USOO9131694B2

(12) United States Patent (10) Patent No.: US 9,131,694 B2 Niyaz et al. (45) Date of Patent: Sep. 15, 2015

(54) INSECTICIDAL PYRIDINE COMPOUNDS 5,723.450 A 3/1998 Reuschling et al. 5,994,373 A 1 1/1999 Olesen (71) Applicant: pyroscience, LLC, Indianapolis, 6,878,7266,004,977 AB2 12/19994/2005 KurysG. etet al.al. 7,087.616 B2 8, 2006 Fischer et al. 7,119,098 B2 10/2006 Nagarajan et al. (72) Inventors: Noormohamed M. Niyaz, Indianapolis, 7,238,697 B2 7/2007 Bretschneider et al. IN (US); Francis E. Tisdell, Carmel, IN 7,371,759 B2 5/2008 Ahmad et al. (US); Gerald B. Watson, Zionsville, IN (US); James M. Renga, Indianapolis, IN FOREIGN PATENT DOCUMENTS SIR.US); William C. H. C.Yap Lo, Zionsville Fishers. IN N (US): GS, DE 10/2008/OOO872 11, 2008 e is savs s EP 1273580 A1 1/2003 EP 1775293 A1 4/2007 (73) Assignee: Dow AgroSciences LLC, Indianapolis, EP 17831 14 A1 5/2007 IN (US) WO 2005/063736 7/2005 WO 2009,025823 A1 1, 2009 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. U.S. Appl. No. 12/799,478, filed Apr. 26, 2010, Niyaz et al. European Patent Office. Patent Cooperation Treaty International (21) Appl. No.: 14/070,254 Search Report and Written Opinion of the International Searching Authority. PCT Patent Application No. PCT/US2010/001232. Jul. (22) Filed: Nov. 1, 2013 28, 2010. Allan, J.R. Paton, A.D. Preparation, structural characterisation, ther (65) Prior Publication Data mal and electrical studies of Some first row transition metal com US 2014/O141975 A1 May 22, 2014 plexes of 2,3-bis(2-pyridyl)pyrazine. Thermochimica Acta, 214 s (1993), pp. 227-233. Related U.S. Application Data Katritzky, A.R., Jiang, J.; Greenhill, J.V. 1.2- and 1,3- Monoazabisylides as Novel Synthones. Journal of Organic Chemis (62) Division of application No. 12/799,478, filed on Apr. try, 1993, vol. 58, pp. 1987-1988. 26, 2010, now Pat. No. 8,604,199. Heirtzler, F.; Neuburger, M.; Kulike, K. Insights on the synthesis and organisational phenomena of twisted pyrazine-pyridine hybrids. J. (60) Provisional application No. 61/172,958, filed on Apr. Chem. Soc., Perkin Trans. 1, 2002. p. 809-820. 27, 2009. Sumengen, D. The Preparation of 3, 4-Diaryl Furoxans and 3.5- diaryl-1,2,4-Oxadiazol-4-Oxides. Chimica Acta Turcica 13 (1985), (51) Int. Cl. pp. 3939-402. CO7D 413/4 (2006.01) Colonna, M., Risaliti, A. Recerche Sugli azocomosti AOIN 43/76 (2006.01) N-eterociclici. Nota VIII. Reazione con difenilchetene ed AOIN 43/40 (2006.01) autossidazione degli addotti da azoici simmetrici. Gassetta Chimica AOIN 55/00 (2006.01) Italia's Chimica, Italiana, Rome; Italy, vol. 90, Jan. 1, 1960, CO7D 40/4 (2006.01) RefNional Preliminary Report on Patentability, PCT/US2010/ (52) U.S. Cl. 001232, Apr. 26, 2010, Dow AgroSciences, LLC. CPC ...... A0IN 43/76 (2013.01); A0IN 43/40 Dorwald, Side Reactions in Organic Synthesis, 2005, Wiley: VCH (2013.01); A0IN 55/00 (2013.01); C07D Weinheim Preface, pp. 1-15 & Chapter 8, pp. 279-308. 401/14 (2013.01); C07D 413/14 (2013.01) (58) Field of Classification Search Primary Examiner — Patricia L. Morris CPC ...... CO7D 413/14 (74) Attorney, Agent, or Firm — Carl D. Corvin; Maschoff USPC ...... 546/256; 514/333 Brennan See application file for complete search history. (57) ABSTRACT (56) References Cited The invention disclosed in this document is related to the field of pesticides and their use in controlling pests. Novel pyridine U.S. PATENT DOCUMENTS compounds for use in controlling pests are disclosed. 4.474,599 A 10/1984 Rogers et al. 5,084,459 A 1/1992 Uneme et al. 11 Claims, No Drawings US 9, 131,694 B2 1. INSECTICIDAL PYRIDINE COMPOUNDS Formula (I) CROSS REFERENCE TO RELATED APPLICATIONS The present application is a divisional of U.S. patent appli cation Ser. No. 12/799,478 filed 26 Apr. 2009, now U.S. Pat. No. 8,604,199, which claims priority to U.S. Provisional Patent Application No. 61/172,958 filed 27 Apr. 2009. The contents of these applications are incorporated herein by ref erence in their entirety. 10 FIELD OF THE INVENTION wherein A1, A2, and A3, are each independently C or N, with the The inventions disclosed in this document are related to the proviso that A1 and A2 are not simultaneously N: field of pesticides and their use in controlling pests. 15 X and Y are independently C or N: Zand T are each independently C(R6) (where R6 could be BACKGROUND the same or different), C—O, C=NR7, NR7, O, S(O)n' (n'=0-2); Pests cause millions of human deaths around the world n=0, 1, 2 and 3 (X, Y, T and Z together form a 3- or 4- or 5 each year. Furthermore, there are more than ten thousand or 6-membered heteroaryl or a fully or partially saturated species of pests that cause losses in agriculture. These agri heterocyclic ring); cultural losses amount to billions of U.S. dollars each year. R1 is (provided that A1 is not N) H, CN, CHO, SCN, Termites cause damage to various structures such as homes. NO, F, Cl, Br, I, substituted or unsubstituted C1-C4-alkyl, These termite damage losses amount to billions of U.S. dol substituted or unsubstituted halo-C1-C4-alkyl, substituted or lars each year. As a final note, many stored food pests eat and 25 unsubstituted C1-C4-alkoxy, substituted or unsubstituted adulterate stored food. These stored food losses amount to halo-C1-C4-alkoxy, substituted or unsubstituted C1-C4-thio billions of U.S. dollars each year, but more importantly, alkyl, substituted or unsubstituted halo-C1-C4-thioalkyl, deprive people of needed food. substituted or unsubstituted C3-C7-cycloalkyl, substituted or There is an acute need for new pesticides. Insects are devel unsubstituted C2-C4-alkenyl, C2-C4-alkynyl, substituted or oping resistance to pesticides in current use. Hundreds of 30 unsubstituted C1-C4-acylalkyl, C1-C4-acyloxy, C1-C4 insect species are resistant to one or more pesticides. The alkoxycarbonyl, C1-C4-alkoxy-amino, C1-C4-alkyl-S(O) development of resistance to some of the older pesticides, —NH, substituted or unsubstituted aryl, substituted or unsub Such as DDT, the carbonates, and the organophosphates, is stituted heterocyclyl, wherein the substituents are one or well known. But resistance has even developed to some of the more of the following F, C1, Br, OH, CN, NO, CHO,-SCN, newer pesticides. Therefore, a need exists for new pesticides 35 S(O)n-C1-C4-alkyl (where n=0-2). C1-C4-alkyl, halo-C1 and particularly for pesticides that have new modes of action. C4-alkyl, C1-C4-alkylamine, C1-C4-alkoxy, halo-C1-C4 alkoxy, C1-C4-thioalkyl, halo-C1-C4-thioalkyl, C1-C4 SUMMARY alkylacyl, C1-C4-acyloxy, C1-C4 alkoxycarbonyl, C1-C4 alkoxy-imino, hydroxy-imino, C1-C4-alkyl-S(O)—NH, This invention concerns compounds useful for the control 40 (C1-C4-trialkyl)Si; of insects, especially useful for the control of aphids and other R2 is (provided that A2 is not N) H, CN, CHO, SCN, Sucking insects. More specifically, the invention concerns NO, F, C1, Br, I, substituted or unsubstituted C1-C4-alkyl, compounds of formula I: substituted or unsubstituted halo-C1-C4-alkyl, substituted or unsubstituted C1-C4-alkoxy, substituted or unsubstituted 45 halo-C1-C4-alkoxy, substituted or unsubstituted C1-C4-thio alkyl, substituted or unsubstituted halo-C1-C4-thioalkyl, substituted or unsubstituted C3-C7-cycloalkyl, substituted or unsubstituted C2-C4-alkenyl, C2-C4-alkynyl, substituted or unsubstituted C1-C4-acylalkyl, C1-C4-acyloxy, C1-C4 alkoxycarbonyl, C1-C4-alkoxy-amino, C1-C4-alkyl-S(O) —NH, substituted or unsubstituted aryl, substituted or unsub stituted heterocyclyl, wherein the substituents are one or more of the following F, C1, Br, OH, CN, NO, CHO,-SCN, S(O)n-C1-C4-alkyl (where n=0-2). C1-C4-alkyl, halo-C1 wherein A1, A2, A3, X,Y,Z, T, n, R1, R2, R3, R4, R5, R6 and 55 C4-alkyl, C1-C4-alkylamine, C1-C4-alkoxy, halo-C1-C4 R7 are as defined herein. alkoxy, C1-C4-thioalkyl, halo-C1-C4-thioalkyl, C1-C4 The invention also provides new processes for preparing alkylacyl, C1-C4-acyloxy, C1-C4 alkoxycarbonyl, C1-C4 compounds of formula I as well as new compositions and alkoxy-imino, hydroxy-imino, C1-C4-alkyl-S(O)—NH, methods of use, which will be described in detail hereinafter. (C1-C4-trialkyl)Si; Further embodiments, forms, aspects, features, and details of 60 R3 is CN, NO, F, Cl, Br, I, substituted or unsubstituted the present invention shall become apparent from the descrip halo-C1-C4-alkyl, or unsubstituted C3-C7-cycloalkyl, sub tions contained herein. stituted or unsubstituted halo-C1-C4-alkoxy, substituted or unsubstituted halo-C1-C4-thioalkyl substituted or unsubsti DETAILED DESCRIPTION tuted halo-C2-C4-alkenyl, substituted or unsubstituted five 65 membered heteroaryl, wherein the substituents are one or The compounds of this application have the following more of the following F, Cl, Br, OH, CN, NO, CHO,-SCN, molecular structure: S(O)n-C1-C4-alkyl (where n=0-2). C1-C4-alkyl, halo-C1 US 9, 131,694 B2 3 4 C4-alkyl, C1-C4-alkylamine, C1-C4-alkoxy, halo-C1-C4 unsubstituted C1-C4-acylalkyl, C1-C4-acyloxy, C1-C4 alkoxy, C1-C4-thioalkyl, halo-C1-C4-thioalkyl, C1-C4 alkoxycarbonyl, C1-C4-alkyl-S(O)—NH, substituted or alkylacyl, C1-C4-acyloxy, C1-C4 alkoxycarbonyl, C1-C4 unsubstituted aryl, substituted or unsubstituted heterocyclyl, alkoxy-imino, hydroxy-imino, C1-C4-alkyl-S(O)—N: wherein the substituents are one or more of the following F. R4 is (provided that A3 is not N) H, CN, CHO, SCN, Cl, Br, OH, CN, NO, CHO, SCN, S(O)n-C1-C4-alkyl NO, F, Cl, Br, I, substituted or unsubstituted C1-C4-alkyl, (where n=0-2), C1-C4-alkyl, halo-C1-C4-alkyl, C1-C4-alky substituted or unsubstituted halo-C1-C4-alkyl, substituted or lamine, C1-C4-alkoxy, halo-C1-C4-alkoxy, C1-C4-thio unsubstituted C1-C4-alkoxy, substituted or unsubstituted alkyl, halo-C1-C4-thioalkyl, C1-C4-alkylacyl, C1-C4-acy halo-C1-C4-alkoxy, substituted or unsubstituted C1-C4-thio loxy, C1-C4 alkoxycarbonyl, C1-C4-alkoxy-imino, hydroxy alkyl, substituted or unsubstituted halo-C1-C4-thioalkyl, 10 imino, C1-C4-alkyl-S(O)—NH. (C1-C4-trialkyl)Si. substituted or unsubstituted C3-C7-cycloalkyl, substituted or unsubstituted C2-C4-alkenyl, C2-C4-alkynyl, substituted or unsubstituted C1-C4-acylalkyl, C1-C4-acyloxy, C1-C4 Substituents (Non-Exhaustive List) alkoxycarbonyl, C1-C4-alkoxy-amino, C1-C4-alkyl-S(O) —NH, substituted or unsubstituted aryl, substituted or unsub 15 The examples given for the substituents are (except for stituted heterocyclyl, wherein the substituents are one or more of the following F, Cl, Br, OH, CN, NO, CHO,-SCN, halo) non-exhaustive and must not be construed as limiting S(O)n-C1-C4-alkyl (where n=0-2). C1-C4-alkyl, halo-C1 the invention disclosed in this document. C4-alkyl, C1-C4-alkylamine, C1-C4-alkoxy, halo-C1-C4 “alkenyl' means an acyclic, unsaturated (at least one car alkoxy, C1-C4-thioalkyl, halo-C1-C4-thioalkyl, C1-C4 bon-carbon double bond), branched or unbranched, substitu alkylacyl, C1-C4-acyloxy, C1-C4 alkoxycarbonyl, C1-C4 ent consisting of carbon and hydrogen, for example, vinyl, alkoxy-imino, hydroxy-imino, C1-C4-alkyl-S(O)—NH, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, (C1-C4-trialkyl)Si: and decenyl. R5 is H, CN, CHO,-SCN. NO, F, Cl, Br, I, substituted or “alkoxy' means an alkyl further consisting of a carbon unsubstituted C1-C4-alkyl, substituted or unsubstituted halo 25 oxygen single bond, for example, methoxy, ethoxy, propoxy, C1-C4-alkyl, substituted or unsubstituted C1-C4-alkoxy, isopropoxy, 1-butoxy, 2-butoxy, isobutoxy, tert-butoxy, pen substituted or unsubstituted halo-C1-C4-alkoxy, substituted or unsubstituted C1-C4-thioalkyl, substituted or unsubsti toxy, 2-methylbutoxy, 1,1-dimethylpropoxy, hexoxy, hep tuted halo-C1-C4-thioalkyl, substituted or unsubstituted toxy, Octoxy, nonoxy, and decoxy. C3-C7-cycloalkyl, substituted or unsubstituted C2-C4-alk 30 “alkyl means an acyclic, Saturated, branched or enyl, C2-C4-alkynyl, substituted or unsubstituted C1-C4 unbranched, Substituent consisting of carbon and hydrogen, acylalkyl, C1-C4-acyloxy, C1-C4 alkoxycarbonyl, C1-C4 for example, methyl, ethyl, propyl, isopropyl, 1-butyl, 2-bu alkoxy-amino, C1-C4-alkyl-S(O)—NH, substituted or tyl, isobutyl, tert-butyl, pentyl, 2-methylbutyl, 1,1-dimethyl unsubstituted aryl, substituted or unsubstituted heterocyclyl, propyl, hexyl, heptyl, octyl, nonyl, and decyl. wherein the substituents are one or more of the following F. 35 Cl, Br, OH, CN, NO, CHO, SCN, S(O)n-C1-C4-alkyl “alkynyl' means an acyclic, unsaturated (at least one car (where n=0-2). C1-C4-alkyl, halo-C1-C4-alkyl, C1-C4-alky bon-carbon triple bond, and any double bonds), branched or lamine, C1-C4-alkoxy, halo-C1-C4-alkoxy, C1-C4-thio unbranched, Substituent consisting of carbon and hydrogen, alkyl, halo-C1-C4-thioalkyl, C1-C4-alkylacyl, C1-C4-acy for example, ethynyl, propargyl, butynyl, pentynyl, hexynyl, loxy, C1-C4 alkoxycarbonyl, C1-C4-alkoxy-imino, hydroxy 40 heptynyl, octynyl, nonynyl, and decynyl. imino, C1-C4-alkyl-S(O)—NH. (C1-C4-trialkyl)Si; “aryl' means a cyclic, aromatic Substituent consisting of R6 is H, OH, SH, CN, CHO, SCN, NO, F, Cl, Br, I, hydrogen and carbon, for example, phenyl, naphthyl, and substituted or unsubstituted C1-C4-alkyl, substituted or biphenylyl. unsubstituted halo-C1-C4-alkyl, substituted or unsubstituted “cycloalkyl means a monocyclic or polycyclic, Saturated C1-C4-alkoxy, substituted or unsubstituted halo-C1-C4 45 alkoxy, substituted or unsubstituted C1-C4-thioalkyl, substi Substituent consisting of carbon and hydrogen, for example, tuted or unsubstituted halo-C1-C4-thioalkyl, substituted or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep unsubstituted C3-C7-cycloalkyl, substituted or unsubstituted tyl, cyclooctyl, cyclodecyl, norbornyl, bicyclo2.2.2]octyl, C2-C4-alkenyl, C2-C4-alkynyl, substituted or unsubstituted and decahydronaphthyl. C1-C4-acylalkyl, C1-C4-acyloxy, C1-C4 alkoxycarbonyl, 50 "halo' means fluoro, chloro, bromo, and iodo. C1-C4-alkyl-S(O)—NH, substituted or unsubstituted aryl, “haloalkyl means an alkyl further consisting of from one substituted or unsubstituted heterocyclyl, wherein the sub to the maximum possible number of identical or different, stituents are one or more of the following F, Cl, Br, OH, CN, halos, for example, fluoromethyl, difluoromethyl, trifluorom NO, CHO, SCN, S(O)n-C1-C4-alkyl (where n=0-2), ethyl, 1-fluoromethyl 2-fluoroethyl, 2.2.2-trifluoroethyl, C1-C4-alkyl, halo-C1-C4-alkyl, C1-C4-alkylamine, C1-C4 55 alkoxy, halo-C1-C4-alkoxy, C1-C4-thioalkyl, halo-C1-C4 chloromethyl, trichloromethyl, and 1.1.2.2-tetrafluoroethyl. thioalkyl, C1-C4-alkylacyl, C1-C4-acyloxy, C1-C4 alkoxy "heterocyclyl means a cyclic substituent that may be fully carbonyl, C1-C4-alkoxy-imino, hydroxy-imino, C1-C4 saturated, partially unsaturated, or fully unsaturated, where alkyl-S(O)—NH. (C1-C4-trialkyl)Si; and the cyclic structure contains at least one carbon and at least R7 is H, OH, CN, NH2, CHO,-SCN, NO, substituted or 60 one heteroatom, where said heteroatom is nitrogen, Sulfur, or unsubstituted C1-C4-alkyl, substituted or unsubstituted halo oxygen, for example, benzofuranyl, benzoisothiazolyl, ben C1-C4-alkyl, substituted or unsubstituted C1-C4-alkoxy, Zoisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl substituted or unsubstituted halo-C1-C4-alkoxy, substituted cinnolinyl, furanyl, indazolyl, indolyl, imidazolyl, isoindolyl, or unsubstituted C1-C4-alkylamine, substituted or unsubsti isoquinolinyl, isothiazolyl, isoxazolyl, 1.3.4 oxadiazolyl, tuted C1-C4-thioalkyl, substituted or unsubstituted halo-C1 65 oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, C4-thioalkyl, substituted or unsubstituted C3-C7-cycloalkyl, pyrazolyl pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, substituted or unsubstituted C2-C4-alkenyl, substituted or quinazolinyl, quinolinyl, quinoxalinyl, 1.2.3,4-tetrazolyl, US 9, 131,694 B2 5 6 thiazolinyl, thiazolyl, thienyl, 1.2.3-triazinyl, 1,2,4-triazinyl, -continued 1,3,5-triazinyl, 1,2,3-triazolyl, and 1,2,4-triazolyl.

1N R5 SYNTHESIS SCHEMES (NON-EXHAUSTIVE H n Y N Base I LIST) X- V -e-Metal catalyst (I) \ T Solvent Compounds of the formula (I) can be prepared according to ( y) Ligand the following methods. (III) 10 Method 1 Compounds of the formula (I) can be prepared by treating compounds of the formula (IV), where LG is Cl, Br, I, dialky 1borinate, or C1-C4-trialkyl stannane and R1, R2, R3, R4, A1, 15 A2 and A3 are as defined above, and compounds of the Scheme 1 formula (III), where X,Y, T, Z. nand R5 areas defined above, in an aprotic or protic solvent in the presence of a stoicheo R3 metric or catalytic amount of a base, a metal—(for example, R2 1. R4 Pd, Cu, Ni) catalyst and a suitable ligands such as trialkyl N1 N1 phosphines or arsines, at a temperature between -20 and 250° 1, 2 C. (heating under conventional or in a microwave reactor) at R11 sels.NN LG a pressure between 0-300 psi (Scheme 2). Suitable solvents (II) include, but are not limited to, water, tetrahydrofuran, 1.4- dioxane, dimethylformamide, dimethylsulfoxide, acetoni 25 trile, chloroform, 1,2-dichloroethane, methylene chloride, 21 and mixtures thereof. Suitable bases include, but not limited 1) to, metal alkoxides, tertiary amines and metal hydrides. H S B 8Se. (I) N Y -sul X- Solvent y 30 Method 3 (III) Scheme 3 35 Compounds of the formula (I) can be prepared by treating R3 compounds of the formula (II), where LG is a halogen (F, Cl, Br, I) or a sulfone or other leaving group and R1, R2, R3, R4, R2 1. R4 A1, A2 and A3 are as defined above, and compounds of the N1N1 | formula (III), where R5, X,Y,Z and T areas defined above, in 40 R11 A1,NN 2 x 1 Yv. -- anaprotic or protic solvent in the presence of a stoicheometric N T or catalytic amount of a base at a temperature between -20 (z and 250° C. (heating under conventional or in a microwave reactor) and at a pressure (0-300 psi) (Scheme 1). Suitable (V) solvents, include, but are not limited to, water, tetrahydrofu 45 21 -HRS ran, 1.4-dioxane, dimethylformamide, dimethylsulfoxide, N l Base acetonitrile, chloroform, methylene chloride, and mixtures LG N --> (I) Solvent thereof. In some cases the reaction can be carried out in the (VI) presence of excess amine (III) with no solvents. Suitable bases include, but not limited to, metal alkoxides, tertiary 50 amines and metal hydrides, Compounds of the formula (I) can be prepared by treating compounds of the formula (V), where Y—N and R1, R2, R3, R4, X, T, Z, n, A1, A2 and A3 are as defined above, and Method 2 compounds of the formula (VI), where R5 is as defined above 55 and LG is Cl, Br, I, a Sulfone or other leaving group, in an protic or aprotic solvent in the presence of a stoicheometric or catalytic amount of a base at a suitable temperature between Scheme 2 -20 and 250° C. (heating conventionally or in a microwave R3 60 reactor) and at a pressure between 0-300 psi (Scheme 3). Suitable solvents include, but are not limited to, water, tet R2 N1,N11. R4 rahydrofuran, 1.4-dioxane, dimethylformamide, dimethyl sulfoxide, acetonitrile, chloroform, methylene chloride, and 1, 2 mixtures thereof. In some cases the reaction can be carried out R11'NNsels. LG 65 in the presence of excess amine (VI) with no solvents. Suit (IV) able bases include, but not limited to, metal alkoxides, tertiary amines and metal hydrides, US 9, 131,694 B2 8 Method 4 Compounds of the formula (I) can be prepared by treat ment of the compounds of the formula (VIII), where R1,R2, R3, R4, X, Z, n, A1, A2, and A3 are as defined above, and compounds of the formula (IX), where M is H or C, in an Scheme 4 aprotic solvent in the presence of an acid catalyst under dehy drating conditions such as in a Dean-Stark set-up or additives R2 1. R4 Such as molecular sieves, anhydrous magnesium Sulfate N1N1 | (Scheme 5). Suitable acid catalysts include, but are not 10 A1, 2 Y + limited to, hydrochloric acid, Sulfonic acids and Sulfuric acid. R11 'selsNN x1 V Preferred solvents include but are not limited to, benzene, N v-T toluene, hexanes, pentane, tetrahydrofuran, dialkylethers, 1,4-dioxane, chloroform, methylene chloride, 1,2-dichloro (V) Base 15 ethane, dimethylformamide, and mixtures thereof. 21 R5 Solvent (I) o -e- N l Metal catalyst Method 6 LG N Ligand (VII)

Scheme 6 Compounds of the formula (I) can be prepared by treating compounds of the formula (V), where Y—N and R1, R2, R3, R3 R6 R4, X, T, Z, n, A1, A2 and A3 are as defined above and 25 compounds of the formula (VII), where LG is Cl, Br, I, Rin's-R 8. dialkylborinate, or C1-C4-trialkyl stannane and R5 is as - Na + 1 1" - " - defined above, in an aprotic or protic solvent in the presence R1 N C H of a stoicheometric or catalytic amount of a base, a metal— (XI) (XII) (for example, Pd, Cu, Ni) catalyst and a suitable ligands Such 30 as trialkyl phosphines or arsenes, at a temperature between -20 and 250°C. (eating under conventional or in a microwave reactor) at a pressure between 0-300 psi (Scheme 4). Suit R2 1. R4 able solvents include, but are not limited to, water, tetrahy 35 N1 N1 R, drofuran, 1.4-dioxane, dimethylformamide, dimethylsulfox ide, acetonitrile, chloroform, 1,2-dichloroethane, methylene R11'NNA1,'sels 2 --- O NH chloride, and mixtures thereof. Suitable bases include, but not limited to, metal alkoxides, tertiary amines and metal H hydrides. 40 (XIII)

Method 5

45

Scheme 5 R5 R3 R2 R4 R2 N1,N11. R4 50 N1s1ul- leNY, A1,'sels 2 R11 A1,NN 2 x1 H -- R11'NN N X -U/ (z pi H 55 R6 (VIII) (X)

Compounds of the formula (X) can be prepared by a two 21 Solvent 60 step process that includes treatment of compounds of the ---> (1) M Sa acid or base formula (XI) and compounds of the formula (XII), where R1, N catalyst R2, R3, R4, R5, A1, A2, and A3 are as defined above, in a O sealed tube to selectively displace the chlorine at position 6. 65 Condensation with a pyridine carboxaldehyde under Dean Stark conditions catalyzed by para-toluenesulfonic acid pro duces the compound of formula (X). US 9, 131,694 B2 9 10 Method 7 Example I

Preparation of 6-2-(2-Pyridyl)-1-pyrrolidinyl-4- trifluoromethyl-2,3-dichloropyridine (Compound 1) Scheme 7 N R3 2N CF / \ 10 C N FN i-Pr2(Et)N -- Hip 2 N p -dioxane C N C

15 3 4 CF N-1 n / \ R3 H RN R4 d 2 isN1N1 1. C N N

25 1 CF CO R5 (XVII) ls-Cl ( Y 30 EN 2 C N N

35

To a solution of 1.25 g (0.005 mol) of 2,3,6-trichloro-4- trifluoromethypyridine in 7.5 mL of anhydrous p-dioxane 40 was added 0.889 g (0.006 mol) of 2-(pyrrolidine-2-yl)pyri dine followed by 0.97 g (0.0075 mol) of diisopropylethy lamine. The mixture was magnetically stirred and heated in a microwave chamber to 130° C. for 45 min. Upon cooling to room temperature, the red reaction mixture was diluted with 45 50 mL of ethyl acetate, washed with a saturated solution of NaCl, and dried (MgSO). Solvent removal gave 1.81 g of a 6:1 mixture of 6-2-(2-pyridyl)-1-pyrrolidinyl-4-trifluorom (XIV) ethyl-2,5-dichloropyridine (Compound 2) and 6-2-(2-py ridyl)-1-pyrrolidinyl-4-trifluoromethyl-2,3-dichloropyri Compounds of the formula (XIV) can be prepared by a 50 dine (Compound 1). Column chromatography on silica gel two-step process that includes treatment of compounds of the eluting with 20% ethyl acetate/hexane gave 1.05 g of 98% pure Compound 2 and 0.41 g of 1:1 mixture of Compound formula (XV) and compounds of the formula (XVI), where 2:Compound 1. This mixture was further separated as above R1, R2, R3, R4, A1, A2, and A3 are as defined above, in a to give 0.18 g of Compound 2 and 0.15g of Compound 1. sealed tube to selectively displace the chlorine at position 6. 55 Compound 1: "H NMR (300 MHz, CDC1) & 8.58 (dd, Condensation with a carboxaldehyde (R6CHO) under Dean J=4.8, 1.0 Hz, 1H), 7.61 (dt, J=2.0, 7.9 Hz, 1H), 7.17 (ddd, Stark conditions catalyzed by para-toluenesulfonic acid pro J=4.8, 2.0, 1.OH), 7.11 (d. J–7.9 Hz, 1H), 6.40 (brs, 1H), 5.04 duces the compound of formula XIV. (brs, 1H), 3.83 (m, 1H), 3.65 (m. 1H), 2.43 (m, 1H), 2.1 (m, 60 3H). Exact mass for C.H.C.F.N. Calcd,316.0355. Found, 361.0358. EXAMPLES Compound 2: "H NMR (300 MHz, CDC1) & 8.54 (dq, J=4.8, 1.0 Hz, 1H), 7.56 (dt, J=2.0, 7.9 Hz, 1H), 7.24 (d. J=7.9 HZ, 1H), 7.16 (ddd, J–4.8, 2.0, 1.0, 1H), 6.84 (brs, 1H), 5.50 The examples are for illustration purposes and are not to be 65 (t, J=6.7 Hz, 1H), 4.22 (m, 1H), 3.81 (m, 1H), 2.43 (m. 1H), construed as limiting the invention disclosed in this document 2.1 (m, 3H). Exact mass for CH2Cl2FN. Calcd. to only the embodiments disclosed in these examples. 316.0355; Found, 361.0357. US 9, 131,694 B2 11 12 Example II Example III Preparation of 2,6-Dichloro-4-trifluoromethyl-3- Preparation of 2-(2-Pyridyl)piperidin-2-yl)-4-trifluo trimethylsilanylpyridine (Compound 8) romethyl-5,6-dichloropyridine (Compound 6) and 2-(2-Pyridyl)piperidin-2-yl)-4-trifluoromethyl-3,6- dichloropyridine (Compound 7) CF CF 1. i-PrNLi MeSi 10 N THF N CF3 -e- 2 2. MeSiCl 2 C N C C N C N RN Hs 9 8 C o -- / \ p-dioxane 2 N 15 C N C A dry 100 mL 3 neck rb flask was charged with diisopro 3 pylamine (2.15 mL, 15.3 mmol) and 40 mL of anhydrous 5 THF. Reaction mixture was cooled at -20°C. under N. A 2.5 M solution of n-Bulli in Hexane (5.90 mL, 14.8 mmol) was added dropwise via a syringe. The resulting reaction mixture CF3 was then cooled at -78° C. A solution of 2,6-dichloro-4- trifluoromethylpyridine (3.0 g, 14 mmol) in 5 mL of anhy Cls-sa ( Y drous THF was added slowly via an addition funnel to give a RN 25 pale yellow solution. Reaction mixture stirred at -78°C. for 2 2 h. After which time, a solution of TMSC1 (2.0 mL, 15.8 C N N mmol) in 5 mL of THF was added dropwise via an addition funnel. The resulting reaction mixture was allowed to slowly warm up to room temperature and stirred over night. Reaction mixture was added to 150 mL of EtO, washed with dilute 6 30 HCl, then washed with aq. NaHCO, dried over MgSO, filtered and concentrated to give 3.80 g (95%) of 2.6- CF3 dichloro-4-trifluoromethyl-3-trimethylsilanylpyridine (Compound 8) as a brown oil: ls-Cl ( Y H NMR (300 MHz, CDC1) & 0.5 (s, 9H), 7.55 (s, 1H). RN 2 Example IV C N N Preparation of 2-(2-Pyridyl)pyrrolidine-2-yl)-4-trif luoromethyl-5-trimethylsilanylpyridine-6-chloropy 40 ridine (Compound 10) 7

To a solution of 1.25 g (0.005 mol) of 2,3,6-trichloro-4- CF trifluoromethypyridine in 7.5 mL of anhydrous p-dioxane 45 MeSi / \ was added 0.973 g (0.006 mol) of 2-(piperidin-2-yl)pyridine N -- FN i-Pr(Et)N -e- followed by 0.97 g (0.0075 mol) of diisopropylethylamine. p-dioxane The mixture was magnetically stirred and heated in a micro C 4. C N wave chamber to 130° C. for 45 min. Upon cooling to room 50 temperature, the red reaction mixture was diluted with 50 mL 8 of ethyl acetate, washed with a saturated solution of NaCl, and dried (MgSO). Solvent removal gave 2.0 g of a 3:2 4 mixture of 2-(2-pyridyl)piperidin-2-yl)-4-trifluoromethyl-5, CF 6-dichloropyridine (Compound 6) and 2-(2-pyridyl)piperi 55 MeSi N / \ din-2-yl)-4-trifluoromethyl-3,6-dichloropyridine (Com RN pound 7). A 0.20 g sample was purified on silica gel eluting 2 with 10% ethyl acetate/hexane to give 0.14 g of 1:1 mixture of C N N Compound 6:Compound 7, which could not be further puri fied. 60 Compound 6: "H NMR (300 MHz, CDC1) 88.58 (m, 1H), 10 7.60 (m. 1H), 7.0 (m, 2H), 6.75 (brs, 1H), 5.04 (brs, 1H), 3.3 (m. 2H), 2.6 (m. 1H), 1.5-2.2 (m, 5H). To a solution of 1.44 g (0.005 mol) of 2,6-dichloro-4- Compound 7: "H NMR (300 MHz, CDC1,) 88.54 (m, 1H), 65 trifluoromethyl-3-trimethylsilanylpyridine (Compound 8) in 7.56 m, 1H), 7.3 (m. 1H), 7.1 (m,2H), 7.05 (brs, 1H), 5.60(m, 7.5 mL of anhydrous p-dioxane was added 0.889 g (0.006 1H), 4.20(m, 1H), 3.5 (m. 1H), 2.60 (m, 1H), 1.5-2.1 (m, 4H). mol) of 2-(pyrrolidine-2-yl)pyridine followed by 0.97 g US 9, 131,694 B2 13 14 (0.0075 mol) of diisopropylethylamine. The mixture was Example VI magnetically stirred and heated in a microwave chamber to 150° C. for 1 hr. Upon cooling to room temperature, the red Synthesis of 2-chloro-6-4-isopropyl-2-(2-pyridyl) reaction mixture was diluted with 50 mL of ethyl ether, oxazolidin-3-yl)-4-(trifluoromethyl)pyridine-3-car washed with a saturated solution of NaCl, and dried 5 (MgSO4). Solvent removal gave 2.05 g of an orange oil. bonitrile (Compound 12) Column chromatography on silica gel eluting with 10% ethyl acetate/hexane gave 0.95 g (48% yield) of 2-(2-pyridyl)pyr rolidine-2-yl)-4-trifluoromethyl-5-trimethylsilanylpyridine 10 F 6-chloropyridine (Compound 10). F F "H NMR (300 MHz, CDC1) 88.58(dd, J=4.8, 1.0 Hz, 1H), 7.62 (dt, J=2.0, 7.5 Hz, 1H), 7.15 (m, 2H), 6.45 (brs, 1H), 5.04 s HO N 1 (brs, 1H), 3.8 (m. 1H), 3.72 (m, 1H), 2.45 (m. 1H), 2.05-2.22 N -- Ho (m, 3H), 0.4 (s.9H). Exact mass for CHCIFN.Si. Calcd, 15 2 399.1140. Found, 399.1146. C N C 14 F Example V F F

N Preparation of 2-(2-Pyridyl)pyrrolidino-2-yl)-4-trif Šs OH luoromethyl-5-trimethylsilanylpyridinepyridine N 2 (Compound 11) Her 2 C N 25 H CF 13 F MeSi N / \ F F 30 FN HCONH N | N n N C 4. N PC N le

2 35 C N N 10 O CF3 MeSi / \ N 40 12 FN 2 N N Step 1: Preparation of 2-chloro-6-1-(hydroxym 45 ethyl)-2-methyl-propylamino-4-(trifluoromethyl) 11 pyridine-3-carbonitrile intermediate

To a solution of 0.24 g (0.6 mmol) 2-(2-pyridyl)pyrroli Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine dino-2-yl)-4-trifluoromethyl-5-trimethylsilanylpyridine-6- 50 (0.641 g, 6 mmol) (Compound 14) was added by pipette at a chloropyridine (Compound 10) in 5 mL of methanol was dropwise rate over 3 minutes to 2-amino-3-methyl-butan-1- added 0.252 g (4 mmol) of ammonium formate followed by ol (1.5 g. 6 mmol) (Compound 15). Di-isopropylamine (0.9 g, 0.1 g of 5% Pd on carbon. The mixture was magnetically 7 mmol) was added after 10 minutes and the resultant mixture stirred and heated in a microwave chamber to 100° C. for 1.5 was heated in a sealed tube at 70° C. for 30 minutes to hr. Upon cooling to room temperature, the reaction mixture 55 selectively displace the chlorine at position 6 before quench ing in ice-cold water and extracted with dichloromethane. was filtered through a plug of Celite and solvent was Organic extracts were washed twice with water, dried over removed. The residue was dissolved in methylene chloride Sodium sulfate and concentrated under reduced pressure. The washed with a saturated solution of NaCl and dried (MgSO). residue was washed with diethylether and the resultant solid Solvent removal gave 0.185 g (84% yield) of a 95% pure was used in the next step without further purification. 2-(2-pyridyl)pyrrolidine-2-yl)-4-trifluoromethyl-5-trimeth 60 2-Chloro-6-1-(hydroxymethyl)-2-methyl-propylamino ylsilanylpyridinepyridine (Compound 11). 4-(trifluoromethyl)pyridine-3-carbonitrile (Compound 13) H NMR (300 MHz, CDC1) 88.58(dd, J=4.8, 1.0 Hz, 1H), was isolated in 50% yield. 8.37 (s, 1H), 7.62 (dt, J=2.0, 7.5 Hz, 1H), 7.15 (m, 2H), 6.55 'HNMR (CDC1,400 MHz) 8/ppm 6.66 (s, 1H), 5.63 (br. (brs, 1H), 5.20(brs, 1H), 3.91 (m. 1H), 3.70 (m. 1H), 2.45 (m, 65 1H), 4.09 (br, 0.7H), 3.81 (t, J=4.5 Hz, 2.4H), 2.01 (octet, 1H), 2.22 (m. 1H), 2.10 (m 2H), 0.4 (s, 9H). Exact mass for J=6.9 Hz, 1H), 1.70 (brt, J–49 Hz, 0.9H), 1.03 (d. J=6.7 Hz, CHIFN.Si. Calcd, 365.1535. Found,399.1532. 3H), 1.00 (d. J=6.8 Hz, 3H). US 9, 131,694 B2 15 16 Step 2: Synthesis of 2-chloro-6-4-isopropyl-2-(2- Step 2: Synthesis of 2-chloro-6-4-methyl-2-(2-py pyridyl)oxazolidin-3-yl)-4-(trifluoromethyl)pyridine ridyl)oxazolidin-3-yl)-4-(trifluoromethyl)pyridine-3- 3-carbonitrile carbonitrile Pyridine-2-carboxaldehyde (207 mg, 1.9 mmol) was added 5 Pyridine-2-carboxaldehyde (207 mg, 1.9 mmol) was added to a toluene solution (15 mL) of 2-chloro-6-1-(hydroxym to a toluene solution (15 mL) of 2-chloro-6-1-(hydroxym ethyl)-2-methyl-propylamino-4-(trifluoromethyl)pyridine ethyl)-2-methylamino-4-(trifluoromethyl)pyridine-3-car 3-carbonitrile (400 mg, 1.3 mmol) (Compound 13) followed bonitrile (400 mg, 1.3 mmol) followed by a catalytic amount by a catalytic amount of para-toluene Sulfonic acid (50 mg). of para-toluene sulfonic acid (50 mg). The reactants were The reactants were refluxed for 6 hours in a Dean-Stark 10 refluxed for 6 hours in a Dean-Stark apparatus, concentrated apparatus, concentrated under reduced pressure, adsorbed under reduced pressure, adsorbed onto silica and purified onto Silica and purified using a neutral alumina column, elut using a neutral alumina column, eluting with a mobile phase ing with a mobile phase of 10% ethyl acetate in hexane. of 10% ethyl acetate in hexane. 2-Chloro-6-4-methyl-2-(2- 2-Chloro-6-4-isopropyl-2-(2-pyridyl)oxazolidin-3-yl)-4- pyridyl)oxazolidin-3-yl)-4-(trifluoromethyl)pyridine-3-car (trifluoromethyl)pyridine-3-carbonitrile (Compound 12) was 15 bonitrile (Compound 16) was isolated as a solid in 55% yield. isolated as a solid in 20% yield. mp 112-115°C. mp 90-93° C. 'HNMR (CDC1, 400 MHz) 8/ppm 8.49 (br, 0.7H), 7.73 'HNMR (CDC1, 400 MHz) S/ppm 8.63 (d. J=4.8 Hz, (dt, J'=6.7 Hz, J’=1.8 Hz, 0.8H), 7.42 (br, 0.8H), 7.26 (br), 0.2H), 8.52 (br, 0.6H), 7.78-7.73 (m, 1H), 7.54 (d. J=7.9 Hz, 0.2H), 7.43 (br, 0.8H), 7.34-7.26 (m), 6.85 (br, 0.2H), 6.67 6.61 (br, 0.4H), 6.38 (br, 0.9H), 4.52 (br, 1.5H), 4.21 (d. J–8.4 (m, 0.5H), 6.42-6.17 (br, 1.4H), 4.71-4.43 (br, 2H), 4.29 (t, HZ, 1.3H), 2.42 (br, 0.8H), 1.06 (d. J=6.6 Hz, 3H), 0.97 (d. 0.3H), 4.11-4.10 (m, 0.2H), 3.98 (d. J=8.2 Hz, 1H), 1.49 (d. J=6.6 Hz, 3-1); ES/MS 397.0 (M). J=6.3 Hz, 3H); ES/MS 369.0 (M). Example VII 25 Example VIII Synthesis of 2-chloro-6-4-methyl-2-(2-pyridyl)ox azolidin-3-yl)-4-(trifluoromethyl)pyridine-3-carboni Synthesis of 2-chloro-6-5-ethyl-2-(2-pyridyl)oxazo trile (Compound 16) lidin-3-yl)-4-(trifluoromethyl)pyridine-3-carbonitrile 30 (Compound 17)

16 N | 17 F 35 C N F C Na2 40 Z \ N CH3 Y CH3 S. O r 45 Step 1: Synthesis of 2-chloro-6-1-(hydroxym ethyl)-2-methylamino-4-(trifluoromethyl)pyridine Step 1: Synthesis of 2-chloro-6-(2-hydroxybuty 3-carbonitrile lamino)-4-(trifluoromethyl)pyridine-3-carbonitrile 50 Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine (0.641 g, 6 mmol) was added by pipette at a dropwise rate Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine over 3 minutes to 2-aminopropanol (1.5 g. 6 mmol). Di (0.641 g, 6 mmol) was added by pipette at a dropwise rate isopropylamine (0.9 g, 7 mmol) was added after 10 minutes over 3 minutes to 2-aminobutanol (1.5 g. 6 mmol). Di-iso and the resultant mixture was heated in a sealed tube at 70° C. 55 propylamine (0.9 g, 7 mmol) was added after 10 minutes and for 30 minutes to selectively displace the chlorine at position the resultant mixture was heated in a sealed tube at 70° C. for 6 before quenching in ice-cold water and extracted with 30 minutes to selectively displace the chlorine at position 6 dichloromethane. Organic extracts were washed twice with before quenching in ice-cold water and extracted with dichlo water, dried over Sodium Sulfate and concentrated under romethane. Organic extracts were washed twice with water, dried over sodium sulfate and concentrated under reduced reduced pressure. The residue was washed with diethylether 60 and the resultant solid was used in the next step without pressure. The residue was washed with diethylether and the further purification. 2-Chloro-6-1-(hydroxymethyl)-2-me resultant solid was used in the next step without further puri thylamino-4-(trifluoromethyl)pyridine-3-carbonitrile was fication. 2-Chloro-6-(2-hydroxybutylamino)-4-(trifluorom isolated in 52% yield. ethyl)pyridine-3-carbonitrile was isolated in 55% yield. 'HNMR (CDC1,400 MHz) 8/ppm 6.63 (s, 1H), 4.27 (br. 65 'HNMR (CDC1,400 MHz) 8/ppm 6.64 (s, 1H), 5.96 (br. 0.8H), 3.84-3.79 (m. 1.2H), 3.70–3.65 (m. 1.3H), 1.80 (brt, 1H), 3.78 (br. 1H), 3.32 (br. 1H), 1.94 (brid, J=4.1 Hz, 1H), 0.8H), 1.58 (s, 1.3H), 1.30 (d. J=6.7 Hz, 3H). 1.65-1.50 (m, 4H), 1.02 (t, J=7.5 Hz, 3H). US 9, 131,694 B2 17 18 Step 2: Synthesis of 2-chloro-6-5-ethyl-2-(2-py Step 2: Synthesis of 2-chloro-6-4-phenyl-2-(2-py ridyl)oxazolidin-3-yl)-4-(trifluoromethyl)pyridine-3- ridyl)oxazolidin-3-yl)-4-(trifluoromethyl)pyridine-3- carbonitrile carbonitrile

Pyridine-2-carboxaldehyde (207 mg, 1.9 mmol) was added 5 Pyridine-2-carboxaldehyde (207 mg, 1.9 mmol) was added to a toluene solution (15 mL) of 2-chloro-6-(2-hydroxybuty to a toluene solution (15 mL) of 2-chloro-6-1-(hydroxym lamino)-4-(trifluoromethyl)pyridine-3-carbonitrile (400 mg. ethyl)-2-phenylamino-4-(trifluoromethyl)pyridine-3-car 1.3 mmol) followed by a catalytic amount of para-toluene bonitrile (400 mg, 1.3 mmol) followed by a catalytic amount sulfonic acid (50mg). The reactants were refluxed for 6 hours of para-toluene sulfonic acid (50 mg). The reactants were in a Dean-Stark apparatus, concentrated under reduced pres 10 refluxed for 6 hours in a Dean-Stark apparatus, concentrated Sure, adsorbed onto Silica and purified using a neutral alumina under reduced pressure, adsorbed onto silica and purified column, eluting with a mobile phase of 10% ethyl acetate in using a neutral alumina column, eluting with a mobile phase hexane. 2-Chloro-6-5-ethyl-2-(2-pyridyl)oxazolidin-3-yl)- of 10% ethyl acetate in hexane. 2-Chloro-6-4-phenyl-2-(2- 4-(trifluoromethyl)pyridine-3-carbonitrile (Compound 17) 15 pyridyl)oxazolidin-3-yl)-4-(trifluoromethyl)pyridine-3-car was isolated as a solid in 37% yield. mp 115-118°C. bonitrile (Compound 18) was isolated as a solid in 19% yield. 'HNMR (CDC1, 400 MHz) 8/ppm 8.59 (d. J=4.5 Hz, mp 198-200° C. 0.7H), 7.76 (t, J=7.5 Hz, 0.8; H), 7.46 (dd, J =7.8 Hz, J–1.0 'HNMR (CDC1, 400 MHz) 8/ppm 8.53 (br, 0.8H), 7.79 HZ, 0.8H), 7.31 (br, 0.7H), 6.84 (br, 0.6H), 6.66 (br, 0.2H), (dt, J'=7.6 Hz, J’=1.4 Hz, 1H), 7.57 (br, 1.1H), 742-7.37 (m, 6.12 (br, 0.7H), 4.75 (br, 0.1H), 4.44 (br, 0.6H), 4.24 (br. 7.2H), 7.29 (br), 6.78 (br, 0.9H), 6.43 (br, 1.2H), 5.60 (br. 0.9H), 4.03 (t, J=9.6 Hz, 0.3H), 3.53 (br. 1H), 1.97-1.80 (m, 0.2H), 5.23 (br. 1H), 5.00 (br, 1.1H), 4.17-4.13 (m. 1.4H); 2.1H), 1.10-1.02 (m, 3H); ES/MS 383.0 (M). ES/MS 431.0 (M). Example IX Example X 25 2-chloro-6-4-phenyl-2-(2-pyridyl)oxazolidin-3-yl)- 2-Chloro-6-5-ethyl-2-(2-pyridyl)oxazolidin-3-yl)-4- 4-(trifluoromethyl)pyridine-3-carbonitrile (Com (trifluoromethyl)pyridine-3-carbonitrile (Compound pound 18) 19)

30

18 19 |N |N F 35 F C N C N F F Na2 Na2 Z \ N 40 Z \ N SN sN O O

45 CH3 Step 1: Synthesis of 2-chloro-6-1-(hydroxym ethyl)-2-phenyl)amino-4-(trifluoromethyl)pyridine Step 1: Synthesis of 2-chloro-6-(2-hydroxybuty 3-carbonitrile lamino)-4-(trifluoromethyl)pyridine-3-carbonitrile 50 Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine (0.641 g, 6 mmol) was added by pipette at a dropwise rate Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine over 3 minutes to 2-amino-2-phenylethanol (1.5 g. 6 mmol). (0.641 g, 6 mmol) was added by pipette at a dropwise rate Di-isopropylamine (0.9 g, 7 mmol) was added after 10 min over 3 minutes to 1-aminopropane-2-ol (1.5 g. 6 mmol). utes and the resultant mixture was heated in a sealed tube at 55 Di-isopropylamine (0.9 g, 7 mmol) was added after 10 min 70° C. for 30 minutes to selectively displace the chlorine at utes and the resultant mixture was heated in a sealed tube at position 6 before quenching in ice-cold water and extracted 70° C. for 30 minutes to selectively displace the chlorine at with dichloromethane. Organic extracts were washed twice position 6 before quenching in ice-cold water and extracted with water, dried over sodium sulfate and concentrated under with dichloromethane. Organic extracts were washed twice reduced pressure. The residue was washed with diethylether 60 with water, dried over sodium sulfate and concentrated under and the resultant solid was used in the next step without reduced pressure. The residue was washed with diethylether further purification. 2-Chloro-6-1-(hydroxymethyl)-2-phe and the resultant solid was used in the next step without nyl)amino-4-(trifluoromethyl)pyridine-3-carbonitrile was further purification. isolated in 60% yield. 2-chloro-6-(2-hydroxybutylamino)-4-(trifluoromethyl) 'HNMR (CDC1, 400 MHz) 8/ppm 7.42-7.33 (m, 5H), 65 pyridine-3-carbonitrile was isolated in 55% yield. 6.51 (br, 2H), 406-4.03 (m. 1.4H), 3.96 (br, 1.1H), 1.89 (br. HNMR (CDC1,400 MHz) 8/ppm 6.64 (s, 1H), 5.63 (br. 0.96H), 1.60 (m. 1.1H). 1H), 4.21 (br, 0.7H), 3.83-3.73 (m, 2.5H), 2.18 (d. J=0.8 Z, US 9, 131,694 B2 19 20 2H), 1.76-1.61 (m, 3.2H), 1.54-1.51 (m, 0.6H), 1.44 (d. J–6.7 upon the surface of 1 mL of lepidopteran diet (Southland HZ, 0.3H), 1.00 (t, J=7.4 Hz, 3H). Multi-Species Lepidopteran Diet) contained in each of eight wells per insect species (one well-1 replication). A second Step 2: Synthesis of 2-chloro-6-5-ethyl-2-(2-py instarbeet armyworm was placed upon the treated diet in each ridyl)oxazolidin-3-yl)-4-(trifluoromethyl)pyridine-3- 5 well (one insect per well) once the solvent had air-dried. Trays carbonitrile containing the treated diet and larvae were covered and then Pyridine-2-carboxaldehyde (207 mg, 1.9 mmol) was added held in a growth chamber at 25°C., 50-55% RH, and 16 hr to a toluene solution (15 mL) of 2-chloro-6-(2-hydroxybuty light:8 hr dark for 5 days. Observation were conducted 2 and lamino)-4-(trifluoromethyl)pyridine-3-carbonitrile (400 mg. 10 5 days after treatment and infestation to score the number of 1.3 mmol) followed by a catalytic amount of para-toluene dead insects per 8-well treatment. sulfonic acid (50mg). The reactants were refluxed for 6 hours The results of this test are set forth in the column labelled in a Dean-Stark apparatus, concentrated under reduced pres “Beet Armyworm” in Table 1 below, in which letter designa Sure, adsorbed onto Silica and purified using a neutral alumina tions represent ranges of percent control as set forth above. column, eluting with a mobile phase of 10% ethyl acetate in 15 hexane. 2-Chloro-6-5-ethyl-2-(2-pyridyl)oxazolidin-3-yl)- TABLE 1 4-(trifluoromethyl)pyridine-3-carbonitrile (Compound 19) was isolated as a solid in 46% yield. mp 99-102°C. Beet Green HNMR (CDC1, 400 MHz) 8/ppm 8.62-8.63 (m, 0.4H), Compound Army- Peach 8.51 (br, 0.2H), 7.79-7.74 (m, 0.8H), 7.54(d.J=7.9 Hz, 0.5H), 7.42(br, 0.3H), 7.34-7.31 (m, 0.5H), 6.92 (br, 0.5H), 6.64 (br. No. STRUCTURE worm Aphid 0.2H), 6.40 (br, 0.4H), 6.12 (br, 0.5H), 4.66 (br, 0.4H), 4.38 (br, 0.6H), 4.21-4.20 (m. 1.4H), 4.11 (d. J=8.6 Hz, 0.5H): 1 F B A. 2.09-198 (m 0.8H), 1.87-1.78 (m. 1.3H), 1.05-1.00 (m, 3H): F F N ES/MS 383.0 (M). 25 C | Example XI N leN 2 Insecticidal Testing C N N 30 Insecticidal Test for Green Peach Aphid (Myzus persicae) in Foliar Spray Assay Cabbage seedlings grown in 3-inch pots, with 2-3 small 2 F B C (3-5 cm) true leaves, were used as test substrate. The seed lings were infested with 20-50 green peach aphids (wingless 35 F F N adult and nymph) 1-2 days prior to chemical application. Four C | seedlings were used for each treatment. Selected compounds N leN (2 mg), many of which are described above, were dissolved in 2 ml of acetone:methanol (1:1) solvent, forming Stock solu 2 C N N tions of 1000 ppm. The stock solutions were diluted 5x with 40 0.025% Tween 20 in HO to obtain a solution at 200 ppm. A hand-held Devilbiss aspiratorsprayer was used for spraying a solution to both sides of cabbage leaves until runoff. Refer ence plants (solvent check) were sprayed with the diluent F D D only. Treated plants were held in a holding room for three 45 F F N days at approximately 23°C. and 40% relative humidity prior to grading. Evaluation was conducted by counting the num C 2N ber of live aphids per plant under a microscope. Insecticidal activity was measured by using Abbott’s cor r 2 rection formula: 50 C N N N Corrected% Control=100*(X-Y)/X where X=No. of live aphids on solvent check plants Y=No. of live aphids on treated plants 55 The results of this test are set forth in the column labelled 6 F A. D “Green Peach Aphid' in Table 1 below, in which letter des F F ignations represent ranges of percent control as follows: N A=80-100% control C N B=60-79% control 60 N 2 C=40-59% control D=20-39% control 2 E=0-19% control C N N Insecticidal Test for Beet Armyworm (Spodoptera exigua). To prepare test solution, the test compound was formulated 65 at 2000 ppm solution in 2 mL of 9 acetone: 1 tap water. 50 uL of the test solution (50 g/cm dose for each well) was pipetted US 9, 131,694 B2 21 22 TABLE 1-continued TABLE 1-continued

Beet Green Beet Green Compound Army- Peach Compound Army- Peach No. STRUCTURE worm Aphid No. STRUCTURE worm Aphid

10 E E 17 N| E E F 10 C N F N 21

15 Z \ N F E D F F S. N r | N O 12 N E D Br N leN | 2 F C C N N N F

25 N 2 11 F A. A. F F Z CH

CH3 CH | N S. N \ S CH3. O N leN 30 CH3 18 N E E 2 N N | F C 35 N F D E F F F N 2 | N C Z \ N N leN 40 SN 2 O N N 19 C C

45 F F B E F C F F N | N F C N C leN N 2 50 2 Z \ N N N sN O

55 CH3. 16 N| E E F. C N ACID & SALT DERIVATIVES, AND SOLVATES F 60 Na2 The compounds of Formula I can be in the form of pesti cidally acceptable acid addition salts. Z \ N CH3 By way of non-limiting example, an amine function can 65 form salts with hydrochloric, hydrobromic, Sulfuric, phos phoric, acetic, benzoic, citric, malonic, Salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, US 9, 131,694 B2 23 24 maleic, aspartic, benzenesulfonic, methanesulfonic, ethane to, Acanthoscelides spp. (weevils), Acanthoscelides Obtectus Sulfonic, hydroxymethanesulfonic, and hydroxyethane (common bean weevil), Agrilus planipennis (emerald ash Sulfonic, acids. borer), Agriotes spp. (wireworms). Anoplophora glabripen Additionally, by way of non-limiting example, an acid nis (Asian longhorned beetle), Anthonomus spp. (weevils), function can form salts including those derived from alkali or 5 Anthonomus grandis (boll weevil), Aphidius spp., Apion spp. alkaline earth metals and those derived from ammonia and (weevils), Apogonia spp. (grubs), Ataenius sprelulus (Black amines. Examples of preferred cations include Sodium, potas Turgrass Ataenius), Atomaria linearis (pygmy mangold sium, magnesium, and aminium cations. beetle), Aulacophore spp., Bothy noderes punctiventris (beet The salts are prepared by contacting the free base form with root weevil), Bruchus spp. (weevils), Bruchus pisorum (pea a sufficient amount of the desired acid to produce a salt. The 10 weevil), Cacoesia spp., Callosobruchus maculatus (Southern free base forms may be regenerated by treating the salt with a cowpea weevil), Carpophilus hemipteras (dried fruit beetle), Suitable dilute aqueous base solution Such as dilute aqueous Cassida vittata, Cerosterna spp., Cerotoma spp. (chry NaOH, potassium carbonate, ammonia, and sodium bicar Someids), Cerotoma trifiurcata (bean leaf beetle), Ceutorhyn bonate. chus spp. (weevils), Ceutorhynchus assimilis (cabbage seed As an example, in many cases, a pesticide is modified to a 15 pod weevil), Ceutorhynchus napi (cabbage curculio), more water Soluble form e.g. 2,4-dichlorophenoxyacetic acid Chaetocnema spp. (chrysomelids), Colaspis spp. (soil dimethyl amine salt is a more water soluble form of 2,4- beetles), Conoderus scalaris, Conoderus stigmosus, dichlorophenoxyacetic acid a well known herbicide. Conotrachelus menuphar (plum curculio), Cotinus initidis The compounds disclosed in this application can also form (Green June beetle), Crioceris asparagi (asparagus beetle), stable complexes with solvent molecules that remain intact Cryptolestes ferrugineus (rusty grain beetle), Cryptolestes after the non-complexed solvent molecules are removed from pusillus (flat grain beetle), Cryptolestes turcicus (Turkish the compounds. These complexes are often referred to as grain beetle), Ctenicera spp. (wireworms), Curculio spp. “Solvates. (weevils), Cyclocephala spp. (grubs), Cylindrocpturus adspersus (Sunflower stem weevil), Deporaus marginiatus STEREOISOMERS 25 (mango leaf-cutting weevil), Dermestes lardarius (larder beetle), Dermestes maculates (hide beetle), Diabrotica spp. Certain compounds disclosed in this application can exist (chrysolemids), Epilachna varivestis (Mexican bean beetle), as one or more stereoisomers. The various stereoisomers Faustinus cubae, Hylobius pales (pales weevil), Hypera spp. include geometric isomers, diastereomers, and enantiomers. (weevils), Hypera postica (alfalfa weevil), Hyperdoes spp. Thus, the compounds disclosed in this application include 30 (Hyperodes weevil), Hypothenemus hampei (coffee berry racemic mixtures, individual stereoisomers, and optically beetle), Ips spp. (engravers), Lasioderma serricorne (ciga active mixtures. rette beetle), Leptinotarsa decemlineata (Colorado potato It will be appreciated by those skilled in the art that one beetle), Liogeny's fiscus, Liogenys suturalis, Lissorhopirus stereoisomer may be more active than the others. Individual Oryzophilus (rice water weevil), Lyctus spp. (wood beetles/ Stereoisomers and optically active mixtures may be obtained 35 powder post beetles), Maecolaspis joliveti, Megascelis spp., by selective synthetic procedures, by conventional synthetic Melanotus communis, Melligethes spp., Melligethes aeneus procedures using resolved starting materials, or by conven (blossom beetle), Melolontha melolontha (common Euro tional resolution procedures. pean cockchafer), Oberea brevis, Oberea linearis, Oryctes rhinoceros (date palm beetle), Oryzaephilus mercator (mer PESTS 40 chant grain beetle), Oryzaephilus Surinamensis (sawtoothed grain beetle), Otiorhynchus spp. (weevils), Oulema melano In another embodiment, the invention disclosed in this pus (cereal leaf beetle), Oulema Oryzae, Pantomorus spp. document can be used to control pests. (weevils), Phyllophaga spp. (May/June beetle), Phyllophaga In another embodiment, the invention disclosed in this cuyabhana, Phyllotreta spp. (chrysomelids), Phynchites spp. document can be used to control pests of the Phylum Nema 45 Popillia japonica (Japanese beetle), Prostephanus truncates toda. (larger grain borer), Rhizopertha dominica (lesser grain In another embodiment, the invention disclosed in this borer), Rhizotrogus spp. (Eurpoean chafer), Rhynchophorus document can be used to control pests of the Phylum Arthro spp. (weevils), Scolytus spp. (wood beetles). Shenophorus poda. spp. (Billbug), Sitona lineatus (pea leaf weevil), Sitophilus In another embodiment, the invention disclosed in this 50 spp. (grain weevils), Sitophilus granaries (granary weevil), document can be used to control pests of the Subphylum Sitophilus Oryzae (rice weevil), Stegobium paniceum (drug Chelicerata. store beetle), Tribolium spp. (flour beetles), Tribolium casta In another embodiment, the invention disclosed in this neum (red flour beetle), Tribolium confilsum (confused flour document can be used to control pests of the Class Arachnida. beetle), Trogoderma variabile (warehouse beetle), and In another embodiment, the invention disclosed in this 55 Zabrus tenebioides. document can be used to control pests of the Subphylum In another embodiment, the invention disclosed in this Myriapoda. document can be used to control Dermaptera (earwigs). In another embodiment, the invention disclosed in this In another embodiment, the invention disclosed in this document can be used to control pests of the Class Symphyla. document can be used to control Dictyoptera (cockroaches). In another embodiment, the invention disclosed in this 60 A non-exhaustive list of these pests includes, but is not lim document can be used to control pests of the Subphylum ited to, Blattella germanica (German cockroach), Blatta ori Hexapoda. entalis (oriental cockroach), Parcoblatta pennylvanica, In another embodiment, the invention disclosed in this Periplaneta americana (American cockroach), Periplaneta document can be used to control pests of the Class Insecta. australoasiae (Australian cockroach), Periplanela brunnea In another embodiment, the invention disclosed in this 65 (brown cockroach), Periplaneta idliginosa (Smokybrown document can be used to control Coleoptera (beetles). A cockroach), Pvnc.oselus Suninamensis (Surinam cockroach), non-exhaustive list of these pests includes, but is not limited and Supella longipalpa (brownbanded cockroach). US 9, 131,694 B2 25 26 In another embodiment, the invention disclosed in this phax striatellus (Smaller brown planthopper), Lepidosaphes document can be used to control Diptera (true flies). A non spp., Macrosiphum spp., Macrosiphum euphorbiae (potato exhaustive list of these pests includes, but is not limited to, aphid), Macrosiphum granarium (English grain aphid), Mac Aedes spp (mosquitoes), Agromyza frontella (alfalfa blotch rosiphum rosae (rose aphid), Macrosteles quadrilineatus (as leafminer), Agromyza spp. (leafminer flies), Anastrepha spp. ter leafhopper), Mahanarva fimbiolata, Metopolophium (fruit flies), Anastrepha suspensa (Caribbean fruit fly), dirhodun (rose grain aphid), Mictis longicornis, Myzus per Anopheles spp. (mosquitoes), Batrocera spp. (fruit flies), sicae (green peach aphid), Nephotettix spp. (leafhoppers), Bactrocera cucurbitae (melon fly), Bactrocera dorsalis (ori Nephotettix cinctipes (green leafhopper), Nilaparvata lugens ental fruit fly), Ceratitis spp. (fruit flies), Ceratitis capitata (brown planthopper), Parlatoria pergandii (chaff scale), Par (Mcditcrranca fruit fly), Chrysops spp. (deer flies), 10 latoria Ziziphi (ebony scale), Peregrinus maidis (corn delpha Cochliomyia spp. (screwworms), Contarinia spp. (Gall cid), Philaenus spp. (spittlebugs), Phylloxera vitifoliae midges), Culex spp. (mosquitoes), Dasineura spp. (gall (grape phylloxera), Physokermes piceae (spruce bud scale), midges), Dasineura brassicae (cabbage gall midge), Delia Planococcus spp. (mealybugs), Pseudococcus spp. (mealy spp., Delia platura (seedcorn maggot), Drosophila spp. (vin bugs), Pseudococcus brevipes (pine apple mealybug), Ouad egar flies), Fannia spp. (filth flies), Fannia canicularis (little 15 raspidiotus perniciosus (San Jose scale), Rhapalosiphun house fly), Fannia scalaris (latrine fly), Gasterophilus intes spp. (aphids), Rhapalosiphum maida (corn leaf aphid), tinalis (horse botfly), Gracillia perseae, Haematobia irritans Rhapalosiphum padi (oat bird-cherry aphid), Saissetia spp. (horn fly), Hvlemyia spp. (root maggots), Hypoderma linea (scales), Saissetia oleae (black scale), Schizaphis graminum tum (common cattle grub), Liriomyza spp. (leafminer flies), (greenbug), Sitobion avenae (English grain aphid), Sogatella Liriomyza brassica (serpentine leafminer), Mellophagus Ovi fircifera (white-backed planthopper). Therioaphis spp. nus (sheep ked), Musca spp. (muscid flies), Musca autumna (aphids), Toumeyella spp. (scales), Toxoptera spp. (aphids), lis (face fly), Musca domestica (house fly), Oestrus Ovis Trialeurodes spp. (whiteflies), Trialeurodes vaporariorum (sheep bot fly), Oscinella frit (frit fly), Pegomyia betae (beet (greenhouse whitefly), Trialeurodes abutiloneus (banded leafminer), Phorbia spp., Psila rosae (carrotrust fly), Rhago wing whitefly). Unaspis spp. (scales), Unaspis vanonensis letis cerasi (cherry fruit fly), Rhagoletis pomonella (apple 25 (arrowhead scale), and Zulia entreriana. maggot), Sitodiplosis mosellana (orange wheat blossom In another embodiment, the invention disclosed in this midge), Stomoxys calcitrans (stable fly), Tabanus spp. (horse document can be used to control Hymenoptera (ants, wasps, flies), and Tipula spp. (crane flies). and bees). A non-exhaustive list of these pests includes, but is In another embodiment, the invention disclosed in this not limited to, Acromyrrmex spp., Athalia rosae, Atta spp. document can be used to control Hemiptera (true bugs). A 30 (leafcutting ants), Camponotus spp. (carpenterants), Diprion non-exhaustive list of these pests includes, but is not limited spp. (sawflies), Formica spp. (ants), Iridomyrmex humilis to. Acrosternum hilare (green Stink bug), Blissus leucopterus (Argentine ant), Monomorium ssp., Monomorium minumum (chinch bug), Calocoris norvegicus (potato mirid), Cimex (little black ant), Monomorium pharaonis (Pharaoh ant), hemipterus (tropical bedbug), Cimex lectularius (bed bug), Neodiprion spp. (sawflies), Pogonomyrmex spp. (harvester Dagbertus fasciatus, Dichelops furcatus, Dysdercus suturel 35 ants), Polistes spp. (paper wasps), Solenopsis spp. (fire ants), lus (cotton stainer), Edessa meditabunda, Eurygaster maura Tapoinoma sessile (odorous house ant), Tetranomorium spp. (cereal bug). Euschistus heros, Euschistus servus (brown (pavementants), Vespula spp. (yellowjackets), and Xylocopa Stink bug), Helopeltis antonii, Helopeltis theivora (tea blight spp. (carpenter bees). plantbug), Lagynotomus spp. (Stink bugs), Leptocorisa Ora In another embodiment, the invention disclosed in this torius, Leptocorisa varicornis, Lygus spp. (plant bugs), Lygus 40 document can be used to control Isoptera (termites). A non hesperus (western tarnished plant bug), Maconellicoccus hir exhaustive list of these pests includes, but is not limited to, sutus, Neurocolpus longirostris, Nezara viridula (Southern Coptotermes spp., Coptotermes curvignathus, Coptotermes green Stink bug), Phytocoris spp. (plant bugs), Phytocoris frenchi, Coptotermes formosanus (Formosan Subterranean Californicus, Phytocoris relativus, Piezodorus guildingi, termite). Cornitermes spp. (nasute termites), Cryptotermes Poecilocapsus lineatus (fourlined plant bug), Psallus vaccini 45 spp. (drywood termites), Heterotermes spp. (desert Subterra cola, Pseudacy.sta perseae, Scaptocoris Castanea, and Tri nean termites), Heterotermes aureus, Kalotermes spp. (dry atoma spp. (bloodsucking conenose bugs/kissing bugs). wood termites), Incistitermes spp. (drywood termites). Mac In another embodiment, the invention disclosed in this rotermes spp. (fungus growing termites), Marginitermes spp. document can be used to control Homoptera (aphids, Scales, (drywood termites), Microcerotermes spp. (harvester ter whiteflies, leafhoppers). A non-exhaustive list of these pests 50 mites), Microtermes obesi, Procornitermes spp., Reticuliter includes, but is not limited to, Acrythosiphon pisum (pea mes spp. (Subterranean termites), Reticulitermes banyulensis, aphid), Adelges spp. (adelgids), Aleurodes proletella (cab Reticulitermes grassei, Reticulitermes flavipes (eastern Sub bage whitefly), Aleurodicus disperses, Aleurothrixus flocco terranean termite), Reticulitermes hageni, Reticulitermes sus (woolly whitefly), Aluacaspis spp., Amrasca biguitella hesperus (western Subterranean termite), Reticulitermes San biguitella, Aphrophora spp. (leafhoppers), Aonidiella aurantii 55 tonensis, Reticulitermes speratus, Reticulitermes tibialis, (California red scale), Aphis spp. (aphids), Aphis gossypii Reticulitermes virginicus, Schedorhinotermes spp., and Zoo (cotton aphid), Aphis pomi (apple aphid), Aulacorthun Solani termopsis spp. (rotten-wood termites). (foxglove aphid), Bemisia spp. (whiteflies), Bemisia argenti In another embodiment, the invention disclosed in this folii, Bemisia tabaci (sweetpotato whitefly), Brachycolus document can be used to control Lepidoptera (moths and noxius (Russian aphid), Brachycorynella asparagi (aspara 60 butterflies). A non-exhaustive list of these pests includes, but gus aphid), Brevennia rehi, Brevicoryne brassicae (cabbage is not limited to, Achoea janata, Adoxophyes spp., Adoxo aphid), Ceroplastes spp. (scales), Ceroplastes rubens (red phyes Orana, Agrotis spp. (cutworms), Agrotis ipsilon (black wax scale), Chionaspis spp. (scales). Chrysomphalus spp. cutworm), Alabama argillacea (cotton leafworm), Amorbia (scales), Coccus spp. (scales), Dysaphis plantaginea (rosy cuneana, Amyelosis transitella (navel orangeworm), Ana apple aphid), Empoasca spp. (leafhoppers), Eriosoma lani 65 camptodes defectaria, Anarsia lineatella (peach twig borer), gerum (woolly apple aphid), Icerva purchasi (cottony cush Anomis Sabulifera (jute looper), Anticarsia gemmatalis (vel ion scale), Idioscopus initidulus (mango leafhopper), Laodel vetbean caterpillar), Archips argyrospila (fruit tree leafrol US 9, 131,694 B2 27 28 ler), Archips rosana (rose leafroller), Argyrotaenia spp. (tor In another embodiment, the invention disclosed in this tricid moths), Argyrotaenia citrana (orange tortrix), document can be used to control Mallophaga (chewing lice). Autographa gamma, Bonagota Cranaodes, Borbo cinnara A non-exhaustive list of these pests includes, but is not lim (rice leaf folder), Bucculatrix thurberiella (cotton leaf perfo ited to, Bovicola Ovis (sheep biting louse), Menacanthus stra rator), Caloplilia spp. (leaf miners), Capua reticulana, Car mineus (chicken body louse), and Menopon gallinea (com posina niponensis (peach fruit moth), Chilo spp., Chlumetia mon hen house). transversa (mango shoot borer), Choristoneura rosaceana In another embodiment, the invention disclosed in this (oblique banded leaf roller), Chrysodeixis spp., Cnaphalo document can be used to control Orthoptera (grasshoppers, cerus medinalis (grass leafroller), Colias spp., Conpomorpha locusts, and crickets). A non-exhaustive list of these pests cramerella, Cossus Cossus (carpenter moth), Crambus spp. 10 includes, but is not limited to, Anabrus simplex (Mormon (Sod webworms), Cydia funebrana (plum fruit moth), Cydia cricket), Gryllotalpidae (mole crickets). Locusta migratoria, molesta (oriental fruit moth), Cydia nignicana (pea moth), Melanoplus spp. (grasshoppers), Microcentrum retinerve Cydia pomonella (codling moth), Darna diducta, Diaphania (angular winged katydid), Pterophylla spp. (kaydids), chis spp. (stem borers), Diatraea spp. (stalk borers), Diatraea tocerca gregaria, Scudderia furcata (fork tailed bush katy saccharalis (Sugarcane borer), Diatraea graniosella (South 15 did), and Valanga nigricorni. wester corn borer), Earias spp. (bollworms), Earias insulata In another embodiment, the invention disclosed in this (Egyptian bollworm), Earias vitella (rough northern boll document can be used to control Phthiraptera (Sucking lice). worm), Ecdytopopha aurantianum, Elasmopalpus lignosel A non-exhaustive list of these pests includes, but is not lim lus (lesser cornstalk borer), Epiphysia's postruttana (light ited to, Haematopinus spp. (cattle and hog lice), Linognathus brown apple moth), Ephestia spp. (flour moths), Ephestia Ovillus (sheep louse), Pediculus humanus capitis (human cautella (almond moth), Ephestia elutella (tobbaco moth), body louse), Pediculus humanus humanus (human body lice), Ephestia kuehniella (Mediterranean flour moth), Epimeces and Pthirus pubis (crab louse), spp., Epinotia aporema, Erionota thrax (banana skipper), In another embodiment, the invention disclosed in this Eupoecilia ambiguella (grape berry moth), Euxoa auxiliaris document can be used to control Siphonaptera (fleas). A (army cutworm), Feltia spp. (cutworms), Gortyna spp. (stem 25 non-exhaustive list of these pests includes, but is not limited borers), Grapholita molesta (oriental fruit moth), Hedylepta to, Ctenocephalides canis (dog flea), Ctenocephalides felis indicata (bean leaf webber), Helicoverpa spp. (noctuid (cat flea), and Pulex irritans (human flea). moths), Helicoverpa armigera (cotton bollworm), Helicov In another embodiment, the invention disclosed in this erpa zea (bollworm/corn earworm), Heliothis spp. (noctuid document can be used to control Thysanoptera (thrips). A moths), Heliothis virescens (tobacco budworm), Hellula 30 non-exhaustive list of these pests includes, but is not limited undalis (cabbage webworm), Indarbela spp. (root borers), to, Frankliniella fisca (tobacco thrips), Frankliniella occi Keiferia lycopersicella (tomato pinworm), Leucinodes dentalis (western flower thrips), Frankliniella Shultzei Fran Orbonalis (eggplant fruit borer), Leucoptera malifoliella, Kliniella williamsi (corn thrips), Heliothrips haemorrhaidalis Lithocollectis spp., Lobesia botrana (grapefruit moth), Loxia (greenhouse thrips), Riphiphorothrips cruentatus, Scirto grotis spp. (noctuid moths), Loxagrotis albicosta (western 35 thrips spp., Scirtothrips citri (citrus thrips), Scirtothrips dor bean cutworm), Lymantria dispar (gypsy moth), Lyonetia salis (yellow tea thrips). Taeniothrips rhopalantennalis, and clerkella (apple leaf miner), Mahasena corbetti (oil palm Thrips spp. bagworm), Malacosoma spp. (tent caterpillars), Mamestra In another embodiment, the invention disclosed in this brassicae (cabbage armyworm), Maruca testulalis (bean pod document can be used to control Thysanura (bristletails). A borer), Metisa plana (bagworm), Mythinna unipuncta (true 40 non-exhaustive list of these pests includes, but is not limited armyworm), Neoleucinodes elegantalis (Small tomato borer), to, Lepisma spp. (silverfish) and Thermobia spp. (firebrats). Nymphula depunctalis (rice caseworm), Operophthera bru In another embodiment, the invention disclosed in this mata (winter moth), Ostrinia nubilalis (European corn document can be used to control Acarina (mites and ticks). A borer), Oxydia vesulia, Pandemis cerasana (common currant non-exhaustive list of these pests includes, but is not limited tortrix), Pandemis heparana (brown apple tortrix), Papilio 45 to, Acarapsis woodi (tracheal mite of honeybees), Acarus demodocus, Pectinophora gossypiella (pink bollworm), spp. (food mites), Acarus siro (grain mite), Aceria Peridroma spp. (cutworms), Peridroma saucia (variegated mangiferae (mango bud mite), Aculops spp. Aculops lycoper cutworm), Perileucoptera coffeella (white coffee leafminer), Sici (tomato russet mite), Aculops pelekasi, Aculus pelekassi, Phthorimaea operculella (potato tuber moth), Phyllocnisitis Aculus Schlechtendali (apple rust mite), Amblyomma ameri citrella, Phyllonorycler spp. (leafminers), Pieris rapae (im 50 canum (lone star tick), Boophilus spp. (ticks), Brevipalpus ported cabbageworm), Plathypena scabra, Plodia interpunc Obovatus (privet mite), Brevipalpus phoenicis (red and black tella (Indian meal moth), Plutella xylostella (diamondback flat mite), Demodex spp. (mange mites), Dermacentor spp. moth), Polychrosis viteana (grape berry moth), Prays (hard ticks), Dermacentor variabilis (american dog tick), endocarpa, Prays oleae (olive moth), Pseudaletia spp. (noc Dermatophagoides pteronyssinus (house dust mite), Eotet tuid moths), Pseudaletia unipunctata (armyworm), 55 ranycus spp., Eotetranychus carpini (yellow spider mite), Pseudoplusia includens (soybean looper), Rachiphusia nu, Epitimerus spp., Eriophyes spp., Ixodes spp. (ticks), Metatet Scirpophaga incertulas. Sesamia spp. (stemborers), Sesamia ranycus spp., Notoedres cati, Oligonychus spp., Oligonychus inferens (pink rice stem borer), Sesamia nonagrioides, Setora coffee, Oligonychus ilicus (Southern red mite), Panonychus nitens, Sitotroga cerealella (Angoumois grain moth), Spar spp., Panonychus citri (citrus red mite), Panonychus ulmi ganothis pilleriana, Spodoptera spp. (armyworms), 60 (European red mite), Phylocoptruta oleivOra (citrus rust Spodoptera exigua (beet armyworm), Spodoptera fugiperda mite), Polyphagotarisonemun latus (broad mite), Rhipiceph (fall armyworm), Spodoptera oridania (Southern army alus sanguineus (brown dog tick), Rhizoglyphus spp. (bulb worm), Synanthedon spp. (root borers). Thecla basilides, mites), Sarcoptes scabiei (itch mite), Tegolophus perseaflo Thermisia gemmatalis, Tineola bisselliella (webbing clothes rae, Tetranychus spp., Tetranychus urticae (twospotted Spider moth). Trichoplusia ni (cabbage looper), Tuta absoluta, 65 mite), and Varroa destructor (honey bee mite). Yponomeuta spp., Zeuzera cofeae (red branch borer), and In another embodiment, the invention disclosed in this Zeuzera pyrina (leopard moth). document can be used to control Nematoda (nematodes). A US 9, 131,694 B2 29 30 non-exhaustive list of these pests includes, but is not limited banolate, carbaryl, carbofuran, carbon disulfide, carbon tet to, Aphelenchoides spp. (bud and leaf & pine wood nema rachloride, carbophenothion, carbosulfan, cartap, cartap todes), Belonolaimus spp. (sting nematodes), Criconemella hydrochloride, chlorantraniliprole, chlorbicyclen, chlordane, spp. (ring nematodes), Dirofilaria immitis (dog heartworm), chlordecone, chlordimeform, chlordimeform hydrochloride, Dity lenchus spp. (stem and bulb nematodes), Heterodera spp. chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluaZu (cyst nematodes), Heterodera zeae (corn cyst nematode), ron, chlormephos, chloroform, chloropicrin, chlorphoxim, Hirschmanniella spp. (root nematodes), Hoplolaimus spp. chlorpraZophos, chlorpyrifos, chlorpyrifos-methyl, chlor (lance nematodes), Meloidogyne spp. (root knot nematodes), thiophos, chromafenozide, cinerin I, cinerin II, cinerins, cis Meloidogyne incognita (root knot nematode). Onchocerca methrin, cloethocarb, closantel, clothianidin, copper volvulus (hook-tail worm), Pratylenchus spp (lesion nema 10 acetoarsenite, copper arsenate, copper naphthenate, copper todes), Radopholus spp. (burrowing nematodes), and Roty oleate, coumaphos, coumithoate, crotamiton, crotoxyphos, lenchus reniformis (kidney-shaped nematode). crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate, In another embodiment, the invention disclosed in this cyantraniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyha document can be used to control Symphyla (Symphylans). A lothrin, cypermethrin, cyphenothrin, cyromazine, cythioate, non-exhaustive list of these pests includes, but is not limited 15 DDT, decarbofuran, deltamethrin, demephion, demephion to, Scutigerella immaculata. O, demephion-S, demeton, demeton-methyl, demeton-O. For more detailed information consult "HANDBOOK OF PEST demeton-O-methyl, demeton-S, demeton-S-methyl, deme CONTROL THE BEHAVIOR, LIFE HISTORY, AND CONTROL OF HOUSE ton-S-methylsulphon, diafenthiuron, dialifos, diatomaceous HOLD PESTs' by Arnold Mallis, 9th Edition, copyright 2004 by earth, diazinon, dicapthon, dichlofenthion, dichlorvos, dicr GIE Media Inc. esyl dicrotophos, dicyclanil, dieldrin, diflubenZuron, dilor, dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dim MIXTURES ethylvinphos, dimetilan, dinex, dinex-diclexine, dinoprop, dinosam, dinotefuran, diofenolan, dioxabenzofos, dioxacarb, The compounds of Formula I can also be used with various dioxathion, disulfoton, dithicrofos, d-limonene, DNOC, insecticides, both for reasons of economy and synergy. Such 25 DNOC-ammonium, DNOC-potassium, DNOC-sodium, dor insecticides include, but are not limited to, antibiotic insecti amectin, ecdysterone, emamectin, emamectin benzoate, cides, macrocyclic lactone insecticides (for example, avern EMPC, empenthrin, endosulfan, endothion, endrin, EPN, mectin insecticides, milbemycin insecticides, and spinosyn epolfenonane, eprinomectin, esdepalethrine, esfenvalerate, insecticides), arsenicual insecticides, botanical insecticides, etaphos, ethiofencarb, ethion, ethiprole, ethoate-methyl, carbamate insecticides (for example, benzofuranyl methyl 30 ethoprophos, ethyl formate, ethyl-DDD, ethylene dibromide, carbamate insecticides, dimethylcarbamate insecticides, ethylene dichloride, ethylene oxide, etofemprox. etrimfos, oxime carbamate insecticides, and phenyl methylcarbamate EXD, famphur, fenamiphos, fenazaflor, fenchlorphos, insecticides), diamide insecticides, desiccant insecticides, fenethacarb, fenfluthrin, fenitrothion, fenobucarb, fenoxac dinitrophenol insecticides, fluorine insecticides, formami rim, fenoxycarb, fempirithrin, fenpropathrin, fensulfothion, dine insecticides, fumigant insecticides, inorganic insecti 35 fenthion, fenthion-ethyl, fenvalerate, fipronil, flonicamid, cides, insect growth regulators (for example, chitin synthesis flubendiamide (additionally resolved isomers thereof), fluco inhibitors, juvenile hormone mimics, juvenile hormones, furon, flucycloxuron, flucythrinate, flufenerim, flufenoxuron, moulting hormone agonists, moulting hormones, moulting flufenproX, fluvalinate, fonofos, formetanate, formetanate inhibitors, precocenes, and other unclassified insect growth hydrochloride, formothion, formparanate, formparanate regulators), nereistoxin analogue insecticides, nicotinoid 40 hydrochloride, fosmethilan, fospirate, fosthietan, fufenozide, insecticides (for example, nitroguanidine insecticides, furathiocarb, furethrin, gamma-cyhalothrin, gamma-HCH, nitromethylene insecticides, and pyridylmethylamine insec halfenprox, halofenozide, HCH, HEOD, heptachlor, hep ticides), organochlorine insecticides, organophosphorus tenophos, heterophos, hexaflumuron, HHDN, hydramethyl insecticides, oxadiazine insecticides, oxadiazolone insecti non, hydrogen cyanide, hydroprene, hyduincarb, imidaclo cides, phthalimide insecticides, pyrazole insecticides, pyre 45 prid, imiprothrin, indoxacarb, iodomethane, IPSP, isazofos, throid insecticides, pyrimidinamine insecticides, pyrrole isobenzan, isocarbophos, isodrin, isofenphos, isofenphos insecticides, tetramic acid insecticides, tetronic acid insecti methyl, isoprocarb, isoprothiolane, isothioate, isoxathion, cides, thiazole insecticides, thiazolidine insecticides, thio ivermectin, jasmolin I, jasmolin II, jodfenphos, juvenile hor urea insecticides, urea insecticides, as well as, other unclas mone I, juvenile hormone II, juvenile hormone III, kelevan, sified insecticides. 50 kinoprene, lambda-cyhalothrin, lead arsenate, lepimectin, Some of the particular insecticides that can be employed leptophos, lindane, lirimfos, lufenuron, lythidathion, beneficially in combination with the compounds of Formula malathion, malonoben, mazidox, mecarbam, mecarphon, I include, but are not limited to, the following:—1,2-dichlo menazon, meperfluthrin, mephosfolan, mercurous chloride, ropropane, abamectin, acephate, acetamiprid, acethion, meSulfenfos, metaflumizone, methacrifos, methamidophos, acctoprole, acrinathrin, acrylonitrile, alanycarb, aldicarb, 55 methidathion, methiocarb, methocrotophos, methomyl. aldoxycarb, aldrin, allethrin, allosamidin, allyxycarb, alpha methoprene, methothrin, methoxychlor, methoxyfenozide, cypermethrin, alpha-ecdysone, alpha-endosulfan, methyl bromide, methyl isothiocyanate, methylchloroform, amidithion, aminocarb, amiton, amiton oxalate, amitraz, ana methylene chloride, metofluthrin, metolcarb, metoxadiaz basine, athidathion, azadirachtin, azamethiphos, azinphos one, mevinphos, mexacarbate, milbemectin, milbemycin ethyl, azinphos-methyl, azothoate, barium hexafluorosili 60 Oxime, mipafox, mirex, moloSultap, monocrotophos, cate, barthrin, bendiocarb, benfuracarb, bensultap, beta monomehypo, monosultap, morphothion, moxidectin, nafta cyfluthrin, beta-cypermethrin, bifenthrin, bioallethrin, lofos, naled, naphthalene, nicotine, nifluridide, nitenpyram, bioethanomethrin, biopermethrin, bistrifluoron, borax, boric nithiazine, nitrilacarb, novaluron, noviflumuron, omethoate, acid, bromfenvinfos, bromocyclen, bromo-DDT, bromophos, oxamyl, oxydemeton-methyl, oxydeprofos, oxydisulfoton, bromophos-ethyl, bufencarb, buprofezin, butacarb, butathio 65 para-dichlorobenzene, parathion, parathion-methyl, penfluo fos, butocarboxim, butonate, butoxycarboxim, cadusafos, ron, pentachlorophenol, permethrin, phenkapton, pheno calcium arsenate, calcium polysulfide, camphechlor, car thrin, phenthoate, phorate, phosalone, phosfolan, phosmet, US 9, 131,694 B2 31 32 phosnichlor, phosphamidon, phosphine, phoxim, phoxim document: piperonylbutoxide, piprotal, propyl isome, sesa methyl, pirimetaphos, pirimicarb, pirimiphos-ethyl, pirimi mex, Sesamolin, and Sulfoxide. phos-methyl, potassium arsenite, potassium thiocyanate, pp'- DDT, prallethrin, precocene I, precocene II, precocene III, FORMULATIONS primidophos, profenofos, profluralin, profluthrin, promacyl, promecarb, propaphos, propetamphos, propoXur, prothi A pesticide is rarely suitable for application in its pure dathion, prothiofos, prothoate, protrifenbute, pymetrozine, form. It is usually necessary to add other Substances so that pyraclofos, pyrafluprole, pyrazophos, pyresmethrin, pyre the pesticide can be used at the required concentration and in thrin I, pyrethrin II, pyrethrins, pyridaben, pyridalyl, an appropriate form, permitting ease of application, handling, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyrimitate, 10 transportation, storage, and maximum pesticide activity. pyriprole, pyriproxyfen, quassia, quinalphos, quinallphos Thus, pesticides are formulated into, for example, baits, con centrated emulsions, dusts, emulsifiable concentrates, fumi methyl, quinothion, rafoxanide, resmethrin, rotenone, ryania, gants, gels, granules, microencapsulations, seed treatments, Sabadilla, Schradan, Selamectin, silafluofen, silica gel. Suspension concentrates, Suspoemulsions, tablets, water Sodium arsenite, Sodium fluoride, sodium hexafluorosilicate, 15 soluble liquids, water dispersible granules or dry flowables, Sodium thiocyanate, sophamide, spinetoram, spinosad, wettable powders, and ultra low volume solutions. spiromesifen, Spirotetramat, Sulcofuron, Sulcofuron-sodium, For further information on formulation types see "CATA sulfluramid, sulfotep, sulfoxaflor, sulfuryl fluoride, sulpro LOGUE OF PESTICIDE FORMULATION TYPES AND INTERNATIONAL COD fos, tau-fluvalinate, tazimcarb, TDE, tebufenozide, tebufen ING SYSTEM Technical Monograph n°2, 5th Edition by pyrad, tebupirimfos, teflubenZuron, tefluthrin, temephos, CropLife International (2002). TEPP, terallethrin, terbufos, tetrachloroethane, tetrachlorvin Pesticides are applied most often as aqueous Suspensions phos, tetramethrin, tetramethylfluthrin, theta-cypermethrin, or emulsions prepared from concentrated formulations of thiacloprid, thiamethoxam, thicrofos, thiocarboxime, thiocy Such pesticides. Such water-soluble, water-Suspendable, or clam, thiocyclam oxalate, thiodicarb, thiofanox, thiometon, emulsifiable formulations, are either solids, usually known as thiosultap, thiosultap-disodium, thiosultap-monosodium, 25 wettable powders, or water dispersible granules, or liquids thuringiensin, tolfenpyrad, tralomethrin, transfluthrin, usually known as emulsifiable concentrates, or aqueous Sus transpermethrin, triarathene, triazamate, triaZophos, trichlo pensions. Wettable powders, which may be compacted to rfon, trichlormetaphos-3, trichloronat, trifenofos, tritlumu form water dispersible granules, comprise an intimate mix ron, trimethacarb, triprene, vamidothion, vaniliprole. XMC, ture of the pesticide, a carrier, and Surfactants. The concen Xylylcarb, Zeta-cypermethrin, and ZolaprofoS. 30 tration of the pesticide is usually from about 10% to about Additionally, any combination of the above insecticides 90% by weight. The carrier is usually chosen from among the can be used. attapulgite clays, the montmorillonite clays, the diatoma The compounds of Formula I can also be used with herbi ceous earths, or the purified silicates. Effective surfactants, cides and fungicides, or both for reasons of economy and comprising from about 0.5% to about 10% of the wettable Synergy. 35 powder, are found among Sulfonated lignins, condensed The compounds of Formula I can also be used, for reasons naphthalenesulfonates, naphthalenesulfonates, alkylbenze of economy and synergy, with acaricides, algicides, antifeed nesulfonates, alkyl Sulfates, and nonionic Surfactants such as ants, avicides, bactericides, bird repellents, chemosterilants, ethylene oxide adducts of alkyl phenols. fungicides, herbicide Safeners, herbicides, insect attractants, Emulsifiable concentrates of pesticides comprise a conve insect repellents, mammal repellents, mating disrupters, mol 40 nient concentration of a pesticide, such as from about 50 to luscicides, plant activators, plant growth regulators, rodenti about 500 grams per liter of liquid dissolved in a carrier that cides, synergists, defoliants, desiccants, disinfectants, semio is either a water miscible solvent or a mixture of water chemicals, and virucides (these categories not necessarily immiscible organic solvent and emulsifiers. Useful organic mutually exclusive). Solvents include aromatics, especially Xylenes and petroleum For more information consult "COMPENDIUM OF PESTICIDE 45 fractions, especially the high-boiling naphthalenic and ole COMMON NAMEs' located at http://www.alanwood.net/pesti finic portions of petroleum Such as heavy aromatic naphtha. cides/index.html. Also consult “THE PESTICIDE MANUAL 14th Other organic Solvents may also be used, such as the terpenic Edition, edited by CD S Tomlin, copyright 2006 by British Solvents including rosin derivatives, aliphatic ketones Such as Crop Production Council. cyclohexanone, and complex alcohols such as 2-ethoxyetha 50 nol. Suitable emulsifiers for emulsifiable concentrates are SYNERGISTIC MIXTURES chosen from conventional anionic and nonionic Surfactants. Aqueous Suspensions comprise Suspensions of water-in The compounds of Formula I can be used with other com soluble pesticides dispersed in an aqueous carrier at a con pounds such as the ones mentioned under the heading "Mix centration in the range from about 5% to about 50% by tures” to form synergistic mixtures where the mode of action 55 weight. Suspensions are prepared by finely grinding the pes of the compounds in the mixtures are the same, similar, or ticide and vigorously mixing it into a carrier comprised of different. water and Surfactants. Ingredients, such as inorganic salts and Examples of mode of actions include, but are not limited to: synthetic or natural gums, may also be added, to increase the acetylcholine esterase inhibitor, sodium channel modulator, density and Viscosity of the aqueous carrier. It is often most chitin biosynthesis inhibitor; GABA-gated chloride channel 60 effective to grind and mix the pesticide at the same time by antagonist; GABA or glutamate-gated chloride channel ago preparing the aqueous mixture and homogenizing it in an nist; acetylcholine receptor agonist; MET I inhibitor; Mg implement Such as a sand mill, ball mill, or piston-type stimulated ATPase inhibitor; nicotinic acetylcholine receptor homogenizer. agonist or antagonist; Midgut membrane disrupter; and oxi Pesticides may also be applied as granular compositions dative phosphorylation disrupter. 65 that are particularly useful for applications to the soil. Granu Additionally, the following compounds are known as Syn lar compositions usually contain from about 0.5% to about ergists and can be used with the invention disclosed in this 10% by weight of the pesticide, dispersed in a carrier that US 9, 131,694 B2 33 34 comprises clay or a similar Substance. Such compositions are of less than 800 nanometers. Further information on the usually prepared by dissolving the pesticide in a Suitable embodiment is disclosed in U.S. patent publication Solvent and applying it to a granular carrier which has been 20070027034 published Feb. 1, 2007, having patent applica pre-formed to the appropriate particle size, in the range of tion Ser. No. 1 1/495,228. For ease of use this embodiment from about 0.5 to 3 mm. Such compositions may also be 5 will be referred to as “OIWE. formulated by making a dough or paste of the carrier and For further information consult “INSECT PEST MANAGEMENT' compound and crushing and drying to obtain the desired 2nd Edition by D. Dent, copyright CAB International (2000). granular particle size. Additionally, for more detailed information consult “HAND Dusts containing a pesticide are prepared by intimately BOOK OF PEST CONTROL THE BEHAVIOR, LIFE HISTORY, AND CON mixing the pesticide in powdered form with a suitable dusty 10 TROL OF HOUSEHOLDPESTs' by Arnold Mallis, 9th Edition, copy agricultural carrier, Such as kaolin clay, ground Volcanic rock, right 2004 by GIE Media Inc. and the like. Dusts can suitably contain from about 1% to about 10% of the pesticide. They can be applied as a seed OTHER FORMULATION COMPONENTS dressing, or as a foliage application with a dust blower machine. 15 Generally, the invention disclosed in this document when It is equally practical to apply a pesticide in the form of a used in a formulation, such formulation can also contain other Solution in an appropriate organic solvent, usually petroleum components. These components include, but are not limited oil. Such as the spray oils, which are widely used in agricul to, (this is a non-exhaustive and non-mutually exclusive list) tural chemistry. wetters, spreaders, Stickers, penetrants, buffers, sequestering Pesticides can also be applied in the form of an aerosol agents, drift reduction agents, compatibility agents, anti composition. In Such compositions the pesticide is dissolved foam agents, cleaning agents, and emulsifiers. A few compo or dispersed in a carrier, which is a pressure-generating pro nents are described forthwith. pellant mixture. The aerosol composition is packaged in a A wetting agent is a Substance that when added to a liquid container from which the mixture is dispensed through an increases the spreading or penetration power of the liquid by atomizing valve. 25 reducing the interfacial tension between the liquid and the Pesticide baits are formed when the pesticide is mixed with Surface on which it is spreading. Wetting agents are used for food oran attractant or both. When the pests eat the bait they two main functions in agrochemical formulations: during also consume the pesticide. Baits may take the form of gran processing and manufacture to increase the rate of wetting of ules, gels, flowable powders, liquids, or Solids. They are used powders in water to make concentrates for soluble liquids or in pest harborages. 30 Suspension concentrates; and during mixing of a product with Fumigants are pesticides that have a relatively high vapor water in a spray tank to reduce the wetting time of wettable pressure and hence can exist as a gas in sufficient concentra powders and to improve the penetration of water into water tions to kill pests in soil or enclosed spaces. The toxicity of the dispersible granules. Examples of wetting agents used in fumigant is proportional to its concentration and the exposure wettable powder, Suspension concentrate, and water-dispers time. They are characterized by a good capacity for diffusion 35 ible granule formulations are: sodium lauryl Sulphate; sodium and act by penetrating the pest's respiratory system or being dioctyl Sulphosuccinate; alkyl phenol ethoxylates; and ali absorbed through the pest’s cuticle. Fumigants are applied to phatic alcohol ethoxylates. control stored product pests under gas proof sheets, in gas A dispersing agent is a Substance which adsorbs onto the sealed rooms or buildings or in special chambers. Surface of a particles and helps to preserve the state of dis Pesticides can be microencapsulated by Suspending the 40 persion of the particles and prevents them from reaggregat pesticide particles or droplets in plastic polymers of various ing. Dispersing agents are added to agrochemical formula types. By altering the chemistry of the polymer or by chang tions to facilitate dispersion and Suspension during ing factors in the processing, microcapsules can be formed of manufacture, and to ensure the particles redisperse into water various sizes, Solubility, wall thicknesses, and degrees of in a spray tank. They are widely used in wettable powders, penetrability. These factors govern the speed with which the 45 Suspension concentrates and water-dispersible granules. Sur active ingredient within is released, which, in turn, affects the factants that are used as dispersing agents have the ability to residual performance, speed of action, and odor of the prod adsorb strongly onto a particle Surface and provide a charged uct. or steric barrier to reaggregation of particles. The most com Oil Solution concentrates are made by dissolving pesticide monly used surfactants are anionic, non-ionic, or mixtures of in a solvent that will hold the pesticide in solution. Oil solu 50 the two types. For wettable powder formulations, the most tions of a pesticide usually provide faster knockdown and kill common dispersing agents are sodium lignoSulphonates. For of pests than other formulations due to the solvents them Suspension concentrates, very good adsorption and stabiliza selves having pesticidal action and the dissolution of the tion are obtained using polyelectrolytes, such as Sodium waxy covering of the integument increasing the speed of naphthalene Sulphonate formaldehyde condensates. uptake of the pesticide. Other advantages of oil solutions 55 Tristyrylphenol ethoxylate phosphate esters are also used. include better storage stability, better penetration of crevices, Non-ionics such as alkylarylethylene oxide condensates and and better adhesion to greasy Surfaces. EO-PO block copolymers are sometimes combined with Another embodiment is an oil-in-water emulsion, wherein anionics as dispersing agents for Suspension concentrates. In the emulsion comprises oily globules which are each pro recent years, new types of very high molecular weight poly vided with a lamellar liquid crystal coating and are dispersed 60 meric Surfactants have been developed as dispersing agents. in an aqueous phase, wherein each oily globule comprises at These have very long hydrophobic backbones and a large least one compound which is agriculturally active, and is number of ethylene oxide chains forming the teeth of a individually coated with a monolamellar or oligolamellar comb surfactant. These high molecular weight polymers layer comprising: (1) at least one non-ionic lipophilic Sur can give very good long-term stability to Suspension concen face-active agent, (2) at least one non-ionic hydrophilic Sur 65 trates because the hydrophobic backbones have many anchor face-active agent and (3) at least one ionic Surface-active ing points onto the particle Surfaces. Examples of dispersing agent, wherein the globules having a mean particle diameter agents used in agrochemical formulations are: Sodium ligno US 9, 131,694 B2 35 36 Sulphonates; Sodium naphthalene Sulphonate formaldehyde ethyl cellulose (HEC). Other types of anti-settling agents are condensates; tristyrylphenol ethoxylate phosphate esters; ali based on modified starches, polyacrylates, polyvinyl alcohol phatic alcohol ethoxylates; alky ethoxylates; EO-PO block and polyethylene oxide. Another good anti-settling agent is copolymers; and graft copolymers. Xanthan gum. An emulsifying agent is a Substance which stabilizes a 5 Microorganisms cause spoilage of formulated products. Suspension of droplets of one liquid phase in another liquid Therefore preservation agents are used to eliminate or reduce phase. Without the emulsifying agent the two liquids would their effect. Examples of such agents include, but are limited separate into two immiscible liquid phases. The most com to: propionic acid and its sodium salt; Sorbic acid and its monly used emulsifier blends contain alkylphenol oraliphatic Sodium or potassium salts; benzoic acid and its sodium salt; alcohol with 12 or more ethylene oxide units and the oil- 10 p-hydroxybenzoic acid sodium salt; methyl p-hydroxyben soluble calcium salt of dodecylbenzene sulphonic acid. A Zoate; and 1,2-benzisothiazalin-3-one (BIT). range of hydrophile-lipophile balance (“HLB) values from 8 The presence of surfactants, which lower interfacial ten to 18 will normally provide good stable emulsions. Emulsion Sion, often causes water-based formulations to foam during stability can sometimes be improved by the addition of a mixing operations in production and in application through a small amount of an EO-PO block copolymer surfactant. 15 spray tank. In order to reduce the tendency to foam, anti-foam A solubilizing agent is a Surfactant which will form agents are often added either during the production stage or micelles in water at concentrations above the critical micelle before filling into bottles. Generally, there are two types of concentration. The micelles are then able to dissolve or solu anti-foam agents, namely silicones and non-silicones. Sili bilized water-insoluble materials inside the hydrophobic part cones are usually aqueous emulsions of dimethyl polysilox of the micelle. The type of surfactants usually used for solu- 20 ane while the non-silicone anti-foam agents are water-in bilization are non-ionics: Sorbitan monooleates; Sorbitan soluble oils, such as octanol and nonanol, or silica. In both monooleate ethoxylates; and methyl oleate esters. cases, the function of the anti-foam agent is to displace the Surfactants are sometimes used, either alone or with other surfactant from the air-water interface. additives such as mineral or vegetable oils as adjuvants to For further information see "CHEMISTRY AND TECHNOLOGY OF spray-tank mixes to improve the biological performance of 25 AGROCHEMICAL FORMULATIONS' edited by D. A. Knowles, copy the pesticide on the target. The types of Surfactants used for right 1998 by Kluwer Academic Publishers. Also see “INSEC bioenhancement depend generally on the nature and mode of TICDES IN AGRICULTURE AND ENVIRONMENT—RETROSPECTS AND action of the pesticide. However, they are often non-ionics PROSPECTS’ by A. S. Perry, I. Yamamoto, I. Ishaaya, and R. Such as: alky ethoxylates; linear aliphatic alcohol ethoxy Perry, copyright 1998 by Springer-Verlag. lates; aliphatic amine ethoxylates. 30 A carrier or diluent in an agricultural formulation is a APPLICATIONS material added to the pesticide to give a product of the required strength. Carriers are usually materials with high The actual amount of pesticide to be applied to loci of pests absorptive capacities, while diluents are usually materials is generally not critical and can readily be determined by with low absorptive capacities. Carriers and diluents are used 35 those skilled in the art. In general, concentrations from about in the formulation of dusts, wettable powders, granules and 0.01 grams of pesticide per hectare to about 5000 grams of water-dispersible granules. pesticide per hectare are expected to provide good control. Organic solvents are used mainly in the formulation of The locus to which a pesticide is applied can be any locus emulsifiable concentrates, ULV formulations, and to a lesser inhabited by a pest, for example, vegetable crops, fruit and nut extent granular formulations. Sometimes mixtures of Sol- 40 trees, grape vines, ornamental plants, domesticated animals, vents are used. The first main groups of solvents are aliphatic the interior or exterior surfaces of buildings, and the soil paraffinic oils such as kerosene or refined paraffins. The sec around buildings. Controlling pests generally means that pest ond main group and the most common comprises the aro populations, activity, or both, are reduced in a locus. This can matic solvents such as Xylene and higher molecular weight come about when: pest populations are repulsed from a locus; fractions of C9 and C10 aromatic solvents. Chlorinated 45 when pests are incapacitated, partially or completely, tempo hydrocarbons are useful as cosolvents to prevent crystalliza rarily or permanently, in or around a locus; or pests are exter tion of pesticides when the formulation is emulsified into minated, in whole or in part, in or around a locus. Ofcourse a water. Alcohols are sometimes used as cosolvents to increase combination of these results can occur. Generally, pest popu Solvent power. lations, activity, or both are desirably reduce more than fifty Thickeners or gelling agents are used mainly in the formu- 50 percent, preferably more than 90 percent, even more prefer lation of suspension concentrates, emulsions and Suspoemul ably more than 99 percent. sions to modify the rheology or flow properties of the liquid Generally, with baits, the baits are placed in the ground and to prevent separation and settling of the dispersed par where, for example, termites can come into contact with the ticles or droplets. Thickening, gelling, and anti-settling bait. Baits can also be applied to a Surface of a building, agents generally fall into two categories, namely water-in- 55 (horizontal, Vertical, or slant, Surface) where, for example, soluble particulates and water-soluble polymers. It is possible ants, termites, cockroaches, and flies, can come into contact to produce Suspension concentrate formulations using clays with the bait. and silicas. Examples of these types of materials, include, but Because of the unique ability of the eggs of some pests to are limited to, montmorillonite, e.g. bentonite; magnesium resist pesticides repeated applications may be desirable to aluminum silicate; and attapulgite. 60 control newly emerged larvae. Water-soluble polysaccharides have been used as thicken Systemic movement of pesticides in plants may be utilized ing-gelling agents for many years. The types of polysaccha to control pests on one portion of the plant by applying the rides most commonly used are natural extracts of seeds and pesticides to a different portion of the plant, or to a location seaweeds or are synthetic derivatives of cellulose. Examples where the root system of a plant can uptake pesticides. For of these types of materials include, but are not limited to, guar 65 example, control of foliar-feeding insects can be controlled gum, locust bean gum, carrageenam; alginates; methyl cel by drip irrigation or furrow application, or by treating the seed lulose; sodium carboxymethyl cellulose (SCMC); hydroxy before planting. Seed treatment can be applied to all types of US 9, 131,694 B2 37 38 seeds, including those from which plants genetically trans it does not cause the effect to an unacceptable degree it is formed to express specialized traits will germinate. Repre considered substantially absent for the practice of this inven sentative examples include those expressing proteins toxic to tion. invertebrate pests, such as Bacillus thuringiensis or other insecticidal toxins, those expressing herbicide resistance, 5 What is claimed is: such as “Roundup Ready’ seed, or those with “stacked' for 1. A compound according to the following formula: eign genes expressing insecticidal toxins, herbicide resis tance, nutrition-enhancement and/or any other beneficial traits. Furthermore, such seed treatments with a compound or R3 composition of the present application can further enhance 10 the ability of a plant to better withstand stressful growing conditions. This results in a healthier, more vigorous plant, ess." y which can lead to higher yields at harvest time. - in els2 Y S7-Rs It should be readily apparent that the invention can be used R1 N X- V with plants genetically transformed to express specialized 15 (y-V traits, such as Bacillus thuringiensis or other insecticidal toxins, or those expressing herbicide resistance, or those with 'stacked' foreign genes expressing insecticidal toxins, her wherein bicide resistance, nutrition-enhancement and/or any other A1, A2 and A3 are each C: beneficial traits. An example of Such a use is spraying Such plants with the invention disclosed in this document. X is N: The invention disclosed in this document is suitable for Y is C; controlling endoparasites and ectoparasites in the Veterinary T is O: medicine sector or in the field of animal keeping. Compounds 25 Z is C(R6) (where R6 could be the same or different); according to the present application are applied in a known n=2; manner, Such as by oral administration in the form of, for example, tablets, capsules, drinks, granules, by dermal appli R1 is F, Cl, Br or I; cation in the form of for example, dipping, spraying, pouring R2 is CN: on, spotting on, and dusting, and by parenteral administration 30 R3 is a substituted or unsubstituted halo-C1-C4-alkyl, in the form of for example, an injection. wherein the halo-C1-C4-alkyl when substituted fur The invention disclosed in this document can also be ther consists of one or more substituents selected from employed advantageously in livestock keeping, for example, the group consisting of F, Cl, Br, OH, CN, NO, CHO, cattle, sheep, pigs, chickens, and geese. Suitable formulations —SCN, S(O)n-C1-C4-alkyl (where n=0-2), C1-C4 are administered orally to the animals with the drinking water 35 alkyl, halo-C1-C4-alkyl, C1-C4-alkylamine, C1-C4 or feed. The dosages and formulations that are suitable alkoxy, halo-C1-C4 alkoxy, C1-C4-thioalkyl, halo depend on the species. C1-C4-thioalkyl, C1-C4 alkylacyl, C1-C4-acyloxy, Before a pesticide can be used or sold commercially, Such C1-C4 alkoxycarbonyl, C1-C4 alkoxy-imino, pesticide undergoes lengthy evaluation processes by various 40 hydroxy-imino, and C1-C4-alkyl-S(O)—N: governmental authorities (local, regional, state, national, R4 is H: international). Voluminous data requirements are specified by regulatory authorities and must be addressed through data R5 is H; and generation and Submission by the product registrant or by R6 is selected from the group consisting of H. Substi another on the product registrant's behalf. These governmen 45 tuted or unsubstituted C1-C4 alkyl, and substituted or tal authorities then review such data and if a determination of unsubstituted aryl, wherein the C1-C4 alkyl or aryl safety is concluded, provide the potential user or seller with when substituted further consists of one or more sub product registration approval. Thereafter, in that locality stituents selected from the group consisting of F, Cl, where the product registration is granted and Supported. Such Br, OH, CN, NO, CHO,-SCN, S(O)n-C1-C4-alkyl user or seller may use or sell Such pesticide. 50 (where n=0-2), C1-C4-alkyl, halo-C1-C4-alkyl, The headings in this document are for convenience only C1-C4-alkylamine, C1-C4 alkoxy, halo-C1-C4 and must not be used to interpret any portion thereof. All lists alkoxy, C1-C4-thioalkyl, halo-C1-C4 thioalkyl, herein are inclusive of any and all combinations of two or C1-C4-alkylacyl, C1-C4-acyloxy, C1-C4 alkoxycar more members of the list and all ranges are inclusive of any bonyl, C1-C4-alkoxy-imino, hydroxy-imino, C1-C4 and all Subsets within the range having endpoints within the 55 alkyl-S(O)—NH, and (C1-C4-trialkyl)Si. range as if each combination and Subset were expressly stated 2. A compound according claim 1, wherein R1 is Cl. herein. Unless stated otherwise or recognized by those skilled 3. A compound according to claim 2, wherein R3 is trif in the art as otherwise impossible, steps of processes luoromethyl. described herein are optionally carried out in sequences dif 60 ferent from the sequence in which the steps are discussed 4. A compound according to claim3, wherein R6 is chosen herein. Furthermore, steps optionally occur separately, simul from H. methyl, ethyl, propyl and phenyl. taneously or with overlap in timing. For instance. Such steps 5. A method of controlling insects which comprises apply as heating and admixing are often separate, simultaneous, or ing to a locus where control is desired an insect-inactivating partially overlapping in time in the art. Unless stated other 65 amount of a compound according to claim 1. wise, when an element, material, or step capable of causing 6. A compound according to claim 1 having the following undesirable effects is presentinamounts or in a form Such that Structure US 9, 131,694 B2 39 40 9. A compound according to claim 1 having the following CN Structure C N CF 5 N 21 21 CN

N N CH3. C CF N 3 N 10 O 21 N 21 7. A compound according to claim 1 having the following N Structure N 15 O CN C CF 10. A compound according to claim 1 having the following Na2rs Structure 21

Sa N N CH3 O r 25 CN C N CF 8. A compound according to claim 1 having the following Structure N 30 21 2

CN S N

C N CF O 35 21 Na2 CH3. CH S. N N CH. 40 11. A compound according to claim 1, wherein R3 and R6 O are unsubstituted.