OA16335A - Pesticidal compositions. - Google Patents

Abstract

Molecules according to formula one :

Description

PESTICIDAL COMPOSITIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application daims priority from U.S, provisional application 61/378,528 filed on August 31, 2010. The entire content of this provisional application is hereby incorporated by reference into this Application.

FIELD OF THE INVENTION

The invention disclosed in this document is related to the field of processes to produce molécules that are useful as pesticides (e.g., acaricides, insecticides, molluscicides, and nematicides), such molécules, and processes of using such molécules to control pests.

BACKGROUND OF THE INVENTION

Pests cause millions of human deaths around the world each year. Furthermore, there are more than ten thousand species of pests that cause losses in agriculture. The world-wide agricultural losses amount to billions of U.S. dollars each year.

Termites cause damage to ail kinds of private and public structures. The world-wide termite damage losses amount to billions of U.S. dollars each year.

Stored food pests eat and adulterate stored food. The world-wide stored food losses amount to billions of U.S. dollars each year, but more importantly, deprive people of needed food.

There is an acute need for new pesticides. Certain pests are developing résistance to pesticides in current use. Hundreds of pest species qre résistant to one or more pesticides. The development of résistance to some of the older pesticides, such as DDT, the carbamates, and the organophosphates, is well known. But résistance has even developed to some of the newer pesticides.

Therefore, for many reasons, including the above reasons, a need exists for new pesticides.

DEFINITIONS

The examples given in the définitions are generaliy non-exhaustive and must not be construed as îimiting the invention disclosed in this document. It is understood that a substituent should comply with chemical bonding rules and steric compatibility constraints in relation to the particular molécule to which it is attached. ,

Acaricide Group is defined under the heading “ACARICIDES”.

AI Group” is defined after the place în this document where the Herbicide Group is defined. ,. _>i;. ., , .,.. , . -116335 “Alkenyl” means an acyclic, unsaturated (at least one carbon-carbon double bond), branched or unbranched, substituent consîsting of carbon and hydrogen, for example, vinyl, allyl, butenyl, pentenyl, and hexenyl.

“Alkenyloxy” means an alkenyl further consîsting of a carbon-oxygen single bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy.

“Alkoxy” means an alkyl further consîsting of a carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy.

Alkyl means an acyclic, saturated, branched or unbranched, substituent consîsting of carbon and hydrogen, for example, methyl, ethyl,'propyl, isopropyl, butyl, and tert-butyl.

“Alkynyl” means an acyclic, unsaturated .(at least one carbon-carbon triple bond), branched or unbranched, substituent consîsting df carbon and hydrogen, for example, ethynyl, propargyl, butynyl, and pentynyl.

Alkynyloxy means an alkynyl further consîsting of a carbon-oxygen single bond, for example, pentynyloxy, hexynyloxy, heptynyloxy, and octynyloxy.

“Aryl means a cyclic, aromatic substituent consîsting of hydrogen and carbon, for example, phenyl, naphthyl, and biphenyl.

“Cycloalkenyl” means a monocyclic or polycyclic, unsaturated (at least one carboncarbon double bond) substituent consîsting of carbon and hydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, ibicyclo[2.2.2]octenyl, tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.;. .· _u;·

Cycloalkenyloxy means a cycloalkenyl further consîsting of a carbon-oxygen single bond, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.

“Cycloalkyl means a monocyclic or _t polycyclic, saturated substituent consîsting of carbon and hydrogen, for example, çyc|opropyl, cyclobutyl, cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.

“Cycloalkoxy” means a cycloalkyl further consîsting of a carbon-oxygen single bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyl oxy, norbornyloxy, and bicyclo[2.2.2]octyloxy.

Fungicide Group is defined under the heading “FUNGIC1DES.” “Halo” means fluoro, chloro, bromo, and iodo.

“Haloalkoxy” means an alkoxy further consîsting of, from one to the maximum possible number of identical or different, halos, for example, fluoromethoxy, trifluoromethoxy, 2,2difluoropropoxy, chloromethoxy, . trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, and i

pentafluoroethoxy. _; ,<

“Haloalkyl” means an alkyl further consîsting of, from one to the maximum possible number of, identical or different, halos, for example, fluoromethyl, trifluoromethyl, 2,2difluoropropyl, chloromethyl, trichloromethyl, and 1,1.,2,2-tetrafluoroethyl.

• -,2 .-r ' i’l·,

“Herbicide Group is defined under the heading “HERBICIDES.

“Heterocyclyl means a cyclic substituent that may be fully saturated, partially unsaturated, or fully unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfur, or oxygen. Examples of aromatic heterocyclyls include, but are not limited to, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl cinnolinyl, furanyl, indazolyl, indolyl, imidazolyl, isoindolyl, isoquinolinyl, isothiazolyi isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, .pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, .thiazolinyl, thiazolyl, thienyl, triazinyl, and triazolyl. Examples of fully saturated heterocyclyls include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyi, and tetrahydropyranyl. Examples of partially unsaturated heterocyclyls include,. but are not limited to, 1,2,3,4-tetrahydro-quinolinyl, 4,5-dihydro-oxazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-isoxazolyl, and 2,3-dihydro-[1,3,4]oxadiazolyl. , _i(, “Insecticide Group is defined under the heading “INSECTICIDES.

“Nematicide Group” is defined under the heading “NEMATICIDES”

Synergist Group is defined under the heading “SYNERGISTIC MIXTURES AND SYNERGISTS

DETAILED DESCRIPTION OF THE INVENTION

This document discloses molécules having the following formula (“Formula One):

RIO

R5

R3

Formula One wherein . ·.

R10 is selected from the following group

(a)

(b)

(c)

R1 is selected from H, F, Cl,' Br, I, CN, NO₂₁ substituted or unsubstituted CrCg alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C_VC_B alkoxy, substituted

or unsubstîtuted C₂-C₆ alkenyloxy, substituted or unsubstîtuted C₃-C₁₀ cycloalkyl, substituted or unsubstîtuted C₃-C₁₀ cycloalkenyl, substituted or unsubstîtuted C_e-C₂₀ aryl, substituted or unsubstîtuted Ci-C₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1 )N(R9)_Z| N(R9)₂₁

N(R9)C(=X1)R9, SR9, S(O)_nOR9, or R9S(O)_nR9, ^: wherein each said R1, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, Ci-C_e alkyl, C₂-C₆ alkenyl, Ci-Ce haloalkyl, C₂-C₆ haloalkenyl, Ci-C_e haloalkyloxy, C_z-C₆ haloalkenyloxy, C₃-Ci₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C3-C10 halocycloalkenyl, OR9, S(O)_nOR9, C₆-C₂₀ aryl, or C_rC₂₀ heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9);

i : · · f

R2 is H, F, Cl, Br, I, CN, NO₂, substituiez₍ογ unsubstîtuted C_rC₆ alkyl, substituted or unsubstîtuted C₂-C₆ alkenyl, substituted or unsubstîtuted C_rC₆ alkoxy, substituted or unsubstîtuted C₂-C₆ alkenyloxy, substituted or unsubstîtuted C₃-C₁₀ cycloalkyl, substituted or unsubstîtuted C₃-C₁₀ cycloalkenyl, substituted or unsubstîtuted C₆-C₂₀ aryl, substituted or unsubstîtuted C_rC₂o heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_nOR9, or R9S(O)_nR9,. _: wherein each said R2, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO_Z, CpCg alkyl, C₂-C₆ alkenyl, Ci-C₆ haloalkyl, C₂-C₆ haloalkenyl, C--C_ë haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃'Ci₀ halocycloalkenyl, OR9, S(O)_nOR9, C₆-C₂₀ aryl, or CpC^ heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9);

i

R3 is H, substituted or unsubstîtuted C_rC_e alkyl, substituted or unsubstîtuted C₂-C₆ alkenyl, substituted or unsubstîtuted C_rC₆ alkoxy, substituted or unsubstîtuted C₂-C₆ alkenyloxy, substituted or unsubstîtuted CrCi» cycloalkyl, substituted or unsubstîtuted C₃-C₁₀ cycloalkenyl, substituted or unsubstîtuted Ce-C^ aryl, substituted or unsubstîtuted C1-C20 heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(~X1)N(R9)_Z, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_nOR9, R9S(O)_nR9, Ci-C₆ alkyl C₆-C₂q aryl (wherein the alkyl and aryl can independently be substituted or unsubstîtuted), C(=X2)R9, C(fX1)X2R9, R9X2C(=X1)R9, R9X2R9, C(=O)(C_rC₆ alkylJSiOJniCpCe alkyl), C(=O)(C₁-C₆ 3^1)ΰ(=Ο)Ο(^-0₆ alkyl), (C_rC₆ alkyl)OC(=O)(C_e-C₂₀ aryl), (Ci-C₆ alkyl) OC (=O)(C_rC₆ alkyl),. C-i-Cs alkyl-(C₃-C₁₀ cyclohaloalkyl), or (Ci-C₆ alkenyl)C(=O)O(Ci-C_B alkyl), or R9X2C(=X1)X2R9;., wherein each said R3, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO_Z, C-i-C₆ alkyl, C₂-C₅ alkenyl, Ci-C_e haloalkyl, C₂-C₆ haloalkenyl, C_rC₆ haloalkyloxy, C₂-C_s haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_nOR9, C_e-C₂o aryl, or C1-C20 heterocyclyl, (each of which that can be substituted,, may optionally be substituted with R9);

R4 is O, S, NR9, or NOR9;

R5 is (C_rCi2 alkenyl)S(O)_n(Ci-Ci2 alkyl), (Ci-C₁₂ alkyKRSJjSiOUCrCis alkyl); . ' _; .

(C,-C₁₂ alkyl)(S(C,-C₁₂ alkyl(each indépendant from the other)))₂, (CrC₁₂ alkyl)C(=NO(C,-C,₂ alkyl))(C,-Ç₁₂ alkyl), (C_rc₁₂ alkyl)C(=O)(CrCi2 alkyl), i .

(CrCi₂ alkyl)C(=O)O(C_rC₁₂ alkyl), (CrCi₂ alkyl)N(R9)₂, (C_rC₁₂ alkyl)N(R9)C(=O)O(C,-C₁₂ alkyl), (C_rCi₂ a(kyl)N(R9)C(=O)O(C,-C,₂ alkyl)R6, (C_rC₁₂ alkyl)O(C,-C₁₂ alkyl), (Ci-C₁₂ alkyl)OC(=O)(C,-C,₂ alkyl)S(O)_n(C,-C₁₂ alkyl), (Ci-C-j₂ alkyl)OSi((Ci-C-i₂ alkyl)₃ each indepêndent from the other), (Ci-C₁₂ alkyl)S(O)_n(C,-C,₂ haloalkyl), (Ci-C₁₂ alkyl)S(O)_n(=NCN)(Ci-Ct₂ alkyl), _t , (C1-C12 alkyl)S(O)n(Ci-C₃₂ alkenyl), (C1-C12 alkyl)S(O)_n(C·γΟ·)₂ alkyl), (C₃-C,₂ cydoalkyl)(C_rC.i2 alkyl)(S(O)_?(C,-$_12i alkyl), (C_rC₁₂ alkyl)S(O)_n(C,-C₁₂ alkyl)R6, , (C-j-C-12 alkyl)S(0)_n(C6-C2o aryl), ;

(C_rC₁₂ alkyl)S(O)_nR6, (Ci-Cw alkyl)S(O)_nC(=O)(C,-C,₂ alkyl), (C,-C₁₂ alkylCN)S(O)_n(C,-C₁₂ alkyl), (C,-C₁₂ alkylN(R9)₂)S(O)_n(Ç₁-C₁₂ alkyl),

N(R9)(C,-C,₂ alkyl)O(Ci-Ci₂ alkyl),

N(R9)(Ci-Ci2 alkyl)S(O)_n(C,-Ç₁₂ alkyl),

0(0,-0,2 alkyl), ; ;

O(C,-Ci₂ alkyl)O(Ci-C,2 alkyl),

O(Ci-Ci₂ alkyl)S(O)n(Ci-Ci₂ alkyl), or.

S(O)_n(CrC,₂ alkyl);

R6 is H, substituted or unsubstituted C^C₂₀: aryl, substituted or unsubstituted C,-C_2Q '·,·'· JJ ' 1 . ¹ · heterocyclyl;

R7 is H, F, Cl, Br, I, CN, N0₂, substituted or unsubstituted C,-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C,-C₆ alkoxy, substituted or -516335 unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-Ci₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C_rC₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂,

N(R9)C(=X1 )R9, SR9, S(O)_nOR9, or R9S(O)_nR9, >

wherein each said R7, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, CrCe alkyl, C₂-C₆ alkenyl, C_rC_e haloalkyl, C₂-C_e haloalkenyl, Ci-C₆ haloalkyloxy, : C₂-C_s haloalkenyloxy, C₃-Ci₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl? ÔR9, S(O)_nOR9, C₆-C₂₀ aryl, or Ci-C₂₀ heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9);

R8 is H, F, Cl, Br, I, CN, NO₂, substituted or unsubstituted C_rC₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted CrC₆ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-Ci₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted Ci-C₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_nOR9, or R9S(O)_nR9, wherein each said R8, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, CrC₈ alkyl, C₂-C₅ alkenyl, C_rC₈ haloalkyl, C₂-C_e haloalkenyl, C_rC_e haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-Cw cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-Ci₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_nOR9, C_e-C₂₀ aryl, or C_rC₂o heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9);

R9 (each independently) is H, CN, substituted or unsubstituted Ci-C₅ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted Ci-C_c alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C3-C10 cycloalkenyl, substituted or unsubstituted C₆-C_2Û aryl, substituted or unsubstituted Ci-C₂₀ heterocyclyl, S(O)_nCi-C_e alkyl, N(C_rC₆alkyl)₂, wherein each said R9, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, CrC_e alkyl, C₂-C₆ alkenyl, C_rCe haloalkyl, C_z-C₆ haloalkenyl, C_rC₆ haloalkyloxy, C₂-Ç₆ haloalkenyloxy, C₃-Ci₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OC_?-Ç₆ alkyl, OC_rC_e haloalkyl, StO^Ci-Cealkyl, S(O)_nOCi-C₆ alkyl, C₆-C₂₀ aryl, or CrC₂₀ heterocyclyl;

X1 is (each independently) O or S;

î. 'n·

X2 is (each independently) Q, S, =NR9,:o_ir ~NOR9; and n is (each independently) 0, 1, or 2,

-616335

In another embodiment RI is H or a CpCe haloalkyl.

In another embodiment R2 is H or Cl.

In another embodiment R3 is H, an unsubstituted C_rC_e alkyl, an unsubstituted C_e-C₂₀ aryl, or R9S(O)_nR9.

In another embodiment R3 is H, an unsubstituted Ci-C_e alkyl, phenyl, or a (Ci-C₆ alkyl)S(O)_n(CrC₅ alkyl). ^: <

In another embodiment R4 is O or S.

In another embodiment R5 is (Ci-C₁₂ alkyl)S(O)_n(Ci-C₁₂ alkyl).

In another embodiment R6 is H or phenyl.

In another embodiment R7 is H, F, Cl, unsubstituted C;-C« alkyl, C1-C6 haloalkyl, or N(R9)₂, ^: V ' ^{; ;}

In another embodiment R8 is H or Cl.

In another embodiment R10 is

(a)

The molécules of Formula One will generally hâve a molecular mass of about 100 Daltons to about 1200 Daltons. However, it is generally preferred if the molecular mass is from )· .

about 120 Daltons to about 900 Daltons, and it is even more generally preferred if the molecular mass is from about 140 Daltons to about 600 Daltons.

^Λ;.^: i ..-‘T? ’

In the following schemes,

(a) (b) or (^c)

The following scheme illustrâtes approaches to generating 2-amino-1,3,4-thiadiazoles. In step a of Scheme I, treatment of the appropriate carboxylic acid of Formula lia with a thiosemicarbazide of Formula III in an acid such as sulfuric acid or polyphosphoric acid afforded

the 2-amino-1,3,4-thiadiazoles of Formula IV which was subsequently converted to the bromide via a diazonium intermediate in step b of Scheme I. The 2-amino-1,3,4-thiadiazole may also be converted to the chloride via a diazonium intermediate and copper in hydrochloric acid, These halothiadiazoles are reacted with the appropriate amines in step cto provide the 2-amino-1,3,4thiadiazoles of Formula Va in Scheme I.

RI	0	H S
A	Λο	+ H'N'bJÂKH	a
	R2	H H '	F
lia		m

Scheme I

£andc

IV

Yet another approach to 2-amino-1,3,4-thiadiazoles is illustrated in Scheme II. In step a of Scheme 11 treatment of the appropriate carboxaldehyde of Formula 11b can be condensed with a r thiosemicarbazide of Formula VI in a polar aprotic solvent such as dimethylsulfoxide to give compounds of Formula VII. In step b compounds of Formula VII were subsequently cyclized using an oxidizing agent such as iron (III) chloride hexahydrate in a polar protic solvent such as éthanol to give the 2-amino-1,3,4-thiadiazole of Formula Vb in Scheme II.

Scheme II

Vil

Vb

11b VI

In step a of Scheme III, compounds. of Formula ,Vç can be treated with an acid chloride of Formula VIII in the presence of a base such as Ν,.Ν-dimethylaminopyridine in a polar aprotic . L solvent such as dichloroethane to yield compounds of Formula la. The acid chlorides used in the acylation reaction herein are either commercially available or can be synthesized by those skilled in the art.

Scheme III

i ή · >; » : : Tr ^1[; ' / «-N „ ,_a ] N-N Y!

x-V-V + ^R5y^c1 —

Q_Y4 ^S R3 J ^S R3 ^Y R2 ’ . ^Y R2 · / <Vc VIII ' la

In step a and b of Scheme IV, ureas, thioureas, carbamates and thiocarbamates are prepared from the 2-amino-1,3,4-thîadiazoles of Formula Vd. Compounds of Formula Vd, wherein R1, R2 5 and R3 are as previously defined, are allowed to react with phosgene or thiophosgene to provide the intermediate carbamoyl chlorides or thiocarbamoyl chlorides, respectively. Alternatively, compounds of Formula Vd can be treated with a chloroformate, such as methyl chloroformate, and base, such as triethylamine, in an aprotic solvent, such as dichloromethane, to give a carbamate of Formula le as in step c. în step e of Scheme IV a compound of Formula 10 Ib is treated with an amine to generate a urea or thiourea of Formula ld, wherein R4 = O or S, respectively. Alkylation of the urea nitrogen of compounds of Formula ld, wherein R4 = O with an alkyl halide such as iodomethane, in the presence of a base such as sodium hydride and in a polar aprotic solvent such as DMF yields the compounds of Formula If wherein R4 = O as shown in step g of Scheme IV. In step d and f of Scheme IV the carbamoyl chloride is treated 15 with an alcohol or thiol to give the carbamate of Formula le or a thiocarbamate of Formula le, respectively.

-916335 ί

Scheme IV

Oxidation of the sulfide to the sulfoxide or sulfone is accomplished as in Scheme V. The sulfide of Formula Ig, wherein X, R1, R2, and R3 are as previously defined, is treated with an oxidant such as sodium perborate tetrahydrate in a polar protic solvent such as glacial acetic acid to give the sulfoxide of Formula lh as in step a of Scheme V. The sulfoxide of Formula Ih can be further oxidized to the sulfone of Formula li by sodium perborate tetrahydrate in a polar protic 10 solvent such as glacial acetic acid as in step b’of Scheme V. Aitematively, the sulfone of Formula li can be generated in a one-step procedure from the sulfide of Formula Ig by using the aforementioned conditions with >2 équivalents of the sodium perborate tetrahydrate as in step c of Scheme V. , .·!

. ν'?··'·' ' A-' . J

I _

Scheme V

- 1016335

EXAMPLES

The examples are for illustration purposes and are not to be construed as limrting the invention disclosed in this document to only the embodiments disclosed in these examples.

Starting materials, reagents, and solvents that were obtained from commercial sources were used without further purification. Anhydrous solvents were purchased as Sure/Seal™ from Aldrich and were used as received. Melting points were obtained on a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated Melting Point System from Stanford Research Systems and are uncorrected. Molécules are given their known names, named according to naming programs within ISIS Draw, ChemDraw or ACD Name Pro. If such programs are unable to name a molécule, the molécule is named using conventional naming rules. ¹H NMR spectral data are in ppm (δ) and were recorded at 300, 400 or 600 MHz, and ¹³C NMR spectral data are in ppm (□) and were recorded at 75, 100 or 150 MHz, unless otherwise stated.

Example 1: Préparation of 5-pyridin-3-yl-[1,3,4]thiadiazol-2-ylamine

as described

t

-7 : i

5-pyndin-3-yl-[1,3,4]thiadiazol-2-ylamine was prepared

Chem. 1988, 31, 898. Nicotinic acid (30 g, 0.24 mol) was added in portions to polyphosphoric acid (60 mL) under mechanical stirring. After,stirring for 5 minutes, thiosemicarbazide (22.2 g, 0.24 mol) was added in portions. The réaction mixture was heated to 90 °C for 6 hours, cooled -11by Turner et al. J. Med.

to room température over 14 hours, and re-heated to 40 °C to melt the solid yellow cake. Water was added (50 mL) dropwise via Pasteur pipette while stirring. The solution was cooled to 0 °C,

NH₄OH (29 % solution, approx 250 mL) was added dropwise over 2.5 hours to bring the pH to

14. The solids were collected by filtration, washed with water (150 mL) and dried in vacuo at 65 °C for 16 hours to afford the title compound as a beige-colored solid (21.7 g, 50 %): mp 201211 °C; IR (KBr thin film) 1508 cm'¹; ¹H NMR (300 MHz, DMSO-d₆) □ 8.95 (d, J = 2.1 Hz, 1H), 8.62 (dd, J = 4.5, 0.9 Hz, 1H), 8.14 (dt, J = 8.4, 1.5 Hz, 1H), 7.51 (dd, J = 8.1, 1.5 Hz, 1H); ESIMS m/z 179 ([M+H]*). j.

Example 2: Préparation of 2-amino-5-(3-pyridyl)-1,3,4-thiadiazole

A mixture of the thiosemicarbazide (1.01 g, 4.34 mmol) in 5 mL of concentrated sulfuric acid was heated to 100 °C for 3 h. The reaction mixture was cooled to 23 °C and a 50% aqueous solution of sodium hydroxide was added until pH = 9. The solid was collected, washed with 15 water, and air dried to give 620 mg of 2-amino-5-(3-pyridyl)-1,3,4-thiadiazole. The filtrate was extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over MgSO4, and concentrated to dryness to give 0.120 g of 2-amino-5-(3-pyridyl)-1,3,4-thiadiazole. The lots were combined to give (0.738 g, 95%) of 2-amino-5-(3-pyfidyl)-1,3,4-thiadiazole: ¹H NMR (300 MHz, DMSO-gQ δ 8.9 (d, 1H), 8.6 (dd, 1H); 8.1 (td, 1H), 7.57 (s, 2H), 7.5 (m, 1H).

Example 3: Préparation of N-Phenyl-5-(py ridin-3-y 1)-1,3,4-thiadiazol-2-a mi ne

Préparation of (E)-4-Phenyl-1-(pyridin-3-ylmethylene)-thiosemicarbazide: 4Phenylthiosemicarbazide (890 mg, 5.3 mmol, 1.0 equiv) was added to a stirred solution of 25 nicotinaldehyde (500 pL, 5.3 mmol, 1.0 equiv) in méthanol (2.5 mL) at 23 °C. The resulting pale yellow solution was heated to 65 °C and stirred for 3 h. Thé cooled reaction mixture was concentrated under vacuum. The residue was rinsed with cold ethyl acetate and vacuum-filtered to afford the title compound as off-white crystals (1)3^Tg, 93%): mp 208-210 °C; IR (KBr thin film) 3442 (w), 3298 (m), 3125 (w), 2940'(w), 2791 (W), .1594 (s), 1532 (s) cm’¹; ¹H NMR (300 MHz, 30 DMSO-de) δ 11.98 (s, 1H), 10.22 (s, 1H), 9.03 (d, J = 2 Hz, 1H), 8.59 (dd, J~ 5, 2 Hz, 1H), 8.38

(dt, J = 8, 2 Hz, 1H>, 8.18 (s, 1 H), 7.55 (m, 2H), 7.45 (dd, J= 8, 5 Hz, 1H), 7.21 (m, 1 H); ESIMS m/z 257 ([M+H]^-). ·' '

Préparation of N-Phenyi-5-(pyridin-3-yl)-1,3,4~thiadiazol-2-amine - Powdered iron(lll) chloride hexahydrate (5.1 g, 19 mmol, 4.0 equiv) was added to a stirred suspension of (E)-4phenyl-1-(pyridin-3-ylmethylene)thiosemicarbazidë (1.2 g, 4.7 mmol, 1.0 equiv) in absolute éthanol (47 mL) at 23 °C. The resulting dark brown'suspension was heated to 95 °C and stirred ί · : 1 for 2 h. The cooled reaction mixture was concentrated by rotary évaporation. The residue was diluted with a 1M solution of sodium hydroxide (200 mL) and extracted with dichloromethane (8 x 75 mL). The combined organic layers were dried (Na₂SO₄), gravîty-filtered, and concentrated by rotary évaporation to afford the title compound as a tan solid (300 mg, 25%): mp 252-255 °C; IR (KBr thin film) 3460 (w), 3260 (w), 3198 (w), 2921 (w), 2851 (w), 2788 (w), 1620 (m), 1566 (m), 1501 (s) cm’¹; ¹H NMR (300 MHz, DMSO-d_e) δ 10.65 (s, 1H), 9.05 (d, J= 2 Hz, 1H), 8.67 (dd, J = 5, 2 Hz, 1H), 7.66 (m, 2H), 7.56 (dd, J = 8, 5 Hz, 1H), 7.38 (m, 2H), 7.05 (m, 1H); ESIMS m/z 255 ([M+H]*).

Precursors N-methyl-5-[4-(trifluoromethyl)pyridin-3-yl]-1,3,4-thiadiazol-2-amine, A/-methyl-5-[4(trifluoromethyl)pyridin-3-yl]-1,3,4-thiadiazol-2-amine, A/-methyl-5-pyrimidin-5-yl-1,3,4-thiadiazol2-amine, 5-(6-chloropyridin-3-yl)-/V-methyl-1,3,4-thiadiazol-2-amine, 5-(5-fluoropyridin-3-yl)-A/methyl-1,3,4-thiadiazol-2-amine, 5-(5-chloropyridin-3-yl)-A/-methyl-1,3,4-thiadiazol-2-amine, Nmethyl-5-(2-methylpyrimidin-5-yl)-1,3,4-thiadiazol-2-amine, N,A/-dirnethyl-5-[5-(methylamino)1,3,4-thiadiazol-2-yl]pyrimidin-2-amine, W-methyl-5-[5-(tnfluoromethyl)pyridin-3-yl]-1,3,4V '· ' thiadiazol-2-amine, N-methyl-5-pyridin-4-yl-1,3,4rthiadiazol-2-amine, and /V-methy 1-5-(5methyIpyridin-3-yI)-1,3,4-thiadiazol-2-amine. were prepared as described in Example 3.

Example 4: Préparation of 3-(5-bromo-[1,3,4]thiadiazol-2-yl)pyridinium hydrobromide

To a solution of aqueous hydrobromic acid (48 %, 17 mL) at 5 °C in an ice bath was added 5pyridin-3-yl-[1,3,4]thiadiazol-2-ylamine (6 g, 33 mmol) followed by bromine (12 .8 mL, 0.24 mol)

at a rate such that the reaction mixture was kept at a température below 11 °C. A solution of sodium nitrite (6 g, 85 mmol) in water (8.5 mL) was added at a rate such that the reaction mixture maintained a température of around 5 °C. The reaction mixture was kept at 2°C for 2 hours, and then made basic to pH 8.9 using dijute NaOH at a rate needed to maintain the température between 5 °C and 15 °C. The reçulting solids were collected by filtration, washed with ice-cold water (200 mL) until filtrate was acidic (pH 4), and dried in vacuo at 35 °C to afford the title compound as an orange powder (8.68 g, 80 %): mp 124-129 °C; IR (KBr thin film) 1374, 1026 cm'¹; ¹H NMR (300 MHz, DMSO-d₆) □ 9.17 (d, J= 1.8 Hz, 1H), 8.80 (dd, J- 4.5, 0.9 Hz, 1H), 8.42 (dt, J = 8.4, 1.8 Hz, 1H), 7.67 (ddd, J = 7.2, 4.8,0.9 Hz, 1H); ESIMS m/z 244 (M+2).

i

Example 5: Préparation of 2-chloro-5-(3-pyridyl)-[1,3,4]-thiadiazole

To a mixture of 5-pyridin-3-yl-[1,3,4]thiadiazol-2-ylamine (5.5 g, 30.9 mmol) and copper powder (0.335 g, 5.27 mmol), in a mixture of glacial acetic acid (93 mL) and concentrated hydrochloric acid (19 mL) at 0 ’C, was added dropwise a solution of sodium nitrite (10.67 g, 154.6 mmol) dissolved in water (13 mL). The reaction mixture was then allowed to warm to 23 °C overnight. The reaction mixture was diluted with 300 g of ice, resulting in an émulsion, and extracted with dichloromethane (3 x 200 mL). The émulsion was then passed through a medium porosity scintered glass funnel containing celite. The cake was stirred and washed well with chloroform. The filtrate was combined with the organic extràcts. The organic phase was dried over MgSO₄ and concentrated to dryness to give the title compound as a yellow solid (4.42 g, 72%): ¹H NMR (300 MHz, CDCI₃) δ 9.08 (br s, 1H), 8.78 (br s,’ 1 H), 8.29 (dt, J = 8, 2 Hz, 1H), 7.49 (dd, J- 8, 5 Hz, 1 H).

Example 6 - Préparation of N-ethyl-S-pyridin-S-yl-ljS^-thiadiazol^-amme

-1416335

A/-ethyl-5-pyridin-3-yl-1,3,4-thiadiazol-2-amine can be prepared from 2-chloro-5-(3-pyridyl)- [1,3,4]-thiadiazole as described by Chapleo et al.^th ïhMed. Chem, 1987, 30(5), 951.

Example 6A -- Préparation of /V-fcyclopropylmethyl )-5-( 3-pyridyl)-1,3,4-thiadiazol-2-amine

N-N

N-N

A suspension of cyclopropylmethanamine (0.528g, 0.743 mmol), 2-bromo-5-(3-pyridyl)-1,3,4thiadiazole hydrobromide (0.2 g, 0.619 mmol) and triethylamine (0.3 ml, 2.16 mmol) in éthanol (20 mL) was heated to 125 °C for 42 minutes in a microwave reaction vessel, cooled to room température, concentrated under reduced pressure and resuspended in 2:1 saturated aqueous sodium bicarbonate : ethyl acetate (100 mL). Thë suspension was shaken vigorously and the organic extract collected and washed with water (50 mL) and brine (30 mL) before drying over magnésium sulfate. The solution was concentrated under, reduced pressure and purified by .7 ' μ ijj silica column chromatography, élutirig with a^gradleht of methanol in ethyl acetate. The slower eluting fraction was concentrated under reduced pressure to afford the title compound as a yellow solid (38 mg, 26%): mp 162-165 °C; IR (ATR) 1573(8), 1549(s), 1464(m), 1063(m) cm'¹; ¹H NMR (400 MHz, CDCI3) δ 8.97 (d, J = 1.6 Hz, 1H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H), 8.18 (ddd, J= 8.0, 2.2, 1.7 Hz, 1H), 7.38 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 5.68 (s, 1H), 3.29 (d, J = 7.1 Hz, 2H), 1.26 - 1.09 (m, 1H), 0.72 - 0.53 (m, 2H), 0.42 - 0.25 (m, 2H); ¹³C NMR (101 MHz, CDCI3) δ 170.01, 154.19, 150.61, 147.94, 133.64, 127.47, 123.76, 52.20, 10.76, 3.73; ESIMS m/z 231.8 ([M-H]’).

Example 7: Préparation of N-2-DÎmethyl-3-(met(iylthio)-N-(5-(pyridin-3-yl)-1,3,4-thiacliazol-

2-yl)propanamide (Compound 28) i ;

- 15 16335

Oxalyl chloride (980 pL, 11 mmol, 1,5 equiv) and A/,A/-dimethylformamide (29 pL, 0.37 mmol, 0.05 equiv) were sequentially added to a stirred suspension of 2-methyl-3-(methylthio)propanoic acid (1.0 g, 7.5 mmol, 1.0 equiv) in dichloromethane (13 mL) at 23 °C. The resulting bubbling yellow solution was stirred at 23 “C for 2 h. The reaction mixture was concentrated by rotary évaporation. A portion ofthe resulting product, 2-methyl-3-(methylthio)propanoyl chloride (120 mg, 0.79 mmol, 1.5 equiv), was added to a stirred suspension of A/-methyl-5-(pyridin-3-yl)-1,3,4thiadiazol-2-amine (100 mg, 0.52 mmol, 1.0 equiv) and 4-dimethylaminopyridine (130 mg, 1.1 mmol, 2.0 equiv) in 1,2-dichloroethane (3.0 mL) at 23 ’C. The resulting yellow solution was heated to 75 ^DC for 3 h. The cooled reaction mixture was diluted with a saturated solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried (MgSO4), gravity filtered^ and concentrated by rotary évaporation. The residue was purified by silica gel column chromatography (ethyl acetate) to afford a brown semisolid (70 mg, 44% ): IR (KBr thin film) 2975 (w), 2917 (w), 1667 (m) cm'¹; ¹H NMR (300 MHz, CDCI3) δ 9.15 (d, J = 2 Hz, 1H), 8.69 (dd, J =5, 2 Hz, 1H), 8.28 (dt, 7=8, 2 Hz, 1H), 7.42 (dd, J = 8, 5 Hz, 1H), 3.94 (s, 3H), 3.33 (m, 1H), 3.01 (dd, J = 13, 8 Hz, 1H), 2.69 (dd, J = 13, 6 Hz, 1 H), 2.15 (s, 3H), 1.37 (d, J = 7 Hz, 3H); ESIMS m/z 309 ([M+Hf).

Example 8: Préparation of N-2,2-trimethyl-3-(methylthio)-N-(5-(pyridin-3-yl)-1,3,4thiadiazol-2-yl)propanamide (Compound 24)

O.

Oxalyl chloride (500 pL, 5.8 mmol, 1.5 equiv) ànid ?y,N-dimethylformamide (15 pL, 0.19 mmol, 0.05 equiv) were sequentially added to a' stirred suspension of 2,2-dimethyl-3(methylthio)propanoic acid (570 mg, 3.8 mmol, 1,0 equiv) in dichloromethane (13 mL) at 23 °C. The resulting bubbling yellow solution was stirred at 23 °C for 1.5 h. The reaction mixture was concentrated by rotary évaporation. A portion of the resulting product, 2,2-dimethyl-3(methylthio)propanoyl chloride (110 mg, 0.66 mmol, 1.3 equiv), was added to a stirred suspension of N-methyl-5-(pyridin-3-yl)-1,3,4-thiadiazol-2-amine (100 mg, 0.52 mmol, 1.0 equiv) and 4-dimethylaminopyridine (95 mg, 0.78 mmol, 1.5 equiv) in 1,2-dichloroethane (3.0 mL) at 23 °C. The resulting yellow solution was heated to 75 °C for 17 h. The cooled reaction mixture was diluted with a saturated solution of sodium bicarbonate (40 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried (MgSO₄), gravity-filtered, and concentrated by rotary évaporation. The residue was purified by silica gel column chromatography (ethyl acetate) to afford pale yellow crystals (140 mg, 82%): mp 89-91 °C; ¹H NMR (300 MHz, CDCI₃) δ 9.13 (d, J = 2 Hz, 1H)„ 8.66 (dd, J = 5, 2 Hz, 1H), 8.25 (dt, J = 8, 2 Hz, .J -^rÿ^:;'

1H), 7.40 (dd, J = 8, 5 Hz, 1H), 3.95 (s, 3H), 2.95 (s, 2H), 2.15 (s, 3H), 1.54 (s, 6H); ESIMS m/z 323 ([M+H]⁺).

Compounds 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 17, 19, 24, 29, 30, 31, 34, 35, 44, 47, 49, 53, 57, 58, 60, 62, 64, 66, 67, 70, 71, 72, 73, 74, 75, 81, 84, 88, 90, 91, 92, 93, 94, and 96 were prepared as described in Example 8.

Example 9: Préparation of methyl 4-(methyl-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)amino)4-oxobutanoate (Compound 56)

4-methoxy-4-oxobutanoîc acid (69 mg, 0.52 mmol, 2.0 equiv) and 4-dimethylamino-pyridine (64 mg, 0.52 mmol, 2.0 equiv) were sequentially added to a stirred suspension of N-methyl-5(pyridin-3-yl)-1,3,4-thiadiazol-2’amine (50 mg, 0.26 mmol, 1.0 equiv) and 1 -ethyl-3-(3dimethylaminopropyl)-carbodiimide hydrochloride (200 mg, 1.0 mmol, 4.0 equiv) in 1,2dichloroethane (2.6 mL) at 23 °C. The resulting orange solution was stirred at 23 °C for 18 h. The reaction mixture was directly subjected to silica gel column chromatography (ethyl acetate) to afford an off-white powder (59 mg, 74% yield): mp 152-154 °C; IR (KBr thin film) 3032 (w), 2951 (w), 1737 (s), 1667 (s) cm'¹; ¹H NMR (300 MHz, CDCI₃) δ 9.14 (dd, 1H, J= 2, 1 Hz), 8.69 (dd, 1H, J = 5. 2 Hz), 8.28 (m, 1H), 7.42 (ddd, 1H,J = 8, 5, 1 Hz), 3.90 (s, 3H), 3.74 (s, 3H), 3.03 (dd, 2H, J = 8, 6 Hz), 2.83 (dd, 2H, J = 8, 6-Hz).; ESIMS m/z 307 ([M+H]⁺).

Compounds 38, 59, 61, 63, 65, 68, 69, 97 and 98 were prepared as described in Example 9.

Example 10: Préparation of N-methyl-3-(methylsulfinyl)-N-(5-(pyridin-3-yl)-1,3,4thiadiazol-2-yl)propanamide (Compound 18)

Sodium perborate tetrahydrate (52mg, 0.34 mmol, 1.0 equiv) was added to a stirred solution of N-methyl-3-(methylthio)-/V-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanamide (100 mg, 0.34 mmol, 1.0 equiv) in glacial acetic acid (1.8 mL) at 23 °C. The resulting suspension was stirred at 23 °C for 3 h. The reaction mixture was diluted with 'a saturated solution of sodium bicarbonate

(50 mL) and extracted with dichloromethane (5 x 20 mL). The combined organic layers were dried (Na₂SO₄), gravity-filtered, and çoncentr^dfoy rotary évaporation. The residue was rinsed with cold ethyl acetate and vacuum-filtered to .afford the title compound as an off-white powder (82 mg, 78% yield): mp 138-140 °C; ¹H NMR (300 MHz, DMSO-d_e) δ 9.12 (d, J = 2 Hz, 1H), 8.71 (dd, J = 5, 2 Hz, 1 H), 8.34 (m, 1 H), 7.56 (dd, J = 8, 5 Hz, 1 H), 3.80 (s, 3H), 2.90-3.30 (m, 3H), 2.62 (s, 3H); ESIMS m/z 311 ([M+H]*).

Compounds 32, 45, 51, and 77 were prepared as described in Example 10.

Example 11: Préparation of N-methy|-3-(methylsulfonyl)-N-(5-(pyridin-3-yl)-1,3,4thiadiazol-2-yl)propanamide (Compound 20)

ί ii.·' V < î . ii,·

Sodium perborate tetrahydrate (130 mg, 0.84 mmpl, 2.4 equiv) was added to a stirred solution of N-methyl-3-(methylthio)-N-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanamide (100 mg, 0.34 mmol, 1.0 equiv) in glacial acetic acid (1.8 mL) at 23 °C. The resulting yellow suspension was heated to 60 “C for 15 h. The cooled reaction mixture was diluted with a saturated solution of sodium bicarbonate (50 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried (sodium sulfate), gravity filtered, and concentrated by rotary évaporation. The residue was rinsed with cold ethyl acetate and vacuum-filtered to afford the title compound as an off-white powder (90 mg, 82% yield): mp 199-201 °C; ¹H NMR (300 MHz, DMSO-Gfe) δ 9.15 (d, J = 2 Hz, 1H), 8.73 (dd, J = 6, 2 Hz, 1H), 8.32 (dt, J = 8, 2 Hz, 1H), 7.46 (dd, J = 8, 5 Hz, 1H), 3.94 (s, 3H), 3.59 (t, J = 7 Hz, 2H), 3.33 (t, J = 7 Hz, 2H), 3.09 (s, 3H); ESIMS m/z 327 ([M+H]*).

Compounds 33, 36, 37, 40, 43, 46, 52, 76 were prepared as described in Example 11.

Example 12: Préparation of 2-(Methylthio)ethyl methyl(5-(pyridin-3-yl)-1,3,4-thiadiazol-2yl)carbamate (Compound 50)

t

-1.8 -

2-Methylthioethanol (100 μΙ_, 1.2 mmol, 1.5 equiv) was added to a stirred 20% solution of phosgene in toluene (1.2 mL, 2.3 mmol, 3.0 equiv) àt 0 °C. The resulting colorless solution was allowed to warm to 23 ’C and stirred for 1.5 h. The reaction mixture was concentrated by rotary évaporation. The residue was added to a stirred suspension of N-methyl-5-(pyridin-3-yl)-1,3,4thiadiazol-2-amine (150 mg, 0.78 mmol, 1.0 equiv) and 4-dimethylaminopyridine (190 mg, 1.6 mmol, 2.0 equiv) in 1,2-dichloroethane (7.8 mL) at 23 °C. The resulting yellow solution was heated to 75 °C for 18 h. The côoléd réaction 'mixture was diluted with a saturated solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried (MgSO₄), gravity filtered, and concentrated by rotary évaporation. The residue was purified by silica gel column chromatography (ethyl acetate) to afford the title compound as a white powder (190 mg, 79%): mp 126-128 °C; IR (KBr thin film) 3044 (w), 2958 (w), 2910 (w), 1700 (s), 1572 (w) cm¹; ¹H NMR (300 MHz, CDCI₃) δ 9.12 (br s, 1H), 8.70 (d, J5 Hz, 1H), 8.27 (dt, J = 8, 2 Hz, 1H), 7.42 (dd, J = 8, 5 Hz, 1 H), 4.51 (t, J = 7 Hz, 2H), 3.75 (s, 3H), 2.87 (t, J = 7 Hz, 2H), 2.21 (s, 3H); ESIMS m/z 311 ([M+H]*).

· t

Compounds 14, 15, and 16 were prepared as described in Example 12.

Example 13: Préparation of [5-(5-f1uoropyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-methylcarbamic acid 2-methylsuifanyl-ethyl ester (Compound 78)

A solution of phosgene (20 %, 0.39 mL, 0.8 mmol) in toluene was pipetted at a dropwise rate into a suspension of methyl-[5-(5-fluoropyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-amine (0.15 g, 0.7 mmol) in dichloroethane (10 mL) at 1 ⁰C, stirred for 5 minutes and treated with a solution of 4A/,A/-dimethylaminopyridine ( 0.192 g, 1.6 mmol) in dichloroethane (3 mL). The ice bath was removed after 30 minutes. The reaction mixture was stirred at 23 °C for 90 minutes, refluxed under nitrogen for 14 hours, cooled to 0 °C and reacted with 2-methylthio éthanol (0.033 g, 0.35 mmol). The ice bath was removed after 10 minutes. The reaction mixture was stirred at 23 °C for 1 hour, refluxed for 1 hour, cooled, and diluted^ with dichloroethane (30 mL). The reaction mixture was washed with dilute hÿdrochloric acid (0.1 N, 2 X 20 mL), saturated aqueous NaHCO3(40 mL), and brine (30 mL), and then dried over MgSO4and chromatographed on silica to afford the title compound as a White solid (0/125 g, 53 %): mp 104-106 °C; ¹H NMR (400 MHz, CDCI3) □ 8.90 (brt, 1H), 8.56 (d, J = 2.8 Hz, 1H), 8.04 (ddd, J = 9.1,2.5, 1.0 Hz, 1H), 4.52 (t, J = 6.8 Hz, 2H), 3.75 (s, 3H), 2.87 (t, J = 6.8 Hz, 2H), 2.21 (s. 3H); ESIMS m/z 329 ([M+H]⁺).

-1916335

Example 14: Préparation of methylthiomethyl methyl(5-(pyridin-3-y 1)-1,3,4-thiadiazol-2yl)carbamate (Compound 54)

A 37% aqueous solution of formaldéhyde (400 ,μί., ,4.8 mmol, 6.0 equiv) was added to a stirred solution of sodium methanethiolate (170 mg, 2:4 mmol, 3.0 equiv) in water (2.0 mL) at 23 °C. The resulting colorless solution was stirred at 23' “C for 2 h. Thé reaction mixture was extracted with diethyl ether (3 x 2 mL). The combined organic layers were dried (magnésium sulfate) and gravity-filtered. Pyridine (320 pL, 3.9 mmol, 5.0 equiv) was added and the resulting solution was added to a stirred 20% solution of phosgene in toluene (4.0 mL, 7.8 mmol, 10 equiv) at 0 °C. The resulting white mixture was allowed to warm to 23 °C and stirred for 2 h. The reaction mixture was gravity filtered and concentrated under vacuum. The residue was added to a stirred suspension of /V-methyl-5-(pyridin-3-yl)-1,3,4-thiadiazol-2-amine (150 mg, 0.78 mmol, 1.0 equiv) and 4-dimethylaminopyridine (290 mg, 2.4 mmol, 3.0 equiv) in 1,2-dichloroethane (7.8 mL) at 23 °C. The resulting yellow solution was heated to 75 °C for 18 h. The cooled reaction mixture was diluted with a saturated solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried (MgSO₄), gravity-filtered, and concentrated by rotary évaporation. The residue was purified by silica gel column chromatography (ethyl acetate) to afford the ₍titlé compound as a yellow film (27 mg, 12%): IR (KBr thin film) 2919 (w), 1647 (s), 1570 (w) cm'¹; NMR (300 MHz, CDCI₃) δ 8.89 (br s, 1H), 8.64 (brs, 1H), 7.97 (dt, J = 8, 2 Hz, 1H), 7.37 (dd, J= 8, 5 Hz, 1H), 5.12 (s, 2H), 3.14 (s, 3H), 2.32 (s, 3H).

Example 15: Préparation of yl)carbamothioate (Compound 55)

S-methyl methyl(5-(pyrïdin-3-yl)-1,3,4-thiadiazol-2-

4-Dimethylaminopyridine (81 mg, 0.66 mmol, 1.5 equiv) and methyl chlorothiolformate (50 pL, 0.57 mmol, 1.3 equiv) were sequentially added to a stirred suspension of A/-methyl-5-(pyridin-3yl)-1,3,4-thiadiazol-2-amine (85 mg, 0.44 mmol, 1.0_;équiv) in dîchloroethane (3.4 mL) at 23 °C. The resulting solution was heated to^;75 °C and stirrèd for 72 h. The cooled reaction mixture was

-20,-

directly subjected to silica gel column chromatography (55% ethyl acetate in hexane spiked with 5% triethylamine) to afford the title compound as an off-white powder (100 mg, 83%): mp 192— 194 °C; IR (KBr thin film) 2931 (w), 1727 (w), 1634 (s), 1570 (w) cm’¹; ¹H NMR (300 MHz, CDCIa) 5 9.13 (d, J = 2 Hz, 1H), 8.70 (dd, 7 = 5, 2 Hz, 1 H>, 8.28 (dt, J = 8, 2 Hz, 1H), 7.43 (dd, J = 8, 5 Hz, 1 H), 3.86 (s, 3H), 2.53 (s, 3H); ESIMS m/z 267 ([M+H]⁺).

Compound 87 was prepared as described in Example 15.

Example 16: Préparation of [5-(5-fluoro-pyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-methylthiocarbamic acid 2-methylsulfanyl-ethyl ester - (Compound 85)

A solution of thiophosgene (0.086 g, 0.7 mmol) in dichloroethane (1 mL) was pipetted at a dropwise rate into an ice-cold suspension of methyl-[5-(5-fluoropyridin-3-yl)-[1,3,4]thiadiazol-2yl]-amine (0.15 g, 0.7 mmol) in dichloroethane (1 mL), stirred for 10 minutes and treated with a solution of 4-A/,A/-dimethylaminopyridine (0.105 g, 0.8 mmol) in dichloroethane (1 mL). The ice bath was removed after 10 minutes and, after stirring at room température for 30 minutes, the reaction was refluxed under nitrogen for 2 hours: The reaction mixture was then cooied to 0 °C and reacted with a solution of 2-methylthio éthanol (0.072 g, 0.8 mmol) in dichloroethane (1 mL). After stirring the reaction mixture for 10 minutes, a solution of /V,N-dimethylaminopyridine (0.105 g, 0.8 mmol) in dichloroethane (1 mL) was added via pipette. The ice bath was removed after 10 minutes. The reaction mixture was stiired at room température for 15 minutes, refluxed under nitrogen for 14 hours, cooied,· concentrated under reduced pressure and purified using reversed phase chromatography to, afford the title compound as a yellow solid (0.043 g, 17 %): mp 150-152 °C; ¹H NMR (400 MHz, CDCI₃,) Π 8.91 (s, 1 H), 8.57 (d, J = 2.5 Hz, 1H), 8.05 (ddd, J = 8.8, 2.8, 1.8 Hz, 1H), 3.86 (s, 3H), 3.33 -3.30 (m, 2H), 2.84 -2.80 (m, 2H), 2.22 (s, 3H); ESIMS m/z 345 ([M+Hf).

Example 17: Préparation of [5-(5-fluoro-pyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-metliylthiocarbamic acid ethyl ester - (Compound 80) i

A 20 % solution of phosgene in toluene (0.26 mL, 0.5 mmol) was pipetted at a dropwise rate into an ice-cold suspension of methyl-[5-(5'-fluoropyridin-3'yl)-[1,3,4]thiadiazol-2-yl]-amine (0.1 g, 0.5 mmol) in dichloroethane (3 mL), stirred for 10 minutes, and treated with a solution of N,Ndimethylaminopyridine (0.128 g, 1 mmol) in dichloroethane (2 mL). The ice bath was removed after 10 minutes and, after stirring at room température for 30 minutes, the reaction was refluxed under nitrogen for 2 hours, cooled to T°C^:,^;and reacted with neat ethanethiol (0.031 g, 0,5 mmol). The ice bath was removed after 10 minutes and, after stirring at room température for 30 minutes, the reaction was refluxed under nitrogen for 9 hours, cooled to room température, and diluted with dichloroethane (40 mL). The reaction mixture was washed with dilute hydrochloric acid (0.1 N, 2 X 20 mL), saturated aqueous sodium bicarbonate (50 mL), brine (30 mL), dried over MgSO4and chromàtogràphed on silica to give the title compound as a white solid (0.154 g, 100 %): ¹H NMR (CDCI3, 400 MHz) □ 8.91 (s, 1H), 8.56 (d, J- 2.8 Hz, 1H), 8.06 (ddd, J = 8.8, 2.8, 1.8 Hz, 1H), 3.84 (s, 3H), 3.10 (q, J = 7.4 Hz, 2H), 1.41 (t, J = 7.4 Hz, 2H); ESIMS m/z 299 ([M+H]⁺)..

Example 18: Préparation of1-[5-(5-fluoro-pyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-1-methyl-3-(2methylsulfanyl-ethyl)-thiourea - (Compound 86)

A solution of thiophosgene (0.13 mL, 1.7 mmol) in dichloroethane (1 mL) was pipetted at a dropwise rate into an ice-cold suspension of methÿl-[5-(5-fluoropyridin-3-yl)-[1,3,4]thiadiazol-2yl]-amine (0.319 g, 1.5 mmol) in dichloroethane (5 rhL). The reaction mixture was stirred for 10 minutes and treated with a solution of 4-A/,/V-dirriethylaminopyridine (0.222 g, 1.8 mmol) in dichloroethane (2 mL). The ice bath was removed after 15 minutes. The reaction mixture was stirred at room température for 20 minutes, refluxed under nitrogen for 4 hours, cooled to 0 °G, and treated with a solution of 2-methylsulfanyl-ethylamine (0.145 g, 1.6 mmol) in dichloroethane (1 mL). The reaction mixture was stirred for 5 minutes before adding a solution of 4-N,Ndimethylaminopyridine (0.222g, 1.8 mmol) in dichloroethane (2 mL), followed by removal of the ice bath after 15 minutes. The reaction mixture was stirred at room température for 20 minutes,

refluxed under nitrogen for 14 hours, cooled, concentrated under reduced pressure, and purified by reversed phase high performance liquid chromatography to give the title compound as a brown glass (0.051 g, 10 %): ¹H NMR (400 MHz, DMSO-d₆) ΠΟ9.22 (t, J= 5.3 Hz, 1H), 8.98 (s, 1H), 8.72 (d, J = 2.8 Hz, 1H), 8.26 (dt, J = 9.4, 2.3 Hz, 1H). 3.88 (s, 3H), 3.83 - 3.78 (m, 2H), 2.77 (t, J= 7.3 Hz, 2H), 2.14 (s, 3H); ESIMS m/z 344 ([M+H]*).

• ⁵ . Fl 5 .

Compound 95 was prepared as described in Example 18.

Example 19: Préparation of1-[5-(5-fluoro-pyrÎdin-3-ylH1,3₎4]thiadiazol-2-yl]-1-methyl-3-(2methylsulfanyl-ethyl)-urea - (Compound 79)

A suspension of methyl-[5-(5-fluoropyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-amine (0.2 g, 0.9 mmol) in ice-cold dichloroethane (3 mL) was treated with a 20 % solution of phosgene in toluene (0.52 mL, 1 mmol) and stirred for 10 minutes before the addition of a solution of 4-Λ/,Λ/dimethylaminopyridine (0.256 g, 2.1 mmol) Ίπ/clictirloroethane (2 mL). The cooling bath was removed after 10 minutes. The reaction mixture was stirred at room température for 30 minutes, refluxed under nitrogen for 2 hours, cooled to 1 °C and treated with a solution of 2methylsulfanyl-ethylamine (91 mg, 1 mmol) in dichloroethane (3 mL) at a dropwise rate via a pipette. The ice bath was removed after 10 minutes and after stirring for 30 minutes at room température, the reaction mixture was refluxed under nitrogen for 3 hours, cooled, and diluted with dichloroethane (30 mL). The reaction mixture was washed with dilute hydrochloric acid (0.1 N, 2 X 15 mL), saturated aqueous sodium bicarbonate (30 mL), brine (20 mL), and then dried over MgSO₄ and chromatographed on silica to afford the title compound as a white solid (0.26 g, 84 %): mp 100-104 °C; ¹H NMR (400 MHz, CDCl₃) □ 8.88 (s, 1H), 8.55 (d, J= 2.8 Hz, 1H), 8.02 (ddd, J =8.9, 2.7, 1.7 Hz, 1H), 6.92 (br, 1 H), 3.71 (s, 3H), 3.65-3.59 (m, 2H), 2.76 (t, J = 6.6 Hz, 2H), 2.16 (s, 3H); ESIMS m/z 328 ([M+tjlf).

Example 20: Préparation of 1-[5-(5-fluoro-pyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-1,3-dimethyl-

3-(2-methylsulfanyl-ethyl)-urea (Compound 83} ’

-2316335

An ice-cold solution of 1-[5-(5-fluorOrpyridin-3-yl)-[1,3,4]thiadrazol-2-yl]-1-methyl-3-(2' r £ methylsulfanyl-ethyl)-urea (0.132 g, 0.4 mmol) in N./V-dimethylformamide (0.6 mL) was treated .- -. i i . ;

with sodium hydride (60% in minerai oil, 0.018 g, 0.4 mmol) and stirred for 5 minutes before addition of a solution of iodomethane (0.063 g, 0.4 mmol) in A/,A/-dimethylformamide (0.1 mL). The ice bath was removed after 5 minutes. The reaction mixture was stirred at room température for 14 hours, diluted with water (30 mL) and extracted with EtOAc (3 X 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO₄, purified by normal and reversed phase chromatography to give the title compound as a colorless gum (0.027 g, 20 %): IR (KBr thin film) 1658 cm’¹; ¹H NMR (400 MHz, CDCI₃) □ 8.87 (s, 1H), 8.53 (d, J- 3.2 Hz, 1H), 8.02 (ddd, J= 9.1,4.5, 1.7 Hz, 1H), 3.66 (s, 3H), 3.59 (t, J= 6.8 Hz, 2H), 3.06 (s, 3H), 2.78 (t, J = 7.1 Hz, 2H), 2.14 (s, 3H); ESIMS_; m/z 342 ([M+H]*).

Example 21: Synthesis of N-methÿl-4-oxo-N-[5-(3-pyridyl)-1,3,4-thiadiazol-2-

4-oxopentanoyl chloride (0.378 g, 2.8 mmol) was added to a suspension of N-methyl-5-(3pyridyl)-1,3,4-thiadiazol-2-amine (0.3 g, 1.6 mmol) and 4-N,N-dimethylaminopyridine (0.229 g, 1.9 mmol) in dichloroethane (5 mL), stirred under nitrogen at room température for 30 minutes, refluxed for 14 hours, cooled, diluted with dichloroethane (50 mL) and washed with saturated aqueous sodium bicarbonate (70 mL). The aqueous layer was extracted with dichloroethane (30 mL) and the combined organic layers were dried over MgSO₄, adsorbed on silica, applied to a Michel-Miller column and eluted with 9:1 ethyl acetate / hexane. The major fraction was collected and recrystallized from ethyl acetate / hexane to afford yellow needles. Yield 0.21 g (46 %): mp 146-147 °C; IR (KBr, thin film) 1701, 1659 cm’¹; ^qHNMR (400MHz, CDCI₃) □ 9.13 (d, J = 1.8 Hz, 1H), 8.69 (dd, J = 4.8, 1.5 Hz, 1H), 8.28 (dt, J = 6.2, 1.9 Hz, 1H), 7.42 (dd, J = 8.O., 5.1 Hz, 1H), 3.90 (s, 3H), 2.96 (br, 4H),, 2.29 (s, 3H); ESIMSm/z291 ([M+H]*).

. Il ψί * ' T'' 1'

Example 22: Préparation of 3-(cÿanoamino)-N’methyl-N-[5-(3-pyridyl)-1₍3,4-thiadiazol-2i yljpropanamide (Compound 23)

Cyanamide (42 mg, 1.0 mmol ) and /V-methyl-S-methylsulfanyl-AHS-fS-pyridylJAS^-thiadiazol; ¹ ‘

2-yl]propanamide (294 mg, 1.0 mmol) were suspended in THF and cooled in a -10 °C bath. lodobenzene diacetate (322 mg, 1.0 mmol) was added and the resulting suspension was stirred 5 at for 4 h. The reaction mixture was concentrated under reduced pressure and purified by reversed phase silica chromatography elutirig with an aqueous acetonitrile mobile phase to yield a white solid (84 mg, 29%): mp 155-159 °C; ÎH NMR (300 MHz, CDCI₃) δ 9.15 (m, 1H), 8.72 (m, 1H), 8.35 (m, 1H), 7.45 (m, 1 H), 4.70 (bs,' IH), 3.90 (s, 3H), 3.55 (m, 2H), 3.05 (m, 2H);

ESIMS m/z 289 ([M+H]⁺). .

Example 23: Préparation of 4-[(E)-methoxyimino]-pentanoic acid methyl-(5-pyridin-3-yl- [1,3,4] thiadiazol-2-yl)-amide (Cornpound 48)

O O

4-[(E)-methoxyimino]-pentanoic acid methyl-(5-pÿridin-3-yl-[1,3,4] thiadiazol-2-yl)-amide was prepared as described in JFW Keana et al. in J, Org. Chem., 1985, 50, 2346. A suspension of O-methylhydroxylamine hydrochloride (0.065 g, .0.9 mmol), 4-oxo-pentanoic acid methyl-(5pyridin-3-yl-[1_l3,4]thiadiazol·2-yl)-qrnide (0.18 9;jp-6· mmol) and sodium acetate (0.076 g, 0.9 mmol) in anhydrous éthanol was refluxed under nitrogen for 14 hours, cooled, concentrated under reduced pressure and chromatographed on silica to afford the title cornpound as an amorphous yellow solid (0.071 g, 36 %): mp 114-121 °C; H NMR (400 MHz, CDCI₃) ΠΟ9.15 (d,J= 1.8 Hz, 1H), 8.70 (dd, J = 4.8, 1.8 Hz, 1H), 8.29 (dt, J = 5.9, 1.8 Hz, 1H), 7.43 (dd, J =

7.7, 5.2 Hz, 1H), 3.92 (s, 3H), 3.86, 3.83 and 3.77 (ail s, 1H), 2.95 (q, J =7.0 Hz, 2H), 2.71 (q, J = 7.4 Hz, 2H), 2.11, 1.98 and 1.89 (ails, 3H); ESIMS m/z 320 ([M+H]⁺).

Example 24: Préparation of (E)-N-methyl-3-(methylthio)-N-(5-(pyridin-3-yl)-1,3,4thiadiazol-2-yl)acrylamide (Cornpound 21) ?<· I . -k .’ | • . > tJ· '-25-

/V-Chlorosuccinimide (100 mg, 0.75 mmol, 1.1 equiv) was added to a stirred solution of Nmethyl-3-(methylthio)-A/-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanamide (200 mg, 0.68 mmol, 1.0 equiv) in benzene (3.3 mL) at 23 °C. The resulting cloudy yellow solution was stirred at 23 5 °C for 30 m. Triethylamine (210 pL, 1.5 mmol, 2.2 equiv) was added and the resulting bright yellow mixture was stirred at 23 °C for 24 h. The réaction mixture was directly subjected to silica gel column chromatography (ethyl acetate) to afford the title compound as a tan powder (80 mg, 40%): ¹H NMR (300 MHz, DMSO-cfc) δ 9.14 (brs/IH), 8.67 (m, 1H), 8.27 (m, 1H), 8.11 (d, J =

Hz, 1H), 7.41 (m, 1H), 6.30 (d, J = 14 Hz, 1 H), 3.91 (s, 3H), 2.46 (s, 3H); ESIMS m/z 293 10 ([M+H]*). \ '

Example 25: Préparation of /V-methyl-/V-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-(tritylthio) propanamide (Compound 22)

Oxalyl chloride (380 pL, 4.3 mmol, 1.5 equiv)'and /V,/V-dimethylformamide (11 pL, 0.14 mmol,

0.05 equiv) were sequentially added to a stirred suspension of 3-(tritylthio)propanoic acid (1.0 g,

2.9 mmol, 1.0 equiv) in toluene (10 mL) at 23 °C. Thé resulting bubbling white suspension was stirred at 23 °C for 17 h. The reaction mixture was concentrated by rotary évaporation. A portion of the resulting product, 3-(tritylthio)propanoyl chloride (400 mg, 1.1 mmol, 1.1 equiv), was added to a stirred suspension of N-methyl-5-(pyridin“3-yl)-1,3,4-thiadiazol-2-amine (190 mg, 1.0 mmol, 1.0 equiv) and 4-diméthylaminopyridïâe^t (150 mg, 1.2 mmol, 1.2 equiv) in dichloromethane (3.0 mL) at 23 °C. The resulting yellow solution was stirred at 23 °C for 15 h.

The reaction mixture was diluted with a saturated solution of sodium bicarbonate (40 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried (Na2SO₄), 25 gravity-filtered, and concentrated by rotary évaporation. The residue was purified by silica gel column chromatography (ethyl acetate) to afford the title compound as a white foam (450 mg, 87%): mp 60-75 °C; IR (KBr thin film) 3438 (w), 3024 (w), 2909 (w), 2742 (w), 2649 (w), 2565 (w), 1701 (s) cm'¹; ¹H NMR (300 MHz, CDCI₃) δ 9.12 (d, J = 2 Hz, 1H), 8.67 (dd, J = 5, 2 Hz,

1H), 8.25 (dt, J = 8, 2 Hz, 1H), 7.18-7.50 (m. 16H), 3.58 (s, 3H), 2.73 (t, J = 7 Hz, 2H), 2.34 (t, J 30 = 7 Hz, 2H); ESIMS m/z 523 ([M+H]*). . ...

i

J

Ί i

ΐ i J i

Example 26: Préparation of S-mercapto-N-methyl-N-ÎS-Îpyridin-S-ylJ-I^Athiadiazol^yl)propanamide (Compound 25) ,

SH

Triethylsilane (76 pL, 0.48 mmol, 5.0 equiv) and trifluoroacetic acid (710 pL, 5.7 mmol, 100 equiv) were sequentially added to a stirred solution of N-methyl-N-(5-(pyridin-3-yl)-1,3,4thiadiazol-2-yl)-3-(tritylthio)propanamide (50 mg; 0.096 mmol, 1.0 equiv) in dichloromethane (1.3 10 mL) at 23 °C. The resulting solution was stirred at 23 °C for 30 m. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (40 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried (Na₂SO₄), gravity-filtered, and concentrated by rotary évaporation. The residue was purifîed by silica gel column chromatography (ethyl acetate) to afford the titlè compound as a white powder (23 mg, 85%): 15 mp 149-151 °C; ¹H NMR (300 MHz, CDCI₃) δ 9.17 (br s, 1H), 8.71 (m, 1H), 8.29 (m, 1H), 7.44 (dd, J = 8, 5 Hz, 1 H), 3.87 (s, 3H), 2.91-310 (m, 4H), 1.87 (t, J = 8 Hz, 1H); ESIMS m/z 281 ([M+H]⁺).

Example 27: Préparation of S-3-(methyl(5-(pyridin-3-y 1)-1,3,4-thiadiazol-2-yl)amino)-320 oxopropyl ethanethioate (Compound 26)

Triethylamine (12 pL, 0.086 mmol, 1.2 equiv) and acetyl chloride (6 pL, 0.08 mmol, 1 equiv) were sequentially added to a stirred solution pfi;3-mercapto-/V-methyl-N-(5-(pyridin-3-yl)-1,3,4thiadiazol-2-yl)propanamide (20 mg, 0.071 mmol, 1.0 equiv) in 1,2-dichloroethane (1.4 mL) at 25 23 °C. The resulting pale yellow solution was stirred at 23 °C for 16 h. The reaction mixture was directly subjected to silica gel column chromatography (ethyl acetate) to afford the title compound as a white powder (23 mg, 99%): mp 133-135 °C; ¹H NMR (300 MHz, CDCI₃) δ 9.14 (d, J = 2 Hz, 1H), 8.69 (dd, J =5, 2 Hz, 1H), 8.27 (dt, J = 8, 2 Hz, 1H), 7.42 (dd, J = 8, 5 Hz, 1H), 3.82 (s, 3H), 3.26 (t, J = 7 Hz, 2H), 3.03 (t. J = 7 Hz, 2H), 2.36 (s, 3H); ESIMS m/z 323 30 ([M+H]*).

Example 28: Préparation of /V-methyl-/V-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3(trifluoromethylthio) propanamide {Compound 27)

A 2M solution of sodium hydroxide (40 pL, 0.078 mmol, 1.1 equiv) was added to a stirred suspension of 3-mercapto-A/-methyl-/V-(5-(pyridin'3-yl)-1,3,4-thiadiazol-2-yl)propanamide (20 mg, 0.071 mmol, 1.0 equiv) in acetonitrile (2.1 mL) at 23 °C. Gaseous trifluoromethyl iodide was bubbled into the resulting solution at a steady rate for 5 m. The glass reaction vessel was sealed and the resulting cloudy pale yellow solution was exposed to a Sylvania sun lamp at a distance of ~6 inches for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried (MgSO₄), gravityfiltered, and concentrated by rotary évaporation. The residue was purified by silica gel column chromatography (ethyl acetate) to afford a yellow,film (6 mg, 24% yield): ¹H NMR (300 MHz, CDCI3) δ 9.15 (d, J = 2 Hz, 1H), 8.70 (dd, J = 5, 2 Hz, 1H), 8,28 (dt, J = 6,2 Hz, 1H), 7.43 (dd, 1 H, J = 8, 5 Hz, 1 H), 3.86 (s, 3H), 3.30 (t, J = 7 Hz, 2H), 3.16 (t, J = 7 Hz, 2H); ESIMS m/z 349 ([M+Hf).

Example 29: Préparation of N-2,2-trimethyl-3-(methyl-/V-cyano-sulfilimÎnyl)-N-(5-(pyridin3-yl)-1,3,4-thiadiazol-2-yl)propanamide (Compound 39)

' ? f

Cyanamide (8 mg, 0.19 mmol, 1.2 equiv) and.iodobenzene diacetate (55 mg, 0.17 mmol, 1.1 equiv) were sequentially added to a stirred solution of AI,2,2-trimethyl-3-(methylthio)-/V-(5i · ? f ' (pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanamide (50 mg, 0.16 mmol, 1.0 equiv) in 1,4-dioxane (2.0 mL) at 23 °C. The resulting solution was stirred at 23 °C for 3 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (40 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried (Na₂SO₄), gravityfiltered, and concentrated by rotary évaporation. The residue was dissolved in acetonitrile (30 mL) and washed with hexane (5 x 20 mL). The acetonitrile layer was concentrated by rotary évaporation to afford the title compound as a white foam (56 mg, 99% ): mp 42-52 °C; IR (KBr thin film) 2994 (w), 2143 (s), 1638 (m) cm'¹; ¹H NMR (300 MHz, CDCI₃) δ 9.13 (d, J = 2 Hz, 1H),

-2816335

872 (dd, J = 5, 2 Hz, 1H), 8.31 (dt, J = 8, 2 Hz, 1H), 7.44 (dd, J = 8, 5 Hz, 1H), 4.00 (s, 3H),

3.59 (d, J= 13 Hz, 1H), 3.24 (d, J = 13 Hz, 1 H), 3.09 (s, 3H). 1.88 (s, 3H), 1.66 (s, 3H); ESIMS m/z 363 ([M+H]*).

* J fj,·· i J j !

Example 30: Préparation of 2-(aminomethyl)-N-[5-(5-fluoro-3-pyridyl)-1,3,4~thiadiazol-2yl]-N,2-dimethyl-3-methylsulfanyl-propanamide (Compound 89)

suspension of 2-cyano-N-[5-(5-fluoro-'3-pyridyl)-1,3.4-thiadiazol-2-yl]-N,2-dimethyl-3 methylsulfanyl-propanamide (157 mg, 0.4 mmol) and platinum oxide (131 mg, 0.6 mmol) in glacial acetic acid (8 mL) was reduced under 45 psi of hydrogen at room température for 16 hours, filtered through Celîte and concentrated under reduced pressure. The residue was treated with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (3

X 50 mL). Organic extracts were concentrated under reduced pressure and purified by reversed phase silica chromatography eluting with an aqueous acetonitrile mobile phase. Yield 33 mg (21 %): mp 154-157 °C; IR (KBr thin film) 1656,, 1383 cm'¹; ¹H NMR (400 MHz, CDCI₃) □ 11.17 (br, 1H), 9.02 (t, J= 1.6 Hz, 1H), 8.43 (d, J = 2.8 Hz, 1H), 8.11 (ddd, J = 9.8, 2.8, 1.8 Hz, 1H), 3.87 (d, J = 2.9 Hz 1H), 3.48 (s, 3H), 3.47 (d, J = 2,9 HZ, 1H), 2.99 (d, J = 12.7 Hz, 1H), 2.78 (d, J = 13.6 Hz, 1H), 2.20 (s, 3H), 1.41 (s, 3H); ESIMS (m/z) 356 [M+H]⁺.

Example 31: Préparation of 3-amino-N-methyl-N-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2yl)propanamide (Compound 41)

Triethylsilane (530 pL, 3.3 mmol, 5.0 equiv)-and'trifluoroacetic acid (4.9 mL, 66 mmol, 100 equiv) were sequentially added to a stirred solution of tert-butyl 3-(methyl(5-(pyridin-3-yl)-1,3,4thiadiazol-2-yl)amino)-3-oxopropylcarbamate (24Ô^! mg, 0.66 mmol, 1.0 equiv) in dichloromethane (8.8 mL) at 23 °C. The resulting colorless solution was stirred at 23 °C for 30 -29’-,

m. The reaction mixture was concentrated bÿ rotary évaporation. The residue was diiuted with a saturated solution of sodium bicarbonate (80 mL) and extracted with dichloromethane (8 x 50 mL). The combined organic layers were dried (Na₂SO₄), gravity filtered, and concentrated by rotary évaporation to afford the title compound as a tan powder (86 mg, 49%): mp 110-112 °C; IR (KBr thin film) 3047 (w), 2926 (w), 1682 (sj, 1591 (m) cm'¹; ¹H NMR (300 MHz, CDCI₃) δ 9.15 (d, J = 2 Hz, 1H), 8.69 (dd, J = 5, 2 Hz, IH), 8.28 (dt, J = 8, 2 Hz, 1H), 7.43 (dd, J = 8, 5 Hz, 1H), 3.86 (s, 3H), 3.17 (m, 2H), 2.86 (t, J= 6 Hz,‘2H); ESIMS m/z 264 ([M+H]⁺).

Example 32: Préparation of N-2,2-trimethyl-3-(methyl-N-cyano-sulfoximinyl)-/V-(5-(pyridin3-yl)-1,3,4-thiadiazol-2-yl)propanamide (Compound 42)

A solution of N_]2,2-trimethyl-3-(methyl-A/-cyano-sùlfiliminyl)-A/-(5-(pyridin-3-yl)-1,3,4-thiadiazol2-yl)propanamide (100 mg, 0.29 mmol, 1.0 equiv) in absolute éthanol (2.0 mL) was added to a stirred suspension of powdered potassium çarbonate (87 mg, 0.63 mmol, 2.2 equiv) and metachloroperoxybenzoic acid (73 mg, 0.32 mmol, ,1.1, equiv) in water (1.0 mL) at 23 °C. The resultîng yellow solution was stirred at 23 °C fof Ί h. The réaction mixture was diiuted with a saturated solution of sodium bicarbonate (40'mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried (Na₂SO₄), gravity-filtered, and concentrated by rotary évaporation. The residue was purified by silica gel column chromatography (ethyl acetate) to afford the title compound as a white foam (36 mg, 33%): IR (KBr thin film) 2992 (w), 2926 (w), 2192 (s), 1649 (s) cm’¹; ¹H NMR (300 MHz, CDCI₃) δ 9.12 (br s, 1H), 8.70 (dd, J = 5 Hz, 1H), 8.29 (dt, J = 8, 2 Hz, 1H), 7.43 (dd, J = 8, 5 Hz, 1H), 4.21 (d, J = 14 Hz, 1H), 3.97 (s, 3H), 3.68 (d, J = 14 Hz, 1H), 3.53 (s, 3H), 1.92 (s_f 3H), 1.63 (s, 3H); ESIMS m/z 379 ([M+H]⁺).

Example 33: Préparation of 2-(methylthiomethyl)-3-phenylpropanoic acid

Préparation of diethyl 2-benzyl-2-(methylthiomethyl)malonate - Chloromethyl methyl sulfide (1.4 mL, 17 mmol, 1.0 equiv) and 60% sqdium hydride in minerai oil (750 mg, 19 mmol, 1.1 equiv) were sequentially added to a stirred solution of diethyl 2-benzylmalonate (4.0 mL, 17 mmol, 1.0 equiv) in A/,A/-dimethylformamide (34 mL) at 0 °C. The resulting mixture was warmed

ί to 23 °C and stirred for 18 h. The réaction mixture was concentrated under vacuum. The residue was diluted with water (150 mL) and extracted with diethyl ether (4 x 70 mL). The combined organic layers were dried (MgSO₄), gravity-filtered, and concentrated by rotary évaporation to afford a yellow oil (5.3 g, 99%): ¹H NMR (300 MHz, CDCI₃) δ 7.13-7.30 (m, 5H), 4.22 (q, J = 7 Hz, 4H), 3.36 (s, 2H), 2.94 (s, 2H), 2,11 (s, 3H), 1.27 (t, J= 7 Hz, 6H).

Préparation of 2-benzyl-2-(methylthiomethyI)malonic acid - Powdered potassium hydroxide (4.8 g, 86 mmol, 5.0 equiv) was added to a stirred solution of diethyl 2-benzyl-2(methylthiomethyl)malonate (5.3 g, 17 mmol, 1.0 equiv) in 3:1 methanol : water (28 mL) at 23 °C. The resulting pale yellow suspension was heated to 100 °C and stirred for 4 h. The cooled reaction mixture was acidified to pH=9 with concentrated hydrochloric acid and washed with diethyl ether (4 x 50 mL). The aqueous layer_t was acidified to pH=1 with concentrated hydrochloric acid and extracted with dichlorométhane (4 x 60 mL). The combined organic layers were dried (Na₂SO₄), gravity-filtered, and concentrated by rotary évaporation to afford the title compound as a white powder (3.1 g, 72%):.¹H NMR.(300.MHz, DMSO-cfe) δ 7.13-7.34 (m, 5H), 3.15 (s, 2H), 2.73 (s, 2H), 2.08 (s, 3H). j

Préparation

(methylthiomethyl)malonic acid (3.1 g, 12 mmol, 1.0 equiv) was placed in a 50 mL round bottom flask and heated to 170 °C via heating mantle.· Thé resulting liquid was heated neat for 1 h, until bubbling had ceased. The residue was cooled to, afford the title compound as an off-white powder (2.6 g, 99%): ¹H NMR (300 MHz, DMSO-.d₆) δ 12.36 (brs, 1H), 7.16-7.33 (m, 5H), 2.74

2.88 (m, 3H), 2.52-2.69 (m, 2H), 2.04 (s, 3H).

Example 34: Préparation of 1-(methylthiomethÿl)çyclopropanecarboxylic acid

o o ' '
EtO OEt			^OH

-31 16335

Préparation of ethyl 1-(hydroxymethyl)cyclopropanecarboxylate - A 1M solution of lithium aluminum tri-tert-butoxyhydride in tetrahydrofuran (12 mL, 12 mmol, 2.2 equiv) was added to a stirred solution of diethyl cyclopropane-1,1’-dicârboxylate (1.0 mL, 5.7 mmol, 1.0 equiv) in tetrahydrofuran (19 mL) at 23 °C. The resulting solùtion was heated to 65 °C and stirred for 24

h. The cooled reaction mixture was diluted with à 1Ô% solution of sodium bisulfate (100 mL) and extracted with ethyl acetate (4 x 50 mL). The cohibined organic layers were dried (MgSO₄), gravity-filtered, and concentrated by rotary évaporation to afford the title compound as a pale yellow oil (850 mg, 88%): *H NMR (300 MHz, ’CDCI₃) δ 4.16 (q, J = 7 Hz, 2H), 3.62 (s, 2H), 2.60 (br s, 1 H), 1.22-1.30 (m, 5H), 0.87 (dd, J = 7, 4 Hz, 2H). ¹ ίο

Préparation of ethyl 1-((methylsulfonyloxy)methyl)cyclopropanecarboxylate

Triethylamine (990 pL, 7.1 mmol, 1.2 equiv) and methanesulfonyl chloride (500 pL, 6.5 mmol,

1.1 equiv) were sequentially added to a stirred solution of ethyl 1' i . / i; :

(hydroxymethyl)cyclopropanecarboxÿlate (840 mg, 5.7 mmol, 1.0 equiv) in dichloromethane (15 mL) at 23 °C. The resulting bright yellow solution/was stirred at 23 °C for 20 h. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried (MgSO₄), gravity-filtered, and concentrated by rotary évaporation to afford the title comp'ound as a ’b/oivrïOil (1.1 g, 85%): ¹H NMR (300 MHz, CDCI₃) δ 4.33 (s, 2H), 4.16 (q, J= 7 Hz, 2H), 3.08 (s, 3H), 1.43 (dd, J = 7, 4 Hz, 2H), 1.26 (t, J = 7 Hz,

3H), 1.04 (dd, J = 7, 4 Hz, 2H).

Préparation of ethyl 1-(methylthiomethyl)cyclopropanecarboxylate - Sodium methanethiolate (700 mg, 9.9 mmol, 2.0 equiv) was added to a stirred solution of ethyl 1((methylsulfonyloxy)methyl) cyclopropanecarboxylate (1.1 g, 4.9 mmol, 1.0 equiv) in N,N25 dimethylformamide (10 mL) at 23 °C. The resulting brown suspension was stirred at 23 °C for

h. The reaction mixture was diluted with water (500. mL) and extracted with diethyl ether (4 x

100 mL). The combined organic layers were dried (MgSO₄), gravity-filtered, and concentrated l

by rotary évaporation to afford the title compound as a brown oil (860 mg, 99%): ¹H NMR (300

MHz, CDCI₃) 5 4.14 (q, J- 7 Hz, 2H), 2.83 (s, 2H), 2.16 (s, 3H), 1.31 (dd, 7= 7, 4 Hz, 2H), 1.25 (t, 7 = 7 Hz, 3H), 0.89 (dd, 7 = 7, 4 Hz, 2H).

Préparation of 1-(methylthiomethyl)cyclopropanecarboxylic acid - A 50% solution of sodium hydroxide (2.0 mL, 38 mmol, 7.8 equiv) was added to a stirred solution of ethyl 1(methylthiomethyl)cyclopropanecarboxylate (86p-jrng; 4.9 mmol, 1.0 equiv) in absolute éthanol (10 mL) at 23 °C. The resulting solution was stirred at 23 °C for 20 h. The reaction mixture was diluted with a 0.5M solution of sodium hydroxide (100 mL) and washed with dichloromethane (3 x 100 mL). The aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and extracted with dichloromethane (4 x 100 mL). The combined organic layers were dried (Na₂SO₄), gravity-filtered, and concentrated by rotary évaporation to afford a light brown oil (420 mg, 58%): ¹H NMR (300 MHz, CDCI₃) 5 2.82 (s, 2H), 2.17 (s, 3H), 1.41 (dd, 7 = 7, 4 Hz, 2H), 0.99 (dd, 7=7, 4 Hz, 2H).

2-Ethyl-2-[(methylthio)methyl]butanoic acid was prepared as described in Example 34.

Example 35: Préparation of 2-methyl-3-(methylthio)propanoic acid

Powdered potassium hydroxide (1.0 g, 18 mmol, 2.2 equiv) and iodomethane (570 pL, 9.2 mmol, 1.1 equiv) were sequentially added to a stirred solution of 3-mercapto-2-methylpropanoic acid (1.0 g, 8.3 mmol, 1.0 equiv) in methanol (3.7 mL) at 23 °C. The resulting white suspension was heated to 65 °C and stirred for 2 h. The cooled reaction mixture was diluted with a 1M 25 solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried (Na₂SO₄), gravity-filtered, and concentrated by rotary évaporation to afford the title compound as â yellow oil (1.0 g, 91%): ¹H NMR (300 MHz, CDCI₃) δ 2.70-2.89 (m, 2H), 2.57 (dd, J = 12, 6 Hz, 1H); 2.13 (s, 3H), 1.30 (d, 7 = 7 Hz, 3H).

Example 36: Préparation of 2,2-dimethyl-3-(methylthio)propanoic acid

ί '7-

Sodium methanethiolate (1.0 g, 14 mmol, 2.0 equiv) was added to a stirred solution of 3-chloro2,2-dimethylpropanoîc acid (1.0 g, 7.2 mmol, 1.0 equiv) in Λ/,/V-dimethylformamide (3.7 mL) at 0 ’C. The reaction resulting brown suspension was allowed to warm to 23 °C and stirred for 24 h. mixture was diluted with a saturated solution of sodium bicarbonate with diethyl ether (3 x 75 mL). The aqueous layer was acidified

The and with (300 mL) to pH=1 washed concentrated hydrochlorrc acid and extracted with idiethyl ether (3 x 75 mL). The combined organic layers were dried (Na₂SO₄), gravity-filtered/and concentrated by rotary évaporation to afford the title compound as a colorless oil (1.2 g, 99%): *H NMR (300 MHz, CDCI₃) δ 2.76 (s, 2H), 2.16 (s, 3H), 1.30 (s, 6H).

Example 37: Préparation of 3-(tritylthio)proparioÎc acid

Triphenylmethyl chloride (2.7 g, 9.5 mmol, 1.0'equiv) was added to a stirred solution of 3thiopropanoic acid (1.0 g, 9.5 mmol, 1.0 equiv) in Λ/,Ν-dimethylformamide (15 mL) at 23 ’C. The resulting colorless solution was stirred at 23 “G for, 17 h. The reaction mixture was diluted with water (300 mL) and extracted with diethyl ether (4 x 150 mL). The combined organic layers were diluted with dichloromethane (100 mL) and methanol (100 mL) in order to dissolve ail solids, dried (MgSO₄), gravity filtered, and concentrated by rotary évaporation. The residue was rinsed with dichloromethane and vacuum-filtered to afford the title compound as white crystals (2.9 g, 88%): mp 205-208 ’C; ÎR (KBr thin film)'^438 (w), 3024 (w), 2909 (w), 2742 (w), 2649 (w), 2565 (w), 1701 (s) cm'¹; 'H NMR (300 MHz, DMSO-d₆) δ 12.24 (br s, 1H), 7.20-7.40 (m, 15H), 2.28 (t, J = 7 Hz, 2H), 2.16 (t, J = 1 Hz, 2H); ESIMS m/z 347 ([M-H]').

Example 38: Préparation of 3-(tert-Butyl-dimethyl-si la nyloxy)-2,2-di methyl-propion ic acid

HO

OH

HO

3-(tert-Butyl-dimethyl-silanyloxy)-2.2-dimethyl-propiônic acid can be prepared from 3-hydroxy2,2-dimethylpropanoic acid as described in Bioorganîc & Médicinal Chemistry Letters. 2004,

14(12), 3231. '..^Λ·^ί5

Example 39: Préparation of 3-{[2,2-dimethyl-3-(methylth io) propan oyl]oxy}-2,2dimethylpropanoic acid

O

OH

HO

3-{[2,2-d imethyl-3-(methylthio)propanoyl]oxy}-2,2-dimethyl pro pa noie acid can be prepared from 3-hydroxy-2,2-dimethylpropanaic acid as described in Goel, et al. U.S. Patent Application Publication 2005/101572 A1.

Example 40: Préparation of 4-oxopentanoyl chloride

O

OH

O

Cl

O

4-Oxopentanoyl chloride was prepared from 4-oxopentanoic acid as described by Tanaka et al. Biochim Biophys Acta, 1993, 1166, 264. The desired product was isolated as a yellow liquid in 92 % yield: ¹H NMR (300 MHz, CDCI₃) δ 3.00-2.92 (m, 1H), 2.77-2.71 (m, 1H), 2.66-2.59 (m, 1H), 2.46-2.39 (m, 1H), 2.07 (s, 3H); EIMS m/z 131 ([M+H]⁺).

Example 41: Préparation of ethyl 2-cyano-2-methyl-3-methylsulfanyl-propanoate n-Butyllithium (24.2 mL, 60 mmol, 2.5 M solution in hexanes) was added to a solution of isopropylamine (8.1 mL, 58 mmol) in dry ether (70 mL) under nitrogen at a rate needed to maintain température below -60 °C. Upon completion, the reaction was allowed to warm to 10 °C, recooled to -78 °C before addition of ethyl 2-cyanopropanoate (7g, 55 mmol). After stirring at -78 °C for 90 minutes, chloromethylsulfide (4.61 mL, 55 mmol) was added and the mixture was warmed to room température over 14 hours, diluted With ether (350 mL), washed with water (100 mL), brine (100 mL), dried over MgSO₄, concentrated under reduced pressure and distilled at 0.04 mm Hg. Yield of yellow liquid 3.95 g. (38 %): bp 145 °C; IR (KBr thin film) 1751 cm'¹; ¹H NMR (400 MHz, CDCI₃) δ 4.30 (q, J = 7.1 Hz, 2H), 3.08 (d, J = 13.9 Hz, 1H), 2.91 (d, J = 13.9 Hz, 1H), 2.30 (s, 3H), 1.67 (s, 3H), 1.35 (t, J = 7.4 Hz, 3H); EIMS m/z 187.

-3516335

Example 42: Préparation of 2-cyano-2-methyl-3-methylsulfanyl-propanoic acid

i ,l

Ethyl 2-cyano-2-methyl-3-methylsulfanyl-propanoate (2.3 g, 12.3 mmol) was added to ice-cold sodium hydroxide (5 mL, 2N) under stirririg. Methanol (10 mL) was added and the ice bath j 5 removed after an hour. After 45 minutes at room température, volatiles were removed under

J reduced pressure and the residue diluted with water (20 mL). Impurities were removed by ether j extraction (2 X 30 mL). The aqueous layer was cooled in ice, acidified to pH 3 with dilute HCl and extracted with ethyl acetate (3 X 30 mL). Combined organic extracts were dried over j MgSO₄ and concentrated under reduced pressure to leave a brown gum. Yield 1.32 g (68 %): IR ! 10 (KBr thin film) 1735 cm'¹; ¹H NMR (400 MHz, CDCI₃) δ 10.19 (br, 1H), 3.10 (d, J = 14.2 Hz, 1H), i 2.94 (d, J = 13.9 Hz, 1H), 2.33 (s, 3H), 1.73 (s, 3H); ¹³C NMR (400 MHz, CDCI₃) δ 173.33,

I 118.82, 45.86,41.66, 23.05, 17.62.

Example 43: Préparation of 3-allyIsulfanyl-2-methyl-propanoic acid

O o

3-Allylsulfanyl-2-methyl-propanoic acid was prepared as described by Zhou et al. J. Org. Chem.

2004, 69, 7072. An ice-cold mixture of 2-methyl-3-sulfanyl-propanoic acid (5g, 42 mmol) and sodium hydroxide (3.33 g, 83 mmol) in water (50 mL) was treated with a solution of allyl bromide (5.98 g, 49 mmol) in éthanol (100 mL) over 30 minutes. Ice bath was removed after 45 minutes and after 14 hours at room température, volatiles were removed under reduced pressure. The 25 residue was cooled in ice, acidified to pH 6 with 1N HCl and extracted with ethyl acetate, washed with water, dried over MgSO₄, concentrated under reduced pressure and dried in vacuo at room température for 14 hours to leave a clear liquid. Acidification ofthe aqueous layer to pH afforded an additional 2.7 g of material. Total yield 4.44 g (74 %): IR (KBr thin film) 1708 cm'¹;

¹H NMR (400 MHz, CDCI₃) δ 5.83-5.73 (m, 1H), 5.14-5.13 (m, 1H), 5.10-5.09 (m, 1H), 3.15 (d, J 30 = 7.3 Hz, 2H), 2.80 (dd, J = 13:2, 7.0 Hz, 2H), 2.69 (sextet, J = 7.1 Hz, 1H), 2.53 (dd, J = 12.8,

6.5 Hz, 1H), 1.28 (d, J =7.1 Hz, 3H); ¹³C NMR (400 MHz, CDÇI₃) δ 179.01, 131.63, 114.92, 37.38, 32,72, 31.00, 14.19; EIMS m/z 160. Y

Example 44: Préparation of 3-((benzyloxycarbonyl)(methyl)amino)propanoic acid

3-((benzyloxycarbonyl)(methyl)amino)propanoic , acid

was prepared from

3(benzyloxycarbonylamino)propanoic acid as described by Lerchen et al., PCT Int. Appl. 2007/W02007093328 A1. , ' _{r Ί} ¹ . j ' · -i · {' i.C • ··'? ri

Example 45: Insecticidal test for green peach aphid (Myzus persicae) in foliar spray assay

Green peach aphid (MYZUPE) is the most significant aphid pest of peach trees, causing decreased growth, shriveling çf the leaves, and the death of various tissues, It is also hazardous 10 because it acts as a vector for the transport of plant viruses, such as potato virus Y and potato leafroll virus to members of the nightshade/potato family Solanaceae, and various mosaic viruses to many other food crops. MYZUPE attacks such plants as broccoli, burdock, cabbage, carrot, caulifîower, daikon, eggplant, green beans, lettuce, macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, and zucchini, among other plants. MYZUPE also attacks many 15 ornamental crops such as carnation, chrysanthemum, flowering white cabbage, poinsettia, and roses. MYZUPE has developed résistance to man^ pesticides.

Certain molécules disclosed in this document were tested against MYZUPE using procedures described in the following example. ln the reporting of the results, the “MYZUPE, APHIGO and BEMITA Rating Table was used (See Table Section).

Cabbage seedlings grown in 3-inch pots, .with 2-3 small (3-5 cm) true leaves, were used as test substrate. The seedlings were infested with 20-50 green peach aphids (wingless adult and nymph stage) one day prior to chemical application. Four pots with individus! seedlings were used for each treatment. Compounds (2 mg) were dissolved in 2 mL of acetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm. The stock solutions were diluted 5X with 25 0.025% Tween 20 in H₂O to obtaîn the test solution at 200 ppm. A hand-held Devilbiss sprayer was used for spraying a solution to both sides of cabbage leaves until runoff. Reference plants (solvent check) were sprayed with the diluent.only. Treated plants were held in a holding room for three days at approximately 25 ^eC and 40% relative humidity (RH) prior to grading. Evaluation was conducted by counting the number of live aphids per plant under a microscope.

Insecticidal activity data presented in Table 3 were generated by using Abbott’s correction formula:

Corrected % Control = 100 * (X - Y) / X where X = No: of live aphids on solvent check plants

Y = No. of live aphids on treated plants

Example 46: InsecticideI test for cotton aphid (Aphîs gossypit) in a foliar spray assay

Squash or cotton seedlings with fully expanded cotylédon leaves were trimmed to one cotylédon per plant and infested with wingîess adult and nymph stage cotton aphid (APHIGO) one day prior to chemical application. Each plant was examined before chemical application to ensure uniform infestation (ca. 30-70 aphids per plant). Compounds (2 mg) were dissolved in 2 mL of acetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm. The stock solutions were diluted 5X with 0.025% Tween 20 in H₂O to obtain a solution at 200 ppm. A hand-held Devilbiss aspirator type sprayer was used to apply the spray solutions until runoff to both sides of the squash cotylédon leaves. Four plants (4 réplications) were used for each concentration of each compound. Reference plants (solvent check) were sprayed with the diluent only. Treated plants were held in a holding room for three days at approximately 25 °C and 40% RH before the number of live cotton aphids on each plant was recorded. Insecticidal activity data presented in Table 3 were generated by using Abbott's correction formula:

Corrected % Control = 100 * (X - Y) / X where X = No. of live aphids on solvent check plants

Y = No. of live aphids on treated plants

Example 47: Insecticidal test for sweetpotato whitefly (Bemisia tabaci) in foliar spray assay

Cotton plants were used as test substrate and were grown in 3-inch pots and pruned until only 1 small (3-5 cm) true leaf remained_: The. plants were then placed in a room with whitefly (BEMITA) adults and allowed to be infested with eggs. After a 2-3 day egg-laying period, plants were taken from the adult whitefly room and the adults were removed from the leaves using compressed air delivered through a hand-held Devilbiss sprayer (23 psi). Plants infested with eggs (100-300 eggs per plant) were, placed in a controlled-environment room for 56 days at 82 °F and 50% RH, until approxirp.^ely, 50% egg hatch. Four cotton plants (4 replicates) were used for each treatment. Compounds (2 mg) were dissolved in 1 mL of acetone solvent, forming stock solutions of 2000 ppm. The stock solutions were diluted 10X with 0.025% Tween 20 in H₂O to obtain the test solution of 200 ppm. A hand-held Devilbiss sprayer was used for spraying a solution to both sides of cotton leaf until runoff. Reference plants (solvent check) were sprayed with the diluent only. Treated plants were held in a holding room for 8-9 days at approximately 82°F and 50% RH prior to grading. Evaluation was conducted by counting the number of live nymphs per plant under a microscope. Insecticidal activity data presented in Table 3 were generated by using Abbott’s correction formula:

Corrected % Control = 100 * (X - Y) / X where X = No. ,of live nymphs pn solvent check plants

Y = No. of live nymphs on treated plants

PESTICIDALLY ACCEPTABLE ACID ADDITION SALTS, SALT DERIVATIVES, SOLVATES,

ESTER DERIVATIVES, POLYMORPHS, ISOTOPES AND RADIONUCLIDES

Molécules of Formula One may be formulated into pesticidally acceptable acid addition salts. By way of a non-limiting example, an amine function can form salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxymethanesulfonic, and hydroxyethanesulfonic acids. Additionally, by way of a non-limiting example, an acid function can form salts including those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Examples of preferred cations include sodium, potassium, and magnésium.

Molécules of Formula One may be formulated into sait dérivatives. By way of a nonlimiting example, a sait dérivative can be prepared by contacting a free base with a sufficient amount of the desired acid to produce a sait. .A free base may be regenerated by treating the sait with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide (NaOH), potassium carbonate, ammonia, and: sodium bicarbonate. As an example, in many cases, a pesticide, such as 2,4-D, is made more water-soluble by converting it to its dimethylamine sait..

Molécules of Formula One may be formulated into stable complexes with a solvent, such that the complex remains intact after the non-complexed solvent is removed. These complexes are often referred to as solvatés. However, it is particularly désirable to form stable hydrates with water as the solvent.

Molécules of Formula One may be made into ester dérivatives. These ester dérivatives can then be applied in the same manner as the invention disclosed in this document is applied.

Molécules of Formula One may be made as various crystal polymorphs. Polymorphism is important in the development of agrochemiçals since different crystal polymorphs or structures of the same molécule can hâve vastly different physical properties and biological performances.

Molécules of Formula One may be made. with different isotopes. Of particular importance are molécules having ²H (also known as deuterium) in place of ¹H.

Molécules of Formula One ï may be' made with different radionuclides. Of particular importance are molécules having ¹⁴C.

STEREOISOMERS

Molécules of Formula One may exist as one or more stereoisomers. Thus, certain molécules can be produced as racemic mixtures. It will be appreciated by those skilled in the art that one stereoisomer may be more active than the other stereoisomers. Individual

- 39 16335 stereoisomers may be obtained by known sélective synthetic procedures, by conventional synthetic procedures using resolved starting materials, or by conventional resolution procedures,

INSECTICIDES

Molécules of Formula One may also be used in combination (such as, in a compositional i. i . t mixture, or a simultaneous or sequential application) with one or more of the following £ j ! .r L ,_t insecticides - 1,2-dichloropropane; abameçtin, ^céphate, acetamiprid, acethion, acetoprole, acrinathrin, acrylonitrile, alanycarb, aldicarb, aldôxycarb, aldrin, allethrin, allosamidin, allyxycarb, a/p/ïa-cypermethrin, a/pha-ecdysone, a/pba-endosulfan, amidithion, aminocarb, amiton, amiton oxalate, amitraz, anabasine, athidathion, azadirachtin, azamethiphos, azinphos-ethyl, azinphosmethyl, azothoate, barium hexafluorosilicate, barthrin, bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin, bifenthrin, bioallethrin, bioethanomethrin, biopermethrin, bistrifluron, borax, boric acid, bromfenvinfos, bromocyclen, bromo-DDT, bromophos, bromophos-ethyl, bufencarb, buprofezin, butacarb, butathipfos, butocarboxim, butonate, butoxycarboxim, cadusafos, calcium arsenate, calcium polysulfide, camphechlor, carbanolate, carbaryl, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, cartap, cartap hydrochloride, chlorantraniliprole', chlorbicyclen, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chîorfluazuron, chlormephos, chloroform, chloropicrin, chlorphoxim, chlorprazophos, chlorpyrifos, chlorpyrifos-methyl, chiorthiophqs.ichrpmafenozide, cinerin I, cinerin II, cinerins, cismethrin, cloethocarb, closantel.clothianidin/copper .acetoarsenite, copper arsenate, copper naphthenate, copper oleate, coumaphos, coumithoate, crotamiton, crotoxyphos, crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate,, cyantraniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, diafenthiuron, dialifos, diatomaceous earth, diazinon, dicapthon, dichlofenthion, dichlorvos, dicresyl, dicrotophos, dicyclanil, dieldrin, diflubenzuron, dilor, dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dimethylvinphos, dimetilan, dinex, dinex-diclexine, dinoprop, dinosam, dinotefuran, diofenolan, dioxabenzofos, dioxacarb, dioxathion, disulfoton, dithicrofos, d-limonene, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodïum, doramectin, ecdysterone, emamectin, emamectin benzoate, EMPC, empenthrin, endosylfan, endothion, endrin, EPN, epofenonane, eprinomectin, esdepalléthrine, esfenvalerate, etaphos, ethiofencarb, ethion, ethiprole, ethoatemethyl, ethoprophos, ethyl formate, ethyl-DDQ, ethylene dibromide, ethylene dichloride, ethylene oxide, etofenprox, etrimfos, EXD,. famphur, fenamiphos, fenazaflor, fenchlorphos, fenethacarb, fenfluthrin, fenitrothion^, fenobucarb, fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin, fensulfothion, fenthion, fenthipn-ethyl, fenvalerate, fipronil, flonicamid, -40-

flubendiamide (additionallv resolved isomers thereof), flucofuron, flucycloxuron, flucythrinate, flufenerim, flufenoxuron, flufenprox, fluvalinate, fonofos, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosmethilan, fospirate, fosthietan, fufenozide, furathiocarb, furethrin, gamma-cyhalothrin, gamma-HCH, halfenprox, halofenozide, HCH, HEOD, heptachlor, heptenôphos, heterophos, hexaflumuron, HHDN, hydramethylnon, hydrogen cyanide, hydroprefie, hyquincarb, imidacloprid, imiprothrin, indoxacarb, iodomethane, IPSP, isazofos, isobenzan, isocarbophos, isodrin, isofenphos, i “ q isofenphos-methyl, isoprocarb, isoprothiolane, usothioate, isoxathion, ivermectin, jasmolin I, jasmolin II, jodfenphos, juvénile hormone I, juvehilë hormone II, juvénile hormone III, kelevan, kinoprene, lambda-cyhalothrin, lead arsenatë, lëpimectin, leptophos, lindane, lirimfos, lufenuron, lythidathion, malathion, malonoben, mazidox, mecarbam, mecarphon, menazon, meperfluthrin, mephosfolan, mercurous chloride, mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion, methiocarb, methocrotophos, methomyl, methoprene, methothrin, methoxychlor, methoxyfenozide, methyl bromide, methyl isothiocyanate, methylchloroform, methylene chloride, metofluthrin, metolcarb, metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime, mipafox, mirex, molosultap, monocrotophos, monomehypo, monosultap, morphothion, moxidectin, naftalofos, naled, naphthalene, nicotine, nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron, noviflumuron. omethoate, oxamyl, oxydemeton-methyl, oxydeprofos, oxydisulfoton, para-dichlorobenzenç; parathion, parathion-methyl, penfluron, pentachlorophenol, permethrin, phenkapton, phenothrin, phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor, phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite, potassium thîocyanate, pp'-DDT, prallethrin,. precocene, Ι_Γ; precocene II, precocene III, primidophos, profenofos, profluralin, profluthrin, promacyl, promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos, prothoate, protrifenbute, pymetrozine, pyraclofos, pyrafluprole, pyrazophos, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyridaben, pyridalyl, pyridaphenthion, pyrîfluquinazon, pyrimidifen, pyrimitate, pyriprole, pyriproxyfen, quassia, quinalphos, quinalphos-methyl, quinothion, rafoxanide, resmethrin, rotenone, ryania, sabadilla, schradan, selamectin, silafluofen, silica gel, sodium arsenite, sodium fluoride, sodium hexafluorosilicate, sodium thîocyanate, sophamide, spinetoram, spinosad, spiromesifen, spirotetramat, sulcofuron, sulcofuron-sodium, sulfluramid, sulfotep, sulfoxaflor, sulfuryl fluoride, sulprofos, tau-fluvalinate, tazimcarb, TDE, tebufenozide, tebufenpyrad, tebupirimfos, teflubenzuron, tefluthrin, temephos, ΤξΡΓ?,< gterallethrin, terbufos, tetrachloroethane, tetrachlorvinphos, tetramethrin, tetramethylfluthrin, ffiefa-cypermethrin, thiacloprid, thiamethoxam, thicrofos, thiocarboxime, thîocyclam, thiocyclam oxalate, thiodicarb, thiofanox, thiometon, thiosultap, thiosultap-disodium. Thiosultap-monosodium, thuringiensin, tolfenpyrad, tralomethrin, transfluthrin, transpermethrin,tri^athene,, triazamate, triazophos, trichlorfon, trichlormetaphos-3, trichloronat, trifenofos, triflumuron, trimethacarb, triprene, vamidothion, ' A MH;'. ' vaniliprole, XMC, xylylcarb, zeta-cypermethriri/ ancl zolaprofos (collectively these commonly named insecticides are defined as the Insecticide Group”).

ACARICIDES

Molécules of Formula One may also be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more of the following acaricides - acequinocyl, amidoflumet, arsenous oxide, azobenzene, azocyclotin, benomyl, benoxafos, benzoximate, benzyl benzoate,' bifenazate, binapacryl, bromopropylate, chinomethionat, chlorbenside, chlorfenethol, chlôrfenson, chlorfensulphide, chlorobenzilate, chloromebuform, chloromethiuron, chloropropyJate·, clofentezine, cyenopyrafen, cyflumetofen, cyhexatin, dichlofluanid, dicofol, dienochlor,' diflovidazin, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinopenton, dinosulfon,: dinoterbon, diphenyl sulfone, disulfiram, dofenapyn, etoxazole, fenazaquin, fenbutatin oxide, fenothiocarb, fenpyroximate, fenson, fentrifanil, fluacrypyrim, fluazuron, flubenzimine, fluenetil, flumethrin, fluorbenside, hexythiazox, mesulfen, MNAF, nikkomycins, proclonol, propàrgite, quintiofos, spirodiclofen, suifiram, sulfur, tetradifon, tetranactin, tetrasul, and thioquinox (collectively these commonly named acaricides are defined as the Acaricide Group”).

NEMATICIDES

Molécules of Formula One may also be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more of the following nematicides - 1,3-dichloropropene, benclothiaz, dazomet, dazomet-sodium, DBCP, DCIP, diamidafos, fluensulfone, fosthiazate, furfural, imicyafos, isamidofos, isazofos, metam, metamammonium, metam-potassium, metam-sodium,,· phosphocarb, and thionazin (collectively these commonly named nematicides are defined as the “Nematicide Group”)

FUNGICIDES J, J ;

Molécules of Formula One may also Iqe u?éç|4n combination (such as, in a compositional mixture, or a simultaneous or sequential· application) with one or more of the following fungrcides - (3-ethoxypropyl)mercury bromide, ,-2-methoxyethyl mercury chloride, 2-phenylphenol, 8-hydroxyquinoline sulfate, 8-phenylmercurioxyquinoline, acibenzolar, acibenzolar-S-methyl, acypetacs, acypetacs-copper, acypetacs-zinc, aldimorph, allyl alcohol, ametoctradin, amisulbrom, ampropylfos, anilazine, aureofungin, azaconazole, azithiram, azoxystrobin, barium polysulfide, benalaxyl, benalaxyl-M, benodanil, benomyl, benquinox, bentaluron, benthiavalicarb, benthiavalicarb-isopropyl, benzalkonium chloride, benzamacril, benzamacrilisobutyl, benzamorf, benzohydroxamic acid, bethoxazin, binapacryl, biphenyl, bitertanol, bithionol, bixafen, blasticidin-S, Bordeaux mixtMjre, boscalid, bromuconazole, bupirimate, Burgundy mixture, buthîobate, butylamine, calcium: polysulfide, captafol, captan, carbamorph,

. ϊ L-i¹ :

carbendazim, carboxin, carpropamid, carvone, Cheshunt mixture, chinomethionat, chlobenthiazone, chloraniformethan, chloranil, chlorfenazole, chlorodinitronaphthalene, chloroneb, chloropicrin, chlorothalonil, chlorquinox, chlozolinate, climbazole, clotrimazole, copper acetate, copper carbonate, basic, copper hydroxide, copper naphthenate, copper oleate, copper oxychloride, copper silicate, copper sulfate, copper zinc chromate, cresol, cufraneb, cuprobam, eu prous oxide, cyazofamid, cyclafuramid, cycloheximide, cyflufenamid, cymoxanil, cypendazole, cyproconazole, cyprodinil, dazomet, dazomet-sodium, DBCP, debacarb, decafentin, dehydroacetic acid, dichlofluanid, dictilone, dichlorophen, dichlozoline, diclobutrazol, diclocymet, diclomezine, diclomezine-sodium, diclôran, diethofencarb, diethyl pyrocarbonate, ’ ï : i difenoconazole, diflumetorim, dimethirimot, 'dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinopenton, dinosulfon, dinoterbon, diphenylamine, dipyrithione, disulfiram, ditalimfos, dithianon, DNOC, DNOCammonium, DNOC-potassium, DNOC-sodium, dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicin-sodium, dodine.Y ^drazoxolon, edifenphos, epoxiconazole, etaconazole, etem, ethaboxam, ethirimol, éthdxyquin, ethylmercury 2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercury .bfomide, ethylmercury chloride, ethylmercury phosphate, etridiazole, famoxadone, fenamidone, fenaminosulf, fenapanil, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenitropan, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fentin, fentin chloride, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumetover, flumorph, fluopicolide, fluopyram, fluoroimide, fluotrimazole, fluoxastrobin, fluquinconazole, flusilazole, flus.ulfamide, flutîanil, flutolanil, flutriafol, fluxapyroxad, folpet, formaldéhyde, fosetyl, fosetyl-a lu minium, fuberidazole, furalaxyl, furametpyr, furcarbanil, furconazole, furconazole-cis, furfural, furmecyclox, furophanate, glyodin, griseofulvin, guazatine, halacrinate, hexachlorobenzene, hexachlprobutadiene, hexaconazole, hexylthiofos, hydrargaphen, hymexazol, imazalil, imazalil «nitrate, imazalil sulfate, imibenconazole, iminoctadine, imînoctadine triacetate, iminoctadine trialbesilate, iodomethane, ipconazole, iprobenfos, iprodione, iprovalicarb, isoprpthiolane, isopyrazam, isotianil, isovaledione, kasugamycin, kresoxim-methyl, mancopper, maneozeb, mandipropamid, maneb, mebenil, mecarbinzid, mepanipyrim, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, metalaxyl, metalaxyl-M,j metam, metam-ammonium, metam-potassium, metam-sodium, metazoxolon, metconazole, methasulfocarb, methfuroxam, methyl bromide, methyl isothiocyanate, methylmercury benzoate, methylmercury dicyandiamide, methylmercury pentachlorophenoxide, metiram, metominostrobin, metrafenone, metsulfovax, milneb, myclobutanil, myclozolin, N-(ethylmercury)-p-toluenesulphonanilide, nabam, natamycin, nitrostyrene, nitrothal-isopropyl, nuarimol, OÇH, octhilinone, ofurace, orysastrobin, oxadixyl, oxine-copper, oxpoconazole, oxpoconazole fumàrate, oxycarboxin, pefurazoate, penconazole, pencycuron, penflufen, pentachlorophenol, penthjppyrad, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercuryj,dérivative of pyrocatechol, phenylmercury

i j · A j nitrate, phenylmercury salicylate, phosdiphén, phthalide, picoxystrobin, piperalin,

I polycarbamate, polyoxins, polyoxorim, polyoxQrim-zinc, potassium azide, potassium polysulfide,

I potassium thiocyanate, probenazole, prochloraz, procymidone, propamocarb, propamocarb i hydrochloride, propiconazole, propineb, proquinazjd, prothiocarb, prothiocarb hydrochloride, { 5 prothioconazole, pyracarbolid, pyrâclostrobhn, pÿraclostrobin, pyrametostrobin, pyraoxystrobin,

I pyrazophos, pyribencarb, pyridinitril, pyrifenox, pyrimethanil, pyriofenone, pyroquilon, pyroxychlor, pyroxyfur, quinacetol, quinacetol sulfate, quinazamid, quinconazole, quinoxyfen, quintozene, rabenzazole, salicylanilide, sedaxane, silthiofam, simeconazole, sodium azide, sodium orthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide, spiroxamine, 10 streptomycin, sulfur, sultropen, TCMTB, tebuconazole, tebufloquin, tecloftalam, tecnazene, tecoram, tetraconazole, thiabendazoîe, thiadifluor, thicyofen, thifluzamide, thiochlorfenphim, thiomersal, thiophanate, thiophanate-methyl, thioquinox, thiram, tiadinil, tioxymid, tolclofosmethyl, tolylfluanid, tolylmercury acetate, triadimefon, triadimenol, triamiphos, triarimol, triazbutil, triazoxide, tributyltin oxide, trichlamide, tricyçlazole, tridemorph, trifloxystrobin, triflumizole, 15 triforine, triticonazole, uniconazole, uniconazole-P, validamycin, valifenalate, vinclozolin, zarilamid, zinc naphthenate, zineb, ziram, zoxamide (collectively these commonly named fungicides are defîned as the Tungjcide Group). _;, /'FA·:· / /·Η^!

HERBICIDES v

Molécules of Formula One may also be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more of the following herbicides - 2,3,6-TBA, 2,3,6-TBA-di méthylammonium, 2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2butoxypropyl, 2,4,5-T-2-ethylhexyl, 2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-Tbutotyl, 2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl, 2,4,5-T-methyl, 2,4,5-T25 pentyl, 2,4,5-T-sodium, 2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D, 2.4-D-2butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl, 2,4-D-ammonium, 2,4-DB, 2,4-DBbutyl, 2,4-DB-dimethylammonium, 2,4-DB-isoctyl,._u2,4-DB-potassium, 2,4-DB-sodium, 2,4-Dbutotyl, 2,4-D-butyl, 2,4-D-diethylammonium. 2,4-D-dimethylammomum, 2,4-D-diolamine, 2,4-Ddodecyîammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethy^ 2,4-D-heptylammonium, 2,4-D-isobutyl, 2,430 D-isoctyl, 2,4-D-isopropyl, 2,4-D-isopropylammonium, 2,4-D-lithium, 2,4-D-meptyl, 2,4-D-methyl,

2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,,4;D-propyl, 2,4-D-sodium, 2,4-D-tefuryî, 2,4-Dtetradecylammonium, 2,4-D-triethylammonium, _;2,4_J-D-tris(2-hydroxypropyl)ammonium, 2,4-Dtrolamine, 3,4-DA, 3,4-DB, 3,4-DP,.4-ÇPA, 4-CPB..4-CPP, acetochlor, acifluorfen, acifluorfenmethyl, acifluorfen-sodium, aclonifen, acrolein, alachlor, allidochlor, alloxydim, alloxydim35 sodium, allyl alcohol, alorac, ametridlone, ametryn, amibuzin, amicarbazone, amidosulfuron, aminocyclopyrachlor, aminocyclopyrachlor-methy], aminocyclopyrachlor-potassium, aminopyralid, aminopyralid-potassium, aminopyralid-tris(2-hydroxypropyl)ammonium, ! ami prof os-methyl, amitrole, ammonium suifamate, anilofos, anisuron, asulam, asulam-

potassium, asulam-sodium, atraton, atrazine, azafenidin, azimsulfuron, aziprotryne, barban, BCPC, beflubutamîd, benazolin, benazolin-dimethylammoniurri, benazolin-ethyl, benazolinpotassium, bencarbazone, benfluralin, benfuresate. bensulfuron, bensulfuron-methyl, bensulide, bentazone, bentazone-sodium, benzadox, benzadox-ammonium, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzoylprop, benzoylprop-ethyl, benzthiazuron, bicyclopyrone, bifenox, bilanafos; bilariafos-sddiüm, bis py ri bac, bispyribac-sodium, borax, bromacil, bromacil-lithium, bromacil-sodium, bromobonil, bromobutide, bromofenoxim, bromoxynil, bromoxynil butyrate, bromoxynil heptànoate, bromoxynil octanoate, bromoxynilpotassium, brompyrazon, butaçhlor, butafenacil, bùtamifos, butenachlor, buthidazole, buthiuron, butralin, butroxydim, buturoni butylate, cacodylic acid, cafenstrole, calcium chlorate, calcium cyanamide, cambendichlor, carbasulam, carbetamide, carboxazole, carfentrazone, carfentrazone-ethyl, CDEA, CEPC, chlomethoxyfen, chloramben, chloramben-ammonium, chloramben-diolamine, chloramben-methyl, chloramben-methylammonium, chloramben-sodium, chloranocryl, chlorazifop, chlorazifop-propargyl, chlorazine, chlorbromuron, chlorbufam, chloreturon, chlorfenac, chlorfenac-sodium, chlorfenprop, chlorfenprop-methyl, chlorflurazole, chlorflurenol, chlorflurenol-methyl, çhloridazonj chlorimuron, chlorimuron-ethyl, chlornitrofen, chloropon, chlorotoluron, chloroxuron, chloroxynih chlorprocarb, chlorpropham, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, cinidon-ethyl, cinmethylin, cinosulfuron, cisanilide, clethodim, cliodinate. clodinafop, clodinafop-propargyl, clofop, clofopisobutyl, clomazone, clomeprop, cloprop, cloproxydjm, clopyralid, clopyralid-methyl, clopyralidolamine, clopyralid-potassium, clopyralidⁱtris(2-hydroxypropyl) ammonium, cloransulam, cloransulam-methyl, CMA, copper sulfate, CPMF, CPPC, credazine, cresol, cumyluron, cyanamide, cyanatryn, cyanazine, cycloate, cyclosulfamuron, cycloxydim, cycluron, cyhalofop, cyhalofop-butyl, cyperquat, cyperquat chloride, cyprazine, cyprazole, cypromid, daimuron, dalapon, dalapon-calcium, dalapon-magnesium, dalapon-sodium, dazomet, dazomet-sodium, delachlor, desmedipham, desmetryn, di-allate, dicamba, dicamba-dimethylammonium, dicambadiolamine, dicamba-isopropylammonium, dicamba-methyl, dicamba-olamine, dicambapotassium, dicamba-sodium, dicamba-trolamine, dichlobenil, dichloralurea, dichlormate, dichlorprop, dichlorprop-2-ethylhexyl, dichlorprqp-butotyl, dichlorprop-dimethylammoniurn, dichlorprop-ethylammonium, dichlorprop-isoctyl,_; diçhlorprop-methyl, dichlorprop-P, dichlorpropP-dimethylammonium, dichlorprop-potassium, _; diçhlorprop-sodium, diclofop, diclofop-methyl, diclosulam, diethamquat, diethamquat dichloride, diethatyl, diethatyl-ethyl, difenopenten, difenopenten-ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate, diflufenican, diflufenzopyr, diflufenzopyr-sodium,. dimefuron, ,;dijpepiperate, dimethachlor, dimethametryn, dimethenamid, dimethenamid-R, dimexanq, dimidazon, dinitramine, dinofenate, dinoprop, dinosam, dinoseb, dinoseb acetate, dinoseb-ammpnium, dinoseb-diolamine, dinoseb-sodium, dinoseb-trolamine, dinoterb, dinoterb acetate, idiphacinone-sodium, diphenamid, dipropetryn, diquat, diquat dibromide, disul, disul-sodium, dithiopyr, diuron, DMPA, DNOC, DNOC-45 16335 f

I ammonium, DNOC-potassium, DNOC-sodium, DSMA, EBEP, eglinazine, eglinazine-ethyl, endothal, endothal-diammonium, endothal-dipotassium, endothal-disodium, epronaz, EPTC, erbon, esprocarb, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethidimuron, ethiolate, ethofumesate, ethoxyfen, ethoxyfen-ethyl, ethoxysulfuron, etinofen, etnipromid, etobenzanid,

EXD, fenasulam, fenoprop, fenoprop-3-butoxypr6pyl, fenoprop-butometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl,fenoprop-mèthÿl, fenoprop-potassium, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, fenteracol, fenthiaprop, fenthiaprop-ethyl, fentrazamide, fenuron, fenuron TCA, ferrous sulfate, flamprop, flampropisopropyl, flamprop-M, flamprop-methyl; ^lV. flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, florasulam, fluazifop, fluazifop-bütylr fluazifop-m ethyl, fluazifop-P, fluazifop-Pbutyl, fluazolate, flucarbazone, flücarbazohe-sodiüm, flucetosulfuron, fluchloralin, flufenacet, flufenican, flufenpyr, flufenpyr-ethyl, flumetslilam, flumezin, flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, fluometuron, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoromidine, fluoronitrofen, ’fluothiuron, flupoxam, flupropacil, flupropanate, flupropanate15 sodium, flupyrsulfuron, flupyrsulfuron-methyl-sodium, fluridone, flurochîoridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurtamone, fluthiacet, fluthiacet-methyl, fomesafen, fomesafen-sodium, foramsuifuron, fosamine, fosamine-ammonium, furyloxyfen, glufosinate, glufosinate-ammonium, glufosinate-P, glufosinate-P-ammonium, glufosinate-P-sodium, glyphosate, glyphosate-diammonium, ' glyphosate-dimethyl ammonium, glyphosate20 isopropylammonium, glyphosate-monoammôniiirri, glyphosate-potassium, glyphosatesesquisodium, glyphosate-trimesium, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl, haloxyfop-Pmethyl, haloxyfop-sodium, héxachloroacetphe; hexaflurate, hexazinone, imazamethabenz, imazamethabenz-methyl, imazamôx, imazarno^mmonium, imazapic, imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaduih, imàzaquin-ammonium, imazaquin-methyl, imazaquin-sodium, imazethapyr, imazethapyr-arrynonium, imazosulfuron, indanofan, indaziflam, iodobonil, iodomethane, iodosulfuron, iodosulfurori-methyl-sodium, ioxynil, ioxynil octanoate, ioxynil-lithium, ioxynil-sodium, ipazine, ipfencarbazone, iprymidam, isocarbamid, isocil, isomethiozin, isonoruron, isopolinate, isopropalin, isoproturon, isouron, isoxaben, isoxachlortole, isoxaflutole, isoxapyrifop, karbutilate, ketospiradox, lactofen, lenacil, linuron, MAA, ΜΑΜΑ, MCPA, MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium, MCPAdiolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl, MCPA-methyl, MCPAolamine, MCPA-potassium, MCPA-sodium, MCPA+fhioethyl, MCPA-trolamine, MCPB, MCPBethyl, MCPB-methyl, MCPB-sodium, mecoprop, mecoprop-2-ethylhexyl, mecoprop35 dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl, mecopropmethyl, mecoprop-P, mecoprop-P-dimethylanpmonium, mecoprop-P-isobutyl, mecoproppotassium, mecoprop-P-potassium, < mecoprop-sodium, mecoprop-trolamine, medinoterb, medinoterb acetate, mefenaGet,. mefluidide, ^rpefluidide-diolamine, mefluidide-potassium, .-46-,

mesoprazine, mesosulfuron, mesosulfuron-methyL mesotrione, metam, metam-ammonium, metamifop, metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron, metflurazon, methabenzthiazuron, methalpropalin, methazole, methiobencarb, methiozolin, methiuron, methometon, methoprotryne, methyl bromïde, methyl isothiocyanate, methyldymron, metobenzuron, metolachlor, metosulam, metoxuron, metribuzin, metsulfuron, metsulfuronmethyl, molinate, monalide, monisouron, monochloroacetic acid, monolinuron, monuron, monuron TCA, morfamquat, morfamquat diçhloride, MSMA, naproanilide, napropamide, naptalam, naptalam-sodium, neburon, nicosulfurorïAnipyraclofen, nitralin, nitrofen, nitrofluorfen, norflurazon, noruron, OCH, orbencarb, ortho-diChlorobenzene, orthosulfamuron, oryzalin, oxadîargyl, oxadiazon, oxapyrazon, oxapyrazoh-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone, oxyfluorfen, parafluron, paraquât,- paraquat diçhloride, paraquat dimetilsulfate, pebulate, pelargonic acid, pendimethalih, ^pehoxsulam, pentachlorophenol, pentanochlor, pentoxazone, perfluidone, pethoxamid, phenisophâm, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenylmercury acetate, piclôram, picloram-2-ethylhexyi, picloram-isoctyl, picloram-methyl, picloram-oiamine, picloram-potassium, picloram-triethylammonium, piclôramtris(2-hydroxypropyl)ammonium, picolinafen, pinoxaden, piperophos, potassium arsenite, potassium azide, potassium cyanate, pretilachlor, primisulfuron, primisulfuron-methyl, procyazine, prodîamine, profluazol, profluralin, profoxydim, proglinazine, proglinazine-ethyl, prometon, prometryn, propachlor, propanil, propaquizafop, propazine, propham, propisochlor, propoxycarbazone, propoxycarbazone-sodium, propyrisulfuron, propyzamide, prosulfalin, prosulfocarb, prosulfuron, proxan, proxan-sodium, prynachlor, pydanon, pyraclonil, pyraflufen, pyraflufen-ethyl, pyrasulfotoie, pyrazolynate, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazoxyfen, pyribenzoxim, pyributicarb, pyriclof* pyridafoljpyrjdate, pyriftalid, pyriminobac, pyriminobacmethyl, pyrimisulfan, pyrithiobac, pyrithiobac-sodipm, pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine, quinonamid, quizaiofop, quizalofop-ethyl, quizalofop-P, quizalofop-Pethyl, quizalofop-P-tefuryl, rhodethanil, rimsiilfuron, saflufenacil, sebuthylazine, secbumeton, sethoxydim, siduron, simazine, , simeton, simetçytk SMA, S-metolachlor, sodium arsenite, sodium azide, sodium chlorate, sulcotrione, ' sulfallate, sulfentrazone, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfuric acid, .sulglycapin, swep, TCA, TCA-ammonium, TCA-calcium, TCA-ethadyl, TCA-magnesium, TCA-sodium, tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim, terbacil, terbucarb, terbuchlor, terbumeton, terbuthylazine, terbutryn, tetrafluron, thenylchlor, thiazafluron, thiazopyr, thidiazimin, thidiazuron, thiencarbazone, thiencarbazone-methyl, thîfensulfuron, thifensulfuron-methyl, thiobencarb, tiocarbazil, tioclorim, topramezone, tralkoxydim, tri-allate, triasulfuron, triaziflam, tribenuron, tribenuron-methyl, tricamba, triclopyr, triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium, tridiphane, trietazine, trifloxysulfuron, trifloxysulfuron-sodium, .trifluralin, triflusulfuron, triflusulfuron-methyl, trifop, trifop-methyl, trifopsime, trihydroxytriazine, .tnmeturon, tripropindan, tritac, tritosulfuron,

-47;16335 vernolate, xylachlor, (collectively these commonly named herbicides are defined as the “Herbicide Group”).

.· ' ! ' '

BIOPESTICIDES '

Molécules of Formula One may also bé used in combination (such as in a compositional mixture, or a simultaneous or sequential application) with one or more biopesticides. The term “biopesticide” is used for microbial biological pest control agents that are applied in a similar manner to chemical pesticides. Commonly these are bacterial, but there are also examples of fungal control agents, including Trichoderma spp. and Ampelomyces quisqualis (a control agent for g râpe powdery mildew). Bacillus subtilis are used to control plant pathogens. Weeds and rodents hâve also been controlled with microbial agents. One well-known insecticide example is Bacillus thuringiensis, a bacterial disease of Lépidoptère, Coleoptera, and Diptère. Because it f : - has little effect on other organisms, it is considered ïinore environmentally friendly than synthetic pesticides. Biological insecticides include products based on:

1. entomopathogenic fungi (e.g. Metarhizium anisopliae);

2. entomopathogenic nematodés (e.g. Steinernema feltiae); and

3. entomopathogenic viruses (e.g. Cydià pomonella granulovirus).

Other examples of entomopathogènîc organisms include, but are not limited to, baculoviruses, bacteria and other prokaryotic organisms, fungi, protozoa and Microsproridia. Biologically derived insecticides include, but not limited to, rotenone, veratridine, as well as microbial toxins; insect tolérant or résistant plant varieties; and organisms modified by recombinant DNA technology to either produce insecticides or to convey an insect résistant property to the genetically modified organism. In one embodiment, the molécules of Formula One may be used with one or more biopesticides in the area of seed treatments and soil amendments. The Manual of Biocontrol Agents gives a review of the available biological insecticide (and other biology-based control) produits. Copping L.G. (ed.) (2004). The Manual of Biocontrol Agents (formerly the Biopesticide Mbnual) 3rd Edition. British Crop Production Council (BCPC), Farnham, Surrey UK.

OTHER ACTIVE COMPOUNDS

Molécules of Formula One,(pay also Çe used'in combination (such as in a compositional mixture, or a simultaneous or sequential application) with one or more of the following:

1. 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxyr8-oxa-1-azaspiro[4,5]dec-3-en-2-one;

2. 3-(4’-chloro-2,4-dimethyl[1,1 ’-biphenyl]-3-yl)-4-hydroxy-8-oxa-1 -azaspiro[4,5]dec-3-en-2one;

3. 4-[[(6-chloro-3-pyridinyl)methyl]methylamino]-2(5H)-furanone;

4. 4-[[(6-chloro-3-pyridinyl)methyl]cyclopropylamino]-2(5H)-furanone;

-4816335

5. 3-chloro-/V2-[(1 S)-1-methyl-2-(methylsülfonyi)ethyl]-A/1-[2-methy 1-4-(1,2,2,2-tetrafluoro-1(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxâmide;

6. 2-cyano-N-ethyl-4-fluoro-3-methoxy-benenesulfonamide;

7. 2-cyano-/V-ethyl-3-methoxy-benzenesulfôhamide;

8. 2-cyano-3-difluoromethoxy-N-ethyl-4-flupre-benzenesulfonamide;

9. 2-cyano-3-fluoromethoxy-/V-ethyl-benzenesulfonamide;

10. 2-cyanO’6-fluoro-3-niethoxy-N,/V-dimethyl-benzenesulfonannide;

11. 2-cyano-/V-ethyl-6-fluoro-3-methoxy-A/-methyl-benzenesulfonamide;

12. 2-cyano-3-difluoromethoxy-/V,/V-dimethylbenzenesulfon-amide;

13. 3-(difluoromethyl)-A/-[2-(3,3-dimethylbutyl)phenyl]-1 -methyl-1 /-/-pyrazole-4-carboxamide;

14. W-ethyl-2,2-dimethylpropionamide-2-(2,6-dichloro-a,a,a-trifluoro-p-tolyl) hydrazone;

15. W-ethyl-2,2-dichloro-1 -methylcyclopropane-carboxamide-2-(2,6-dichloro-a,a,a-trifluoro-ptolyl) hydrazone nicotine;

16. O-{(E-)-[2-(4-chloro-phenyl)-2-cyano-1 -(2-trifluoromethylphenyl)-vinyl]} S-methyl thiocarbonate; < :

17. (E)-N1-[(2-chloro-1,3-thiazol-5-ylmethyl)]-N2-cyano-N1-methylacetamidine;

18. 1-(6-ch!oropyridin-3-ylmethyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydro-imidazo[1,2-

a]pyridin-5-ol; A

19. 4-[4-chlorophenyl-(2-butylidine-hydrazono)methyl)] phenyl mesylate; and

20. N-Ethyl-2,2-dichloro-1-methylcyclopropanecarboxamide-2-(2,6-dichloroa/pha,a/p/ïa,a/pria-trifluoro-p-tolyl)hydrazone. . >.· i

Molécules of Formula One may also be used in combination (such as in a compositional mixture, or a simultaneous ûr sequential application) with one or more compounds in the following groups: algicides, antifeedants, avicides, bactéricides, bird repellents, chemosterilants, 25 herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, molluscicides, plant activators, plant growth regulators, rodenticides, and/or virucides (collectively these commonly named groups are,defined as the “AI Group”). It should be noted that compounds falling within the Al Group, Insepticide Group, Fungicide Group, Herbicide Group, Acaricide Group, or Nematicide Group ^might be în more than one group, because of 30 multiple activités the compound has. For more information consult the “Compendium of Pesticide Common Names” located at http://www.alanwood.net/pesticides/index.html. Also consult The Pesticide Manual 14th Edition, edited by C D S Tomlin, copyright 2006 by British Crop Production Council, or its prior or more reçent éditions.

SYNERGISTIC MIXTURES AND SYNERGISTS

Molécules of Formula One may be used with the compounds in the Insecticide Group to form synergistic mixtures where the mode of action of such compounds compared to the mode of action of the molécules of Formula One are the same, similar, or different. Examples of -4916335 modes of action include, but are not limited to: acetylcholinesterase inhibitor; sodium channel modulator; chitin biosynthesis inhibitor; GABA-gated chloride channel antagonist; GABA and glutamate-gated chloride channel agonist; acétylcholine receptor agonist; MET I inhibitor; Mgstimuîated ATPase inhibitor; nicotinic acétylcholine receptor; Midgut membrane disrupter; oxidative phosphorylation disrupter, and ryanodine receptor (RyRs). Additionally, molécules of Formula One may be used with compounds in the Fungicide Group, Acaricide Group, Herbicide Group, or Nematicide Group to form synergisticr mixtures. Furthermore, molécules of Formula One may be used with other active compounds,; such as the compounds under the heading “OTHER ACTIVE COMPOUNDS, algicides, avicides, bactéricides, molluscicides, rodenticides, virucides, herbicide safeners, adjuvants, and/or surfactants to form synergistic mixtures. Generally, weight ratios of the molécules of Formula One in a synergistic mixture with another compound are from about 10:1 to about 1:10, preferably from about 5:1 to about 1:5, and more preferably from about 3:1, and even more preferably about 1:1. Additionally, the following compounds are known as synergists and may be used with the molécules disclosed in Formula One: piperonyl butoxide, piprotal, propyl isome, sesamex, sesamolin, sulfoxide, and tribufos (collectively these synergists are defined as the “Synergists Group).

T

FORMULATIONS , q ;

A pesticide is rarely suitable for application in its pure form. It is usually necessary to add other substances so that the pesticide can be used at the required concentration and in an appropriate form, permitting ease of application, handling, transportation, storage, and maximum pesticide activity. Thus, pesticides^,are formulated into, for example, baits, concentrated émulsions, dusts, _; emulsifiable’. concentrâtes,, fumigants, gels, granules, microencapsulations, seed treatments, suspension concentrâtes, suspoemulsions, tablets, water soluble liquids, water dispersible granules or dry flowables, wettable powders, and ultra low volume solutions. For further information on formulation types see “Catalogue of Pesticide Formulation Types and International Coding System Technical Monograph n°2, 5th Edition by CropLife International (2002).

Pesticides are applied most often as aqueous suspensions or émulsions prepared from concentrated formulations of such pesticides.. Such water-soluble, water-suspendable, or emulsifiable formulations are either solids, usually known as wettable powders, or water dispersible granules, or liquids usually known as emulsifiable concentrâtes, or aqueous suspensions. Wettable powders, which may be copnpacted to form water dispersible granules, comprise an intimate mixture ofthe pesticide,.a carrier, and surfactants. The concentration of the pesticide is usually from about 10% to about, 90% by weight. The carrier is usually chosen from among the attapulgite clays, the moritmorilloqite clays, the diatomaceous earths, or the purified silicates. Effective surfactants, comprising from about 0.5% to about 10% of the wettable powder, are found among sulfonated lignins, condensed naphthalenesulfonates,

-5016335 naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and non-ionic surfactants such as ethylene oxide adducts of alkyl phénols.

Emulsifiable concentrâtes of pesticides comprise a convenient concentration of a pesticide, such as from about 50 to about 500 grams per liter of liquid dissolved in a carrier that is either a water miscible solvent or a mixture : of water-immiscible organic solvent and emulsifiers. Useful organic solvents include aromatics, especially xylenes and petroleum fractions, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents,may also be used, such as the terpenic solvents including rosin dérivatives, aliphatic ketçnes such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiable concentrâtes are chosen from conventional anionic and non-ionic surfaçtants.

Aqueous suspensions comprise suspensions of water-insoluble pesticides dispersed in an aqueous carrier at a concentration in the range from about 5% to about 50% by weight. Suspensions are prepared by finely grinding the pesticide and vtgorously mixing it into a carrier comprised of water and surfactants. Ingrédients, such as inorganic salts and synthetic or natural gums may also be added, to increase the density and viscosity ofthe aqueous carrier. It is often most effective to grind and mix the pesticide at the same time by preparing the aqueous mixture and homogenizing it in an implement such as a sand mill, bail mill, or piston-type homogenizer.

Pesticides may also be applied as granular compositions that are particularly useful for applications to the soil. Granular compositions usually contain from about 0.5% to about 10% by weight of the pesticide, dispersed in a carrier that comprises clay or a similar substance. Such compositions are usually prepared by dissolying the pesticide in a suitable solvent and applying it to a granular carrier which has been pre-formed to the appropriate particle size, in the range of from about 0.5 to about 3 mm. Such compositions may also be formulated by making a dough or paste of the carrier and compound and crushing and drying to obtain the desired granular particle size. . ...

Dusts containing a pesticide are prepared· by intimately mixing the pesticide in powdered form with a suitable dusty agricultural carrier, such as kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1% to about 10% of the pesticide. They can be applied as a seed dressing or as a foliage application with a dust blower machine.

It is equally practical to apply a pesticide in the form of a solution in an appropriate organic solvent, usually petroleum oil, such as the spray oils, which are widely used in agricultural chemistry.

Pesticides can also be applied in the form of an aérosol composition. In such compositions the pesticide is dissolved or dispersed in a carrier, which is a pressure-generating propellant mixture. The aérosol composition is paçkaged in a container from which the mixture is dispensed through an atomizing valve.

Pesticide baits are formed when the pesticide is mixed with food or an attractant or both.

When the pests eat the bait they also consume the pesticide. Baits may take the form of granules, gels, flowable powders, liquids, or solids. They can be used in pest harborages.

Fumigants are pesticides that hâve a relatively high vapor pressure and hence can exist as a gas in sufficient concentrations to kill pests in soil or enclosed spaces. The toxicity of the fumigant is proportional to its concentration and the exposure time. They are characterized by a good capacity for diffusion and act by penetrating the pest’s respiratory system or being absorbed through the pest’s cuticle. Fumigants are applied to control stored product pests under gas proof sheets, in gas sealed rooms or buildings or in spécial chambers.

I0 Pesticides can be microencapsulated by'suspending the pesticide particles or droplets in plastic polymers of various types. By altering the chemistry of the polymer or by changing factors in the processing, microcapsules can be formed of various sizes, solubility, wall thicknesses, and degrees of penetrability. These factors govern the speed with which the active ingrédient within is released, which in turn, affeçts the residual performance, speed of action, and odorof the product. γ ^; Y

Oil solution concentrâtes are made by dissolving pesticide in a solvent that will hold the pesticide in solution. Oil solutions of a pesticide usually provide faster knockdown and kill of pests than other formulations due to the solvents themselves having pesticidal action and the dissolution of the waxy covering of the integument increasing the speed of uptake of the 20 pesticide. Other advantages of oil solutions include better storage stability, better pénétration of crevices, and better adhesion to greasy surfaces.

Another embodiment is an oil-in-water émulsion, wherein the émulsion comprises oily globules which are each provided with a lamellar liquid crystal coating and are dispersed in an aqueous phase, wherein each oily globule comprises at least one compound which is 25 agriculturally active, and is individually coated with a monolamellar or oligolamellar layer comprising: (1) at least one non-îonic lipophilie surface-active agent, (2) at least one non-ionic hydrophilic surface-active agent, and (3) at least one ionic surface-active agent, wherein the globules having a mean particle diameter of less than 800 nanometers. Further information on the embodiment is disclosed in U,S. patent publiçation 20070027034 published February 1, 30 2007, having Patent Application serial number 11/495,228. For ease of use, this embodiment will be referred to as OIWE.

For further information consult “Insect Pest Management” 2nd Edition by D. Dent, copyright CAB International (2000). Additionally, for more detailed information consult Handbook of Pest Control - The Behavior, Life History, and Control of Household Pests” by 35 Arnold Mallis, 9th Edition, copyright 2004 by GIE Media Inc.

OTHER FORMULATION COMPONENTS

Generally, when the molécules disclosed in Formula One are used in a formulation, such formulation can also contain other components. These components include, but are not limited to, (this is a ποπ-exhaustive and.· non-mutually. exclusive list) wetters, spreaders, stickers, pénétrants, buffers, sequestering agents, drift réduction agents, compatibility agents, anti-foam agents, cleaning agents, and emulsifiers. A few components are described forthwith.

A wetting agent is a substance that when added to a liquid increases the spreading or pénétration power of the liquid by reducing the interfacial tension between the liquid and the surface on which it is spreading. Wetting agents are used for two main fonctions in agrochemical formulations: during processing and manufacture to increase the rate of wetting of powders in water to make concentrâtes for soluble liquids or suspension concentrâtes; and during mixing of a product with water in a spray tank to reduce the wetting time of wettable powders and to improve the pénétration of water into water-dispersible granules. Examples of wetting agents used in wettable powder, suspension concentrate, and water-dispersible granule formulations are: sodium lauryl sulfate; sodium;dioctyl sulfosuccinate; alkyl phénol ethoxylates; and aliphatic alcohol ethoxylates.

A dispersîng agent is a substance whiçh adsorbs onto the surface of particles and helps to preserve the state of dispersion of the particles and prevents them from reaggregating. Dispersîng agents are added to agrochpmical· formulations to facilitate dispersion and suspension during manufacture, and to ensurerthe particles redisperse into water in a spray tank. They are widely used in wettable powders, suspension concentrâtes and water-dispersible granules. Surfactants that are^used as dispersîng agents hâve the ability to adsorb strongly onto a particle surface and provide a charged or steric barrier to reaggregation of particles. The most commonly used surfactants are anionic, non-ionic, or mixtures of the two types. For wettable powder formulations, the most common dispersîng agents are sodium lignosulfonates. For suspension concentrâtes, very good adsorption and stabilization are obtained using polyelectrolytes, such as sodium naphthalene sulfonate formaldéhyde condensâtes. Tristyrylphenol ethoxylate phosphate esters ,arejalsq used. Non-ionics such as alkylarylethylene oxide condensâtes and EO-PO block copolymers _f;are sometimes combined with anionics as dispersîng agents for suspension concentrâtes. In recent years, new types of very high molecular weight polymeric surfactants hâve been developed as dispersing agents. These hâve very long hydrophobie ‘backbones’ and a large number of ethylene oxide chains forming the ‘teeth’ of a ‘comb’ surfactant. These high mplecylar weight polymers can give very good iongterm stability to suspension concentrâtes because the hydrophobie backbones hâve many anchoring points onto the particle surfaces.; Examples of dispersing agents used in agrochemical formulations are: sodium lignosulfonates; sodium naphthalene sulfonate formaldéhyde condensâtes; tristyrylphenol ethoxylate phosphate esters; aliphatic alcohol ethoxylates; alkyl ethoxylates; EO-PO block copolymers; and graft copolymers.

- 5316335

An emulsifying agent is a substance which stabilizes a suspension of droplets of one liquid phase in another liquid phase. Without ithe emulsifying agent the two Iiquids would separate into two immiscible liquid phases. The most commonly used emulsifier blends contain alkylphenol or aliphatic alcohol with twelve or, more ethylene oxide units and the oil-soluble 5 calcium sait of dodecylbenzenesulfonic acid. A range of hydrophile-lipophile balance (HLB”) values from 8 to 18 will normally provide good stable émulsions. Emulsion stabiiity can sometimes be improved by the addition of a small amouqt of an EO-PO block copolymer surfactant. , .; ..

. ^{! h} H . · • x 1

A solubilizing agent is a surfactant which will form micelles in water at concentrations above the critical micelle concentration. The mice|les are then able to dissolve or solubilize water-insoluble materials inside the hydrophobie part of the micelle. The types of surfactants usually used for solubilization are non-ionics, sorbitan monooleates, sorbitan monooleate ethoxylates, and methyl oleate esters.

Surfactants are sometimes used, either alone or with other additives such as minerai or 15 vegetable oils as adjuvants to spray-tank mixes to improve the biological performance of the pesticide on the target. The types of surfactants used for bioenhancement dépend generally on the nature and mode of action of the pesticide. However, they are often non-ionics such as: alkyl ethoxylates; linear aliphatic alcohol ethoxylated; aliphatic amine ethoxylates.

A carrier or diluent in an agricultural formulation is a material added to the pesticide to give a product of the required strength. Carriers are usually materials with high absorptive capacities, while diluents are usually materials . with low absorptive capacities. Carriers and diluents are used in the formulation of dusts,. wettable powders, granules and water-dispersible granules.

Organic solvents are used mainly in the formulation of emulsifiable concentrâtes, oil-in25 water émulsions, suspoemulsions,. and ultra low volume formulations, and to a lesser extent, granular formulations. Sometimes . mixtures of solvents are used. The first main groups of solvents are aliphatic paraffinic oils such as kerosene or refined paraffine. The second main group (and the most common) comprises the aromatic solvents such as xylene and higher molecular weight fractions of C9 and C10 aromatic solvents. Chlorinated hydrocarbons are useful as cosolvents to prevent crystallization of pesticides when the formulation is emulsified into water. Alcohols are sometimes used as cosolvents to increase solvent power. Other solvents may include vegetable oils, seed oils, and esters of vegetable and seed oils.

Thickeners or gelling agents are used?mainly in the formulation of suspension concentrâtes, émulsions and suspoemulsions to. modify the rheology or flow properties of the 35 liquid and to prevent séparation and settling. of thp dispersed particles or droplets. Thickening, gelling, and anti-settling agents ..generally fall 'into two categories, namely water-insoluble i· L ) particulates and water-soluble polymers. It is possible to produce suspension concentrate formulations using clays and silicas. Examples of these types of materials, include, but are not -54-

limited to, montmorillonite, bentonîte, magnésium aluminum silicate, and attapulgite. Watersoluble polysaccharides hâve been used as thickening-gelling agents for many years. The types of polysaccharides most commonly used are natural extracts of seeds and seaweeds or are synthetic dérivatives of cellulose. Examples of these types of materials include, but are not limited to, guar gum; locust bean gum; carragêénam; alginates; methyl cellulose; sodium carboxymethyl cellulose (SCMC); hydroxyethyl cellulose (HEC). Other types of anti-settling agents are based on modified starches, polyacrylates, polyvinyl alcohol and polyethylene oxide. Another good anti-settling agent is xanthan gum.

• ' i | · j J

Microorganisms can causé spoilagé of’formulated products. Therefore préservation agents are used to eliminate or redüce their effécï.: Éxamples of such agents include, but are not limited to: propionic acid and its sodium sait; sorbic acid and its sodium or potassium salts; benzoic acid and its sodium sait; p-hydroxybenzoic acid sodium sait; methyl p-hydroxybenzoate; and 1,2-benzisothiazolin-3-one (BIT).

The présence of surfactants often causes water-based formulations to foam during mixing operations in production and in application through a spray tank. In order to reduce the tendency to foam, anti-foam agents are often added either during the production stage or before filling into bottles. Generally, there are two types of anti-foam agents, namely silicones and nonsilicones. Silicones are usually aqueous émulsions of dimethyl polysiloxane, while the nonsilicone anti-foam agents are water-insoluble oils, süch as octanol and nonanol, or silica. In both cases, the fonction of the anti-foam agent- is- to /displace the surfactant from the air-water interface. , r “Green” agents (e.g., adjuvants, surfactants, solvents) can reduce the overall environmental footprint of crop protection formùlations. Green agents are biodégradable and generally derived from natural and/or sustainable¹ sources, e.g. plant and animal sources. Spécifie examples are: vegetable oils, seêd oils, and esters thereof, also alkoxylated alkyl polyglucosides. . τ

For further information, see “Chemistry and Technology of Agrochemical Formulations” edited by D.A. Knowles, copyright 1998 by Kluwer Academie Publishers. Also see Insecticides in Agriculture and Environment - Retrospects and Prospects” by A.S. Perry, I. Yamamoto, I. Ishaaya, and R. Perry, copyright 1998 by Springer-Verlag.

PESTS

In general, the molécules of Formula One_;may be used to control pests e.g. beetles, earwigs, cockroaches, flies. aphids, scales, whiteflies, leafhoppers, ants, wasps, termites, moths, butterflies, lice, grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites, ticks, nematodes, and symphylans.

In another embodiment, the molécules of: Formula One may be used to control pests in the Phyla Nematoda and/or Arthropoda · , , ;

-n 5516335

In another embodiment, the molécules· of;Formula One may be used to control pests in the Subphyla Chelicerata, Myriapoda, and/or Hexapoda.

In another embodiment, the molécules of Formula One may be used to control pests in the Classes of Arachnida, Symphyla, and/or Insecta.

In another embodiment, the molécules of Formula One may be used to control pests of the Order Anoplura. A non-exhaustive list of particular généra includes, but is not limited to, Haematopinus spp., Hoplopleura spp., Linognathus spp., Pediculus spp., and Polyplax spp. A non-exhaustive list of particular species includes, ' but is not limited to, Haematopinus asini, Haematopinus suis, Linognathus setosus, -Linognathus ovillus, Pediculus humanus capitis, Pediculus humanus humanus, and Pthirus pubis. ?

In another embodiment, the molécules of Formula One may be used to control pests in the Order Coleoptera. A non-exhaustive list of .particular généra includes, but is not limited to, Acanthoscelides spp., Agriotes spp., Anthonomus spp., Apion spp., Apogonia spp., Aulacophora spp., Bruchus spp., Cerosterna spp.. Cerotoma spp., Ceutorhynchus spp., Chaetocnema spp., Co/aspis spp., Ctenicera spp,., Curculio spp., Cyclocephala spp., Diabrotica spp., Hypera spp., Ips spp., Lyçtus spp., Megascelis spp., Meligethes spp., Otiorhynchus spp., Pantomorus spp., Phyllophaga spp., Phyllotreta spp., Rhizotrogus spp., Rhynchites spp., Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp., and Tribolium spp. A non-exhaustive list of particular species includes, but is not limited to, Acanthoscelides obtectus, Agrilus planipennis, Anoplophora glabripennis, Anthonomus grandis, Ataenius spretulus, Atomaria linearis, Bothynoderes punctiventris, Bruchus pisorum, Callosobruchus maculatus, Carpophilus hemipterus, Cassida vittata, Cerotoma trifurcata, Ceutorhynchus assimilis, Ceutorhynchus napi, Conoderus scalaris, Cor iode ru s stigmosus, Conotrachelus nénuphar, Cotinis nitida, Crioceris asparagi, Cryptolestes ferrugineus, Cryptolestes pusillus, Cryptolestes turcicus, Cylindrocopturus adspersus, Deporaus marginatus, Dermestes lardarius, Dermestes maculatus, Epilachna varivestis, Faustlnus·,? cubae, Hylobius pales, Hypera postica, Hypothenemus hampei, Lasioderma serricorne.ÿLgptinotarsa decemlineata, Liogenys fuscus, Liogenys suturalis, Lissorhoptrus oryzophilus, Maecolaspis joliveti, Melanotus commuais, Meligethes aeneus, Melolontha melolontha, Oberea brevls, Oberea linearis, Oryctes rhinocéros, Oryzaephilus mercator, Oryzaephilus surinamensis, Ouléma melanopus, Ouléma oryzae, Phyllophaga cuyabana, Popillia japonica, Prostephanus truncatus, Rhyzopertha dominica,, Sitona lineatus, Sitophilus granarius, Sitophilus oryzae, Sitophilus zeamais, Stegobium paniceum, Tribolium castaneum, Tribolium confusum, Trogoderma variabile, and Zabrus tenebrioides.

In another embodiment, the molécules ofFormula One may be used to control pests of the Order Dermaptera.

In another embodiment, the molécules of .Formula One may be used to control pests of the Order Blattaria. A non-exhaustive list of partjcular species includes, but is not limited to,

Blattella germanica, Blatta orientalis, Parcoblatta pennsylvanica, Periplaneta americana,

Periplaneta australasiae, Periplaneta 'brûnnea, Periplaneta fuliginosa, Pycnoscelus surinamensis, and Supella longipalpa. .

In another embodiment, the moleculès of'Formula One may be used to control pests of the Order Diptera. A non-exhaustive list of particular généra includes, but is not limited to, Aedes spp., Agromyza spp., Anastrepha spp., Anopheles spp., Bactrocera spp., Ceratitis spp., Chrysops spp., Cochliomyia spp., Contarinia spp., Culex spp., Dasineura spp., Délia spp., Drosophile spp., Fannia spp., Hylemyia spp., Liriomyza spp., Musca spp., Phorbia spp., Tabanus spp., and Tipula spp. A non-exhaustive list of particular species includes, but is not limited to, Agromyza frontella, Anastrepha suspensa, Anastrepha ludens, Anastrepha obliqa, Bactrocera cucurbitae, Bactrocera dorsalis, Bactrocera invadens, Bactrocera zonata, Ceratitis capitata, Dasineura brassicae, Délia platura, Fannia canicularis, Fannia scalaris, Gasterophilus intestinalis, Gracillia perseae, Haematobia irritans/Hypoderma lineatum, Liriomyza brassicae, Melophagus ovinus, Musca autumnalis, Musca domestica, Oestrus ovis, Oscinella frit, Pegomya betae, Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletis mendax, Sitodiplosis mosellana, and Stomoxys calcitrans. + y ,

In another embodiment, the molécules of Formula One may be used to control pests of the Order Hemiptera. A non-exhaustive list of particular généra includes, but is not limited to, Adelges spp., Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastes spp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp., Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp., Nephotettix spp., Nezara spp., Philaenus spp., Phytocoris spp., Piezodorus spp., Planococcus spp., Pseudococcus spp., Rhopalosiphum spp., Saissetia spp., Therioaphis spp., Toumeyella spp., Toxoptera spp., Trialeurodes spp., Triatoma spp. and Unaspis spp. A non-exhaustive list of particular species includes, but is not limited to, Acrosternum hilare, Acyrthosiphon pisum, Aleyrodes proletella, Aleurodicus dispersus, Aleurothrixus floccosus, Amrasca biguttula biguttula, Aonidiella aurantii, Aphis gossypii, Aphis glycines, Aphis pomi, Aulacorthum-solani, Bemisia argentifolii, Bemisia tabac!, Blissus leucopterus, Brachycorynella asparagi, Breyennia rehi, Brevicoryne brassicae, Calocoris norvegicus, Ceroplastes rubens, Cimex hemipterus, Cimex lectularius, Dagbertus fasciatus, Dichelops furcatus, Diuraphis noxia, Diaphorina citri, Dysaphis plantaginea, Dysdercus suturellus, Edessa meditabunda, Eriosoma ianigerum, Eurygaster maura, Euschistus héros, Euschistus servus, Helopeltis antonii, Helopeltis theivora, Icerya purchasi, Idioscopus nitidulus, Laodelphax striatellus, Leptocorisa oratorios, Leptocorisa varicornis, Lygus hesperus, Maconellicoccus hirsutus, Macrosiphum euphorbiae, Macrosiphum granarium, Macrosiphum rosae, Macrosteles quadrilineatus, Mahanarva frimbiolata, Metopolophium dirhodum, Midis longicornis, Myzus persicae, Nephotettix cinctipes, Neurocolpus longirostris, Nezara viridula, Nilaparvata lugens, Pariatoria pergandii, Parlatoria ziziphi, Peregrinus maidis, Phylloxéra vitifoliae, Physokermes piceae,, Phytocoris, californicus, Phytocoris relativus, Piezodorus

-5716335 guildinii, Poecilocapsus lineatus, Psallus vacàinicola, Pseudacysta perseae, Pseudococcus brevipes, Quadraspidiotus perniciosus, Rhopalosiphum maidis, Rhopalosiphum padi, Saissetia o/eae, Scaptocoris castanea, Schizaphis graminum, Sitobion avenae, Sogatella furcifera, Trialeurodes vaporariorum, Trialeurodes abutiloneus, Unaspis yanonensis, and Zulia entrerriana. àP· (n another embodiment, the'molécules of Formula One may be used to control pests of the Order Hymenoptera. A non-exhaustive liât of particular généra includes, but is not limited to, Acromyrmex spp., Atta spp., Camponotus spp., Diprion spp., Formica spp., Monomorium spp., Neodiprion spp,, Pogonomyrmex spp,, Polistes spp,, So/enopsis spp., Vespula spp., and Xylocopa spp. A non-exhaustive list of particular species includes, but is not limited to, Athalia rosae, Atta texana, Iridomyrmex humilis, Monomorium minimum, Monomorium pharaonis, So/enopsis invicta, So/enopsis geminata, So/enopsis molesta, So/enopsis richtery, So/enopsis xyloni, and Tapinoma sessile.

In another embodiment, the molécules of Formula One may be used to control pests of the Order Isoptera. A non-exhaustive list of particular généra includes, but is not limited to, Coptotermes spp., Cornitermes spp,, Cryptotermes spp,, Heterotermes spp., Kalotermes spp., Incisitermes spp,, Macrotermes spp,, Marginitermes spp., Microcerotermes spp., Procornitermes spp., Reticutitermes spp., Schedorhinotermes spp., and Zootermopsis spp. A non-exhaustive list of particular.. species includes, but is not limited to, Coptotermes curvignathus, Coptotermes frcnchi. Coptotermes formosanus, Heterotermes aureus, Microtermes obesi, Reticulitermes banyulensis, Reticulitermes grasse/, Reticulitermes flavipes, Reticulitermes hageni, Reticulitermes hesperus, Reticulitermes santonensis, Reticulitermes speratus, Reticulitermes tibialis, and Reticulitermes virginicus.

In another embodiment, the molécules of Formula One may be used to control pests of the Order Lepidoptera. A non-exhaustive list of particular généra includes, but is not limited to, Adoxophyes spp., Agrotls spp., Argyrotaenia spp., Cacoecia spp., Caloptilia spp., Chilo spp., Chrysodeixis spp,, Colias spp., Crambus spp., Diaphania spp., Diatraea spp., Earias spp., Ephestia spp., Epimecis spp,, Feltia spp., Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela spp., Lithocolletis spp., Loxagrotis spp., Malaçosoma spp., Peridroma spp., Phyllonorycter spp., Pseudaletia spp., Sesamia spp., Spodoptera spp., Synanthedon spp., and Yponomeuta spp. A non-exhaustive list of particular species includes, but is not limited to, Achaea janata, Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbia cuneana, Amyelois transitella, Anacamptodes defectana, Anarsia lineatella, Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archips rpsapa, -,Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes, Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Carposina niponensis, Chlumetia transversa, Choristoneura rosaceana, Cnaphalocrocis medinalis, Conopomorpha cramerella, Cossus cossus, Cydia caryana, Cydia funebrana, Cydia molesta, Cydia nigricana, Cydia pomonella, Darna diducta, Diatraea saccharalis, Diatraea grandiosella,

-58 16335

Earias insulana, Earias vittella, Ecdytolopha aurantianum, Elasmopalpus lignosellus, Ephestia cautella, Ephestia elutetta, Ephestia kuehniella, Epinotia aporema, Epiphyas postvittana, Erionota thrax, Eupoecilia ambiguella, Euxoa auxiliaris, Grapholîta molesta, Hedylepta indicata, Helicoverpa armigera, Helicoverpa zea, Heliothis virescens, Hellula undalis, Keiferia lycopersicella, Leucinodes orbonalis, LeuGoptera^çoffeella, Leucoptera malifoliella, Lobesia botrana, Loxagrotis albicosta, Lymantria dlspap, Lyonetia clerkella, Mahasena corbetti, Mamestra brassicae, Maruca testulalis, Metisa plana, Mythimna unipuncta, Neoleucinodes elegantalis, Nymphula depunçtalis, Operophtera brumata, Ostrinia nubilalis, Oxydia vesulia, Pandemis cerasana, Pandemis heparçna,. Papilip demodocus, Pectinophora gossypiella, Perldroma saucia, Perileucoptera coffeella, Phthprimaea operculella, Phyllocnistis citrella, Pieris rapae, Plathypena scabra, Plodia Interpunctella, Plutella xylostella, Polychrosis viteana, Prays endocarpe, Prays oleae, Pseudaletia unipuncta, Pseudoplusia includens, Rachiplusia nu, Scirpophaga incertulas, Sesamia inferens, Sesamia nonagrioides, Setora nitens, Sitotroga cerealella, Sparganothis pilleriana, Spodoptera exigua, Spodoptera frugiperda, Spodoptera eridania, Thecla basîlîdes, Tineola bisselliella, Trichoplusia ni, Tuta absoluta, Zeuzera coffeae, and Zeuzera pyrina.

In another embodiment, the molécules of₄Formula One may be used to control pests of the Order Mallophaga. A non-exhaustive list of particular généra includes, but is not limited to, Anaticola spp., Bovicola spp., Ghelopistep spp,, Goniodes spp., Menacanthus spp., and Trichodectes spp. A non-exhaustive list of particjjlar species includes, but is not limited to, Bovicola bovis, Bovicola caprae, Bovicola ovis, .Chelopistes meleagridis, Goniodes dissimilis, Goniodes gigas, Menacanthus strarnineus, Menopon gallinae, and Trichodectes canis.

In another embodiment, the molécules of Formula One may be used to control pests of the Order Orthoptera. A non-exhaustive list of particular généra includes, but is not limited to, Melanoplus spp., and Pterophylla spp. A non-exhaustive list of particular species includes, but is not limited to, Anabrus simplex, Gryllotalpa ^fricana, Gryllotalpa australis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla, Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria, and Scudderia furcata.

In another embodiment, the molécules of Formula One may be used to control pests of the Order Siphonaptera. A non-exhaustive list of particular species includes, but is not limited to, Ceratophyllus gallinae, Ceratophyllus niger·,. Çtenocephalides canis, Ctenocephalides felis, and Pulex irritons.

In another embodiment, the molécules of Formula One may be used to control pests of the Order Thysanoptera. A non-exhaustive list of^particular généra includes, but is not limited to, Caliothrips spp., Frankliniella spp., Scirtothrips spp., and Thrips spp. A non-exhaustive list of particular sp. includes, but is not₍ limited to, Frankliniella fusca, Frankliniella occidentalis, Frankliniella schultzei, Frankliniella Williams!, Heliothrips haemorrhoidalis, Rhipiphorothrips .! ' ' ' . .A, 3 ¹ .· ^J fi A^:

-_r59 16335 cruentatus, Scirtothrips citri, Scirtothrips dorsalis, and Taeniothrips rhopalantennalis, Thrips hawaiiensis, Thrips nigropilosus, Thrips orientalis, Thrips tabaci.

In another embodiment, the molécules of Formula One may be used to control pests of the Order Thysanura. A non-exhaustive list of particular généra includes, but is not limited to, Lepisma spp. and Thermobia spp.

In another embodiment, the molécules of Formula One may be used to control pests of the Order Acarina. A non-exhaustive list of particular généra includes, but is not limited to, Acarus spp., Aculops spp., Boophilus spp., Demodex spp., Dermacentor spp., Epitrimerus spp., Eriophyes spp., Ixodes spp.,. Oligonychus spp.,’Panonychus spp., Rhizoglyphus spp., and Tetranychus spp. A non-exhaustive list of particular species includes, but is not limited to, Acarapis woodi, Acarus siro, Aceria mangifëraef Aculops, lycopersici. Aculus pelekassi, Aculus schlechtendali, Amblyomma americanum, Brevipalpus obovatus, Brevipalpus phoenicis, Dermacentor variabilis, Dermatophagoides pteronyssinus, Eotetranychus carpini, Notoedres cati, Oligonychus coffeae, Oligonychus ilicis, Panonychus citri, Panonychus ulmi, Phyllocoptruta oleivora, Polyphagotarsonemus latus, Rhipicephalus sanguineus, Sarcoptes scabiel, Tegolophus perseaflorae, Tetranychus urticae, and Varroa destructor.

In another embodiment, the molécules of Formula One may be used to control pest of the Order Symphyla. A non-exhaustive list of particular sp. includes, but is not limited to, Scutigerella immaculata.

In another embodiment, the molécules of Formula One may be used to control pests of the Phylum Nematoda. A non-exhaustive list of particular généra includes, but is not limited to,

Aphelenchoides spp., Belonolaimus spp., Cricopemella spp., Ditylenchus spp., Heterodera spp., Hirschmanniella spp., Hoplolaimus spp., Meloidogyne spp., Pratylenchus spp., and Radopholus spp. A non-exhaustive list of particular sp. ipclüdes, but is not limited to, Dirofilaria immitis, Heterodera zeae, Meloidogyne incognita, Meloidogyne javanica, Onchocerca volvulus, Radopholus similis, and Rotylenchulus reniformis., For additional information consult “Handbook of Pest Control - The Behavior, Life History, and Control of Household Pests by Arnold Mallis, 9th Edition, copyright 2004 by GIE Media Inc.

APPLICATIONS

Molécules of Formula One are generally used in amounts from about 0.01 grams per hectare to about 5000 grams per hectare to provide control. Amounts from about 0.1 grams per hectare to about 500 grams per hectare are generally preferred, and amounts from about 1 gram per hectare to about 50 grams per hectare, are generally more preferred.

The area to which a molécule of Formula Qne is applied can be any area inhabited (or maybe inhabited, or traversed by) a pest, for example: where crops, trees, fruits, cereals, fodder species, vines, turf and ornemental plants, are growing; where domesticated animais are residing; the interior or exterior surfaces of buildings (such as places where grains are stored), the materials of construction used in building (such as impregnated wood), and the soil around buildings. Particular crop areas to use a molécule of Formula One include areas where apples, corn, sunflowers, cotton, soybeans, canota, wheat, rice, sorghum, barley, oats, potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes, peppers, crucifers, pears, tobacco, almonds, sugar beets, beans and other valuable crops are growing or the seeds thereof are going to be planted. It is also advantageous to use alumînum sulfate with a molécule of Formula One when growing various plants.

Controlling pests generally means that pest populations, pest activity, or both, are reduced in an area. This can corne about when; pest populations are repulsed from an area; when pests are incapacitated in or around an area; or pests are exterminated, in whole, or in part, in or around an area. Of course, a combinatipn of these results can occur. Generally, pest populations, activity, or both are desirably reduced more than fifty percent, preferably more than 90 percent. Generally, the area is not in or on a. human; consequently, the locus is generally a non-human area. i .

The molécules of Formula One may be used in mixtures, applied simultaneously or sequentially, alone or with other compounds to enhance plant vigor (e.g. to grow a better root system, to better withstand stressful growing conditions). Such other compounds are, for example, compounds that modulate plant ethylene receptors, most notably 1methylcyclopropene (also known as 1-MCP).

The molécules of Formula One can be applied to the foliar and fruiting portions of plants to control pests. The molécules will either corne in direct contact with the pest, or the pest will consume the pesticide when eating leaf, fruit mass, or extracting sap, that contains the pesticide. The molécules of Formula One can also be applied to the soil, and when applied in this manner, root and stem feeding pests can be çontrolled. The roots can absorb a molécule taking it up into the foliar portions of the plant to control above g round chewing and sap feeding pests. .,’··!

Generally, with baits, the baits are placed. jn the ground where, for example, termites can corne into contact with, and/or be attracted to, the bait. Baits can also be applied to a surface of a building, (horizontal, vertical, or. slant surface) where, for example, ants, termites, cockroaches, and flies, can corne into contact with, and/or be attracted to, the bait. Baits can comprise a molécule of Formula One.

The molécules of Formula One can be encapsulated inside, or placed on the surface of a capsule. The size of the capsules can range from nanometer size (about 100-900 nanometers in diameter) to micrometer size (about 10-900 microns in diameter).

Because of the unique ability of the eggs of some pests to resist certain pesticides, repeated applications of the molécules of Formula One may be désirable to control newly emerged larvae. . ,

Systemic movement of pesticides in plants may be utilized to control pests on one portion of the plant by applying (for example by spraying an area) the molécules of Formula One to a different portion of the plant. For example, control of foliar-feeding insects can be achieved by drip irrigation or furrow application, by treating' thtè soil with for example pre- or post-planting soil drench, or by treating the seeds of a plant before planting,

Seed treatment can be applied to ail types of seeds, including those from which plants genetically modified to express specialized traits will germinate. Représentative examples include those expressing proteins toxic to invertebrate pests, such as Bacillus thuringiensis or other insecticidal toxins, those expressing herbicide résistance, such as Roundup Ready” seed, or those with “stacked” foreign genes expressing insecticidal toxins, herbicide résistance, nutrition-enhancement, drought résistance, or any other bénéficiai traits. Furthermore, such seed treatments with the molécules of Formula One may further enhance the ability of a plant to better withstand stressful growing conditions. This results in a healthier, more vigorous plant, which can lead to higher yields at harvest time. Generally, about 1 gram of the molécules of Formula One to about 500 grams per 100,000 seeds is expected to provide good benefits, amounts from about 10 grams to about 100 grams per 100,000 seeds is expected to provide better benefits, and amounts from about 25 grams to about 75 grams per 100,000 seeds is expected to provide even better benefits. .

It should be readily apparent that the molécules of Formula One may be used on, in, or around plants genetically modified to express specialized traits, such as Bacillus thuringiensis or other insecticidal toxins, or those expressing herbicide résistance, or those with “stacked” foreign genes expressing insecticidal toxins, herbicide résistance, nutrition-enhancement, or any other bénéficiai traits.

The molécules of Formula One may be used for controlling endoparasites and ectoparasites in the veterînary medicine sector or in the field of non-human animal keeping. The molécules of Formula One are applied, such as by oral administration in the form of, for example, tablets, capsules, drinks, granules, by dermal application in the form of, for example, dipping, spraying, pouring on, spotting on, and dusfing, and by parentéral administration in the form of, for example, an injection.

The molécules of Formula One may,also be employed advantageously in livestock keeping, for example, cattle, sheep, pigs, chickens, and geese. They may also be employed advantageously in pets such as, horses, dogs, and cats. Particular pests to control would be fleas and ticks that are bothersome to such animais. Suitable formulations are administered orally to the animais with the drinking water or feed. The dosages and formulations that are suitable dépend on the species.

The molécules of Formula One may also be employed in therapeutic methods for human health care. Such methods include, but are limited to, oral administration in the form of, for example, tablets, capsules, drinks, granules, and by dermal application.

-6216335

Pests around the world hâve been migrating to new environments (for such pest) and thereafter becoming a new invasive species in such new environment. The molécules of

Formula One may also be used on such new. invasive species to control them in such new environment.

The molécules of Formula One may also be used in an area where plants, such as crops, are growing (e.g. pre-planting, planting, pre-harvesting) and where there are low levels (even no actual presence) of pests .that can comrpercially damage such plants, The use of such molécules in such area is to benefit the plants being grown in the area. Such benefits, may include, but are not limited to, improving the health of a plant, improving the yield of a plant (e.g. increased biomass and/or increased content of valuable ingrédients), improving the vigor of a plant (e.g. improved plant growth and/or greener leaves), improving the quality of a plant (e.g. improved content or composition of certain ingrédients), and improving the tolérance to abiotic and/or biotic stress of the plant.

Before a pesticide can be used or sold. commerciaîly, such pesticide undergoes lengthy évaluation processes by various governmental authorities (local, régional, state, national, and international). Voluminous data requirements are specified by regulatory authorities and must be addressed through data génération and submission by the product registrant or by a third party on the product registrant’s behalf, often using a computer with a connection to the World Wide Web. These governmental authorities then review such data and if a détermination of safety is concluded, provide the potential, user; or seller with product registration approval. Thereafter, in that locality where the product registration is granted and supported, such user or seller may use or sell such pesticide:

A molécule according to Formula One can be tested to détermine its efficacy against pests. Furthermore, mode of action studies can be conducted to détermine if said molécule has a different mode of action than other pesticides. Thereafter, such acquired data can be disseminated, such as by the internet, to third parties.

The headings în this document are for convenience only and must not be used to interpret any portion hereof.

TABLE SECTION _}

TABLE 1. Compound number and structure

Compound No.

Structure

-6316335

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Structure

-6616335

Cornpound No.

Structure

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-6716335

Compound No,

Structure

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TABLE 2. Analytical Data

Compound No.	Appea rance	mp (°C)	IR (KBr thin film) cm'1	MS (ESIMS m/z)	'H NMR
1	yellow solid	99-101		295.12
2	white solid	70-72		310.1 (M+2)
3	white solid	92-97.5		279.1
4	white solid	100-105
5	white solid	105-108		385.5
6	tan solid	93-95		309.4
7	light brown solid	211-212
8	pale yellow solid	87-92		294.7
9	tan solid	116-120		308.7
10	yellow film				(300 MHz, CDCI3) δ 9.19 (br s, 1H), 8.74 (br s, 1H), 8.30 (br d, J = 8 Hz, 1H), 7.20- 7.50 (m, 6H), 3.80 (s, 3H), 3.37 (t, J = 7 Hz, 2H), 3.03 (t, J=7Hz, 2H).
11	cream solid	116-118		371.19
12	light brown crystals	137-139		321.02

I

-97-5

Compound No.	Appearance	mp (°C)	IR(KBr thin film) cm'1	MS (ESIMS m/z)	1H NMR
13	brown paste			323.02	(300 MHz, CDCh) δ 9.15 (br d, J = 2 Hz, 1H), 8.70 (dd, J = 2, 5 Hz, 1H), 8.30 (m, 1H), 7.43 (dd, J = 5, 8 Hz, 1H), 3.87 (s, 3H), 2.60-3.50 (m, 5H), 1.42 (d, J = 7 Hz, 3H), 1.26 (t, J = 7 Hz, 3H).
14	cream powder	127-132		251.11
15	tan powder	162-164
16	white film			295.16	(300 MHz, CDCI3) δ 9.10 (br S, 1H), 8.68 (br s, 1H), 8.25 (m, 1H), 7.40 (m, 1H), 4.48 (m, 2H), 3.71 (m, 5H), 3.42 (s, 3H).
17	yellow oil			337.12	(300 MHz, CDCh) δ 9.15 (d, 2 Hz, 1H), 8.68 (dd, J = 2, 5 Hz, 1H), 8.27 (dt, J = 2, 8 Hz, 1H), 7.41 (dd, J = 5,8 Hz, 1H), 3.97 (s, 3H), 2.98 (s, 2H), 2.58 (q, J = 7 Hz, 2H), 1.55 (s, 6H), 1.25 (t, J = 7 Hz, 3H).
18	off-white powder	138-140		310.93
19	light brown solid	92-95		293.2
20	white powder	199-201		292.96

-9816335

Compound No.	Appearance	mp (°C)	IR (KBr thin film) çrri1	MS (ESIMS m/z)	1H NMR
21	white powder			292.96	(300 MHz, (CD3)2SO) δ 9.14 (brs, 1H), 8.67 (m, 1H), 8.27 (m, 1H), 8.11 (d, J = 14 Hz, 1H), 7.41 (m, 1H), 6.30 (d, J = 14 Hz, 1H), 3.91 (s, 3H), 2.46 (s, 3H).
22	white foam	60-75		523.18
23	white sotid	155-159		288
24	pale yellow crystals	89-91		323.21
25	white powder	149-151		281.16
26	white powder	133-135		323.14
27	pale yellow film			349.12	(300 MHz, CDCI3) δ 9.15 (d, J = 2 Hz, 1H), 8.70 (dd, J = 2, 5 Hz, 1H), 8.28 (dt, J = 2, 8 Hz, 1 H), 7.43 (dd, J = 5, 8 Hz, 1H), 3.86 (S, 3H), 3.30 (t, J = 7 Hz, 2H), 3.16 (t, J = 7 Hz, 2H).
28	brown semi- solid			309.2	(300 MHz, CDCI3) δ 9.15 (d, J = 2 Hz, 1H), 8.69 (dd, J = 2, 5 Hz, 1H), 8.28 (dt, J = 2, 8 Hz, 1H), 7.42 (dd, J = 5, 8 Hz, 1H), 3.94 (s, 3H), 3.33 (m, 1H), 3.01 (dd, J = 8, 13 Hz, 1H), 2.69 (dd, J = 6, 13 Hz, 1H), 2.15 (s, 3H), 1.37 (d, J = 7 Hz, 3H).

-9916335

Compound No.	Appearance	mp(°C)	IR (KBr thîn film) cm1	MS (ESIMS m/z)	1H NMR
29	tan solid	135-139		281.18
30	pale yellow foam			398.05	(300 MHz, CDCI3) δ 9.14 (d, J = 2 Hz, 1H), 8.70 (dd, J = 2, 5 Hz, 1H), 8.28 (dt, J = 2, 8 Hz, 1H), 7.31-7.45 (m, 6H), 5.45 (brs, 1H), 5.10 (s, 2H), 3.82 (s, 3H), 3.65 (m, 2H), 2.94 (m, 2H).
31	off-white semisolid			412.06	(300 MHz, CDCI3) 5 9.14 (d, J= 2 Hz, 1H), 8.70 (dd, J = 2, 5 Hz, 1H), 8.28 (dt, J = 2, 8 Hz, 1H), 7.31-7.45 (m, 6H), 5.14 (br s, 2H), 3.673.87 (m, 5H), 2.85-3.08 (m, 5H).
32	brown oil			ί 339	(300 MHz, CDCI3) δ 9.13 (m, 1H), 8.69 (dd, 1H, J = 2, 5 Hz), 8.28 (m, 1H), 7.42 (ddd, 1H, J = 1, 5,8 Hz), 3.98 (s, 3H), 3.50 (d, 1H, J = 13 Hz), 2.81 (d, 1H, J = 13 Hz), 2.78 (s, 3H), 1.83 (s, 3H), 1.64 (s, 3H).
33	white crystals			355	(300 MHz, CDCI3) δ 9.14 (br s, 1H), 8.70 (br s, 1H), 8.29 (m, 1H), 7.43 (m, 1H), 3.98 (s, 3H), 3.64 (s, 2H), 3.09 (s, 3H), 2.78 (s, 3H), 1.74 (s, 6H).
34	tan powder	121-123		236.04

-100 16335

Compound No.	Appearance	mp (°C)	IR (KBr thin film) cm'1	MS (ESIMS m/z)	1H NMR
35	pale yellow powder	182-188		309,2
36	white powder			341.18	(300 MHz, CDCI3) δ 10.48 (br s, 1H), 9.14 (br s, 1H), 8.72 (m, 1H), 8.27 (m, 1H), 7,45 (m, 1H), 3.65 (s, 2H), 2.99 (s, 3H), 1.69 (s, 6H).
37	pale yellow film			340.99	(300 MHz, CDCI3) δ 9.14 (br s, 1H), 8.71 (br s, 1H), 8.29 (d, J = 8 Hz, 1H), 7.42 (br s, 1H), 3.79-4,01 (m, 5H), 3.16 (dd, J =3, 13 Hz, 1H), 2.96 (s, 3H), 1.43 (d, J = 7 Hz, 3H).
38	tan foam	41-48		364.08
39	off-white foam	42-52		326.9
40	white powder	198-201		403
41	tan powder	110-112		264.1
42	white foam			379.19	(300 MHz, CDCI3) δ 9.12 (br s, 1H), 8.70 (d, J = 4 Hz, 1H), 8.29 (dt, J = 2, 8 Hz, 1H), 7.43 (dd, J = 8, 5 Hz, 1H), 4.21 (d, J= 15 Hz, 1H), 3.97 (s, 3H), 3.69 (d, J = 15 Hz, 1H), 3.53 (s, 3H), 1.92 (s, 3H), 1.63 (s, 3H).
43	white solid	175-177		355

Compound No,	Appearance	mp (’C)	IR (KBr thin film) . cm'1	MS (ESIMS m/z)	1H NMR
44	tan powder	144-147		321.03
45	white powder	166-168		337
46	white powder	208-212		353
48	Yellow amorphous solid	114-121		320,1
49	Yellow needles	146-147		291,16
50	white powder	126-128		311.12
51	white powder	170-172		327
52	white powder	198-200		343
53	yellow oil			351.23	(300 MHz, CDCI3) δ 8.98 (d, J = 2 Hz, 1H), 8.75 (dd, J = 2, 5 Hz, 1H), 7.99 (dt, J = 2, 8 Hz, 1H), 7,46 (dd, J = 5, 8 Hz, 1H), 3.32 (s, 3H), 3.11 (s, 2H), 2.12 (s, 3H), 1.962.11 (m, 4H), 0.84 (t, J = 7 Hz, 6H).
54	yellow film			282 (M- Me)	(300 MHz, CDC13) δ 8.89 (br s, 1H), 8.64 (br s, 1 H), 7,97 (dt, J = 2, 8 Hz, 1H), 7.37 (dd, J = 5, 8 Hz, 1H), 5.12 (s, 2H), 3.14 (s, 3H), 2,32 (s, 3H).
55	off-white	192-194		267.1

-10216335

Compound No.	Appearance	mp (°C)	IR (KBr thin film) cm'1	MS (ESIMS m/z)	1H NMR
	powder
56	off-white powder	152-154		307
57	yellow oil			385	(300 MHz, CDCI3) δ 9.15 (d, J = 2 Hz. 1H), 8.70 (dd, J = 2, 5 Hz, 1H), 8.28 (dt, 7=2, 8 Hz, 1H), 7.42 (dd, J = 5, 8 Hz, 1H), 7.11-7.28 (m, 5H), 3.52-3.61 (m, 4H), 2.98-3.07 (m, 3H), 2.82 (dd, J = 5, 13 Hz, 1H), 2.13 (s, 3H).
58	tan film	117-120		357.18
59	brown powder	152-155		369.2
60	yellow film			363	(300 MHz, CDCI3) δ 8.96 (s, 1H), 8.92 (d, 7 = 5 Hz, 1H), 7.71 (d, J = 5 Hz, 1H), 3.90 (s, 3H), 2.90-3.05 (m, 4H), 2.20 (s, 3H),
61	yellow film		; ‘	375	(300 MHz, CDCI3) δ 8.95 (s, 1H), 8.92 (d, J = 5 Hz, 1 H), 7.71 (d, J = 5 Hz, 1H), 3.93 (s, 3H), 3.74 (s, 3H), 3.04 (t, J = 7 Hz, 2H), 2.83 (t, J = 7 Hz, 2H).
62	tan powder	137-140		328.9
63	off-white powder	130-132		341

-103 -

Compound No.	Appearance	mp (°C)	IR (KBr thin film) cm'1	MS (ESIMS m/z)	1H NMR
64	off-white powder	153-155		328.9
65	off-white powder	176-178		341
66	tan powder	99-102		296
67	Yellowish solid		1674	329
68	off-white powder	177-180		308
69	pale yellow film			323.94	(300 MHz, CDCI3) δ 9.29 (s, 1H), 9.27 (s, 2H), 4.00 (s, 3H), 2.98 (s, 2H), 2.18 (s, 3H), 1.57 (s, 6H).
70	yellow solid	108-110		312.39
71	yellow solid	165-167		338.45
72	yellow solid	163		309.41
73	yellow oil			340.44
74	dark oil			336.48
75	yellow solid	114-115		390.45
76	white solid	169-175		372.44
77	white solid	135-137	1	356.44
78	Yellowish solid	104-106		329.1

-104-

Compound No.	Appearance	mp CC)	IR (KBr thin film) cm1	MS (ESIMS m/z)	1H NMR
79	White solid	100-104		328.1
80	White solid	137-140		299.1
81	tan solid	74-76		326.41
83	Colorless gum		1658	342.2
84	light brown solid	145-147		374.46
85	Yellow solid	150-152		345.1
86	Brown glass		1478	344.1
87	White solid			283.1	(CDCI3] 400 MHz) δ ppm 8.90 (br s, 1H), 8.55 (br s, 1H), 8.05 (ddd, J = 8.9, 2.6, 1.6 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.73 (s, 3H), 1.43 (t, J =7.4 Hz, 3H).
88	Beige solid	109-111	1665	352.1
89	Beige solid	154-157		356.2	(CDCI3] 400 MHz) δ ppm 11.17 (br, 1H), 9.02 (t, J = 1.6 Ηζ,ΊΗ), 8.43 (d, J = 2.8 Hz, 1H), 8.11 (ddd, J = 9.8, 2.8, 1.8 Hz, 1H), 3.87 (d, J = 2.9 Hz, 1H), 3.48 (s, 3H), 3.47 ( d, J = 2.9 Hz, 1H), 2.99 (d, J = 12.7 Hz, 1H), 2.78 (d, J = 13.6 Hz, 1 H), 2.20 (s, 3H), 1.41 (s, 3H).

T

Compound No.	Appearance	mp (°C)	IR (KBr thin film) cm'1	MS (ESIMS m/z)	1H NMR
90	white solid	102-105	1654	425.3
91	white solid	90-93	1724, 1644	441.2
92	Yellow solid	176	1694	295.45
93	Yellow solid	143-147	1691	322.37
94	Waxy white solid	43-46	1667	336.52
95	Yellow solid	118-121	1571	310.7
96	tan powder	152-154	1667		(CDCI3, 300 MHz) δ ppm 8.84 (brs, 2H), 7.86 (m, 2H), 3.88 (s, 3H), 2.91-3.06 (m, 4H), 2.20 (s, 3H).
97	brown powder	175-177	1725, 1667	307.0
98	yellow gum		1666, 1436	334.1	(400 MHz, CDCI3) δ 9.16 (d, J= 1.5 Hz, 1H), 8.70 (d, J = 3.5 Hz, 1H), 8.28 (dt, J = 7.9, 2.0 Hz, 1H), 7.42 (ddd, J = 8.0, 4.8, 0.6 Hz, 1H), 4.31 (d, J = 6.9 Hz, 2H), 3.11 - 3.03 (m, 2H), 3.01 2.92 (m, 2H), 2.20 (s, 3H), 1.37 - 1.26 (m, 1H), 0.67 0.61 (m, 2H), 0.61 -0.55 (m, 2H).

TABLE 3. Biologieal Data.

- 10616335

Corn-	APHIGO	MYZI^PE	BEMITA %
poun	% Ctrl @	% Ctrl ©	Ctrl @ 200
d No.	200 ppm	200 ppm	PPm
1	A	A j	B
2	A	A	B
3	A	A	B
4	A	A	B
5	B	B	B
6	A	A	B
7	B	B.	B
8	A	' A	D
9	A	A	B
10	B	A:	C
11	B	B	B
12	A	B	B
13	A	A	B
14	B	D	C
15	B	D	C
16	A	1 b:	C
17	A	A	B
18	A	A;	B
19	A	, B	B
20	A	A	B

-10716335

Com-	APHÎGO	MYZUPE	BEMITA %
pou η	% Ctrl ©	% Ctrl ©	Ctrl @ 200
d No.	200 ppm	200 ppm	PPm
21	B		C
22	D	B	C
23	A	A	C
24	A	À	B
25	A	A	C
26	B	B	C
27	A	B	c
28	A	A	B
29	A	À	B
30	B	D	c
31	D	D	C
32	A	A	A
33	A	A	B
34	D	D	C
35	A	B	C
36	A	B	C
37	A	A	B
38	A	A'	B
39	A	A	B
40	D	D	C

- 108i

Com-	APHIGO	MYZUPE	BEMITA %
poun	% Ctrl ©	% Ctrl @	Ctrl © 200
d No,	200 ppm	200 ppm	ppm
41	A	B	C
42	B	A	B
43	A	B	D
44	A	i A	D
45	A	A^	B
46	A	C	B
47	B	D	C
48	A	A	B
49	A	B	B
50	A	A	B
51	A	A il ’	B
52	B	P	C
53	A	B	B
54	B	D	C
55	B	D	C
56	A	B	D
57	B	B	C
58	D	C	C
59	B	D	C
60	B	D	C

-109-

Com-	APHIGO	MYZUPE	BEMITA %
pou η	% Ctrl @	% Ctrl @	Ctrl @ 200
d No.	200 ppm	200 ppm	ppm
61	A	B	B
62	B	B	C
63	B	B	D
64	D	C	C
65	B	B.	B
66	B	C	C
67	A	A • i . ,	D
68	B	’ 'B	B
69	B	B	C
70	A	B	B
71	C	A	B
72	C	B	C
73	C	B	C
74	c	À f	B
75	c	A	B
76	c	B Γ v	B
77	c	A	B
78	c	A	A
79	c	A	B
80	c	A	B

-110-

Com-	APHIGO	MYZUPE	BEMITA %
pou η	% Ctrl ©	% Ctrl ©	Ctrl @ 200
d No.	200 ppm	200 ppm	PPm
81	C	.....f · B	B
83	C	A	B
84	c	B	B
85	c	B	B
86	c	A	A
87	c	C	A
88	c	A	B
89	c	B	B
90	c	C	C
91	c	A	A
92	c	B	B
93	c	A	B
94	c	A	A
95	c	A	B
96	B	C	C
97	B	D	C
98	C	A	D

-11116335

MYZUPE, APHIGO and BEMITA Rating Table
% Control (or Mortality)	Rating
80-100	A
More than 0 - Less than 80	B
Not Tested	C
No activity noticed in this bioassay	D

Claims (12)

1. WE CLAIM

   1. A molécule according to Formula One:

   Formula One ί wherein

   R10 is selected from the following group (b) (^c)

   R1 is selected from H, F, Cl, Br, I, CN, NO₂, substituted or unsubstituted Ci-C₆ alkyl, substituted or unsubstituted C₂-C_e alkenyl, substituted or unsubstituted Ci-C_e alkoxy, substituted 10 or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C_zo aryl, substituted or unsubstituted C_rC₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂₁ N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_nOR9, or R9S(O)_nR9, wherein each said R1, which is substituted, has one or more substituents selected from 15 F, Cl, Br, I, CN, NO₂, CrCe alkyl, C₂-C₆ alkenyl, Ci-C₆ haloalkyl, C₂-C_e haloalkenyl, CrC₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-Ci₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_nOR9, C₆-C₂₀.aryl, or CrCao heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9);

   20 R2 is H, F, Cl, Br, I, CN, NO_2] substituted or unsubstituted C_rC_B alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C_rC₆ alkoxy, substituted or unsubstituted C₂-C_e alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C_e-C₂₀ aryl, substituted or unsubstituted C_rC₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂,

   25 N(R9)C(=X1)R9, SR9, S(O)nOR9, or R9S(O)_nR9, wherein each said R2, which is substituted,-'has one or more substituents selected from F, Cl, Br, I, CN, NO₂, Ci-Ce alkyl, C₂-C₆ alkenyl, Ci-C₆ haloalkyl, C₂-C₆ haloalkenyl, Ci-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, Cs-C₃₀ cycloalkyl, C₃-Ci₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl,

   C₃-Ciq halocycloalkenyl, OR9, S(O)_nOR9, C₆-C_2O aryl, or Cj-C^ heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9);

   R3 is H, substituted or unsubstituted Ci-C_B alkyl, substituted or unsubstituted C₂-C₆

   5 alkenyl, substituted or unsubstituted C_rC_e alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-Ci_D cycloalkenyl, substituted or unsubstituted C₆-C₂o aryl, substituted or unsubstituted C-i-C₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_nOR9, R9S(O)_nR9, C_rC₆ alkyl C₆-C₂₀ aryl (wherein the alkyl and aryl can independently be 10 substituted or unsubstituted). C(=X2)R9, C(=X'Î)X2R9, R9X2C(=X1)R9, R9X2R9, C(=O)(C,-C_e alkyl)S(O)_n(C_rC₆ alkyl), C(=O)(C_rC₆ alkyl)C(=O)0(C₁-C₅ alkyl), (CrC₆ alkyl)OC(=O)(C_e-C₂₀ aryl), (C_rC₆ alkyl)OC(=0)(C₁-C₆ alkyl), Ci-C₆' alkyl-(C₃-C₁₀ cyclohaloalkyl), or (C_rC₆ alkenyl)C(=O)O(C_rC₆ alkyl), or R9X2C(=X1)X2R9;

   wherein each said R3, which ïs substituted, has one or more substituents

   15 selected from F, Cl, Br, I, CN, NO₂, C,-C₆ alkyl, C₂-C_e alkenyl, Cj-C₆ haloalkyl, C₂-C₆ haloalkenyl, C_rC₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-Ci₀ cycloalkyl, C₃-Ci₀ cycloalkenyl, C₃-C_w halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_nOR9, C_e-C₂₀ aryl, or C-rC» heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9);

   R4 is O, S, NR9, or NOR9;

   R5 is (C1-C12 alkenyl)S(O)_n(Ci-C_t2 alkyl), i <_;· (C_rC₁₂ alkyl(R6))S(O)_n(C_rCj₂ alkyl), (CrC₁₂ alkyl)(S(Ci-C₃₂ alkyl(each independent from the other)))₂, (CrC₁₂ alkyl)C(=NO(C₁-Ci_Z alkyl))(Ci-C₁₂ alkyl), (CrC-,2 alkyl)C(=O)(Ci-C₁₂ alkyl), (CrCi₂ alkyl)C(=O)O(C₁-Ci₂ alkyl), « .=>

   (C_rC₁₂ alkyl)N(R9)_z, (C_rC₁₂ alkyl)N(R9)C(=O)O(Ci-C₁₂ alkyl), _l!: (Ci-C₁₂ alkyl)N(R9)C(=O)O(Ci-C₁₂ alkyl)R6, (CiC-j₂ alkyl)O(C_rC₁₂ alkyl), (C_rC₁₂ alkyl)OC(=O)(C_rC₁₂ alkyl)S(O)_n(C_rC₁₂ alkyl), (Ci-Ci₂ alkyl)OSi((Ci-C₁₂ alkyl)₃ each independent from the other) (CtC₁₂ alkyl)S(O)_n(C_rCi₂ haloalkyl), (C_rC₁₂ alkyl)S(O)_n(=NCN)(C_rC₁₂ alkyl), (C_rCi₂ alkyOSfOJniCrC^ alkenyl), (CrC-,2 alkyl)S(O)_n(Ci-C₁₂ alkyl), f (C₃-Cj2 cycloalkyl)(CrC₁₂ 8^1)(5(0),,(0,-0,2 alkyl), (0,-0,₂ alkyl)S(O)_n(C_rC₁₂ alkyl)R6, (C1-C12 alkyl)S(O)_n(C_e-C₂₀ aryl), (01-0,2 alkyl)S(0)_nR6, (0,-0,2 alkyl)S(0)_nC(=0)(Ci-C,2 alkyl), (0,-0,2 alkylCN)S(0)_n(Ci-C,2 alkyl).

   (C,-C,₂ alkylN(R9)₂)S(O)_n(Ci-Ci2 alkyl), . J

   N(R9)(C,-C,₂ alkyl)O(C_rC₁₂ alkyl),

   N(R9)(C,-Ci2 alkyl)S(0)_n(Ci-C,2 alkyl),

   0(0,-0,2 alkyl),

   0(0,-0,2 alkyl)O(C,-C,₂ alkyl),

   0(0,-0,2 alkyl)S(0)_n(C,-Ci2 alkyl), or

   S(0)_n(C,-Ci2 alkyl);

   R6 is H, substituted or unsubstituted Ce-C_2û aryl, substituted or unsubstituted Ci-C₂₀ heterocyclyl;

   R7 is H, F, Cl, Br, I, CN, N0₂, substituted or unsubstituted C,-C₆ alkyl, substituted or unsubstituted C₂-C_e alkenyl, substituted or unsubstituted Ο,-Ο_θ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-Cio cycloalkyl, substituted or unsubstituted Ο₃-Ο,₀ cycloalkenyl, substituted or unsubstituted C_e-C₂₀ aryl, substituted or unsubstituted Οι-Ο₂₀ heterocyclyl, 0R9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_nOR9, or R9S(O)_nR9, wherein each said R7, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, N0₂, C,-C₆ alkyl, C₂-C₆ alkenyl, C,-C₆ haloalkyl, C₂-C_e haloalkenyl, C,-C₆ haloalkyloxy, C^-Ce haloàlkenyloxy, C₃-C,_o cycloalkyl, C₃-Ciq cycloalkenyl, C3-C10 halocycloalkyl, C₃-C,_o halocycloalkenyl, 0R9, S(O)_nOR9, Ο_δ-Ο₂₀ aryl, or 0,-0₂ο heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9);

   R8 is H, F, Cl, Br, I, CN, N0₂, substituted or unsubstituted C,-C₆ alkyl, substituted or unsubstituted Ο₂-Ο₆ alkenyl, substituted or unsubstituted C,-C₆ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted Ο₃-Ο₁₀ cycloalkyl, substituted or unsubstituted Ο₃-Ο₁₀ cycloalkenyl, substituted or unsubstituted C_e-C₂₀ aryl, substituted or unsubstituted Οι-Ο₂₀ heterocyclyl, 0R9, C(=X1)R9, C(=X1)0R9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)|OR9, or R9S(O)_nR9, . <

   wherein each said R8, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂,. Ο,-Ο_δ alkyl, Ο₂-Ο_δ alkenyl, 0,-0₆ haloalkyl, C₂-C₆ haloalkenyl, C,-C_e haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C_w cycloalkyl, C3-C,_Q cycloalkenyl,

   -115 -

   C₃-C₁₀ halocycloalkyl, C₃-Ci₀ halocycloalkenyl, OR9, S(O)_nOR9, C₆-C₂₀ aryl, or C1-C20 heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9);

   R9 (each independently) is H, CN, substituted or unsubstituted Ci-C_s alkyl, substituted

   5 or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted Ci-Ce alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C_rC₂₀ heterocyclyl, S(O)_nCi-C₆ alkyl, N(CrC₆alkyl)₂, wherein each said R9, which is substituted, has one or more substituents

   10 selected from F, Cl, Br, I, CN, NO₂, C_rC_e alkyl, C₂-C₆ alkenyl, Ci-C₆ haloalkyl, C₂-C₆ haloalkenyl, CrCe haloalkyloxy, C_z-C₆ haloaikenyloxy, C₃-C₁₀ cycloalkyl, C₃-C_1Q cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OCrC₆ alkyl, OCi-C₆ haloalkyl, SiOJnCrCealkyl, S(O)_nOCi-Ce alkyl, C₆-C₂₀ aryl, or C_rC₂₀ heterocyclyl;

   15 X1 is (each independently) O or S;

   X2 is (each independently) O, S, =NR9, or =NOR9; and n is (each independently) 0, 1, or 2.

   20 .· .
2. 2. A molécule according to claim 1 having oneofthe following structures

   Compound No. . ?) ( : ; · Structure 1 N—-⁷ , | CH₃ k ch₃

   -11716335

   -11816335

   Compound No.

   Structure

   -11916335

   Compound No.

   Structure

   -12116335

   Compound No. Structure 38 Ο ^ΗΛ ' ° k Λ™ \ < X CH, N 39 N--N . . \\ _z ^CH3 U ch₃ N : ; 44 o N--N IL a b N

   -12316335

   Compound No. Structure 45 0 N— N X.......... < sA G CH₃ N 48 o ch₃ ^N—^N X ^{: ch}3 ch₃ 50 0 N---N | _zK'n^/^'^ij/X/' ^^CH’ 1 CH, N

   -12416335

   Compound No. Structure 51 0 W //~\\ L yJ ch₃ N 67 Vh, \ ^CH3 L_NL -
3. 3. A process comprising applying a molécule according to claim 1 to an area to control a pest in an amount sufficient to control such pest.
4. 4. A molécule that is a pesticidally acceptable acid addition sait, a sait dérivative, a solvaté, or an ester dérivative, of a molécule according to claim 1.
5. 5. A polymorph of a molécule according to claim 1.
6. 6. A molécule according to claim 1 wherein at least one H is ²H or at least one C is ¹⁴C.

   -125 16335
7. 7, A composition comprising a molécule according to claim 1 and at least one other compound selected from the Insecticide Group, Acaricide Group, Nematicide Group, Fungicide

   Group, Herbicide Group, Al Group, or Synergist Group.

   5
8. 8. A composition comprising a molécule according to claim 2 and at least one other compound selected from the Insecticide Group, Acaricide Group, Nematicide Group, Fungicide Group, Herbicide Group, Al Group, or Synergist Group.
9. 9. A composition comprising a molécule according to claim 1 and a seed.
10. 10. A composition according to claim 9 wherein said seed has been genetically modified to express one or more spectalized traits.
11. 11. A process comprising applying a molécule according to claim 1 to a genetically modified 15 plant that has been genetically modified to express one or more specialized traits.
12. 12. A process comprising: orally administering; ortopically applying; a molécule according to claim 1, to a non-human animal, to control endoparasites, ectoparasites, or both.

    -126