USOO62745.36B1 (12) United States Patent (10) Patent No.: US 6,274,536 B1 Nebel et al. (45) Date of Patent: Aug. 14, 2001

(54) PYRAZOLE DERIVATIVES AS HERBICIDES Tetrahedron Lett. 36(49), 8917 (1995); idem. 31(14), 1965 (1990). (75) Inventors: Kurt Nebel, Hochwald; Alain De Bull. Soc. Chim. Fr. 1953, 1001, in French language (the Mesmaeker, Kaenerkinden, both of english language abstract is also enclosed). (CH); Jirgen Schaetzer, Rheinfelden Heterocycles 30(2), 875 (1990). (DE) Can. J. Chem. 31, 457 (1953). (73) Assignee: Syngenta Crop Protection, Inc., J. Chem. Soc. 1939, 1858. Greensboro, NC (US) J. Het. Chem. 25, 511 (1988); idem. 22, 268 (1985). J. prakt. Chem. 330, 293 (1988); idem. 334, 119 (1992). (*) Notice: Subject to any disclaimer, the term of this Chem. Ber. 62,2732 (1929) (the english language abstract patent is extended or adjusted under 35 is also enclosed). U.S.C. 154(b) by 0 days. Chem. Heterocycl. Compd. (Engl. Transl.) 1988, 658. (21) Appl. No.: 09/380,678 Pharmazie 45,731 (1990) (the english language abstract is also enclosed). (22) PCT Filed: Mar. 19, 1998 (List continued on next page.) (86) PCT No.: PCT/EP98/O1611 Primary Examiner Jane Fan S371 Date: Sep. 7, 1999 (74) Attorney, Agent, or Firm William A. Teoli, Jr. S 102(e) Date: Sep. 7, 1999 (57) ABSTRACT (87) PCT Pub. No.: WO98/42698 Compounds of the following formula I PCT Pub. Date: Oct. 1, 1998 (30) Foreign Application Priority Data (I) Mar. 21, 1997 (CH) ...... 695/97 (51) Int. Cl...... A01N 43/40; CO7D 401/04 (52) U.S. Cl...... 504/252; 504/246; 546/275.4; 546/276.1; 54.6/113; 54.6/115 (58) Field of Search ...... 546/275.4, 276.1; 504/252 (56) References Cited wherein U.S. PATENT DOCUMENTS W is a group 2,742,476 4/1956 Bernstein et al. . (W1) 2,809,971 10/1957 Bernstein et al. . 3,047,579 7/1962. Witman. 4,526,895 7/1985 Jarreau et al...... 514/341 5,032,165 7/1991 Miura et al...... 546/22 FOREIGN PATENT DOCUMENTS O 361 114 4/1990 (EP). (W2) WO 92/O2509 2/1992 (WO). WO 92/06962 4/1992 (WO). S(O) R, or WO95/33728 12/1995 (WO). WO 96/O1254 1/1996 (WO). 97/00246 1/1997 (WO). OTHER PUBLICATIONS (W3) Org. Synth. 4,828 (1963); idem. 3,619 (1955). B. Iddon and H. Suschitzky in “Polychloroaromatic Com pounds”, Editor H. Suschitzky, Plenum Press, London 1974, p. 197. Quart. Rev. 10, 395 (1956). J. Am. Chem. Soc. 85,958 (1963); idem. 73,3681 (1951); idem. 72, 4362 (1950). J. Am. Chem. 26, 428 (1961); idem. 35,2517 (1970); idem. wherein all variables are as defined in the Specification and 32, 4040 (1967); idem. 19, 1633 (1954); idem. 54, 4330 the pyrazoleN-oxides, agrochemically acceptable Salts and (1989). Stereisomers thereof useful as herbisdes. Tetrahedron 37, 187 (1981); idem. 1991, 7091. Org. Prep. Proced. Int. 9(1), 5-8 (1977). 6 Claims, No Drawings US 6,274,536 B1 Page 2

OTHER PUBLICATIONS “Methoden der Organischen Chemie” (Houben-Weyl), vol. J. Chem. Soc., Perkin Trans I 1976, 201; idem. 1987, 1159. E 8b, Georg Thieme Verlag Stuttgart, 1994, p. 399ff, idem. Liebigs Ann. Chem. 1978, 1491 (english language abstract vol. E 7B, Georg Thieme Verlag Stuttgart 1992, p. 286 ff also enclosed). Helv. Chim. Acta 73, 1679 (1990) (english language abstract (english language abstracts of each are enclosed). also enclosed). II Farmaco-Ed. Sc. 37, 22 (1982). Sov. Prog. Chem. (Engl. Transl.) 42, 65 (1976). J. Chem. Res. (Miniprint) II, 3368 (1986) (english language abstract also enclosed). * cited by examiner US 6,274,536 B1 1 2 PYRAZOLE DERVATIVES AS HERBICIDES Rs is hydrogen, halogen, C-C alkyl, C-Chaloalkyl, cyano, nitro, amino, NHC(O)-, NHC(S)-, This application is a 371 of PCT/EP98/01611 filed Mar. C-C alkylcarbonyl, C-C alkoxy carbonyl, 19, 1998. C-Chalo alkylcarbonyl, C-C alkenylcarbonyl, The present invention relates to novel, herbicidally active 5 C-C alkyl-CH(OH), OHC , HOC(O), CIC(O), Substituted pyridone derivatives, to a process for the prepa HON=CH-, C-C alkoxy-N=CH-, ration thereof, to compositions comprising those C-Chaloalkenylcarbonyl or C-C alkynylcarbonyl, compounds, and to the use thereof in the control of weeds, R is hydrogen, fluorine, chlorine, bromine or methyl, especially in crops of useful plants, for example, cereals, R is hydrogen, halogen, methyl, halomethyl, nitro, amino, maize, rice, cotton, Soybean, rape, Sorghum, Sugar cane, hydroxy, OHC-, HOC(O)-, cy an O, Sugar beet, Sunflowers, vegetables, plantation crops and C-C alkoxycarbonyl or halomethoxy, fodder plants, or in the inhibition of plant growth. Phenyl X is O, S, RN= or RON=; pyrazole compounds having herbicidal activity are known R is hydroxy, C-C alkoxy, Ca-Calkenyloxy, and are described, for example, in EP-A-0361114, U.S. Pat. C-C alky nyloxy, C-Chalo alkoxy, C-C- No. 5,032,165, WO 92,02509, WO 92,06962, WO haloalkenyl oxy, C-C alkoxy - C - Calkyl, 95/33728, WO 96/O1254 and WO 97/00246. 15 C-C alkenyloxy-C-C alkyl, C-C alkynyloxy Surprisingly, it has now been found that Substituted C-C alkyl, C-C alkoxy-C-Calkoxy-C-C alkyl, pyridono-pyrazole derivatives have excellent herbicidal and B-C-C alkoxy, R (R) N-, C-C alkyl, growth-inhibiting properties. C-C alkenyl, C-C alkynyl, C-Chaloalkyl, The present invention accordingly relates to compounds C - Chaloalkenyl, C - Cecy cloalkyl, of formula I 20 C-Chalocycloalkyl, B-C-C alkyl, OHC-, C-C alkylcarbonyl, C-C alkylcarbonyloxy, (I) C-Chalo alkylcarbonyl, C-C alkenylcarbonyl, R11 C-C alkoxy carbonyl, C-C alkyl-S(O)2-, C-Chaloalkyl-S(O) , (C-Calkyl)-N-N=CH-, R12 / \ W, 25 C - Calkyl N V D-CH-, O s X1 R13 O CH 3O wherein B-CH=N-, (CH) N-CH=N-, (C-C shy droxyalkyl)-CH-, (B- C-C hydroxyalkyl)-CH-, (B-C-Chaloalkyl)- W is a group CH-, (hydroxy-C-C alkyl)-O- or (B- (W1) 35 C-C hydroxyalkyl)-O-, R B is cyano, OHC-, HOC(O), C-C alkylcarbonyl, O n C-C alkoxycarbonyl, C-C alkenyloxycarbonyl, R2, C-C alkynyloxycarbonyl, benzyloxycarbonyl, benzy N 2-N loxycarbonyl mono- to tri-Substituted at the phenyl ring R1 40 by halogen, C-C alkyl or by C-Chaloalkyl, (W2) benzylthio-C(O), benzylthio-C(O)- mono- to tri Substituted at the phenyl ring by halogen, C-C alkyl or R by C-Chaloalkyl, C-Chaloalkoxycarbonyl, S(O)n-R4 or C-Calkylthio-C(O), R(R)NC(O), phenyl, phe 45 nyl mono- to tri-Substituted by halogen, C-C alkyl or by N -N C-Chaloalkyl, C-C-alkyl-S(O)-, C-C alkyl-S R1 (O)-, C-Calkylthio, C-C cycloalkyl, C-Calkoxy, (W3) C-Calkenylthio or C-Calkynylthio; R Ro is hydrogen, C-Calkyl, C-Calkenyl, C-Calkynyl, R5; 50 C2 - Chalo alkyl, cyano, R - (R) N-, C-C alkoxycarbonyl, C-C alkenyloxycarbonyl, C-C alkynyloxycarbonyl, C-Chaloalkoxycarbonyl, 2-N N OHC , C-Calkylcarbonyl, C-Chaloalkylcarbonyl, R1 C-Calkyl-S(O)-, C-Chaloalkyl-S(O)-, phenyl, 55 phenyl mono- to tri-Substituted by halogen, C-C alkyl or R is hydrogen, C-C alkyl, C-Chaloalkyl, cyano by C-Chaloalkyl, phenyl-C-C alkyl, or phenyl C-C alkyl, C- or C-alkenyl, C- or C-haloalkenyl, C C-Calkyl mono- to tri-Substituted at the phenyl ring by or C-alkynyl or C-Cacycloalkyl, halogen, C-C alkyl or by C-Chaloalkyl, R is hydrogen, C-C alkyl, C-Chaloalkyl, C-Calkenyl, R and R are each independently hydrogen, C-C alkyl, C-Chaloalkenyl, C-C alkynyl, C-C alkyl-S(O)- 60 C-C alkenyl, C-C alkynyl, C-C-haloalkyl, or C-Chaloalkyl-S(O) ; C-Chaloalkenyl, C-C cycloalkyl, C-Calkoxy R is hydrogen, C-C alkyl, C-Chaloalkyl, C-Calkenyl, C-C alkyl, OHC-, C-C alkyl carbonyl, C-Chaloalkenyl, C-C alkynyl, halogen, cyano, NHC C-Chaloalkylcarbonyl, C-C alkyl-S(O)- or (S)-, nitro or amino; C-Chaloalkyl-S(O)-; n is 0, 1 or 2, 65 R2 and R2 are each independently as defined for R; R is hydrogen, C-C alkyl, C-Chaloalkyl, C-Calkenyl, Rs is hydrogen, C-Calkyl, C-Calkenyl, C-Calkynyl, C-Chaloalkenyl, C-Calkynyl or C-Cacycloalkyl, C-Chaloalkyl, C-Chaloalkenyl, C-C alkoxy US 6,274,536 B1 3 4 C-C alkyl, benzyl, C-C alkyl-S(O)2- or and also to the pyrazole N-oxides, agrochemically accept C-Chaloalkyl-S(O)-; able Salts and Stereoisomers of those compounds of formula R and R27 are each independently hydrogen, C-C alkyl, I. C-C alkenyl, C-C alkynyl, C-Chalo alkyl, In the above definitions, halogen is to be understood as C-Chaloalkenyl, phenyl, phenyl mono- to tri meaning iodine or, preferably, fluorine, chlorine or bromine. Substituted by halogen, C-C alkyl or by C-Chaloalkyl, The alkyl, alkenyl and alkynyl groups in the Substituent benzyl, or benzyl mono- to tri-substituted at the phenyl definitions may be Straight-chain or branched, this applying ring by halogen, C-C alkyl or by C-Chaloalkyl, or also to the alkyl, alkenyl and alkynyl moiety of the X and R together form a group =N-Y- wherein Y is alkylcarbonyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, bonded to the ring nitrogen atom; alkoxyalkoxyalkyl, alkylthio, alkylthio-C(O)-, alkylsulfonyl, alkylaminocarbonyl, dialkylaminocarbonyl, B-alkyl and HOC(O)-alkyl groups. Alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, Sec butyl, isobutyl, tert-butyl and the various isomers of pentyl and hexyl. Methyl, ethyl, n-propyl, isopropyl and n-butyl are 15 preferred. There may be mentioned as examples of alkenyl radicals Vinyl, allyl, methallyl, 1-methylvinyl, but-2-en-1-yl, pente nyl and 2-hexenyl, with preference being given to alkenyl radicals having a chain length of from 3 to Scarbon atoms. There may be mentioned as examples of alkynyl radicals ethynyl, propargyl, 1-methylpropargyl, 3-butynyl, but-2-yn 1-yl, 2-methylbutyn-2-yl, but-3-yn-2-yl, 1-pentynyl, pent-4- yn-1-yl and 2-hexynyl, with preference being given to alkynyl radicals having a chain length of from 2 to 4 carbon or -C(R)=CH-C(S)-, the right-hand end of the 25 atOmS. bridge members in the above definitions of Y being Suitable haloalkyl radicals are alkyl groups that are mono bonded to the ring nitrogen atom; R is hydrogen, C-C alkyl or C-Chaloalkyl, or poly-Substituted, especially mono- to tri-Substituted, by R is hydrogen, C-Calkyl, C-Calkenyl, C-C alkynyl, halogen, halogen being in particular iodine or especially C-Chaloalkyl, C-Chaloalkenyl, cyano-C-Calkyl, fluorine, chlorine or bromine, for example fluoromethyl, hydroxy-C-C alkyl, C-C alkoxy-C-C alkyl, difluoromethyl, trifluoromethyl, chloromethyl, C-C alkenyloxy-C-C alkyl, C-C alkynyloxy dichloromethyl, trichloromethyl, 2-fluoroethyl, 2,2- C-C alkyl, C-C alkylcarbonyloxy-C-C alkyl, difluoroethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2- C-Chaloalkylcarbonyloxy-C-Calkyl, carboxyl, trifluoroethyl and 2,2,2-trichloroethyl. C-C alkoxycarbonyl, C-C alkenyloxycarbonyl, Suitable haloalkenyl radicals are alkenyl groups mono- or C-C alkynyloxycarbonyl, C-Chaloalkoxycarbonyl, 35 poly-Substituted by halogen, halogen being in particular C-C cycloalkoxy carbonyl, C-C alkoxy bromine, iodine or especially fluorine or chlorine, for C-C alkoxycarbonyl, C-C alkyl-NHC(O)-, example 2- or 3-fluoropropenyl, 2- or 3-chloropropenyl, 2 (C-C alkyl)-NC(O)-, Ca-Calkenyl-NHC(O)-, or 3-bromoprope nyl, 2,3,3-trifluoroprope nyl, 2,3,3- C-C alkyl-(C-C-alkenyl)NC(O)-, Ca-Calkynyl trichloropropenyl, 4,4,4-trifluorobut-2-en-1-yl and 4,4,4- NHC(O)-, aminocarbonyl, C-Calkylthio-C(O)-, 40 trichlorobut-2-en-1-yl. Of the alkenyl radicals mono-, di- or C-C-alkenylthio-C(O), C-C alkynylthio-C(O), tri-Substituted by halogen, preference is given to those benzyloxycarbonyl, benzyloxycarbonyl mono- to tri having a chain length of 3 or 4 carbon atoms. The alkenyl Substituted at the phenyl ring by halogen, C-C alkyl or groups may be Substituted by halogen at Saturated or unsat by C-Chaloalkyl, phenoxycarbonyl, C-C alkyl urated carbon atoms. S(O)NHC(O), C-Calkyl-S(O)(C-Calkenyl)N- 45 Alkylsulfonyl is, for example, methylsulfonyl, C(O)-, C - Chalo alkyl-S(O)NHC(O)-, ethylsulfonyl, propylsulfonyl, isopropyisulfonyl, HON=CH-, C-C alkoxy-N=CH-, C-C alkenyloxy-N=CH-, Ca-Calky nyloxy n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert N=CH-, HOC(O)- C - Calkyl, butylsulfonyl or an isomer of pentylsulfonyl or hexylsulfo C-C alko Xy carbonyl-C-C alkyl, nyl; preferably methylsulfonyl or ethylsulfonyl. C - Coalkenyl oxy carbonyl - C - C alkyl, 50 Haloalkylsulfonyl is, for example, fluoromethylsulfonyl, C-C alky nyloxycarbonyl - C - C alkyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, C-Calkylcarbonyl, ClC(O), H2NC(S)-, OHC , chloromethylsulfonyl, trichloromethylsulfonyl, cyano, phenyl, phenyl mono- to tri-Substituted by 2-fluoroethylsulfonyl, 2.2.2-trifluoroethylsulfonyl or 2.2.2- halogen, C-C alkyl or by C-C-haloalkyl, phenyl trichloroethylsulfonyl. C-C alkyl, or phenyl-C-C alkyl mono- to tri 55 Alkenylsulfonyl is, for example, allyisulfonyl, Substituted at the phenyl ring by halogen, C-C alkyl or methallylsulfonyl, but-2-en-1-ylsulfonyl, pentenylsulfonyl by C-Chaloalkyl; or 2-hexenylsulfonyl. X is O, S, RN= or RON=; Haloalkenylsulfonyl is, for example, 2- or R is hydrogen, C-Calkyl, C-Calkenyl, C-Calkynyl, 3-fluoropropenylsulfonyl, 2- or 3-chloropropenylsulfonyl, C-Chaloalkyl, C-Chaloalkenyl, C-Cacycloalkyl, 60 2- or 3-bromo prope nylsulfonyl, 2,3,3- C-C alkylcarbonyl, C-Chaloalkylcarbonyl, trifluoropropenylsulfonyl, 2,3,3-trichloropropenylsulfonyl, C-Calkyl-S(O)- or B-C-C-alkyl, 4,4,4-trifluorobut-2-en-1-ylsulfonyl or 4,4,4-trichlorobut-2- B is cyano, HOC(O)-, C-C alkoxycarbonyl, en-1-ylsulfonyl. C-Calkylcarbonyl or C-C alkoxy; and Cyanoalkyl is, for example, cyanomethyl, cyanoethyl, R is as defined for R or is halogen, C-Calkoxy, 65 cyanoeth-1-yl or cyanopropyl. Hydroxyalkyl is, for C-Calkenyloxy, C-Chaloalkoxy, C-Calkylthio, example, hydroxy methyl, 2-hydroxyethyl or C-Calkyl-S(O)- or C-Calkyl-S(O), 3-hydroxypropyl. US 6,274,536 B1 S 6 Alkylamino is, for example, methylamino, ethylamino or trifluoropropenyloxy, 2,3,3-trichloropropenyloxy, 4,4,4- an isomer of propyl- or butyl-amino. trifluoro-but-2-en-1-yloxy and 4,4,4-trichlorobut-2-en-1- Dialkylamino is, for example, dimethylamino, diethy yloxy. lamino or an isomer of dipropyl- or dibutyl-amino. The cycloalkyl radicals Suitable as Substituents are, for Alkenylamino is, for example, allylamino, methally example, cyclopropyl, cyclobutyl, cyclopentyl and cyclo lamino or but-2-en-1-ylamino. Alkynylamino is, for example, propargylamino or hexyl. 1-methylpropargylamino. The cycloalkoxycarbonyl radicals Suitable as Substituents Haloalkylamino is, for example, chloroethylamino, trif are, for example, cycloprop oxy carbonyl, luoroethylamino or 3-chloropropylamino. cyclobutoxycarbonyl, cyclopentyloxycarbonyl and cyclo Di(haloalkyl)amino is, for example, di(2-chloroethyl) hexyloxycarbonyl. amino. The halocycloalkyl radicals Suitable as Substituents are, Alkylcarbonyl is especially acetyl or propionyl. for example, mono-, di- or up to perhalogenated cycloalkyl Halo alkylcarbonyl is especially trifluoroacetyl, radicals, for example, fluorocyclopropyl, chlorocyclopropyl, trichloroacetyl, 3,3,3-trifluoropropionyl or 3,3,3- 15 bromocyclopropyl, 2,2-dichlorocyclopropyl, 2,2- trichloropropionyl. difluorocyclopropyl, 2,2-dibromocyclopropyl, 2-fluoro-2- Alkenylcarbonyl is especially vinylcarbonyl, chlorocyclopropyl, 2-chloro-2-bromocyclopropyl, 2,2,3,3- allylcarbonyl, methallylcarbonyl, but-2-en-1-yl-carbonyl, tetrafluorocyclopropyl, 2,2,3,3-tetrachlorocyclopropyl, pentenylcarbonyl or 2-hexenylcarbonyl. pentafluorocyclopropyl, fluorocyclobutyl, chlorocyclobutyl, Alkynylcarbonyl is especially acetylenecarbonyl, 2,2-difluorocyclobutyl, 2,2,3,3-tetrafluorocyclobutyl, 2,2,3- propargylcarbonyl, 1-methylpropargylcarbonyl, trifluoro-3-chlorocyclobuty 1, 2,2-dichloro-3,3- 3-butynylcarbonyl, but-2-yn-1-ylcarbonyl or pent-4-yn-1- difluorocyclobutyl, fluorocyclopentyl, difluorocyclopentyl, ylcarbonyl. chlorocyclopentyl, perfluorocyclopentyl, chlorocyclohexyl Alkoxy is, for example, methoxy, ethoxy, n-propoxy, and pentachlorocyclohexyl. isopropoxy, n-butoxy, isobutoxy, Sec-butoxy, tert-butoxy or 25 Alkylthio is, for example, methylthio, ethylthio, propy an isomer of pentyloxy or hexyloxy. lthio or butylthio or a branched isomer thereof. Alkenyloxy is, for example, allyloxy, methallyloxy or Phenyl or benzyl per Se, or as part of a Substituent, Such but-2-en-1-yloxy. as, for example, phenoxycarbonyl or benzyloxycarbonyl, Alky nyloxy is, for example, propargyloxy or may be unsubstituted or Substituted, in which case the 1-methylpropargyloxy. Substituents may be in the ortho-, meta- or para-position. Alkoxyalkyl is, for example, methoxymethyl, Substituents are, for example, C-C alkyl, C-C alkoxy, methoxyethyl, ethoxy methyl, ethoxyethyl, halogen or C-Chaloalkyl. n-propoxymethyl, n-propoxyethyl, isopropoxymethyl or isopropoxyethyl. Corresponding meanings may also be given to the Sub Stituents in combined definitions, Such as, for example, in Alkenyloxyalkyl is, for example, allyloxyalkyl, methal 35 alkyl-S(O), alkoxy-N=CH-, (alkyl)-N-C(O) , (alkyl) lyloxyalkyl or but-2-en-1-yloxyalkyl. N-N=CH-, alkenyl-NHC(O), alkyl(alkenyl)N-C Alkynyloxyalkyl is, for example, propargyloxyalkyl or (O)-, alkynyl-NHC(O)-, alkylcarbonyloxyalkyl, 1-methylpropargyioxyalkyl. alko Xy carbonylalkyl, halo alko Xy carbonyl, Alkoxycarbonyl is, for example, methoxycarbonyl, haloalkylcarbonyloxyalkyl, haloalkenylcarbonyl, alkyl-S ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl 40 or n-butoxycarbonyl, preferably methoxycarbonyl or (O)-NHC(O), haloalkyl-S(O)NHC(O), B1-alkoxy ethoxycarbonyl. and B-alkyl. Alkenyloxycarbonyl is, for example, allyloxycarbonyl, In the definition of R., (C-C-hydroxyalkyl)-CH-, methallyloxycarbonyl, but-2-en-1-yl-oxycarbonyl, penteny (B-C-C-hydroxyalkyl)-CH- and (B-C-C- loxycarbonyl or 2-hexenyloxycarbonyl. 45 haloalkyl)-CH-signify that only the C1-C5 alkyl moiety Alky nyloxy carbonyl iS, for example, is hydroxylated or halogenated, that is to Say, the methylene propargyloxycarbonyl, 3-butynyloxycarbonyl, but-2-yn-1- group is not hydroxylated or halogenated. yloxycarbonyl or 2-methylbutyn-2-yloxycarbonyl. In the definition of X and R together, a group Alkoxyalko Xy carbonyl iS, for example, =N-Y- wherein Y is bonded to the ring nitrogen atom is methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 50 to be understood as meaning one of the following bicyclic ethoxyethoxycarbonyl, propoxy methoxycarbonyl, ring Systems of formula I: propoxyethoxycarbonyl, propoxypropoxycarbonyl or butoxyethoxycarbonyl. (I) Haloalkoxy is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 55 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy or 2.2.2-trichloroethoxy. R12 Of the alkenyl radicals mono-, di- or tri-substituted by N halogen, preference is given to those having a chain length 4. of 3 or 4 carbon atoms. The alkenyloxy groups may be 60 N;/ Substituted by halogen at Saturated or unsaturated carbon atOmS. Suitable haloalkenyloxy radicals are alkenyloxy groups In the definition of Y, it is always the right-hand end of the mono- or poly-Substituted by halogen, halogen being in bridge member that is bonded to the ring nitrogen atom, as particular bromine, iodine or especially fluorine or chlorine, 65 is illustrated, for example where Y is -C(R)(R)- for example 2- or 3-fluoroprope nyloxy, 2- or CH-, -C(R)(R)-O-and-C(R)=CH-, in the 3-chloropropenyloxy, 2- or 3-bromopropenyloxy, 2,3,3- following bicyclic ring structures: US 6,274,536 B1 7 8 ides of lithium, Sodium, potassium, magnesium and calcium, R11 R11 but especially to the hydroxides of Sodium and potassium. Examples of amines Suitable for ammonium Salt forma R12 / \ W, R12 / \ W and tion include ammonia as well as primary, Secondary and tertiary C1-Calkylamines, C-Chydroxyalkylamines and N N C-C-alkoxyalkylamines, for example methylamine, { -n. { -h ethylamine, n-propylamine, isopropylamine, the four iso C C / \ / \ mers of butylamine, n-amylamine, isoamylamine, R31 R32 R31 R32 hexylamine, heptylamine, octylamine, nonylamine, R11 de cylamine, pentadecylamine, hexadecylamine, heptadecylamine, octadecylamine, methylethylamine, methyl is op ropylamine, methyl he Xyla mine, R12 / \ W. methylnonylamine, methylpent a de cylamine, 15 N methyloctadecylamine, ethylbutylamine, ethylheptylamine, ethyloctylamine, heXylheptylamine, heXyloctylamine, { 2n dimethylamine, diethylamine, di-n-propylamine, f diisopropylamine, di-n-butylamine, di-n-amylamine, R34 diisoamylamine, dihe Xylamine, diheptylamine, dioctylamine, ethanolamine, n-propanolamine, In the definitions of cyanoalkyl, alkylcarbonyl, is op rop a nola mine, N,N- die than olamine, alkenylcarbonyl, haloalkenylcarbonyl, alkynylcarbonyl, N-ethylpropanolamine, N-butylethanolamine, allylamine, alkoxycarbonyl, alkylthiocarbonyl and haloalkylcarbonyl, n-bute nyl-2-amine, n-pentenyl-2-amine, 2,3- the upper and lower limits of the number of carbon atoms 25 given in each case do not include the cyano or carbonyl dimethylbutenyl-2-amine, dibutenyl-2-amine, n-hexenyl-2- carbon atom, as the case may be. amine, propylenediamine, trimethylamine, triethylamine, The compounds of formula I may, in respect of the group tri-n-propylamine, triisopropylamine, tri-n-butylamine, W (W1 to W3), be present in the form of mixtures consisting triisobutylamine, tri-Sec-butylamine, tri-n-amylamine, of the isomers substituted in the 3- and 5-positions of the methoxyethylamine and ethoxyethylamine; heterocyclic pyrazole ring by the pyridone group (pyridone), for example amines, for example pyridine, quinoline, isoquinoline, in the form of regioisomers IW1a and IW1b morpholine, thiomorpholine, piperidine, pyrrollidine, indoline, quinuclidine and azepine, primary arylamines, for (IW1a) example anilines, methoxyanilines, ethoxyanilines, o-, m pyridone R3 35 and p-toluidines, phenylenediamines, benzidines, naphthy 3 4 lamines and o-, m- and p-chloroanilines, especially 2N.W \ 5 triethylamine, isopropylamine and diisopropylamine. N OR2 The Salts of compounds of formula I having basic groups, 40 especially having basic pyrazolyl rings, or of derivatives R1 having amino groups, for example alkylamino and dialky and lamino groups, in the definition of R, Rs or R are, for (IW1b) example, Salts with inorganic or organic acids, for example pyridone R3 hydrohalic acids, Such as hydrofluoric acid, hydrochloric 5 4 45 acid, hydrobromic acid or hydriodic acid, and also Sulfuric N 2 3 acid, phosphoric acid, nitric acid, and organic acids, Such as R1 N OR2 acetic acid, trifluoroacetic acid, trichloroacetic acid, propi 2 onic acid, glycolic acid, thiocyanic acid, citric acid, benzoic 50 acid, oxalic acid, formic acid, benzenesulfonic acid, for the group W1. The ratio of isomers may vary as a p-tolueneSulfonic acid and methaneSulfonic acid. function of the method of synthesis. The possible presence of at least one asymmetrical carbon The invention relates also to the Salts that the compounds atom in the compounds of formula I, for example in the of formula I having azide hydrogen, especially the deriva Substituent R, where R is a branched alkyl, alkenyl, tives having carboxylic acid groups and Sulfonamide groups 55 haloalkyl or alkoxyalkyl group or where R is (B- (for example carboxy-Substituted alkyl, alkoxy and pyridone C-Chydroxyalkyl)-CH2- wherein, for example, B is groups (R) and alkyl-S(O)NH- and haloalkyl-S(O) C-C alkyl-S(O)-, means that the compounds may occur NH- groups), are capable of forming with bases. Those in the form of optically active Single isomers or in the form Salts are, for example, alkali metal Salts, for example Sodium of racemic mixtures. In the present invention, “compounds and potassium Salts, alkaline earth metal Salts, for example 60 calcium and magnesium Salts, ammonium Salts, that is to Say of formula I is to be understood as including both the pure unsubstituted ammonium Salts and mono- or poly optical antipodes and the racemates or diastereoisomers. Substituted ammonium Salts, for example triethylammonium When an aliphatic C=C or C=N-O double bond (syn/ and methylammonium Salts, or Salts with other organic anti) is present, geometric isomerism may occur. The inven bases. 65 tion relates to those isomerS also. Of the alkali metal and alkaline earth metal hydroxides as Preferred compounds of formula I correspond to formula Salt farmers, attention is drawn, for example, to the hydrox 1a US 6,274,536 B1 10

(Ia) (I) R11 R11 R12 / \ Wa, R12 / \ W N N V V X1 R13 X1 R13 wherein wherein R, R and W are as defined for formula I; X is O or S.; R is C-Calkoxy-C-Calkyl, C-C alkoxy Wa is a group C-Calkoxy-C-Calkyl, C-C alkyl, C-Calkenyl, (W1a) C-C alkynyl, C-Chaloalkyl, C-Chaloalkenyl, R 15 O C-C cycloalkyl, C-Chalocycloalkyl, B-C-Calkyl, NS YR, C -Calkyl N -e N YR OD-CH-, 6 CH s (W2a) R S(O-)n-R or (C-C shy droxyalkyl)-CH-, (B- C-C hydroxyalkyl)-CH- or (B-C-Chaloalkyl)- 25 N 1- in CH-; and B is as defined for formula I, is carried out N R1 analogously to known processes and comprises oxidising a (W3a) compound of formula III R3 Rs; and (III) s R11 N - N -in R1 R12 \ / W, N R, R2, R., R., RS, R, R2, Ra, X and n are as defined 35 for formula I. Of the compounds of formula Ia, preference is given to those wherein in the group Wa R is C-C alkyl for example with hydrogen peroxide-urea adduct in the or halogen; and R is methyl or ethyl. presence of carboxylic acids and/or carboxylic acid Special preference is given to compounds of formula Ia anhydrides, organic peracids or perSulfonic acid (Caro's wherein R is methyl, halomethyl, chlorine or bromine. Of 40 those, the compounds wherein Wa is a group W1a or W2a acid) in a Suitable Solvent, to form a compound of formula are especially important. V Also especially important are compounds of formula 1 a wherein Wa is the group W3a; and Rs is C- or (V) C-halomethyl, cyano or H2NC(S)-. Also particularly important are compounds of formula 1 a 45 wherein Wa is the group W1a; R is C-C alkyl; R is C.- or C-haloalkyl, R is chlorine, bromine, methyl or halom ethyl; R is fluorine, chlorine or bromine; and R is halogen, methyl or halomethyl. Of those, compounds in which R is methyl or ethyl; and R is difluoromethyl are 50 more especially important. Special preference is given also to compounds of formula 1a wherein Wa is the group W2a; R is C-C alkyl; R is and Subsequently rearranging that compound in an inert methyl or ethyl, R is chlorine, bromine or methyl, R, is Solvent in the presence of an anhydride or in the presence of fluorine, chlorine or bromine; and R2 is halogen, methyl or 55 antimony pentachloride to yield, after aqueous working up, halomethyl. Of those compounds, those wherein R is a compound of formula II methyl or ethyl, and R is methyl are more especially preferred. Particularly important compounds of formula 1 a (II) are those wherein Wa is the group W3a; R is C-C alkyl; Rs is C- or C-haloalkyl, cyano, HNC(S)- or CHC 60 (O)-; R is chlorine, bromine, methyl or halomethyl; R is fluorine, chlorine or bromine; and R2 is halogen, methyl or halomethyl. Of those, especially compounds wherein R is methyl or ethyl, and Rs is halomethyl or cyano are more especially important. 65 The process according to the invention for the preparation of a compound of formula I US 6,274,536 B1 11 12 the radicals R, R2 and W in the compounds of formulae 11, II and V being as defined above, and then alkylating that (III) compound in the presence of an inert Solvent and a base with R11 a compound of formula VI

R-L (VI), R12 \ ( W wherein R is as defined above and L is a leaving group, preferably chlorine, bromine, iodine, CHSOO- or to yield a compound of formula V

(V)

15 to form the isomeric compounds of formulae I and IV

(I) R11 R-( Y-w chlorinating or brominating that compound to form a com N pound of formula VIII V 25 X1 R13 (VIII) and R11 (IV) R11 R12 \ 4 W, V R12 \ / W, Hal O N

OR 13 35 the radicals R, R2 and W in the compounds of formulae III, V and VIII being as defined above and Hal in the wherein R, R2, R1 and W are as defined above and X is compound of formula VIII being chlorine or bromine, O, and Subsequently, where appropriate after Separating off Subsequently converting the compound of formula VIII with the compound of formula I, functionalising the pyridone 40 a Suitable Sulfur reagent, for example thiourea, Sodium group thereof according to the definition of X and R, if hydrogen sulfide (NaSH) or phosphorus pentasulfide (PS), desired, for example, converting it with the aid of a Suitable in the presence of a Solvent into a compound of formula Ic Sulfur reagent into the corresponding pyridinethione deriva tive (X=S) (Reaction Scheme 1). (Ic) The process according to the invention for the preparation 45 of a compound of formula I

(I) R11 50 R12 / \ W, N V and reacting that compound in the presence of a Solvent and X1 R13 55 a base with a compound of formula XI wherein R, R and W are as defined for formula I; X is R-L (XI), S; R is hydroxy, C-C alkoxy, C-Calkenyloxy, 60 C-C alkynyloxy, C-Chaloalkoxy, C-Chaloalkenyloxy, wherein R is C-Calkyl, C-Calkenyl, C-Calkynyl, B - C - Coalko Xy, C-C alkyl carbonyl, C-Chaloalkyl, C-Chaloalkenyl, B-C-C alkyl or C-C alkylcarbonyloxy, C-Chaloalkylcarbonyl, C-C alkylcarbonyl; B is as defined above; and L is a C-Calkenylcarbonyl or C-Calkoxycarbonyl; and B is leaving group (Reaction Scheme 2). as defined for formula I, is carried out analogously to known 65 processes and comprises first of all oxidising a compound of The process according to the invention for the preparation formula III of a compound of formula I US 6,274,536 B1 13 -continued (I) R11 R11 R11 / \ 5 R12 / \ W + R12 \ / W R12 W N N N V V X1 R13 OR13 X1 R13 I (X1 = O) IV 1O C.S. Lawesson's reagent wherein R, R2, R1 and W are as defined for formula I and (Reaction Scheme 3) XI is S is carried out analogously to known processes and comprises treating a compound of formula I R11 15 (I) R11 N V X1 R13 R12 / \ W 2O I (X1 = S) N V X1 R13 The pyridine N-oxides of formula V (Reaction Scheme 1) can be prepared according to known methods (e.g. Org. Synth. 4, 828 (1963); ibid. 3, 619 (1955); U.S. Pat. No. wherein R, R, R and W are as defined above and X is 25 3,047,579; and B. Iddon and H. Suschitzky in “Polychloro aromatic Compounds”, Editor H. Suschitzky, Plenum Press, O, with a Sulfur reagent in an inert Solvent. London 1974, page 197), advantageously by reaction of a The preparation of compounds of formula I wherein X is pyridine derivative of formula III with an oxidising agent, O or S; and R is C-C alkoxy-C-C alkyl, C-C alkoxy Such as, for example, an organic peracid, for example C-Calkoxy-C-Calkyl, C-C alkyl, C-Calkenyl, 30 m-chloroperbenzoic acid (MCPBA), peracetic acid or per C-C alkynyl, C-Chaloalkyl, C-Chaloalkenyl, trifluoroacetic acid, or aqueous hydrogen peroxide Solution C-C cycloalkyl, C-Chalocycloalkyl, B-C-Calkyl, or hydrogen peroxide-urea adduct together with a carboxylic acid and/or a carboxylic acid anhydride, or an inorganic C-Calkyl peracid, for example pertungstic acid. Solvents Suitable for D-CH- s (A- 1 3 s 35 that reaction are, for example, water, organic acids, for O CH example acetic acid and trifluoroacetic acid, halogenated hydrocarbons, for example dichloromethane and 1,2- dichloroethane, esters, for example ethyl acetate, ethers, for (C-C hydroxyalkyl)-CH2-, (B- example tetrahydrofuran and dioxane, or mixtures of those C-C hydroxyalkyl)-CH- or (B-C-Chaloalkyl)- 40 Solvents. The reaction temperatures are generally in the CH-, and B is as defined for formula I is illustrated in the range from -20° C. to 100 C., depending on the solvent or following Reaction Scheme 1. mixture of Solvents used. The 6-hydroxypyridine derivatives of formula II can be Reaction Scheme 1 prepared according to known methods (e.g. Quart. Rev. 10, o 45 395 (1956); J. Am. Chem. Soc. 85,958 (1963); and J. Org. R11 Chem. 26,428 (1961)), advantageously by rearrangement of the pyridine N-oxides of formula V in the presence of an o O): C.S. H2O'NHC(O)NH2 anhydride, for example acetic anhydride, trifluoroacetic R12 \ / W + carboxylic acidsfanhydrides, anhydride or methaneSulfonic anhydride, in a Suitable inert N solvent 50 Solvent, Such as, for example, a halogenated hydrocarbon, III for example dichloromethane or 1,2-dichloroethane, an R11 amide, for example N,N-dimethylformamide or 1-methyl 2-pyrrolidone (NMP), and, where appropriate, in the pres o 1) anhydride, lvent ence of Sodium acetate. The reaction temperatures are gen R12 / W --> 2) i; 55 erally in the range from -30° C. to 80 C. \ 4 The 6-O-acyl- or 6-O-sulfonyl-pyridines formed first can \ readily be hydrolysed, by aqueous working up of the reac O tion mixture, to form the desired 6-hydroxypyridines of V formula II. Analogously to Tetrahedron 37, 187 (1981), as a R11 60 further variant it is possible to use antimony pentachloride in o R-L the above rearrangement reaction. VI The Subsequent alkylation may be carried out according R12 / W base, solvent \ N to known methods (e.g. Org. Prep. Proced. Int. 9, 5 (1977); J. Org. Chem. 35, 2517 (1970); ibid. 32, 4040 (1967); and OH 65 Tetrahedron Lett. 36, 8917 (1995) as well as Preparation Examples P20 and P21), advantageously using an alkylation reagent of formula VI. The alkylation usually results in an US 6,274,536 B1 15 16 isomeric mixture consisting of the compounds of formulae -continued I (N-alkylation) and IV (O-alkylation). R11 Suitable Solvents are, for example, alcohols, for example methanol, ethanol and isopropanol, amides, for example Sulfur reagent e.g. N,N-dimethylformamide (DMF) and 1-methyl-2- 5 R12 \ W H2S,Her NaHS and NH2C(S)NH2, pyrrolidone (NMP), Sulfoxides, for example dimethyl sul 4 solvent foxide (DMSO), and sulfones, for example sulfolan, or Hal O mixtures of the above Solvents with water, ethers, for VIII (Hal = Clor Br example diethyl ether, tert-butyl methyl ether, dimethoxy R11 ethane (DME), dioxane and tetrahydrofuran (THF), esters, for example ethyl acetate, ketones, for example acetone and / \ R14 XIL, base, methyl ethyl ketone, and hydrocarbons, for example R12 W solvent n-hexane, toluene and Xylenes. N V Suitable bases are organic and inorganic bases, for 15 S OH example alkali metal alcoholates, for example Sodium Ic methanolate, Sodium ethanolate and potassium tert R11 butanolate, trialkylammonium hydroxides, trialkylammo nium halides, for example triethylammonium iodide, alkali metal and alkaline earth metal hydrides, for example Sodium N hydride together with lithium bromide (2 equivalents), alkali V metal carbonates, for example potassium carbonate, alkali X1 R13 metal hydroxides, for example Sodium and potassium hydroxide, and also caesium fluoride. 25 The reaction temperatures for the alkylation are in the The procedure for the preparation of pyridine N-oxides of range from -20° C. to the reflux temperature of the solvent formula V (Reaction Scheme 2) is analogous to that indi used, preferably from 0° C. to 50° C. The isomers of cated under Reaction Scheme 1. formulae I and IV can readily be separated by means of Silica The pyridine N-oxides of formula V can be converted into gel chromatography or fractional crystallisation. the corresponding 6-chloro- or 6-bromo-pyridine derivatives Optionally, the desired pyridone derivative of formula I of formula VIII analogously to known processes (e.g. Het Separated from the Secondary product of formula IV can erocycles 30,875 (1990); Can. J. Chem. 31, 457 (1953); and readily be converted into the corresponding pyridinethione J. Org. Chem. 19, 1633 (1954)), advantageously using a derivative (X=S) according to known methods (e.g. Bull. halogenating agent, for example phosphorus oxychloride, 35 phosphorus oxybromide, sulfuryl chloride, thionyl chloride Soc. Chim. Fr. 1953, 1001; and J. Am. Chem. Soc. 73,3681 or phosphorus pentachloride in phosphorus oxychloride. (1951)), for example with the aid of a suitable sulfur reagent, The halogenation can generally be carried out at tempera for example Lawesson's reagent or phosphorus pentasulfide tures of from 20° C. to 100° C. in an inert Solvent, Such as, for example, a Xylene, pyridine The reaction of the halopyridine N-oxides of formula VII or Sulfolan. The reaction temperatures are generally in the to form the compound of formula Ic can be effected analo range from 20° C. to the boiling temperature of the solvent 40 gously to known processes (e.g. U.S. Pat. No. 2,742,476, used. U.S. Pat. No. 2,809,971, J. Am. Chem. Soc. 72,4362 (1950) The preparation of compounds of formula I wherein X is and J. Chem. Soc. 1939, 1858), advantageously using a S; and R is hydroxy, C-C alkoxy, C-Calkenyloxy, Suitable Sulfur reagent, Such as, for example, hydrogen C-C alkynyloxy, C-Chaloalkoxy, C-Chaloalkenyloxy, Sulfide, Sodium hydrogen Sulfide or thiourea, in a Solvent, B - C - Coalko Xy, C-C alkyl carbonyl, 45 Such as, for example, water, an alcohol, for example ethanol, C-C alkylcarbonyloxy, C-Chaloalkylcarbonyl, or a water/alcohol mixture, or an amide, for example N,N- C-Calkenylcarbonyl or C-Calkoxycarbonyl; and B is dimethylformamide (DMF) or NMP. The reaction is gener as defined for formula I is illustrated in the following ally carried out at temperatures of from -10° C. to 100 C. Reaction Scheme 2. The reaction of the compound of formula Ic with the 50 reactive reagent of formula XI, wherein L is a leaving group, Such as, for example, halogen, for example chlorine, bro Reaction Scheme 2 mine or iodine, R11

O): e.g. H2O2NHC(O)NH2 R12 \ / + carboxylic acidsfanhydrides, CHSOO-, al-K)-oo N solvent III or, in the case where R is C-C alkylcarbonyl and there is R11 60 used as reactive reagent of formula XI the corresponding acid anhydride, C-C alkylcarbonyloxy, can be carried out halogenation e.g. He analogously to known processes (e.g. Tetrahedron Lett. 31, R12 \ / W Pool, or poB 1965 (1990); Tetrahedron 1991, 7091; and J. Org. Chem. 54, N+ 4330 (1989)). Advantageously, equimolar amounts of com O 65 pound of formula Ic and reactive reagent of formula XI are reacted at temperatures of from O C. to 100° C. in the presence of a Solvent and a base. US 6,274,536 B1 17 18 Suitable Solvents include the familiar inert organic Xylene or pyridine, a halogenated aromatic hydrocarbon, for Solvents, Such as, for example, chlorinated hydrocarbons, for example dichlorobenzene, or an amide, for example DMF or example dichloromethane, aromatic hydrocarbons, for NMP. The reaction temperatures are generally in the range example benzene, toluene and pyridine, ethers, for example dioxane and DME, amides, for example N,N- from 20° C. to 200 C. depending on the solvent used. dimethylformamide and NMP, and sulfoxides, for example The compounds lying within the Scope of formula I DMSO. Suitable bases include the known inorganic and wherein X and R together form a group =N-Y- and organic bases, Such as, for example, alkali metal and tri Y is, for example, a bridge member-C(R)(R)-CH2 alkylammonium hydroxides, for example Sodium or potas Sium hydroxide and triethylammonium hydroxide, can be prepared analogously to known processes, as respectively, carbonates, for example Sodium and potassium described, for example, in SoV, Prog. Chem. (Engl. Transl.) carbonate, and alcoholates, for example Sodium ethanolate 42, 65 (1976); J. Chem. Soc., Perkin Trans 1 1976, 201; or potassium isopropanolate. The reaction may also, where Justus Liebigs Ann. 1978, 1491; and Helv. Chim. Acta 73, appropriate, be carried out under phase transfer conditions. 1679 (1990). There may be used as phase transfer catalysts the customary The compounds lying within the Scope of formula I quaternary ammonium Salts, Such as, for example tetraoc 15 tylammonium bromide and benzyltriethylammonium chlo wherein X and R together form a group =N-Y- and ride. Under those conditions, a Suitable organic Solvent is Yis, for example, a bridge member-C(R)=CH- can be any inert non-polar Solvent, Such as, for example, benzene or prepared analogously to known processes, as described, for toluene. example, in Farmaco Ed. Sci. 37, 22 (1982); J. Chem. Res. The preparation of compounds of formula I wherein X is (Miniprint) II, 3368 (1986); and J. Chem. Soc., Perkin Trans S; and R is C-C alkoxy-C-C-alkyl, C-C alkoxy 1 1987, 1159. C-Calkoxy-C-C alkyl, C-C alkyl, Ca-Calkenyl, Taking into consideration the chemical properties of the C-C alkynyl, C-Chaloalkyl, C-Chaloalkenyl, pyridyl or pyridonyl moiety, as the case may be, all other C-C cycloalkyl, C-Chalocycloalkyl, B-C-Calkyl, 25 compounds within the Scope of formula I can readily be prepared, in terms of the construction of the pyrazole rings, C-Calkyl in a manner analogous to that described in Preparation D-CH-, d s Examples P1 to P21, or as described, for example, in O CH “Methoden der Organ-ischen Chemie” (Houben-Weyl), Vol ume E 8b, Georg Thieme Verlag Stuttgart, 1994, page 399 (C-C hydroxyalkyl)-CH-, (B- ff.; or in “Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles C-C hydroxyalkyl)-CH- or (B-C-Chaloalkyl)- and Condensed Rings”, Editor R. H. Wiley, Interscience CH-, and B is as defined for formula I is illustrated in the Publishers, John Wiley & Sons, New York, 1967, page 1 ff.: following Reaction Scheme 3. 35 or as described in the patent specifications WO 96/O1254 and WO 97/00246. Reaction Scheme 3 A large number of known Standard processes are available R11 for the preparation of the pyridine derivatives of formula III, the choice of a Suitable process being governed by the Sulfur reagent e.g. properties (reactivities) of the Substituents in the respective R12 W P2S5, Lawesson's reagent, intermediates. A number of Specimen examples are also N solvent, T given in Preparation Examples P1 to P16. For example, a V X1 R13 compound of formula III I(X1 = O) 45 R11 (III)

N 50 V X1 R13 I (X1 = S)

The conversion of the pyridone derivatives of formula I 55 (W1) wherein R, R2, R1 and W are as defined for formula I and X is O into the corresponding pyridinethione derivatives of formula I wherein X is S (Reaction Scheme 3) can be carried out analogously to known processes (e.g. J. Het. Chem. 25,511 (1988); ibid. 22, 265 (1985); Bull. Soc. Chim. 60 Fr. 1953, 1001; J. Prakt. Chem. 1988, 293; Chem. Ber. 62, 2732 (1929); Chem. Heterocycl. Compd. (Engl. Transl.) 1988, 658; Pharmazie 45,731 (1990); and J. Prakt. Chem./ Chem-Zig 334, 119 (1992)), advantageously with the aid of R, R2, R1 and R2 are as defined for formula I; and R is a Sulfur reagent, Such as, for example, PSs or Lawesson's 65 hydrogen, halogen, C-C alkyl or C-Chaloalkyl, can be reagent, in an organic Solvent, Such as, for example, an prepared Starting from, for example, a compound of formula aromatic hydrocarbon, for example benzene, toluene, a XII US 6,274,536 B1 19 20 wherein R is hydrogen, C-C alkyl or C-Chaloalkyl, (XII) M" is an alkali metal ion, preferably a potassium ion; and R, is C-C alkoxy, to yield the keto ester of formula XIX

(XIX) R11 i R12 / \ C-CH-C-R, wherein R and R2 are as defined above, which is reacted | | in an alcohol of formula XIII N O O Re-OH (XIII), wherein R, R-7, R and R2 are as defined above, and that compound is cyclised in a Solvent, Such as, for example, wherein Rs is C-C alkyl, in the presence of a Suitable glacial acetic acid, with a compound of formula XX palladium or nickel catalyst, Such as, for example, palladium 15 bis(triphenylphosphine) dichloride (PdCl(PPh)) and a NHNH-R (XX), base, Such as, for example, triethylamine, under carbon wherein R is as defined for formula I, to yield a compound monoxide exceSS pressure, to form a compound of formula of formula XXI XIV (XXI) (XIV) 11

COOR3, 25 S2N R1

wherein R, R, R and R2 are as defined above, and wherein R, R and R2 are as defined above, which is Subsequently in accordance with Standard methods the Subjected to acid or basic hydrolysis to form the correspond hydroxyl group is functionalised, especially freonised ing carboxylic acid of formula XV (Example P13), according to the definition of R, and the pyrazole ring is optionally halogenated (R is halogen; (XV) Example P14) or oxidised to the corresponding pyridine R11 N-oxide (Example P17). The compounds of formula XXII 35 (XXII)

R12 \ / COOH 11 N

40 and converted with a carboxylic acid halogenating reagent, Such as, for example, thionyl chloride, phosphorus pen S2N tachloride or oxalyl chloride, into the corresponding car R1 boxylic acid halide of formula XVI wherein R, R, R, R and R are as defined for formula 45 I, are important intermediates for the preparation of com (XVI) pounds of formula III, especially compounds of formula III wherein W is a group W3; Rs is haloalkyl (Example P11); and R, R, R and R2 are as defined for formula I. CO-X, The compounds of formula XXII are prepared according 50 to EP-A-0361 114, U.S. Pat. No. 5,032,165, WO92/O2509, WO92/06962, WO95/33728 and WO 96/O1254. The compounds of formula XIX wherein R and R are as defined above and X is halogen, (XIX) preferably chlorine, and that compound is reacted in a 55 Solvent, Such as, for example, acetonitrile in the presence of R11 an alkaline earth metal Salt, preferably magnesium chloride, and a base, Such as, for example, triethylamine, with the malonic acid mono ester Salt of formula XVII R12 / \ C-CH-C-R, o | 60 N O O (XVII) COOM" / wherein R and R are as defined for formula I; R is R-CH hydrogen, C-C alkyl or C-C-haloalkyl, and R7 is V CO-R, C-C alkoxy, C- or Chaloalkyl or C-C alkoxycarbonyl, 65 are important intermediates for the preparation of com pounds of formula I, especially compounds of formula I wherein W is a group US 6,274,536 B1 21 22 and the Starting compounds 2,5-dichloro-3-fluoropyridine, (W1) 2,3-dichloro-5-trifluoromethylpyridine and 3,5-dichloro-2- acetylpyridine used in Preparation Examples P1, P2 and P9, are either known or can be prepared analogously to pub lished processes. The reagents of formulae VI and XI used in the Reaction Schemes 1, 2 and 3 are either known or can be prepared analogously to published processes. All other compounds within the Scope of formula I can R, R2, R1 and R2 are as defined for formula I; and R is readily be prepared, taking into consideration the respective hydrogen, halogen, C-C alkyl or C-Chaloalkyl. The chemical reactivities, analogously to the processes accord compounds of formula XXIII ing to Preparation Examples P1 to P25, or analogously to the methods described in “Methoden der Organischen Chemie” (XXIII) (Houben-Weyl), volume E 8b, Georg Thieme Verlag 15 Stuttgart, 1994, page 399 ff.: ibid, volume E7B, Georg Thieme Verlag Stuttgart, 1992, page 286 ff.; in “Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles and Condensed Rings”, Editor R. H. Wiley, Interscience Publishers, John / C- – CH -N(C-C alkyl). Wiley & Sons, New York, 1967, page 1 ff.; or in “Compre hensive Heterocyclic Chemistry”, Editors A. R. Katritzky ( ) and C. W. Rees, Pergamon Press, Oxford, 1987, or by derivatisation according to known Standard methods as wherein R and R are as defined for formula I; and R is described, for example, in "Advanced Organic Chemistry, hydrogen, halogen, C-C alkyl or C-Chaloalkyl, are Third Edition, Editor J. March, John Wiley & Sons, New important intermediates for the preparation of compounds of 25 York, 1985; in “Comprehensive Organic Transformations”, formula 1a wherein Wa is a group W3a; Rs is hydrogen; and Editor R. C. Larock, VCH Publishers, Inc., New York, 1989; R., R., R., and R are as defined for formula I (Example or in “Comprehensive Organic Functional Group 8). Transformations”, Editors A. R. Katritzky, O. Meth-Cohn, C. 'the compounds of formula XXIII are prepared according W. Rees, Pergamon Press, Oxford, 1995, or as described in to EP-A-0361 114, U.S. Pat. No. 5,032,165, WO92/O2509, the Patent Specifications EP-A-0 361 114, U.S. Pat. No. WO92/06962, WO95/33728 and WO 96/O1254. 5,032,165, WO 92/02509, WO 92/06962, WO95/33728 and The compounds of formula XXIV WO 96/O1254. The end products of formula I can be isolated in conven (XXIV) tional manner by concentration or evaporation of the Solvent 35 and purified by recrystallisation or trituration of the solid residue in Solvents in which they are not readily Soluble, Such as ethers, aromatic hydrocarbons or chlorinated hydrocarbons, by distillation or by means of column chro matography and a Suitable eluant. The Sequence in which it 40 is advantageous for certain reactions to be carried out So as to avoid possible Secondary reactions will also be familiar to wherein R and R are as defined for formula I; and R is the perSon Skilled in the art. Unless the Synthesis is specifi hydrogen, C-C alkyl or C-C-haloalkyl, are important cally aimed at the isolation of pure isomers, the product may intermediates for the preparation of compounds of formula be obtained in the form of a mixture of two or more isomers. I wherein W is a group 45 The isomers can be separated according to methods known per Se. (W3) For the use according to the invention of the compounds of formula I or of compositions comprising them, there come into consideration all methods of application custom 50 ary in agriculture, for example pre-emergence application, post-emergence application and Seed dressing, and also various methods and techniques Such as, for example, the controlled release of active ingredient. For that purpose a Solution of the active ingredient is applied to mineral granule R is hydrogen, C-C alkyl or C-Chaloalkyl, Rs is amino; 55 carriers or polymerised granules (urea/formaidehyde) and and R, R and R are as defined for formula I. dried. If required, it is also possible to apply a coating The compounds of formula XXIV are prepared according (coated granules), which allows the active ingredient to be to EP-A-0361 114, U.S. Pat. No. 5,032,165, WO92/O2509, released in metered amounts over a Specific period of time. WO92/06962, WO95/33728 and WO 96/O1254. The compounds of formula I may be used in unmodified Alarge number of known Standard processes are available 60 form, that is to Say as obtained in the Synthesising process, for the preparation of the pyridonylpyrazoles of formula I but they are preferably formulated in customary manner Substituted at the pyridone ring, the choice of a Suitable together with the adjuvants conventionally employed in preparation process being governed by the properties formulation technology, for example into emulsifiable (reactivities) of the Substituents in the respective intermedi concentrates, directly sprayable or dilutable Solutions, dilute ateS. 65 emulsions, wettable powders, Soluble powders, dusts, gran A number of Specimen examples are also given in Prepa ules or microcapsules. Such formulations are described, for ration Examples P19 to P24. The compound of formula XII, example, in WO97/34485, pages 9 to 13. As with the nature US 6,274,536 B1 23 24 of the compositions, the methods of application, Such as Setaria, Sinapis, Lolium, Solanum, Phaseolus, Echinochloa, Spraying, atomising, dusting, Wetting, Scattering or pouring, Scirpus, Monochoria, Sagittaria, Bromus, Alopecurus, Sor are chosen in accordance with the intended objectives and ghum halepense, Rottboellia, Cyperus, Abutilon, Sida, the prevailing circumstances. Xanthium, Amaranthus, Chenopodium, Ipomoea, The formulations, that is to Say the compositions, prepa Chrysanthemum, Galium, Viola and Veronica. rations or mixtures comprising the compound (active ingredient) of formula I or at least one compound of formula The following Examples further illustrate but do not limit I and, usually, one or more Solid or liquid formulation the invention. adjuvants, are prepared in known manner, e.g. by homoge neously mixing and/or grinding the active ingredients with PREPARATION EXAMPLES the formulation adjuvants, for example Solvents or Solid carriers. Surface-active compounds (Surfactants) may also Example P1 be used in addition in the preparation of the formulations. 3-Fluoro-5-chloro-2-pyridinecarboxylic Acid Ethyl Ester Examples of Solvents and Solid carriers are given, for example, in WO 97/34485, page 6. 15 Depending on the nature of the compound of formula I to F be formulated, Suitable Surface-active compounds are non ionic, cationic and/or anionic Surfactants and Surfactant C COOCHs mixtures having good emulsifying, dispersing and wetting / properties. Examples of Suitable anionic, non-ionic and N cationic surfactants are listed, for example, in WO97/34485, pages 7 and 8. In addition, the Surfactants conventionally An autoclave is charged with 31.4 g of 2,5-dichloro-3- employed in formulation technology, which are described in, fluoropyridine, 400 ml of dry ethanol, 27.8 ml of triethy inter alia, uMcCutcheon's Detergents and Emulsifiers lamine and 3.5 g of palladium bis(triphenylphosphine) Annual” MC Publishing Corp., Ridgewood New Jersey, 25 1981, Stache, H., “Tensid-Taschenbuch, Carl Hanser dichloride (PdCl(PPh3)) and then a pressure of 180 bars is Verlag, Munich/Vienna 1981, and M. and J. Ash, “Encyclo applied with carbon monoxide. The mixture is maintained at pedia of Surfactants”, Vol. I-III, Chemical Publishing Co., 90° C. for 4 days. After cooling and releasing the pressure, New York, 1980-81, are also suitable for the preparation of a further 3.5g of PdCl(PPh3) are added, a pressure of 130 the herbicidal compositions according to the invention. bars is applied with carbon monoxide, and the mixture is The herbicidal formulations generally contain from 0.1 to maintained at 90° C. for 3 days, after which it is cooled to 99% by weight, especially from 0.1 to 95% by weight, of 25 C., the pressure is released and the mixture is dis herbicide, from 1 to 99.9% by weight, especially from 5 to charged. After concentration in vacuo, absorption from ethyl 99.8% by weight, of a solid or liquid formulation adjuvant, acetate onto Silica gel is carried out. The Silica gel is applied and from 0 to 25% by weight, especially from 0.1 to 25% by 35 to a flash chromatography column (Silica gel) and then weight, of a Surfactant. Whereas commercial products will eluted with n-hexanelethyl acetate 3/1. 24.3 g of the desired preferably be formulated as concentrates, the end user will target compound having a melting point of 48–50 C. are normally employ dilute formulations. The compositions obtained. may also comprise further ingredients, Such as Stabilisers, for example vegetable oils or epoxidised vegetable oils 40 Example P2 (epoxidised coconut oil, rape oil or Soybean oil), anti-foams, for example Silicone oil, preservatives, Viscosity regulators, 3-Chloro-5-trifluoromethyl-2-pyridinecarboxylic Acid binders, tackifiers, and also fertilisers or other active ingre Ethyl Ester dients. The compounds of formula I can be used Successfully 45 C either in the form of a mixture comprising the isomers IW1a o O and IW1b or in the form of pure isomer IW1a or IW1b, generally on plants or the locus thereof, at rates of applica tion of from 0.001 to 4 kg/ha, especially from 0.005 to 2 OCHs kg/ha. The concentration required to achieve the desired 50 effect can be determined by experiment. It is dependent on the nature of the action, the Stage of development of the An autoclave is charged with 200 g of 2,3-dichloro-5- cultivated plant and of the weed and on the application trifluoromethylpyridine, 1.85 liters of ethanol, 260 ml of (place, time, method) and may vary within wide limits as a trie thylamine and 6.5 g of palladium b is function of those parameters. 55 (triphenylphosphine) dichloride (PdCl(PPh)). At 25 C. a The compounds of formula I and, generally, the isomers pressure of 110 bars is then applied with carbon monoxide of formula 1a especially, are distinguished by herbicidal and and the mixture is maintained at 110° C. for 24 hours. After growth-inhibiting properties, allowing them to be used in cooling to 25 C., the crude mixture is concentrated to a crops of useful plants, especially cereals, cotton, Soybeans, thick slurry, which is then partitioned between dilute sodium Sugar beet, Sugar cane, plantation crops, rape, maize and 60 chloride Solution and ethyl acetate. After extraction by rice, and also for non-Selective weed control. Shaking, and Separation of the phases, the ethyl acetate phase “Crops” is to be understood as meaning also crops that is washed with water, dried over Sodium Sulfate and con have been made tolerant to herbicides or classes of herbi centrated to dryneSS. The crude product is distilled under a cides as a result of conventional methods of breeding or high vacuum of 0.035 mbar. 200 g of the desired product are genetic techniques. The weeds to be controlled may be either 65 obtained in the form of a yellow oil having a boiling point monocotyledonous or dicotyledonous Weeds, Such as, for of 67–70° C./0.035 mbar (yield 85% of the theoretical example, Stellaria, Nasturtium, Agrostis, Digitaria, Avena, yield). US 6,274,536 B1 25 26 Example P3 Example P6 3-Chloro-5-trifluoromethyl-2-pyridinecarboxylic Acid 3-Fluoro-5-chloro-2-pyridinecarboxylic Acid Chloride C C

o O CF / COOH C 4. N \ / \C

423 g of 3-chloro-5-trifluoromethyl-2-pyridinecarboxylic 71.38 g of 3-fluoro-5-chloro-2-pyridinecarboxylic acid acid ethyl ester (Example P2) is placed in a mixture of 800 (Example P4) are placed in a round-bottomed flask and ml of water and 160 ml of ethanol. 800 ml of a 2N Sodium heated to 90° C. 59 ml of thionyl chloride are added hydroxide solution are added dropwise at below 35 C. After 15 dropwise from a dropping funnel over a period of 30 3 hours, the mixture is washed twice with dichloromethane minutes, and the gas formed is introduced into Sodium and then rendered acidic with exceSS concentrated hydro hydroxide solution. Stirring is then carried out for 5 hours at chloric acid while cooling with an ice-bath. The resulting 100 C., after which the thionyl chloride is distilled off at slurry is filtered, washed with water and dried in vacuo. 318 normal pressure. After the addition of 50 ml of dry toluene, g of the desired product are obtained in the form of a white 20 ml thereof are distilled off. The resulting solution is Solid having a melting point of 135 C. (decomposition). poured into 200 ml of n-hexane and stirred overnight. After cooling in an ice-bath, the mixture is filtered and the Example P4 filtration residue is washed twice with n-hexane. 68.7 g of 3-Fluoro-5-chlorotyridine-2-carboxylic Acid the desired compound are obtained in the form of a brown 25 Solid. F 'H-NMR (CDC1): 8.60 ppm (d. 1H); 7.69 ppm (dxd, 1H). C M COOH Example P7 N 5-Chloro-3-fluoro-2-pyridinecarbaldehyde

70 g of 3-fluoro-5-chloro-2-pyridinecarboxylic acid ethyl F ester (Example P1) are placed in 105 ml of dimethyl 35 sulfoxide (DMSO). 230 ml of a 2N sodium hydroxide C / solution are added dropwise at 40 C. over a period of 30 minutes. The resulting yellow Suspension is introduced into N O a mixture of 2 liters of ice-water and 400 ml of 2N hydrochloric acid. After subsequently stirring for 20 40 110 g of 5-chloro-3-fluoro-2-pyridinecarboxylic acid minutes, the mixture is filtered and the filtration residue is ethyl ester (Example P1) are dissolved in 180 ml of tert washed twice with water. 56.4 g of the desired target butanol. 27.4 g of sodium borohydride (NaBH4, 97%) are compound are obtained in the form of a white solid. added to the slightly brown solution, in the course of which "H-NMR (DMSO-D): 13.79 ppm (broad signal, 1H); a weak exothermic reaction is observed. By cooling occa 45 Sionally with an ice-bath, the internal temperature is main 8.60 ppm (d. 1H); 8.27 ppm (dxd, 1H). tained below 30° C. The exothermic reaction has subsided after 1% hours. The reaction mixture is then stirred overnight Example P5 at 22 C. and subsequently cold water is added slowly, while 3-Chloro-5-trifluoromethyl-2-pyridine carboxylic Acid Stirring well. Extraction is carried out with diethyl ether, and Chloride 50 the combined ethereal phases are washed with dilute Sodium hydrogen carbonate Solution and brine, dried over Sodium C Sulfate, filtered and concentrated in vacuo. 58 g of a tacky

o O Solid are isolated. After digestion with n-hexane/-diethyl CF 4 ether 50/1 and drying in vacuo, 48.6 g of a yellow solid are 55 obtained having an R value on silica gel 60 F2s (eluant: N / \C n-hexane/ethyl acetate 1/1 (v/v)) of 0.40. 160.7 g of active manganese(IV) oxide (90%) are added to 22.4 g of the alcohol obtained as intermediate in 300 ml 89.3 g of 3-chloro-5-trifluoromethyl-2- of methylene chloride, and a slight exothermic reaction can pyridinecarboxylic acid (Example P3) are slowly heated to 60 be detected. After stirring for 3 hours, the mixture is filtered reflux with 60 ml of thionyl chloride and the mixture is then over Hyflo and the filtrate is concentrated in vacuo. The stirred at that temperature for 4 hours, after which it is residue (20g) is purified by means of flash chromatography cooled to 25 C. and concentrated to dryness in vacuo. (silica gel; eluant: n-hexane/ethyl acetate 4/1 (V/v)). In that Twice, toluene is added and the mixture is again concen manner 11.0 g of the desired target compound are obtained trated to dryness. 94.0 g of the desired product are obtained 65 in the form of a white solid having a melting point of 70-72 in the form of a yellow residue. C. The Rf value of the product on silica gel 60 F2s (eluant: "H-NMR (CDC1): 8.91 ppm (d. 1H); 8.13 ppm (d. 1H). n-hexane/ethyl acetate 3/1 (v/v)) is 0.61. US 6,274,536 B1 27 28 Example P8 Example P10 3-(3.5-Dichloro-2-pyridyl)-5-trifluoromethyl-1H-pyrazole 3-Chloro-5-trifluoromethyl-2-acetylpyridine C C CF o O N

CF 4 N -NH 3 \ ( VCH 15.8 g of 3,5-dichloro-2-acetylpyridine are introduced together with 12.0 ml of trifluoroethyl acetate into 125 ml of 55.3 ml of malonic acid dimethyl ester are stirred with absolute ether. With Stirring, the mixture is cooled using an 129 ml of triethylamine and 24.9 g of anhydrous magnesium ice-bath and 46.6 ml of, a 21% sodium ethanolate Solution chloride for 2 hours in 250 ml of dry toluene. With the in ethanol are added dropwise. The ice-bath is then removed exothermic reaction, the reaction temperature rises to 45 C. 15 and the mixture is subsequently stirred overnight at 25 C. At 25 C. 94.0 g of 3-chloro-5-trifluoromethyl-2- After cooling the reaction mixture in an ice-bath and adding pyridinecarboxylic acid chloride (Example P5) in 150 ml of dropwise 7.5 ml of glacial acetic acid, the mixture is concentrated in vacuo. 39.0 g of 1-(3,5-dichloro-2-pyridyl)- toluene are added dropwise thereto and the reaction mixture 3-trifluoromethylpropane-1,3-dione are obtained, which can is further Stirred overnight. An excess of concentrated hydro be used directly for the following cyclisation Step. chloric acid is then added dropwise, and the mixture is 39.0 g of 1-(3,5-dichloro-2-pyridyl)-3- diluted with water and extracted with ethyl acetate. The trifluoromethylpropane-1,3-dione organic phase is washed with brine, dried over Sodium Sulfate, filtered and concentrated to yield 142 g of a red oil C which is slowly introduced into a mixture of 20 ml of water 25 and 400 ml of dimethyl sulfoxide, which is under gentle reflux by means of an oil bath of a temperature of 150 C. C \ / C-CH-C-CF, When the evolution of gas can no longer be detected, water N O O is added and extraction is carried out with ether. The combined ethereal phases are washed with water, dried over are introduced into ethanol and 4.85 ml of hydrazine hydrate Sodium Sulfate, filtered and concentrated. The residue is are slowly added. The reaction mixture is then heated at purified by means of column chromatography (silica gel; reflux with Stirring. After one hour, the mixture is concen eluant: n-hexane/ethyl acetate 15/1 (v/v)), yielding 61 g of trated to dryneSS in vacuo and the residue is partitioned the desired product in the form of a yellow oil (70% of the 35 between dilute Sodium hydrogen carbonate Solution and theoretical yield). ethyl acetate. After extraction by Shaking, and Separation of the phases, the organic phase is washed with brine, dried "H-NMR (CDC1): 8.81 ppm (d. 1H); 8.05 ppm (d. 1H); over Sodium Sulfate, filtered and concentrated to dryneSS. 2.72 ppm (s, 3H). 22.25 g of a yellow oil are obtained, which is purified by 40 means of flash chromatgraphy (silica gel; eluant: n-hexane/ Example P9 ethyl acetate 4/1 (v/v)) to yield 15.0 g of the desired product in the form of a yellow solid. 1-(3-Chloro-5-trifluoromethyl-2-pyridyl)-3-dimethylamino "H-NMR (DMSO-D): 8.81 ppm (m, 1H); 8.64 ppm (m, 2-propen-1-one 1H); 8.26 ppm (m, 1H); 7.45 ppm (broad signal, 1H). 45 Example P11 C 3-(3,5-Dichloro-2-pyridyl)-5-trifluoromethyl-1-methyl o /O 1H-pyrazole and 5-(3,5-dichloro-2-pyridyl)-3- CF \ / V trifluoromethyl-1-methyl-1H-pyrazole N CHE Q 50 - CH CH

55 5.0 g of 3-chloro-5-trifluoromethyl-2-acetylpyridine and

(Example P8) are introduced into 30 ml of toluene and 3.60 ml of N,N-dimethylformamide-dimethylacetal are added. The resulting yellow solution is stirred overnight at 100 C. After cooling to 25 C., the mixture is concentrated to 60 dryneSS in vacuo, yielding 6.17 g of the desired target compound in the form of a dark-yellow oil which later Solidifies. "H-NMR (CDC1): 8.74 ppm (d. 1H); 7.98 ppm (d. 1H); 65 7.92 ppm (broad signal, 1H); 5.54 ppm (broad d, 1H); 3.17 8.88 g of 3-(3,5-dichloro-2-pyridyl)-5-trifluoromethyl ppm (broad signal, 3H); 2.94 ppm (broad Signal, 3H). 1H-pyrazole (Example P10) are introduced into 35 ml of US 6,274,536 B1 29 30 N-methylpyrrolidone. After the addition of 13.0 g of potas triethylamine are added dropwise. 84.3 g of anhydrous sium carbonate, the mixture is stirred and heated to 55 C. magnesium chloride are then added. A slight exothermic 2.36 ml of methyl iodide in 5.0 ml of N-methylpyrrolidone reaction is observed. After removal of the ice-bath, the are then slowly added dropwise. After Subsequently Stirring mixture is stirred for 2 hours at 25 C. After cooling again for 2 hours, diethyl ether and water are added, the mixture is extracted by Shaking and the organic phase is separated in an ice-bath, 68.7 g of 3-fluoro-5-chloro-2- off. The separated ethereal phase is washed with brine, dried pyridinecarboxylic acid chloride (Example P6) are added in over Sodium Sulfate, filtered and concentrated. The crude several portions and 300 ml of absolute acetonitrile are product is purified by means of flash chromatography (Silica added. A thick Slurry gradually forms. The cooling bath is gel; eluant: toluene/ethyl acetate 100/1). First of all 3.96 g of removed and the slurry is then stirred for 5 hours. The the 5-pyridylpyrazole isomer (yield 42%) are isolated in the reaction mixture is Subsequently poured into 3 liters of form of a yellow oil and then 1.96 g of the 3-pyridylpyrazole ice-water and 200 ml of concentrated hydrochloric acid, and (yield 21%) are isolated in the form of a yellow solid. The then stirred for 15 minutes and extracted with ethyl acetate. R values of the 3- and 5-pyridylpyrazole isomers on silica The organic phase is washed with water and brine, dried gel 60 F2s using toluene/ethyl acetate 30/1 as eluant (UV) 15 over Sodium Sulfate, filtered and concentrated to dryneSS in C. R value of 5-pyridylpyrazole: O.50 vacuo. 110 g of a brown oil are obtained, which is used R value of 3-pyridylpyrazole: 0.35 directly for the next reaction Step. Example P12 For that reaction step, the brown oil obtained above is 3-(3,5-Dichloro-2-pyridyl)-4-chloro-5-trifluoromethyl-1- introduced at 25 C. into a solution of 20.5 ml of methyl methyl-1H-pyrazole hydrazine in 300 ml of glacial acetic acid and then stirred for 2 hours at 85 C. After the resulting brown suspension has CI Cl been cooled to 25 C. it is introduced in portions into 2.5 liters of ice-water, stirred for 1 hour, filtered and washed CF 25 N with water and n-hexane. After drying at 60° C. in vacuo, C 65.8g of the desired title compound having a melting point N N N1e Net, of 195-199 C. are obtained. Example P14 2.0 g of 3-(3,5-dichloro-2-pyridyl)-5-trifluoromethyl-1- methyl-1H-pyrazole (Example P11) are introduced into glacial acetic acid at 40 C. and, with Stirring, chlorine gas 3-(3-Fluoro-5-chloro-2-pyridyl)-5-difluoromethoxy-1- is slowly passed over the Solution. The reaction can be methyl-1H-pyrazole monitored analytically by means of thin-layer chromatog 35 raphy (silica gel 60 Fs, eluant: n-hexanelethyl acetate 4/1, F UV). Once starting material can no longer be detected, glacial acetic acid is removed in vacuo and the residue is o N-OCHF: partitioned between dilute aqueous Sodium hydroxide Solu c \ y \, tion and ethyl acetate. After extraction by Shaking, the 40 N N-N Separated organic phase is washed with brine, dried over V Sodium sulfate, filtered and concentrated. The yellow oil is CH purified by means of flash chromatography (silica gel, eluant: n-hexane/ethyl acetate 5/1). 1.6 g of of the desired compound are obtained in the form of a yellow oil (70% of 45 46.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-hydroxy-1- the theoretical yield). methyl-1H-pyrazole (Example P13) and 84 g of potassium "H-NMR (DMSO-D): 8.80 ppm (d. 1H); 8.48 ppm (d. carbonate are introduced into 250 ml of dry dimethylforma 1H); 4.11 ppm (s, 3H). mide and heated to 85 C. While stirring well, Freon 22 The 5-pyridylpyrazole isomer is obtained in an analogous (chlorodifluoromethane) is then introduced for a period of 2 manner in a 90% yield (crude). H-NMR (CDC1): 8.66 ppm 50 hours. TLC analysis of a worked-up Sample (silica gel 60 (d. 1H); 7.95 ppm (d. 1H); 3.83 ppm (s, 3H). F2s, eluant: n-hexane/ethyl acetate/glacial acetic acid 20/20/ Example P13 1, UV) shows that there is no starting material present. The 3-(3-Fluoro-5-chloro-2-pyridyl)-5-hydroxy-1-methyl-1H reaction mixture is partitioned between water and diethyl pyrazole ether (foaming occurs on the addition of water). After 55 extraction by Shaking, and Separation of the phases, the F ethereal phase is washed twice with water and once with brine. After drying the organic phase over Sodium Sulfate o N OH and filtration, concentration in vacuo is carried out and the C \ / \ 60 residue is purified by means of flash chromatography (silica N N-N gel; eluant: n-hexane/ethyl acetate 2/1 (v/v)). 22.0 g of the V desired title compound are obtained in the form of a light CH yellow solid.

110.6 g of malonic acid monomethyl esterpotassium Salt 65 "H-NMR (CDC1): 8.51 ppm (broad signal, 1H); 7.56 are introduced into 500 ml of absolute acetonitrile. With ppm (dxd, 1H); 6.61 ppm (t, 1H); 6.53 ppm (d. 1H); 3.89 stirring, the mixture is cooled in an ice-bath and 109 ml of ppm (s, 3H). US 6,274,536 B1 31 32 Example P15 Example P17 3-(3-Fluoro-5-chloro-2-pyridyl)-4-chloro-5- 3-(3-Fluoro-5-chloro-2-pyridyl)-4-difluoromethyl-5- difluorometho)-1-methyl-1H-pyrazole difluoromethoxy-1-methyl-1H-pyrazole OCHF F C

o N OCHF c \ y \, N N-N V 1O CH 0.13 g of 3-(3-fluoro-5-chloro-2-pyridyl)-4-formyl-5- difluoromethoxy-1-methyl-1H-pyrazole (Example P16) is 17.92 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5- introduced into 3.0 ml of dry 1,2-dichlorethane. With difluoromethoxy-1-methyl-1H-pyrazole (Example P14) 15 stirring, 0.11 ml of diethylamino-sulfur trifluoride (DAST) is added dropwise using a Syringe, the reaction mixture are introduced into 60 ml of glacial acetic acid together with taking on a dark colour. The mixture is then Stirred for 1 hour 10.6 g of sodium acetate. With stirring, the mixture is heated at 50 C. The reaction solution is cooled to 25 C. and to 60° C. and a Saturated Solution of chlorine in glacial acetic applied directly to a flash chromatography column (silica acid is added until TLC analysis of a worked-up Sample gel) and eluted with n-hexane/ethyl acetate 5/1 (v/v). 0.07 g. shows that the reaction is complete (silica gel 60 Fs, of the desired compound is obtained in the form of a eluant: n-hexane/ethyl acetate 2/1; UV, R value of the light-yellow oil having a melting point of 79-81 C. starting material 0.34; R value of the product 0.48). The mixture is then concentrated to dryneSS in vacuo and the Example P18 residue obtained is partitioned between Sodium hydrogen 3-(3-Fluoro-5-chloro-2-pyridyl)-5-bromo-1-methyl-1H carbonate Solution and ethyl acetate. The organic phase is 25 pyrazole washed with brine, dried over Sodium Sulfate, filtered and concentrated to dryneSS by evaporation in vacuo. 19.8g of the desired target compound (pure according to TLC) having a melting point of 95-96 C. are obtained. Example P16 3-(3 - Fluoro-5-chloro-2-pyridyl)-4-formyl-5- difluoromethoxy-1-methyl-1H-pyrazole 35 20.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-hydroxy-1- F CHO OCHF methyl-1H-pyrazole (Example P13) are introduced into 80 ml of tetrachloroethane. A total of 25.2 g of phosphorus oxybromide (POBr.) is added in portions to the brown Suspension. The mixture is then Stirred for 2 hours at an 40 internal temperature of 130 C., after which it is cooled and, with cooling with an ice-bath, 150 ml of a 2M Sodium hydroxide solution are added dropwise. After the addition of With cooling in an ice-bath, 2.41 ml of phosphorus diethyl ether and Separation of the phases, the organic phase oxychloride are introduced into 5 ml of N,N- is washed in Succession with water, dilute hydrochloric acid dimethylformamide and the mixture is then stirred for 2 45 and brine, dried over Sodium Sulfate, filtered and concen hours at 25 C. The mixture is then added dropwise at 80 trated to dryness in vacuo. 19.94 g of a brown solid (crude C. to 5.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-hydroxy-1- product) are obtained, which is purified by means of diges methyl-1H-pyrazole (Example P13) in 15 ml of N,N- tion with 50 ml of n-hexane. 12.65 g of the desired com dimethylformamide over a period of 30 minutes. After pound are obtained in the form of a brown Solid having a Subsequently stirring for 1.5 hours at 80 C., the mixture is 50 melting point of 110-111 C. cooled to 25 C. and ice and then water are added and Example P19 extraction is carried out with diethyl ether. The organic 5-(5-Chloro-3-fluoro-2-pyridyl)-2-methyl-2H-pyrazole-3- phase is washed with water and dried over Sodium Sulfate to carboxylic Acid Ethyl Ester yield 1.1 g of a yellow solid as intermediate. The Solid is introduced together with 1.72 g of pulverised anhydrous 55 potassium carbonate into 10 ml of dry N,N- dimethylformamide. While stirring well, the mixture is heated to 75° C. and freon 22 (CHCIF) is slowly introduced for a period of 7 hours. The mixture is then cooled to 25 C. and taken up in diethyl ether. The ethereal phase is washed 60 with water and then with brine, dried over Sodium Sulfate, filtered and concentrated. 1.50 g of crude product are obtained in the form of a brown solid, which is purified using 5.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-bromo-1- a flash chromatography column (Silica gel; eluant: n-hexane/ methyl-1H-pyrazole (Example P18) are introduced into an ethyl acetate 4/1 (v/v)). In that manner 0.14 g of the desired 65 autoclave together with 7.2 ml of triethylamine, 0.48 g of target compound is obtained in the form of a yellow Solid bis-triphenylphosphinepalladium dichloride (PdCl(PPh3)) having a melting point of 111-116 C. and 70 ml of absolute ethanol. At 22 C. a pressure of 100 US 6,274,536 B1 33 34 bar is applied with carbon monoxide and the reaction Example P22 mixture is maintained at 100° C. for 48 hours. In the 3-(3-Fluoro-5-chloro-2-pyridyl)-4-chloro-5- meantime a further 0.48 g of bis trifluoromethyl-1-methyl-1H-pyrazole triphenylphosphinepalladium dichloride is added, and the

mixture is then cooled to 22 C. and the pressure is released. The reaction mixture is filtered over Hyflo and, after evapo rating off the ethanol, taken up in ethyl acetate. The ethyl acetate phase is washed with dilute hydrochloric acid and then with brine, dried over Sodium Sulfate, filtered and N -N finally concentrated to dryneSS in vacuo. 3.17 g of a brown N N YCH, solid are obtained, which is purified by means of flash chromatography (silica gel; eluant: n-hexane/ethyl acetate 2/1 (v/v)). 2.31 g of the desired title compound are obtained 8.63 g of 5-(5-chloro-3-fluoro-2-pyridyl)-4-chloro-2- in the form of a light-yellow Solid having a melting point of methyl-2H-pyrazole-3-carboxylic acid (Example P21) are 117-118° C. introduced into a fluorination unit with 27 g of hydrogen Example P20 15 fluoride (HF), 16.2 g of sulfur tetrafluoride (SF) and 270 ml 5-(5-Chloro-3-fluoro-2-pyridyl)-4-chloro-2-methyl-2H of methylene chloride. The mixture is maintained at 80 C. for 5 hours. It is then cooled to 22 C. and the SF is pyrazole-3-carboxylic Acid Ethyl Ester removed by way of a gas destroying unit (argon Stream) and the HF is removed using a water-jet vacuum. After the addition of methylene chloride, the reaction mixture is extracted three times with ice-water, and the organic phase is dried over Sodium Sulfate and then concentrated to dry neSS in vacuo together with 40 g of Silica gel. After applying the Silica gel to a flash chromatography column, elution is 25 carried out with an n-hexane/ethyl acetate 5/1 (v/v) mixture. 5.48g of the desired title compound are obtained in the form 22.9 g of 5-(5-chloro-3-fluoro-2-pyridyl)-2-methyl-2H of a beige solid having a melting point of 76–78 C. pyrazole-3-carboxylic acid ethyl ester (Example P19) are introduced together with 19.9 g of sodium acetate into 300 Example P23 ml of glacial acetic acid at a temperature of 65 C. With 3-(5,6-Dichloro-2-pyridyl)- and 3-(4,5-dichloro-2-pyridyl)- Stirring, 6.3 g of chlorine gas are passed over the Solution at 4-chloro-5-trifluoromethyl-1-methyl-1H-pyrazole that temperature in the course of 1 hour. The reaction (isomers A and B) mixture is then poured into 2.5 liters of ice-water and Subsequently Stirred for 20 minutes. The resulting precipi tate is filtered off, washed with ice-water and then dried in 35 vacuo at 50 C. 24.4 g of the desired title compound are obtained in the form of a yellow Solid having a melting point (isomer A) of 77-79° C. Example P21 5-(5-Chloro-3-fluoro-2-pyridyl)-4-chloro-2-methyl-2H 40 and pyrazole-3-carboxylic Acid

45 (isomer B)

20 ml of phosphorus oxychloride are heated to 90° C. 50 With stirring, 10.37 g of 3-(5-chloro-2-pyridyl-N-oxide)-4- 11.0 g of 5-(5-chloro-3-fluoro-2-pyridyl)-4-chloro-2- chloro-5-trifluoromethyl-1-methyl-1H-pyrazole (Example methyl-2H-pyrazole-3-carboxylic acid ethyl ester P25) are introduced in Several portions at that temperature (Example P20) are introduced into 60 ml of dimethyl and the mixture is then stirred for 1 hour at 90° C. The sulfoxide at 22 C. With stirring, 25.9 ml of a 2N aqueous phosphorus oxychloride is then evaporated off in vacuo, the Sodium hydroxide Solution are added dropwise, in the course 55 residue is taken up in diethyl ether and the ethereal phase is of which an exothermic reaction can be detected. After Subsequently washed in succession with water, 0.5M sodium Subsequently Stirring for one hour, TLC analysis of a Sample hydroxide Solution and brine. After drying over Sodium shows that all the Starting material has reacted. The reaction Sulfate and filtering, concentration in vacuo is carried out mixture is introduced into 2 liters of ice-cold dilute hydro and the residue obtained (8.93 g) is purified by column chloric acid, then stirred for 15 minutes and filtered over a 60 chromatography (silica gel; eluant: n-hexane/ethyl acetate paper filter. The filtration residue is washed with cold water 10/1). First 0.57g of isomer B and then 5.11 g of isomer A and, after drying overnight at 60° C. in vacuo, 8.7 g of the are isolated in the form of a white Solid. desired title compound having a melting point of 230 C. On Silica gel 60 Fis using the eluant n-hexane/ethyl (decomposition) are obtained. acetate 4/1 (v/v), the R value of isomer A is 0.31 and the R The R value of the starting material on silica gel 60 F2s 65 value of isomer B is 0.41. (eluant: n-hexane/ethyl acetate 1/1 (v/v)) is 0.75; and the R The treatment of 6.3 g of 3-(5-chloro-2-pyridyl-N-oxide)- value of the desired title compound is 0.36. 4-chloro-5-trifluoromethyl-1-methyl-1H-pyrazole US 6,274,536 B1 35 36 (Example P25) for 1 hour at 90° C. with 6.3 g of phosphorus (5-chloro-2-pyridyl-N-oxide)-4-chloro-3-trifluoromethyl-1- pentachloride in 20 ml of phosphorus oxychloride yields, methyl-1H-pyrazole isomer can be obtained in a yield of after working up as above, 4.36 g of isomer A and 1.01 g of 70%. isomer B. C Example P24 3-(3-Fluoro-5,6-dichloro-2-pyridyl-N-oxide)-4-chloro-5- o 21 CF difluoromethoxy-1-methyl-1H-pyrazole V / f N N-N 1O VO c?,

Example P26 15 3-(3-Fluoro-5-chloro-2-pyridyl-N-oxide)-4-chloro-S- difluoromethoxy-1-methyl-1H-pyrazole

F 1.5 g of 3-(3-fluoro-5,6-dichloro-2-pyridyl)-4-chloro-5- C difluoromethoxy-1-methyl-1H-pyrazole are dissolved in o OCHF 10 ml of 1,2-dichloroethane and 0.5g of hydrogen peroxide/ C N 2 urea adduct is added. With cooling in an ice-bath, 0.66 ml of N / \ trifluoroacetic anhydride is then metered in using a Syringe N N-N and the mixture is stirred at 22 C. for 3 hours. According to \ TLC analysis there is only partial reaction of the Starting O CH material. Consequently, 0.5 g of hydrogen peroxide/urea 25 adduct and 0.66 ml of trifluoroacetic anhydride are added to 0.57 g of 3- (3-fluoro-5-chloro-2-pyridyl)-4-chloro-5- the reaction mixture one after the other, in the manner difluoromethoxy-1-methyl-1H-pyrazole (Example P15) is described above, four times, followed each time by Stirring introduced into 5 ml of methylene chloride and 0.63 g of a for 3 hours at 22 C., in the course of which a yellow 55% m-chloro- perbenzoic acid is added. After stirring for 4 Suspension is formed which is taken up in ethyl acetate. The days at 25 C., the crude mixture is taken up in ethyl acetate organic phase is washed in Succession with 1 N Sodium and washed in Succession with Sodium hydrogen carbonate hydroxide Solution, water and brine, dried over Sodium Solution, water and brine. After drying over Sodium Sulfate Sulfate, filtered and concentrated in vacuo. The crude prod and filtering, concentration is carried out and the residue is uct is purified by means of flash chromatography (Silica gel, 35 purified by means of flash chromatography. 0.45 g of the eluant: hexane/ethyl acetate 3/2). 0.25 g of the desired desired target compound is obtained in the form of a white product is obtained in the form of yellow crystals having a solid having a melting point of 115-120° C. melting point of 114-118 C. Example P27 Example P25 40 3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-1H 3-(5- Chloro-2-pyridyl-N-oxide)-4-chloro-5- pyrazol-3-yl)-5-fluoropyridin-2-ol trifluoromethyl-1-methyl-1H-pyrazole OCHF Cl 45 o CF C \ \ N 3 N N-N Y. V CH 50 1.0 g of 3-(3-fluoro-5-chloro-2-pyridyl-N-oxide)-4- chloro-5-difluoromethoxy-1-methyl-1H-pyrazole 6.82 g of 3-(5-chloro-2-pyridyl)-4-chloro-5- (Example P26) is introduced into 12 ml of dry N.N- trifluoromethyl-1-methyl-1H-pyrazole are introduced into dimethylformamide. With stirring and cooling with an ice 30 ml of methylene chloride at 25° C. With stirring, 7.23g 55 bath, 4.2 ml of trifluoroacetic anhydride are added dropwise of m-chloroperbenzoic acid are added. After 48 hours a from a Syringe and the mixture is Subsequently Stirred further 2.50 g of m-chloroperbenzoic acid are added. After overnight at 25 C. The mixture is then concentrated by a further 24 hours the reaction mixture is taken up in ethyl evaporation in vacuo and the residue is partitioned between acetate and extracted twice with dilute Sodium hydroxide diethyl ether and water. After extraction by Shaking, and Solution, then washed with brine, dried over Sodium Sulfate 60 Separation of the phases, the ethereal phase is washed with and concentrated. Chromatography is then carried out (silica dilute aqueous Sodium hydrogen carbonate Solution and gel; eluant: n-hexane/ethyl acetate 1/1 (v/v)). 6.31 g of the brine, dried over Sodium Sulfate, filtered and concentrated. desired compound are isolated in the form of a white Solid. 1.23g of a yellow oil are obtained, which is purified using "H-NMR (DMSO-D): 8.75 ppm (d. 1H); 7.66 ppm (d. a flash chromatography column (silica gel; eluant: n-hexane/ 1H); 7.59 ppm (dxd, 1H); 4.08 ppm (s, 3H). 65 ethyl acetate 2/3 (v/v) and 1% glacial acetic acid). 0.59 g of Starting from the S-(5-chloro-2-pyridyl)-4-chloro-3- the desired compound is obtained in the form of a yellow trifluoromethyl-1-methyl-1H-pyrazole isomer, the 5 solid having a melting point of 126-128 C. US 6,274,536 B1 37 38 Example P28 suspended in 20 ml of dioxane. With cooling with an 5-(5-Chloro-3-fluoropyridin-2-yl)-2,4-dimethyl-2H ice-bath, first 1.65 ml of pyridine and then 1.44 ml of pyrazole-3-carboxylic Acid trifluoroacetic anhydride are added. After 5 minutes the cooling bath is removed and the mixture is Subsequently stirred for 1 hour at 22 C. The brownish-red solution is diluted with diethyl ether and washed with 1 N hydrochloric acid and then with brine. The mixture is dried over Sodium sulfate and filtered and then directly concentrated with twice the amount of Silica gel. After application of the Silica gel to a flash chromatography column, elution is carried out with n-hexane/ethyl acetate 4/1 (v/v). 1.60 g of the desired title 6.75 g of 5-(5-chloro-3-fluoropyridin-2-yl)-2,4-dimethyl compound are obtained in the form of a beige Solid having 2H-pyrazole-3-carboxylic acid ethyl ester are Suspended in a melting point of 144-146 C. 40 ml of dimethyl sulfoxide. With occasional cooling in an Example P31 ice-bath (internal temperature <30° C.), 14.3 ml of a 2N 15 3-(3 - Fluoro-5-methyl-2-pyridyl)-4-chloro-5- Sodium hydroxide Solution are added dropwise. The thick, difluoromethoxy-1-methyl-1H-pyrazole yellowish-brown suspension is stirred at 22 C. for 2 hours. The Suspension is then introduced into ice-water and OCHF adjusted to pH 1 with 2N hydrochloric acid. The resulting slurry is filtered, washed well with cold water and then dried in vacuo at 60° C. 5.97g of the desired title compound are obtained in the form of a beige Solid having a melting point of 194-196° C. Example P29 25 2.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-4-chloro-5- 5-(5-Chloro-3-fluoropyridin-2dl)-2,4-dimethyl-2H difluoromethoxy-1-methyl-1H-pyrazole (Example P15) pyrazole-3-carboxylic Acid Amide are introduced into 6 ml of absolute dioxane. In order to remove the oxygen, gentle evacuation is carried out three times (water-jet pump) and the mixture is gassed with argon. 6.4 ml of a 2M solution of trimethylaiuminium in toluene and 0.10 g of tetrakistriphenylphosphinepalladium (Pd (PPh3)) are added thereto. The mixture is heated to 90° C., with stirring, in an argon atmosphere. The next day the mixture is cooled to 22°C., a further 0.10g of Pd(PPh3) and 35 6.4 ml of a 2M solution of trimethylaluminium in toluene are added and the mixture is stirred at 110° C. After 4 hours, 3.0 g of 5-(5-chloro-3-fluoropyridin-2-yl)-2,4-dimethyl TLC analysis of a worked-up sample shows that all the 2H-pyrazole-3-carboxylic acid (Example P28) are intro Starting material has reacted. The reaction mixture is intro duced into 25 ml of 1,2-dichloroethane and, at 80 C., a total duced carefully into cold, dilute hydrochloric acid and is of 1.21 ml of thionyl chloride is added and the mixture is 40 then extracted with ethyl acetate. The combined organic Subsequently stirred for 5 hours at 80 C. The mixture is phases are washed with brine, dried over Sodium Sulfate, concentrated in vacuo, 20 ml of carbon tetrachloride are filtered and concentrated by evaporation in vacuo. The crude added three times and each time the mixture is concentrated product obtained is purified over a flash chromatography to dryneSS by evaporation. The resulting acid chloride is column (silica gel; eluant: n-hexane/ethyl acetate 1/1 (V/v)). introduced into 35 ml of tetrahydrofuran. With cooling in an 45 1.36 g of the desired compound are obtained in the form of ice-bath, ammonia gas is introduced. A brown precipitate a yellow oil, which slowly crystallises; melting point 41-42 forms. Stirring is carried out overnight at 22 C. The C. resulting Suspension is introduced into five times its Volume The Rf value of the starting material on silica gel 60 F2s of ice-water. After then stirring briefly, filtration is carried (eluant: n-hexane/ethyl acetate 2/1 (v/v)) is 0.37 and the R out and the filtration residue is Subsequently washed with 50 cold water and dried in vacuo at 60° C. 2.0 g of the desired value of the title compound is 0.15. title compound are obtained in the form of a brown solid Example P32 having a melting point of 201-204 C. 3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-1H pyrazol-3-yl)-5-fluoro-1-hydroxy-1H)-2-pyridin-2-one Example P30 55 5-Chloro-3-fluoropyridin-2-yl)-2,4-dimethyl-2H (Compd. No. 1.397) pyrazole-3-carbonitrile

F CH N 2 60

Cl / e N YCH, 65 0.50 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1- 1.82 g of 5-(5-chloro-3-fluoropyridin-2-yl)-2,4-dimethyl methyl-11-pyrazol-3-yl)-5-fluoropyridin-2-ol (Example 2H-pyrazole-3-carboxylic acid amide (Example P29) are P27) is introduced into 4 ml of 1,2-dichloroethane, and 0.15 US 6,274,536 B1 39 40 g of hydrogen peroxide/urea adduct (30%) and 0.22 ml of glacial acetic acid is added, the phases are separated, the trifluoroacetic anhydride are added. The mixture is stirred aqueous phase is extracted again, and the combined organic overnight at 22 C. and then a further 0.15 g of hydrogen phases are washed with water. After drying over magnesium peroxide/urea adduct is added together with 0.22 ml of Sulfate, filtration and concentration to dryneSS in vacuo are trifluoroacetic anhydride. The mixture is Subsequently carried out. 51 g of the desired compound are obtained in the stirred for 5 hours and then partitioned between ethyl acetate form of an oil (crude product). and dilute hydrochloric acid. The Separated organic phase is washed with brine, dried over Sodium Sulfate, filtered and The Rf value of the starting material on silica gel 60 F2s concentrated to dryneSS. 0.55g of the desired compound is (eluant: n-hexanelethyl acetate 3/1 (v/v)) is 0.46, and the R obtained in the form of a yellow resinous precipitate (crude value of the product is 0.63. product). "H-NMR (CDC1): 7.65 ppm (d. 1H); 6.74 ppm (t, 1H); 3.90 ppm (s, 3H). Example P35 Example P33 3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-1H 15 3-(5-Chloro-3-fluoropyridin-2-yl)-2-methyl-3-oxopropionic pyrazol-3-yl)-5-fluoro-1-methoxy-1H-pyridin-2-one acid

(Compa. No. 1.400)

OH

25 O OCH 25.5 g of 3- (5-chloro-3-fluoropyridin-2-yl)-2-methyl-3- oxopropionic acid tert-butyl ester (Example P34) are added 0.20 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1- dropwise to 30 ml of a 33% solution of hydrogen bromide methyl-1H-pyrazol-3-yl)-5-fluoro-1-hydroxy-1H (HBr) in glacial acetic acid to form a Suspension. The pyridin-2-one (Example P32) is introduced into 2 ml of mixture is subsequently stirred for 90 minutes and then N-methylpyrrolidone (NMP) at 22 C. and 0.16 g of anhy introduced into 300 ml of ice-water. The resulting precipitate drous potassium carbonate is added. With stirring, 0.10 g of is filtered off, washed with water and dried. 15.9 g of the methyl iodide in 0.5 ml of NMP is then added dropwise. The desired title compound are obtained in the form of a solid reaction mixture is stirred for 2 hours at 22 C. and then having a melting point of 101-102 C. partitioned between 20 ml of water and diethyl ether. The 35 Separated ethereal phase is washed with brine, dried over Sodium Sulfate, filtered and concentrated to dryneSS by Example P36 evaporation in vacuo. 0.13 g of the desired crude product is obtained in the form of a yellow oil which, after purification 2-Chloro-1-(5-chloro-3-fluoropyridin-2-yl)- propan-1-one by means of flash chromatography (silica gel; eluant: 40 n-hexane/ethyl acetate 1/1 (v/v)), yields 0.08 g of pure product in the form of a colourless oil. F CH "H-NMR (CDC1): 7.62 ppm (d. 1H); 6.74 ppm (t, 1H); C 4.00 ppm (s, 3H); 3.90 ppm (s, 3H). C / 45 Example P34 N O 3-(5-Chloro-3-fluoropyridin-2-yl)-2-methyl-3-oxopropionic Acid Tert-Butyl Ester 20.8 g of 3-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-3- F CH O 50 oxopropionic acid (Example P35) are introduced into 125 ml of glacial acetic acid. 6.3 g of chlorine gas are introduced / into the Solution in the course of 1 hour. The mixture is then poured into 700 ml of water and extracted with tert-butyl N O methyl ether. The combined ethereal phases a rewashed with 55 water and dried over magnesium Sulfate, filtered and con 32.3 g of diisopropylamine are introduced into 200 ml of centrated by evaporation in vacuo. The crude product is tetrahydrofuran and, with cooling with a CO/acetone cool dissolved in 180 ml of tert-butyl methyl ether, 45g of silica ing bath, 200 ml of a 1.6M solution of n-butyllithium in gel are added and the mixture is stirred for 30 minutes, in the hexane are added dropwise. 49.2 ml of propionic acid course of which the evolution of gas observed initially tert-butyl ester are then added dropwise at approximately 60 comes to a halt. The silica gel is then filtered off and -75 C. and the mixture is stirred at that temperature for 45 Subsequently washed and the combined ethereal phases are minutes. At approximately -75 C. a solution of 32.6 g of concentrated to dryneSS in vacuo. 20.1 g of an oily crude 3-fluoro-5-chloro-2-pyridinecarboxylic acid ethyl ester product are obtained, which is purified over a flash chro (Example P1) in 40 ml of tetrahydrofuran (THF) is then matography column (Silica gel; eluant: n-hexane/ethyl added dropwise and the mixture is stirred at that temperature 65 acetate 411 (v/v)). 17.0 g of the desired title compound are for 1 hour, after which it is diluted with 250 ml of tert-butyl obtained in the form of a Solid having a melting point of methyl ether. A mixture of 100 ml of water and 200 ml of 29-32 C. US 6,274,536 B1 41 42 Example P37 are washed with water, dried over magnesium Sulfate, fil 5-(5-Chloro-3-fluoropyridin-2-yl)-3,6-dimethyl-3,6- tered and concentrated in vacuo. 1.8g of an oil are obtained, dihydro-1,3,4)-thiadiazine-2-thione which is purified over a flash chromatography column (Silica gel; eluant: n-hexane/ethyl acetate 2/1 (v/v)). 1.3 g of the F CH desired title compound are obtained in the form of a solid having a melting point of 61-64 C. Example P39 5-Chloro-2-(1,4-dimethyl-5-methylsulfanyl-1H-pyrazol ( )-V CH 3-yl)-3-fluororyridine

19.1 ml of a 4N Sodium hydroxide solution and 3.5g of methyl hydrazine are introduced into 76 ml of ethanol. At an internal temperature of <5 C., 4.5 ml of carbon disulfide are 15 added dropwise with Stirring, and the mixture is then Stirred for 30 minutes. 17.0 g of 2-chloro-1-(5-chloro-3- fluoropyridin-2-yl)-propan-1-one (Example P36) are subse and quently added in the course of 15 minutes at an internal temperature of <5 C. The temperature is then allowed to F CH O.V/ O rise to 22 C. and the mixture is Subsequently stirred for 30 Sn minutes. TLC analysis (silica gel 60 F2s, eluant: n-hexane/ / \ /s1 YCH, ethyl acetate, UV) of a worked-up sample shows that C Starting material is no longer present. 2.5 ml of a concen o N N-NCH trated hydrochloric acid Solution are then added dropwise to 25 form a yellow precipitate. Stirring is carried out for 1 hour and the mixture is then poured into water and extracted with 2.1 g of 5chloro-2-(1,4-dimethyl-5-methylsulfanyl-1H tert-butyl methyl ether. The combined ethereal phases are pyrazol-3-yl)-3-fluoropyridine (Example P38) are dissolved washed with water, dried over magnesium Sulfate, filtered in 40 ml of methylene chloride, and 2.84 g of 70% meta and concentrated to dryneSS in vacuo. 20.3 g of the desired chloroperbenzoic acid are added in portions. The mixture is title compound are obtained in the form of a Solid having a then stirred for 4 hours at 22 C. and Subsequently stirred melting point of 107-112 C. with 1N sodium hydrogen carbonate solution for 30 min utes. The organic phase is separated off, washed with water, Example P38 dried over magnesium Sulfate, filtered and concentrated in 5-Chloro-2-(1,4-dimethyl-5-methylsulfanyl-1H-pyrazol 35 vacuo. 1.7 g of a Solid are obtained, which is purified over 3-yl)-3-fluoropyridine a flash chromatography column (silica gel; eluant: n-hexane/ ethyl acetate 1/1 (v/v)). 0.80 g of the desired sulfone having a melting point of 145-147 C. and 0.70 g of the Sulfoxide having a melting point of 112-114 C. are obtained. 40 Example P40 5-Chloro-3-fluoro-2-(5-methanesulfonyl-1,4-dimethyl 1H-pyrazol-3-yl)-pyridine-1-oxide 21.6 g of crude 5-(5-chloro-3-fluoropyridin-2-yl)-3,6- 45 dimethyl-3,6-dihydro-1.3.4-thia diazine-2-thione F CH O. O (Example P37) are introduced into 70 ml of tert-butanol, 3 \/ 19.1 g of triphenylphosphine are added and the mixture is / \ S1 NoH, stirred at an internal temperature of 65 C. for approximately C N N+ N-inN 15 minutes, a clear Solution forming. After cooling to 22°C., 50 CH a Suspension again forms, to which 8.2 g of potassium Y. tert-butanolate are added in portions at an internal tempera ture of <40° C. (cooling with an ice-bath). The mixture is then stirred overnight, Subsequently poured into 600 ml of 5.3 g of 5-chloro-2-(1,4-dimethyl-5-methylsulfanyl-1H water, Stirred, filtered and washed, and the aqueous phase is 55 pyrazol-3-yl)-3-fluoropyridine (Example P39) are dissolved extracted thoroughly with tert-butyl methyl ether. The aque in 50 ml of methylene chloride. With stirring, 19.2 g of 70% ous phase is rendered Strongly acidic with concentrated m-chloroperbenzoic acid (MCPBA) are introduced in por hydrochloric acid and extracted with tert-butyl methyl ether. tions at 22°C. with exothermic reaction. The mixture is then The combined ethereal phases are washed with water, dried stirred overnight at 22 C. The next day, a further 4.9 g of over magnesium Sulfate, filtered and concentrated to dryneSS 60 MCPBA are added and the mixture is stirred overnight. The in vacuo. 6.8 g of a crude intermediate are obtained. mixture is Subsequently extracted with dilute Sodium hydro 1.9 g of the intermediate are dissolved in 10 ml of gen carbonate Solution and then with Sodium thiosulfate dimethylformamide (DMF) and 2.2 g of potassium carbon Solution. The extract is dried over magnesium Sulfate and ate are added. 0.5 ml of methyl iodide in 2 ml of DMF is then then filtered and concentrated to dryneSS in vacuo. The crude added dropwise. The mixture is subsequently stirred at 22 65 product (6 g) is purified over Silica gel using ethyl acetate as C. for 5 hours, poured into 120 ml of ice-water, and eluant. 3.6 g of the desired title compound having a melting extracted with diethyl ether. The combined ethereal phases point of 174-176 C. are obtained. US 6,274,536 B1 43 44 Example P41 Example P43 5-(5-Chloro-3-fluoro-1-methyl-6-oxo-1,6-dihydropyridin 3-Chloro-5-fluoro-6-(5-methanesulfonyl-1,4-dimethyl 2-yl)-2,4-dimethyl-2H-pyrazole-3-carbonitrile 1H-pyrazol-3-yl)-1H-pyridin-2-one (Compd. No. 22.100)

F CH V / Sn

2.6 go 5-chloro-3-fluoro-2-(5-methanesulfonyl-1,4- 1.54 g of 3-chloro-6-(1,4-dimethyl-5-cyano-1H dimethyl-1H-pyrazol-3-yl)-pyridine-1-oxide (Example 15 pyrazol-3-yl)-5-fluoropyridin-2-ol are introduced into a mixture of 20 ml of absolute 1,2-dimethoxyethane and 5 ml P40) are introduced into 35 ml of dry dimethylformamide. of absolute dimethylformamide at 22 C. With stirring, first At a temperature of 10° C., 16.8 g of trifluoroacetic anhy 1.20 g of lithium bromide are added and then, 10 minutes dride are added dropwise and the mixture is then Stirred later, in portions, 0.28g of a 60% sodium hydride dispersion overnight at 22 C., Subsequently poured into 2 liters of in oil. After a further 10 minutes, 0.86 ml of methyl iodide ice-water and extracted with tert-butyl methyl ether. After is added, after which the mixture is stirred overnight at 90 drying over magnesium Sulfate, filtering and concentrating C. The mixture is then cooled to 22 C., carefully poured to dryneSS by evaporation in vacuo, 1.8 g of the desired into dilute hydrochloric acid, and extracted with diethyl compound are obtained as crude product, which can be used ether. The combined ethereal phases are washed with brine, directly in the next Step. 25 dried over Sodium Sulfate, filtered and concentrated in vacuo together with 4 g of Silica gel. The Silica gel is applied to a flash chromatography column and fractionated by means of Example P42 gradient elution using n-hexane/ethyl acetate 3/1 to 1/1 3-Chloro-5-fluoro-6-(5-methanesulfonyl-1,4-dimethyl (v/v). 0.68g of the desired compound is obtained in the form 1H-pyrazol-3-yl)-1-propyn-2-yl-1H-pyridin-2-one of a white solid having a melting point of 190-191 C. Example P44 (Compd. No. 28.100) 1-Allyl-3-chloro-6-(4-chloro-5-difluoromethoxy-1-methyl 1H-pyrazol-3-yl)-5-fluoro-1H-pyridin-2-one O. O 35 CH \/ (Compd. No. 1.080) I / \ S1 NoH, C N N N NY, 40 A CH 45 V 1.8 g of 3-chloro-5-fluoro-6-(5-methanesulfonyl-1,4- CH2 dimethyl-1H-pyrazol-3-yl)-1H-pyridin-2-one (Example P41) are dissolved in 10 ml of dimethylsulfoxide and 3.0 ml 1.50 g of 3-(3-fluoro-5-chloro-6-hydroxy-2-pyridyl)-4- of a 2N acqueous Sodium hydroxide Solution are added chloro-5-difluoromethoxy-1-methyl-1H-pyrazole 50 (Example P27) are suspended in a dry mixture of 16 ml of (slightly exothermic reaction). After Subsequently stirring dimethoxyethane and 4 ml of N,N-dimethylformamide for 30 minutes at 22 C., 0.46 ml of propargyl bromide is (DMF). With stirring, a total of 0.20 g of a 55% sodium added dropwise and the mixture is further Stirred overnight hydride dispersion is added, in portions, at 25 C. The at 22 C. The reaction mixture is then introduced into 120 ml Suspension is Subsequently Stirred for ten minutes, 0.79g of of ice-water, filtered, and washed with water. It is taken up 55 anhydrous lithium bromide is then added and, after a further in ethyl acetate, dried over magnesium Sulfate, filtered and fifteen minutes stirring, 0.77 ml of allyl bromide is added concentrated to dryneSS by evaporation in vacuo. The crude dropwise. The mixture is Subsequently Stirred overnight at product is purified by means of Silica gel chromatography 65 C. The next day, TLC analysis of a worked-up sample (eluant: n-hexane/ethyl acetate 1/1 (v/v)). 0.74 g of the shows that Starting material is no longer present. The reac desired title compound, which still contains 20% of the 60 tion mixture is cooled to 2500 and partitioned between dilute isomeric 0-propargyl derivative, is obtained; m.p. 189-192 hydrochloric acid and tert-butyl methyl ether. After extrac C. tion by Shaking, and Separation of the phases, the ethereal phase is washed with brine, dried over Sodium Sulfate, The Rf value of the title compound on silica gel 60 F2s filtered, and concentrated in vacuo together with 5 g of Silica (eluant: n-hexane/ethyl acetate 1/1 (v/v)) is 0.28, the R 65 gel. The Silica gel is applied to a flash chromatography value of the O-propargyl isomer is 0.55, and the R value of column and chromatography is carried out (silica gel; eluant: the starting compound is 0.05. n-hexane/ethyl acetate 2/1 (v/v)). 0.95 g of the target com US 6,274,536 B1 45 46 pound is obtained in the form of a slightly yellowish-brown Subsequently dried over Sodium Sulfate, filtered, and con coloured oil, the R value of which on silica gel 60 F2s centrated to dryneSS in vacuo. 24.3 g of a yellow oil are (eluant: n-hexane/ethyl acetate 1/1 (v/v)) is 0.33. obtained, which is purified by means of flash chromatogra phy (silica gel; eluant: n-hexane/-ethyl acetate 2/1 (v/v)). Example P45 7.67 g of the desired compound are obtained in the form of 1-Ethyl-3-chloro-6-(4-chloro-5-difluoromethoxy-1-methyl a yellow oil which crystallises on being left to Stand; m.p. 1H-pyrazol-3-yl)-5-fluoro-1H-pyridin-2-one 83-85 C. The R value of the starting material on silica gel 60 Fasa (Compa. No. 1.004) (eluant: n-hexane/ethyl acetate/-glacial acetic acid 20/20/1 (v/v/v)) is 0.45, and the R value of the title compound is 0.60. The isomeric O-alkyl derivative is isolated as second ary product. Example P47 3-(3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl 15 1H-pyrazol-3-yl)-5-fluoro-2-oxo-2H-pyridin-1-yl)- O CH5 acetic acid

1.5 g of 3-(3-fluoro-5-chloro-6-hydroxy-2-pyridyl)-4- (Compd. No. 1.177) chloro-5-difluoromethoxy-1-methyl-1H-pyrazole (Example P27) are introduced into 6 ml of dimethylsulfox ide (DMSO). 2.5 ml of a 2N aqueous sodium hydroxide solution are added thereto. 0.78g of ethyl iodide in 2 ml of DMSO is then added dropwise, with stirring, and the mix ture is further stirred overnight at 70° C. The next day, the reaction mixture is partitioned between dilute hydrochloric 25 acid and diethyl ether. After extraction by Shaking, and Separation of the phases, the ethereal phase is washed with OH brine, dried over Sodium Sulfate, filtered and concentrated in vacuo. Finally, the residue is purified over a flash chroma tography column (silica gel; elution gradient: n-hexane/ethyl 6.0 g of 3-(3-chloro-6-(4-chloro-5-difluoromethoxy-1- acetate 4/1 to 1/1 (v/v)). 0.54 g of the desired target methyl-1H-pyrazol-3-yl)-5-fluoro-2-oxo-2H-pyridin-1- compound is obtained in the form of a yellow oil having an yl)-acetic acid benzyl ester (Example P46) are hydrogenated R value of 0.17 on silica gel 60 Fasa (eluant: n-hexane/- at normal pressure and 22 C. with 0.35 g of 5% palladium ethyl acetate 2/1 (v/v)). on-active carbon in 90 ml of tetrahydrofuran (THF). After 2.5 hours, the reaction mixture is filtered over Hyflo and Example P46 35 washed with THF. 5.11 g of the desired title compound are 3-(3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl obtained in the form of a colourless resin, which Solidifies on 1H-pyrazol-3-yl)-5-fluoro-2-oxo-2H-pyridin-1-yl)- being left to Stand. acetic acid benzyl ester 'H-NMR (CDC1): 7.58 ppm (d. 1H); 6.66 ppm (t, 1H); 4.73 ppm (s, 2H); 3.77 ppm (s, 3H). 40 (Compa. No. 1.195) Example P48 3-(3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl 1H-pyrazol-3-yl)-5-fluoro-2-oxo-2H-pyridin-1-yl)- acetic acid imidazolide 45

50

55 10.0 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1- methyl-1H-pyrazol-3-yl)-5-fluoropyridin-2-ol (Example P27) are introduced into a mixture of 100 ml of dimethoxy ethane and 25 ml of dimethylformamide at 22 C. 1.22 g of 2.0 g of 3-(3-chloro-6-(4-chloro-5-difluoromethoxy-1- sodium hydride (60%, moistened in oil) are then added in 60 methyl-1H-pyrazol-3-yl)-5-fluoro-2-oxo-2H-pyridin-1- portions, evolution of gas being observed. After Subse yl)-acetic acid (Example P47) are suspended in 20 ml of quently stirring for 15 minutes at 22 C., 5.3 g of dry lithium 1,2-dichloroethane. With stirring, 0.92 g of 1,1'- bromide are added (slightly exothermic reaction) and, after carbonyidiimidazole is added at 22°C. The mixture is stirred 10 minutes, 9.6 ml of bromoacetic acid benzyl ester are overnight and the resulting Solution is concentrated to dry added. The mixture is then stirred for 5 hours at 75 C. After 65 neSS by evaporation in vacuo. 2.40 g of the desired title cooling to 22 C., the mixture is taken up in ethyl acetate, compound are obtained in the form of a beige Solid, which washed with dilute hydrochloric acid and then with brine, contains 20% by weight imidazole. US 6,274,536 B1 47 48 "H-NMR (DMSO-D): 8.51 ppm (s, 1H); 8.41 ppm (d. Sulfate, filtration and concentration by evaporation in vacuo 1H); 7.77 ppm (m, 1H); 7.33 ppm (t, 1H); 7.13 ppm (m, 1H); yield 0.77 g of the desired compound in the form of a white 5.46 ppm (s, 2H); 3.60 ppm (s, 3H). solid having a melting point of 146-148 C. Example P49 Example P51 3-(3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl 3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-1H 1H-pyrazol-3-yl)-5-fluoro-2-oxo-2H-pyridin-1-yl)- pyrazol-3-yl)-5-fluoro-1-methanesulfanylmethyl)-1H acetic Acid Diethylamide pyridin-2-one

(Compa. No. 1.234) (Compd. No. 1.147)

F C OCHF C \ -N 15 N N nCH O ) v CH

1.0 g of 3-(3-chloro-6-(4-chloro-5-difluoromethoxy-1- 4.0 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1- methyl-1H-pyrazol-3-yl)-5-fluoro-2-oxo-2H-pyridin-1- methyl-1H-pyrazol-3-yl)-5-fluoropyridin-2-ol (Example yl)-acetic acid (Example P47) is introduced into 8 ml of P27) are introduced into a mixture of 40 ml of dry 1,2-dichloroethane. 0.50 g of carbonyidiimidazole is added dimethoxyethane and 10 ml of dry dimethylformamide at to the white Suspension and the mixture is stirred for one 25 22 C., and 0.49 g of a 60% sodium hydride (NaH) disper hour at 22 C., in the course of which all undissolved Sion in hexane is added. After 15 minutes Stirring, 2.12 g of components dissolve. 0.39 ml of diethylamine is then added lithium bromide are added and the mixture is Subsequently and the mixture is stirred overnight at 22 C. The next day, stirred for 10 minutes. 2.0 ml of chlorodimethylsulfide are the reaction mixture is taken up in ethyl acetate and washed then added and the mixture is further stirred overnight at 70 in Succession with dilute Sodium hydrogen carbonate C. After cooling to 22 C., a sample is removed and analysed Solution, dilute hydrochloric acid and brine. After drying in a thin-layer chromatogram (TLC). Since starting material over Sodium Sulfate, filtration is carried out and the residue is still present, a further 0.30g of sodium hydride dispersion is concentrated to dryness in vacuo. 1.20 g of a yellow oil is (60%) and 0.60 ml of chlorodimethylsulfide are added and obtained which is purified over a flash chromatography the mixture is then again stirred overnight at 70° C. After column (silica gel; 35 cooling to 22 C., the mixture is taken up in ethyl acetate, eluant: ethyl acetate). 1.27g of the desired title compound and dilute hydrochloric acid is added carefully. After extrac are obtained in the form of a colourless resin. tion by Shaking, and Separation of the phases, the ethyl "H-NMR (CDC1): 7.61 ppm (d. 1H); 6.72 ppm (t, 1H); acetate phase is washed with brine, dried over Sodium 4.99 ppm (s, 2H); 3.82 ppm (s.3H); 3.27 ppm (m, 4H); 1.13 Sulfate, filtered and concentrated to dryneSS in vacuo. The ppm (t, 3H); 1.04 ppm (t, 3H). 40 crude product is purified over Silica gel (eluant: n-hexane/ Example P50 ethyl acetate 2/1 (v/v)). First 0.51 g of the 0-alkyl isomer is 3-(3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl eluted and then 3.04 g of the desired title compound in the 1H-pyrazol-3-yl)-5-fluoro-2-oxo-2H-pyridin-1-yl-acetic form of a yellow oil, which slowly crystallises out. The Rf value of the title compound on silica gel 60 Fasa Acid Allylamide 45 (eluant: n-hexane/ethyl acetate/glacial acetic acid 20/20/1 (Compa. No. 1.244) (v/v/v)) is 0.37, the R-value of the O-alkyl isomer is 0.70 and F Cl the R value of the starting material is 0.31. Example P52 50 3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-1H pyrazol-3-yl)-5-fluoro-1-methanesulfonylmethyl)-1H pyridin-2-one

(Compd. No. 1.153)

55

i \ C

CH 1.0 g of 3-(3-chloro-6-(4-chloro-5-difluoromethoxy-1- 60 methyl-1H-pyrazol-3-yl)-5-fluoro-2-oxo-2H-pyridin-1- 'ss yl)-acetic acid imidazolide (crude product) (Example P43) is o2\2 introduced into 6 ml of 1,2-dichloroethane at 22 C. After CH the addition of 0.21 ml of allylamine, the mixture is stirred overnight and then taken up in ethyl acetate and washed in 65 Succession with dilute Sodium hydroxide Solution, brine, 1.97 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1- dilute hydrochloric acid and brine. Drying over sodium methyl-1 H-pyrazol-3-yl)-5-fluoro-1- US 6,274,536 B1 49 SO methanesulfanylmethyl)-1H-pyridin-2-one (Example P51) mixture is cooled to 22 C., diluted with methylene chloride are introduced into 25 ml of dichloroethane at 22 C. 3.75 g and, after the addition of 3 g of Silica gel, concentrated to of m-chloroperbenzoic acid (70%) are added to the yellow dryneSS in vacuo. The Silica gel is applied to a flash Solution with a slight exothermic reaction. The mixture is chromatography column and eluted first with toluene/ethyl stirred overnight at 22°C. The next day, the reaction mixture acetate 30/1 (v/v) and then with n-hexane/ethyl acetate 2/1 is taken up in ethyl acetate and washed with dilute Sodium (v/v). 0.32 g of the desired title compound is obtained in the hydroxide solution and then with brine. After drying over form of a yellow solid having a melting point of 135-138 Sodium Sulfate, filtration is carried out followed by concen C. tration to dryness in vacuo. 2.05 g of the desired title The R value of the starting material on silica gel 60 Fasa compound are obtained in the form of a white Solid having (eluant: toluenelethyl acetate 30/1 (v/v)) is 0.02 and the R a melting point of 171-172 C. value of the title compound is 0.18. Example P53 Example P55 3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-1H 3-(3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl pyrazol-3-yl)-5-fluoro-1-methanesulfinylethyl)-1H 1H-pyrazol-3-yl)-5-fluoro-2-oxo-2H-pyridin-1-yl)- pyridin-2-one 15 propionaldehyde

(Compa. No. 1.161) (Compd. No. 1.294)

F C OCHF C / \ N/s N N N- YCH, O 25

SFO M CH 1.18 g o 3-chloro-6-(4-chloro-5-difluoromethoxy-1- 0.40 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1- methyl-1 H-pyrazol-3-yl)-5-fluoro-1- methyl-1H-pyrazol-3-yl)-1-(2-1.3-dioxolan-2-ylethyl)- methanesulfanylethyl)-1H-pyridin-2-one are introduced 5-fluoro-1H-pyridin-2-one is stirred overnight at 22 C. in into 7 ml of glacial acetic acid. After the addition of 0.27g a mixture of 6 ml of 2N hydrochloric acid and 6 ml of diethyl of hydrogen peroxide/urea adduct, the mixture is stirred 35 ether. The next day, the same amount of the mixture together overnight at 22 C. The next day, the reaction mixture is with 2 ml of tetrahydrofuran are added and the mixture is taken up in ethyl acetate and washed in Succession with again Stirred overnight. The mixture is Subsequently diluted dilute sodium hydroxide solution, dilute hydrochloric acid with diethyl ether and washed three times with brine, dried and brine. After drying over Sodium Sulfate, the mixture is over Sodium Sulfate, filtered and concentrated to dryneSS in filtered and concentrated to dryneSS in vacuo. The residue 40 vacuo. 0.23g of the desired compound (crude) is obtained (1.12 g of a yellow solid) is stirred with 10 ml of diethyl in the form of a yellow oil. ether, and then filtered and washed with n-hexane. 1.05 g of 'H-NMR (CDC1): 9.73 ppm (s, 1H); 7.61 ppm (d. 1H); the desired compound are obtained in the form of a white 6.73 ppm (t, 1H); 4.15 ppm (broad signal, 2H); 3.85 ppm (s, solid having a melting point of 143-145 C. 3H); 2.98 ppm (t, 2H). 45 Example P54 Example P56 1-Benzyl-3-chloro-6-(4-chloro-5-difluoromethoxy-1- 2-(3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl methyl-1H-pyrazol-3-yl)-5-fluoro-1H-pyridine-2-thione 1H-pyrazol-3-yl)-5-fluoropyridin-2-yloxy)-acetamide

(Compa. No. 1.494) 50

55

NH2 60 20.0 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1- 0.50 g of 1-benzyl-3-chloro-6-(4-chloro-5- methyl-1H-pyrazol-3-yl)-5-fluoropyridin-2-ol (Example difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-5-fluoro P27) are placed together with 18.9 g of potassium carbonate 1H-pyridin-2-one is introduced into 5 ml of toluene, 0.63 65 and 6.4 g of chloroacetamide at 22 C. and the mixture is g of Lawesson's reagent is added and the resulting yellow stirred overnight at 50 C. The next day, the mixture is suspension is stirred overnight at 120° C. The next day, the cooled to 22 C. and then introduced into 2 liters of US 6,274,536 B1 S1 52 ice-water. After Subsequently stirring for 10 minutes at 22 washed with dilute Sodium hydrogen carbonate Solution and C., the resulting slurry is filtered. The filtration residue is then with brine. The organic phase is dried over Sodium washed with cold water and then dried in vacuo at 60° C. Sulfate and then filtered and concentrated to dryneSS in vacuo. The residue obtained is digested in n-hexane, filtered, 20.2 g of the desired title compound are obtained in the form washed and dried. 1.88 g of the title compound are obtained of a white solid having a melting point of 178-180° C. in the form of a beige Solid having a melting point of Example P57 140-143° C. 3-Chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-1H Example P59 pyrazol-3-yl)-5-fluoropyridin-2-ylamine 8-Chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H pyrazol-3-yl)-6fluoro-imidazol,2-apyridine-2-carboxylic Acid

(Compd. No. 72.113)

15

7.1 g of potassium carbonate are introduced into 200 ml of dry N-methylpyrrolidone (NMP) and the mixture is heated to a temperature of 150° C. With stirring, 19.6 g of 2-(3-chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-1H pyrazol-3-yl)-5-fluoropyridin-2-yloxy)-acetamide (Example O OH P56) are introduced in portions in the course of 2 hours and then the mixture is stirred for 10 hours at 150 C., Subse 25 0.51 g of 8-chloro-5-(4-chloro-5-difluoromethoxy-1- quently cooled to 22 C. and partitioned between diethyl methyl-1H-pyrazol-3-yl)-6-fluoro-imidazo 1,2-a ether and water. After extraction by Shaking, and Separation pyridine-2-carboxylic acid ethyl ester (Example P58) is of the phases, the ethereal phase is washed with brine, dried dissolved in 3 ml of dimethylsulfoxide and, with cooling in over Sodium Sulfate, filtered and concentrated together with an ice-bath, 0.63 ml of a 2N acqueous sodium hydroxide twice the amount of Silica gel. The Silica gel is applied to a Solution is added. The mixture is then stirred for 1 hour at flash chromatography column and then elution is carried out 22 C. Because the TLC analysis of a worked-up sample with a n-hexane/ethyl acetate 111 (v/v) mixture. 9.3 g of the indicates that Starting material is still present, a further 0.1 desired title compound having a melting point of 100-101 ml of 2N Sodium hydroxide Solution is added. After Subse C. are obtained. quently Stirring for 30 minutes, the mixture is rendered The Rf value of the starting material on silica gel 60 F2s 35 Strongly acidic with dilute hydrochloric acid, the resulting (eluant: n-hexane/ethyl acetate 1/1 (v/v)) is 0.14 and the R Slurry is filtered, and the filtration residue is Subsequently value of the target compound is 0.43. washed with cold water and dried in vacuo at 50° C. 0.35g of the desired title compound is obtained in the form of a Example P58 white Solid (crude product). 8-Chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H 40 Example P60 pyrazol-3-yl)-6-fluoro-imidazol,2-apyridine-2-carboxylic 8-Chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H Acid Ethyl Ester pyrazol-3-yl)-6-fluoro-imidazol,2-apyridin-2-yl)methanol

(Compd. No. 72.133) (Compd. No. 72.083) 45 F C

N 50 - l 2 Na2

O OCHs CH2OH 55 0.56 g of 8-chloro-5-(4-chloro-5-difluoromethoxy-1- 1.96 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1- methyl-1H-pyrazol-3-yl)-6-fluoro- imidazo 1,2-a methyl-1H-pyrazol-3-yl)-S-fluoropyridin-2-ylamine pyridine-2-carboxylic acid ethyl ester (Example P58) is (Example P57) are placed together with 1.25 ml of bro introduced at 22 C. into 5 ml of diethyl ether and then mopyruvic acid ethyl ester (90%) in 20 ml of absolute 60 treated with a total of 0.18 g of lithium aluminium hydride ethanol. The mixture is stirred for 6 hours at 90° C. and then in portions with Stirring. The resulting reddish-brown Sus cooled to 22 C. and concentrated to dryness in vacuo. The pension is Subsequently Stirred for 1 hour and then first an residue is crystallised by the addition of diethyl ether and excess of ethyl acetate and then dilute hydrochloric acid are Stirred, and n-hexane is added until precipitation is com added dropwise. The Separated organic phase is washed with plete. The crystal fraction is filtered off, washed with 65 brine, filtered and concentrated to dryneSS in vacuo. 0.14g n-hexane and dried in vacuo. 2.52 g of a yellowish-brown of a yellowish-brown oil is obtained, which is purified over Solid are obtained, which is dissolved in ethyl acetate and Silica gel using ethyl acetate as eluant. 0.40 g of the desired US 6,274,536 B1 S3 S4 compound is obtained in the form of a beige Solid having a melting point of 152-153 C. (IA)

The preferred compounds listed in the following Tables can also be prepared in an analogous manner, and according to methods Such as are illustrated in the general Reaction Schemes 1-3 and in the references quoted. Table 1: A preferred group of compounds of formula I corresponds to the general formula in which the Sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com (I1) pounds of formula I. 15 Table 5: Another preferred group of compounds of formula I corresponds to the general formula

(Is)

F, in which the sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com pounds of formula I. 25 Table 2: in which the Sets of correlated Substituents R, X and R. Another preferred group of compounds of formula I are given in Table A, thus disclosing 654 specific com corresponds to the general formula pounds of formula Is. Table 6: (I2) Another preferred group of compounds of formula I corresponds to the general formula 35 (I6)

F,

40 in which the Sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com pounds of formula I. 45 in which the sets of correlated Substituents R, X and R. Table 3: are given in Table A, thus disclosing 654 specific com Another preferred group of compounds of formula I pounds of formula I. corresponds to the general formula Table 7: Another preferred group of compounds of formula I (I) 50 corresponds to the general formula

(I-7)

55

in which the Sets of correlated Substituents R, X and R. 60 are given in Table A, thus disclosing 654 specific com in which the sets of correlated Substituents R, X and R. pounds of formula I. are given in Table A, thus disclosing 654 specific com Table 4: pounds of formula I-7. 65 Table 8: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 SS S6

(Is) (I12)

1O in which the Sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com in which the Sets of correlated Substituents R, X and R. pounds of formula Is. are given in Table A, thus disclosing 654 specific com Table 9: pounds of formula I. 15 Table 13: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula (Ig) (I13)

25 in which the Sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com in which the Sets of correlated Substituents R, X and R. pounds of formula Io. are given in Table A, thus disclosing 654 specific com Table 10: pounds of formula I. Table 14: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula (I10) 35 (I14)

40

in which the Sets of correlated Substituents R, X and R. 45 are given in Table A, thus disclosing 654 specific com in which the Sets of correlated Substituents R, X and R. pounds of formula I. are given in Table A, thus disclosing 654 specific com Table 11: pounds of formula I. Table 15: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula (I11) (I15)

55

60 in which the sets of correlated Substituents R, X and R. in which the Sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com are given in Table A, thus disclosing 654 specific com pounds of formula I. pounds of formula Is. Table 12: 65 Table 16: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 57 58

(I16) (I.20)

1O in which the Sets of correlated Substituents R, X and R. in which the Sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com are given in Table A, thus disclosing 654 specific com pounds of formula I. pounds of formula I. Table 17: 15 Table 21: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula (I17) (I21)

25 in which the Sets of correlated Substituents R, X and R. in which the Sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com are given in Table A, thus disclosing 654 specific com pounds of formula Iz. pounds of formula I. Table 18: Table 22: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 35 (I18) (I22)

40

in which the Sets of correlated Substituents R, X and R. 45 in which the sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com are given in Table A, thus disclosing 654 specific com pounds of formula Is. pounds of formula I. Table 19: Table 23: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula (I19) (I23)

55

60 in which the Sets of correlated Substituents R, X and R. in which the sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com are given in Table A, thus disclosing 654 specific com pounds of formula Io. pounds of formula I. Table 20: 65 Table 24: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 59

(I.24) (I28)

1O in which the sets of correlated Substituents R, X and R. in which the sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com are given in Table A, thus disclosing 654 specific com pounds of formula I. pounds of formula Is. Table 25: 15 Table 29: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general corresponds to the general formula (I-29) (I25)

25 in which the sets of correlated substituents R, X and R3 in which the Sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com are given in Table A, thus disclosing 654 specific com pounds of formula Is. pounds of formula Io. Table 26: Table 30: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general corresponds to the general formula 35 (I30) (126)

40

in which the Sets of correlated Substituents R, X and R. 45 in which the Sets of correlated Substituents R, X and R. are given in Table AX thus disclosing 654 specific com are given in Table A, thus disclosing 654 specific com pounds of formula I. pounds of formula I. Table 27: Table 31: Another preferred group of compounds of formula i Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula (I27) (I31)

55

60 in which the Sets of correlated Substituents R, X and R. in which the Sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com are given in Table A, thus disclosing 654 specific com pounds of formula I-7. pounds of formula I. Table 28: 65 Table 32: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 61 62

(I32) (I36)

in which the Sets of correlated Substituents R, X and R. in which the Sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com are given in Table A, thus disclosing 654 specific com- pounds of formula I. pounds of formula I. 15 Table 37: Table 33: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula (I37) (I33) 20

25

in which the Sets of correlated Substituents R, X and R. are given in Table A, thus disclosing 654 specific com in which the Sets of correlated Substituents R, X and R. 3O pounds of formula I-7. are given in Table A, thus disclosing 654 specific com pounds of formula I. TABLE A Table 34: Another preferred group of compounds of formula I corresponds to the general formula 35 No. R11 X Rs OO1 H O CH, OO2 F O CH

(I34) OO3 C O CH OO4 F O CHCH OO5 C O CHCH, 0 006 H O CHCH OO7 F O CHCHCH O08 C O CHCHCH, O09 H O CHCHCH O1O F O CHCHCHCH O11 C O CHCHCHCH 45 012 F O CHCHCHCHCH, O13 C O CHCHCHCHCH in which the Sets of correlated Substituents R, X and R. O14 F O CHCHCHCHCHCH are given in Table A, thus disclosing 654 specific com- O15 F O CHCH-CH(CH), O16 C O CHCHCH(CH), pounds of formula I. O17 H O CHCH-CH(CH), Table 35: Another preferred group of compounds of 50 .018 F O CHCH(CH)CHCH, formula I corresponds to the general formula O19 C O CHCH(CH)CHCH, O2O H O CHCH(CH)CHCH, O21 F O CHCH(CH)CHCHCH,

(I35) O22 F O CHCH-CH(CH)CHCH, O23 F O CHCHCH-CH(CH), 55 .024 F O CH(CH)CHCHCHCH, O25 Cl O CH(CH)CHCHCHCH, O26 H O CH(CH)CHCHCHCH, O27 F O CHC(CH), O28 CI O CHC(CH), O29 H O CHCH(CH), O3O Cl O CHCH(CH), 60 031 F O CHCH(CH), O32 F O CHC(CH),CHCH, O33 Cl O CHC(CH),CHCH, in which the Sets of correlated Substituents R, X and R. O34 H O CHC(CH),CHCH, are given in Table A, thus disclosing 654 specific com- O35 F O CHCHC(CH), O36 Cl O CHCHC(CH), pounds of formula Is. 65 037 F O CHCHCHCH, Table 36: Another preferred group of compounds of O38 C1 O CHCHCHCH, formula I corresponds to the general formula

US 6,274,536 B1 71 72 in which the Sets of correlated Substituents R, R2 and R TABLE A-continued are given in Table B, thus disclosing 264 specific com Compd. pounds of formula Iss. No. R. X1 R1s Table 39: 6O1 F S OCHSCH. Another preferred group of compounds of formula I 6O2. Cl S OCHCHCH, corresponds to the general formula 603 F S OCHCHCH, 604 H S OCHCCH 605 Cl S OCHCCH (I39) 606 F S OCHCCH 6O7 F S OCH(CH)CHCH, 608 F S OCH(CH)CCH .609 F S OCHCHCl 610 F S OCHCHCF .611 F S OCHCHCH(CI) 612 H S OCHCHO 15 613 H S OCHCHO .614 H S OCHCHO 615 H S OCHCOOH 616 Cl S OCHCOOH 617 F S OCHCOOH 618 H S OCHCOOCHCH 619 Cl S OCHCOOCHCH, 62O F S OCHCOOCHCH in which the Sets of correlated Substituents R, R and R. 621 F S OCH(CH)COOH are given in Table B, thus disclosing 264 specific com 622 F S OCH(CH)COOCHCH, 623 F S OCH(CH)COOCHCCH pounds of formula Iso. .624 F S OCHC(O)NH, Table 40: .625 F S OCHC(O)NH(CH.) 25 626 F S OCHC(O)N(CHCH.), Another preferred group of compounds of formula I 627 F S OCHC(O)NHCCHCCH) 628 C S OCHC(O)N(CH), corresponds to the general formula 629 F S OCHC(O)N(CH), 630 F S OCHC(O)N(CH)(CH(o-F-CH)) (140) 631 C S OCHC(O)SCH, 632 F S OCHC(O)SCH, 633 F S OCH(O)SCHCH, 634 H S OCHC(O)SCH(CH), 635 C S OCHC(O)SCH(CH), 636 F S OCHC(O)SCH(CH), 637 C S OCHC(O)SCHCHs 35 .638 F S OCH(CH)C(O)SCHCHs 639 H S OCHCH-OH 640 C S OCHCH-OH .641 F S OCHCH-OH .642 H S OCHCHCCH)OH 643 C S OCHCHCCH)OH 40 .644 F S OCHCHCCH)OH .645 F S OCHCHCl in which the Sets of correlated Substituents R, R and R. .646 F S OCHCF, are given in Table B, thus disclosing 264 specific com 647 C S OCHCN 648 F S OCHCN pounds of formula I. 649 H S OCHCHCN Table 41: .650 C S OCHCHCN 45 651 F S OCHCHCN Another preferred group of compounds of formula I 652 C S OCHCHCF corresponds to the general formula 653 F S OCHCHCF .654 F S OCHCH(OH)(CH.) (141) 50 Table 38: A preferred group of compounds of formula I corresponds to the general formula 55 (I38)

60 in which the Sets of correlated Substituents R, R and R. are given in Table B, thus disclosing 264 specific com pounds of formula I.

65 Table 42 Another preferred group of compounds of formula I corresponds to the general formula US 6,274,536 B1 73 74

(I42) (I45)

1O

in which the Sets of correlated Substituents R, R2 and R 15 in which the Sets of correlated Substituents R, R and R. are given in Table B, thus disclosing 264 specific com are given in Table B. thus disclosing 264 specific com pounds of formula I. pounds of formula Is. Table 43: Table 46: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula (I43) (146) 25

35 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula I. pounds of formula I. 40 Table 44: Table 47: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 45 (I47) (I44)

50

55

in which the Sets of correlated Substituents R, R2 and R 60 in which the Sets of correlated Substituents R, R and R. are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula I. pounds of formula Iz.

Table 45: Table 48: 65 Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1

(I48) (Isi)

1O

in which the Sets of correlated Substituents R, R2 and R 15 in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula Is. pounds of formula Is. Table 49: Table 52: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

(I49) (I52)

25

35 in which the Sets of correlated Substituents R, R2 and R in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula I. pounds of formula Is. 40 Table 50: Table 53: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 45 (ISO) (I53)

50

55

in which the Sets of correlated Substituents R, R and R. 60 in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula Iso. pounds of formula Is.

Table 51: Table 54: 65 Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 77 78

(154) (Is)

1O

in which the Sets of correlated Substituents R, R and R. 15 in which the Sets of correlated Substituents R, R and R. are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula Is. pounds of formula Isz. Table 55: Table 58: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula (158) (Iss) 25

35 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula Iss. 40 pounds of formula Iss. Table 56: Table 59: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 45 (159) (156)

50

55

in which the Sets of correlated Substituents R, R and R. 60 in which the Sets of correlated Substituents R, R2 and R are given in Table e, thus disclosing 264 Specific compounds are given in Table B, thus disclosing 264 specific com of formula Is. pounds of formula Iso. Table 57: Table 60: 65 Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 79 80

(160) (I63)

1O

in which the Sets of correlated Substituents R, R2 and R 15 in which the Sets of correlated Substituents R, R and R. are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula Ico. pounds of formula I. Table 64: Table 61: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula (164) (I61) 25

35 in which the Sets of correlated Substituents R, R2 and R in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula Is. 40 pounds of formula I. Table 62: Table 65: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 45 corresponds to the general formula (165) (I62)

50

55

in which the Sets of correlated Substituents R, R2 and R 60 in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula I. pounds of formula Is. Table 63: Table 66: 65 Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 81 82

(166) (169)

1O

in which the Sets of correlated Substituents R, R2 and R 15 in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula I. pounds of formula Iso. Table 67: Table 70: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

(I67) (I70)

25

35 in which the Sets of correlated Substituents R, R2 and R in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula Iz. 40 pounds of formula Izo. Table 68 Table 71: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 45 corresponds to the general formula (168) (I-71)

50

55

in which the Sets of correlated Substituents R, R2 and R 60 in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula Is. pounds of formula I-7. Table 69: Table 72: 65 Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 83 84

(I72) R11 Cl O F, R12 / \ N N N-N F f Na 1O R34 in which the Sets of correlated Substituents R, R2 and R 15 in which the Sets of correlated Substituents R, R and R. are given in Table B. thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula Iz. pounds of formula I-7s. Table 73: Table 76: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

(I73) (I-76) R11 Br 25

R12 / F t N N1N R34 35 in which the Sets of correlated Substituents R, R and R. are given in Table B, thus disclosing 264 specific com in which the Sets of correlated Substituents R, R and R. pounds of formula I-7. are given in Table B, thus disclosing 264 specific com 40 pounds of formula I-7. Table 74: Table 77: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 45 corresponds to the general formula (I74) (I-77)

50

55

in which the Sets of correlated Substituents R, R and R. 60 in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 264 specific com are given in Table B, thus disclosing 264 specific com pounds of formula Iz. pounds of formula I-77. Table 75: Table 78: 65 Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 85 86

(I78) (181)

R 11 C ey

R-( N) {N1N f N2 1O R34 in which the Sets of correlated Substituents R, R2 and R 15 in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 254 specific com are given in Table B, thus disclosing 264 specific com pounds of formula I-7s. pounds of formula Is. Table 79: Table 82: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

(I-79) (182) 25

35 in which the Sets of correlated Substituents R, R and R. are given in Table B. thus disclosing 264 specific com in which the Sets of correlated Substituents R, R2 and R pounds of formula Izo. are given in Table B, thus disclosing 264 specific com 40 pounds of formula Is. Table 80: Table 83: Another preferred group of compounds of formula I corresponds to the general formula Another preferred group of compounds of formula I 45 corresponds to the general formula (180) (Is3) R11 Cl S 50 R12 / \ n N N1N f Na 55

in which the Sets of correlated Substituents R, R and R. 60 in which the Sets of correlated Substituents R, R2 and R are given in Table B, thus disclosing 264 specific com are given in Table B. thus disclosing 264 specific com pounds of formula Iso pounds of formula Is. Table 81: Table 84: 65 Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 87 88

(184) (Is7)

O R11 Cl | SN R12 / \ s N N1N f Na 1O

R34

in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R2 and R 15 are given in Table B. thus disclosing 264 specific com are given in Table B. thus disclosing 264 specific com pounds of formula Isz. pounds of formula Is. Table 88: Another preferred group of compounds of formula I Table 85: corresponds to the general formula Another preferred group of compounds of formula I (188) corresponds to the general formula

(185) 25 R11 Cl O WN - SkiN N1N s

R34 in which the Sets of correlated Substituents R, R and R. 35 are given in Table B, thus disclosing 264 specific com pounds of formula Iss. in which the Sets of correlated Substituents R, R2 and R TABLE B are given in Table B, thus disclosing 264 specific com pounds of formula Iss. 40 Compd. No. R. R12 R32 or Rs Table 86: OO1 H C H OO2 Cl C H OO3 F C H Another preferred group of compounds of formula I OO4 H Br H corresponds to the general formula 45 OOS Cl Br H OO6 F Br H OO7 C1 CF H (186) O08 F CF H O09 F CH H O1O F OCF, H O11. H C CH O12 Cl C CH O13 F C CH O14 H Br CH, O15 Cl Br CH O16 F Br CH 55 O17 Cl CF CH O18 F CF, CH, O19 F CH CH O2O F OCF, CH O21 H C CHCHCH, O22 Cl C CHCHCH, 60 O23 F C CHCHCH, in which the Sets of correlated Substituents R, R2 and R O24 H Br CHCHCH, are given in Table B, thus disclosing 264 specific com O25 Cl Br CHCHCH, pounds of formula Is. O26 F Br CHCHCH, O27 Cl CF CHCHCH, Table 87: O28 F CF CHCHCH, O29 F CH CHCHCH, 65 O3O F OCF, CHCHCH, Another preferred group of compounds of formula I O31 H C CHCH(CH), corresponds to the general formula US 6,274,536 B1 89 90

TABLE B-continued TABLE B-continued Compd. Compd. No. Rs2 or Rs No. R R12 Rs2 or Rs CHCH(CH), 108 CF CHOCHCHCH, CHCH(CH), 109 CHOCHCHCH, CHCH(CH), 110 CHOCHCHCH, CHCH(CH), ..111 : COOH CHCH(CH), .112 I COOH CHCH(CH), 1O 113 COOH CHCH(CH), .114 COOH CHCH(CH), 115 COOH CHCH(CH), .116 COOH CHCCH 117 COOH CHCCH 118 COOH CHCCH 15 119 COOH CHCCH 12O COOH CHCCH .121 COOCH, CHCCH 122 COOCH, CHCCH 123 COOCH, CHCCH .124 COOCH, CHCCH 125 COOCH, CHCCH 126 COOCH, CF, 127 COOCH, CF, 128 COOCH, CF, 129 COOCH, CF, 130 COOCH, CF, 131 COOCHCH CF, 25 132 COOCHCH CF, 133 COOCHCH CF, 134 COOCHCH, CF, 135 COOCHCH CF, 136 COOCHCH CHCI 137 COOCHCH CHCI 138 COOCHCH, CHCI 139 COOCHCH CHCI 140 COOCHCH CHCI .141 COOCH(CH), CHCI 142 COOCH(CH), CHCI 143 COOCH(CH), CHCI 35 .144 COOCH(CH), CHCI 145 COOCH(CH), CHCI .146 COOCH(CH), CHCN 147 COOCH(CH), CHCN 148 COOCH(CH), CHCN 149 COOCH(CH), CHCN 150 COOCHCHCH, CHCN 40 151 COOCHCCH CHCN 152 COOCH(o-F-CHs) CHCN 153 COOCHCH CHCN 154 I COOCHCH CHCN 155 COOCHCH CHCN 156 COOCHCH CHOH 45 157 COOCHCH CHOH 158 COOCHCH CHOH 159 I COOCHCH CHOH 160 COOCHCH CHOH .161 COOCHCH CHOH 162 COOCHCH CHOH 50 163 COOCHCHCI CHOH .164 COSCH(CH), CHOH 165 I COSCH(CH), CHOH 166 COSCH(CH), CHOC(O)CH, 167 COSCH(CH), CHOC(O)CH, 168 COSCH(CH), CHOC(O)CH, 55 169 COSCH(CH), CHOC(O)CH, 170 COSCH(CH), CHOC(O)CH, 171 COSCH(CH), CHOC(O)CH, 172 COSCH(CH), CHOC(O)CH, 173 COSCH(CH), CHOC(O)CH, 74 CONHCHCCH CHOC(O)CH, 175 CONHCHCCH CHOC(O)CH, 60 176 CONHCHCCH CHOCHCHCH, 177 CONHCHCCH CHOCHCHCH, 178 CONHCHCCH CHOCHCHCH, 179 CONHCHCCH CHOCHCHCH, 18O CONHCHCCH CHOCHCHCH, 181 CONHCHCCH CHOCHCHCH, 65 182 CONHCHCCH CHOCHCHCH, 183 CONHCHCCH US 6,274,536 B1 91

TABLE B-continued TABLE B-continued Compd. Compd. No. Rs2 or Rs No. R. R12 Rs2 or Rs 184 CONCHCH.), 26O F C C(O)CH, .185 CONCHCH.), .261 F C CN 186 CONCHCH.), .262 Cl CF CN 187 CONCHCH.), .263 F C C(S)NH, 188 CONCHCH.), .264 Cl CF C(S)NH, 189 CONCHCH.), 190 CONCHCH.), 191 CONCHCH.), Table 89: .192 CONCHCH.), 193 CONCHCH.), A preferred group of compounds of formula I corresponds 194 CONCHCHCH.), 195 CONCCHCH.)CHCHCH, 15 to the general formula 196 CONHCHCHCCH), 197 CONH(SOCH.) 198 CHO (189) 199 CHO 2OO CHO 2O1 CHO 2O2 CHO 2O3 CHO .204 CHO 205 CHO 2O6 CHO 2O7 CHO 208 CHNOH 25 209 CHNOH 210 CHNOH in which the Sets of correlated Substituents R, R and R. .211 CHNOH are given in Table C, thus disclosing 627 specific com 212 CHNOH pounds of formula Iso. 213 CHNOH .214 CHNOH Table 90: 215 CHNOH 216 CHNOH Another preferred group of compounds of formula I 217 CHNOH corresponds to the general formula .218 CHNOCHCCH 219 CHNOCHCCH (190) 22O CHNOCHCCH 35 221 CHNCCHCCH .222 CHNOCHCCH .223 CHNOCHCCH .224 CHNOCHCCH 225 CHNOCHCCH 226 CHNOCHCCH 40 227 CHNOCHCCH 228 CHNOCH, .229 CHNOCHCHCH, 230 CHCOOH 231 CHCOOH in which the Sets of correlated Substituents R, R2 and R. 232 CHCOOH 233 CHCOOH 45 are given in Table C, thus disclosing 627 specific com 234 CHCOOH pounds of formula I. 235 CHCOOH Table 91: 236 CHCOOH 237 CHCOOH Another preferred group of compounds of formula I .238 CHCOOH .239 CHCOOH 50 corresponds to the general formula 240 CHCOOCH .241 CHCOOCH(CH), (191) .242 CHCOOCHCHCH, 243 CHCHCOOH .244 CHCHCOOH .245 CHCHCOOH 55 .246 CHCHCOOH .247 CHCHCOOH 248 g CHCHCOOH 249 CHCHCOOH 250 CHCHCOOH 251 CHCHCOOH 252 CHCHCOOH 60 .253 CHCHCOOCHCH in which the Sets of correlated Substituents R, R2 and R. .254 CHCHCOOCH(CH), are given in Table C, thus disclosing 627 specific com 255 CHCHCOOCHCHCH, .256 CHCHCOOCHC(CH)CH, pounds of formula I. 257 CHCHCOOCHCCH Table 92: 258 CHCHCOOCH(CH)CCH 65 259 CH(OH)CH, Another preferred group of compounds of formula I corresponds to the general formula US 6,274,536 B1 93 94

(I92) (196)

1O in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula Io. pounds of formula Io. Table 93: Table 97: Another preferred group of compounds of formula I 15 Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula (I93) (I97)

25 in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula Io. pounds of formula Ioz. Table 94: Table 98: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

35 (I98) (194)

40

in which the Sets of correlated Substituents R, R2 and R. 45 in which the Sets of correlated Substituents R, R and R. are given in Table C, thus do sing 627 Specific compounds are given in Table C, thus disclosing 627 specific com of formula Io. pounds of formula Is. Table 95: Table 99: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula (I99) (195)

55

60 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula Ios. pounds of formula Iloo. Table 96: 65 Table 100: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 95 96

(1100) (1104)

1O in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula I. pounds of formula I. Table 101: 15 Table 105: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula (I101) (1105)

25 in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula I. pounds of formula Ios. Table 102: Table 106: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 35 (1102) (1106)

40

in which the Sets of correlated Substituents R, R and R. 45 in which the Sets of correlated Substituents R, R and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula I. pounds of formula Io. Table 103: Table 107: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula

(1103) (I107)

55

60 in which tire Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula Ios. pounds of formula Ioz. Table 104: 65 Table 108: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 97 98

(I.108) (I112)

1O in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula Ios. pounds of formula I. Table 109: Table 113: Another preferred group of compounds of formula I 15 Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

(I109) (I113)

25 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula Iloo. pounds of formula I. Table 110: Table 114: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 35 (I110) (I114)

40

in which the Sets of correlated Substituents R, R2 and R. 45 in which the Sets of correlated Substituents R, R2 and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula Io. pounds of formula I. Table 111: Table 115: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula

(I111) (I115)

55

60 in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula I. pounds of formula Is. Table 112: 65 Table 116: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 99 100

(I116) (I120)

1O in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula I. pounds of formula I. Table 117: Table 121: Another preferred group of compounds of formula I 15 Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

(I117) (I121)

25 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula I-7. pounds of formula I. Table 118: Table 122: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 35 (I122) (1118)

40

in which the Sets of correlated Substituents R, R2 and R. 45 in which the Sets of correlated Substituents R, R and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula Is. pounds of formula I. Table 119: Table 123: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula

(I123)

(1119)

55

60 in which the Sets cf correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula Io. pounds of formula I. Table 120: 65 Table 124: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 101 102

(I124) (I128)

1O in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula I. pounds of formula Is. Table 125: 15 Table 129: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

(I125) (I129)

25 in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula Is. pounds of formula Io. Table 126: Table 130: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 35 (I126) (I130)

40

in which the Sets of correlated Substituents R, R and R. 45 in which the Sets of correlated Substituents R, R2 and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula I. pounds of formula Iso. Table 127: Table 131: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula

(I127) (I131)

55

60 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula I-7. pounds of formula I. Table 128: 65 Table 132: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the genera; formula corresponds to the general formula US 6,274,536 B1 103 104

(I132) (I136)

1O in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula I. pounds of formula I. Table 133: 15 Table 137: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

(I133) (I137)

25 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula I. pounds of formula I-7. Table 134: Table 138: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

35 (I138) (I134)

40

in which the Sets of correlated Substituents R, R and R. 45 in which the Sets of correlated Substituents R, R and R. are given in Table C. thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula I. pounds of formula Is Table 135: Table 139: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula (I139) (I135)

55

60 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table C, thus disclosing 627 specific com are given in Table C, thus disclosing 627 specific com pounds of formula Is. pounds of formula Iso. Table 136: 65 Table 140: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 105 106

(I140) TABLE C-continued

Compd. No. R R12 R13 CHO CHCHCH, CHO CHCHCH, CHO CHCHCH, CHF, CHCHCH, CHF, CHCHCH, CHF, CHCHCH, COOH CHCHCH, COOH CHCHCH, COOH CHCHCH, in which the Sets of correlated Substituents R, R2 and R. COOCHCH CHCHCH, are given in Table C, thus disclosing 627 specific com COOCHCH CHCHCH, pounds of formula Io. COOCHCH CHCHCH, Table 141: 15 CN CHCHCH, CN CHCHCH, Another preferred group of compounds of formula I CN CHCHCH, corresponds to the general formula C CHCH C CHCH (I141) CHCH CHCH CHCH CHCH CHCH CHCH CHCH CH CHCH 25 CH CHCH CH CHCH OH CHCH OH CHCH in which the Sets of correlated Substituents R, R and R. OH CHCH are given in Table C, thus disclosing 627 specific com OCF, CHCH OCF, CHCH pounds of formula I. OCF, CHCH Table 142: CHO CHCH Another preferred group of compounds of formula I CHO CHCH CHO CHCH corresponds to the general formula CHF, CHCH 35 CHF, CHCH (I142) CHF, CHCH COOH CHCH COOH CHCH COOH CHCH COOCHCH, CHCH COOCHCH CHCH 40 COOCHCH CHCH CN CHCH CN CHCH CN CHCH C CHCCH C CHCCH in which the Sets of correlated Substituents R, R2 and R. 45 CHCCH are given in Table C, thus disclosing 627 specific com CHCCH CHCCH pounds of formula I. CHCCH CHCCH TABLE C CHCCH 50 CHCCH Compd. No. R11 R12 R13 CH CHCCH CH, CHCCH OO1 H C CHCHCH, CH CHCCH OO2 C C CHCHCH, OH CHCCH OO3 F C CHCHCH, OH CHCCH OO4 H Br CHCHCH, 55 OH CHCCH OOS C Br CHCHCH, OCF, CHCCH OO6 F Br CHCHCH, OCF, CHCCH OO7 H I CHCHCH, OCF, CHCCH O08 C I CHCHCH, CHO CHCCH O09 F I CHCHCH, CHO CHCCH CHO O10 H CH CHCHCH, 60 CHCCH O11 C CH CHCHCH, CHF, CHCCH O12 F CH, CHCHCH, CHF, CHCCH O13 H OH CHCHCH, CHF, CHCCH O14 C OH CHCHCH, COOH CHCCH O15 F OH CHCHCH, COOH CHCCH O16 H OCF, CHCHCH, COOH CHCCH O17 C OCF, CHCHCH, 65 COOCHCH CHCCH O18 F OCF, CHCHCH, COOCHCH CHCCH US 6,274,536 B1 107 108

TABLE C-continued TABLE C-continued Compd. No. R R12 R13 Compd. No. R R12 R13 O96 COOCHCH, CHCCH 173 I OH O97 CN CHCCH 174 I OH O98 CN CHCCH 175 CH OH O99 CHCCH 176 CH OH 1OO CHCOOH 177 CH, OH 101 CHCOOH 178 OH OH 102 CHCOOH 179 OH OH 103 CHCOOH 18O OH OH 104 CHCOOH 181 OCF, OH 105 CHCOOH 182 OCF, OH 106 CHCOOH 183 OCF, OH 107 CHCOOH 184 CHO OH 108 CHCOOH 15 .185 CHO OH 109 CHCOOH 186 CHO OH 110 CHCOOH 187 CHF, OH ..111 CHCOOH 188 CHF, OH .112 CHCOOH 189 CHF, OH 113 CHCOOH 190 COOH OH .114 OH CHCOOH 191 COOH OH 115 OCF, CHCOOH .192 COOH OH .116 OCF, CHCOOH 193 COOCHCH OH 117 OCF, CHCOOH 194 COOCHCH OH 118 CHO CHCOOH 195 COCCHCH, OH 119 CHO CHCOOH 196 CN OH 12O CHO CHCOOH 197 CN OH .121 CHF, CHCOOH 25 198 CN OH 122 CHF, CHCOOH 199 C OCHCHCH, 123 CHF, CHCOOH 2OO C OCHCHCH, .124 COOH CHCOOH 2O1 OCHCHCH, 125 COOH CHCOOH 2O2 OCHCHCH, 126 COOH CHCOOH 2O3 OCHCHCH, 127 COOCHCH, CHCOOH 204 OCHCHCH, 128 COOCHCH CHCOOH 205 OCHCHCH, 129 COOCHCH CHCOOH 2O6 OCHCHCH, 130 CN CHCOOH 2O7 OCHCHCH, 131 CN CHCOOH 208 CH, OCHCHCH, 132 CN CHCOOH 209 CH OCHCHCH, 133 C CHCOOCH 35 210 CH OCHCHCH, 134 C CHCOOCH .211 OH OCHCHCH, 135 CHCOOCH 212 OH OCHCHCH, 136 CHCOOCH 213 OH OCHCHCH, 137 CHCOOCH .214 OCF, OCHCHCH, 138 CHCOOCH, 215 OCF, OCHCHCH, 139 216 CHCOOCH 40 OCF, OCHCHCH, 140 CHCOOCH 217 CHO OCHCHCH, .141 CHCOOCH 218 CHO OCHCHCH, .142 CHCOOCH, 219 CHO OCHCHCH, 143 CHCOOCH 22O CHF, OCHCHCH, .144 CHCOOCH 221 CHF, OCHCHCH, 145 CHCOOCH 222 CHF, OCHCHCH, .146 CHCOOCH, 45 .223 COOH OCHCHCH, 147 OH CHCOOCH .224 COOH OCHCHCH, 148 OCF, CHCOOCH 225 COOH OCHCHCH, 149 OCF, CHCOOCH 226 COOCHCH OCHCHCH, 150 OCF, CHCOOCH, 227 COOCHCH, OCHCHCH, 151 CHO CHCOOCH 228 COOCHCH OCHCHCH, 152 CHO CHCOOCH 50 229 CN OCHCHCH, 153 CHO CHCOOCH 230 CN OCHCHCH, 154 CHF, CHCOOCH, 231 CN OCHCHCH, 155 CHF, CHCOOCH 232 C OCHCH 156 CHF, CHCOOCH 233 C OCHCH 157 COOH CHCOOCH 234 OCHCH 158 COOH CHCOOCH, 55 235 OCHCH 159 COOH CHCOOCH 236 OCHCH 160 COOCHCH CHCOOCH 237 OCHCH .161 COOCHCH, CHCOOCH, .238 OCHCH 162 COOCHCH CHCOOCH 239 OCHCH 163 CN CHCOOCH 240 OCHCH .164 CN CHCOOCH .241 OCHCH 165 CHCOOCH, 60 .242 OCHCH 166 OH 243 OCHCH 167 OH .244 OCHCH 168 OH .245 OCHCH 169 OH .246 OCHCH 170 OH .247 OCF, OCHCH 171 OH 65 248 OCF, OCHCH 172 OH 249 OCF, OCHCH US 6,274,536 B1 109 110

TABLE C-continued TABLE C-continued Compd. No. R R12 R13 Compd. No. R R12 R13 250 CHO OCHCH 327 COOCHCH, OCHCOOCH, 251 CHO OCHCH 328 CN OCHCOOCH, 252 CHO OCHCH 329 CN OCHCOOCH, .253 CHF, OCHCH 330 CN QCHCOOCH .254 CHF, OCHCH .331 C CHCHO 255 CHF, OCHCH .332 CHCHO .256 COOH OCHCH .333 CHCHO 257 COOH OCHCH 334 CHCHO 258 COOH OCHCH .335 CHCHO 259 COOCHCH OCHCH 336 CHCHO 260 COOCHCH OCHCH .337 CHCHO .261 COOCHCH OCHCH .338 CHCHO 262 CN OCHCH 15 .339 CHCHO .263 CN OCHCH 340 CH CHCHO .264 CN OCHCH 341 CH CHCHO 265 C OCHCOOH 342 CH, CHCHO .266 OCHCOOH 343 OH CHCHO .267 OCHCOOH .344 OH CHCHO 268 OCHCOOH .345 OH CHCHO 269 OCHCOOH 346 OCF, CHCHO 270 OCHCOOH 347 OCF, CHCHO 271 OCHCOOH 348 OCF, CHCHO 272 OCHCOOH 349 CHO CHCHO 273 OCHCOOH 350 CHO CHCHO .274 OCHCOOH 351 CHO CHCHO 275 OCHCOOH 25 352 CHF, CHCHO .276 OCHCOOH .353 CHF, CHCHO 277 OCHCOOH 354 CHF, CHCHO 278 OCHCOOH 355 COOH CHCHO 279 OH OCHCOOH 356 COOH CHCHO 28O OCF, OCHCOOH 357 COOH CHCHO 281 OCF, OCHCOOH 358 COOCHCH, CHCHO .282 OCF, OCHCOOH 359 COOCHCH CHCHO .283 CHO OCHCOOH 360 COOCHCH CHCHO 284 CHO OCHCOOH 361 CN CHCHO 285 CHO OCHCOOH 362 CN CHCHO 286 CHF, OCHCOOH 363 CN CHCHO 287 CHF, OCHCOOH 35 364 C OCHCHO 288 CHF, OCHCOOH 365 C OCHCHO .289 COOH OCHCOOH 366 OCHCHO 290 COOH OCHCOOH 367 OCHCHO .291 COOH OCHCOOH 368 OCHCHO .292 COOCHCH, OCHCOOH 369 OCHCHO .293 370 COOCHCH OCHCOOH 40 OCHCHO 294 COOCHCH OCHCOOH 371 OCHCHO 295 CN OCHCOOH 372 OCHCHO .296 CN OCHCOOH 373 CH, OCHCHO 297 CN OCHCOOH 374 CH OCHCHO .298 C OCHCOOCH, 375 CH OCHCHO .299 OCHCOOCH, 376 OH OCHCHO 3OO OCHCOOCH, 45 377 OH OCHCHO 301 OCHCOOCH, 378 OH OCHCHO 3O2 OCHCOOCH, 379 OCF, OCHCHO 303 OCHCOQCH 38O OCF, OCHCHO 304 OCHCOOCH, 381 OCF, OCHCHO 305 OCHCOOCH, .382 CHO OCHCHO 306 OCHCOOCH, 50 383 CHO OCHCHO 307 OCHCOOCH, 384 CHO OCHCHO 3O8 OCHCOOCH, 385 CHF, OCHCHO .309 OCHCOOCH, 386 CHF, OCHCHO 310 OCHCOOCH, 387 CHF, OCHCHO 311 OCHCOOCH, 388 COOH OCHCHO 312 OH OCHCOOCH, 55 389 COOH OCHCHO 313 OCF, OCHCOOCH, 390 COOH OCHCHO 314 OCF, OCHCOOCH, .391 COOCHCH OCHCHO 315 OCF, OCHCOOCH, 392 COOCHCH, OCHCHO 316 CHO OCHCOOCH, 393 COOCHCH OCHCHO 317 CHO OCHCOOCH, 394 CN OCHCHO 3.18 CHO OCHCOOCH, .395 CN OCHCHO 319 CHF, OCHCOOCH, 60 396 CN OCHCHO 32O CHF, OCHCOOOH, 397 C OCH 321 CHF, OCHCOOCH, 398 C OCH 322 COOH OCHCOOCH, .399 OCH 323 COOH OCHCOOCH, 400 OCH, 324 COOH OCHCOOCH, 4O1 OCH 325 COOCHCH OCHCOOCH, 65 4O2 OCH 326 COOCHCH OCHCOOCH, 403 OCH US 6,274,536 B1 111 112

TABLE C-continued TABLE C-continued Compd. No. R R12 Compd. No. R R12 R13 O4 I OCH, 81 CHO CHSCH. 05 I OCH 82 CHO CHSCH. O6 CH OCH 83 CHO CHSCH. O7 CH OCH 84 CHF, CHSCH. O8 CH, OCH, 85 CHF, CHSCH. O9 OH OCH 86 CHF, CHSCH. 1O OH OCH 87 COOH CHSCH. 11 OH OCH 88 COOH CHSCH. 12 OCF, OCH, 89 COOH CHSCH. 13 OCF, OCH 90 COOCHCH CHSCH. 14 OCF, OCH 91 COOCHCH CHSCH. 15 CHO OCH 92 COOCHCH CHSCH. 16 CHO OCH 15 93 CN CHSCH. 17 CHO OCH 94 CN CHSCH. 18 CHF, OCH 95 CN CHSCH. 19 CHF, OCH, 96 C OCHOCH, 2O CHF, OCH 97 C OCHOCH 21 COOH OCH 98 OCHOCH 22 COOH OCH OCHOCH 23 COOH OCH, SOO OCHOCH, 24 COOCHCH OCH SO1 OCHOCH 25 COOCHCH OCH 502 OCHOCH 26 COOCHCH OCH SO3 OCHOCH 27 CN OCH, SO4 OCHOCH, 28 CN OCH 505 CH OCHOCH 29 CN OCH 25 SO6 CH OCHOCH 3O C CHOCH 507 CH OCHOCH 31 C CHOCH, 508 OH OCHOCH, 32 CHOCH 509 OH OCHOCH 33 CHOCH 510 OH OCHOCH 34 CHOCH 511 OCF, OCHOCH 35 CHOCH, 512 OCF, OCHOCH, 36 CHOCH 513 OCF, OCHOCH 37 CHOCH .514 CHO OCHOCH 38 CHOCH 515 CHO OCHOCH 39 CHOCH, 516 CHO OCHOCH, 40 CHOCH 517 CHF, OCHOCH 41 CHOCH 35 518 CHF, OCHOCH 42 CHOCH 519 CHF, OCHOCH 43 CHOCH 520 COOH OCHOCH 44 OH CHOCH 521 COOH OCHOCH 45 OCF, CHOCH 522 COOH OCHOCH 46 OCF, CHOCH, 523 COOCHCH, OCHOCH, 47 524 OCF, CHOCH 40 COOCHCH OCHOCH 48 CHO CHOCH 525 COOCHCH OCHOCH 49 CHO CHOCH .526 CN OCHOCH 50 CHO CHOCH, 527 CN OCHOCH, 51 CHF, CHOCH 528 CN OCHOCH 52 CHF, CHOCH 529 C OCHSCH. 53 CHF, CHOCH 530 C OCHSCH. 54 COOH CHOCH, 45 531 OCHSCH. 55 COOH CHOCH 532 OCHSCH. 56 COOH CHOCH 533 OCHSCH. 57 COOCHCH CHOCH 534 OCHSCH. 58 COOCHCH, CHOCH, 535 OCHSCH. 59 COOCHCH CHOCH 536 OCHSCH. 60 CN CHOCH 50 537 OCHSCH. 61 CN CHOCH .538 CH OCHSCH. 62 CHOCH, 539 CH, OCHSCH. 63 CHSCH. 540 CH OCHSCH. 64 CHSCH. .541 OH OCHSCH. 65 CHSCH. 542 OH OCHSCH. 66 CHSCH. 55 543 OH OCHSCH. 67 CHSCH. .544 OCF, OCHSCH. 68 CHSCH. 545 OCF, OCHSCH. 69 CHSCH. .546 OCF, OCHSCH. 70 CHSCH. 547 CHO OCHSCH. 71 CHSCH. 548 CHO OCHSCH. 72 CHSCH. 549 CHO OCHSCH. 73 CHSCH. 60 550 CHF, OCHSCH. 74 CHSCH. 551 CHF, OCHSCH. 75 CHSCH. 552 CHF, OCHSCH. 76 CHSCH. 553 COOH OCHSCH. 77 CHSCH. 554 COOH OCHSCH. 78 OCF, CHSCH. 555 COOH OCHSCH. 79 OCF, CHSCH. 65 556 COOCHCH OCHSCH. 8O OCF, CHSCH. 557 COOCHCH OCHSCH. US 6,274,536 B1 113 114

TABLE C-continued (I143) Compd. No. R11 R12 R13 558 F COOCHCH, OCHSCH. 559 H CN OCHSCH. 560 C CN OCHSCH. 561 F CN OCHSCH. 562 H C OCHCHCN .563 C C OCHCHCN .564 F C OCHCHCN 1O 565 H Br OCHCHCN 566 C Br OCHCHCN in which the Sets of correlated Substituents R, R2 and R. 567 F Br OCHCHCN are given in Table D, thus disclosing 627 specific com 568 H I OCHCHCN pounds of formula I. .569 C I OCHCHCN Table 144: 570 F I OCHCHCN 15 571 H CH OCHCHCN Another preferred group of compounds of formula I 572 C CH OCHCHCN corresponds to the general formula 573 F CH, OCHCHCN 574 H OH OCHCHCN 575 C OH OCHCHCN (I144) 576 F OH OCHCHCN 577 H OCF, OCHCHCN 578 C OCF, OCHCHCN 579 F OCF, OCHCHCN 58O H CHO OCHCHCN 581 C CHO OCHCHCN 582 F CHO OCHCHCN .583 H CHF, OCHCHCN 25 584 C CHF, OCHCHCN 585 F CHF, OCHCHCN 586 H COOH OCHCHCN 587 C COOH OCHCHCN in which the Sets of correlated Substituents R, R and R. 588 F COOH OCHCHCN are given in Table D, thus disclosing 627 specific com 589 H COOCHCH, OCHCHCN pounds of formula I. 590 C COOCHCH OCHCHCN Table 145: 591 F COOCHCH OCHCHCN 592 H CN OCHCHCN Another preferred group of compounds of formula I 593 C CN OCHCHCN corresponds to the general formula 594 F CN OCHCHCN 595 H C CHCHCN 35 596 C C CHCHCN (I145) 597 F C CHCHCN 598 H Br CHCHCN 599 C Br CHCHCN 6OO F Br CHCHCN 6O1 H I CHCHCN 40 6O2 C I CHCHCN 603 F I CHCHCN 604 H CH, CHCHCN 605 C CH CHCHCN 606 F CH CHCHCN 6O7 H OH CHCHCN 608 C OH CHCHCN 45 in which the Sets of correlated Substituents R, R and R. .609 F OH CHCHCN are given in Table D, thus disclosing 627 specific com 610 H OCF, CHCHCN pounds of formula Is. .611 C OCF, CHCHCN Table 146: 612 F OCF, CHCHCN 613 H CHO CHCHCN Another preferred group of compounds of formula I .614 C CHO CHCHCN 50 corresponds to the general formula 615 F CHO CHCHCN 616 H CHF, CHCHCN 617 C CHF, CHCHCN (1146) 618 F CHF, CHCHCN 619 H COOH CHCHCN 62O C COOH CHCHCN 55 621 F COOH CHCHCN 622 H COOCHCH CHCHCN 623 C COOCHCH, CHCHCN .624 F COOCHCH CHCHCN .625 H CN CHCHCN 626 C CN CHCHCN 60 627 F CN CHCHCN in which the Sets of correlated Substituents R, R and R. are given in Table D, thus disclosing 627 specific com Table 143: pounds of formula I. 65 Table 147: A preferred group of compounds of formula I corresponds Another preferred group of compounds of formula I to the general formula corresponds to the general formula US 6,274,536 B1 115 116

(I147) (I151)

1O in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Is. pounds of formula I-7. Table 152: Table 148: 15 Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula (I152) (I148)

25

in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Is. pounds of formula Is. Table 153: Table 149: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 35 (I-153) (I149)

40

45 in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Is. pounds of formula Io. Table 154: Table 150: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula (I154) (I150)

55

60 in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Iso pounds of formula Is. Table 151: 65 Table 155: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 117 118

(I155) (I159)

1O in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Iss. pounds of formula Iso Table 156: Table 160: Another preferred group of compounds of formula I 15 Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

(I156) (I160)

25 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Is. pounds of formula Igo. Table 157: Table 161: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 35 (I157) (I161)

40

in which the Sets of correlated Substituents R, R and R. 45 in which the Sets of correlated Substituents R, R and R. are given in Table D, thus disclosing 327 specific com are given in Table D, thus disclosing 627 specific com pounds of formula I-7. pounds of formula I. Table 158: Table 162: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula

(I158) (I162)

55

60 in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Iss. pounds of formula I. Table 159: 65 Table 163: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 119 120

(I163) (I167)

1O in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula I. pounds of formula Iz. Table 164: Table 168: Another preferred group of compounds of formula I 15 Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

(I164) (I.168)

25 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula I. pounds of formula Is. Table 165: Table 169: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 35 (I165) (I169)

40

in which the Sets of correlated Substituents R, R and R. 45 in which the Sets of correlated Substituents R, R and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Is. pounds of formula Io. Table 166: Table 170: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula

(I166) (I170)

55

60 in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula I. pounds of formula Izo. Table 167: 65 Table 171: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 121 122

(I171) (I175)

1O in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Iz. pounds of formula I-7s. Table 172: 15 Table 176: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula

(I172) (I176)

25 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Iz. pounds of formula Ize. Table 173: Table 1.77: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 35 (I173) (I177)

40

in which the Sets of correlated Substituents R, R and R. 45 in which the Sets of correlated Substituents R, R2 and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Iz. pounds of formula I-77. Table 174: Table 178: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula (I174) (I178)

55

60 in which the Sets of correlated Substituents R, R2 and R. in which the rets of correlated Substituents R, R and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Iz. pounds of formula Is Table 175: 65 Table 179: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 123 124

(I179) (I.183)

1O in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Izo. pounds of formula Is. Table 184: Table 180: 15 Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula (I.184) (I.180)

25 in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Iso. pounds of formula Is. Table 181: Table 1.85: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 35 (I.18) (I.185)

40

in which the Sets of correlated Substituents R, R and R. 45 in which the Sets of correlated Substituents R, R and R. ate given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Is. pounds of formula Iss. Table 182: Table 186: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula

(I.182) (1186)

55

60 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Is. pounds of formula Is. Table 183: 65 Table 187: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 125 126

(I187) (I191)

1O in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Isz. pounds of formula Io. Table 188: Table 192: Another preferred group of compounds of formula I 15 Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula (I192)

(I.188)

25 in which the Sets of correlated Substituents R, R2 and R. in which the Sets of correlated Substituents R, R and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Iss. pounds of formula I. Table 189: Table 193: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula 35 (I193) (I189)

40

in which the Sets of correlated Substituents R, R and R. 45 in which the Sets of correlated Substituents R, R2 and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Iso pounds of formula Ios. Table 190: Table 194: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula 50 corresponds to the general formula (I194) (I190)

55

60 in which the Sets of correlated Substituents R, R and R. in which the Sets of correlated Substituents R, R2 and R. are given in Table D, thus disclosing 627 specific com are given in Table D, thus disclosing 627 specific com pounds of formula Ico. pounds of formula Io. Table 191: 65 Table 195: Another preferred group of compounds of formula I Another preferred group of compounds of formula I corresponds to the general formula corresponds to the general formula US 6,274,536 B1 127 128

(I195) TABLE D-continued

Compd. No. R H12 R13 O40 I CHCH O41 I CHCH O42 I CHCH O43 CH CHCH .044 CH, CHCH O45 CH CHCH O46 OH CHCH O47 OH CHCH in which the Sets of correlated Substituents R, R2 and R. O48 OH CHCH are given in Table D, thus disclosing 627 specific com O49 OCF, CHCH pounds of formula Ios. OSO OCF, CHCH O51 Table 196: OCF, CHCH 15 O52 CHO CHCH Another preferred group of compounds of formula I O53 CHO CHCH O54 CHO CHCH corresponds to the general formula O55 CHF, CHCH O56 CHF, CHCH (1196) O57 CHF, CHCH O58 COOH CHCH O59 COOH CHCH O60 COOH CHCH O61 COOCHCH CHCH O62 COOCHCH CHCH O63 COOCHCH, CHCH O64 CN CHCH 25 O65 CN CHCH O66 CN CHCH O67 C CHCCH O68 CHCCH in which the Sets of correlated Substituents R, R2 and R. O69 CHCCH are given in Table D, thus disclosing 627 specific com O70 CHCCH O71 CHCCH pounds of formula Io. O72 CHCCH O73 CHCCH TABLED O74 CHCCH O75 CHCCH Compd. No. R R13 O76 CH CHCCH 35 O77 CH CHCCH CHCHCH, O78 CH CHCCH CHCHCH, O79 OH CHCCH CHCHCH, O8O OH CHCCH CHCHCH, O81 OH CHCCH CHCHCH, O82 OCF, CHCCH O83 CHCHCH, 40 OCF, CHCCH CHCHCH, O84 OCF, CHCCH CHCHCH, O85 CHO CHCCH CHCHCH, O86 CHO CHCCH CH CHCHCH, O87 CHO CHCCH CH CHCHCH, O88 CHF, CHCCH CH CHCHCH, O89 CHF, CHCCH OH CHCHCH, 45 O90 CHF, CHCCH OH CHCHCH, O91 COOH CHCCH OH CHCHCH, O92 COOH CHCCH OCF, CHCHCH, O93 COOH CHCCH OCF, CHCHCH, O94 COOCHCH, CHCCH OCF, CHCHCH, 095 COOCHCH CHCCH CHO CHCHCH, 50 O96 COOCHCH CHCCH CHO CHCHCH, 097 CN CHCCH CHO CHCHCH, O98 CN CHCCH CHF, CHCHCH, O99 CN CHCCH CHF, CHCHCH, 1OO C CHCOOH CHF, CHCHCH, 101 C CHCOOH COOH CHCHCH, 55 102 CHCOOH COOH CHCHCH, 103 CHCOOH COOH CHCHCH, 104 CHCOOH COOCHCH CHCHCH, 105 CHCOOH COOCHCH CHCHCH, 106 CHCOOH COOCHCH CHCHCH, 107 CHCOOH CN CHCHCH, 108 CHCOOH CN CHCHCH, 60 109 CHCOOH CN CHCHCH, 110 CHCOOH C CHCH ..111 CHCOOH C CHCH .112 CHCOOH CHCH 113 CHCOOH CHCH .114 CHCOOH CHCH 65 115 OCF, CHCOOH CHCH .116 OCF, CHCOOH US 6,274,536 B1 129 130

TABLE D-continued TABLE D-continued Compd. No. R H12 R13 Compd. No. R H12 R13 117 OCF, CHCOOH 194 COOCHCH, OH 118 CHO CHCOOH 195 COOCHCH OH 119 CHO CHCOOH 196 CN OH 12O CHO CHCOOH 197 CN OH .121 CHF, CHCOOH 198 CN OH 122 CHF, CHCOOH 199 Cl OCHCHCH, 123 CHF, CHCOOH 2OO Cl OCHCHCH, .124 COOH CHCOOH 2O1 OCHCHCH, 125 COOH CHCOOH 2O2 OCHCHCH, 126 COOH CHCOOH 2O3 OCHCHCH, 127 COOCHCH CHCOOH .204 OCHCHCH, 128 COOCHCH CHCOOH 205 OCHCHCH, 129 COOCHCH CHCOOH 15 2O6 OCHCHCH, 130 CN CHCOOH 2O7 OCHCHCH, 131 CN CHCOOH 208 CH OCHCHCH, 132 CN CHCOOH 209 CH, OCHCHCH, 133 C CHCOOCH 210 CH OCHCHCH, 134 C CHCOOCH .211 OH OCHCHCH, 135 CHCOOCH 212 OH OCHCHCH, 136 CHCOOCH, 213 OH OCHCHCH, 137 CHCOOCH .214 OCF, OCHCHCH, 138 CHCOOCH 215 OCF, OCHCHCH, 139 CHCOOCH 216 OCF, OCHCHCH, 140 CHCOOCH, 217 CHO OCHCHCH, .141 CHCOOCH .218 CHO OCHCHCH, .142 CH CHCOOCH 25 219 CHO OCHCHCH, 143 CH CHCOOCH 22O CHF, OCHCHCH, .144 CH, CHCOOCH, 221 CHF, OCHCHCH, 145 OH CHCOOCH .222 CHF, OCHCHCH, .146 OH CHCOOCH .223 COOH OCHCHCH, 147 OH CHCOOCH .224 COOH OCHCHCH, 148 OCF, CHCOOCH, 225 COOH OCHCHCH, 149 OCF, CHCOOCH 226 COOCHCH OCHCHCH, 150 OCF, CHCOOCH 227 COOCHCH OCHCHCH, 151 CHO CHCOOCH 228 COOCHCH OCHCHCH, 152 CHO CHCOOCH, 229 CN OCHCHCH, 153 CHO CHCOOCH 230 CN OCHCHCH, 154 CHF, CHCOOCH 35 231 CN OCHCHCH, 155 CHF, CHCOOCH 232 C OCHCH 156 CHF, CHCOOCH 233 C OCHCH 157 COOH CHCOOCH 234 OCHCH 158 COOH CHCOOCH 235 OCHCH 159 COOH CHCOOCH, 236 OCHCH 160 237 COOCHCH CHCOOCH 40 OCHCH .161 COOCHCH CHCOOCH .238 OCHCH 162 COOCHCH CHCOOCH .239 OCHCH 163 CN CHCOOCH, 240 OCHCH .164 CN CHCOOCH .241 CH OCHCH 165 CN CHCOOCH .242 CH OCHCH 166 C OH 243 CH OCHCH 167 C OH 45 .244 OH OCHCH 168 OH .245 OH OCHCH 169 OH .246 OH OCHCH 170 OH .247 OCF, OCHCH 171 OH 248 OCF, OCHCH 172 OH 249 OCF, OCHCH 173 OH 50 250 CHO OCHCH 174 OH 251 CHO OCHCH 175 CH, OH 252 CHO OCHCH 176 CH OH .253 CHF, OCHCH 177 CH OH .254 CHF, OCHCH 178 OH OH 255 CHF, OCHCH 179 OH OH 55 .256 COOH OCHCH 18O OH OH 257 COOH OCHCH 181 OCF, OH 258 COOH OCHCH 182 OCF, OH 259 COOCHCH, OCHCH 183 OCF, OH 260 COOCHCH OCHCH 184 CHO OH .261 COOCHCH OCHCH .185 CHO OH 262 CN OCHCH 186 CHO OH 60 .263 CN OCHCH 187 CHF, OH .264 CN OCHCH 188 CHF, OH 265 C OCHCOOH 189 CHF, OH .266 C OCHCOOH 190 COOH OH .267 OCHCOOH 191 COOH OH 268 OCHCOOH .192 COOH OH 65 269 OCHCOOH 193 COOCHCH OH 270 OCHCOOH US 6,274,536 B1 131 132

TABLE D-continued TABLE D-continued Compd. No. R H12 R13 Compd. No. R H12 R13 271 I OCHCOOH 348 OCF, CHCHO 272 I OCHCOOH 349 CHO CHCHO 273 I OCHCOOH 350 CHO CHCHO .274 CH OCHCOOH 351 CHO CHCHO 275 CH, OCHCOOH 352 CHF, CHCHO .276 CH OCHCOOH 353 CHF, CHCHO 277 OH OCHCOOH 354 CHF, CHCHO 278 OH OCHCOOH 355 COOH CHCHO 279 OH OCHCOOH 356 COOH CHCHO 28O OCF, OCHCOOH 357 COOH CHCHO 281 OCF, OCHCOOH 358 COOCHCH CHCHO .282 OCF, OCHCOOH 359 COOCHCH CHCHO .283 CHO OCHCOOH 15 360 COOCHCH CHCHO 284 CHO OCHCOOH 361 CN CHCHO .285 CHO OCHCOOH 362 CN CHCHO 286 CHF, OCHCOOH 363 CN CHCHO 287 CHF, OCHCOOH 364 C OCHCHO 288 CHF, OCHCOOH 365 C OCHCHO .289 COOH OCHCOOH 366 OCHCHO 290 COOH OCHCOOH 367 OCHCHO .291 COOH OCHCOOH 368 OCHCHO .292 COOCHCH OCHCOOH 369 OCHCHO .293 COOCHCH OCHCOOH 370 OCHCHO 294 COOCHCH, OCHCOOH 371 OCHCHO 295 CN OCHCOOH 372 OCHCHO .296 CN OCHCOOH 25 373 CH OCHCHO 297 CN OCHCOOH 374 CH OCHCHO .298 C OCHCOOCH, 375 CH, OCHCHO .299 OCHCOOCH, 376 OH OCHCHO 3OO OCHCOOCH, 377 OH OCHCHO 3O1 OCHCOOCH, 378 OH OCHCHO 3O2 OCHCOOCH, 379 OCF, OCHCHO 303 OCHCOOCH, 38O OCF, OCHCHO 3O4 OCHCOOCH, 381 OCF, OCHCHO 305 OCHCOOCH, .382 CHO OCHCHO .306 OCHCOOCH, 383 CHO OCHCHO 3O7 CH OCHCOOCH, 384 CHO OCHCHO 3O8 CH OCHCOOCH, 35 385 CHF, OCHCHO .309 CH OCHCOOCH, 386 CHF, OCHCHO 310 OH OCHCOOCH, 387 CHF, OCHCHO 311 OH OCHCOOCH, 388 COOH OCHCHO 312 OH OCHCOOCH, 389 COOH OCHCHO 313 OCF, OCHCOOCH, 390 COOH OCHCHO 314 391 OCF, OCHCOOCH, 40 COOCHCH OCHCHO 315 OCF, OCHCOOCH, 392 COOCHCH OCHCHO 316 CHO OCHCOOCH, 393 COOCHCH OCHCHO 317 CHO OCHCOOCH, 394 CN OCHCHO 318 CHO OCHCOOCH, 395 CN OCHCHO 319 CHF, OCHCOOCH, 396 CN OCHCHO 32O CHF, OCHCOOCH, 397 C OCH 321 CHF, OCHCOOCH, 45 398 C OCH, 322 COOH OCHCOOCH, .399 OCH 323 COOH OCHCOOCH, OCH 324 COOH OCHCOOCH, O1 OCH 325 COOCHCH, OCHCOOCH, O2 OCH, 326 COOCHCH OCHCOOCH, O3 OCH 327 COOCHCH OCHCOOCH, 50 O4 OCH 328 CN OCHCOOCH, 05 OCH 329 CN OCHCOOCH, O6 CH, OCH, 330 CN OCHCOOCH, O7 CH OCH 331 CHCHO O8 CH OCH 332 CHCHO O9 OH OCH .333 CHCHO 55 1O OH OCH, 334 CHCHO 11 OH OCH 335 CHCHO 12 OCF, OCH 336 CHCHO 13 OCF, OCH, 337 CHCHO 14 OCF, OCH .338 CHCHO 15 CHO OCH 339 CHCHO 16 CHO OCH 340 CHCHO 60 17 CHO OCH, 341 CHCHO 18 CHF, OCH 342 CHCHO 19 CHF, OCH 343 CHCHO 2O CHF, OCH .344 CHCHO 21 COOH OCH, 345 CHCHO 22 COOH OCH 346 OCF, CHCHO 65 23 COOH OCH 347 OCF, CHCHO 24 COOCHCH OCH US 6,274,536 B1 133 134

TABLE D-continued TABLE D-continued Compd. No. R H12 R13 Compd. No. R H12 R13 25 COOCHCH, OCH, 5O2 I OCHOCH, 26 COOCHCH OCH 503 1. OCHOCH 27 CN OCH .504 I OCHOCH 28 CN OCH 505 CH OCHOCH 29 CN OCH, 506 CH, OCHOCH, 3O Cl CHOCH 507 CH OCHOCH 31 Cl CHOCH 508 OH OCHOCH 32 CHOCH 509 OH OCHOCH 33 CHOCH, 510 OH OCHOCH, 34 CHOCH 511 OCF, OCHOCH 35 CHOCH 512 OCF, OCHOCH 36 CHOCH 513 OCF, OCHOCH 37 CHOCH 15 .514 CHO OCHOCH 38 CHOCH 515 CHO OCHOCH 39 CH CHOCH 516 CHO OCHOCH 40 CH, CHOCH, 517 CHF, OCHOCH, 41 CH CHOCH 518 CHF, OCHOCH 42 OH CHOCH 519 CHF, OCHOCH 43 OH CHCCH 52O COOH OCHOCH 44 OH CHOCH, 521 COOH OCHOCH, 45 OCF, CHOCH 522 COOH OCHOCH 46 OCF, CHOCH 523 COOCHCH OCHOCH 47 OCF, CHOCH 524 COOCHCH OCHOCH 48 CHO CHOCH, 525 COOCHCH, OCHOCH, 49 CHO CHOCH 526 CN OCHOCH 50 CHO CHOCH 25 527 CN OCHOCH 51 CHF, CHOCH 528 CN OCHOCH 52 CHF, CHOCH, 529 C OCHSCH. 53 CHF, CHOCH 530 OCHSCH. 54 COOH CHOCH 531 OCHSCH. 55 COOH CHOCH 532 OCHSCH. 56 COOH CHOCH, 533 OCHSCH. 57 COOCHCH CHOCH 534 OCHSCH. 58 COOCHCH CHOCH 535 OCHSCH. 59 COOCHCH CHOCH 536 OCHSCH. 60 CN CHOCH, 537 OCHSCH, 61 CN CHOCH .538 CH OCHSCH. 62 CN CHOCH 35 539 CH OCHSCH. 63 C CHSCH. 540 CH OCHSCH. 64 C CHSCH. .541 OH OCHSCH. 65 CHSCH. 542 OH OCHSCH. 66 CHSCH. 543 OH OCHSCH. 67 CHSCH. .544 OCF, OCHSCH. 68 545 CHSCH. 40 OCF, OCHSCH. 69 CHSCH. .546 OCF, OCHSCH. 70 CHSCH. 547 CHO OCHSCH. 71 CHSCH. 548 CHO OCHSCH. 72 CH CHSCH. 549 CHO OCHSCH. 73 CH CHSCH. 550 CHF, OCHSCH. 74 CH CHSCH. 551 CHF, OCHSCH. 75 OH CHSCH. 45 552 CHF, OCHSCH. 76 OH CHSCH. 553 COOH OCHSCH. 77 OH CHSCH. 554 COOH OCHSCH. 78 OCF, CHSCH. 555 COOH OCHSCH. 79 OCF, CHSCH. 556 COOCHCH, OCHSCH. 8O OCF, CHSCH. 557 COOCHCH OCHSCH. 81 CHO CHSCH. 50 558 COOCHCH OCHSCH. 82 CHO CHSCH. 559 CN OCHSCH. 83 CHO CHSCH. 560 CN OCHSCH. 84 CHF, CHSCH. 561 CN OCHSCH. 85 CHF, CHSCH. 562 C OCHCHCN 86 CHF, CHSCH. .563 C OCHCHCN 87 COOH CHSCH. 55 .564 OCHCHCN 88 COOH CHSCH. 565 OCHCHCN 89 COOH CHSCH. 566 OCHCHCN 90 COOCHCH, CHSCH. 567 OCHCHCN 91 COOCHCH CHSCH. 568 OCHCHCN 92 COOCHCH CHSCH. .569 OCHCHCN 93 CN CHSCH. 570 OCHCHCN 94 CN CHSCH. 60 571 OCHCHCN 95 CN CHSCH. 572 OCHCHCN 96 C OCHOCH 573 OCHCHCN 97 C OCHOCH 574 OCHCHCN 98 OCHOCH, 575 OCHCHCN OCHOCH 576 OCHCHCN SOO OCHOCH 65 577 OCF, OCHCHCN 5O1 OCHOCH 578 OCF, OCHCHCN US 6,274,536 B1 135 136

TABLE D-continued TABLE E-continued Compd. No. R H12 R13 Prepared compounds from the above Tables with physicochemical data. The numbers in front of the point designates the number 579 OCF, OCHCHCN of the Table e.g. 1.150 signifies in Table 1 the compound No. 150 58O CHO OCHCHCN of Table A and 72.133 signifies in Table 72 the compound 581 CHO OCHCHCN No. 133 of Table B. 582 CHO OCHCHCN .583 CHF, OCHCHCN Compd. No. Physicochemical data 584 CHF, OCHCHCN 585 CHF, OCHCHCN 1O 126 m.p. 104-106 C. 586 COOH OCHCHCN 137 m.p. 89-93 C. 587 COOH OCHCHCN 147 resin. (Example P51) 588 COOH OCHCHCN 150 m.p. 137-138 C. 589 COOCHCH OCHCHCN 152 m.p. 167-168 C. 590 COOCHCH OCHCHCN 153 m.p. 171-172° C. (Example P52) 591 COOCHCH OCHCHCN 15 155 m.p. 102-104°C. 592 CN OCHCHCN 156 m.p. 113-114 C. 593 CN OCHCHCN .161 m.p. 143-145° C. (Example P53) 594 CN OCHCHCN 162 m.p. 180-182 C. 595 C CHCHCN 168 m.p. 122-124 C. 596 C CHCHCN 177 solid (Example P47) 597 CHCHCN 181 amorphous 598 CHCHCN 182 m.p. 98-100° C. 599 CHCHCN 190 oil 6OO CHCHCN 195 m.p. 83-85 C. (Example P46) 6O1 CHCHCN 205 resin 6O2 CHCHCN 216 m.p. 80-86 C. 603 CHCHCN 234 amorphous (Example P49) 604 CH CHCHCN 25 .244 m.p. 146-148 C. (Example P50) 605 CH CHCHCN 294 oil (Example P55) 606 CH, CHCHCN 3O2 m.p. 102-104°C. 6O7 OH CHCHCN 397 resin (Example P32) 608 OH CHCHCN 400 resin (Example P33) .609 OH CHCHCN .422 m.p. 100-101C. 610 OCF, CHCHCN 494 m.p. 135–138°C. (Example P54) .611 OCF, CHCHCN 7.1OO m.p. 111-113 C. 612 OCF, CHCHCN 9.OO2 resin 613 CHO CHCHCN 9.1OO m.p. 110-112 C. .614 CHO CHCHCN 10.100 m.p. 126-127 C. 615 CHO CHCHCN 22.OO2 m.p. 131-133° C. 616 CHF, CHCHCN 35 22.100 m.p. 190–191° C. (Example P43) 617 CHF, CHCHCN 28.100 m.p. 189-192 C. (Example P42) 618 CHF, CHCHCN 72.083 m.p. 152-153 C. (Example P60) 619 COOH CHCHCN 72.113 m.p. 250° C. (decomposition) (Example P59) 62O COOH CHCHCN 72.133 m.p. 140-143° C. (Example P58) 621 COOH CHCHCN 622 COOCHCH CHCHCN 40 623 COOCHCH, CHCHCN Examples of Specific formulations of the compounds of .624 COOCHCH CHCHCN formula I, Such as emulsifiable concentrates, Solutions, .625 CN CHCHCN wettable powders, coated, granules, extruder granules, dusts 626 CN CHCHCN and Suspension concentrates, are described in WO97/34485, 627 CN CHCHCN pages 9 to 13. 45 BIOLOGICAL EXAMPLES TABLE E Example B1: Prepared compounds from the above Tables with physicochemical Herbicidal Action Prior to Emergence of the Plants (Pre data. The numbers in front of the point designates the number 50 Emergence Action) of the Table e.g. 1.150 signifies in Table 1 the compound No. 150 Monocotyledonous and dicotyledonous test plants are of Table A and 72.133 signifies in Table 72 the compound Sown in Standard Soil in plastics pots. Immediately after No. 133 of Table B. Sowing, the test compounds, each in the form of an aqueous Compd. No. Physicochemical data Suspension or emulsion prepared from a 25% emulsifiable 55 concentrate (Example F1, c) in WO 97/34485, pages 9 and 1.OO1 m.p. 137–139° C. 1.OO2 m.p. 142-146 C. 10), are applied by spraying at a rate of application of 2000. 1.OO3 m.p. 122-124 C. g of active ingredient/ha (500 liters water/ha). The test plants 1.OO)4 amorphous (Example P45) are then grown in a greenhouse under optimum conditions. 1.OO7 solid After 3 weeks’ test duration, the test is evaluated in accor 1.010 resin 1.015 m.p. 76–78° C. 60 dance with a scale of nine ratings (1=total damage, 9=no 1.031 m.p. 88-90° C. action). Ratings of from 1 to 4 (especially from 1 to 3) 1.045 m.p. 85-86 C. indicate good to very good herbicidal action. 1.08O resin (Example P44) Test plants: Avena, Setaria, Sinapis, Stellaria 1.100 m.p. 104-106 C. 1.105 m.p. 105-107 C. The compounds according to the invention exhibit a good 1106 resin 65 herbicidal action. 1.111 m.p. 93–94 C. Examples of the good herbicidal activity of the com pounds of formula I are given in Table B1. US 6,274,536 B1 137 138

TABLE B1 TABLE B2-continued Pre-emergence action: Post-emergence action: Test plant Concentration Test plant Concentration Compd. No. Avena Setaria Sinapis Stellaria ga.i./ha Compd. No. Avena Setaria Sinapis Stellaria ga.i./ha OO1 2OOO O8O 2OOO OO2 2OOO 1OO 2OOO OO3 2OOO 105 2 2OOO OO4 2OOO 1O 106 3 3 2OOO O10 2OOO ..111 2 2 2OOO O8O 2OOO 126 2OOO 1OO 2OOO 147 2OOO 105 2OOO 150 2OOO 106 2 2OOO 152 2OOO ..111 2 2OOO 15 153 2OOO 126 2OOO 156 2OOO 147 2OOO 168 2OOO 150 2OOO 181 2OOO 152 2OOO 190 2OOO 153 2OOO 195 2OOO 156 2OOO 168 2OOO 205 2OOO 181 2OOO 3O2 2OOO 190 2 2OOO 400 2 2OOO 195 3 2OOO 7.1OO 2OOO 205 2OOO 9.OO2 3 2OOO 3O2 2OOO 9.1OO 2 2 2OOO 400 2OOO 25 10.100 2 2OOO 7.1OO 2OOO 28.1OO 2OOO 9.OO2 3 2OOO 9.1OO 2OOO 10.100 2OOO 28.1OO 2OOO The Same results are obtained when the compounds of The same results are obtained when compounds of for formula I are formulated according to Examples F2 to F8 in mula I are formulated according to Examples F2 to F8 in WO 97/34485, pages 10 to 12. WO 97/34485, pages 10 to 12. Example B2: 35 What is claimed is: Post-Emergence Herbicidal Action 1. A compound of formula I Monocotyledonous and dicotyledonous test plants are grown in a greenhouse in plastics pots containing Standard (I) R11 Soil and at the 4- to 6-leaf Stage are sprayed with an aqueous 40 Suspension or emulsion of the test Substances of formula I, prepared from a 25% emulsifiable concentrate (Example F1, R12 / \ W, c) in WO97/34485, pages 9 and 10), at a rate of application N corresponding to 2000 g of active ingredient/ha (500 liters V water/ha). The test plants are then grown on in the green 45 X1 R13 house under optimum conditions. After approximately 18 days test duration, the test is evaluated in accordance with a Scale of nine ratings (1=total damage, 9=no action). Ratings of from 1 to 4 (especially from 1 to 3) indicate good to very good herbicidal action. 50 wherein Test plants: Avena, Setaria, Sinapis, Stellaria In this test, too, the compounds of formula I exhibit a W is a group Strong herbicidal action. (W1) Examples of the good herbicidal activity of the com R pounds of formula I are given in Table B2. 55 O YR, TABLE B2 N -N Post-emergence action: R1 60 Test plant Concentration (W2) Compd. No. Avena Setaria Sinapis Stellaria ga.i./ha R 1.OO1 1. 1. 1. 1. 2OOO S(O)-R or 1.OO2 1. 1. 1. 1. 2OOO 1.OO3 1. 1. 1. 1. 2OOO -N 1.OO4 1. 2 1. 1. 2OOO 65 N 1.010 1. 1. 1. 1. 2OOO R1

US 6,274,536 B1 141 142 -continued antimony pentachloride to yield, after aqueous working up, R a compound of formula II R5 N (II) N N (W3a); and 5 R11 N- YR o R12 \ / W, R, R2, R., R., RS, R, R2, Ra, X and n are as defined N in claim 1. 1O 3. A process for the preparation of a compound of formula OH I according to claim 1 the radicals R, R2 and W in the compounds of formulae (I) 15 II, III and V being as defined above, and then alkylating that R11 compound in the presence of an inert Solvent and a base with / \ a compound of formula VI R12 W N R-L (VI), V 2O X1 R13 wherein R is as defined above and L is a leaving group, to form the compounds of formulae I and IV wherein R, R and W are as defined in claim 1; X is O or S.; R is C-C alkoxy-C-C-alkyl, C-C alkoxy- 25 (I) C-C alkoxy-CC alkyl, C-C alkyl, C-Calkenyl, R11 C-C alkynyl, C-C-haloalkyl, C-Chaloalkenyl, C-C cycloalkyl, C-Chalocycloalkyl, B-C-Calkyl, R12 / \ W

C-Caky 3O N D-CH- s (AC alky s X1 R13 O CH- and (IV) (C-C hydroxyalkyl)-CH2-, (B- R11 C-C hydroxyalkyl)-CH- or (B-C-Chaloalkyl)- 35 o CH-, and B is as defined in claim 1, which comprises oxidising a compound of formula III R12 \ / W, N (III) 40 OR 13 R11

R W wherein R, R, R and W are as defined above and X is 12 \ / O, and Subsequently, where appropriate after Separating off N 45 the compound of formula I, functionalising the pyridone group thereof according to the definition of X and R. in a suitable solvent to form a compound of formula V 4. A herbicidal and plant-growth-inhibiting composition having a herbicidally effective content of a compound of (V) formula I according to claim 1 and comprising an inert R11 carrier. o 5. A composition according to claim 6 comprising from W 0.1% to 95% of a compound of formula I. 6. A method of controlling undesired plant growth, which 55 comprises applying a compound of formula I, or a compo Sition comprising that compound, in a herbicidally effective amount to the crops of useful plants or to the locus thereof. and Subsequently rearranging that compound in an inert Solvent in the presence of an anhydride or in the presence of k . . . .