., (1986), 51, 5467. The thiono esters of of Formula 33 can be converted into the corresponding Formula 37b can be prepared from esters of Formula 37a by dibromo-compound of Formula 34 as illustrated in Scheme 50 converting the carbonyl oxygen of the ester to a thiocarbonyl 23 (see Synthesis, (1988), 330). The dibromo-compound can (see Chem. Rev., (1984), 84, 17 and Tetrahedron Lett., be hydrolyzed to the carbonyl compound of Formula 35, (1984), 25, 2639). 6,057,352

Scheme 23 CHR39 CR391 E1 1) Bror NBS E1 2 equiv., CCl4 X G W light X G W 2/ h- 2/ Y 2) Con.Morpholine HCl, H2O Y A-N NBS = N-bromosuccinimide A-N R2 R2 33 34: J = Br, R39 - R0 or R29 CHs). P=C(R)Z 35: J = (FO) (C6H5)3 (R") Base 36 O O hal /

M* (RO)B-C(R0)Z co-cr-0.2 37 37a: J= O R40- R0 or R29 37b:4=S. T2 -CR'=CR-Z R39 J2 -- C OZ

R2 A-N Ig V 2 Rand R' are R and R', respectively, or I R R39 and R0 are R29 and R, respectively R39 - R6 R= C1-C4 alkyl J?= O, S hal = F, Cl, Br, I

Oximes of Formula Ik (Formula I wherein Y is C(R) Carbamates of Formula Il can be prepared by reacting aryl =N-O) can be prepared from carbonyl compounds of 40 alcohols of Formula 30 with isothiocyanates of Formula 39 Formula 38 by condensation with hydroxylamine, followed (Scheme 25). A base such as triethylamine can be added to by O-alkylation with electrophiles of Formula Z-(Cl, Br, or catalyze the reaction. AS shown, carbamates of Formula Il I) (Scheme 24). Alternatively, the O-substituted hydroxy- can be further alkylated to provide the carbamates of For lamine can be condensed with the carbonyl compound of mula Im. Formula 38 to yield oximes of Formula Ik directly. 45 Scheme 25 SchClele 24 -CHR 15OH -CR=O 1) HN-OHo 50 X G W ZNCS39 2) Z-hal g- Her X ne G YW ---HN-OZ A-N A-N \,. V R R2 55 3O 38 hall = Cl, Br or I i CR31=N-OZ CN E1 -CHRISO1 NHZ 60 E X G W Ris-hal g X e W base A-N Y

Ik 65 R II hal = Cl, Br or I 6,057,352 32 -continued pp. 433-435 and references therein.) The organometallic S compounds of Formula 44 may be prepared by reductive metallation or halogen-metal eXchange of a halogen 15 ul o -CHR O N Z. containing compound of Formula 43 using, for example, E magnesium or an organolithium reagent, or by deprotona R15 tion of compounds of Formula 39a using a strong base Such X AG W as a lithioarnide or an organolithium reagent, followed by g- Y transmetallation. Compound 40 corresponds to Compound A-N 14a in Scheme 8, while compound 4.0a corresponds to Ye O=C(R')Z in Scheme 22. Im. Scheme 27 Compounds of Formula I wherein Y is -CHRO Z-H -R“COC I (42) - OSCR+1-Z.- St 41 N=C(R)--C(=N-A-Z")—A-, -CHRO-N=C 15 39a 3 40 R1 R7 (R)- C(R)=N-A—A- or -CHRO-N=C(-C 4.0a R1-R6 (R)=N-A-Z")- can be prepared by methods known in the art or obvious modifications (see, for example, WO Z-hal -> Z -M1 ErR41 95/18789, WO95/21153, and references therein) together 43 45 OCR+1-Z. with the methods disclosed herein. 44 40 R1-R7or R31 Compounds of Formula I wherein Yis-CHROC(=O) 4.0a R1-Roor R29 O-, -CHROC(=S)O-, -CHR'OC(=O)S-, hal-Cl, Br, I Ml=MgX T3=C| –CHROC(=S)S-, -CHR'SC(=O)N(R)-, CuILZ. OCOR1 –CHRSC(=S)N(R)-, -CHRISC(=O) O-, CdZ OR –CHR SC(=S)O-, -CHR SC(=O)S.-, SnR3 NR –CHRSC(=S)S-, -CHRSC(=NR)S- or 25 —CHRN(R')C(=O)N(R')— can be prepared by meth ods known in the art or obvious modifications (see, for example, U.S. Pat. No. 5,416,110, EP 656,351-A1 and references therein) together with the methods disclosed herein. Compounds of Formula 43 may be prepared by reaction The compounds of the present invention are prepared by combinations of reactions as illustrated in the Schemes 1-25 of compounds of Formula 39a (Scheme 28) with, for in which Z is a moiety as described in the Summary. example, bromine or chlorine, with or without additional Preparation of the compounds containing the radical Z as catalysts, under free-radical or aromatic electrophilic halo described in the Summary, Substituted with L (defined as any genation conditions, depending on the nature of Z. Alterna group attached to Z as depicted in each of the individual 35 tive Sources of halogen, Such as N-haloSuccinimides, tert Schemes) can be accomplished by one skilled in the art by butyl hypohalites or SOCl, may also be used. (See March, the appropriate combination of reagents and reaction J. Advanced Organic Chemistry; 3rd ed., John Wiley: New Sequences for a particular Z-L. Such reaction Sequences can York, (1985), pp. 476–479, 620–626; and references therein.) be developed based on known reactions available in the For a review of free-radical halogenation, See Huyser, in chemical art. For a general reference, See March, J. 40 Patai, “The Chemistry of the Carbon-Halogen Bond,” Part 1, Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985) and references therein. See the following Wiley, New York (1973) pp 549–607. For electrophilic paragraphs for Some examples of how,L is defined in indi substitutions, see de la Mare, “Electrophilic Halogenation,” vidual Schemes, and the preparation of representative Z-L Cambridge University Press, London (1976). Compounds of examples. 45 Formula 43 correspond to compounds of Formula 15 in Compounds of Formula 41 in Scheme 26 can be prepared Scheme 7 where Lg=Br, Cl, or I and reagent Z-hal in from compounds of Formula 40 by reaction with hydroxy Scheme 24. Compounds of Formula 47 can be prepared larnine or hydroxylarnine Salts. See Sandler and Karo, from compounds of Formula 46 by Similar procedures. “Organic Functional Group Preparations,” Vol. 3 Academic Compounds of Formula 36 or 37 in Scheme 23 can be Press, New York, (1972) 372-381 for a review of methods. 50 prepared by reaction of compounds of Formula 47 with Compounds of Formula 41 correspond to compounds of triphenylphosphine or trialkyl phosphites, respectively, fol Formula 13 in Scheme 6 when Y=O-N=C(R) and in lowed by deprotonation with base. See Cadogen, “Organo Scheme 21, reagent HO-N=CR'. phosphorus Reagents in Organic Synthesis,” Academic Scheme 26 Press, New York (1979) for a general treatise on these 55 reagents. 31 HNOH or 31 O E R Z. Ho-HNOHHCI/base HO-NHND 41 CR-Z. Scheme 28 O Compounds of Formula 40 can be prepared from com pounds of Formula 39a (Scheme 27) by Friedel-Crafts 60 acylation with compounds of Formula 42. (See Olah, G. NH-hal “Friedel-Crafts and Related Reactions.” InterScience, New York (1963-1964) for a general review). Compounds of 7-H hal, or t-BuO hal Z-hal Formula 40 may also be prepared by reaction of acyl halides, 39a O 43 anhydrides, esters, or amides of Formula 45 with organo 65 or SO2Cl2 metallic reagents of Formula 44. (See March, J. Advanced optional catalyst halCl, Br, I Organic Chemistry; 3rd ed., John Wiley: New York, (1985), 6,057,352 33 34 -continued of Formula 48. (Cohen, Dietz, and Miser, J. Org. Chem, H-CHR0-Z He hal-CHR0-Z (1977), 42, 2053). Treatment of Formula 54 compounds 46 47 with (S) yields compounds of Formula 52. 1) (C6H5)3P O Scheme 30 (RO)3P HNO2 CuBr, CuC or I 2) base Z-NH - -- Z-N* - - 53 54 RFC -C alkyl 36 or 37 in Scheme 23 R40-R29 or R6 Z-halhall hal=B.C.hal=Br, Cl, i -He St. S)2 Compounds of Formula 48 can be prepared from com HO-z S- HS-Z pounds of Formula 40b by treatment with peracids such as 48 52 perbenzoic or peracetic acid, or with other peroxy com pounds in the presence of an acid catalysts, followed by 15 hydrolysis of the resultant ester. For a review, see Plesnicar, Compounds of Formula 53 can be prepared from com in Trahanovsky, “Oxidation in Organic Chemistry, pt. C, pounds of Formula 39a by nitration, followed by reduction Academic Press, New York (1978) pp. 254-267. Formula 48 (Scheme 31). A wide variety of nitrating agents is available corresponds to reagent HO-Z in Scheme 21. Compounds (see Schofield, “Aromatic Nitration,” Cambridge University of Formula 52 can be prepared from compounds of Formula Press, Cambridge (1980)). Reduction of nitro compounds 48 by conversion to the dialkylthiocarbamates of Formula can be accomplished in a number of ways (see March, J. 50 followed by rearrangement to Formula 51 and subsequent Advanced Organic Chemistry; 3rd ed., John Wiley: New hydrolysis. See M. S. Newman and H. A. Karnes, J. Org. York, (1985), pp 1103-4 and references therein). Formula 53 Chem. (1966), 31, 3980-4. Formula 52 corresponds to corresponds to Formula 13 in Scheme 6 when Y=NR'' and reagent HS-Z in Scheme 21. R= 25 Scheme 29 Scheme 31 O=C(CH)-Z 1) O HO-Z 40b 2) hydrolysis 48 Z-H -> Z -NO -> Z -NH2 39a 55 53 CICSN (R) heat HO-Z 49 Z-O-CSN(R) - - 50 Iodides of Formula 8 can be prepared from compounds of Z-S-CONCR) -- HS-Z Formula 58 by the methods described above in Schemes 51 52 21-25 for various Y-Z combinations. Compounds of For RFC -C alkyl mula 58 can in turn be prepared from compounds of Formula 35 57 by functional group interconversions which are well Compounds of Formula 53 can be converted to com known to one skilled in the art. The compounds of Formula pounds of Formulae 43, 48 or 52 via the diazonium com 57 can be prepared by treating compounds of Formula 56 pounds 54, by treatment with nitrous acid followed by with an organolithium reagent Such as n-BuLi or LDA Subsequent reaction (Scheme 30). See reviews by Hegarty, followed by trapping the intermediate with iodine (Beak, P., pt. 2, pp 511-91 and Schank, pt. 2, pp 645-657, in Patai, 40 Snieckus, V. Acc. Chem. Res., (1982), 15,306). Additionally, “The Chemistry of Diazonium and Diazo Groups,” Wiley, lithiation via halogen metal eXchange of compounds of New York (1978). Treatment of Formula 54 compounds with Formula 56, where H is replaced by Br, will produce an cuprous halides or iodide ions yield compounds of Formula intermediate which can be trapped with iodine to prepare 43. Treatment of Formula 54 compounds with cuprous oxide compounds of Formula 57 (Parham, W. E., Bradsher, C. K. in the presence of exceSS cupric nitrate provides compounds Acc. Chem. Res., (1982), 15, 300 (Scheme 32).

Scheme 32 T4 T4 T5 E1 Organolithium E1 Functional 1. reagent, HeGroup H I2 I Interconversion I 56 57 58 y-Z construction 6,057,352

-continued T=COH, CONR, CONHR, 1YS O E Z. CSNHR, -( CHRNR, I 8 N CH T=CHR"-(C1,5- 42 Br, I), CHO HC CHROH, OH R=C-C alkyl t1 or 2 -( ) (CH2)NR2, R42=R37 or R39 N R7 and Rare as defined in Schemes 21–22 R CHOH, OMe, OCHOMe

15 Conversion of compounds of Formula In to compounds of One skilled in the art will also recognize that compounds Formula Io is Summarized in Scheme 33. Reaction of the of Formula I and the intermediates described herein can be Secondary amides with Sillylating agents, Such trimethylsilyl Subjected to various electrophilic, nucleophilic, radical, chloride in the presence of base or hexamethyldisilaZane in organometallic, oxidation, and reduction reactions to add the presence of acid, provides the Sillylated intermediate Substituents or modify existing Substituents. which is oxidized in situ with the peroxo-molybdenum Without further elaboration, it is believed that one skilled compound MoCs-HMPA complexed with pyridine or dim in the art using the preceding description can utilize the ethylformamide. Subsequent hydrolysis with aqueous EDTA present invention to its fullest extent. The following (ethylenediaminetetraacetic acid) liberates the hydroxylated Examples are, therefore, to be construed as merely amides (see S. A. Martin, P. G. Sammes and R. M. Upton, illustrative, and not limiting of the disclosure in any way J. Chem. Soc., Perkin Trans. 1 (1979), 2481 and J. H. Rigby 25 whatsoever. Percentages are by weight except for chromato and M. Qabar, J. Org. Chem. (1984), 54,5852). Optional graphic Solvent mixtures or where otherwise indicated. Parts alkylation with C-C alkyl halides in the presence of base and percentages for chromatographic Solvent mixtures are or acylation with acetic anhydride can be performed on the by volume unless otherwise indicated. "H NMR spectra are hydroxyl amides Io where R’=OH. reported in ppm downfield from tetramethylsilane; S=Singlet, d=doublet, t=triplet, q=quartet, m=multiplet, Scheme 33 dd=doublet of doublets, dt =doublet of triplets, td=triplet of E Z. 1) SiMe3Clor (MeSi)NH doublets, brS=broad Singlet. 2) MoOspy. HMPA EXAMPLE 1. X e W 3) aq. EDTA Step A: Preparation of 2,2-dimethyl-N-(2-methylphenyl) & optional: 35 hydrazine carboxamide A-N 4) (C -C alkyl)-I, base o-Tolyl isocyanate (10.0 g) was dissolved in 75 mL Ye or (CH3OCFO))2O toluene under N. The solution was cooled to 5 C. and to In this was slowly added a Solution in toluene of 1,1- Y. dimethylhydrazine (5.7 mL). After addition, the ice-bath 40 was removed and the resulting slurry allowed to Stir an rs, additional 10 minutes. The solid was collected by filtration X es W and rinsed Successively with hexane, a Small amount of 20% g W diethyl ether/hexane, and then hexanes again. This afforded A-N 11.1 g of the title compound of Step A. H NMR (CDC1): 45 88.1 (bris,1H), 7.94 (d.1H), 7.21–7.15 (m,3H), 6.99 (t, 1H), Y: 5.23 (bris,1H), 2.63 (S.6H), 2.27 (s.3H). Step B: Preparation of 5-chloro-2,4-dihydro-2-methyl-4-(2- methylphenyl)-3H-1,2,4-triazol-3-one To a solution of 11.1 g of the title compound of Step A It is recognized that Some reagents and reaction condi 50 dissolved in 600 mL methylene chloride under N was added tions described above for preparing compounds of Formula 17.1 g of triphosgene. The Solution was heated at reflux I may not be compatible with certain functionalities present overnight, cooled, and then concentrated under reduced in the intermediates. In these instances, the incorporation of preSSure. The resulting residue was dissolved in ethyl acetate protection/deprotection Sequences or functional group inter and washed with water and then with Saturated aqueous conversions into the Synthesis will aid in obtaining the NaCl. The organic phase was dried (MgSO), filtered, and desired products. The use and choice of the protecting 55 concentrated under reduced pressure. The residue was puri groups will be apparent to one skilled in chemical Synthesis fied by flash chromatography (30-50% ethyl acetate/ (see, for example, Greene, T. W.; Wuts, P. G. M. Protective hexanes as eluent) to afford 8.25 g of the title compound of Groups in Organic Synthesis, 2nd ed., Wiley: New York, Step B. "H NMR (CDC1): 8 742–7.30 (m,3H), 7.17 (d.1H), 1991). One skilled in the art will recognize that, in some 3.54 (s.3H), 2.22(s.3H). cases, after the introduction of a given reagent as it is 60 depicted in any individual Scheme, it may be necessary to Step C: Preparation of 2,4-dihydro-5-methoxy-2-methyl-4- perform additional routine Synthetic Steps not described in (2-methylphenyl)-3H-1,2,4-triazol-3-one detail to complete the Synthesis of compounds of Formula I. 8.25 g of the title compound of Step B was dissolved in One skilled in the art will also recognize that it may be 80 mL of 1:1 dimethoxyethane/methanol under N. 14.0 mL necessary to perform a combination of the Steps illustrated of sodium methoxide (30% solution in methanol) was added in the above schemes in an order other than that implied by 65 and the Solution was heated at reflux for 3 h. The mixture the particular Sequence presented to prepare the compounds was allowed to cool, diluted with ethyl acetate, washed with of Formula I. water and then with Saturated acqueous NaCl. The combined 6,057,352 37 38 organic extracts were dried (MgSO), filtered, and concen removed and Stirring was continued for 1 h. The reaction trated under reduced pressure. The residue was purified by mixture was extracted with hexane (5 times) and the com flash chromatography (50–70% ethyl acetate/hexanes as bined organic phase was dried (MgSO), filtered and con eluent) and triturated with 50% diethyl ether/hexanes to centrated to afford 18.4 g of the title compound of Step Bas afford 6.7 g of the title compound of Step C (about 95% a colorless oil. H NMR (300 MHz, CDC1): 8 4.41-4.36 pure). H NMR (CDC1): 8 7.35-7.27 (m,3H), 7.18 (d.1H), (m.4H), 1.57 (s.9H), 1.40 (t,6H, J=7.2 Hz). 3.94 (s.3H), 3.46 (s.3H), 2.22 (s.3H). Step C: Preparation of (1,1-dimethylethyl) chloro Step D: Preparation of 4-2-(bromomethyl)phenyl-2,4- (diethoxyphosphinyl)acetate dihydro-5-methoxy-2-methyl-3H-1,2,4-triazol-3-one The title compound of Step B (18.4g, 0.0572 mol) was To a Solution/Suspension of 6.7 g of the title compound of dissolved in ethanol (140 mL) and cooled to 0°C. A solution Step C dissolved in 95 mL of carbon tetrachloride under N of sodium sulfite (14.4g, 0.1144 mol) in HO (63 mL) was was added N-bromosuccinimide (6.53 g) followed by a added with Stirring Such that the internal temperature catalytic amount of benzoyl peroxide. The Solution was remained below 14 C. The cooling bath was removed and heated at reflux for 2 h. Another 1.63 g of the mixture was stirred at room temperature for 30 min. The N-bromoSuccinimide and a catalytic amount of benzoyl reaction mixture was extracted with chloroform (5x), and peroxide were added and the Solution was heated at reflux 15 the combined organic phase was dried (MgSO), filtered and for an hour. After cooling, methylene chloride was added concentrated to afford 16.4 g of the title compound of Step and the organic layer was washed Successively with water, C as a clear oil. H NMR (300 MHz, CDC1): 8 4.43 (d.1H, then with 0.1 N Sodium thiosulfate Solution, and then with J=15.9 Hz), 4.30-4.24 (m.4H), 1.52 (s.9H), 1.38 (t,6H, J=6.9 Saturated acqueous NaCl. The combined organic extracts Hz). were dried (MgSO), filtered, and concentrated under Step D: Preparation of 1,1-dimethylethyl 2-chloro-3-2-(1, reduced pressure. The residue was purified by flash chro 5-dihydro-3-methoxy-1-methyl-5-oxo4H-1,2,4-triazol-4-yl) matography (3-10% diethyl-ether/methylene chloride as phenyl)-2-propenoate eluent) to afford 3.12 g of the title compound of Step D. "H A solution of the title compound in Step C (0.43 g, 0.0015 NMR (CDC1): 8 7.5 (m.1H), 7.44 (m.2H), 7.22 (m,1H), mol) in ethyl acetate (3 mL) was added to a mixture of 4.60 (d.1H), 4.36 (d.1H), 3.96 (s.3H), 3.47 (s.3H). 25 calcium hydroxide (0.110 g, 0.0015 mol) and the title Step E: Preparation of 2-(1,5-dihydro-3-methoxy-1- compound of Step A (0.350 g, 0.0015 mol) in ethyl acetate methyl-5-oxo4H-1,2,4-triazol-4-yl)phenyl)methyl N-(4- (5 mL). The resulting mixture was stirred at 45° C. overnight chlorophenyl)propanimidothioate and then poured into ice water and extracted three times with To a solution of 0.50 g of the title compound of Step D in ethyl acetate. The combined organic phase was washed 2 mL of THF was added 0.37 g of Successively with Saturated aqueous NaCl and then a 1/1 4'-chlorothiopropionanilide and then 0.23 g of potassium mixture of Saturated aqueous NaCl and Saturated acqueous tert-butoxide. (An exotherm occurred during this addition). Sodium hydrogen carbonate, dried (Na2SO), filtered and The reaction was allowed to Stir at room temperature over concentrated to a light yellow oil. The crude product was night and then was heated briefly to reflux and allowed to purified by flash column chromatography on Silica gel to cool. The reaction mixture was diluted with ethyl acetate and give 0.320 g of the title compound of Step D, a compound washed Successively with water and then with Saturated 35 of the invention, as a white Semisolid consisting of a 1:1 aqueous NaCl. The organic phase was dried (MgSO), ratio of E- and Z-isomers. "H NMR (300 MHz, CDC1; for filtered, and concentrated under reduced preSSure. The resi the E/Z mixture): 8 7.66 and 7.21 (2s, 1H total), 7.25-7.54 due was purified by flash chromatography (50-60% ethyl (m.4H total). 3.93 and 3.91 (2s.3H total), 3.44 (s.3H), 1.54 acetate/hexanes) to afford 0.48g of the title compound of and 1.25 (2s.9H total). Step E (about 95% pure), a compound of the invention. H 40 NMR (CDC1): 8 7.58 (m.1H), 7.37 (m.2H), 7.23 (m,3H), EXAMPLE 3 6.60 (d.2H), 4.23 (s.2H), 3.86 (s.3H), 3.41 (s.3H). Step A: Preparation of B-oxo-3-(trifluoromethyl) benzenepropanenitrile EXAMPLE 2 To a suspension of 7.6 g of sodium hydride (60% disper Step A: Preparation of 2-(1,5-dihydro-3-methoxy-1-methyl 45 sion in oil) in 200 mL of tetrahydrofuran under a nitrogen 5-oxo-4H-1,2,4-triazol-4-yl)benzaldehyde atmosphere was added dropwise at room temperature a A solution of the title compound of Step D in Example 1 Solution consisting of 7.8 g of acetonitrile and 38.8 g of (1.03 g, 0.0036 mol) in carbon tetrachloride (3 mL) was methyl 3-(trifluoromethyl)benzoate in 50 mL of tetrahydro added to a solution of 4-methylmorpholine N-oxide (1.09 g, furan. Following addition, the Suspension was stirred 1 h at 0.0093 mol) in dimethyl sulfoxide (9 mL) at 7° C. The 50 ambient temperature, refluxed about 5 h, and then cooled to mixture was stirred at 7 C. for 30 min, at room temperature room temperature. Isopropyl alcohol (20 mL) was added for 18 h, and then poured into cold, half-Saturated aqueous dropwise at room temperature. After Stirring about 15 min, sodium chloride and extracted with diethvil ether (4x). The the Solvent was removed in vacuo, and about 200 mL of combined organic phase was washed with Saturated aqueous water was added to the residue. The aqueous Suspension was NaCl, dried (NaSO), filtered and concentrated to a light washed with 3x50 mL diethyl ether and then acidified with brown oil that was purified by flash column chromatography 55 concentrated hydrochloric acid to form a solid. The solid on Silica gel to give 0.37 g of the title compound of Step A was isolated by filtration, washed 2x100 mL with water and as a white solid melting at 82-84° C. "H NMR (300 MHz, then dissolved in methylene chloride. The organic Solution CDC1): 8 9.97 (s.1H), 8.00 (dd.1H, J=1.5, 8.5 Hz), 7.73 was dried (MgSO), filtered and concentrated to give 30.0 g (dt, 1H, J=1.6, 7.8 Hz), 7.61 (t, 1H, J=7.5 Hz), 7.42 (d.1H, of the title compound of Step A as a white Solid melting at J=7.8 Hz), 3.95 (s.3H), 3.47 (s.3H). 60 51–55° C. "H NMR (CDC1): 88.1–8.2 (m.2H), 7.95 (d.1H), Step B: Preparation of (1,1-dimethylethyl) dichloro 7.7 (m.1H), 4.15 (s.2H); IR (mineral oil) 1704.1 cm. (diethoxyphosphinyl)acetate Step B: Preparation of C.-(hydroxyimino)-f-oxo-3- A solution of 5.25% sodium hypochlorite (Clorox(R) (trifluoromethyl)benzenepropanenitrile bleach; 421.5g, 0.2973 mol) was adjusted to pH 7.1 with 3N To a solution of 30.0 g of the title compound of Step A in HCl and then tert-butyl diethylphosphonoacetate (15.0 g, 65 200 mL of glacial acetic acid was added dropwise a Solution 0.0595 mol) was added dropwise at 0° C. with vigorous of 11.7 g of sodium nitrite in 35 mL of water while Stirring. After the addition was complete, the ice-bath was maintaining the reaction temperature at about 15 C. with 6,057,352 39 40 external cooling. Following addition, the external cooling (d.1 H.J-8 Hz), 7.33 (dd.1 H.J-2, 8 Hz), 2.16 (s.3H). The was removed and the Suspension was stirred at room tem crude material was not further purified before Step F. perature overnight and then poured into excess water (about Step D: Preparation of N-2-(bromomethyl)phenyl-2,2- 400 mL). The aqueous Suspension was acidified by dropwise dimethylhydrazinecarboxamide addition of concentrated hydrochloric acid (until red to o-Tolyl isocyanate (50.4 g) and 75.2 g of litmus paper) and then extracted with methylene chloride. N-bromosuccinimide dissolved in 800 mL of carbon tetra The organic Solution was dried (MgSO), filtered and con chloride were heated to reflux. Benzoyl peroxide (1.1 g) was centrated to give 32.5g of the title compound of Step Bas added and the mixture was heated to reflux for 1.5 h. The an oil. "H NMR (CDC1): 8 8.3 (s.1H), 82 (m.1H), 7.9 Solution was cooled to room temperature and the precipitate (m.1H), 7.65 (m.1H); IR (neat) 1670.2 cm. was removed by filtration. The filtrate was concentrated in Step C: Preparation of C-2-(1,5-dihydro-3-methoxy-1- vacuo and redissolved in 500 mL of toluene and cooled to methyl-5-oxo-4H-1,2,4-triazol-4-yl)phenyl)methoxy 5 C. 1,1-Dimethylhydrazine, (30 mL in 20 mL of toluene) imino-B-OXO-3-(trifluoromethyl)benzenepropanenitrile was added dropwise. The reaction mixture was stirred at The title compound of Step B was dissolved in 5 mL of room temperature overnight. The precipitated Solid was DMF and 0.07 g (1.74 mmol) of sodium hydride as a 60% collected by filtration and redissolved in 1 L of dichlo dispersion in oil was added to the solution. Then 0.400 g 15 romethane. The organic solution was washed with 500 mL (1.34 mmol) of the title compound of Step D in Example 1 of water and then 500 mL of Saturated aqueous sodium was added and the reaction mixture was stirred at room chloride. The organic layer was dried (MgSO), filtered and temperature for 5 h. The reaction mixture was diluted with concentrated to give 58 g of the title compound of Step D as ethyl acetate, then washed Successively with water and a beige solid. "H NMR (CDC1): 8 8.6 (br s.1H), 8.00 Saturated acqueous NaCl. The combined organic extracts (d.1H), 7.30 (m.2H), 7.04 (t, 1H), 5.70 (bris,1H), 4.52 (s.2H), were dried over magnesium Sulfate, filtered, and concen 2.67 (S,6H). The material was used in Step E without further trated. The crude product was purified by flash chromatog characterization. raphy using ethyl acetate:hexane 1:1 to give 0.48g of the Step E: Preparation of 5-chloro-4-2-(chloromethyl) title compound of Step C, a compound of invention. "H phenyl-2,4-dihydro-2-methyl-3H-1,2,4-triazol-3-one NMR (CDC1): 8 8.18 (s.1H), 7.98 (m.1H), 7.82 (m,1H), 25 The product from Step D (58 g) was dissolved in 800 mL 7.50 (m.4H), 7.30 (d.1H), 5.59 (d.1H), 5.46 (d.1H), 3.93 of dichloromethane and 86 g of triphosgene was added in (s.3H), 3.41 (s.3H). one portion. A slight exotherm was observed and then the EXAMPLE 4 mixture was heated to reflux overnight. The reaction mixture Step A: Preparation of 3,4-dichlorobenzaldehyde oxime was cooled and the Solvent removed in vacuo. The resulting 3,4-Dichlorobenzaldehyde (5.25 g) and 2.1 g of hydroxy solid was dissolved in 1 L of ethyl acetate and washed with lamine hydrochloride were dissolved in 75 mL of pyridine. 500 mL of water, 500 mL of Saturated aqueous sodium The mixture was stirred at room temperature for 18 h. The bicarbonate and then 500 mL of Saturated aqueous sodium Solvent was removed in vacuo and the residue was taken up chloride. The organic layer was dried (MgSO), filtered, and in 100 mL of 1N HCl and extracted 3x with 75 mL portions concentrated to give a dark oil which Solidified on Standing. of ethyl acetate. The combined organic extracts were dried The solid was triturated in 2:1 hexane: n-butyl chloride to (MgSO), filtered, and concentrated to give a Solid. The 35 yield 32 g of a beige solid. Recrystallization of the solid crude material was triturated in hexane and collected by from 150 mL of hot methanol yielded 21 g of the title filtration to yield 5.8 g of the title compound of Step A as a compound of Step E as a white fluffy solid melting at white solid melting at 118-119 C. 122-124 C. A second crop was obtained from recrystalli Step B: Preparation of 3,4-dichloro-N- zation of the mother liquors. H NMR (CDC1): 8 7.45-7.6 hydroxybenzenecarboximidoyl chloride 40 (m,3H), 7.25 (m,1H), 4.68 (d.1H), 4.46 (d.1H), 3.56 (s.3H). The title compound of Step A (3.7g) was dissolved in 100 Approximately 10% of 5-chloro-4-2-(bromomethyl) mL of dimethylformamide and 2.6 g of N-chlorosuccinimide phenyl-2,4-dihydro-2-methyl-3H-1,2,4-triazol-3-one was was added. The reaction mixture was stirred at about 30° C. observed in the H NMR spectrum. "H NMR (CDC1): 8 for 2 hand then at room temperature overnight. The mixture 7.56 (m.2H), 7.44 (m,3H), 7.25 (m.2H), 5.26 (AB quartet, was diluted with 200 mL of water and extracted with three 45 2H), 3.9 (s.3H), 3.41 (s.3H), 2.1 (s.3H) 100 mL portions of diethyl ether. The combined organic Step F: Preparation of S-methyl 3,4-dichloro-N-2-(3- extracts were dried (MgSO), filtered, and concentrated to chloro-1,5-dihydro-1-methyl-5-oxo-4H-1,2,4-triazol-4-yl) give 5.8g of the title compound of Step B as an oil. "H NMR phenylmethoxybenzenecarboximidothioate (CDC1): 8 10.41 (s.1H), 7.95 (d.1H.J-2 Hz), 7.69 (dd.1H, The product from Step C (2.07 g) was dissolved in 10 mL J=2, 8 Hz), 7.46 (d.1 H.J-8 Hz). The crude oil also contained 50 of tetrahydrofuran and 10 mL of 1.0 M potassium t-butoxide DMF. The crude material was triturated in hexane and in THF was added dropwise. After the addition was collected by filtration to yield 5.2 g of white solid, still complete, the mixture was stirred 15 min, and then the title containing DMF, which was used in the next step without compound of Step E (2.06 g) was added. The reaction additional purification or characterization. mixture was stirred at room temperature overnight, and then Step C: Preparation of S-methyl 3,4-dichloro-N- diluted with 20 mL of water and extracted with three 30 mL hydroxybenzenecarboximidothioate 55 portions of ethyl acetate. The combined organic extracts The product from Step B (5.2 g) was dissolved in 70 mL were dried (MgSO), filtered, and concentrated to give 3.53 of tetrahydrofuran and 2.9 g of sodium thiomethoxide and 7 g of the title compound of Step F as an oil. "H NMR mL of methanol were added. The reaction mixture was (CDC1): 8 7.5 (m.5H), 7.25 (m.2H), 5.34 (d.1H), 5.18 stirred at room temperature for 2 h. Water (20 mL) was (d.1H), 3.49 (s.3H), 2.08 (s.3H). The crude product con added and the mixture clarified to a yellow solution. The 60 tained minor amounts of impurities and Solvent, but the solution was diluted with 100 mL of methylene chloride and material was not further purified before Step G. the aqueous phase was made acidic with 1 NHCl. The phases Step G: Preparation of S-methyl 3,4-dichloro-N-2-(1,5- were separated and the aqueous phase extracted with three dihydro-3-methoxy-1-methyl-5-oxo-4H-1,2,4-triazol-4-yl) 50 mL portions of methylene chloride. The combined phenylmethoxybenzenecarboximidothioate organic layers were dried (MgSO), filtered, and concen 65 The crude product from Step F (3.53 g) was dissolved in trated to give 5.1 g of the title compound of Step C as an oil. 25 mL of dimethoxyethane and 25 mL of methanol. Sodium H NMR (CDC1): 89.09 (bris,1H), 7.59 (d.1H,J-2Hz), 7.51 methoxide (25% in methanol, 4.4 mL) was added dropwise. 6,057,352 41 42 The mixture was heated to reflux for 3 h, then stirred at room dropwise via addition funnel at 0 °C. The resulting precipi temperature overnight. An additional 1.1 mL of 25% sodium tate was collected by filtration affording the title compound methoxide in methanol was added and the mixture was of Step C (5.56 g) as a yellow solid melting at 117-120° C. heated to reflux for 6 h, and then Stirred at room temperature 400 MHz H NMR (MeSO-d): 8 7.57 (m,3H), 7.43 overnight. The Solvents were removed in vacuo and the (m.1H), 4.92 (s.2H), 3.89 (s.3H), 3.33 (s.3H). residue taken up in 100 mL of ethyl acetate. The mixture was extracted with 50 mL of water and then with 50 mL of Step D: Preparation of 4-2-2-(3,5-dichlorophenoxy)-1- Saturated aqueous Sodium chloride. The organic layer was methylethylideneaminooxymethylphenyl-2,4-dihydro dried (MgSO), filtered, and concentrated to give 2.8g of an 5-methoxy-2-methyl-3H-1,2,4-triazol-3-one oil. Trituration in hexane/n-butyl chloride formed a solid To a stirred solution of the title compound of Step A (0.33 which was collected by filtration to yield 2.19 g of the title g, 1.5 mmol) in pyridine (30 mL) under a nitrogen atmo compound of Step G, a compound of the invention. "H NMR sphere was added the title compound of Step C (0.43 g, 1.5 (CDC1): 8 7.56 (m.2H), 7.44 (m,3H), 7.25 (m.2H), 5.26 mmol) and the resulting mixture was heated at 90° C. for 2 (AB quartet,2H), 3.9 (s.3H), 3.41 (s.3H), 2.1 (s.3H). h. The reaction mixture was allowed to cool to room EXAMPLE 5 temperature overnight. The reaction mixture was concen Step A: Preparation of 1-(3,5-dichlorophenoxy)-2- 15 trated under reduced pressure and the residue was diluted propanone with 1 Naqueous HCl and was extracted three times with To a stirred solution of 3,5-dichlorophenol (0.49 g, 3 ethyl acetate. After drying (MgSO), the combined organic mmol) in acetone (10 mL) under a nitrogen atmosphere was extracts were concentrated under reduced preSSure. Chro added potassium carbonate (0.42 g, 3 mmol). In a separate matography of the residue on Silica gel (200 g) with 1:1 flask, chloroacetone (0.34 mL, 4.2 mmol) and potassium hexane: ethyl acetate afforded 0.14 g of the title compound iodide (0.02 g, 0.12 mmol) were dissolved in acetone (15 of Step D, a compound of the invention, as an oil. 300 MHz mL), heated at reflux for 10 min and then allowed to cool to H NMR CDC1): 87.44 (m,3H), 7.23 (m.1H), 6.96 (m.1H), room temperature. The chloroacetone Solution was then 6.81 (m.2H), 5.12 (q.2H), 4.44 (s.2H), 3.9 (s.3H), 3.43 added to the dichlorophenol Solution dropwise via an addi (s.3H), 1.89 (s.3H). tion funnel. The resulting mixture was Stirred at room 25 temperature overnight. The resulting Solids were filtered off EXAMPLE 6 and the filtrate was concentrated under reduced pressure to Step A: Preparation of 2,2-dimethyl-N-(2-methylphenyl) yield the title compound of Step A (0.65 g) as a semisolid. hydrazinecarboxamide 400 MHz H NMR (CDC1): 8 7.01 (t, 1H), 6.8 (d.2H), 4.5 o-Tolyl isocyanate (10.0 g) was dissolved in 75 mL of (s.2H), 2.3 (s.3H). This material was used in Step D without toluene under nitrogen. The solution was cooled to 5 C. and further characterization. to this was slowly added a solution of 1,1- Step B: Preparation of N-2-(1,5-dihydro-3-methoxy-1- dimethylhydrazine (5.7 mL) in toluene. After addition, the methyl-5-oxo 4H-1,2,4-triazol4-yl)phenyl)methoxy ice-bath was removed and the resulting slurry was allowed benzamide to stir an additional 10 minutes. The Solid was filtered off To a solution of benzohydroxamic acid (6.03 g., 44 mmol) and rinsed Successively with hexane, a Small amount of 20% in methanol (60 mL) under a nitrogen atmosphere was added 35 diethyl ether/hexane, and then hexanes again. This afforded sodium methoxide (25% solution in methanol, 37 mL, 160 11.1 g (77%) of the title compound of Step A. H NMR mmol) via an addition funnel. The resulting mixture was (CDC1): 8 8.1 (bris,1H), 7.94 (d.1H), 7.21–7.15 (m,3H), stirred at room temperature for 15 min. The title compound 6.99 (t, 1H), 5.23 (bris,1H), 2.63 (S.6H), 2.27 (s.3H). of Step E in Example 4 (10.32 g, 40 mmol) and then DME Step B: Preparation of 5-chloro-2,4-dihydro-2-methyl-4-(2- (40 mL) were added and the resulting mixture was heated 40 methylphenyl)-3H-1,2,4-triazol-3-one under reflux for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced preSSure. To a solution of 11.1 g of the title compound of Step A The residue was diluted with 1 N acqueous HCl and was dissolved in 600 mL of methylene chloride under nitrogen extracted three times with ethyl acetate. After drying was added 17.1 g of triphosgene. The Solution was heated at (MgSO), the combined organic extracts were concentrated 45 reflux overnight, cooled, and then concentrated under under reduced preSSure to yield the title compound of Step reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water and then washed with B (11.6 g) as an oil. 400 MHz H NMR (CDC1): 8 9.86 Saturated aqueous NaCl. The organic phase was dried (s.1H), 7.59 (d.2H), 7.5 (m.4H), 7.3 (m,3H), 5.16 (d.1H), (MgSO), filtered, and concentrated under reduced pressure. 4.94 (d.1H), 3.94 (s.3H), 3.41 (s.3H). Minor impurity sig The residue was purified by flash chromatography (30-50% nals: 4.4 (q.4H), 3.45 (s.3H), 3.31 (s.3H). This material was 50 used in Step C without further characterization. ethyl acetate/hexanes as eluent) to afford 8.25 g (64% yield) Step C. Preparation of 4-2-(aminooxy)methylphenyl-2, of the title compound of Step B. "H NMR (CDC): 8 4-dihydro-5-methoxy-2-methyl-3H-1,2,4-triazol-3-one 7.42–7.30 (m,3H), 7.17 (d.1H), 3.54 (s.3H), 2.22 (s.3H). hydrochloride Step C: Preparation of 2,4-dihydro-5-methoxy-2-methyl-4- To a stirred solution of the title compound of Step B (11.6 (2-methylphenyl)-3H-1,2,4-triazol-3-one g, 32.7 mmol) in ethanol (200 mL) under a nitrogen atmo 55 8.25 g of the title compound of Step B was dissolved in sphere was added concentrated Sulfuric acid (4 mL). The 80 mL of 1:1 dimethoxyethane/methanol under N. 14.0 mL resulting mixture was Stirred at room temperature overnight. of sodium methoxide (30% solution in methanol) was added The reaction mixture was concentrated under reduced pres and the Solution was heated at reflux for 3 h. The mixture Sure and the residue was partitioned between water and was allowed to cool, diluted with ethyl acetate, washed with diethyl ether. The aqueous phase was basified with 1 N 60 water, and then washed with Saturated aqueous NaCl. The acqueous NaOH and was extracted three times with ethyl combined organic extracts were dried (MgSO), filtered, and acetate and then three times with methylene chloride. The concentrated under reduced pressure. The residue was puri ethyl acetate and methylene chloride extracts were fied by flash chromatography (50–70% ethyl acetate/ combined, dried (MgSO), and then concentrated under hexanes as eluent) and triturated with 50% diethyl ether reduced pressure. The resulting residue was dissolved in 65 lhexanes to afford 6.7 g of the title compound of Step C diethyl ether (300 mL) and isopropanol (6 mL). To this (95% pure). H NMR (CDC1): 8 7.35–7.27 (m,3H), 7.18 solution was added 1 N HCl in diethyl ether (35 mL) (d.1H), 3.94 (s.3H), 3.46 (s.3H), 2.2 (s.3H). 6,057,352 43 44 Step D: Preparation of 4-2-(bromomethyl)phenyl-2,4- and finally concentrated under reduced pressure. Purification dihydro-5-methoxy-2-methyl-3H-1,2,4-triazol-3-one of the resulting residue by flash chromatography on Silica To a Solution/Suspension of 6.7 g of the title compound of gel using 50% ethyl acetate in hexane afforded 0.75 g of the Step C dissolved in 95 mL of carbon tetrachloride under N title compound of Example 7, a compound of the invention, was added N-bromosuccinirnide (6.53 g) followed by a as a white solid melting at 177-178° C. "H NMR (CDC1): catalytic amount of benzoyl peroxide. The Solution was 88.05 (s.2H), 7.9 (s.1H), 7.6 (m.1H), 7.4-7.55 (m.2H), 7.3 heated at reflux for 2 h. Another 1.63 g of (1H), 5.1 (m.2H), 5.05 (brs.2H), 3.92 (s.3H), 3.42 (s.3H). N-bromoSuccinimide and a catalytic amount of benzoyl peroxide were added and the Solution was heated at reflux EXAMPLE 8 for an hour. After cooling, methylene chloride was added and the organic layer was washed Successively with water, Step A: Preparation of 2-(3-chloro-1,5-dihydro-1-methyl-5- 0.1 NSodium thiosulfate Solution, and then Saturated acque oxo-4H-1,2,4-triazol-4-yl)benzaldehyde ous NaCl. The combined organic extracts were dried The title compound of Step E in Example 4 (0.50 g, 1.9 (MgSO), filtered, and concentrated under reduced pressure. mmol) was dissolved in carbon tetrachloride (15 mL) and The residue was purified by flash chromatography (3-10% then 4-methylmorpholine N-oxide (0.54 g, 4.6 mmol) was diethyl ether/methylene chloride as eluent) to afford 3.12 g 15 added. The mixture was heated at reflux for 5 h, then cooled of the title compound of Step D. "H NMR (CDC1): 8 7.5 to room temperature and stirred for 18 h. The solution was (m.1H), 7.44 (m.2H), 7.22 (m.1H), 4.60 (d.1H), 4.36 (d.1H), diluted with water and extracted three times with ethyl 3.96 (s.3H), 3.47 (s.3H). acetate. The combined organic phase was washed with Step E: Preparation of methyl (4-bromophenyl) Saturated aqueous NaCl, dried (MgSO), filtered and con carbamodithioate centrated to an oil which was purified by flash column To a stirred solution of carbon disulfide (6 mL, 100 mmol) chromatography on Silica gel to give 0.22 g of the title at 0 °C. under a nitrogen atmosphere was added a mixture compound of Step A as a white solid melting at 136-138 C. of p-bromoaniline (1.72 g, 10 mmol) and triethylamine (1.4 H NMR (300 MHz, CDC1): 89.98 (s.1H), 8.02 (dd.1H, mL, 10 mmol) dropwise via an addition funnel. The reaction J=8, 2 Hz), 7.79 (td.1 H, J=8, 2 Hz), 7.72 (td, 1H, J=8, 2 Hz), mixture was stirred at 0 °C. for 1.5 h, and then allowed to 25 7.40 (dd.1 H, J=8, 1 Hz), 3.56 (s.3H). warm to room temperature overnight. To the reaction mix Step B: Preparation of 5-chloro-2,4-dihydro-2-methyl-4-2- ture was added iodomethane (0.62 mL, 10 mmol). The methyl 3-(trifluoromethyl)-2-pyridinylhydrazono reaction mixture was Stirred at room temperature for 2 h. The methylphenyl-3H-1,2,4-triazol-3-one reaction mixture was diluted with diethyl ether (40 mL), and the resulting precipitate was filtered off. The filtrate was The title compound of Step A (0.20 g, 0.80 mmol) was concentrated under reduced pressure and trituration of the dissolved in absolute ethanol (7 mL) and a solution of residue with hexane afforded the title compound of Step E 1-3-(trifluoromethyl)pyridin-2-yl)-1-methylhydrazine in (2.34 g) as a solid melting at 111-112 C. 300 MHz. "H ethanol (3 mL) was added followed by 3 drops of glacial NMR (CDC1): 88.67 (s.1H), 7.53 (d. 2H), 7.38 (d.2H), 2.67 acetic acid. The mixture was warmed to 50 C. for 1 h, (s.3H). cooled to room temperature and then diluted with aqueous Step F: Preparation of 2-(1,5-dihydro-3-methoxy-1- 35 Sodium bicarbonate and extracted three times with ethyl methyl-5-oxo-4H-1,2,4-triazol-4-yl)phenyl)methyl)methyl acetate. The combined organic phases were dried (MgSO), (4-bromophenyl)carbonimidodithioate filtered and concentrated to give 0.38g of the title compound To a stirred solution of the title compound of Step E of Step B as a yellow solid. "H NMR (300 MHz. CDC1): 8 (0.088 g., 0.33 mmol) in THF (25 mL) under a nitrogen 8.42 (d.1 H. J=5 Hz), 8.16 (d.1H, J=8 Hz), 8.01 (d.1 H, J=8 atmosphere was added 60% sodium hydride (0.02 g, 0.40 40 Hz), 7.51 (t, 1H, J=8 Hz), 7.42 (t, 1H), J=8 Hz), 7.35 (s.1H), mmol) and the resulting mixture was stirred at room tem 7.21 (d.1 H, J=8 Hz), 7.03 (dd. 1H, J=8, 5 Hz), 3.56 (s,6H). perature for 15 min. To this solution was added the title Step C: Preparation of 2,4-dihydro-5-methoxy-2-methyl-4- compound of Step D and the mixture was stirred for 4 h. The 2-methyl 3-(trifluoromethyl)-2-pyridinylhydrazono reaction mixture was diluted with water (100 mL) and methylphenyl-3H-1,2,4-triazol-3-one extracted two times with ethyl acetate. After drying 45 The title compound of Step B (0.38 g., 0.93 mmol) was (MgSO), the combined organic extracts were concentrated dissolved in THF (10 mL) and then sodium methoxide (25% under reduced pressure. The residue was purified by passing in methanol, 0.56 mL) was added dropwise. The mixture through a 150 mL medium-fritted filter funnel containing 50 was heated at reflux for 1 h, cooled to room temperature and g of Silica gel with 1:1 hexane:ethyl acetate. This afforded then diluted with water and extracted three times with ethyl 0.16 g of the title compound of Step F, a compound of the 50 acetate. The combined organic phases were washed with invention, as an oil. 400 MHz H NMR (CDC1): 8 7.55 Saturated aqueous NaCl, dried (MgSO), filtered and con (s.1H), 7.4 (m.4H), 7.2 (m.1H), 6.7 (m.2H), 4.33 (m.2H), centrated to an oil which was purified by flash column 3.86 (s.3H), 3.43 (s.3H), 2.44 (s.3H). chromatography on Silica gel to afford 0.27 g of the title compound of Step C, a compound of the invention, as a pale EXAMPLE 7 yellow solid melting at 185-187° C. "H NMR (300 MHz, 55 CDC1): 8 8.41 (dd.1 H, J=5, 1.5 Hz), 8.12 (dd.1H, J=8, 1.5 N'-(2-(1,5-dihydro-3-methoxy-1-methyl-5-oxo-4H Hz), 8.01 (dd.1H, J=8, 1.5Hz), 7.42 (m,3H), 7.23 (d.1H J=8 1,2,4-triazol-4-yl)phenyl)methoxy-3,5-bis Hz), 15 7.02 (dd. 1H, J=8, 5Hz), 3.93 (s.3H), 3.56 (s.3H), (trifluoromethyl)benzenecarboximidamide 3.48 (s.3H). To a stirred solution of 0.95g of 3,5-bis(trifluoromethyl) By the procedures described herein together with methods benzarnidoxime in 9 mL of tetrahydrofuran under N was 60 known in the art, the following compounds of Tables 1 to 14 added 0.15g of 60% sodium hydride and then 0.75 g of the can be prepared. The following abbreviations are used in the title compound of Step E in Example 4. The reaction mixture Tables which follow: t=tertiary, n=normal, i=iso, c=cyclo, was allowed to stir overnight, then 1.7 mL of 30% sodium Me=methyl, Et=ethyl, Pr=propyl, i-Pr=isopropyl, Bu=butyl, methoxide in methanol was added and the reaction again Ph=phenyl, nap=naphthalenyl, MeO and OMe=methoxy, was allowed to Stir overnight. The reaction mixture was then 65 EtO=ethoxy, PhO=phenoxy, MeS and SMe=methylthio, diluted with ethyl acetate, washed with distilled water, then EtS=ethylthio, CN=cyano, NO=nitro, and SOMe= washed with Saturated aqueous NaCl, dried over MgSO, methylsulfonyl.

6,057,352 75 76

TABLE 14-continued Compounds of Formula I where E = 1,2-phenylene, Z = 3,5-diCl-Ph, Y = CHO-N-C(Me)CHS, G = C, the floating double bond is attached to G and X A X A X A X A. HC–CHCHO O HC–CHCHS O HC–CHCHO S HC–CHCHS S HC=CCHO O HC=CCHS O HC=CCHO S HC=CCHS S CFO O CFS O CFO S CFS S (c-Pr)O O (c-Pr)S O (c-Pr)O S (c-Pr)S S R2 = Et, W = S MeO O MeS O MeO S MeS S EtO O EtS O EtO S EtS S n-Pro O n-PrS O n-Pro S. n-PrS S HC–CHCHO O HC–CHCHS O HC–CHCHO S HC–CHCHS S HC=CCHO O HC=CCHS O HC=CCHO S HC=CCHS S CFO O CFS O CFO S CFS S (c-Pr)O O (c-Pr)S O (c-Pr)O S (c-Pr)S S

Formulation/Utility 20 NJ ., as well as Sisely and Wood, Encyclopedia of Surface Compounds of this invention will generally be used as a Active Agents, Chemical Publ. Co., Inc., New York, 1964, formulation or composition with an agriculturally Suitable list Surfactants and recommended uses. All formulations can carrier comprising at least one of a liquid diluent, a Solid contain minor amounts of additives to reduce foam, caking, diluent or a Surfactant. The formulation or composition corrosion, microbiological growth and the like, or thickeners ingredients are Selected to be consistent with the physical 25 to increase Viscosity. properties of the active ingredient, mode of application and Surfactants include, for example, polyethoxylated environmental factorS Such as Soil type, moisture and tem alcohols, polyethoxylated alkylphenols, polyethoxylated perature. Useful formulations include liquids Such as Solu Sorbitan fatty acid esters, dialkyl SulfoSuccinates, alkyl tions (including emulsifiable concentrates), Suspensions, Sulfates, alkylbenzene Sulfonates, organosilicones, N,N- emulsions (including micro emulsions and/or dialkyltaurates, lignin Sulfonates, naphthalene Sulfonate Suspoemulsions) and the like which optionally can be thick formaldehyde condensates, polycarboxylates, and ened into gels. Useful formulations further include solids polyoxyethylene/polyoxypropylene block copolymers. Such as dusts, powders, granules, pellets, tablets, films, and Solid diluents include, for example, clays Such as bentonite, the like which can be water-dispersible (“wettable”) or montmorillonite, attapulgite and kaolin, Starch, Sugar, Silica, water-Soluble. Active ingredient can be (micro)encapsulated 35 talc, diatomaceous earth, urea, calcium carbonate, Sodium and further formed into a Suspension or Solid formulation; carbonate and bicarbonate, and Sodium Sulfate. Liquid dilu alternatively the entire formulation of active ingredient can ents include, for example, water, N,N-dimethylformarnide, be encapsulated (or "overcoated'). Encapsulation can con dimethyl Sulfoxide, N-alkylpyrrollidone, ethylene glycol, trol or delay release of the active ingredient. Sprayable polypropylene glycol, paraffins, alkylbenzenes, formulations can be extended in Suitable media and used at alkylnaphthalenes, oils of olive, castor, linseed, tung, Spray Volumes from about one to Several hundred liters per 40 Sesame, corn, peanut, cotton-Seed, Soybean, rape-Seed and hectare. High-strength compositions are primarily used as coconut, fatty acid esters, ketones Such as cyclohexanone, intermediates for further formulation. 2-heptanone, isophorone and 4-hydroxy-4-methyl-2- The formulations will typically contain effective amounts pentanone, and alcohols Such as methanol, cyclohexanol, of active ingredient, diluent and Surfactant within the fol decanol and tetrahydrofurfuryl alcohol. lowing approximate ranges which add up to 100 percent by 45 Solutions, including emulsifiable concentrates, can be weight. prepared by Simply mixing the ingredients. Dusts and pow derS can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wet-milling, See, for example, U.S. Pat. No. Weight Percent 50 3,060,084. Granules and pellets can be prepared by Spraying Active the active material upon preformed granular carriers or by Ingredient Diluent Surfactant agglomeration techniques. See Browning, "Agglomeration', Chemical Engineering, Dec. 4, 1967, pp 147-48, Perry's Water-Dispersible and 5-90 O-94 1-15 Water-soluble Granules, Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, Tablets and Powders. 55 New York, 1963, pages 8-57 and following, and WO Suspensions, Emulsions, Solutions 5-50 40-95 0-15 91/13546. Pellets can be prepared as described in U.S. Pat. (including Emulsifiable No. 4,172,714. Water-dispersible and water-soluble granules Concentrates) can be prepared as taught in U.S. Pat. No. 4,144,050, U.S. Dusts 1-25 70-99 O-5 Pat. No. 3,920,442 and DE 3,246,493. Tablets can be Granules and Pellets O.O1-99 5-99.99 0-15 prepared as taught in U.S. Pat. No. 5,180,587, U.S. Pat. No. High Strength Compositions 90-99 0-10 0-2 60 5,232,701 and U.S. Pat. No. 5,208,030. Films can be pre pared as taught in GB 2,095,558 and U.S. Pat. No. 3,299, Typical solid diluents are described in Watkins, et al., 566. Handbook of Insecticide Dust Diluents and Carriers, 2nd For further information regarding the art of formulation, Ed., Dorland Books, Caldwell, N.J. Typical liquid diluents see U.S. Pat. No. 3,235,361, Col. 6, line 16 through Col. 7, are described in Marsden, Solvents Guide, 2nd Ed., 65 line 19 and Examples 10–41; U.S. Pat. No. 3,309,192, Col. Interscience, New York, 1950. McCutcheon's Detergents 5, line 43 through Col. 7, line 62 and Examples 8, 12, 15, 39, and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, 41, 52, 53, 58, 132, 138–140, 162–164, 166, 167 and 6,057,352 77 78 169-182; U.S. Pat. No. 2,891,855, Col. 3, line 66 through lactucae and other generea and Species closely related to Col. 5, line 17 and Examples 1-4; Klingman, Weed Control these pathogens. as a Science, John Wiley and Sons, Inc., New York, 1961, Compounds of this invention can also be mixed with one pp. 81-96; and Hance et al., Weed Control Handbook, 8th or more other insecticides, fungicides, nematocides, Ed., Blackwell Scientific Publications, Oxford, 1989. bactericides, acaricides, growth regulators, chemosterilants, In the following Examples, all percentages are by weight Semiochemicals, repellents, attractants, pheromones, feed and all formulations are prepared in conventional ways. ing Stimulants or other biologically active compounds to Compound numbers refer to compounds in Index Tables form a multi-component pesticide giving an even broader A-B. Spectrum of agricultural protection. Examples of Such agri cultural protectants with which compounds of this invention can be formulated are: insecticides Such as abamectin, acephate, azinphoS-methyl, bifenthrin, buprofe Zin, Example A carbofuran, chlorpyrifos, chlorpyrifoS-methyl, cyfluthrin, beta-cy fluthrin, deltamethrin, diafenthiuron, diaZinon, Wettable Powder diflubenzuron, dimethoate, esfenvalerate, fenpropathrin, Compound 19 65.0% 15 fenvalerate, fipronil, flucy thrrinate, tau-fluvalinate, dodecylphenol polyethylene glycol ether 2.0% fonophos, imidacloprid, isofen phos, malathion, sodium ligninsulfonate 4.0% metaldehyde, methamidophos, methidathion, methomyl, sodium silicoaluminate 6.0% methoprene, methoxychlor, monocrotophos, oxamyl, montmorillonite (calcined) 23.0%. parathion, parathion-methyl, perme thrin, phorate, Example B phosalone, phoSmet, phosphamidon, pirimicarb, profenofoS, Granule rotenone, SulprofoS, tebufenozide, tefluthrin, terbufos, tetrachlorVinphos, thiodicarb, tralomethrin, trichlorfon and Compound 19 10.0% attapulgite granules 90.0%. triflumuron; fungicides such as azoxystrobin (ICIA5504), (low volatile matter, 0.71/0.30 mm: benomyl, blasticidin-S, Bordeaux mixture (tribasic copper U.S.S. No. 25–50 sieves) Sulfate), bromuconazole, captafol, captan, carbendazim, Example C 25 chloroneb, chlorothalonil, copper oxychloride, copper Salts, cymoxanil, cyproconazole, cyprodinil (CGA 219417), Extruded Pellet diclomeZine, dicloran, difenoconazole, dimethomorph, Compound 19 25.0% diniconazole, diniconazole-M, dodine, edifenphos, epoxy anhydrous sodium sulfate 10.0% conazole (BAS 480F), fenarimol, fenbuconazole, crude calcium ligninsulfonate 5.0% fenpiclonil, fenpropidin, fenpropimorph, fluguinconazole, sodium alkylnaphthalenesulfonate 1.0% flusilaZole, flutolanil, flutriafol, folpet, foSetyl-aluminum, calcium/magnesium bentonite 59.0%. furalaxyl, hexaconazole, ipconazole, iprobenfoS, iprodione, Example D isoprothiolane, kasugamycin, kresoxim-methyl (BAS Emulsifiable Concentrate 490 F), manco Zeb, maneb, me pronil, metalaxyl, 35 metconazole, my clobutanil, neo-a Sozin (ferric Compound 19 20.0% methane arsonate), oxadixyl, penconazole, pency curon, blend of oil soluble sulfonates 10.0% probe nazole, prochloraZ, propiconazole, pyrife nox, and polyoxyethylene ethers pyroquilon, Sulfur, tebuconazole, tetraconazole, isophorone 70.0%. thiabendazole, thiophanate-methyl, thiram, triadimefon, triadimenol, tricyclazole, triticonazole, uniconazole, valida The compounds of this invention are useful as plant 40 mycin and VincloZolin; nematocides Such as aldoxycarb and disease control agents. The present invention therefore fur fenamiphos, bactericides Such as Streptomycin; acaricides ther comprises a method for controlling plant diseases Such as amitraz, chinomethionat, chlorobenzilate, cyhexatin, caused by fungal plant pathogens comprising applying to the dicofol, die nochlor, fena Zaquin, fenbutatin oxide, plant or portion thereof to be protected, or to the plant Seed fenpropathrin, fenpyroximate, heXythiaZOX, propargite, or Seedling to be protected, an effective amount of a com 45 pyridaben and tebufenpyrad; and biological agents Such as pound of the invention or a fungicidal composition contain Bacillus thuringiensis, Bacillus thuringiensis delta ing Said compound. The compounds and compositions of endotoxin, baculovirus, and entomopathogenic bacteria, this invention provide control of diseases caused by a broad Virus and fungi. Spectrum of fungal plant pathogens in the Basidiomycete, In certain instances, combinations with other fungicides Ascomycete, Oomycete and Deuteromycete classes. They 50 having a similar spectrum of control but a different mode of are effective in controlling a broad spectrum of plant action will be particularly advantageous for resistance man diseases, particularly foliar pathogens of ornamental, agement. vegetable, field, cereal, and fruit crops. These pathogens Preferred for better control of plant diseases caused by include Plasmopara viticola, Phytophthora infestans, Per fungal plant pathogens (e.g., lower use rate or broader On Ospora tabacina, Pseudoperonospora cubensis, Pythium spectrum of plant pathogens controlled) or resistance man aphanidermatum, Alternaria brassicae, Septoria nodorum, 55 agement are mixtures of a compound of this invention with Septoria tritici, CercoSporidium perSonatum, Cercospora a fungicide Selected from the group cyproconazole, cyprodi arachidicola, Pseudocercosporella herpotrichoides, Cer nil (CGA 2 19417), epoxyconazole (BAS 480F), cospora beticola, Botrytis cinerea, Moniliniafructicola, fenpropidin, fenpropimorph, flusilaZole and tebuconazole. Pyricularia Oryzae, Podosphaera leucotricha, Venturia Specifically preferred mixtures (compound numbers refer to inaequalis, Erysiphe graminis, Uncinula necatur, Puccinia 60 compounds in Index Tables A-B) are selected from the recondita, Puccinia graminis, Hemileia vastatrix, Puccinia group: compound 2 and cyproconazole; compound 2 and Striformis, Puccinia arachidis, Rhizoctonia Solani, cyprodinil (CGA219417); compound 2 and epoxyconazole Sphaerotheca fuliginea, Fusarium oxysporum, Verticillium (BAS 480F); compound 2 and fenpropidin; compound 2 and dahliae, Pythium aphaniden natum, Phytophthora fenpropimorph, compound 2 and flusilaZole, compound 2 megasperma, Sclerotinia Sclerotiorum, Sclerotium rolfsii, 65 and tebuconazole; compound 3 and cyproconazole; com Erysiphe polygoni, Pyrenophora teres, Gaeumannomyces pound 3 and cyprodinil (CGA 219417); compound 3 and graminis, RynchoSporium Secalis, Fusarium roseum, Bremia epoxyconazole (BAS 480F); compound 3 and fenpropidin; 6,057,352 79 80 compound 3 and fenpropimorph, compound 3 and flusila Rates of application for these compounds can be influ Zole; compound 3 and tebuconazole; compound 5 and enced by many factors of the environment and should be cyproconazole; compound 5 and cyprodinil (CGA219417); compound 5 and epoxyconazole (BAS 480F); compound 5 determined under actual use conditions. Foliage can nor and fenpropidin; compound 5 and fenpropimorph, com mally be protected when treated at a rate of from less than pound 5 and flusilaZole; compound 5 and tebuconazole; 1 g/ha to 5,000 g/ha of active ingredient. Seed and Seedlings compound 19 and cyproconazole; compound 19 and can normally be protected when Seed is treated at a rate of cyprodinil (CGA219417); compound 19 and epoxyconazole from 0.1 to 10 g per kilogram of Seed. (BAS 480F); compound 19 and fenpropidin; compound 19 The following TESTS demonstrate the control efficacy of and fempropimorph, compound 19 and flusilaZole; and com compounds of this invention on Specific pathogens. The pound 19 and tebuconazole. 1O Plant disease control is ordinarily accomplished by apply pathogen control protection afforded by the compounds is ing an effective amount of a compound of this invention not limited, however, to these species. See Index Tables either pre- or post-infection, to the portion of the plant to be A-B for compound descriptions. The following abbrevia protected Such as the roots, Stems, foliage, fruit, Seeds, tion is used in the Index Tables which follow: Ph=phenyl. tubers or bulbs, or to the media (soil or sand) in which the 15 The abbreviation “Ex.' stands for “Example” and is fol plants to be protected are growing. The compounds can also lowed by a number indicating in which example the com be applied to the Seed to protect the Seed and Seedling. pound is prepared.

INDEX TABLE A

Z. C n1Y

NYN-y CH

Cmpd. No. X Y Z. m.p. (C.)

1. CHO -C(=O)- Ph 126-134 2 (Ex. 2) CHO -CH=C(CI)-C(=O)-O- C(CH)3 semisolid 3 (Ex. 1) CHO -CHS-C(CHCH)=N- 4-Cl-Ph gum 4 (Ex. 3) CHO CHO-N=C(CN)-C(=O)- 3-CF-Ph gum 5 (Ex. 4) CHO -CHO-N=C(SCH)- 3,4-diCl-Ph solid 6 CHO -CHO-N=C(SO2CH)- 3,4-diCl-Ph semisolid 7 CHO -CHS-C(CH)=N- 3-CF-Ph O* 8 CHO CHO-N=C(CH)-CHO- 3-CF-Ph O* 9 CHO -CHO-N=C(CH)-CHS- 1-CH-1H-tetrazol-5-yl O* 1O CHO -CHO-N=C(CH)-CHS- 2-benzoxazolyl O* 11 CHO -CHO-N=C(5CH)- 3,5-diC-Ph O* 12 (Ex. 5) CHO CHO-N=C(CH)-CHO- 3,5-diCl-Ph o1* 13 CHO -CHS-C(CHCH)=N- 3-CF-Ph O* 14 CHO -CHO-N=C(CH)-CHS- 3,5-diCF-Ph O* 15 CHO -CHO-N=C(CH)-CHO- 3,5-diCF-Ph O* 16 CHO -CHO-N=C(SCH)- 3-CF-Ph O* 17 CHO -CHO-N=C(CH)-CHS- 2-benzothiazolyl O* 18 CHO CHO-N=C(CH)-CHS- 3,5-diCl-Ph O* 19 CHO -CHO-N=C(SCH)- 3,5-diCF-Ph solid 20 (Ex. 8) CHO -CH=N-N(CH)- 3-CF-pyridin-2-yl 185-187 21 CHO -CH=N-N(CH)- 4-CF-pyridin-2-yl 169-171 22 (Ex. 7) CHO -CHO-N=C(NH)- 3,5-diCF-Ph 177-178

23 Cl O 2-thiazolyl 95-1OO

-CHN N 2 N / (CH2)3

24 Cl O 3-CF-Ph 125-130

-CHN N 2 N /

6,057,352 83 84 incubated in a growth chamber at 20° C. for 7 days, after which disease ratings were made. TABLE A-continued TEST B Cmpd Test Test Test Test Test Test No. A. B C D E F The test Suspension was sprayed to the point of run-off on 11 98 1OO 53 26 95 a 48 wheat Seedlings. The following day the Seedlings were 12 99 1OO 53 O 44 1O inoculated with a spore Suspension of Puccinia recondita 13 76 97 53 O 1OO 1O (the causal agent of wheat leaf rust) and incubated in a 14 61 93 O 26 29a O saturated atmosphere at 20° C. for 24 h, and then moved to 15 91 97 53 26 6a O a growth chamber at 20° C. for 6 days, after which disease 16 99 99 53 99 50a O 17 99 99 32 91 53a 79 ratings were made. 18 25 93 32 25 68a O 19 1OO 1OO 74 70 57a 64 TEST C 2O 86 68 O O 2a O 21 O O O 41 19a O The test Suspension was sprayed to the point of run-off on 15 22 1OO 93 73 16 Oa O rice Seedlings. The following day the Seedlings were inocu 23 34 67 O 73 O lated with a spore Suspension of Pyricularia Orvzae (the 24 34 67 O 16 O 25 O O O O 11 a 7 causal agent of rice blast) and incubated in a Saturated 26 28 67 O 32 11 a O atmosphere at 27 C. for 24 h, and then moved to a growth 27 94 1OO 86 13 35a O chamber at 30° C. for 5 days, after which disease ratings 28 were made. 29 TESTD "Compound was tested at 10 ppm (equivalent to 25 g/ha). Compound was tested at 40 ppm (equivalent to 100 g/ha). The test Suspension was sprayed to the point of run-off on tomato Seedlings. The following day the Seedlings were What is claimed is: inoculated with a spore Suspension of Phytophthora 25 1. A compound selected from Formula I, N-oxides and infeStans (the causal agent of potato and tomato late blight) agriculturally Suitable Salts thereof, and incubated in a saturated atmosphere at 20° C. for 24 h, and then moved to a growth chamber at 20° C. for 5 days, after which disease ratings were made. 1.Y. NZ TEST E X G W The test Suspension was sprayed to the point of run-off on grape Seedlings. The following day the Seedlings were A-NY inoculated with a spore Suspension of Plasmopara viticola 35 V 2 (the causal agent of grape downy mildew) and incubated in a Saturated atmosphere at 20° C. for 24h, moved to a growth chamber at 20° C. for 6 days, and then incubated in a saturated atmosphere at 20° C. for 24 h, after which disease wherein: ratings were made. E is 1,2-phenylene optionally substituted with one of R, 40 R", or both R and R'; TEST F A is N or CR'"; The test Suspension was sprayed to the point of run-off on G is N and the floating double bond is attached to A; cucumber Seedlings. The following day the Seedlings were W is O; S; NH; N(C-C alkyl); or NO(C-C alkyl); inoculated with a spore Suspension of Botrytis cinerea (the 45 X is OR'; S(O).R'; or halogen; causal agent of gray mold on many crops) and incubated in R" is C-C alkyl; C1-C haloalkyl, C-C alkenyl; a saturated atmosphere at 20° C. for 48 h, and moved to a C-C haloalkenyl, C-C alkynyl, C-C haloalky growth chamber at 20° C. for 5 days, after which disease nyl, C-C cycloalkyl, C-C alkylcarbonyl, or C-C, ratings were made. alkoxycarbonyl, Results for Tests A-F are given in Table A. In the table, 50 R is H; C-C alkyl, C-C haloalkyl, C-C alkenyl; a rating of 100 indicates 100% disease control and a rating C-C haloalkenyl, C-C alkynyl, C-C haloalky of 0 indicates no disease control (relative to the controls). A nyl, C-C cycloalkyl, C-C alkylcarbonyl, or C-C, dash (-) indicates no test results. alkoxycarbonyl, R and R" are each independently halogen; cyano; nitro; TABLE A 55 hydroxy; C1-C alkyl, C-C haloalkyl, C-C alk enyl, C-C haloalkenyl, C-C alkynyl, C-C, Cmpd Test Test Test Test Test Test haloalkynyl, C-C alkoxy, C-C haloalkoxy, C-C, No. A. B C D E F alkenyloxy; C-C alkynyloxy; C1-C alkylthio; 1. 39 28 O O O O C-C alkylsulfinyl, C-C alkylsulfonyl; formyl; 2 99 99 86 96 89b O 3 85 1OO 91 63 43a 42 60 C-C alkylcarbonyl, C-C alkoxycarbonyl; NHC 4 39 85 O O 34 37 (O); (C-C alkyl)NHC(O); (C-C alkyl)-NC(O); 5 98 1OO 74 86 100a O Si(R); Ge(R'); (R')Si-C=C-; or phenyl, 6 97 97 O O Oa 47 phenylethynyl, benzoyl, or phenylsulfonyl each Substi 7 91 1OO 53 25 83a O 8 57 1OO 74 74 51 a 45 tuted with R and optionally substituted with one or 9 57 66 O 74 3a O 65 more R'; or 1O 95 99 O O 16a 48 when RandR' are attached to adjacent atoms, Rand R' can be taken together as C-C alkylene, C-C, 6,057,352 85 86 haloalkylene, C-C alkenylene or C-Cs haloalk R is H; 1-2 halogen; C-C alkyl; C-C haloalkyl; enylene each optionally Substituted with 1-2 C-C, C-C alkoxy; C-C haloalkoxy; C-C alkenyl, alkyl, C-C haloalkenyl, C-C alkynyl, C-C alkylthio; C-Chaloalkylthio; C1-C alkylsulfinyl, C-C alkyl Sulfonyl, C-C cycloalkyl, C-C alkenyloxy, CO (C-C alkyl); NH(C-C alkyl); N(C-C alkyl); cyano; nitro; SiR'R'R'; or GeR'R'R'; R’ is H; 1-2 halogen; C-C alkyl; C-C haloalkyl; C-C alkoxy, C-C haloalkoxy, C-C alkenyl, 1O C-C haloalkenyl, C-C alkynyl, C-C alkylthio; C-Chaloalkylthio; C1-C alkylsulfinyl, C-C alkyl Sulfonyl, C-C cycloalkyl, C-C alkenyloxy; CO (C-C alkyl); NH(C-C alkyl); N(C-C alkyl); –C(R)=NOR7; cyano; nitro; SF; SiR'R'R'; or 15 GeR'R'R''; or R is phenyl, benzyl, benzoyl, phenoxy, pyridinyl, pyridinyloxy, thienyl, thienyloxy, (R)-; -CHROC(=O)N(R)-; or -CHROC furanyl, pyrimidinyl, or pyrimidinyloxy each option (=O)N(R-)-; and the directionality of the Y linkage ally substituted with one of R', R', or both R'' and is defined such that the moiety depicted on the left side R12; of the linkage is bonded to E and the moiety on the right each R" is independently halogen; C1-C alkyl; C1-C, Side of the linkage is bonded to Z, haloalkyl, C-C alkoxy; nitro, or cyano; or W' is O or S; when R and an R" are attached to adjacent atoms on Z, A' is O; S; NR'; or a direct bond; R and said adjacently attached R' can be taken each R is independently H; 1-2 CH; C-C alkyl; together as -OCH-O- or -OCHCH-O-, each C-C alkoxy, C-C cycloalkyl, formylamino, C-C, 25 CH group of said taken together R and R' optionally alkylcarbonylamino; C-C alkoxycarbonylamino; Substituted with 1-2 halogen; or NHC(O)NH; (C-C alkyl)NHC(O)NH; (C-C, when Y and an R'' are attached to adjacent atoms on Z alkyl)-NC(O)NH; N(C-C alkyl); piperidinyl; mor and Y is —CHRO-N=C(R)-, R7 and said adja pholinyl, 1-2 halogen; cyano, or nitro, cently attached R' can be taken together as R" is H; C1-C alkyl; C1-C haloalkyl; C1-C alkoxy; -(CH), J- such that J is attached to Z: C-C haloalkoxy; C1-C alkylthio; C1-C alkylsulfi J is -CH-, -CHCH-, -OCH-, -CHO-; nyl, C-C alkylsulfonyl, C-C haloalkylthio; C-C, -SCH-, -CHS-, -N(R')CH-, or -CHN haloalkylsulfinyl, C-C haloalkylsulfonyl, C-C alk (R)-; each CH group of said J optionally substi enyl, C-C haloalkenyl, C-C alkynyl, C-C, 35 tuted with 1 to 2 CH; R'' and R'' are each indepen haloalkynyl, C-C cycloalkyl, C-C alkylcarbonyl, dently halogen; C1-C alkyl, C-C haloalkyl, C-C alkoxycarbonyl; halogen; cyano; or morpholi C-C alkoxy; C1-C, haloalkoxy; nitro; cyano; Si(R); nyl, or Ge(R); Z is selected from: each R" is independently H; C-C alkyl; C-C, a) C-C cycloalkyl and phenyl each Substituted with 40 haloalkyl; or phenyl optionally substituted with R” and optionally substituted with one or more R'; halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, b) a ring system selected from 3 to 14-membered C-C haloalkoxy, nitro or cyano; monocyclic, fused bicyclic and fused tricyclic non R" is H.; halogen; C1-C alkyl; C1-C haloalkyl, C-C, aromatic heterocyclic ring Systems and 5 to alkenyl, C-C haloalkenyl, C-C alkynyl, C-C, 14-membered monocyclic, fused bicyclic and fused 45 haloalkynyl; or C-C cycloalkyl, tricyclic aromatic heterocyclic ring Systems, each each R" is independently H; C-C alkyl; C-C, heterocyclic ring System containing 1 to 6 heteroa cycloalkyl, or phenyl or benzyl, each optionally Sub toms independently Selected from the group Stituted on the phenyl ring with halogen, C-C alkyl, nitrogen, oxygen, and Sulfur, provided that each C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, heterocyclic ring System contains no more than 4 50 nitro or cyano; nitrogens, no more than 2 Oxygens, and no more than R", R7, and Rare each independently H; C-C alkyl; 2 Sulfurs, each nonaromatic or aromatic heterocyclic C-C cycloalkyl, or phenyl optionally Substituted with ring system substituted with R and optionally sub halogen, C-C alkyl, C-Chaloalkyl, C-C alkoxy, stituted with one or more R', and C-C haloalkoxy, nitro or cyano; c) a multicyclic ring System selected from 8 to 55 14-membered fused-bicyclic and fused-tricyclic ring R. R. R. R. R., and R' are each independently Systems which are an aromatic carbocyclic ring C-C alkyl, C-C alkoxy, or phenyl, System, a nonaromatic carbocyclic ring System, or a each R is independently C-C alkyl or phenyl; ring System containing one or two nonaromatic rings R’ is H; C-C alkyl; C-C cycloalkyl; or phenyl that each include one or two Q as ring members and 60 optionally Substituted with halogen, C-C alkyl, one or two ring members independently Selected C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, from C(=O) and S(O), and any remaining rings as nitro or cyano; aromatic carbocyclic rings, each multicyclic ring R7 and Rare each independently C-C alkoxy; C-C, system substituted with Rand optionally substituted cycloalkyl, formylamino; C-C alkylcarbonylamino; with one or more R'; 65 C-C alkoxycarbonylamino; NHC(O)NH; (C-C, each Q is independently Selected from the group alkyl)NHC(O)NH; (C-C alkyl)-NC(O)NH; N(C-C, CHR'-, -NR'-, -O-, and -S(O)-; alkyl); piperidinyl; morpholinyl, cyano; or nitro, 6,057,352 87 88 R’ is C-C alkoxy; C-C cycloalkyl; formylamino; ii) a 8 to 14-membered multicyclic ring System selected C-C alkylcarbonylamino; C-C alkoxycarbony from fused-bicyclic and fused-tricyclic ring Systems lamino; NHC(O)NH; (C-C alkyl)NHC(O)NH; which are an aromatic carbocyclic ring System, a (C-C alkyl)-NC(O)NH; N(C-C alkyl); piperidi nonaromatic carbocyclic ring System, or a ring Sys nyl; morpholinyl; halogen; cyano, or nitro, tem containing one or two nonaromatic rings that R is C-C cycloalkyl; or phenyl optionally substituted each include one or two Q as ring members and one with halogen, C-C alkyl, C-C haloalkyl, C-C, or two ring members independently Selected from alkoxy, C-C haloalkoxy, nitro or cyano; C(=O) and S(O) substituted with Rand optionally R is C-C alkylthio; C1-C alkylsulfinyl; C-C alkyl substituted with one or more R'; Sulfonyl; C-C haloalkylthio; C-C haloalkylsulfi 7) when Yis-C(R)=N-O-or-O-N=C(R) nyl, C-C haloalkylsulfonyl, or halogen; and R is C-C alkylthio, C-C alkylsulfinyl, C-C, R is C-C cycloalkyl; alkylsulfonyl, C-C halo alkylthio, C-C, m, n and each p are each independently 0, 1 or 2, haloalkylsulfinyl, C-C haloalkylsulfonyl or halogen, r is 0 or 1; and then Z is other than S is 2 or 3; 15 i) an N-oxide of a 5 to 14-membered aromatic hetero provided that cyclic ring system substituted with Rand optionally 1) when Yis-NR'-, R' is H or C-C alkyl, and R' substituted with one or more R'; or is SiR'R'R' or GeR'R'R'', then Z is other than ii) a 8 to 14-membered multicyclic ring System selected phenyl or a 5 to 14-membered aromatic heterocyclic from fused-bicyclic and fused-tricyclic ring Systems ring system each substituted with R and optionally which are an aromatic carbocyclic ring System, a substituted with one or more R'; nonaromatic carbocyclic ring System, or a ring Sys 2) when Y is –C(=O)- and R is SiR'R'R' or tem containing one or two nonaromatic rings that GeR'R'R'', then Z is other than phenyl or a 5 to each include one or two Q as ring members and one 14-membered aromatic heterocyclic ring System each or two ring members independently Selected from substituted with R and optionally substituted with one 25 C(=O) and S(O) substituted with Rand optionally or more R'; substituted with one or more R'; and 3) when Yis-CH(OR)-, R is Hor C-C alkyl, and 8) when Yis-CH(OR)- and R is H or C-C alkyl, R’ is SiR'R'R' or GeR'R'R'', then Z is other then Z is other than than phenyl or a 5 to 14-membered aromatic hetero i) an N-oxide of a 5 to 14-membered aromatic hetero cyclic ring system each Substituted with R and option cyclic ring system substituted with Rand optionally ally substituted with one or more R'; substituted with one or more R'; or 4) when Yis-NR'- and R' is H or C-C alkyl, then ii) a 8 to 14-membered multicyclic ring System selected Z is other than from fused-bicyclic and fused-tricyclic ring systems i) an N-oxide of a 5 to 14-membered aromatic hetero which are an aromatic carbocyclic ring System, a cyclic ring system substituted with Rand optionally 35 nonaromatic carbocyclic ring System, or a ring Sys substituted with one or more R'; or tem containing one or two nonaromatic rings that ii) a 8 to 14-membered multicyclic ring System selected each include one or two Q as ring members and one from fused-bicyclic and fused-tricyclic ring Systems or two ring members independently Selected from which are an aromatic carbocyclic ring System, a C(=O) and S(O) substituted with R and optionally nonaromatic carbocyclic ring System, or a ring Sys 40 tem containing one or two nonaromatic rings that substituted with one or more R'. each include one or two Q as ring members and one 2. A compound of claim 1 wherein: or two ring members independently Selected from W is O; C(=O) and S(O) substituted with R and optionally R" is C-C alkyl or C-C haloalkyl; substituted with one or more R'; 45 R’ is H; C-C alkyl, C-C haloalkyl; or C-C, 5) when Y is –CHRO-N=C(R)- or -(R) cycloalkyl, C=N-OCH(R)-, R is Hor C-C, alkyl and R' R and R" are each independently halogen; cyano; nitro; is C-C alkylthio, C-C alkylsulfinyl, C-C, C-C alkyl, C-C haloalkyl, C-C alkoxy; C-C, alkylsulfonyl, C-C halo alkylthio, C-C, haloalkoxy; C1-C alkylsulfonyl, C-C alkylcarbo haloalkylsulfinyl, C-C haloalkylsulfonyl or halogen, 50 nyl; C-C alkoxycarbonyl; (C-C alkyl)NHC(O); then Z is other than (C-C alkyl)-NC(O); benzoyl; or phenylsulfonyl; i) an N-oxide of a 5 to 14-membered aromatic hetero Y is –CHS-C(R)=N-, -CH=CR-C(=W) cyclic ring system substituted with Rand optionally A-, -CHO-N=C(R)-; —(R7)C=N-OCH substituted with one or more R'; or (R)-; or -C(R)=N-O-; ii) a 8 to 14-membered multicyclic ring System selected 55 R’ is H; C1-C alkyl, C-C haloalkyl, C-C alkoxy; from fused-bicyclic and fused-tricyclic ring Systems C-C alkylthio; C-C alkenyl, C-C alkynyl, C-C, which are an aromatic carbocyclic ring System, a cycloalkyl, halogen; or cyano; nonaromatic carbocyclic ring System, or a ring Sys Z is Selected from the group C-C cycloalkyl, phenyl, tem containing one or two nonaromatic rings that naphthale nyl; anthrace nyl, phenanthrenyl, each include one or two Q as ring members and one 60 1H-pyrrolyl; furanyl; thienyl; 1 H-pyrazolyl; or two ring members independently Selected from 1H-imidazolyl; isoxazolyl, oxazolyl; isothiazolyl; thia C(=O) and S(O) substituted with Rand optionally zolyl; 1H-1,2,3-triazolyl; 2H-1 2,3-triazolyl; 1H-1,2,4- substituted with one or more R'; triazolyl; 4H-1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4- 6) when Y is -C(=O), then Z is other than OXadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1.2, i) an N-oxide of a 5 to 14-membered aromatic hetero 65 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, cyclic ring system substituted with R and optionally 1,3,4-thiadiazolyl; 1H-tetrazolyl; 2H-tetrazolyl; pyridi substituted with one or more R'; or nyl, pyridaZinyl, pyrimidinyl, pyrazinyl, 1,3,5-