USO09550739B2

(12) United States Patent (10) Patent No.: US 9,550,739 B2 Fischer et al. (45) Date of Patent: Jan. 24, 2017

(54) MOLECULES HAVING CERTAIN (58) Field of Classification Search PESTICIDALUTILITIES, AND CPC ... C07D 249/08; C07D 213/56; C07D 401/12: INTERMEDIATES, COMPOSITIONS, AND AO1N 43/653 PROCESSES RELATED THERETO See application file for complete search history. (56) References Cited (71) Applicant: Dow AgroSciences LLC, Indianapolis, IN (US) U.S. PATENT DOCUMENTS (72) Inventors: Lindsey G. Fischer, Indianapolis, IN 2016/0024027 A1 1/2016 Fischer ...... CO7D 249,08 (US); Gary D. Crouse, Noblesville, IN 504,100 (US); Thomas C. Sparks, Greenfield, FOREIGN PATENT DOCUMENTS IN (US); Miriam E. Goldsmith, Indianapolis, IN (US) WO WO2014.?004.064 A1 * 1, 2014 ...... CO7D 403/12 (73) Assignee: Dow AgroSciences LLC, Indianapolis, * cited by examiner IN (US) Primary Examiner — Jane C Oswecki (74) Attorney, Agent, or Firm — Yung H. Lee: Carl D. (*) Notice: Subject to any disclaimer, the term of this Corvin patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. (57) ABSTRACT This disclosure relates to the field of molecules having (21) Appl. No.: 14/810,775 pesticidal utility against pests in Phyla Nematoda, Arthro poda, and/or Mollusca, processes to produce Such molecules (22) Filed: Jul. 28, 2015 and intermediates used in Such processes, compositions containing Such molecules, and processes of using Such (65) Prior Publication Data molecules against Such pests. These molecules may be used, for example, as nematicides, acaricides, insecticides, miti US 2016/002402.6 A1 Jan. 28, 2016 cides, and/or molluscicides. This document discloses mol ecules having the following formula (“Formula One'). Related U.S. Application Data

(60) Provisional application No. 62/029,763, filed on Jul. 28, 2014. (51) Int. Cl. CO7D 249/08 (2006.01) CO7D 40/12 (2006.01) AOIN 43/653 (2006.01) (52) U.S. Cl. CPC ...... C07D 249/08 (2013.01); A0IN 43/653 (2013.01); C07D 401/12 (2013.01) 3 Claims, No Drawings US 9,550,739 B2 1. 2 MOLECULES HAVING CERTAIN culture, Genomic and Molecular Genetics of Plant Nema PESTICIDALUTILITIES, AND tode Interactions (Eds. Jones, J. et al.), Chapter 2, (2011)). INTERMEDIATES, COMPOSITIONS, AND It is noted that gastropods (slugs and Snails) are pests of PROCESSES RELATED THERETO less economic importance than insects or nematodes, but in certain areas, gastropods may reduce yields Substantially, CROSS REFERENCE TO RELATED severely affecting the quality of harvested products, as well APPLICATIONS as transmitting human, animal, and plant diseases. While only a few dozen species of gastropods are serious regional This application claims the benefit of, and priority from, pests, a handful of species are important pests on a world U.S. Provisional Patent Application Ser. No. 62/029,763 10 wide scale. In particular, gastropods affect a wide variety of filed 28 Jul. 2014, the entire disclosure of which is hereby agricultural and horticultural crops, such as arable, pastoral, expressly incorporated by reference. and fiber crops; vegetables; bush and tree fruits; herbs; and ornamentals (Speiser, B., Molluscicides, Encyclopedia of FIELD OF THE DISCLOSURE Pest Management (2002)). 15 Termites cause damage to all kinds of private and public This disclosure relates to the field of molecules having structures, as well as to agricultural and forestry resources. pesticidal utility against pests in Phyla Nematoda, Arthro In 2003, it was estimated that termites cause over USS20 poda, and Mollusca, processes to produce Such molecules billion in damage world-wide each year (Su, N. Y., Over and intermediates used in Such processes, compositions view of the global distribution and control of the Formosan containing Such molecules, and processes of using Such subterranean termite, Sociobiology 2003, 41, 177-192). molecules against Such pests. These molecules may be used, Therefore, for many reasons, including the above reasons, for example, as nematicides, acaricides, insecticides, miti a need exists for new pesticides. cides, and molluscicides. DEFINITIONS BACKGROUND OF THE DISCLOSURE 25 The examples given in the definitions are generally non “Many of the most dangerous human diseases are trans exhaustive and must not be construed as limiting the mol mitted by insect vectors” (Rivero, A. et al., Insect Control of ecules disclosed in this document. It is understood that a Vector-Borne Diseases: When is Insect Resistance a Prob Substituent should comply with chemical bonding rules and lem? Public Library of Science Pathogens, 6(8) (2010)). 30 steric compatibility constraints in relation to the particular Historically, vector-borne diseases, such as, malaria, den molecule to which it is attached. gue, yellow fever, plague, and louse-borne typhus, among “Alkenyl' means an acyclic, unsaturated (at least one others, were responsible for more human disease and death carbon-carbon double bond), branched or unbranched, sub from the 1600's through the early 1900's than all other stituent consisting of carbon and hydrogen, for example, causes combined (Gubler D., Resurgent Vector-Borne Dis 35 vinyl, allyl, butenyl, pentenyl, and hexenyl. eases as a Global Health Problem, Emerging Infectious “Alkenyloxy' means an alkenyl further consisting of a Diseases, Vol. 4, No. 3, July-September (1998)). Currently, carbon-oxygen single bond, for example, allyloxy, buteny vector-borne diseases are responsible for about 17% of the loxy, pentenyloxy, hexenyloxy. global parasitic and infectious diseases. It has been esti "Alkoxy' means an alkyl further consisting of a carbon mated that about 250 million people around the world have 40 oxygen single bond, for example, methoxy, ethoxy, propoxy, malaria and about 800,000 deaths occur each year 85% of isopropoxy, butoxy, isobutoxy, and tert-butoxy. those deaths are children under the age of five. A further “Alkyl means an acyclic, saturated, branched or 250,000 to 500,000 cases of dengue hemorrhagic fever unbranched, Substituent consisting of carbon and hydrogen, occur each year (Matthews, G., Integrated Vector Manage for example, methyl, ethyl, propyl, isopropyl, butyl, and ment: controlling vectors of malaria and other insect vector 45 tert-butyl. borne diseases (2011)). Vector control plays a critical role in “Alkynyl' means an acyclic, unsaturated (at least one the prevention and control of infectious diseases. However, carbon-carbon triple bond), branched or unbranched, sub insecticide resistance, including resistance to multiple insec stituent consisting of carbon and hydrogen, for example, ticides, has arisen in all insect species that are major vectors ethynyl, propargyl, butynyl, and pentynyl. of human diseases (Rivero, A. et al.). 50 “Alkynyloxy' means an alkynyl further consisting of a Each year insects, plant pathogens, and weeds destroy carbon-oxygen single bond, for example, pentynyloxy, more than 40% of all potential food production. This loss hexynyloxy, heptynyloxy, and octynyloxy. occurs despite the application of pesticides and the use of a "Aryl means a cyclic, aromatic Substituent consisting of wide array of non-chemical controls, such as crop rotations hydrogen and carbon, for example, phenyl, naphthyl, and and biological controls. If just some of this food could be 55 biphenyl. saved, it could be used to feed the more than three billion “Cycloalkenyl' means a monocyclic or polycyclic, people in the world who are malnourished (Pimental, D. unsaturated (at least one carbon-carbon double bond) sub Pest Control in World Agriculture, Agricultural Sciences— stituent consisting of carbon and hydrogen, for example, Vol. II (2009)). cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, Plant parasitic nematodes are among the most widespread 60 bicyclo2.2.2]octenyl, tetrahydronaphthyl, hexahydronaph pests, and are frequently one of the most insidious and thyl, and octahydronaphthyl. costly. It has been estimated that losses attributable to “Cycloalkenyloxy' means a cycloalkenyl further consist nematodes are from about 9% in developed countries to ing of a carbon-oxygen single bond, for example, cyclobute about 15% in undeveloped countries. However, in the nyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo United States of America, a survey of 35 States on various 65 2.2.2]octenyloxy. crops indicated nematode-derived losses of up to 25% “Cycloalkyl means a monocyclic or polycyclic, Saturated (Nicol, J. et al., Current Nematode Threats to World Agri Substituent consisting of carbon and hydrogen, for example, US 9,550,739 B2 3 4 cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, bicyclo with one or more substituents independently selected from a 2.2.2]octyl, and decahydronaphthyl. group consisting of H, F, Cl, Br, I, CN, NO, OH, C-C, “Cycloalkoxy' means a cycloalkyl further consisting of a alkyl, C-C alkenyl, C-C alkenyloxy, C-C alkynyl, carbon-oxygen single bond, for example, cyclopropyloxy, C-C alkynyloxy, C-C haloalkyl, C-C alkoxy, C-C, cyclobutyloxy, cyclopentyloxy, norbornyloxy, and bicyclo haloalkoxy, C-C cycloalkyl, C-C cycloalkoxy, C-C, 2.2.2]octyloxy. cycloalkenyl, or C-C cycloalkenyloxy; "Halo' means fluoro, chloro, bromo, and iodo. (B) R is H: "Haloalkoxy' means an alkoxy further consisting of, from (C) L is a linker that is bond connecting nitrogen to the one to the maximum possible number of identical or differ carbon in the ring, or L is a C-C alkyl that is optionally ent, halos, for example, fluoromethoxy, trifluoromethoxy, 10 substituted with one or more substituents independently 2,2-difluoropropoxy, chloromethoxy, trichloromethoxy, 1.1, selected from a group consisting of F, Cl, CN, OH, or oxo; 2.2-tetrafluoroethoxy, and pentafluoroethoxy. (D) R' is selected from H., (C-C)alkyl, (C-C)alkenyl, "Haloalkyl means an alkyl further consisting of, from (C-C)alkenyloxy, (C-C)alkynyl, (C-C)alkynyloxy, one to the maximum possible number of identical or dif (C-C)haloalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C- ferent, halos, for example, fluoromethyl, trifluoromethyl, 15 C.)alkyl (C-C)alkoxy, (C-C)cycloalkyl, (C-C)cy 2,2-difluoropropyl, chloromethyl, trichloromethyl, and 1.1, cloalkoxy, (C-C)cycloalkenyl, (C-C)cycloalkenyloxy, 2.2-tetrafluoroethyl. ((C-C)alkyl)) (C-C)cycloalkyl), C(O)(C-C)alkyl, “Heterocyclyl means a cyclic substituent that may be C(O)phenyl, ((C-C)alkyl)C(O)(C-C)alkyl, and ((C-C) fully saturated, partially unsaturated, or fully unsaturated, alkyl)C(O)C((C-C)alkyl). where the cyclic structure contains at least one carbon and wherein each alkyl, alkenyl, alkenyloxy, alkynyl, alkyny at least one heteroatom, where said heteroatom is nitrogen, loxy, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, Sulfur, or oxygen. Examples of aromatic heterocyclyls cycloalkenyl, cycloalkenyloxy, and phenyl, are optionally include, but are not limited to, benzofuranyl, benzoisothi azolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl, ben substituted with one or more substituents independently Zothiazolyl, cinnolinyl, furanyl, indazolyl, indolyl, imida 25 selected from H, F, Cl, Br, I, CN, NO, OH, oxo, and Zolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, OC(O)(C-C)alkyl: oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, (E) X is selected from N or CR'', wherein R' is selected pyrazolinyl, pyrazolyl pyridazinyl, pyridyl, pyrimidinyl, from a group consisting of H, F, Cl, Br, I, CN, NO, OH, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, C-C alkyl, C-C alkenyl, C-C alkenyloxy, C-C alky 30 nyl, C-C alkynyloxy, C-C haloalkyl, C-C alkoxy, thiazolinyl, thiazolyl, thienyl, triazinyl, and triazolyl. C-C haloalkoxy, C-C cycloalkyl, C-C cycloalkoxy, Examples of fully saturated heterocyclyls include, but are C-C cycloalkenyl, or C-C cycloalkenyloxy: not limited to, piperazinyl, piperidinyl, morpholinyl, pyrro (F) R' is selected from a group consisting of H. phenyl, lidinyl, tetrahydrofuranyl, and tetrahydropyranyl. Examples or substituted phenyl, of partially unsaturated heterocyclyls include, but are not 35 wherein said substituted phenyl is substituted with one or limited to, 1.2.3,4-tetrahydro-quinolinyl, 4.5-dihydro-OX more Substituents independently selected from a group con azolyl. 4,5-dihydro-1H-pyrazolyl. 4,5-dihydro-isoxazolyl, sisting of H. F. Cl, Br, I, CN, NO, OH, C-C alkyl, C-C, and 2,3-dihydro-1,3,4-oxadiazolyl. alkenyl, C-C alkenyloxy, C-C alkynyl, C-C alkyny DETAILED DESCRIPTION OF THE loxy, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, 40 C-C cycloalkyl, C-C cycloalkoxy, C-C cycloalkenyl, DISCLOSURE C-C cycloalkenyloxy, OC-C alkylphenyl, C(O)C-C, alkyl, or N(C-C alkyl)(C-C alkyl); This document discloses molecules having the following (G) Q is selected from O or S. formula (“Formula One') In another embodiment R is C-C haloalkyl, C-C, 45 alkoxy, or C-Chaloalkoxy. This embodiment may be used in combination with the other embodiments of R', R. R. Formula One R, R, R7, R8, R, R10, Ril, R13, R14, R15, R16, X, Q. and 8 R7 R R9 L. R6 N R10 R 16 In another embodiment R is CF, OCH(CH), OCF, or Q R 15 50 OCFCF. This embodiment may be used in combination Na s with the other embodiments of R', R. R. R. R. R. R. R5 N L \ NN R, R10, Ril, R13, R14, R15, R16, X, Q. and L. R3 R2 X /NR 14 In another embodiment L is C-C alkyl. This embodi R4 R1 R R13 ment may be used in combination with the other embodi 55 ments of R. R. R. R. R. R7, R. R. R. R. R. R', R", R', X, and Q. wherein: In another embodiment L is a bond, —CH2—, or (A) R", R°, R, R, R, R, R7, R, R10, R14, R15, and R' —CH2CH2—. This embodiment may be used in combina is each independently selected from a group consisting of H, tion with the other embodiments of R', R. R. R. R. R. F, Cl, Br, I, CN, NO, OH, C-C alkyl, C-C alkenyl, 60 R, R, Rio, Ril, R13, R14, R15, R16, X, and Q. C-C alkenyloxy, C-C alkynyl, C-C alkynyloxy, C-C, In another embodiment R' is H. C-C alkyl, C-C alkyl haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C, C-C cycloalkyl, or C(O)C-C alkyl. This embodiment cycloalkyl, C-C cycloalkoxy, C-C cycloalkenyl, or may be used in combination with the other embodiments of C-C cycloalkenyloxy, R", R°, R, R, R, R°, R7, R, R, R10, R13, R14, R15, R16, wherein each alkyl, alkenyl, alkenyloxy, alkynyl, alkyny 65 X, Q, and L. loxy, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, In another embodiment R' is CH, CHCH, cycloalkenyl, or cycloalkenyloxy, are optionally Substituted CHCHCH, CH(cyclopropyl), or C(O)CH. This US 9,550,739 B2 5 6 embodiment may be used in combination with the other (D) R' is independently selected from a group consisting embodiments of R', R,R,R,R,R, R7, R,R,R,R, of H. C-C alkyl, C-C alkyl C-C cycloalkyl, or C(O) R'', R', R, X, Q, and L. C-C alkyl; In another embodiment Q is O. This embodiment may be (E) X is selected from N or CR'', wherein R' is selected used in combination with the other embodiments of R. R. from a group consisting of H or C-C alkyl: R, R, R5, R, R7, R, R, Rio, Ril, R13, R14, R15, R16, X, (F) R' is selected from a group consisting of H. phenyl, and L. or substituted phenyl, In another embodiment Q is S. This embodiment may be wherein said substituted phenyl is substituted with one or used in combination with the other embodiments of R', R, more Substituents independently selected from a group con R, R, R, R, R7, R, R, R10, Ril, R, R14, R15, R16, X, 10 sisting of H. F. Cl, Br, I, C-C alkyl, C-C alkoxy, C-C, and L. haloalkoxy, OC-C alkyl phenyl, C(O)C-C alkyl, or In another embodiment X is N. This embodiment may be N(C-C alkyl)(C-C alkyl); used in combination with the other embodiments of R', R, (G) Q is selected from O or S. R, R, R5, R, R7, R8, R, R10, Ril, R, R14, R15, R16, Q. 15 In another embodiment and L. (A) R", R°, R, R, R, R, R7, R, Rio, R14, R15, and R' In another embodiment X is CR' wherein R' is H or is each independently selected from a group consisting of H, C-C alkyl. This embodiment may be used in combination F. Cl, Br, I, C-C haloalkyl, C-C alkoxy, or C-C, with the other embodiments of R', R. R. R. R. R. R. haloalkoxy, R, R, Rio, Ril, R13, R14, R15, R16, Q, and L. In another embodiment X is CR' wherein R' is CH. (B) R is H: This embodiment may be used in combination with the other (C) L is a bond or C-C alkyl: embodiments of R', R,R,R,R,R,R,R,R,R,R'', (D) R' is independently selected from a group consisting R. R. R. R', Q, and L. of H. C-C alkyl, C-C alkyl C-C cycloalkyl, or C(O) In another embodiment R' is H or phenyl. This embodi 25 C-C alkyl: ment may be used in combination with the other embodi (E) X is CR', wherein R' is selected from a group ments of R', R. R. R. R. R. R7, R. R. R. R'', R', consisting of H or C-C alkyl; R", R', X, Q, and L. (F) R' is a phenyl or substituted phenyl, In another embodiment R' is substituted phenyl that is wherein said substituted phenyl is substituted with one or substituted with one or more substituents selected from the 30 more Substituents independently selected from a group con group consisting of H. F. Cl, C-C alkyl, C-C alkoxy, sisting of H, F, Cl, Br, I, C-C alkyl, C-C alkoxy, C(O) C-C haloalkoxy, OC-C alkyl phenyl, C(O)C-C alkyl, C-C alkyl, or N(C-C alkyl)(C-C alkyl); or N(C-C alkyl)(C-C alkyl). This embodiment may be (G) Q is selected from O or S. used in combination with the other embodiments of R', R, 35 In another embodiment R, R*, R5, R, R7, R8, R, R10, Ril, R14, R15, R16, X, Q. and (A) R", R°, R, R, R, R, R7, R, Rio, R14, R15, and R' L. is each independently selected from a group consisting of H, In another embodiment R' is substituted phenyl that is F. Cl, Br, I, C-C haloalkyl, C-C alkoxy, or C-C, substituted with one or more substituents selected from the haloalkoxy, group consisting of CH, CHCH, OCH, OCHCH 40 (B) R is H: OCF, OCHCHs, C(O)CH, or N(CH). This embodi ment may be used in combination with the other embodi (C) L is a bond or C-C alkyl: ments of R', R. R. R. R. R. R. R. R. R. R'', R', (D) R' is independently selected from a group consisting R", R', X, Q, and L. of H, C-C alkyl, or C(O)C-C alkyl: In another embodiment R'' is H. F. Cl, or C-C alkoxy. 45 (E) X is CR'', wherein R' is H; This embodiment may be used in combination with the other (F) R' is a phenyl or substituted phenyl, embodiments of R', R,R,R,R,R, R7, R. R. R. R'', wherein said substituted phenyl is substituted with one or R', R', R', X, Q, and L. more Substituents independently selected from a group con In another embodiment R'' is OCH. This embodiment sisting of H, F, Cl, Br, I, C-C alkyl, C-C alkoxy, C(O) may be used in combination with the other embodiments of 50 C-C alkyl, or N(C-C alkyl)(C-C alkyl); R", R°, R, R, R5, R, R7, R, R, R10, Ril, R13, R15, R16, X, Q, and L. (G) Q is selected from O or S. In another embodiment R' is H, F, or Cl. This embodi Preparation of Amides ment may be used in combination with the other embodi The amide products of Formula One can be prepared from ments of R', R. R. R. R. R. R. R. R. R. R'', R', 55 the corresponding amine (1-3), wherein R', R. R. R. R. R'', R', X, Q, and L. R. R. R. R. and R'' are as previously defined, and acid In another embodiment R' is H, F, or Cl. This embodi chloride (1-2), wherein X, R', R'', R', and R'' are as ment may be used in combination with the other embodi previously defined. Usually, these acid chlorides can be ments of R', R. R. R. R. R. R7, R. R. R. R'', R, generated and isolated from a Suitable precursor and used R'', R', X, Q, and L. 60 directly without purification in the preparation of the amide. In another embodiment One such suitable precursor is a carboxylic acid (1-1) which (A) R", R°, R, R, R, R, R7, R, R10, R14, R15, and R' can be converted into an acid chloride by using a reagent is each independently selected from a group consisting of H, Such as oxalyl chloride in a polar aprotic solvent Such as F. Cl, Br, I, C-C haloalkyl, C-C alkoxy, or C-C, dichloromethane or tetrahydrofuran, in the presence of a haloalkoxy, 65 catalytic amount of dimethylformamide, at temperatures (B) R is H: from about -78° C. to about 30° C. (Scheme 1, step a), (C) L is a bond or C-C alkyl: followed by removal of solvent by concentration. US 9,550,739 B2

Scheme 1 R 15 R 15 RS R 14 RS R 14 21 21 HO s R13 8. C s R13

O O 1-1 1-2

-- 8 R9 R7 R R9 EN R10 R 16 R6 =N R10 ( )- O R15 b N N na s -e- na N L. N. \ R5 N LN N Z R 14 NH2 R3 R2 X R3 R2 R1 R4 R R13 1-4 1-3

25 Alternatively, the carboxylic acid can also be converted dicyclohexylcarbodiimide, diisopropylcarbodiimide, or into an acid chloride by treatment with thionyl chloride in a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and a tri non-polar aprotic solvent such as toluene, at temperatures from about -10° C. to about 110° C., followed by removal azole such as 1-hydroxy-benzotriazole or 1-hydroxy-7-aza of Solvent by methods such as concentration or distillation. benzotriazole, in the presence of an amine base Such as Accordingly, it is appreciated that the acid chloride may not 30 diisopropylethylamine or triethylamine, in a polar aprotic always be fully characterized, but may simply be used solvent such as dimethylformamide, tetrahydrofuran, or directly without characterization, to generate the amide. The acid chloride (1-2) can be treated directly with an dichloromethane, at temperatures from about -10° C. to aniline or amine (1-4) in the presence of an amine base Such about 30°C. (Scheme 2). The reaction can also be facilitated as diisopropylethylamine, resulting in the formation of an 35 with uronium or phosphonium activating groups such as amide (1-4, Scheme 1, step b). The reaction can be per O-(7-azabenzotriazol-1-yl)-N.N.N',N'-tetramethyluronium formed at temperatures from about -10°C. to about 30°C., hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidino preferably from about 15° C. to about 25°C., in an aprotic phosphonium hexafluorophosphate, in the presence of an solvent chosen from tetrahydrofuran, dichloromethane, tolu amine base such as diisopropylethylamine or triethylamine, ene, but use of tetrahydrofuran is preferred. 40 in a polar aprotic solvent Such as dimethylformamide, tet Alternatively, an amine, (1-3), can be coupled directly to rahydrofuran, or dichloromethane, at temperatures from a carboxylic acid, (1-1) with an activating group Such as about -10° C. to about 30° C. to form the amide (1-4).

Scheme 2 R 15 RS R 14 21 HO R8 Sa 13 R7 R9 X R R6 SN R10 R 16 O 15 O N 2 R YN S 1-1 5 8. R LNN \ 14 -- Hs R3 R2 H X Z R R8 R4 RI R7 R9 R13 R 6 )=N R O 1-4

NNn 2 N R 5 NNH, R3 R2 R4 R1 1-3 US 9,550,739 B2 9 10 Preparation of N-Alkyl or N-Acyl Amides -continued 8 6 R7 R R9 O The N-alkyl or N-acyl amide products (3-2, Scheme 3) of R )=N R S R 16 R15 Formula One, wherein R' is as previously defined, may be 5 Né s prepared from the corresponding amide (1-4). The amide R5 L. NN \ 14 can be treated directly with an inorganic base such as sodium R3 R2 H ZR hydride, in a polar aprotic solvent such as dimethylforma- R R R13 mide or tetrahydrofuran, attemperatures from about -10°C. 10 4-1 to about 30°C., followed by treatment with an alkyl source Such as

Scheme 3

R6 R7 t SN R9 R10 11 R X N2 3-1 R5 L 8. NN -- Her 4 R3 R2 R R R7 R8 R9 R6 )=n R10 3-2 NN a 5 YN R NNH, R3 R2 R4 R1 1-3 an alkyl halide, alkyl triflate, or alkyl sulfonate to form the 3s Some of the procedures described above require use of alkylated amide (3-2); or followed by treatment with an acyl triaryl-aniline intermediates, which are novel intermediates. Source Such as acetyl chloride or acetic anhydride to form These may be prepared as described in Scheme 5. An aryl the acylated amide (3-2). halide (5-1) such as 4-trifluoromethylphenyl iodobenzene or Preparation of Thioamides 1-iodo-4-isopropoxybenzene, can be coupled to bromo triazole (5-2, step a) in the presence of cesium carbonate or The thioamide products (4-1, Scheme 4) of Formula One 40 potassium phosphate, in a polar aprotic solvent Such as can be prepared from the corresponding amide (1-4). The dimethylformamide. This reaction is catalyzed by a copper amide can be treated directly with a source of sulfur, such as salt such as copper(I) iodide and a chelator Such as 8-hy phosphorus pentasulfide or 2.4-bis(4-methoxyphenyl)-1.3.2. droxyquinoline, both present in about 0.05 to about 0.25 4-dithiadiphosphetane 2,4-disulfide (Lawesson’s reagent), equivalents, at a temperature ranging between about 80° C. in an aprotic solvent chosen from tetrahydrofuran, dichlo and about 140°C., to form the corresponding triazole (5-3). romethane, chloroform, toluene, or pyridine, attemperatures 45 Coupling of the bromo-heterocycle (5-3) with a boronate from about 60° C. to about 120° C. to form the thioamide ester (5-4, Step b) can be accomplished using a palladium (4-1). catalyst, such tetrakis(triphenylphosphine)palladium(0), in Preparation of Triaryl Intermediates the presence of a base, such as Sodium bicarbonate, in a Triaryl-aniline intermediates can be used to prepare mol Suitable solvent system, such as dioxane?water, at tempera ecules of Formula One. These triaryl intermediates can be 50 tures from about 50° C. to about 120° C. to form the desired prepared by methods previously described in the chemical aniline (5-5). literature, including Crouse, et al., WO2009102736 (the Some of the procedures described below require use of entire disclosure of which is hereby incorporated by refer triaryl bromide intermediates, which are novel intermedi ence). ates. These may be prepared as described 55

Scheme 4 Scheme 5 R7 R7 R8 R9 R6 60 R R6 )=N R10 O R 16 15 Na s R 8. -- Br -e- 5 N L Br, I N- 8. R5 HN R R3 R2 NH X\ /NR 14 NN 4 R3 R R R13 65 R4 1-4 5-1 5-2 US 9,550,739 B2 11 -continued -continued R8 R7 R9 R6 R6 N R10

NNN 2 5 N R Br R3 R2 R4 R1 10 6-3

O Y-\ S potassium phosphate, in a polar aprotic solvent Such as 5-3 + HC7-N N B dimethylformamide. This reaction is catalyzed by a copper 15 salt such as copper(I) iodide and a chelator Such as 8-hy R2 droxyquinoline, both present in about 0.05 to about 0.25 RI equivalents, at a temperature ranging between about 80° C. 5-4 and about 140°C., to form the triaryl bromide intermediate 8 (6-3, step b). R7 R R9 R6 N R10 Preparation of 1-Atom Linked Intermediates Molecules of Formula One wherein L is C alkyl, can be NN 2 5 N N prepared as described in R NH2 25 R3 R2 R4 R1 Scheme 7 5-5 R9 R10 30 Br, I 8. in Scheme 6. Bromotriazole (6-2, step a) may be prepared in NH2 - - two steps from 4-bromobenzamide (6-1) under conditions described previously (Crouse, et al., WO2009102736). This R2 triazole can then be coupled to an aryl halide (5-1) such as R1 35 4-trifluoromethoxyphenyl bromobenzene, in the presence of 7-1 cesium carbonate or R9 R10 Scheme 6 40 Br, I H O R9 O R10 sk 8. R2 O -e- R1 HN Br 45 7-2 R2 b RI 7-2 -- 6-1 H3C CH3 R8 R9 R9 50 R R10 )= N R10 B H O HN 2 N N HS3C o1 sk Br R2 O R2 55 R1 RI 7-3 6-2 R8 R7 R7 R6 60 R6 )=n 6-2 + Br, I b N 2 -e-C -e- 5 YN Br 7-3 R5 R R3 R3 R4 R4 65 5-3 US 9,550,739 B2

-continued 8 Scheme 8 R7 R R9 R6 N R10 R8 O R7 R9 R6 N R10 R5 Né N N. 2 --> R3 R2 O YN R4 R1 R5 Br 7-4 10 R3 R2 d R R1 7-4 -> 8 6-3 R7 R R9 R8 R6 N R10 R7 R9 R6 N R10 N 15 5 Né NH2 NN 2 R YN R3 R2 R5 SN R4 R1 R3 R2 7-5 R RI 8-1 b Scheme 7. Halobenzyl amines (7-1) may be protected using 8-1 --> R8 benzyl chloroformate in the presence of a base such as R7 R9 triethylamine in an aprotic solvent Such as dichloromethane 25 R6 N R10 at about -10°C. to about 10°C. to provide N-carboxybenzyl N protected benzyl amines (7-2, step a). It is appreciated that Né NH2 other N-protecting groups such as tert-butoxycarbonyl or R5 R3 R2 9-fluorenylmethylcarbonyl may be employed in step a using 30 similar conditions described above for carboxybenzyl. The R4 RI N-carboxybenzyl protected boronic ester 7-3 can be pre 7-5 pared using Miyaura conditions (step b). Coupling of the boronate esters with a bromo-heterocycle (5-3) can be Preparation of Ethyl Linked Intermediates accomplished using a palladium catalyst, such tetrakis(tri 35 Preparation of compounds wherein L is C alkyl is phenylphosphine)palladium(0), in the presence of a base, described in Schemes 9. Using conditions first described by Such as sodium bicarbonate, potassium phosphate, or cesium Molander et al. Org. Lett., 2007, 9 (2), pp 203-206, coupling fluoride, in a Suitable solvent system, such as dioxane?water, of a triaryl bromide (6-3, step a), with potassium (2-((tert butoxycarbonyl)amino)ethyl)trifluoroborate in the presence at temperatures from about 50° C. to about 120° C. to form 40 N-protected aminoalkylphenyl intermediates (7-4, step c). of a palladium catalyst Such as palladium(II) acetate, and a base such as cesium carbonate, at temperatures from about Deprotection of the carboxybenzyl group can be accom 80° C. to about 120° C., may result in the formation of the plished under acidic conditions with a strong acid such as corresponding 2-(tert-butoxycarbonyl)amino)ethyl deriva hydrogen bromide, followed by free basing with a base such 45 tive 9-1. Further treatment of this material with about 1 to as sodium bicarbonate or sodium hydroxide, to furnish the about 5 equivalents of an acid such as trifluoroacetic acid, in free amines (7-5, step d). Alternatively, deprotection of the an aprotic solvent such as dichloromethane or dioxane at carboxybenzyl group may be accomplished by treatment temperatures from about 0°C. to about 50° C. may result in with hydrogen in the presence of a transition metal catalyst, the cleavage of the tert-butoxycarbonyl group and formation Such as palladium on carbon. It is appreciated that similar 50 of the corresponding acid salt of the amine (9-3, step b). It methods could be applied to compounds wherein L is C-C, is appreciated that the obtained amine salts may be treated alkyl. with a base. Such as sodium bicarbonate or triethylamine to obtain the free amine. Alternatively, molecules of Formula One wherein L is C alkyl, can be prepared as described in Scheme 8. Incorpo 55 ration of the cyanide from a cyanide source Such as Zinc Scheme 9 cyanide onto a bromo-heterocycle (5-3) can be accom 8 plished using a palladium catalyst Such as tetrakis(triphenyl R7 R R9 phosphine)palladium(0), in a Suitable solvent system, Such 60 R6 )= N RI O as dimethylformamide, attemperatures from about 50° C. to N 8. about 120° C. to form triaryl cyano intermediates (8-1, step YN 2 He a). Reduction of the cyano group can be accomplished by R5 Br treatment with a metal reductant Such as palladium on R3 R2 carbon in the presence of a strong acid such as hydrogen R4 R1 chloride, followed by free basing with a base such as sodium 65 bicarbonate or sodium hydroxide, to furnish the free benzyl amines (7-5, step b). US 9,550,739 B2 16 -continued diluted with ethyl acetate and filtered through Celite(R). The R8 7 9 H3C resulting filter cake was rinsed with additional ethyl acetate R6 R )=N R R10 O y. (100 mL). The filtrate was washed with water (2x50 mL). CH The combined aqueous washes were neutralized with hydro N. 2 X- 3 5 R5 N N chloric acid (2 N) as measured by pH paper. The aqueous solution was extracted with ethyl acetate (2x30 mL) and the R3 R2 organic extracts were combined, and then dried over anhy R4 R1 drous magnesium Sulfate. The organic Solution was concen 9-1 trated onto Celite(R) and purified by silica gel chromatogra b 10 9-1 -> phy using 0-100% ethyl acetate/hexanes as eluent. The 8 relevant fractions were concentrated to obtain the title R7 R 9 compound as a yellow oil (0.540 g, 23%): "H NMR (400 R6 )=N R10 O MHz, CDC1) & 8.31 (s, 1H), 7.51 (d. J=9.1 Hz, 2H), 6.98 15 (d. J=9.0 Hz, 2H), 4.59 (p, J=6.1 Hz, 1H), 1.36 (d. J=6.1 Hz, 6H), ESIMS m/z 283 (IM+H"). Example 2 Preparation of 4-(1-(4-isopropoxyphenyl)-1H-1,2,4- triazol-3-yl)aniline (C2) EXAMPLES

These examples are for illustration purposes and are not 25 to be construed as limiting the disclosure to only the CH ?=N embodiments disclosed in these examples. N Starting materials, reagents, and solvents that were O NH2 obtained from commercial sources were used without fur --O-O- ther purification. Anhydrous solvents were purchased as 30 Sure/SealTM from Aldrich and were used as received. Melt Placed 3-bromo-1-(4-isopropoxyphenyl)-1H-1,2,4-triaz ing points were obtained on a Thomas Hoover Unimelt ole (C1) (0.540 g, 1.91 mmol), 4-(4,4,5,5-tetramethyl-1,3, capillary melting point apparatus or an OptiMelt Automated 2-dioxaborolan-2-yl)aniline (0.510 g, 2.32 mmol), tetrakis Melting Point System from Stanford Research Systems and (triphenylphosphine) palladium(0) (0.240 g, 0.210 mmol), are uncorrected. Examples using "room temperature' were 35 and potassium carbonate (2.65 g, 19.2 mmol) in 1,2-dime conducted in climate controlled laboratories with tempera thoxyethane (8 mL) and water (2 mL) and degassed the tures ranging from about 20° C. to about 24°C. Molecules mixture with nitrogen for 10 minutes. The solution was are given their known names, named according to naming heated at 120° C. for 15 hours. The solution was cooled to programs within ISIS Draw, ChemDraw or ACD Name Pro. room temperature and diluted the mixture with ethyl acetate If Such programs are unable to name a molecule, the 40 (5 mL). The resultant salts were filtered and the layers were molecule is named using conventional naming rules. "H separated. The aqueous layers were extracted with ethyl NMR spectral data are in ppm (ö) and were recorded at 300, acetate (2x5 mL). The combined organic layers were dried 400 or 600 MHz, and 'C NMR spectral data are in ppm (8) over anhydrous magnesium Sulfate and concentrated onto and were recorded at 75, 100 or 150 MHz, unless otherwise Celite R. Purification by silica gel chromatography using stated. 45 0-100% ethyl acetate/hexanes as eluent provided the title compound as a tan solid (0.430 g, 73%); H NMR (400 Example 1 MHz, CDC1) & 8.40 (s, 1H), 7.99 (d. J–8.7 Hz, 2H), 7.60 (d. J=9.1 Hz, 2H), 6.99 (d. J=9.0 Hz, 2H), 6.76 (d. J=8.7 Hz, Preparation of 2H), 4.59 (p, J=6.1 Hz, 1H), 3.83 (s. 2H), 1.37 (d. J=6.1 Hz, 3-bromo-1-(4-isopropoxyphenyl)-1H-1,2,4-triazole 50 6H), ESIMS m/z 295 (IM+H"). Example 3

CH Preparation of N-(4-(1-(4-isopropoxyphenyl)-1H-1, 55 2,4-triazol-3-yl)phenyl)-2'-methoxy-1, 1'-biphenyl - -O A. Br 3-carboxamide (F5)

3-bromo-1H-1,2,4-triazole (1.75 g, 11.8 mmol), copper(I) 60 HC iodide (0.370 g, 1.94 mmol), cesium carbonate (4.98 g. 15.3 O mmol), and 1-iodo-4-isopropoxybenzene (2.04 g, 7.78 mmol) (Katsumatu, T., et al. Macromolecular Chemistry and CH f=N O O Physics, 2009, 210 (22), 1891-1902) was placed in dimeth ylsulfoxide (50 mL) and degassed with nitrogen for 10 65 ne-O-O-O. minutes. The solution was heated at 100° C. for 20 hours. After cooling to room temperature, the reaction mixture was US 9,550,739 B2 17 18 To a mixture of 2'-methoxy-11'-biphenyl-3-carboxylic To a mixture of 1,1'-biphenyl-3-carboxylic acid (0.172 acid (0.140 g, 0.610 mmol) in dichloromethane (5 mL) was g, 0.870 mmol) in dichloromethane (4 mL) was added oxalyl added oxalyl chloride (0.150 mL, 1.75 mmol) and dimeth chloride (0.150 mL, 1.75 mmol) and dimethylformamide (2 ylformamide (2 drops). After stirring for 3 hours at room drops). After stirring for 3 hours at room temperature, the reaction was concentrated to dryness. The resulting yellow temperature, the reaction was concentrated to dryness. The oil was dissolved in anhydrous tetrahydrofuran (1 mL) and resulting yellow oil was dissolved in anhydrous tetrahydro added to a solution of 4-(1-(4-(trifluoromethoxy)phenyl)- furan (2 mL) and added to a solution of 4-(1-(4-isopropoxy 1H-1,2,4-triazol-3-yl)aniline (0.102 g, 0.320 mmol) (WO phenyl)-1H-1,2,4-triazol-3-yl)aniline (C2) (0.134 g. 0.460 2009102736) dissolved in tetrahydrofuran (3 mL) and diiso mmol) dissolved in tetrahydrofuran (3 mL) and diisopropy propylethylamine (0.150 mL, 0.860 mmol) and stirred at lethylamine (0.190 mL, 1.09 mmol) and stirred at room 10 room temperature for 18 hours. The solution was diluted temperature for 18 hours. The solution was diluted with with ethyl acetate (10 mL) and washed with saturated ethyl acetate (10 mL) and washed with Saturated aqueous aqueous sodium bicarbonate. The aqueous wash was Sodium bicarbonate. The aqueous wash was extracted with extracted with ethyl acetate (2x5 mL) and the combined ethyl acetate (2x5 mL) and the combined organic layers organic layers were dried over anhydrous magnesium Sul were dried over anhydrous magnesium sulfate. The Solution fate. The solution was concentrated onto Celite R and puri was concentrated onto Celite(R) and purified by silica gel 15 fied by flash column chromatography using 0-100% ethyl chromatography using 0-100% ethyl acetate/(1:1 hexanes/ acetate/(1:1 hexanes/dichloromethane) as eluent. The rel dichloromethane) as eluent. The relevant fractions were evant fractions were concentrated to give the title compound concentrated to give the title compound as an off-white solid as a white solid (0.0440 g, 28%). (0.151 g, 62%). The following compounds were prepared according to the The following compounds were prepared according to the procedures disclosed in Example 4: procedures disclosed in Example 3: 5-Fluoro-N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H 6-Fluoro-N-(4-(1-(4-isopropoxyphenyl)-1H-1,2,4- 1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3-carbox triazol-3-yl)phenyl)-1,1'-biphenyl-3-carboxamide amide (F25) (F16) 25 - - - - C a - - - O 30

Isolated as a white solid (0.118 g. 52%). 35 Isolated as an off-white solid (0.062 g, 27%). 6-Fluoro-N-(4-(1-(4-isopropoxyphenyl)-1H-1,2,4- 5-Fluoro-2'-methyl-N-(4-(1-(4-(trifluoromethoxy) triazol-3-yl)phenyl)-2'-methoxy-11'-biphenyl-3- phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-1,1'-biphe carboxamide (F4) nyl-3-carboxamide (F39) 40

H3C EN 45 F F O O CH3 f=N O - C a N a YQO NN N H ic-S-O- SC) H O F F 50 Isolated as a white solid (0.106 g, 42%). Isolated as an orange oily solid (0.136 g, 57%). Example 4 5-Chloro-N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H 1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3-carbox Preparation of N-(4-(1-(4-(trifluoromethoxy)phe 55 amide (F43) nyl)-1H-1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3- carboxamide (F24)

60 - - - - C

65 Isolated as an off-white solid (0.148 g. 65%).

US 9,550,739 B2 25 26 Example 5 N-(cyclopropylmethyl)-6-fluoro-2'-methoxy-N-(4- (1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3- Preparation of 2'-methoxy-N-methyl-N-(4-(1-(4- yl)phenyl)-1,1'-biphenyl-3-carboxamide (F66) (trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl) phenyl)-1,1'-biphenyl-3-carboxamide (F19)

HiQ F f= N - O F N > O Or's C-5W C. CH3

To a solution of 2'-methoxy-N-(4-(1-(4-(trifluo Isolated as a colorless oil (0.040 g, 22%). romethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-1,1'-bi phenyl-3-carboxamide (F22) (0.080 g, 0.15 mmol) dis solved in tetrahydrofuran (2 mL) was added sodium hydride N-acetyl-6-fluoro-2'-methoxy-N-(4-(1-(4-(trifluo (60% by weight, 0.0096 g., 0.24 mmol). After stirring at romethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-1, room temperature for 20 minutes, methyl iodide (0.025 mL, 1'-biphenyl-3-carboxamide (F67) 0.40 mmol) was added and the mixture stirred for 18 hours. Saturated aqueous sodium bicarbonate was added to the solution followed by extraction with ethyl acetate (3x5 mL). 25 The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated. Purification by flash column chromatography using 0-40% ethyl acetate? 1:1 hexanes/dichloromethane as eluent provided the title com pound as a colorless oil (0.039 g, 45%). The following example was prepared according to the procedures disclosed in Example 5: s N-Ethyl-6-fluoro-2'-methoxy-N-(4-(1-(4-(trifluo romethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-1, 35 Acetic anhydride used as electrophile. Isolated as a col 1'-biphenyl-3-carboxamide (F64) orless oil (0.214 g, 83%). Example 6 40 Preparation of 2,6'-dimethyl-N-(4-(1-(4-(trifluo romethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-1, 1'-biphenyl-3-carbothioamide (F46)

45

HC N Isolated as a colorless oil (0.163 g, 86%). F. F f= S O 50 F >Q NaN 6-Fluoro-2'-methoxy-N-propyl-N-(4-(1-(4-(trifluo O N CH3 romethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-1, H 1'-biphenyl-3-carboxamide (F65) To a solution of 2,6'-dimethyl-N-(4-(1-(4-(trifluo 55 romethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-1,1'-bi

phenyl-3-carboxamide (F12) (0.132 g, 0.250 mmol) dis solved in tetrahydrofuran (3 mL) was added 2,4-bis(4- methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson’s reagent) (0.129 g, 0.320 mmol) and the mixture 60 was heated at 60° C. for 18 hours. Additional 2.4-bis(4- methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (0.262 g, 0.65 mmol) was added and the reaction was allowed to heat at 60° C. until the reaction was determined to be complete. The reaction mixture was concentrated onto 65 Celite R and purified by flash column chromatography using 0-100% ethyl acetate? (1:1 hexanes/dichloromethane). The Isolated as a colorless oil (0.160 g, 89%). title compound was obtained as a yellow oil (0.043 g, 30%). US 9,550,739 B2 27 28 The following example was prepared according to the N-(4-(1-(4-(Perfluoroethoxy)phenyl)-1H-1,2,4-tri procedures disclosed in Example 6: azol-3-yl)phenyl)-6-phenylpicolinamide (F47) 2-Methoxy-N-(4-(1-(4-(trifluoromethoxy)phenyl)- 1H-1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3-car 5 bothioamide (F21) =N

\ 10 FYk, O ( N NO \ Ns F. F - "C) F H Z Isolated as a white solid (0.102 g. 67%). 15 6-Methoxy-N-(4-(1-(4-(perfluoroethoxy)phenyl)- Isolated as a yellow solid (0.087 g, 48%). 1H-1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3-car boxamide (F13) Example 7 Preparation of N-(4-(1-(4-(perfluoroethoxy)phenyl)- 1H-1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3-car boxamide (F45) =N O 25

F F O N NH O OV R F f=N O O CH 30 Isolated as a white solid (0.094 g. 42%). 2-Methoxy-N-(4-(1-(4-(perfluoroethoxy)phenyl)- To a mixture of 1,1'-biphenyl-3-carboxylic acid (0.172 1H-1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3-car g, 0.870 mmol) in dichloromethane (4 mL) was added oxalyl 35 chloride (0.150 mL, 1.75 mmol) and dimethylformamide (2 boxamide (F26) drops). After stirring for 3 hours at room temperature, the reaction was concentrated to dryness. The resulting yellow oil was dissolved in anhydrous tetrahydrofuran (1 mL) and added to a solution of 4-(1-(4-(perfluoroethoxy)phenyl)-1H 1,2,4-triazol-3-yl)aniline (0.102 g, 0.280 mmol) (WO 40 2009102736) dissolved in tetrahydrofuran (3 mL) and diiso propylethylamine (0.150 mL, 0.860 mmol) and stirred at R F f=N O \, O room temperature for 18 hours. The reaction was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium bicarbonate. The aqueous wash was 45 YX-O Coc extracted with ethyl acetate (2x5 mL) and the combined organic layers were dried over anhydrous magnesium Sul fate. The solution was concentrated onto Celite(R) and puri fied by flash column chromatography using 0-100% ethyl Isolated as a white solid (0.284 g. 67%). acetate/(1:1 hexanes/dichloromethane) as eluent. The rel 50 evant fractions were concentrated to give the title compound as an white solid (0.109 g, 68%). N-(4-(1-(4-(Perfluoroethoxy)phenyl)-1H-1,2,4-tri The following examples were prepared according to the azol-3-yl)phenyl)-2'-(trifluoromethoxy)-1,1'-biphe procedures disclosed in Example 7: nyl-3-carboxamide (F36) 2-Methyl-N-(4-(1-(4-(perfluoroethoxy)phenyl)-1H 55 1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3-carbox amide (F35) 60 y O =N F O tes 'YK, ? F H is-Kri?t - C 65 sko-o-o-c- Isolated as a white solid (0.095 g, 56%). Isolated as an off-white solid (0.057 g. 22%).

US 9,550,739 B2 31 32 Example 9 Example 11

Preparation of 2'-methoxy-N-(4-(1-(4-(perfluoroeth Preparation of 4-(1-(4-(trifluoromethyl)phenyl)-1H oxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-1,1'- 1,2,4-triazol-3-yl)aniline (C4) biphenyl-3-carbothioamide (F23)

C V 10 O =N F R F ? S O Y-X, N N O F H 15 Placed 3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4- triazole (C3) (8.64 g, 29.6 mmol), 4-(4.4.5.5-tetramethyl-1, 3.2-dioxaborolan-2-yl)aniline (7.42 g, 33.9 mmol), tetrakis To a solution of 2'-methoxy-N-(4-(1-(4-(perfluoroethoxy) (triphenylphosphine)palladium(0) (3.30g, 2.86 mmol), and phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3- potassium carbonate (7.82 g, 56.6 mmol) in 1,2-dimethoxy carboxamide (F26) (0.132 g, 0.230 mmol) dissolved in ethane (75 mL) and water (18 mL) and degassed the mixture tetrahydrofuran (2 mL) was added 2.4-bis(4-methoxyphe with nitrogen for 10 minutes. The reaction mixture was nyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (0.129 g, heated at 120° C. for 16 hours. The reaction was cooled to 0.320 mmol) and the mixture was heated at 60° C. for 18 room temperature and diluted with ethyl acetate. The resul hours. Additional 2.4-bis(4-methoxyphenyl)-1,3,2,4-dithi tant salts were filtered and the filtrated layers were separated. adiphosphetane 2,4-disulfide (0.074 g., 0.18 mmol) and the 25 The aqueous layer was separated with ethyl acetate (2x). reaction was allowed to heat at reflux until the reaction was The combined organic layers were dried over anhydrous determined to be complete. The reaction mixture was con magnesium sulfate and concentrated onto Celite(R). Purifi centrated onto Celite(R) and purified by flash column chro cation by flash column chromatography using 0-100% ethyl matography using 0-100% ethyl acetate/(1:1 hexanes/di acetate/hexanes as eluent provided the title compound as a chloromethane). The title compound was obtained as a 30 yellow solid (5.34g, 58%): "H NMR (400 MHz, CDC1) & yellow solid (0.071 g, 49%). 8.60 (s, 1H), 8.03-7.97 (m, 2H), 7.88 (d. J=8.4 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 6.79-6.74 (m, 2H), 3.88 (s, 2H); CNMR Example 10 (101 MHz, CDC1) & 163.94, 148.07, 139.68, 129.67, 129.34, 128.04, 127.07, 127.04, 127.00, 126.96, 125.05, 35 Preparation of 3-bromo-1-(4-(trifluoromethyl)phe 120.50, 119.35, 114.87; 'F NMR (376 MHz, CDC13) nyl)-1H-1,2,4-triazole (C3) 8 -62.43; ESIMS m/z 305 (M+H"). Example 12

40 Preparation of 6-fluoro-2'-methoxy-N-(4-(1-(4-(trif luoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)- 1,1'-biphenyl-3-carboxamide (F20)

45

3-Bromo-1-(4-isopropoxyphenyl)-1H-1,2,4-triazole (7.15 g, 48.3 mmol), copper(I) iodide (1.25 g. 6.56 mmol), cesium carbonate (18.9 g, 58.0 mmol), and 1-iodo-4-(trifluorom 50 ethyl)benzene (8.29 g, 28.8 mmol) were placed in dimeth ylsulfoxide (50 mL) and degassed with nitrogen for 10 minutes. The solution was heated at 100° C. for 20 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through Celite(R). The 55 resulting filter cake was rinsed with additional ethyl acetate To a mixture of 6-fluoro-2'-methoxy-11'-biphenyl-3- (100 mL). Saturated aqueous ammonium chloride was carboxylic acid (0.086 g., 0.35 mmol) in dichloromethane (3 added to the filtrate which was then stirred for 30 minutes. mL) was added oxalyl chloride (0.070 mL, 0.82 mmol) and The layers were separated and the aqueous layer was dimethylformamide (2 drops). After stirring for 3 hours at extracted with ethyl acetate (2x50 mL). The combined 60 room temperature, the reaction was concentrated to dryness. organic extracts were dried over anhydrous magnesium The resulting yellow oil was dissolved in anhydrous tetra sulfate and concentrated onto Celite(R). Purification by flash hydrofuran (2 mL) and added to a solution of 4-(1-(4- column chromatography using 0-100% ethyl acetate/ (trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)aniline (C4) hexanes as eluent provided the title compound as a white (0.16 mg, 0.54 mmol) dissolved in tetrahydrofuran (3 mL) solid (5.64 g. 64%); mp 87-89° C.; H NMR (400 MHz, 65 and diisopropylethylamine (0.20 mL, 1.15 mmol) and stirred CDC1) & 8.53 (s, 1H), 7.85-7.77 (m, 4H); ESIMS m/z 292 at room temperature for 18 hours. The reaction was diluted (M+H"). with ethyl acetate (10 mL) and washed with saturated US 9,550,739 B2 33 34 aqueous sodium bicarbonate. The aqueous wash was 6-Methoxy-N-(4-(1-(4-(trifluoromethyl)phenyl)-1H extracted with ethyl acetate (2x5 mL) and the combined 1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3-carbox organic layers were dried over anhydrous magnesium Sul amide (F61) fate. The solution was concentrated onto Celite(R) and puri fied by flash column chromatography using 0-100% ethyl acetate/(1:1 hexanes/dichloromethane) as eluent. The rel evant fractions were concentrated to give the title compound f=N O as a white solid (0.071 g, 23%). The following examples were prepared according to the 10 FF S-C OilCH procedures disclosed in Example 12: F 6-Fluoro-2'-methyl-N-(4-(1-(4-(trifluoromethyl)phe nyl)-1H-1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3- carboxamide (F58) 15 Isolated as a white solid (0.162 g, 42%). 6-Fluoro-N-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1, f=N O 2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3-carboxam ide (F62) F S-CN F

25

Isolated as a white solid (0.300 g, 58%). 30 2,6-Difluoro-N-(4-(1-(4-(trifluoromethyl)phenyl)- O 1H-1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3-car boxamide (F59) Isolated as a white solid (0.068 g. 25%). 35 N-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-tri azol-3-yl)phenyl)picolinamide (F68)

F NN N2-C NS 45 F N \ Z O F

Isolated as a white solid (0.149 g, 47%). Isolated as a white solid (0.097 g. 40%).

50 Example 13 2-Methoxy-N-(4-(1-(4-(trifluoromethyl)phenyl)-1H 1,2,4-triazol-3-yl)phenyl)-1,1'-biphenyl-3-carbox Preparation of (E)-4-bromo-N-(dimethylamino) amide (F60) methylene)benzamide (C5)

55 f=N O

-O-O-O. 60 CH Br

4-Bromobenzamide (21.9 g, 109 mmol) in dimethylfor 65 mamide dimethylacetal (40 mL) was refluxed for 5 hours. The Solution was cooled to room temperature and concen Isolated as an off-white solid (0.192 g, 58%). trated. Hexanes was added to the residue and stirred for 30 US 9,550,739 B2 35 36 minutes. The solid was filtered, rinsed with hexanes, and Example 16 dried overnight to provide the title compound as a tan Solid (17.2 g, 59%); mp 103-106° C.; H NMR (400 MHz, Preparation of tert-butyl 4-(1-(4-(trifluoromethoxy) CDC1) & 8.63 (s, 1H), 8.17-8.11 (m, 2H), 7.57-7.52 (m, phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate 2H), 3.21 (dd, J=7.2, 0.5 Hz, 6H); ESIMS m/z 257 (M+ 5 2H). (C8) Example 14 Preparation of 3-(4-bromophenyl)-1H-1,2,4-triazole 10 N H3C CH3 (C6) CH F9 - O O-O--H 15 ?— N To a solution of 3-(4-bromophenyl)-1-(4-(trifluo HN N N2 romethoxy)phenyl)-1H-1,2,4-triazole (C7) (0.13 g, 0.32 Br mmol) in toluene (4 mL) and water (1 mL) was added potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluo (E)-4-Bromo-N-((dimethylamino)methylene)benzamide roborate (0.082 g, 0.33 mmol), palladium(II) acetate (0.027 (C5) (17.2g, 67.3 mmol) in acetic acid (35 mL) was cooled g, 0.027 mmol), cesium carbonate (0.33 g, 1.0 mmol), and in an ice bath. Hydrazine.monohydrate (6.50 mL, 104 dicyclohexyl(2,6'-diisopropoxy-11'-biphenyl-2-yl)phos mmol) was slowly added while stirring vigorously. A white phine (0.016 g., 0.034 mmol), and the solution was stirred solid began to form. The reaction was heated at 90° C. for 25 3 hours. The solution was cooled and poured into cold water under nitrogen and heated to 95°C. for 8 hours. The solution (150 mL). The precipitate was filtered, washed with cold was then cooled and diluted with diethyl ether (5 mL) and water, and dried under vacuum overnight to provide the title adsorbed onto a silica gel pre-column. Flash column chro compound as a white solid (14.5 g., 91%): mp>200° C. 30 matography using 0-50% ethyl acetate/hexanes as eluent (dec.); H NMR (400 MHz, DMSO-d) & 14.24 (s, 1H), 8.52 furnished the title compound as a light tan solid (0.095 g, (s, 1H), 8.04-7.91 (m, 2H), 7.75-7.63 (m, 2H); ESIMS m/z 63%); mp 149-153° C.; H NMR (400 MHz, CDC1,) & 8.56 224 (M'.). (s, 1H), 8.18-8.10 (m, 2H), 7.84-7.77 (m, 2H), 743-7.35 (m, Example 15 35 2H), 7.31 (d. J=8.2 Hz, 2H), 4.58 (d. J–8.1 Hz, 1H), 3.49-3.34 (m, 1H), 2.87 (t, J–7.0 Hz, 1H), 1.44 (s, 9H): Preparation of 3-(4-bromophenyl)-1-(4-(trifluo romethoxy)phenyl)-1H-1,2,4-triazole (C7) ESIMS m/z 449 (IM+H").

40 Example 17

Preparation of 2-(4-(1-(4-(trifluoromethoxy)phenyl)- 1H-1,2,4-triazol-3-yl)phenyl)ethylammonium trif

45 luoroacetate (C9)

3-(4-Bromophenyl)-1H-1,2,4-triazole (C6) (10.9 g, 48.5 mmol), copper(I) iodide (2.38 g, 12.5 mmol), and cesium f= N O F F N as a C F carbonate (30.3 g., 93.0 mmol) in a round-bottomed flask 50 > N NH O F was flushed with nitrogen. Dimethylsulfoxide (85 mL) was F O F added, followed by 1-iodo-4-(trifluoromethoxy)benzene (13.2 g, 45.8 mmol). The reaction was degassed for 5 minutes, then heated at 100° C. for 3 days. The reaction was To tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1.2. cooled to room temperature, diluted with ethyl acetate, and 55 4-triazol-3-yl)phenethylcarbamate (C8) (5.76 g, 12.8 mmol) filtered through a plug of Celite(R) rinsing with ethyl acetate. in dichloromethane (60 mL) was added trifluoroacetic acid To the filtrate was added saturated ammonium chloride and (8 mL, 104 mmol) and stirred at room temperature over stirred for 1.5 hours. The layers were separated and the night. The solution was concentrated to give a yellow oil. aqueous layer was extracted with ethyl acetate (3x). The The yellow oil was partially dissolved in dichloromethane combined organic layers were dried over magnesium Sul 60 and water was added, upon which a precipitate began to fate, filtered, and concentrated onto Celite R. Purification by form. Saturated sodium bicarbonate was added and the flash column chromatography using 0-40%. EtOAc/hexanes precipitate was filtered and rinsed with dichloromethane to as eluent provided the title compound as an off-white solid provide the title compound as a white solid (5.43 g, 87%): (9.65 g, 52%); mp 109-112° C.; H NMR (400 MHz, "H NMR (400 MHz, DMSO-d) & 9.41 (s, 1H), 8.11-8.05 CDC1) & 8.56 (s, 1H), 8.10-8.03 (m, 2H), 7.83-7.75 (m, 65 (m, 4H), 7.98 (s. 2H), 7.66-7.59 (m, 2H), 7.43 (d. J=8.3 Hz, 2H), 7.64-7.57 (m, 2H), 7.42-7.35 (m, 2H); ESIMS m/z 386 2H), 3.12 (s. 2H), 2.99-2.91 (m, 2H); 'F NMR (376 MHz, (M+2H). DMSO-d) & -57.00, -73.64; ESIMS m/z 349 (M+H"). US 9,550,739 B2 37 38 Example 18 Preparation of 2'-methoxy-N-(4-(1-(4-(trifluo romethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phen ethyl)-1,1'-biphenyl-3-carboxamide (F50)

> - ) C-C - C

2-Methoxy-11'-biphenyl-3-carboxylic acid (0.488 g. 6-Fluoro-N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H 2.10 mmol) was dissolved in dichloromethane (10 mL) and 1,2,4-triazol-3-yl)phenethyl)-1,1'-biphenyl-3-car oxalyl chloride (0.250 mL, 2.90 mmol) and dimethylforma 2O boxamide (F51) mide (2 drops) were added. Vigorous bubbling occurred and the mixture was stirred at room temperature for 3 hours. The solution was concentrated to give a yellow oil. Half of this solution was added to a solution of 2-(4-(1-(4-(trifluo romethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethylam monium trifluoroacetate (C9) (0.288 g. 0.620 mmol) in anhydrous tetrahydrofuran (5.2 mL) and diisopropylethyl amine (0.970 mL, 5.60 mmol). The reaction mixture was stirred overnight at room temperature, quenched with Satu A.O's O-O-, rated sodium bicarbonate, and extracted with ethyl acetate (3x). The combined organic layers were dried over magne 30 Isolated as a white solid (0.146 g., 46%). sium sulfate and adsorbed onto Celite R. Purification by flash column chromatography using 0-100% ethyl acetate/1:1 dichloromethane/hexanes as eluent provided the title com pound as a white solid (0.181 g, 49%). 2'-(Dimethylamino)-N-(4-(1-(4-(trifluoromethoxy) The following examples were prepared according to the 35 phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)-1,1'-bi procedures disclosed in Example 18: phenyl-3-carboxamide (F52)

N O F > N N O - C - H O H'

50 Isolated as a white solid (0.237 g., 41%). 6-Fluoro-2'-methyl-N-(4-(1-(4-(trifluoromethoxy) phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)-1,1'-bi 55 phenyl-3-carboxamide (F53)

F. F ?=N O 60 FAQO YN NH O F HC O 65 Isolated as a white solid (0.049 g, 5%). US 9,550,739 B2 39 40 6-Fluoro-2'-methoxy-N-(4-(1-(4-(trifluoromethoxy) combined organics were dried over magnesium sulfate, phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)-1,1'-bi filtered, and concentrated to provide the title compound as a phenyl-3-carboxamide (F54) white solid (14.8 g., 10%): 'H NMR (400 MHz, DMSO-d) & 7.92 (t, J=6.0 Hz, 1H), 7.64-7.53 (m, 2H), 747-7.33 (m, 5H), 7.32-7.20 (m, 2H), 5.10 (s. 2H), 4.23 (d. J–6.2 Hz, 2H): 'C NMR (101 MHz, DMSO-d) & 156.33, 139.20, 137.05, 131.10, 129.22, 128.33, 127.72, 119.77, 65.42, 43.19; ESIMS m/z 320, 322 (IM+H"). Example 19 Preparation of benzyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzylcarbamate (C11) Isolated as a colorless oil (0.012 g, 1%). 15 2,6-Difluoro-N-(4-(1-(4-(trifluoromethoxy)phenyl)- 1H-1,2,4-triazol-3-yl)phenethyl)-1,1'-biphenyl-3- carboxamide (F55) s

HC 9NB H3C O 25 HC CH

In a round-bottomed flask (500 mL), benzyl 4-bromoben Zylcarbamate (C10) (14.1 g, 44.0 mmol), 4.4.4.4.5.5.5',5'- Isolated as a white solid (0.094 g. 26%). 30 octamethyl-2,2'-bi(1,3,2-dioxaborolane) (12.3 g, 48.4 6-Methoxy-N-(4-(1-(4-(trifluoromethoxy)phenyl)- mmol), and potassium acetate (8.64 g. 88.0 mmol) were 1H-1,2,4-triazol-3-yl)phenethyl)-1,1'-biphenyl-3- Suspended in dioxane (200 mL). The Suspension was sparged with nitrogen for 5 minutes after which time 1,1'- carboxamide (F56) bisdiphenylphosphinoferrocenepalladium(II) dichloride 35 (1.61 g, 2.20 mmol) was added. The reaction was pumped and purged with nitrogen (2x). The reaction was then warmed to an internal temperature of 70° C., stirring over night. The reaction was cooled to room temperature, poured into a brine solution, and extracted with ethyl acetate (3x250 40 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated onto Celite(R). Purification via flash column chromatography (2x) using 0-22% ethyl acetate/hexanes as eluent provided the title compound as a Isolated as a white solid (0.172 g, 52%). white solid (13.8 g., 81%): 'H NMR (400 MHz, DMSO-d) 45 & 7.87 (t, J=6.2 Hz, 1H), 7.70-7.60 (m, 2H), 7.46-7.22 (m, Example 19 7H), 5.06 (s. 2H), 4.24 (d. J=6.2 Hz, 2H), 1.29 (s, 12H); 'C NMR (101 MHz, DMSO-d) & 156.35, 143.18, 137.12, Preparation of benzyl 4-bromobenzylcarbamate 134.45, 128.31, 127.69, 126.38, 83.51, 66.32, 65.37, 64.89, (C10) 43.83, 24.62: ESIMS m/z. 368 (IM+H"). 50 Example 20 O Preparation of benzyl 4-(1-(4-(trifluoromethoxy) phenyl)-1H-1,2,4-triazol-3-yl)benzylcarbamate N ls O 55 H (C12)

Br

In a round-bottomed flask (500 mL), (4-bromophenyl) 60 methanaminium chloride (10.0 g, 44.9 mmol) and sodium hydroxide (4.00 g, 100 mmol) were dissolved in tetrahy drofuran (80 mL) and water (80 mL). The solution was cooled in an ice water bath and benzyl chloroformate (7.06 mL, 49.4 mmol) was added dropwise. The reaction was 65 allowed to stir for 1 hour. The reaction was poured into a To a round-bottomed flask (100 mL), 3-bromo-1-(4-(tri brine solution and extracted with ethyl acetate (2x). The fluoromethoxy)phenyl)-1H-1,2,4-triazole (5.19 g, 16.8 US 9,550,739 B2 41 42 mmol), benzyl 4-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2- mmol) in dimethylformamide (30 mL) under nitrogen, Zinc yl)benzylcarbamate (C11) (6.80 g, 18.5 mmol) and potas cyanide (1.46 g, 12.4 mmol), tetrakis(triphenylphosphine) sium phosphate (7.15 g, 33.7 mmol) were dissolved in palladium(0) (0.601 g, 0.0500 mmol) were added and the dioxane (140 mL) and water (35.0 mL). The reaction mix reaction was heated to 110°C. for 16 hours after degassing ture was sparged with nitrogen for 5 minutes after which with argon. The reaction mixture was cooled to room time 1,1'-bis(di-tert-butylphosphino) ferrocenedichloropal temperature and was diluted with ethyl acetate and washed ladium(II) (0.329 g, 0.505 mmol) was added. The flask was with water. The aqueous layer was extracted with ethyl sealed and placed under nitrogen atmosphere. The reaction acetate and the combined organic layers were washed with was then heated to an internal temperature of 75° C. for 9 water and brine. The organic layer was dried over Sodium hours. The reaction was poured into a brine solution and 10 sulfate and concentrated under reduced pressure. Purifica extracted with ethyl acetate (4x100 mL). The combined tion by flash column chromatography provided an off-white organics were dried over magnesium Sulfate, filtered, and solid which was further triturated with hexanes to provide concentrated. The resulting residue was purified by flash the title compound as a white solid (3.40 g, 94%): 'H NMR column chromatography using 10-80% ethyl acetate/ (400 MHz, CDC1) & 8.60 (s, 1H), 8.31 (d. J=6.6 Hz 2H) hexanes to provide the title compound as an off-white solid 15 7.81-7.76 (m, 4H), 7.41 (d. J=8.8 Hz, 2H), ESIMS m/z 331 (9.31 g, 94%): 'H NMR (400 MHz, DMSO-d) & 9.40 (s, (IM+H"). 1H), 8.16-8.01 (m, 4H), 7.91 (t, J=6.2 Hz, 1H), 7.67-7.58 (m. 2H), 7.48-7.15 (m, 7H), 5.07 (s. 2H), 4.28 (d. J=6.2 Hz, Example 23 2H); 'F NMR (37.6 MHz, DMSO-d) & -56.96: ESIMS m/z 469 (IM+H"). Preparation of (4-(1-(4-(trifluoromethoxy)phenyl)- 1H-1,2,4-triazol-3-yl)phenyl)methanamine Method Example 21 B (C13) Preparation of (4-(1-(4-(trifluoromethoxy)phenyl)- 1H-1,2,4-triazol-3-yl)phenyl)methanamine Method 25 A (C13)

30 F. -EN To a solution of 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1, O 2,4-triazol-3-yl)benzonitrile (C14) (3.00 g, 9.09 mmol) in ethanol (30 mL), concentrated hydrochloric acid (3 mL), 35 palladium on carbon (10 weight%, 0.500 g) were added and In a round-bottomed flask (200 mL), benzyl 4-(1-(4- the reaction mixture was evacuated and purged with hydro (trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylcar gen. The reaction mixture was stirred under hydrogen (50 bamate (C12) (0.599 g, 1.28 mmol) was diluted with hydro psi) for 24 hours. The reaction mixture was filtered over gen bromide (8.00 mL, 45.7 mmol). The suspension was Celite R, washed with ethanol and concentrated under stirred for 1 hour at room temperature. To this suspension 40 reduced pressure to obtain a crude solid, which was washed was added diethyl ether (100 mL) and the suspension was with diethyl ether to provide the title compound as an stirred for 30 minutes. The precipitate was collected via off-white solid (2.80 g, 93%); H NMR (300 MHz, DMSO filtration through a glass fritted funnel. The collected solid d) & 9.43 (s, 1H), 8.37 (bs, 3H), 8.18 (d. J=8.1 Hz, 2H), 8.08 was then treated with aqueous sodium hydroxide and (d. J=9.3 Hz, 2H), 7.63 (d. J=8.1 Hz 2H), 4.11-4.07 (m, 2H): extracted with ethyl acetate (3x75 mL). The combined 45 ESIMS m/z 335 (IM+H"). organics were dried over magnesium Sulfate, filtered, and concentrated to provide the title compound (0.395 g, 92%): Example 24 "H NMR (400 MHz, DMSO-d) & 9.45 (s, 1H), 8.25-8.03 (m, 4H), 7.74-7.62 (m, 2H), 7.60-748 (m, 2H), 3.85 (s. 2H): Preparation of N-(4-(1-(4-(trifluoromethoxy)phe F NMR (376 MHz, DMSO-d) & -56.97, ESMIS m/z. 318 nyl)-1H-1,2,4-triazol-3-yl)benzyl)-1,1'-biphenyl-3- (M-NH2+H"). carboxamide (F57) Example 22 Preparation of 4-(1-(4-(trifluoromethoxy)phenyl)- 55 1H-1,2,4-triazol-3-yl)benzonitrile (C14)

SN 60 F F N To a solution of 1,1'-biphenyl-3-carboxylic acid (0.213 2 g, 1.08 mmol) in dimethylformamide (3.5 mL) was added F YQ YN diisopropylethylamine (0.406 g, 3.14 mmol), 1-bis(dimeth O SN ylamino)methylene)-1H-1,2,3-triazolo 4,5-b]pyridinium 65 3-oxid hexafluorophosphate (0.409 g, 1.08 mmol), and (4- To a solution of 3-(4-bromophenyl)-1-(4-(trifluo (1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phe romethoxy)phenyl)-1H-1,2,4-triazole (C7) (4.00 g, 10.4 nyl)methanamine (C13) (0.300 g, 0.890 mmol) at room US 9,550,739 B2 43 44 temperature. The resulting reaction mixture was stirred for Cabbage Looper is a member of the moth family Noctuidae. 16 hours, quenched with hydrochloric acid (2 N), and It is found throughout the world. It is attacks cabbage, extracted with ethyl acetate (2x50 mL). The combined cauliflower, broccoli, Brussel sprouts, tomatoes, cucumbers, organic layer was washed with brine, dried over sodium potatoes, kale, turnips, mustard, peppers, eggplant, water Sulfate, and concentrated under reduced pressure. The crude 5 obtained was purified by flash column chromatography to melons, melons, squash, cantaloupe, peas, beans, collards, provide the title compound as an off-white solid (0.0600 g, lettuce, spinach, celery, parsley, beets, peas, alfalfa, Soy 13%). beans, and cotton. This species is very destructive to plants Using the procedures disclosed herein the following list of due to its Voracious consumption of leaves. In the case of prophetic molecules having a structure according to Formula 10 cabbage, however, they feed not only on the wrapper leaves, One may be made (Table 1). but also may bore into the developing head. The larvae TABLE 1.

Structure and Preparation Method for Prophetic Compounds May be Prepared according to No. Structure Example:

P1 5

CH3

P2

P3

s CH

Example A 55 consume three times their weight in plant material daily. The feeding sites are marked by large accumulations of Sticky, Bioassays on Beet Armyworm (Spodoptera exigua, wet fecal material. LAPHEG) (“BAW) and Cabbage Looper Consequently, because of the above factors control of (Trichoplusia ni, TRIPNI) (“CL”) 60 these pests is important. Furthermore, molecules that control these pests (BAW and CL), which are known as chewing BAW has few effective parasites, diseases, or predators to pests, are useful in controlling other pests that chew on lower its population. BAW infests many weeds, trees, plants. grasses, legumes, and field crops. In various places, it is of Certain molecules disclosed in this document were tested economic concern upon asparagus, cotton, corn, Soybeans, 65 against BAW and CEW using procedures described in the tobacco, alfalfa, Sugar beets, peppers, tomatoes, potatoes, following examples. In the reporting of the results, the onions, peas, Sunflowers, and citrus, among other plants. The “BAW & CL Rating Table” was used (See Table Section). US 9,550,739 B2 45 46 Bioassays on BAW room for three days at approximately 25° C. and ambient Bioassays on BAW were conducted using a 128-well diet relative humidity (RH) prior to grading. Evaluation was tray assay, one to five second instar BAW larvae were placed conducted by counting the number of live aphids per plant in each well (3 mL) of the diet tray that had been previously under a microscope. Percent Control was measured by using filled with 1 mL of artificial diet to which 50 g/cm of the Abbott’s correction formula (W. S. Abbott, “A Method of test compound (dissolved in 50 uL of 90:10 acetone-water Computing the Effectiveness of an Insecticide” J. Econ. mixture) had been applied (to each of eight wells) and then Entomol. 18 (1925), pp. 265-267) as follows. allowed to dry. Trays were covered with a clear self adhesive cover and held at 25°C., 14:10 light-dark for five Corrected 96 Control=100*(X-Y)/X to seven days. Percent mortality was recorded for the larvae 10 in each well; activity in the eight wells was then averaged. where The results are indicated in the table entitled “Table ABC: X=No. of live aphids on solvent check plants and Biological Results” (See Table Section). Y=No. of live aphids on treated plants Bioassays on Cabbage Looper in CL The results are indicated in the table entitled “Table ABC: Bioassays on CL were conducted using a 128-well diet 15 Biological Results” (See Table Section). tray assay, one to five second instar CL larvae were placed in each well (3 mL) of the diet tray that had been previously Example C filled with 1 mL of artificial diet to which 50 g/cm of the test compound (dissolved in 50 uL of 90:10 acetone-water Bioassays on Yellow Fever Mosquito (Aedes mixture) had been applied (to each of eight wells) and then aegypti, AEDSAE) (“YFM”) allowed to dry. Trays were covered with a clear self adhesive cover and held at 25°C., 14:10 light-dark for five YFM prefers to feed on humans during the daytime and to seven days. Percent mortality was recorded for the larvae is most frequently found in or near human habitations. YFM in each well; activity in the eight wells was then averaged. is a vector for transmitting several diseases. It is a mosquito The results are indicated in the table entitled “Table ABC: 25 that can spread the dengue fever and yellow fever viruses. Biological Results” (See Table Section). Yellow fever is the second most dangerous mosquito-borne disease after malaria. Yellow fever is an acute viral hemor Example B rhagic disease and up to 50% of severely affected persons Bioassays on Green Peach Aphid (Myzus persicae, 30 without treatment will die from yellow fever. There are an estimated 200,000 cases of yellow fever, causing 30,000 MYZUPE) (“GPA) deaths, worldwide each year. Dengue fever is a nasty, viral GPA is the most significant aphid pest of peach trees, disease; it is sometimes called “breakbone fever” or “break causing decreased growth, shriveling of the leaves, and the heart fever because of the intense pain it can produce. death of various tissues. It is also hazardous because it acts 35 Dengue fever kills about 20,000 people annually. Conse as a vector for the transport of plant viruses, such as potato quently, because of the above factors control of this pest is virus Y and potato leafroll virus to members of the night important. Furthermore, molecules that control this pest shade/potato family Solanaceae, and various mosaic viruses (YFM), which is known as a Sucking pest, are useful in to many other food crops. GPA attacks such plants as controlling other pests that cause human and animal Suffer broccoli, burdock, cabbage, carrot, cauliflower, daikon, egg 40 1ng. plant, green beans, lettuce, macadamia, papaya, peppers, Certain molecules disclosed in this document were tested Sweet potatoes, tomatoes, watercress, and Zucchini, among against YFM using procedures described in the following other plants. GPA also attacks many ornamental crops such paragraph. In the reporting of the results, the “YFM Rating as carnation, chrysanthemum, flowering white cabbage, Table' was used (See Table Section). poinsettia, and roses. GPA has developed resistance to many 45 Master plates containing 400 g of a molecule dissolved pesticides. Consequently, because of the above factors con in 100 uL of dimethyl sulfoxide (DMSO) (equivalent to a trol of this pest is important. Furthermore, molecules that 4000 ppm solution) are used. A master plate of assembled control this pest (GPA), which is known as a sucking pest, molecules contains 15 u per well. To this plate, 135 uL of are useful in controlling other pests that Suck on plants. a 90:10 water:acetone mixture is added to each well. A robot Certain molecules disclosed in this document were tested 50 (Biomek R. NXP Laboratory Automation Workstation) is against GPA using procedures described in the following programmed to dispense 15 LL aspirations from the master example. In the reporting of the results, the “GPA Rating plate into an empty 96-well shallow plate (“daughter plate). Table' was used (See Table Section). There are 6 reps (“daughter plates) created per master. The Cabbage seedlings grown in 3-inch pots, with 2-3 small created daughter plates are then immediately infested with (3-5 cm) true leaves, were used as test substrate. The 55 YFM larvae. seedlings were infested with 20-50 GPA (wingless adult and The day before plates are to be treated, mosquito eggs are nymph stages) one day prior to chemical application. Four placed in Millipore water containing liver powder to begin pots with individual seedlings were used for each treatment. hatching (4 g. into 400 mL). After the daughter plates are Test compounds (2 mg) were dissolved in 2 mL of acetone/ created using the robot, they are infested with 220 uL of the methanol (1:1) solvent, forming stock solutions of 1000 ppm 60 liver powder/larval mosquito mixture (about 1 day-old lar test compound. The stock solutions were diluted 5x with vae). After plates are infested with mosquito larvae, a 0.025% Tween 20 in water to obtain the solution at 200 ppm non-evaporative lid is used to cover the plate to reduce test compound. A hand-held aspirator-type sprayer was used drying. Plates are held at room temperature for 3 days prior for spraying a solution to both sides of cabbage leaves until to grading. After 3 days, each well is observed and scored runoff. Reference plants (solvent check) were sprayed with 65 based on mortality. the diluent only containing 20% by volume of acetone/ The results are indicated in the table entitled “Table ABC: methanol (1:1) solvent. Treated plants were held in a holding Biological Results” (See Table Section). US 9,550,739 B2 47 48 Agriculturally Acceptable Acid Addition Salts, Salt Deriva Combinations tives, Solvates, Ester Derivatives, Polymorphs, Isotopes, and In another embodiment, molecules of Formula One may Radionuclides be used in combination (such as, in a compositional mixture, Molecules of Formula One may be formulated into agri or a simultaneous or sequential application) with one or culturally acceptable acid addition salts. By way of a non more compounds each having a mode of action that is the same as, similar to, or different from, the mode of action limiting example, an amine function can form salts with (“MoA) of the molecules of Formula One. Modes of action hydrochloric, hydrobromic, Sulfuric, phosphoric, acetic, include, for example the following: Acetylcholinesterase benzoic, citric, malonic, Salicylic, malic, fumaric, oxalic, (AChE) inhibitors; GABA-gated chloride channel antago Succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, nists; Sodium channel modulators; Nicotinic acetylcholine benzenesulfonic, methanesulfonic, ethanesulfonic, 10 (nAChR) agonists; Nicotinic acetylcholine receptor hydroxyl-methanesulfonic, and hydroxyethanesulfonic (nAChR) allosteric activators; Chloride channel activators; acids. Additionally, by way of a non-limiting example, an Juvenile hormone mimics; Miscellaneous non-specific acid function can form salts including those derived from (multi-site) inhibitors; Selective homopteran feeding block alkali or alkaline earth metals and those derived from ers; Mite growth inhibitors; Microbial disruptors of insect 15 midgut membranes; Inhibitors of mitochondrial ATP syn ammonia and amines. Examples of preferred cations include thase; Uncouplers of oxidative phosphorylation via disrup Sodium, potassium, and magnesium. tion of the proton gradient; Nicotinic acetylcholine receptor Molecules of Formula One may be formulated into salt (nAChR) channel blockers; Inhibitors of chitin biosynthesis, derivatives. By way of a non-limiting example, a salt type 0; Inhibitors of chitin biosynthesis, type 1; Moulting derivative can be prepared by contacting a free base with a disruptor, Dipteran; Ecdysone receptor agonists; Octo sufficient amount of the desired acid to produce a salt. A free pamine receptor agonists; Mitochondrial complex III elec base may be regenerated by treating the salt with a suitable tron transport inhibitors; Mitochondrial complex I electron dilute aqueous base solution Such as dilute aqueous sodium transport inhibitors; Voltage-dependent sodium channel hydroxide, potassium carbonate, ammonia, and sodium blockers; Inhibitors of acetyl CoA carboxylase; Mitochon bicarbonate. As an example, in many cases, a pesticide. Such 25 drial complex IV electron transport inhibitors; Mitochon as 2,4-D, is made more water-soluble by converting it to its drial complex II electron transport inhibitors; and Ryanodine dimethylamine salt. receptor modulators. Molecules of Formula One may be formulated into stable In another embodiment, molecules of Formula One may complexes with a solvent, Such that the complex remains be used in combination (such as, in a compositional mixture, intact after the non-complexed solvent is removed. These 30 or a simultaneous or sequential application) with one or complexes are often referred to as “solvates.” However, it is more compounds having acaricidal, algicidal, avicidal, bac particularly desirable to form stable hydrates with water as tericidal, fungicidal, herbicidal, insecticidal, molluscicidal, the solvent. nematicidal, rodenticidal, and/or virucidal properties. Molecules of Formula One may be made into ester In another embodiment, the molecules of Formula One derivatives. These ester derivatives can then be applied in 35 may be used in combination (Such as, in a compositional the same manner as the molecules disclosed in this docu mixture, or a simultaneous or sequential application) with ment is applied. one or more compounds that are antifeedants, bird repel Molecules of Formula One may be made as various lents, chemosterilants, herbicide Safeners, insect attractants, crystal polymorphs. Polymorphism is important in the insect repellents, mammal repellents, mating disrupters, development of agrochemicals since different crystal poly 40 plant activators, plant growth regulators, and/or synergists. morphs or structures of the same molecule can have vastly In another embodiment, the molecules of Formula One different physical properties and biological performances. may be used in combination (Such as, in a compositional Molecules of Formula One may be made with different mixture, or a simultaneous or sequential application) with isotopes. Of particular importance are molecules having H "another compound'. Such as one or more of the following (also known as deuterium) in place of H. 45 compounds—(3-ethoxypropyl)mercury bromide, 1,2-di Molecules of Formula One may be made with different chloropropane, 1,3-dichloropropene, 1-methylcyclopro radionuclides. Of particular importance are molecules hav pene, 1-naphthol, 2-(octylthio)ethanol, 2,3,5-tri-iodoben ing ''C. Zoic acid, 2.3.6-TBA, 2.3.6-TBA-dimethylammonium, 2.3, Stereoisomers 6-TBA-lithium, 2.3.6-TBA-potassium, 2.3.6-TBA-sodium, Molecules of Formula One may exist as one or more 50 2,4,5-T 2,4,5-T-2-butoxypropyl. 2,4,5-T-2-ethylhexyl, 2.4. Stereoisomers. Thus, certain molecules can be produced as 5-T-3-butoxypropyl. 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T- racemic mixtures. It will be appreciated by those skilled in butotyl, 2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2.4. the art that one stereoisomer may be more active than the 5-T-isopropyl. 2,4,5-T-methyl, 2,4,5-T-penty1, 2,4,5-T- other stereoisomers. Individual Stereoisomers may be Sodium, 2.4.5-T-triethylammonium, 2,4,5-T-trolamine, 2,4- obtained by known selective synthetic procedures, by con 55 D, 2,4-D-2-butoxypropyl. 2,4-D-2-ethylhexyl, 2,4-D-3- ventional synthetic procedures using resolved starting mate butoxypropyl. 2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, rials, or by conventional resolution procedures. Certain 2,4-DB-dimethylammonium, 2,4-DB-isoctyl, 2,4-DB-po molecules disclosed in this document can exist as two or tassium, 2,4-DB-sodium, 2,4-D-butotyl, 2,4-D-butyl, 2,4-D- more isomers. The various isomers include geometric iso diethylammonium, 2,4-D-dimethylammonium, 2,4-D-di mers, diastereomers, and enantiomers. Thus, the molecules 60 olamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4- disclosed in this document include geometric isomers, race D-ethyl, 2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D- mic mixtures, individual stereoisomers, and optically active isoctyl, 2,4-D-isopropyl. 2,4-D-isopropylammonium, 2.4- mixtures. It will be appreciated by those skilled in the art that D-lithium, 2,4-D-meptyl, 2,4-D-methyl, 2,4-D-octyl, 2,4-D- one isomer may be more active than the others. The struc pentyl, 2,4-D-potassium, 2,4-D-propyl. 2,4-D-Sodium, 2.4- tures disclosed in the present disclosure are drawn in only 65 D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D- one geometric form for clarity, but are intended to represent triethylammonium, 2,4-D-tris(2-hydroxypropyl) all geometric forms of the molecule. ammonium, 2,4-D-trolamine, 2iP, 2-methoxyethylmercury US 9,550,739 B2 49 50 chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP, 4-amin calcium polysulfide, calvinphos, cambendichlor, cam opyridine, 4-CPA, 4-CPA-diolamine, 4-CPA-potassium, phechlor, camphor, captafol, captan, carbamorph, carbano 4-CPA-sodium, 4-CPB, 4-CPP 4-hydroxyphenethyl alco late, carbaryl, carbasulam, carbendazim, carbendazim ben hol, 8-hydroxyquinoline Sulfate, 8-phenylmercurioxyquino Zenesulfonate, carbendazim sulfite, carbetamide, line, abamectin, abscisic acid, ACC, acephate, acequinocyl. carbofuran, carbon disulfide, carbon tetrachloride, carbo acetamiprid, acethion, acetochlor, acetophos, acetoprole, phenothion, carbosulfan, carboxazole, carboxide, carboxin, acilbenzolar, acilbenzolar-S-methyl, acifluorfen, acifluorfen carfentraZone, carfentraZone-ethyl, carpropamid, cartap, methyl, acifluorfen-sodium, aclonifen, acrep, acrinathrin, cartap hydrochloride, carvacrol, carvone, CDEA, cellocidin, acrolein, acrylonitrile, acy petacs, acy petacs-copper, acy CEPC, ceralure, Cheshunt mixture, chinomethionat, chito petacs-zinc, afidopyropen, afoxolaner, alachlor, alanycarb, 10 san, chlobenthiaZone, chlomethoxyfen, chloralose, chloram albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, ben, chloramben-ammonium, chloramben-diolamine, allethrin, allicin, allidochlor, allosamidin, alloxydim, alloxy chloramben-methyl, chloramben-methylammonium, dim-Sodium, allyl alcohol, allyxycarb, alorac, alpha-cyper chloramben-sodium, chloramine phosphorus, chloram methrin, alpha-endosulfan, ametoctradin, ametridione, phenicol, chloraniformethan, chloranil, chloranocryl, chlo ametryn, amibuzin, amicarbazone, amicarthiazol, amidi 15 rantraniliprole, chlorazifop, chloraZifop-propargyl, chlora thion, amidoflumet, amidosulfuron, aminocarb, aminocyc Zine, chlorbenside, chlorbenzuron, chlorbicyclen, lopyrachlor, aminocyclopyrachlor-methyl, aminocyclopyra chlorbromuron, chlorbufam, chlordane, chlordecone, chlor-potassium, aminopyralid, aminopyralid-potassium, chlordimeform, chlordimeform hydrochloride, chlorempen aminopyralid-tris(2-hydroxypropyl)ammonium, amiprofos thrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenac methyl, amiprophos, amisulbrom, amiton, amiton oxalate, ammonium, chlorfenac-sodium, chlorfenapyr, chlorfena amitraz, amitrole, ammonium sulfamate, ammonium Zole, chlorfenethol, chlorfenprop, chlorfenson, C.-naphthaleneacetate, amobam, ampropylfos, anabasine, chlorfensulphide, chlorfenvinphos, chlorfluaZuron, chlorflu anabasine Sulfate, ancymidol, anilazine, anilofos, anisuron, razole, chlorfluren, chlorfluren-methyl, chlorflurenol, chlo anthraquinone, antu, apholate, aramite, arsenous oxide, aso rflurenol-methyl, chloridazon, chlorimuron, chlorimuron mate, aspirin, asulam, asulam-potassium, asulam-Sodium, 25 ethyl, chlormephos, chlormeduat, chlormeduat chloride, athidathion, atraton, atrazine, aureofungin, aviglycine, chlorinidine, chlornitrofen, chlorobenzilate, chlorodini aviglycine hydrochloride, azaconazole, azadirachtin, azaf tronaphthalenes, chloroform, chloromebuform, chlorome enidin, azamethiphos, azimsulfuron, azinphos-ethyl, azin thiuron, chloroneb, chlorophacinone, chlorophacinone-so phos-methyl, aziprotryne, azithiram, azobenzene, azocyclo dium, chloropicrin, chloropon, chloropropylate, tin, azothoate, azoxystrobin, bachmedesh, barban, barium 30 chlorothalonil, chlorotoluron, chloroxuron, chloroxynil, hexafluorosilicate, barium polysulfide, barthrin, BCPC, chlorphonium, chlorphonium chloride, chlorphoxim, chlo beflubutamid, benalaxyl, benalaxyl-M, benazolin, benazo rprazophos, chlorprocarb, chlorpropham, chlorpyrifos, chlo lin-dimethylammonium, benazolin-ethyl, benazolin-potas rpyrifos-methyl, chlorquinox, chlorSulfuron, chlorthal, chlo sium, bencarbazone, benclothiaz, bendiocarb, benfluralin, rthal-dimethyl, chlorthal-monomethyl, chlorthiamid, benfuracarb, benfuresate, benodanil, benomyl, benoxacor, 35 chlorthiophos, chlozolinate, choline chloride, cholecalcif benoxafos, benquinox, benSulfuron, benSulfuron-methyl, erol, chromafenozide, cinerin I, cinerin II, cinerins, cinidon bensulide, benSultap, bentaluron, bentaZone, bentaZone-so ethyl, cinmethylin, cinosulfuron, ciobutide, cisanilide, cis dium, benthiavalicarb, benthiavalicarb-isopropyl, benthiaz methrin, clacy fos, clethodim, climbazole, cliodinate, ole, bentranil, benzadox, benzadox-ammonium, benzalko clodinafop, clodinafop-propargyl, cloethocarb, clofencet, nium chloride, benzamacril, benzamacril-isobutyl, 40 clofencet-potassium, clofentezine, clofibric acid, clofop, benZamorf, benzfendizone, benzipram, benzobicyclon, ben clofop-isobutyl, clomaZone, clomeprop, cloprop, cloproxy Zofenap, benzofluor, benzohydroxamic acid, benzovindif dim, clopyralid, clopyralid-methyl, clopyralid-olamine, lupyr, benzoximate, benzoylprop, benzoylprop-ethyl, benz clopyralid-potassium, clopyralid-tris(2-hydroxypropyl)am thiaZuron, benzyl benzoate, benzyladenine, berberine, monium, cloquintocet, cloquintocet-mexyl, cloranSulam, berberine chloride, beta-cyfluthrin, beta-cypermethrin, 45 cloranSulam-methyl, closantel, clothianidin, clotrimazole, bethoxazin, bicyclopyrone, bifenazate, bifenox, bifenthrin, cloxyfonac, cloxyfonac-sodium, CMA, codlelure, colopho bifujunzhi, bilanafos, bilanafos-Sodium, binapacryl, bingq nate, copper acetate, copper acetoarsenite, copper arsenate, ingxiao, bioallethrin, bioethanomethrin, biopermethrin, copper carbonate, basic, copper hydroxide, copper naphth bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac, enate, copper oleate, copper oxychloride, copper silicate, bispyribac-sodium, bistrifluron, bitertanol, bithionol, bix 50 copper Sulfate, copper Zinc chromate, coumachlor, couma afen, blasticidin-S, borax, Bordeaux mixture, boric acid, furyl, coumaphos, coumatetralyl, coumithoate, coumox boscalid, brassinolide, brassinolide-ethyl, brevicomin, ystrobin, coumoxystrobin, CPMC, CPMF, CPPC, credazine, brodifacoum, brofenvalerate, brofluthrinate, bromacil, bro cresol, crimidine, crotamiton, crotoxyphos, crufomate, cryo macil-lithium, bromacil-sodium, bromadiolone, brometh lite, cue-lure, cufraneb, cumyluron, cuprobam, cuprous alin, bromethrin, bromfenvinfos, bromoacetamide, bromo 55 oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cya bonil, bromobutide, bromocyclen, bromo-DDT, nofenphos, cyanophos, cyanthoate, cyantraniliprole, cyaZo bromofenoxim, bromophos, bromophos-ethyl, bromopropy famid, cybutryne, cyclafuramid, cyclanilide, cyclaniliprole, late, bromothalonil, bromoxynil, bromoxynil butyrate, bro cyclethrin, cycloate, cycloheximide, cycloprate, cyclopro moxynil heptanoate, bromoxynil octanoate, bromoxynil thrin, cyclopyrimorate, cyclosulfamuron, cycloxaprid, potassium, brompyrazon, bromuconazole, bronopol, 60 cycloxydim, cycluron, cyenopyrafen, cyflufenamid, cyflu bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, metofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalo Burgundy mixture, busulfan, butacarb, butachlor, butafena thrin, cyhexatin, cymiazole, cymiazole hydrochloride, cil, butamifos, butathiofos, butenachlor, butethrin, buthida cymoxanil, cyometrinil, cypendazole, cypermethrin, cyper Zole, buthiobate, buthiuron, butocarboxim, butonate, buto quat, cyperquat chloride, cyphenothrin, cyprazine, cypra pyronoxyl, butoxycarboxim, butralin, butroxydim, buturon, 65 Zole, cyproconazole, cyprodinil, cyprofuram, cypromid, butylamine, butylate, cacodylic acid, cadusafos, cafenstrole, cyprosulfamide, cyromazine, cythioate, daimuron, dalapon, calcium arsenate, calcium chlorate, calcium cyanamide, dalapon-calcium, dalapon-magnesium, dalapon-Sodium, US 9,550,739 B2 51 52 daminozide, dayoutong, dazomet, dazomet-Sodium, DBCP. ethyl formate, ethyl C.-naphthaleneacetate, ethyl-DDD, eth d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, ylene, ethylene dibromide, ethylene dichloride, ethylene decarbofuran, dehydroacetic acid, delachlor, deltamethrin, oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl mercap demephion, demephion-O, demephion-S, demeton, deme tide, ethylmercury acetate, ethylmercury bromide, ethylmer ton-methyl, demeton-O, demeton-O-methyl, demeton-S, cury chloride, ethylmercury phosphate, etinofen, etnipro demeton-S-methyl, demeton-S-methylsulphon, desme mid, etobenzanid, etofenproX, etoxazole, etridiazole, dipham, desmetryn, d-fanshiluquebinguzhi, diafenthiuron, etrimfos, eugenol, EXD, famoxadone, famphur, fenami dialifos, di-allate, diamidafos, diatomaceous earth, diazinon, done, fenaminosulf, fenaminstrobin, fenamiphos, fenapanil, dibutyl phthalate, dibutyl succinate, dicamba, dicamba fenarimol, fenasulam, fenaZaflor, fenaZaquin, fenbucon diglycolamine, dicamba-dimethylammonium, dicamba-di 10 azole, fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, olamine, dicamba-isopropylammonium, dicamba-methyl, fenchlorphos, fenclorim, fenethacarb, fenfluthrin, fenfuram, dicamba-olamine, dicamba-potassium, dicamba-Sodium, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobu dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, carb, fenoprop, fenoprop-3-butoxypropyl, fenoprop-bu dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, tometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoc dichlorflurenol, dichlorflurenol-methyl, dichlormate, dichlo 15 tyl, fenoprop-methyl, fenoprop-potassium, fenothiocarb, rmid, dichlorophen, dichlorprop, dichlorprop-2-ethylhexyl, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, dichlorprop-butotyl, dichlorprop-dimethylammonium, fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, fenoxy dichlorprop-ethylammonium, dichlorprop-isoctyl, dichlo carb, fenpiclonil, fempirithrin, fenpropathrin, fenpropidin, rprop-methyl, dichlorprop-P, dichlorprop-P-2-ethylhexyl, fenpropimorph, fenpyraZamine, fenpyroximate, fenduinotri dichlorprop-P-dimethylammonium, dichlorprop-potassium, one, fenridazon, fenridazon-potassium, fenridazon-propyl. dichlorprop-P-potassium, dichlorprop-P-sodium, dichlo fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop rprop-sodium, dichlorvos, dichloZoline, diclobutraZol. ethyl, fenthion, fenthion-ethyl, fentin, fentin acetate, fentin diclocymet, diclofop, diclofop-methyl, diclomeZine, chloride, fentin hydroxide, fentraZamide, fentrifanil, diclomeZine-sodium, dicloran, dicloSulam, dicofol, dicou fenuron, fenuron TCA, fenvalerate, ferbam, ferimzone, fer marol, dicresyl, dicrotophos, dicyclanil, dicyclonon, diel 25 rous Sulfate, fipronil, flamprop, flamprop-isopropyl, flam drin, dienochlor, diethamquat, diethamquat dichloride, prop-M, flamprop-methyl, flamprop-M-isopropyl, flam diethatyl, diethatyl-ethyl, diethofencarb, dietholate, diethyl prop-M-methyl, flazasulfuron, flocoumafen, flometoquin, pyrocarbonate, diethyltoluamide, difenacoum, difenocon flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop azole, difenopenten, difenopenten-ethyl, difenoXuron, difen butyl, fluazifop-methyl, fluazifop-P, fluazifop-P-butyl, flu Zoquat, difenZoquat metilsulfate, difethialone, diflovidazin, 30 aZinam, fluaZolate, fluaZuron, flubendiamide, flubenZimine, diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr flucarbazone, flucarbazone-sodium, flucetosulfuron, sodium, diflumetorim, dikegulac, dikegulac-sodium, dilor, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludi dimatif dimefluthrin, dimefox, dimefuron, dimepiperate, oxonil, fluenetil, fluensulfone, flufenacet, flufenerim, dimetachlone, dimetan, dimethacarb, dimethachlor, dimeth flufenican, flufenoxuron, flufenoxystrobin, flufenprox. ametryn, dimethenamid, dimethenamid-P, dimethipin, dime 35 flufenpyr, flufenpyr-ethyl, flufiprole, fluhexafon, flumethrin, thirimol, dimethoate, dimethomorph, dimethrin, dimethyl flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, carbate, dimethyl phthalate, dimethylvinphos, dimetilan, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclex fluometuron, fluopicolide, fluopyram, fluorbenside, fluorid ine, dingjuneZuo, diniconazole, diniconazole-M, dinit amid, fluoroacetamide, fluorodifen, fluoroglycofen, fluoro ramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, 40 glycofen-ethyl, fluoroimide, fluoromidine, fluoronitrofen, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dino fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flu Seb acetate, dinoseb-ammonium, dinoseb-diolamine, dino propacil, flupropadine, flupropanate, flupropanate-sodium, seb-sodium, dinoseb-trolamine, dinosulfon, dinotefuran, flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl, dinoterb, dinoterb acetate, dinoterbon, diofenolan, diox flupyrsulfuron-methyl-Sodium, fluquinconazole, fluralaner, abenzofos, dioxacarb, dioxathion, diphacinone, diphaci 45 flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone, none-sodium, diphenamid, diphenyl Sulfone, diphenylam flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxy ine, dipropalin, dipropetryn, dipyrithione, diduat, diduat pyr-meptyl, flurprimidol, flurSulamid, flurtamone, flusila dibromide, disparlure, disul, disulfiram, disulfoton, disul Zole, flusulfamide, fluthiacet, fluthiacet-methyl, flutianil, sodium, ditalimfos, dithianon, dithicrofos, dithioether, dith flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, iopyr, diuron, d-limonene, DMPA, DNOC, DNOC-ammo 50 folpet, fomesafen, fomesafen-Sodium, fonofos, foramsulfu nium, DNOC-potassium, DNOC-sodium, dodemorph, ron, forchlorfenuron, formaldehyde, formetanate, formeta dodemorph acetate, dodemorph benzoate, dodicin, dodicin nate hydrochloride, formothion, formparanate, formparanate hydrochloride, dodicin-sodium, dodine, dofenapyn, domini hydrochloride, fosamine, fosamine-ammonium, fosetyl, fos calure, doramectin, drazoxolon, DSMA, dufulin, EBEP, etyl-aluminium, foSmethilan, fospirate, fosthiazate, fosthi EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, 55 etan, frontalin, fuberidazole, fucaojing, fucaomi, funaihe emamectin, emamectin benzoate, EMPC, empenthrin, endo caoling, fuphenthiourea, furalane, furalaxyl, furamethrin, Sulfan, endothal, endothal-diammonium, endothal-dipotas furametpyr, furathiocarb, furcarbanil, furconazole, furcon sium, endothal-disodium, endothion, endrin, enestroburin, azole-cis, furethrin, furfural, furilazole, furmecyclox, furo enoxastrobin, EPN, epocholeone, epolfenonane, epoxicon phanate, furyloxyfen, gamma-cyhalothrin, gamma-HCH, azole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, 60 genit, gibberellic acid, gibberellins, gliftor, glufosinate, glu erluixiancaoan, esdépallethrine, esfenvalerate, esprocarb. fosinate-ammonium, glufosinate-P. glufosinate-P-ammo etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor, nium, glufosinate-P-Sodium, glyodin, glyoxime, glyphosate, ethal fluralin, ethametsulfuron, ethametsulfuron-methyl, glyphosate-diammonium, glyphosate-dimethylammonium, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethio glyphosate-isopropylammonium, glyphosate-monoammo late, ethion, ethiozin, ethiprole, ethirimol, ethoate-methyl, 65 nium, glyphosate-potassium, glyphosate-sesquisodium, gly ethofumesate, ethohexadiol, ethoprophos, ethoxyfen, phosate-trimesium, glyphosine, gossyplure, grandlure, gris ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychloZate, eofulvin, guazatline, guaZatine acetates, halacrinate, US 9,550,739 B2 53 54 halauXifen, halauXifen-methyl, halfenproX, halofenozide, one, mesulfen, mesulfenfos, metaflumizone, metalaxyl, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, metalaxyl-M, metaldehyde, metam, metam-ammonium, haloxyflop, haloxyfop-etotyl, haloxyfop-methyl, haloxyfop metamifop, metamitron, metam-potassium, metam-Sodium, P. haloxyfop-P-etotyl, haloxyfop-P-methyl, haloxyfop-so metaZachlor, metazosulfuron, metaZOXolon, metconazole, dium, HCH, hemel, hempa, HEOD, heptachlor, heptaflu metepa, metflurazon, methabenzthiaZuron, methacrifos, thrin, heptenophos, heptopargil, herbimycin, heterophos, methalpropalin, methamidophos, methasulfocarb, meth hexachloroacetone, hexachlorobenzene, hexachlorobutadi azole, methfuroxam, methidathion, methiobencarb, methio ene, hexachlorophene, hexaconazole, hexaflumuron, carb, methiopyrisulfuron, methiotepa, methioZolin, methi hexaflurate, hexalure, hexamide, hexaZinone, hexylthiofos, uron, methocrotophos, methometon, methomyl, hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, 10 methoprene, methoprotryne, methoduin-butyl, methothrin, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, methoxychlor, methoxyfenozide, methoxyphenone, methyl hydrogen cyanide, hydroprene, hymexaZol, hyduincarb, apholate, methyl bromide, methyl eugenol, methyl iodide, IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalil Sul methyl isothiocyanate, methylacetophos, methylchloroform, fate, imazamethabenz, imazamethabenZ-methyl, imaZamox, methyldymron, methylene chloride, methylmercury benzo imaZamoX-ammonium, imaZapic, imazapic-ammonium, 15 ate, methylmercury dicyandiamide, methylmercury pen imazapyr, imazapyr-isopropylammonium, imaZaquin, tachlorophenoxide, methylneodecanamide, metiram, meto imaZaquin-ammonium, imazaquin-methyl, imaZaquin-So benZuron, metobromuron, metofluthrin, metolachlor, dium, imazethapyr, imazethapyr-ammonium, imaZosulfu metolcarb, metominostrobin, metoSulam, metoxadiaZone, ron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, metoxuron, metrafenone, metribuzin, metSulfovax, metSul iminoctadine, iminoctadine triacetate, iminoctadine trialbe furon, metSulfuron-methyl, mevinphos, mexacarbate, mie silate, imiprothrin, inabenfide, indanofan, indaziflam, indoX shuan, milbemectin, milbemycin oxime, milineb, mipafox, acarb, inezin, iodobonil, iodocarb, iodomethane, iodosulfu mirex, MNAF, moguchun, molinate, moloSultap, momfluo ron, iodosulfuron-methyl, iodosulfuron-methyl-Sodium, rothrin, monalide, monisouron, monochloroacetic acid, iofensulfuron, iofensulfuron-sodium, ioxynil, ioxynil monocrotophos, monolinuron, monosulfuron, monosulfu octanoate, ioxynil-lithium, ioxynil-Sodium, ipazine, ipcon 25 ron-ester, monuron, monuron TCA, morfamquat, morfam azole, ipfencarbazone, iprobenfos, iprodione, iprovalicarb, quat dichloride, moroxydine, moroxydine hydrochloride, iprymidam, ipsdienol, ipsenol, IPSP, isamidofos, isazofos, morphothion, morzid, moxidectin, MSMA, muscalure, isobenzan, isocarbamid, isocarbophos, isocil, isodrin, myclobutanil, mycloZolin, N-(ethylmercury)-p-toluenesul isofenphos, isofenphos-methyl, isofetamid, isolan, isome phonanilide, nabam, naftalofos, naled, naphthalene, naph thiozin, isonoruron, isopolinate, isoprocarb, isopropalin, iso 30 thaleneacetamide, naphthalic anhydride, naphthoxyacetic prothiolane, isoproturon, isopyrazam, isopyrimol, isothio acids, naproanilide, napropamide, napropamide-M, napta ate, isotianil, isouron, isovaledione, isoxaben, lam, naptalam-Sodium, natamycin, neburon, niclosamide, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole, niclosamide-olamine, nicosulfuron, nicotine, nifluridide, isoxapyrifop, isoxathion, ivermectin, iZopamfos, japonilure, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin, japothrins, jasmolin I, jasmolin II, jasmonic acid, jia 35 nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal huangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jie isopropyl, norbormide, norflurazon, nornicotine, noruron, caowan, jiecaoxi, jodfenphos, juvenile hormone I, juvenile novaluron, noviflumuron, nuarimol, OCH, Octachlorodipro hormone II, juvenile hormone III, kadethrin, karbutilate, pyl ether, octhillinone, ofurace, omethoate, orbencarb, karetazan, karetaZan-potassium, kasugamycin, kasugamycin orfralure, ortho-dichlorobenzene, orthosulfamuron, orycta hydrochloride, kejunlin, kelevan, ketospiradox, ketospira 40 lure, orysastrobin, oryzalin, osthol, ostramone, Oxabetrinil, dox-potassium, kinetin, kinoprene, kresoxim-methyl, kui oxadiargyl, oxadiazon, oxadixyl, OXamate, oxamyl, oxapy caoxi, lactofen, lambda-cyhalothrin, latilure, lead arsenate, razon, oxapyrazon-dimolamine, oxapyrazon-sodium, oxas lenacil, lepimectin, leptophos, lindane, lineatin, linuron, ulfuron, oxathiapiprolin, oxaziclomefone, oxine-copper, lirimfos, litlure, loopilure, lufenuron, Ivdingjunzhi, IVXian oXolinic acid, Oxpoconazole, Oxpoconazole fumarate, oxy caolin, lythidathion, MAA, malathion, maleic hydrazide, 45 carboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, malonoben, maltodextrin, MAMA, mancopper, mancoZeb, oxyfluorfen, oxymatrine, oxytetracycline, Oxytetracycline mandipropamid, mandestrobin, maneb, matrine, mazidox, hydrochloride, paclobutraZol, paichongding, para-dichlo MCPA, MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, robenzene, parafluron, paraquat, paraquat dichloride, para MCPA-dimethylammonium, MCPA-diolamine, MCPA quat dimetilsulfate, parathion, parathion-methyl, parinol, ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl, 50 pebulate, pefurazoate, pelargonic acid, penconazole, pency MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA curon, pendimethalin, penflufen, penfluron, penoXSulam, sodium, MCPA-thioethyl, MCPA-trolamine, MCPB, pentachlorophenol, pentachlorophenyl laurate, pentano MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil, chlor, penthiopyriad, pentmethrin, pentoxazone, perfluidone, mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop permethrin, pethoxamid, phenamacril, phenazine oxide, 2-ethylhexyl, mecoprop-dimethylammonium, mecoprop-di 55 phenisopham, phenkapton, phenmedipham, phenmed olamine, mecoprop-ethadyl, mecoprop-isoctyl, mecoprop ipham-ethyl, phenobenzuron, phenothrin, phenproxide, methyl, mecoprop-P, mecoprop-P-2-ethylhexyl, mecoprop phenthoate, phenylmercuriurea, phenylmercury acetate, P-dimethylammonium, mecoprop-P-isobutyl, mecoprop phenylmercury chloride, phenylmercury derivative of pyro potassium, mecoprop-P-potassium, mecoprop-sodium, catechol, phenylmercury nitrate, phenylmercury Salicylate, mecoprop-trolamine, medimeform, medinoterb, medinoterb 60 phorate, phosacetim, phosalone, phosdiphen, phosfolan, acetate, medlure, mefenacet, mefenpyr, mefenpyr-diethyl, phosfolan-methyl, phosglycin, phosmet, phosnichlor, phos mefluidide, mefluidide-diolamine, mefluidide-potassium, phamidon, phosphine, phosphocarb, phosphorus, phostin, megatomoic acid, menazon, mepanipyrim, meperfluthrin, phoxim, phoxim-methyl, phthalide, picarbutraZOX, piclo mephenate, mephosfolan, mepiquat, mepiduat chloride, ram, picloram-2-ethylhexyl, picloram-isoctyl, picloram mepiduat pentaborate, mepronil, meptylidinocap, mercuric 65 methyl, picloram-olamine, picloram-potassium, picloram chloride, mercuric oxide, mercurous chloride, merphos, triethylammonium, picloram-tris(2-hydroxypropyl) mesoprazine, mesosulfuron, mesosulfuron-methyl, mesotri ammonium, picolinafen, picoxystrobin, pindone, pindone US 9,550,739 B2 55 56 Sodium, pinoxaden, piperalin, piperonylbutoxide, piperonyl catol, Sulcofuron, Sulcofuron-sodium, Sulcotrione, Sulfallate, cyclonene, piperophos, piproctanyl, piproctanyl bromide, SulfentraZone, Sulfiram, Sulfluramid, Sulfometuron, Sulfo piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimi meturon-methyl, sulfosulfuron, sulfotep, sulfoxaflor, sulfox phos-ethyl, pirimiphos-methyl, plifenate, polycarbamate, ide, sulfoxime, sulfur, sulfuric acid, sulfuryl fluoride, sul polyoxins, polyoxorim, polyoxorim-zinc, polythialan, glycapin, Sulprofos, Sultropen, Swep, tau-fluvalinate, tavron, potassium arsenite, potassium azide, potassium cyanate, tazimcarb, TCA, TCA-ammonium, TCA-calcium, TCA potassium gibberellate, potassium naphthenate, potassium ethadyl, TCA-magnesium, TCA-sodium, TDE, tebucon polysulfide, potassium thiocyanate, potassium C.-naphthale azole, tebufenozide, tebufenpyrad, tebufloquin, tebupirim fos, tebutam, tebuthiuron, tecloftalam, tecnaZene, tecoram, neacetate, pp'-DDT, prallethrin, precocene I, precocene II, 10 precocene III, pretilachlor, primidophos, primisulfuron, pri teflubenzuron, tefluthrin, tefuryltrione, tembotrione, teme misulfuron-methyl, probenazole, prochloraz, prochloraZ phos, tepa, TEPP, tepraloxydim, terallethrin, terbacil, terbu manganese, proclonol, procyazine, procymidone, prodi carb, terbuchlor, terbufos, terbumeton, terbuthylazine, ter amine, profenofos, profluaZol, profluralin, profluthrin, butryn, tetcyclacis, tetrachloroethane, tetrachlorvinphos, 15 tetraconazole, tetradifon, tetrafluron, tetramethrin, tetram profoxydim, proglinazine, proglinazine-ethyl, prohexadi ethylfluthrin, tetramine, tetranactin, tetraniliprole, tetrasul, one, prohexadione-calcium, prohydrojasmon, promacyl, thallium sulfate, thenylchlor, theta-cypermethrin, thiabenda promecarb, prometon, prometryn, promurit, propachlor, pro Zole, thiacloprid, thiadifluor, thiamethoxam, thiapronil, thi pamidine, propamidine dihydrochloride, propamocarb, pro aZafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, thidi pamocarb hydrochloride, propanil, propaphos, propaquiza aZurOn, thiencarbazone, thiencarbazone-methyl, fop, propargite, proparthrin, propazine, propetamphos, thifensulfuron, thifensulfuron-methyl, thifluzamide, thio propham, propiconazole, propineb, propisochlor, propoXur, bencarb, thiocarboxime, thiochlorfenphim, thiocyclam, propoxycarbazone, propoxycarbazone-sodium, propyl thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole isome, propyrisulfuron, propyZamide, produinazid, proSuler, copper, thiodicarb, thiofanox, thiofluoximate, thiohempa, prosulfalin, prosulfocarb, prosulfuron, prothidathion, proth 25 thiomersal, thiometon, thionazin, thiophanate, thiophanate iocarb, prothiocarb hydrochloride, prothioconazole, proth methyl, thioquinox, thiosemicarbazide, thiosultap, thiosul iofos, prothoate, protrifenbute, proxan, proxan-Sodium, tap-diammonium, thiosultap-disodium, thiosultap-monoso prynachlor, pydanon, pyflubumide, pymetrozine, pyracarbo dium, thiotepa, thiram, thuringiensin, tiadinil, tiafenacil, lid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyra tiaojiean, tiocarbazil, tioclorim, tioxazafen, tioxymid, tir flufen-ethyl, pyrafluprole, pyramat, pyrametostrobin, pyra 30 pate, tolclofoS-methyl, tolfenpyrad, tolprocarb, tolpyralate, oxystrobin, pyrasulfotole, pyrazolynate, pyrazophos, tolylfluanid, tolylmercury acetate, toprameZone, tralkoxy pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothion, pyra dim, tralocythrin, tralomethrin, tralopyril, transfluthrin, ZOxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, transpermethrin, tretamine, triacontanol, triadimefon, triadi pyribambenz-isopropyl, pyribambenZ-propyl, pyribencarb, 35 menol, triafamone, tri-allate, triamiphos, triapenthenol, tri pyribenZoxim, pyributicarb, pyriclor, pyridaben, pyridafol. arathene, triarimol, triasulfuron, triazamate, triaZbutil, tri pyridalyl pyridaphenthion, pyridate, pyridinitril, pyrifenox, aziflam, triazophos, triazoxide, tribenuron, tribenuron pyrifluquinazon, pyriftalid, pyrimethanil, pyrimidifen, methyl, tribufos, tributyltin oxide, tricamba, trichlamide, pyriminobac, pyriminobac-methyl, pyriminostrobin, pyrim trichlorfon, trichlorimetaphos-3, trichloronat, triclopyr, tric 40 lopyr-butotyl, triclopyr-ethyl, triclopyricarb, triclopyr-trieth isulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole, ylammonium, tricyclazole, tridemorph, tridiphane, tri pyripropanol, pyriproxyfen, pyrisoxazole, pyrithiobac, pyri etazine, trifenmorph, trifenofos, trifloxystrobin, thiobac-Sodium, pyrolan, pyroquilon, pyroxasulfone, pyrox trifloxysulfuron, trifloxysulfuron-sodium, trifludimoxazin, Sulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinac triflumeZopyrim, triflumizole, triflumuron, trifluralin, triflu etol Sulfate, quinallphos, quinallphos-methyl, quinaZamid, 45 sulfuron, triflusulfuron-methyl, trifop, trifop-methyl, trifop quinclorac, quinconazole, quinmerac, quinoclamine, qui sime, triforine, trihydroxytriazine, trimedlure, trimethacarb, nonamid, quinothion, quinoxyfen, quintiofos, quintoZene, trimeturon, trinexapac, trinexapac-ethyl, triprene, tripropin quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P- dan, triptolide, tritac, triticonazole, tritosulfuron, trunc-call, ethyl, quizalofop-P-tefuryl, quwenzhi, quyingding, rabenza uniconazole, uniconazole-P. urbacide, uredepa, Valerate, Zole, rafoxanide, rebemide, rescalure, resmethrin, rhodetha 50 validamycin, Valifenalate, valone, vamidothion, Vangard, nil, rhodojaponin-III, ribavirin, rimsulfuron, rotenone, Vaniliprole, Vernolate, VincloZolin, warfarin, warfarin-potas ryania, saflufenacil, Saijunmao, Saisentong, salicylanilide, sium, warfarin-Sodium, Xiaochongliulin, Xinjunan, Xiwoju sanguinarine, Santonin, Schradan, Scilliroside, Sebuthylazine, nan, XMC, Xylachlor, Xylenols, Xylylcarb, yishijing, Zaril amid, Zeatin, Zengxiaoan, Zeta-cypermethrin, Zinc secbumeton, sedaxane, Selamectin, semiamitraz, semiam 55 naphthenate, Zinc phosphide, Zinc thiazole, Zineb, Ziram, itraz, chloride, Sesamex, Sesamolin, Sethoxydim, Shuangji Zolaprofos, Zoxamide, Zuomihuanglong, C-chlorohydrin, aancaolin, Siduron, siglure, Silafluofen, silatrane, silica gel. C-ecdysone, C.-multistriatin, and C-naphthaleneacetic acid. silthiofam, simazine, Simeconazole, simeton, simetryn, For more information consult the “COMPENDIUM OF PESTICIDE sintofen, SMA, S-metolachlor, sodium arsenite, sodium 60 COMMON NAMEs' located at alanwood.net. Also consult “THE azide, Sodium chlorate, Sodium fluoride, sodium fluoroac PESTICIDE MANUAL 15th Edition, edited by CD S Tomlin, etate, sodium hexafluorosilicate, Sodium naphthenate, copyright 2009 by British Crop Production Council, or its Sodium orthophenylphenoxide, sodium pentachlorophenox prior, or more recent editions. ide, sodium polysulfide, Sodium thiocyanate, sodium In another embodiment, molecules of Formula One may C.-naphthaleneacetate, sophamide, spinetoram, spinosad, 65 also be used in combination (Such as in a compositional spirodiclofen, spiromesifen, Spirotetramat, spiroxamine, mixture, or a simultaneous or sequential application) with streptomycin, Streptomycin sesquisulfate, Strychnine, Sul the following compound. US 9,550,739 B2 57 58 more molecules of Formula One and one or more other F F compounds from the above possible combinations.

TABLE A

C S Range of the Weight Ratio of No a molecule of the Formula One to another compound N e y / 1 100:1 to 1:100 N 2 SO:1 to 1:SO N 3 20:1 to 1:20 N ) 10 4 10:1 to 1:10 5 5:1 to 1:5 2 HC 6 3:1 to 1:3 N 7 2:1 to 1:2 8 1:1 In another embodiment, molecules of Formula One may 15 also be used in combination (such as in a compositional Weight ratios of a molecule of the Formula One or any mixture, or a simultaneous or sequential application) with agriculturally acceptable Salt thereof to another compound one or more biopesticides. The term “biopesticide" is used envisioned to be Synergistic pesticidal compositions may be for microbial biological pest control agents that are applied depicted as X:Y; wherein X is the parts by weight of a in a similar manner to chemical pesticides. Commonly these 2 molecule of the Formula One or any agriculturally accept are bacterial, but there are also examples of fungal control able salt thereof, and Y is the parts by weight of another agents, including Trichoderma spp. and Ampelomyces compound. The numerical range of the parts by weight for quisqualis (a control agent for grape powdery mildew). X is 0Lepidoptera, Coleoptera, and Diptera. Because it has little effect on other organisms, it is TABLE B considered more environmentally friendly than synthetic 30 Another 100 x,y X, Y pesticides. Biological insecticides include products based Com- 50 X, Y X, Y X, Y on: entomopathogenic fungi (e.g. Metarhizium anisopliae): pound 20 X, Y X, Y entomopathogenic nematodes (e.g. Steinernema feltiae); and F. by t X, Y X, Y X, Y X, Y entomopathogenic viruses (e.g. Cydia pomonella granulo- weight 3 x, y X, Y X, Y XY X, Y X, Y virus). 35 2 X, Y X, Y X, Y X, Y Other examples of entomopathogenic organisms include, 1 X, Y X, Y X, Y X, Y X, Y X, Y X, Y X, Y but are not limited to, baculoviruses, bacteria and other i 2 3 10 15 2O 50 1OO prokaryotic organisms, fungi, protozoa and Microsproridia. Molecule of the Formula One (X) Parts by weight Biologically derived insecticides include, but not limited to, rotenone, veratridine, as well as microbial toxins; insect 40 Ranges of Weight ratios of a molecule of the Formula One tolerant or resistant plant varieties; and organisms modified or any agriculturally acceptable salt thereof to another by recombinant DNA technology to either produce insecti- compound envisioned to be synergistic pesticidal composi cides or to convey an insect resistant property to the geneti- tions may be depicted as X:Y to X;Y, wherein X and Y cally modified organism. In one embodiment, the molecules are defined as above. In one particular embodiment, the of Formula One may be used with one or more biopesticides 45 range of weight ratios may be X:Y to X;Y, wherein in the area of seed treatments and soil amendments. The X>Y and X-Y. By way of non-limiting example, the Manual of Biocontrol Agents gives a review of the available range of weight ratios of a molecule of the Formula One or biological insecticide (and other biology-based control) any agriculturally acceptable salt thereof to another com products. Copping L. G. (ed.) (2004). The Manual of Bio- pound may be between about 3:1 and about 1:3. In some control Agents (formerly the Biopesticide Manual) 3rd Edi- 50 embodiments, the range of weight ratios may be X:Y to tion. British Crop Production Council (BCPC), Farnham, X;Y, wherein X >Y and X->Y. By way of non-limiting Surrey UK. example, the range of a molecule of the Formula One or any In another embodiment, the above possible combinations agriculturally acceptable salt thereof to another compound may be used in a wide variety of weight ratios. For example, may be between about 15:1 and about 3:1. In further a two component mixture, the weight ratio of a molecule of 55 embodiments, the range of weight ratios may be X:Y to Formula One to another compound, can be from about 100:1 X;Y, wherein X-Y and X-Y. By way of non-limiting to about 1:100; in another example the weight ratio can be example, the range of weight ratios of a molecule of the about 50:1 to about 1:50; in another example the weight ratio Formula One or any agriculturally acceptable salt thereof to can be about 20:1 to about 1 to 20; in another example the another compound may be between about 1:3 and about weight ratio can be about 10:1 to about 1:10; in another 60 1:20. example the weight ratio can be about 5:1 to 1:5; in another Formulations example the weight ratio can be about 3:1 to about 1:3; in A pesticide is rarely Suitable for application in its pure another example the weight ratio can be about 2:1 to about form. It is usually necessary to add other Substances so that 1:2; and in a final example the weight ratio can be about 1:1. the pesticide can be used at the required concentration and However, preferably, weight ratios less than about 10:1 to 65 in an appropriate form, permitting ease of application, about 1:10 are preferred. It is also preferred sometimes to handling, transportation, storage, and maximum pesticide use a three or four component mixture comprising one or activity. Thus, pesticides are formulated into, for example, US 9,550,739 B2 59 60 baits, concentrated emulsions, dusts, emulsifiable concen agricultural carrier. Such as kaolin clay, ground Volcanic trates, fumigants, gels, granules, microencapsulations, seed rock, and the like. Dusts can suitably contain from about 1% treatments, Suspension concentrates, Suspoemulsions, tab to about 10% of the pesticide. They can be applied as a seed lets, water Soluble liquids, water dispersible granules or dry dressing or as a foliage application with a dust blower flowables, wettable powders, and ultra-low volume solu machine. tions. For further information on formulation types see It is equally practical to apply a pesticide in the form of “Catalogue of Pesticide Formulation Types and International a solution in an appropriate organic solvent, usually petro Coding System’ Technical Monograph n° 2, 5th Edition by leum oil. Such as the spray oils, which are widely used in CropLife International (2002). agricultural chemistry. Pesticides are applied most often as aqueous Suspensions 10 Pesticides can also be applied in the form of an aerosol or emulsions prepared from concentrated formulations of composition. In such compositions the pesticide is dissolved Such pesticides. Such water-soluble, water-Suspendable, or or dispersed in a carrier, which is a pressure-generating emulsifiable formulations are either Solids, usually known as propellant mixture. The aerosol composition is packaged in wettable powders, or water dispersible granules, or liquids a container from which the mixture is dispensed through an usually known as emulsifiable concentrates, or aqueous 15 atomizing valve. Suspensions. Wettable powders, which may be compacted to Pesticide baits are formed when the pesticide is mixed form water dispersible granules, comprise an intimate mix with food or an attractant or both. When the pests eat the bait ture of the pesticide, a carrier, and Surfactants. The concen they also consume the pesticide. Baits may take the form of tration of the pesticide is usually from about 10% to about granules, gels, flowable powders, liquids, or Solids. They can 90% by weight. The carrier is usually selected from among be used in pest harborages. the attapulgite clays, the montmorillonite clays, the diato Fumigants are pesticides that have a relatively high vapor maceous earths, or the purified silicates. Effective surfac pressure and hence can exist as a gas in Sufficient concen tants, comprising from about 0.5% to about 10% of the trations to kill pests in soil or enclosed spaces. The toxicity wettable powder, are found among Sulfonated lignins, con of the fumigant is proportional to its concentration and the densed naphthalenesulfonates, naphthalenesulfonates, alky 25 exposure time. They are characterized by a good capacity for Ibenzenesulfonates, alkyl sulfates, and non-ionic Surfactants diffusion and act by penetrating the pest's respiratory system Such as ethylene oxide adducts of alkyl phenols. or being absorbed through the pest’s cuticle. Fumigants are Emulsifiable concentrates of pesticides comprise a con applied to control stored product pests under gas proof venient concentration of a pesticide, such as from about 50 sheets, in gas sealed rooms or buildings or in special to about 500 grams per liter of liquid dissolved in a carrier 30 chambers. that is either a water miscible solvent or a mixture of Pesticides can be microencapsulated by Suspending the water-immiscible organic solvent and emulsifiers. Useful pesticide particles or droplets in plastic polymers of various organic solvents include aromatics, especially Xylenes and types. By altering the chemistry of the polymer or by petroleum fractions, especially the high-boiling naphtha changing factors in the processing, microcapsules can be lenic and olefinic portions of petroleum Such as heavy 35 formed of various sizes, solubility, wall thicknesses, and aromatic naphtha. Other organic Solvents may also be used, degrees of penetrability. These factors govern the speed with Such as the terpenic solvents including rosin derivatives, which the active ingredient within is released, which in turn, aliphatic ketones Such as cyclohexanone, and complex alco affects the residual performance, speed of action, and odor hols such as 2-ethoxyethanol. Suitable emulsifiers for emul of the product. sifiable concentrates are selected from conventional anionic 40 Oil Solution concentrates are made by dissolving pesticide and non-ionic Surfactants. in a solvent that will hold the pesticide in solution. Oil Aqueous Suspensions comprise Suspensions of water Solutions of a pesticide usually provide faster knockdown insoluble pesticides dispersed in an aqueous carrier at a and kill of pests than other formulations due to the solvents concentration in the range from about 5% to about 50% by themselves having pesticidal action and the dissolution of weight. Suspensions are prepared by finely grinding the 45 the waxy covering of the integument increasing the speed of pesticide and vigorously mixing it into a carrier comprised uptake of the pesticide. Other advantages of oil solutions of water and Surfactants. Ingredients, such as inorganic salts include better storage stability, better penetration of crev and synthetic or natural gums may also be added, to increase ices, and better adhesion to greasy Surfaces. the density and Viscosity of the aqueous carrier. It is often Another embodiment is an oil-in-water emulsion, wherein most effective to grind and mix the pesticide at the same 50 the emulsion comprises oily globules which are each pro time by preparing the aqueous mixture and homogenizing it vided with a lamellar liquid crystal coating and are dispersed in an implement such as a sand mill, ball mill, or piston-type in an aqueous phase, wherein each oily globule comprises at homogenizer. least one compound which is agriculturally active, and is Pesticides may also be applied as granular compositions individually coated with a monolamellar or oligolamellar that are particularly useful for applications to the soil. 55 layer comprising: (1) at least one non-ionic lipophilic Sur Granular compositions usually contain from about 0.5% to face-active agent, (2) at least one non-ionic hydrophilic about 10% by weight of the pesticide, dispersed in a carrier Surface-active agent and (3) at least one ionic Surface-active that comprises clay or a similar Substance. Such composi agent, wherein the globules having a mean particle diameter tions are usually prepared by dissolving the pesticide in a of less than 800 nanometers. Further information on the Suitable solvent and applying it to a granular carrier which 60 embodiment is disclosed in U.S. patent publication has been pre-formed to the appropriate particle size, in the 20070027034 published Feb. 1, 2007, having patent appli range of from about 0.5 to about 3 mm. Such compositions cation Ser. No. 1 1/495,228. For ease of use, this embodiment may also be formulated by making a dough or paste of the will be referred to as “OIWE. carrier and compound and crushing and drying to obtain the For further information consult “Insect Pest Manage desired granular particle size. 65 ment 2nd Edition by D. Dent, copyright CAB International Dusts containing a pesticide are prepared by intimately (2000). Additionally, for more detailed information consult mixing the pesticide in powdered form with a suitable dusty “Handbook of Pest Control The Behavior, Life History, US 9,550,739 B2 61 62 and Control of Household Pests” by Arnold Mallis, 9th the oil-soluble calcium salt of dodecylbenzenesulfonic acid. Edition, copyright 2004 by GIE Media Inc. A range of hydrophile-lipophile balance (“HLB) values Other Formulation Components from 8 to 18 will normally provide good stable emulsions. Generally, when the molecules disclosed in Formula One Emulsion stability can sometimes be improved by the addi are used in a formulation, such formulation can also contain 5 tion of a small amount of an EO-PO block copolymer other components. These components include, but are not Surfactant. limited to, (this is a non-exhaustive and non-mutually exclu A solubilizing agent is a Surfactant which will form sive list) wetters, spreaders, Stickers, penetrants, buffers, micelles in water at concentrations above the critical micelle sequestering agents, drift reduction agents, compatibility concentration. The micelles are then able to dissolve or agents, anti-foam agents, cleaning agents, and emulsifiers. A 10 solubilize water-insoluble materials inside the hydrophobic few components are described forthwith. part of the micelle. The types of surfactants usually used for A wetting agent is a Substance that when added to a liquid solubilization are non-ionics, Sorbitan monooleates, Sorbitan increases the spreading or penetration power of the liquid by monooleate ethoxylates, and methyl oleate esters. reducing the interfacial tension between the liquid and the Surfactants are sometimes used, either alone or with other Surface on which it is spreading. Wetting agents are used for 15 additives such as mineral or vegetable oils as adjuvants to two main functions in agrochemical formulations: during spray-tank mixes to improve the biological performance of processing and manufacture to increase the rate of wetting of the pesticide on the target. The types of Surfactants used for powders in water to make concentrates for soluble liquids or bioenhancement depend generally on the nature and mode of Suspension concentrates; and during mixing of a product action of the pesticide. However, they are often non-ionics with water in a spray tank to reduce the wetting time of Such as: alkyl ethoxylates; linear aliphatic alcohol ethoxy wettable powders and to improve the penetration of water lates; aliphatic amine ethoxylates. into water-dispersible granules. Examples of wetting agents A carrier or diluent in an agricultural formulation is a used in wettable powder, Suspension concentrate, and water material added to the pesticide to give a product of the dispersible granule formulations are: Sodium lauryl Sulfate; required strength. Carriers are usually materials with high Sodium dioctyl sulfoSuccinate; alkyl phenol ethoxylates; and 25 absorptive capacities, while diluents are usually materials aliphatic alcohol ethoxylates. with low absorptive capacities. Carriers and diluents are A dispersing agent is a Substance which adsorbs onto the used in the formulation of dusts, wettable powders, granules surface of particles and helps to preserve the state of and water-dispersible granules. dispersion of the particles and prevents them from reaggre Organic solvents are used mainly in the formulation of gating. Dispersing agents are added to agrochemical formu 30 emulsifiable concentrates, oil-in-water emulsions, Suspoe lations to facilitate dispersion and Suspension during manu mulsions, and ultra-low volume formulations, and to a lesser facture, and to ensure the particles redisperse into water in extent, granular formulations. Sometimes mixtures of sol a spray tank. They are widely used in wettable powders, vents are used. The first main groups of solvents are aliphatic Suspension concentrates and water-dispersible granules. paraffinic oils such as kerosene or refined paraffins. The Surfactants that are used as dispersing agents have the 35 second main group (and the most common) comprises the ability to adsorb strongly onto a particle Surface and provide aromatic solvents such as Xylene and higher molecular a charged or Steric barrier to reaggregation of particles. The weight fractions of C9 and C10 aromatic solvents. Chlori most commonly used surfactants are anionic, non-ionic, or nated hydrocarbons are useful as cosolvents to prevent mixtures of the two types. For wettable powder formula crystallization of pesticides when the formulation is emul tions, the most common dispersing agents are sodium ligno 40 sified into water. Alcohols are sometimes used as cosolvents Sulfonates. For Suspension concentrates, very good adsorp to increase solvent power. Other solvents may include tion and stabilization are obtained using polyelectrolytes, vegetable oils, seed oils, and esters of vegetable and seed Such as Sodium naphthalene Sulfonate formaldehyde con oils. densates. Tristyrylphenol ethoxylate phosphate esters are Thickeners or gelling agents are used mainly in the also used. Non-ionics Such as alkylarylethylene oxide con 45 formulation of Suspension concentrates, emulsions and Sus densates and EO-PO block copolymers are sometimes com poemulsions to modify the rheology or flow properties of the bined with anionics as dispersing agents for Suspension liquid and to prevent separation and settling of the dispersed concentrates. In recent years, new types of very high particles or droplets. Thickening, gelling, and anti-settling molecular weight polymeric Surfactants have been devel agents generally fall into two categories, namely water oped as dispersing agents. These have very long hydropho 50 insoluble particulates and water-soluble polymers. It is pos bic backbones and a large number of ethylene oxide chains sible to produce Suspension concentrate formulations using forming the teeth of a comb surfactant. These high clays and silicas. Examples of these types of materials, molecular weight polymers can give very good long-term include, but are not limited to, montmorillonite, bentonite, stability to Suspension concentrates because the hydropho magnesium aluminum silicate, and attapulgite. Water bic backbones have many anchoring points onto the particle 55 soluble polysaccharides have been used as thickening-gell Surfaces. Examples of dispersing agents used in agrochemi ing agents for many years. The types of polysaccharides cal formulations are: sodium lignoSulfonates; Sodium naph most commonly used are natural extracts of seeds and thalene sulfonate formaldehyde condensates; tristyrylphenol seaweeds or are synthetic derivatives of cellulose. Examples ethoxylate phosphate esters; aliphatic alcohol ethoxylates; of these types of materials include, but are not limited to, alkyl ethoxylates; EO-PO block copolymers; and graft copo 60 guar gum, locust bean gum, carrageenam; alginates; methyl lymers. cellulose; sodium carboxymethyl cellulose (SCMC); An emulsifying agent is a Substance which stabilizes a hydroxyethyl cellulose (HEC). Other types of anti-settling Suspension of droplets of one liquid phase in another liquid agents are based on modified starches, polyacrylates, poly phase. Without the emulsifying agent the two liquids would vinyl alcohol and polyethylene oxide. Another good anti separate into two immiscible liquid phases. The most com 65 Settling agent is Xanthan gum. monly used emulsifier blends contain alkylphenol or ali Microorganisms can cause spoilage of formulated prod phatic alcohol with twelve or more ethylene oxide units and ucts. Therefore preservation agents are used to eliminate or US 9,550,739 B2 63 64 reduce their effect. Examples of such agents include, but are particular species includes, but is not limited to, Acanthos not limited to: propionic acid and its sodium salt; Sorbic acid celides Obtectus, Agrilus planipennis, Anoplophora glabrip and its sodium or potassium salts; benzoic acid and its ennis, Anthonomus grandis, Ataenius spretulus, Atomaria Sodium salt; p-hydroxybenzoic acid sodium salt; methyl linearis, Bothynoderes punctiventris, Bruchus pisorum, Cal p-hydroxybenzoate; and 1,2-benzisothiazolin-3-one (BIT). losobruchus maculatus, Carpophilus hemipterus, Cassida The presence of Surfactants often causes water-based vittata, Cerotoma trifurcata, Ceutorhynchus assimilis, Ceu formulations to foam during mixing operations in produc torhynchus mapi, Conoderus scalaris, Conoderus stigmosus, tion and in application through a spray tank. In order to Conotrachelus menuphar, Cotinis initida, Crioceris asparagi, reduce the tendency to foam, anti-foam agents are often Cryptolestes ferrugineus, Cryptolestes pusillus, Crypto added either during the production stage or before filling 10 lestes turcicus, Cylindrocopturus adspersus, Deporaus mar into bottles. Generally, there are two types of anti-foam ginatus, Dermestes lardarius, Dermestes maculatus, Epil agents, namely silicones and non-silicones. Silicones are achina varivestis, Faustinus cubae, Hylobius pales, Hypera usually aqueous emulsions of dimethyl polysiloxane, while postica, Hypothenemus hanpei, Lasioderma serricorne, the non-silicone anti-foam agents are water-insoluble oils, Leptinotarsa decemlineata, Liogeny's fiscus, Liogenys Such as octanol and nonanol, or silica. In both cases, the 15 suturalis, Lissorhoptrus Oryzophilus, Maecolaspis joliveti, function of the anti-foam agent is to displace the Surfactant Melanotus communis, Melligethes aeneus, Melolontha from the air-water interface. melolontha, Oberea brevis, Oberea linearis, Oryctes rhinoc "Green’ agents (e.g., adjuvants, Surfactants, solvents) can eros, Oryzaephilus mercator; Oryzaephilus surinamensis, reduce the overall environmental footprint of crop protection Oulema melanopus, Oulema Oryzae, Phyllophaga cuy formulations. Green agents are biodegradable and generally abana, Popillia japonica, ProStephanus truncatus, Rhyzop derived from natural and/or Sustainable sources, e.g. plant ertha dominica, Sitona lineatus, Sitophilus granarius, Sito and animal sources. Specific examples are: vegetable oils, philus Oryzae, Sitophilus zeanais, Stegobium paniceum, seed oils, and esters thereof, also alkoxylated alkyl polyg Tribolium Castaneum, Tribolium confusum, Trogoderma lucosides. variabile, and Zabrus tenebrioides. For further information, see "Chemistry and Technology 25 In another embodiment, the molecules of Formula One of Agrochemical Formulations' edited by D. A. Knowles, may be used to control pests of the Order Dermaptera. copyright 1998 by Kluwer Academic Publishers. Also see In another embodiment, the molecules of Formula One “Insecticides in Agriculture and Environment—Retrospects may be used to control pests of the Order Blattaria. A and Prospects” by A. S. Perry, I. Yamamoto, I. Ishaaya, and non-exhaustive list of particular species includes, but is not R. Perry, copyright 1998 by Springer-Verlag. 30 limited to, Blattella germanica, Blatta orientalis, Parcob Pests latta pennsylvanica, Periplaneta americana, Periplaneta In general, the molecules of Formula One may be used to australasiae, Periplaneta brunnea, Periplaneta fuliginosa, control pests e.g. ants, aphids, beetles, bristletails, cock Pycnoscelus surinamensis, and Supella longipalpa. roaches, crickets, earwigs, fleas, flies, grasshoppers, leaf In another embodiment, the molecules of Formula One hoppers, lice, locusts, mites, moths, nematodes, Scales, 35 may be used to control pests of the Order Diptera. A Symphylans, termites, thrips, ticks, wasps, and whiteflies. non-exhaustive list of particular genera includes, but is not In another embodiment, the molecules of Formula One limited to, Aedes spp., Agromyza spp., Anastrepha spp., may be used to control pests in the Phyla Nematoda and/or Anopheles spp., Bactrocera spp., Ceratitis spp., Chrysops Arthropoda. spp., Cochliomyia spp., Contarinia spp., Culex spp., In another embodiment, the molecules of Formula One 40 Dasineura spp., Delia spp., Drosophila spp., Fannia spp., may be used to control pests in the Subphyla Chelicerata, Hvlemyia spp., Liriomyza spp., Musca spp., Phorbia spp., Myriapoda, and/or Hexapoda. Tabanus spp., and Tipula spp. A non-exhaustive list of In another embodiment, the molecules of Formula One particular species includes, but is not limited to, Agromyza may be used to control pests in the Classes of Arachnida, frontella, Anastrepha suspensa, Anastrepha ludens, Anas Symphyla, and/or Insecta. 45 trepha Obliga, Bactrocera cucurbitae, Bactrocera dorsalis, In another embodiment, the molecules of Formula One Bactrocera invadens, Bactrocera zonata, Ceratitis capitata, may be used to control pests of the Order Anoplura. A Dasineura brassicae, Delia platura, Fannia canicularis, non-exhaustive list of particular genera includes, but is not Fannia scalaris, Gasterophilus intestinalis, Gracillia limited to, Haematopinus spp., Hoplopleura spp., Linogna perseae, Haematobia irritans, Hypoderma lineatum, Liri thus spp., Pediculus spp., and Polyplax spp. A non-exhaus 50 omyza brassicae, Mellophagus Ovinus, Musca autumnalis, tive list of particular species includes, but is not limited to, Musca domestica, Oestrus ovis, Oscinella frit, Pegomya Haematopinus asini, Haematopinus suis, Linognathus Seto betae, Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, sus, Linognathus Ovillus, Pediculus humanus capitis, Rhagoletis mendax, Sitodiplosis mosellana, and Stomoxys Pediculus humanus humanus, and Pthirus pubis. calcitrans. In another embodiment, the molecules of Formula One 55 In another embodiment, the molecules of Formula One may be used to control pests in the Order Coleoptera. A may be used to control pests of the Order Hemiptera. A non-exhaustive list of particular genera includes, but is not non-exhaustive list of particular genera includes, but is not limited to, Acanthoscelides spp., Agriotes spp., Anthononus limited to, Adelges spp., Aulacaspis spp., Aphrophora spp., spp., Apion spp., Apogonia spp., Aulacophora spp., Bruchus Aphis spp., Bemisia spp., Ceroplastes spp., Chionaspis spp., spp., Cerosterna spp., Cerotoma spp., Ceutorhynchus spp., 60 Chrysomphalus spp., Coccus spp., Empoasca spp., Lepidos Chaetocnema spp., Colaspis spp., Ctenicera spp., Curculio aphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp., Cyclocephala spp., Diabrotica spp., Hypera spp., Ips spp., Nephotettix spp., Nezara spp., Philaenus spp., Phyto spp., Lyctus spp., Megascelis spp., Melligethes spp., Otio coris spp., Piezodorus spp., Planococcus spp., Pseudococ rhynchus spp., Pantomorus spp., Phyllophaga spp., Phyl cus spp., Rhopalosiphum spp., Saissetia spp., Therioaphis lotreta spp., Rhizotrogus spp., Rhynchites spp., Rhyn 65 spp., Toumeyella spp., Toxoptera spp., Trialeurodes spp., chophorus spp., Scolytus spp., Sphenophorus spp., Triatoma spp. and Unaspis spp. A non-exhaustive list of Sitophilus spp., and Tribolium spp. A non-exhaustive list of particular species includes, but is not limited to, Acroster US 9,550,739 B2 65 66 nun hilare, Acyrthosiphon pisum, Aleyrodes proletella, Sesamia spp., Spodoptera spp., Synanthedon spp., and Aleurodicus dispersus, Aleurothrixus floccosus, Amrasca Yponomeuta spp. A non-exhaustive list of particular species biguttula biguttula, Aonidiella aurantii, Aphis gossypii, includes, but is not limited to, Achaea janata, Adoxophyes Aphis glycines, Aphis pomi, Aulacorthum Solani, Bemisia Orana, Agrotis ipsilon, Alabama argillacea, Amorbia argentifolii, Bemisia tabaci, Blissus leucopterus, Brachyco 5 cuneana, Amyelois transitella, Anacamptodes defectaria, rynella asparagi, Brevennia rehi, Brevicoryne brassicae, Anarsia lineatella, Anomis Sabulifera, Anticarsia gemmata Calocoris norvegicus, Ceroplastes rubens, Cimex lis, Archips argyrospilla, Archips rosana, Argyrotaenia cit hemipterus, Cimex lectularius, Dagbertus fasciatus, Dich rana, Autographa gamma, Bonagota Cranaodes, Borbo cin elops fircatus, Diuraphis noxia, Diaphorina citri, Dysaphis nara, Bucculatrix thurberiella, Capua reticulana, plantaginea, Dysdercus suturellus, Edessa meditabunda, 10 Carposina niponensis, Chlumetia transversa, Choris Eriosoma lanigerum, Eurygaster maura, Euschistus heros, toneura rosaceana, Cnaphalocrocis medinalis, Conopomor Euschistus servus, Helopeltis antonii, Helopeltis theivora, pha cramerella, Cossus cossus, Cydia caryana, Cydia fune Icerya purchasi, Idioscopus initidulus, Laodelphax striatel brana, Cydia molesta, Cydia nigricana, Cydia pomonella, lus, Leptocorisa Oratorius, Leptocorisa varicornis, Lygus Darna diducta, Diatraea saccharalis, Diatraea grandio hesperus, Maconellicoccus hirsutus, Macrosiphum euphor 15 sella, Earias insulana, Earias vittella, Ecdytolopha auran biae, Macrosiphum granarium, Macrosiphum rosae, Mac tianum, Elasmopalpus lignosellus, Ephestia cautella, rosteles quadrilineatus, Mahanarva frimbiolata, Metopolo Ephestia elutella, Ephestia kuehniella, Epinotia aporema, phium dirhodium, Mictis longicornis, Myzus persicae, Epiphyas postvittana, Erionota thrax, Eupoecilia ambigu Nephotettix cinctipes, Neurocolpus longirostris, Nezara ella, Euxoa auxiliaris, Grapholita molesta, Hedylepta indi viridula, Nilaparvata lugens, Parlatoria pergandii, Parla cata, Helicoverpa armigera, Helicoverpa zea, Heliothis toria ziziphi, Peregrinus maidis, Phylloxera vitifoliae, virescens, Hellula undalis, Keiferia lycopersicella, Leucino Physokermes piceae, Phytocoris Californicus, Phytocoris des Orbonalis, Leucoptera coffeella, Leucoptera malifoli relativus, Piezodorus guildinii, Poecilocapsus lineatus, ella, Lobesia botrana, Loxagrotis albicosta, Lymantria dis Psallus vaccinicola, Pseudacy.sta perseae, Pseudococcus par, Lyonetia clerkella, Mahasena corbetti, Mamestra brevipes, Ouadraspidiotus perniciosus, Rhopalosiphun 25 brassicae, Maruca testulalis, Metisa plana, Mythinna uni maidis, Rhopalosiphum padi, Saissetia oleae, Scaptocoris puncta, Neoleucinodes elegantalis, Nymphula depunctalis, castanea, Schizaphis graminum, Sitobion avenae, Sogatella Operophtera brumata, Ostrinia nubilalis, Oxydia vesulia, fircifera, Trialeurodes vaporariorum, Trialeurodes Pandemis cerasana, Pandemis heparana, Papilio demodo abutiloneus, Unaspis yanonensis, and Zulia entrerriana. cus, Pectinophora gossypiella, Peridroma Saucia, Perileu In another embodiment, the molecules of Formula One 30 coptera coffeella, Phthorimaea operculella, Phyllocnistis may be used to control pests of the Order Hymenoptera. A citrella, Pieris rapae, Plathylpena scabra, Plodia interpunc non-exhaustive list of particular genera includes, but is not tella, Plutella xylostella, Polychrosis viteana, Prays endo limited to, Acromyrmex spp., Atta spp., Camponotus spp., carpa, Prays oleae, Pseudaletia unipuncta, Pseudoplusia Diprion spp., Formica spp., Monomorium spp., Neodiprion includens, Rachiplusia nu, Scirpophaga incertulas, Sesamia spp., Pogonomyrmex spp., Polistes spp., Solenopsis spp., 35 inferens, Sesamia nonagrioides, Setora initens, Sitotroga Vespula spp., and Xvlocopa spp. A non-exhaustive list of cerealella, Sparganothis pilleriana, Spodoptera exigua, particular species includes, but is not limited to, Athalia Spodoptera frugiperda, Spodoptera eridania, Thecla rosae, Atta texana, Iridomyrmex humilis, Monomorium basilides, Tineola bisselliella, Trichoplusia ni, Tuta abso minimum, Monomorium pharaonis, Solenopsis invicta, luta, Zeuzera coffeae, and Zeuzera pyrina. Solenopsis geminata, Solenopsis molesta, Solenopsis rich 40 In another embodiment, the molecules of Formula One tery, Solenopsis xyloni, and Tapinoma sessile. may be used to control pests of the Order Mallophaga. A In another embodiment, the molecules of Formula One non-exhaustive list of particular genera includes, but is not may be used to control pests of the Order Isoptera. A limited to, Anaticola spp., Bovicola spp., Chelopistes spp., non-exhaustive list of particular genera includes, but is not Goniodes spp., Menacanthus spp., and Trichodectes spp. A limited to, Coptotermes spp., Cornitermes spp., Crypto 45 non-exhaustive list of particular species includes, but is not termes spp., Heterotermes spp., Kalotermes spp., Incisit limited to, Bovicola bovis, Bovicola caprae, Bovicola ovis, ermes spp., Macrotermes spp., Marginitermes spp., Micro Chelopistes meleagridis, Goniodes dissimilis, Goniodes cerotermes spp., Procornitermes spp., Reticulitermes spp., gigas, Menacanthus stramineus, Menopon gallinae, and Schedorhinotermes spp., and Zootermopsis spp. A non Trichodectes canis. exhaustive list of particular species includes, but is not 50 In another embodiment, the molecules of Formula One limited to, Coptotermes curvignathus, Coptotermes frenchi, may be used to control pests of the Order Orthoptera. A Coptotermes formosanus, Heterotermes aureus, Micro non-exhaustive list of particular genera includes, but is not termes obesi, Reticulitermes banyulensis, Reticulitermes limited to, Melanoplus spp., and Pterophylla spp. A non grassei, Reticulitermes flavipes, Reticulitermes hageni, exhaustive list of particular species includes, but is not Reticulitermes hesperus, Reticulitermes Santonensis, Reticu 55 limited to, Anabrus simplex, Gryllotalpa africana, Gryllo litermes speratus, Reticulitermes tibialis, and Reticulitermes talpa australis, Gryllotalpa brachyptera, Gryllotalpa virginicus. hexadactyla, Locusta migratoria, Microcentrum retinerve, In another embodiment, the molecules of Formula One Schistocerca gregaria, and Scudderia furcata. may be used to control pests of the Order Lepidoptera. A In another embodiment, the molecules of Formula One non-exhaustive list of particular genera includes, but is not 60 may be used to control pests of the Order Siphonaptera. A limited to, Adoxophyes spp., Agrotis spp., Argyrotaenia spp., non-exhaustive list of particular species includes, but is not Cacoecia spp., Caloptilia spp., Chilo spp., Chrysodeixis limited to, Ceratophyllus gallinae, Ceratophyllus niger, spp., Colias spp., Crambus spp., Diaphania spp., Diatraea Ctenocephalides canis, Ctenocephalides felis, and Pulex spp., Earias spp., Ephestia spp., Epimecis spp., Feltia spp., irritans. Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela 65 In another embodiment, the molecules of Formula One spp., Lithocolletis spp., LOXagrotis spp., MalacOSoma spp., may be used to control pests of the Order Thysanoptera. A Peridroma spp., Phyllonorycter spp., Pseudaletia spp., non-exhaustive list of particular genera includes, but is not US 9,550,739 B2 67 68 limited to, Calliothrips spp., Frankliniella spp., Scirtothrips or that may become inhabited, or that may be traversed, by spp., and Thrips spp. A non-exhaustive list of particular sp. a pest of Phyla Nematoda, Arthropoda, and/or Mollusca. For includes, but is not limited to, Frankliniella fisca, Franklin example, the locus can be: iella Occidentalis, Frankliniella Schultzei, Frankliniella wil (a) where crops, trees, fruits, cereals, fodder species, liamsi, Heliothrips haemorrhoidalis, Rhipiphorothrips cru vines, turf, and/or ornamental plants, are growing: entatus, Scirtothrips citri, Scirtothrips dorsalis, and (b) where domesticated animals are residing: Taeniothrips rhopalantennalis, Thrips hawaiiensis, Thrips (c) the interior or exterior Surfaces of buildings (such as nigropilosus, Thrips Orientalis, Thrips tabaci. places where grains are stored); In another embodiment, the molecules of Formula One (d) the materials of construction used in buildings (such as 10 impregnated wood); and may be used to control pests of the Order Thysanura. A (e) the Soil around buildings. non-exhaustive list of particular genera includes, but is not Particular crop areas to use a molecule of Formula One limited to, Lepisma spp. and Thermobia spp. include areas where apples, corn, Sunflowers, cotton, Soy In another embodiment, the molecules of Formula One beans, canola, wheat, rice, Sorghum, barley, oats, potatoes, may be used to control pests of the Order Acarina. A 15 oranges, alfalfa, lettuce, Strawberries, tomatoes, peppers, non-exhaustive list of particular genera includes, but is not crucifers, pears, tobacco, almonds, Sugar beets, beans and limited to, Acarus spp., Aculops spp., Boophilus spp., Demo other valuable crops are growing or the seeds thereof are dex spp., Dermacentor spp., Epitrimerus spp., Eriophyes going to be planted. It is also advantageous to use ammo spp., Ixodes spp., Oligonychus spp., Panonychus spp., nium sulfate with a molecule of Formula One when growing Rhizoglyphus spp., and Tetranychus spp. A non-exhaustive various plants. list of particular species includes, but is not limited to, In another embodiment, molecules of Formula One are Acarapis woodi, Acarus siro, Aceria mangiferae, Aculops generally used in amounts from about 0.0001 grams per lycopersici, Aculus pelekassi, Aculus Schlechtendali, Ambly hectare to about 5000 grams per hectare to provide control. Omma americanum, Brevipalpus obovatus, Brevipalpus In another embodiment, it is preferred that molecules of phoenicis, Dermacentor variabilis, Dermatophagoides 25 Formula One are used in amounts from about 0.001 grams pteronyssinus, Eotetranychus carpini, Notoedres cati, Olig per hectare to about 500 grams per hectare. In another Onychus coffeae, Oligonychus ilicis, Panonychus citri, embodiment, it is more preferred that molecules of Formula Panonychus ulmi, Phylocoptruta oleivora, Polyphagotar One are used in amounts from about 0.01 gram per hectare sonemus latus, Rhipicephalus sanguineus, Sarcoptes sca to about 50 grams per hectare. 30 The molecules of Formula One may be used in mixtures, biei, Tegolophus perseaflorae, Tetranychus urticae, and Var applied simultaneously or sequentially, alone or with other roa destructor: compounds to enhance plant vigor (e.g. to grow a better root In another embodiment, the molecules of Formula One system, to better withstand stressful growing conditions). may be used to control pest of the Order Symphyla. A Such other compounds are, for example, compounds that non-exhaustive list of particular sp. includes, but is not 35 modulate plant ethylene receptors, most notably 1-methyl limited to, Scutigerella immaculata. cyclopropene (also known as 1-MCP). Furthermore, such In another embodiment, the molecules of Formula One molecules may be used during times when pest activity is may be used to control pests of the Phylum Nematoda. A low. Such as before the plants that are growing begin to non-exhaustive list of particular genera includes, but is not produce valuable agricultural commodities. Such times limited to, Aphelenchoides spp., Belonolaimus spp., Cri 40 include the early planting season when pest pressure is conemella spp., Dity lenchus spp., Heterodera spp., usually low. Hirschmanniella spp., Hoplolaimus spp., Meloidogyne spp., The molecules of Formula One can be applied to the foliar Pratylenchus spp., and Radopholus spp. A non-exhaustive and fruiting portions of plants to control pests. The mol list of particular sp. includes, but is not limited to, Dirofilaria ecules will either come in direct contact with the pest, or the immitis, Heterodera zeae, Meloidogyne incognita, Meloid 45 pest will consume the pesticide when eating leaf fruit mass, ogyne javanica, Onchocerca volvulus, Radopholus similis, or extracting sap, that contains the pesticide. The molecules and Rotylenchulus reniformis. of Formula One can also be applied to the soil, and when For additional information consult “HANDBOOK OF PEST applied in this manner, root and stem feeding pests can be CONTROL THE BEHAVIOR, LIFE HISTORY AND CONTROL OF HOUSE controlled. The roots can absorb a molecule taking it up into HOLD PESTs' by Arnold Mallis, 9th Edition, copyright 2004 50 the foliar portions of the plant to control above ground by GIE Media Inc. chewing and sap feeding pests. Applications Generally, with baits, the baits are placed in the ground Controlling pests of Phyla Nematoda, Arthropoda, and/or where, for example, termites can come into contact with, Mollusca generally means that pest populations, pest activ and/or be attracted to, the bait. Baits can also be applied to ity, or both, are reduced in an locus. This can come about 55 a Surface of a building, (horizontal, Vertical, or slant Surface) when: where, for example, ants, termites, cockroaches, and flies, (a) pest populations are repulsed from a locus; can come into contact with, and/or be attracted to, the bait. (b) pests are incapacitated in, or around, a locus; or Baits can comprise a molecule of Formula One. (c) pests are exterminated in, or around, a locus. The molecules of Formula One can be encapsulated Of course, a combination of these results can occur. Gen 60 inside, or placed on the Surface of a capsule. The size of the erally, pest populations, activity, or both are desirably capsules can range from nanometer size (about 100-900 reduced more than fifty percent, preferably more than 90 nanometers in diameter) to micrometer size (about 10-900 percent, and most preferably more than 98 percent. Gener microns in diameter). ally, the locus is not in, or on, a human; consequently, the Because of the unique ability of the eggs of Some pests to locus is generally a non-human locus. 65 resist certain pesticides, repeated applications of the mol In another embodiment, the locus to which a molecule of ecules of Formula One may be desirable to control newly Formula One is applied can be any locus that is inhabited, emerged larvae. US 9,550,739 B2 69 70 Systemic movement of pesticides in plants may be uti administered orally to the animals with the drinking water or lized to control pests on one portion of the plant by applying feed. The dosages and formulations that are Suitable depend (for example by spraying an area) the molecules of Formula on the species. One to a different portion of the plant. For example, control The molecules of Formula One may also be used for controlling parasitic worms, especially of the intestine, in of foliar-feeding insects can be achieved by drip irrigation or the animals listed above. furrow application, by treating the soil with for example pre The molecules of Formula One may also be employed in or post-planting soil drench, or by treating the seeds of a therapeutic methods for human health care. Such methods plant before planting. include, but are limited to, oral administration in the form of Seed treatment can be applied to all types of seeds, for example, tablets, capsules, drinks, granules, and by including those from which plants genetically modified to 10 dermal application. express specialized traits will germinate. Representative Pests around the world have been migrating to new examples include those expressing proteins toxic to inver environments (for Such pest) and thereafter becoming a new tebrate pests, such as Bacillus thuringiensis or other insec invasive species in Such new environment. The molecules of Formula One may also be used on Such new invasive species ticidal toxins, those expressing herbicide resistance. Such as 15 to control them in Such new environment. “Roundup Ready’ seed, or those with "stacked' foreign The molecules of Formula One may also be used in an genes expressing insecticidal toxins, herbicide resistance, area where plants, such as crops, are growing (e.g. pre nutrition-enhancement, drought resistance, or any other ben planting, planting, pre-harvesting) and where there are low eficial traits. Furthermore, such seed treatments with the levels (even no actual presence) of pests that can commer molecules of Formula One may further enhance the ability cially damage such plants. The use of Such molecules in Such of a plant to better withstand stressful growing conditions. area is to benefit the plants being grown in the area. Such This results in a healthier, more vigorous plant, which can benefits, may include, but are not limited to, improving the lead to higher yields at harvest time. Generally, about 1 gram health of a plant, improving the yield of a plant (e.g. of the molecules of Formula One to about 500 grams per increased biomass and/or increased content of valuable 100,000 seeds is expected to provide good benefits, amounts 25 ingredients), improving the vigor of a plant (e.g. improved from about 10 grams to about 100 grams per 100,000 seeds plant growth and/or greener leaves), improving the quality is expected to provide better benefits, and amounts from of a plant (e.g. improved content or composition of certain about 25 grams to about 75 grams per 100,000 seeds is ingredients), and improving the tolerance to abiotic and/or expected to provide even better benefits. biotic stress of the plant. It should be readily apparent that the molecules of For 30 Before a pesticide can be used or sold commercially, Such mula One may be used on, in, or around plants genetically pesticide undergoes lengthy evaluation processes by various modified to express specialized traits, such as Bacillus governmental authorities (local, regional, state, national, and thuringiensis or other insecticidal toxins, or those expressing international). Voluminous data requirements are specified herbicide resistance, or those with “stacked foreign genes by regulatory authorities and must be addressed through data expressing insecticidal toxins, herbicide resistance, nutri 35 generation and Submission by the product registrant or by a tion-enhancement, or any other beneficial traits. third party on the product registrant’s behalf often using a The molecules of Formula One may be used for control computer with a connection to the World WideWeb. These ling endoparasites and ectoparasites in the veterinary medi governmental authorities then review Such data and if a cine sector or in the field of non-human animal keeping. The determination of safety is concluded, provide the potential molecules of Formula One are applied, such as by oral 40 user or seller with product registration approval. Thereafter, administration in the form of, for example, tablets, capsules, in that locality where the product registration is granted and drinks, granules, by dermal application in the form of for Supported. Such user or seller may use or sell Such pesticide. example, dipping, spraying, pouring on, spotting on, and A molecule according to Formula One can be tested to dusting, and by parenteral administration in the form of for determine its efficacy against pests. Furthermore, mode of example, an injection. 45 action studies can be conducted to determine if said mol The molecules of Formula One may also be employed ecule has a different mode of action than other pesticides. advantageously in livestock keeping, for example, cattle, Thereafter, such acquired data can be disseminated, such as sheep, pigs, chickens, and geese. They may also be by the internet, to third parties. employed advantageously in pets such as, horses, dogs, and The headings in this document are for convenience only cats. Particular pests to control would be fleas and ticks that 50 and must not be used to interpret any portion hereof. are bothersome to such animals. Suitable formulations are Table Section TABLE 2

Structures for Intermediates Prepared according to No. Structure App. Example:

C1 Yellow 1 Oil US 9,550,739 B2 72 TABLE 2-continued

Structures for Intermediates Prepared according to No. Structure App. Example:

C2 N Tan / Solid NNYN 2 O NH2

CH3

C3 N White 10 N/ 22. Solid F YN Br F F

C4 N Yellow 11 7 Solid N F Né F NH2 F

C7 N Off 15 F F f white N 2 solid > O YN Br

C8 H3C Light N O CH3 tan solid F F N N 2 X- O CH3 F N N O H

C9 SN O White 17 F. solid NN 2 GE) G. F F N NH O O F F

C11 O White 19 ls solid H HC O NB Ori O H3C O

HC CH

C12 Off white N solid US 9,550,739 B2 73 74 TABLE 2-continued

Structures for Intermediates

Prepared according to No. Structure App. Example:

C13 N Off- 21, 23 F F white YQ YN 2 NH2 solid O

TABLE 3

Structures for Molecules of Formula One Prepared according to No. Structure App. Example:

F1 F F Off- 4 F White Solid O N F F ! O 2 YQO YN N H

F2 CH Tan 4 Solid H3C N F F / O N NN 2 s F N O N \ H Z

F3 White 4 Solid

O N F F d O 2 YQO YN N H

F4 H3C White 3 V Solid O CH3 / N O N.N 2 O N - O O H F US 9,550,739 B2 75 76 TABLE 3-continued

Structures for Molecules of Formula One

Prepared according to No. Structure Example:

Off White H' O Solid N CH3 / O - N.YN 2

F6 Off White N Solid F F F / O NN 2 F N O N F H

C

Off F7 H' White O Solid N F F F I O NN 2 F N O N F H

F8 HC White Solid

N F F d O YQ YN 2

F9 O Off White Solid N HC F F F / O NN 2 F N O N F H

F10 H3 Yellow Oil US 9,550,739 B2 77 78 TABLE 3-continued

Structures for Molecules of Formula One Prepared according to No Example:

F11 White 4 Solid

F12 Off White Solid

CH

F13 White Solid

CH N

F14 White Solid

F15 White Solid

C

F16 White Solid

N

F17 Off White Solid

N US 9,550,739 B2 79 80 TABLE 3-continued

Structures for Molecules of Formula One

Prepared according to No. Structure App. Example:

F18 C Off White C

F19 Color less Oil

F2O White 12 Solid

F21 Yellow Solid

F22 White Solid

F23 Yellow Solid

F N 2 O YA re F YN F N US 9,550,739 B2 8 1. 82 TABLE 3-continued

Structures for Molecules of Formula One

Prepared according to App. Example:

White Solid N O N

F25 Off White Solid

N N C N

F

F26 White /O Solid N H3C F O

O O- Né N

F27 White Solid

NN O N \ NZ

F28 Off F White Solid

NN O N H F

Color HC less N Oil F F ? O O O Né CH3 F US 9,550,739 B2 83 84 TABLE 3-continued

Structures for Molecules of Formula One Prepared according to No Structure App Example: F30 White 4 C Solid F. F ? N O YQ NaN O N

F31 Off HC White N Solid R F / O F NN 2 F N CH O N F H

F32 White HC Solid F. F ? N O Na YQO N N H C

F33 White HC Solid N F. F / O N NN 2 s F N O NH \ Z

F34 Tan Solid F. F ? N O 2 YQO O YN N H C

F35 SN White F R F / O Solid NN 2 F N O N F H

HC

F36 R F Off F White Solid US 9,550,739 B2 85 86 TABLE 3-continued

Structures for Molecules of Formula One Prepared according to No. Structure Example:

White Solid

CH3

F38 CH3 White Solid

Orange Oily Solid

F40 Off White Solid

White Solid

Off White Solid

N US 9,550,739 B2 87 88 TABLE 3-continued

Structures for Molecules of Formula One

Prepared according to App. Example:

F43 Off 4 White N Solid F. F ? O YQ NaN O N

C

F44 H3C White V Solid O F. F ? N O YQ NaN

F45 N White F R F / O Solid NN 2 F N O N F H

F46 Yellow HC Oil N F. F ? S YQ NaN CH3 O N

F47 N White F R F / O Solid

F O N N \ F H NZ

F48 White Solid US 9,550,739 B2 89 90 TABLE 3-continued

Structures for Molecules of Formula One

Prepared according to No. Structure App. Example:

F49 H3C White 4 \ Solid O

N F F d O YQ NaN CH3 O N

FSO HC White 18 \ Solid O

N O F F 2 F YQ N N N O H

F51 White 18 Solid

EN O F F N Na F YQO N NH F

F52 N O White 18 F F d Solid 2 F YQ N N N O H H' NNCH,

F53 N O White 18 F F | Solid NNn 2 F YQO N NH F

H3C

F54 HC Color- 18 \ less O oil

SN O F F 2 F >Q N N N O H F US 9,550,739 B2 91 92 TABLE 3-continued

Structures for Molecules of Formula One

Prepared according to No. Structure App. Example:

F55 White 18 solid

F56 White 18 solid

F57 Off 24 N white F F d H solid YQ NaN N O

F58 =N White 12 F 1 - NYN 2 C. O solid F N F

N White 12 / O solid F N n 2 N N F H F F

F

F60 N Off 12 f O white N YN2 solid F N-F N US 9,550,739 B2 93 94 TABLE 3-continued

Structures for Molecules of Formula One

Prepared according to No. Structure App. Example:

F61 N White 12 f solid NN 2 N CH N / F H O

F62 NéC-C O While 12 F

F64 HC Color- 5 \ less O oil N F F t O F > N N2 O ) F H3C

F65 H3C Color- 5 V less O oil N F F d O YQ NaN O N F

CH3

F66 H3C Color- 5 \ less O oil N F F d O F YQ N N2 O N F

US 9,550,739 B2 113 114 2. A molecule having a structure of Formula One wherein Formula One said molecule is in the form of an agriculturally acceptable R8 acid addition salt, a salt derivative, a Solvate, or an ester

6 R7 R9 derivative; R =N 5 Na N Formula One R3 R2 R8 R4 RI 10 R6 R7 ) N R9 R10 R 16 Q R 15 Né s wherein L-N \ 14 (A) R', R,R,R,R,R, R7, R, RO, R', R', and 4 R3 R2 ki ZR R R R" is each independently selected from a group 15 consisting of H. F. Cl, Br, I, CN, NO, OH, C-C, alkyl, C-C alkenyl, C-C alkenyloxy, C-C alky nyl, C-C alkynyloxy, C-C haloalkyl, C-C, wherein alkoxy, C-C haloalkoxy, C-C cycloalkyl, C-C, (A) R', R. R. R. R. R. R7, R, RO, R', R', and cycloalkoxy, C-C cycloalkenyl, or C-C cycloalk R" is each independently selected from a group enyloxy, consisting of H. F. Cl, Br, I, CN, NO, OH, C-C, wherein each alkyl, alkenyl, alkenyloxy, alkynyl, alky nyloxy, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, alkyl, C-C alkenyl, C-C alkenyloxy, C-C alky cycloalkoxy, cycloalkenyl, or cycloalkenyloxy, are nyl, C-C alkynyloxy, C-C haloalkyl, C-C, optionally substituted with one or more substituents alkoxy, C-C haloalkoxy, C-C cycloalkyl, C-C, independently selected from a group consisting of H, 25 cycloalkoxy, C-C cycloalkenyl, or C-C cycloalk F, Cl, Br, I, CN, NO, OH, C-C alkyl, C-C, enyloxy, alkenyl, C-C alkenyloxy, C-C alkynyl, C-C, wherein each alkyl, alkenyl, alkenyloxy, alkynyl, alky alkynyloxy, C-C haloalkyl, C-C alkoxy, C-C, nyloxy, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, haloalkoxy, C-C cycloalkyl, C-C cycloalkoxy, cycloalkoxy, cycloalkenyl, or cycloalkenyloxy, are C-C cycloalkenyl, or C-C cycloalkenyloxy; 30 optionally substituted with one or more substituents (B) R is H: independently selected from a group consisting of H, (C) L is a linker that is a bond connecting nitrogen to F, Cl, Br, I, CN, NO, OH, C-C alkyl, C-C, the carbon in the ring; alkenyl, C-C alkenyloxy, C-C alkynyl, C-C, (D) R' is selected from H., (C-C)alkyl, (C-C) alkynyloxy, C-C haloalkyl, C-C alkoxy, C-C, alkenyl, (C-C)alkenyloxy, (C-C)alkynyl, (C-C) 35 haloalkoxy, C-C cycloalkyl, C-C cycloalkoxy, alkynyloxy, (C-C)haloalkyl, (C-C)alkoxy, (C- C-C cycloalkenyl, or C-C cycloalkenyloxy; C.)haloalkoxy, (C-C)alkyl (C-C)alkoxy, (C-C) (B) R is H: cycloalkyl, (C-C)cycloalkoxy, (C-C) (C) L is a linker that is a bond connecting nitrogen to cycloalkenyl, (C-C)cycloalkenyloxy, ((C-C) the carbon in the ring; alkyl)) (C-C)cycloalkyl), C(O)(C-C)alkyl, C(O) 40 (D) R' is selected from H. (C-C)alkyl, (C-C) phenyl, ((C-C)alkyl)C(O)(C-C)alkyl, and ((C- alkenyl, (C-C)alkenyloxy, (C-C)alkynyl, (C-C) C.)alkyl)C(O)O((C-C)alkyl). alkynyloxy, (C-C)haloalkyl, (C-C)alkoxy, (C- wherein each alkyl, alkenyl, alkenyloxy, alkynyl, alky C.)haloalkoxy, (C-C)alkyl (C-C)alkoxy, (C-C) nyloxy, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkyl, (C-C)cycloalkoxy, (C-C) cycloalkoxy, cycloalkenyl, cycloalkenyloxy, and 45 cycloalkenyl, (C-C)cycloalkenyloxy, ((C-C) phenyl, are optionally substituted with one or more alkyl)) (C-C)cycloalkyl), C(O)(C-C)alkyl, C(O) substituents independently selected from H. F. Cl, phenyl, ((C-C)alkyl)C(O)(C-C)alkyl, and ((C- Br, I, CN, NO, OH, oxo, and OC(O)(C-C)alkyl: C.)alkyl)C(O)O((C-C)alkyl). (E) X is selected from N or CR'', wherein R' is wherein each alkyl, alkenyl, alkenyloxy, alkynyl, alky selected from a group consisting of H. F. Cl, Br, I, 50 nyloxy, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, CN, NO, OH, C-C alkyl, C-C alkenyl, C-C, cycloalkoxy, cycloalkenyl, cycloalkenyloxy, and alkenyloxy, C-C alkynyl, C-C alkynyloxy, C-C, phenyl, are optionally Substituted with one or more haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C, substituents independently selected from H. F. Cl, cycloalkyl, C-C cycloalkoxy, C-C cycloalkenyl, Br, I, CN, NO, OH, oxo, and OC(O)(C-C)alkyl; or C-C cycloalkenyloxy; 55 (E) X is selected from N or CR', wherein R' is (F) R' is selected from a group consisting of H, selected from a group consisting of H. F. Cl, Br, I, phenyl, or Substituted phenyl, CN, NO, OH, C-C alkyl, C-C alkenyl, C-C, wherein said substituted phenyl is substituted with one alkenyloxy, C-C alkynyl, C-C alkynyloxy, C-C, or more substituents independently selected from a haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C, group consisting of H. F. Cl, Br, I, CN, NO, OH, 60 cycloalkyl, C-C cycloalkoxy, C-C cycloalkenyl, C-C alkyl, C-C alkenyl, C-C alkenyloxy, C-C, or C-C cycloalkenyloxy; alkynyl, C-C alkynyloxy, C-C haloalkyl, C-C, (F) R' is selected from a group consisting of H, alkoxy, C-C haloalkoxy, C-C cycloalkyl, C-C, phenyl, or Substituted phenyl, cycloalkoxy, C-C cycloalkenyl, C-C cycloalk wherein said substituted phenyl is substituted with one enyloxy, OC-C alkylphenyl, C(O)C-C alkyl, or 65 or more substituents independently selected from a N(C-C alkyl)(C-C alkyl); and group consisting of H. F. Cl, Br, I, CN, NO, OH, (G) Q is selected from O or S. C-C alkyl, C-C alkenyl, C-C alkenyloxy, C-C,