OA17069A

OA17069A - Pesticidal compositions and processes related thereto.

Info

Publication number: OA17069A
Application number: OA1201400014
Authority: OA
Inventors: Gary D. Crouse; David A. Demeter; Thomas C. Sparks; Nick X. WANG; William Hunter Dent; Carl Deamicis; Noormohamed M. Niyaz; Erich W. BAUM; Lindsey Gayle FISCHER; Natalie Christine GIAMPIETRO
Original assignee: Dow Agrosciences Llc
Priority date: 2011-07-12
Filing date: 2012-07-11
Publication date: 2016-03-23

Abstract

This document discloses molecules having the following formula

Description

FIELD OF THE DISCLOSURE

The molécules disclosed In this document are related to the field of processes to produce molécules that are useful as pesticides (e.g., acaricldes, insecticides, mollusdcldes, and nematiddes), such molécules, and processes of using such molécules to control pests.

BACKGROUND OF THE DISCLOSURE

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

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

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

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

Therefore, for many reasons, Indudîng the above reasons, a need exlsts for new pestlddes.

DEFINITIONS

The exampies given in the définitions are generally non-exhaustive and must not be construed as limiting the molécules disclosed In this document, it ls understood that a substituent should comply with chemical bondlng rules and steric compatibility constraints ln relation to the particular molécule to which It Is attached.

Alkenyl means an acyclic, unsaturated (at least one carbon-carbon double bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, vlnyl, allyt, butenyl, pentenyl, and hexenyl.

’Alkenyloxy means an alkenyl further consisting of a carbon-oxygen single bond, for example, aliyloxy, butenyloxy, pentenyloxy, hexenyloxy.

Alkoxy means an alkyl further consisting 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 consisting 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 consisting of carbon and hydrogen, for example, ethynyl, propargyl, butynyl, and pentynyl.

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

Aryl means a cyclic, aromatic substituent consisting of hydrogen and carbon, for example, phenyl, naphthyl, and blphenyl.

“Cycloalkenyl means a monocyclic or polycyclic, unsaturated (at least one carbon-carbon double bond) substituent consisting of carbon and hydrogen, for example, cyclobutenyl, cydopentenyl, cydohexenyl, norbomenyl, blcyclo[2.2.2]octenyl, tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.

Cycloalkenyloxy means a cycloalkenyl further consisting of a carbon-oxygen single bond, for example, cyclobutenyloxy, cyclopentenyloxy, norbomenyloxy, and blcyclo[2.2.2]octenyloxy.

•Cycloalkyi means a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, for example, cyclopropyl, cydobutyl, cyclopentyl, norbomyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.

Cycloalkoxy means a cycloalkyi further consisting of a carbon-oxygen single bond, for example, cydopropyloxy, cyclobutyloxy, cydopentyloxy, norbomyloxy, and blcydo[2.2.2]octyloxy.

'Halo means fluoro, chloro, bromo, and lodo.

Haloalkoxy means an alkoxy further consisting 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 pentafluoroethoxy.

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

Heterocyclyl means a cyclic substituent that may be fully saturated, partiaily unsaturated, or fuliy 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 heterocydyls Include, but are not limited to, benzofuranyl, benzolsothlazolyl, benzolsoxazolyl, benzoxazolyl, benzothienyl, benzothlazolyl, dnnolinyl, furanyl, Indazolyl, indolyl, Imldazolyl, isoindolyl, isoquinolinyl, Isothlazolyi, Isoxazolyl, oxadiazolyi, oxazolinyl, oxazolyl, phthalazïnyl, pyrazlnyl, pyrazolinyl, pyrazolyl, pyridazlnyl, pyrïdyi, pyrimldinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxaltnyl, tetrazoiyl, thiazolinyl, thiazolyl, thlenyl, triazinyl, and triazolyl. Examples of fully saturated heterocydyls include, but are not limited to, plperazlnyl, piperidtnyf, morphoiinyl, pyrrolldinyl, tetrahydrofuranyl, and tetrahydropyranyl. Examples of partiaily unsaturated heterocydyls indude, but are not limited to, 1,2,3,4-tetrahydro-quinolinyl, 4,5-dihydro-oxazolyl, 4,5dihydro-1H-pyrazolyl, 4,5-dihydro-lsoxazolyl, and 2,3-dihydro-[1,3,4]-oxadiazolyl.

DETAILED DESCRIPTION OF THE DISCLOSURE

This document disdoses molécules having the following formula (Formula One) _ZQ²-R²

Formula One wherein:

(A) Ar¹ Is selected from (1) furanyl, phenyl, pyridazinyl, pyridyl, pyrimidinyl, thienyl, or (2) substituted furanyl, substituted phenyl, substituted pyridazinyl, substituted pyridyl, substituted pyrimidinyl, or substituted thienyl, wherein said substituted furanyl, substituted phenyl, substituted pyridazinyl, substituted pyridyl, substituted pyrimidinyl, and substituted thienyl hâve one or more substituents Independently selected from H, F, Cl, Br, I, CN, NO_Z, CyCe alkyl, Cj-Ce haloalkyl, C3-Ce cycloalkyl, C3-Ce halocydoalkyl, C3-Ce cydoalkoxy, CyCe halocydoalkoxy, CyC_e alkoxy, CyCe haioalkoxy, CyCe alkenyl, CyCe alkynyl, S(=O)_n(CyCe alkyl), S(=O)_n(CyCe haloalkyl), OSO₂(C_rCe alkyl), OSO₂(CyCe haloalkyl), C(=O)NR^xR^y, (CyCe alkyl)NR^xR^y, C(=O)(CyCe alkyl), C(*O)O(CrCe alkyl), C(=O)(C₁-C_B haloalkyl). C(=O)O(CyCe haloalkyl), C(=O)(CyCe cydoalkyl), C(®O)O(CyCe cydoalkyl), C(=O)(CrCe alkenyl), C(=O)O(CrCe alkenyl), (Ci-Ce alkyl)O(CyCe alkyl), (Ci-Ce afkyl)S(CyC6 alkyl), CÎ=O)(CyCe alkyl)C(=O)O(CyCe alkyl), phenyl, phenoxy, substituted phenyl, and substituted phenoxy, wherein such substituted phenyl and substituted phenoxy hâve one or more substituents Independently selected from H, F, Cl, Br, I, CN, N0₂, CyCe alkyl, CyCe haloalkyl, C3Ce cydoalkyl, CyCe halocydoalkyl, CyCe cydoalkoxy, CyCe halocydoalkoxy, CyCe alkoxy, CyCe haioalkoxy, CyCe alkenyl, CyCe alkynyl, S(=O)_n(CyCe alkyl), S(=O)_n(CyCe haloalkyl), OSO₂(CyCe alkyl), OSO^CyCe haloalkyl), C(=O)NR^xR^y, (CyCe alky1)NR^xR^y. C{=0)(CyCe alkyl), C{=O)O{CyCe alkyl), C(=O)(CyCe haloalkyl), C(=O)O{CyCe haloalkyl). C(=O)(CyCe cycloalkyl), C(=O)O(CyCe cydoalkyl), C(=O)(CyCe alkenyl), C(=O)O(CyCe alkenyl), (Ct-Ce alkyt)O(CyCe alkyl), (CyCe alkyOSfCi-Ce alkyl), C(=O)(CyCe alkyl)C(=O)O(CyC_e alkyl) phenyl, and phenoxy;

(B) Het is a 5- or 6-membered, saturated or unsaturated, heterocydic ring, containing one or more heteroatoms independently selected from nitrogen, sulfur, or oxygen, and where Ar¹ and Ar²are not ortho to each other (but may be meta or para, such as, for a five-membered ring they are 1,3 and for a 6-membered ring they are either 1,3 or 1,4), and where said heterocyclic ring may also be substituted with one or more substituents Independently selected from H, F, Cl, Br, I, CN, N02, 0x0, CyCe alkyl. CyCe haloalkyl, CyCe cycloalkyl, CyCe halocydoalkyl, CyCe cydoalkoxy, Cy Ce halocydoalkoxy, Ci-Ce alkoxy, CyCe haioalkoxy, CyCe alkenyl, CyCe alkynyl, S(=0)n(CyCe alkyl), S(=O)n(CyCe haloalkyl), OSO2(CyCe alkyl), OSO2(C,-Ce haloalkyl), C(=O)NR^xR^y, (CyCe alky1)NR^xR^y C(=O)(C1-C_fi alkyl), C(=O)O(CyCe alkyl), C(=O)(CyCe haloalkyl), CÎ=O)O(CyCe haloalkyl), C(=0)(CyC_e cydoalkyl), C(=O)O(CyCe cydoalkyl), C(=O)(CyCe alkenyl), C(=O)O(CyCe alkenyl), (CyCe alkyi)O(C,-Ce aikyl), (CyCe alkyfJSfq-Ce alkyl), C{=0)(CyCe alkyt)C(=O)O(CyCe alkyl), phenyl, phenoxy, substituted phenyl and substituted phenoxy, wherein such substituted phenyl and substituted phenoxy hâve one or more substituents Independently selected from H, F, Cl, Br, I, CN, NO₂₁ C_rCe alkyl, CrCe haloalkyl, CrCe cycloalkyl, CrCe halocycloalkyl, CrCe cycloalkoxy, CrCe halocycloalkoxy, C_rCe alkoxy, CrCe haloalkoxy, Cr Ce alkenyl, CrCe alkynyl, S(=O)_n(C₁-C_e alkyl), S(=O)n(C_rCe haloalkyl), OSO₂(CrCe alkyl), OSO₂(C,-Ce haloalkyl), C(=O)H, C(=O)NR^MR^y, {CrCe alkyONR’R’, C(=O)(C₁-C_i alkyl), C(=O)O(C_rCe alkyl), C(=O)(CrCe haloalkyl), C(=O)O(CrCe haloalkyl), C(=O)(CrCe cycloalkyl), C(=O)O(CrCe cycloalkyl), C(=O)(CrCe alkenyl), C(=O)O(CrCe alkenyl), (C_rCe alkylJO^-Ce alkyl), (CrCe alkyt)S(CrCe alkyl), phenyl, and phenoxy, (C) Ar² Is selected from (1) furanyl, phenyl, pyridazînyl, pyridyl, pyrimldinyl, thienyl, or (2) substituted furanyl, substituted phenyl, substituted pyridazînyl, substituted pyridyl, substituted pyrimldinyl, or substituted thienyl, wherein said substituted furanyl, substituted phenyl, substituted pyridazînyl, substituted pyridyl, substituted pyrimldinyl, and substituted thienyl, hâve one or more substituents independently selected from H, F, Ci, Br, I, CN, NO₂, Ci-C_e alkyl, CrCe haloalkyl, Cy-Ce cycloalkyl, CrCe halocycloalkyl, CrCe cycloalkoxy, CrCe halocycloalkoxy, C,-C_e alkoxy, CrCe haloalkoxy, CrCe alkenyl, CrCe alkynyl, S(=O)_n(C₁-C_e alkyl), S(=O)_n(Ci-Ce haloalkyl), OSO₂(CrCe alkyl), OSO₂(CrCe haloalkyl), C(=O)NR*R^y, (CrCe alkyl)NR^xR^y, C(=O)(CrCe alkyl), C(=O)O(CrCe alkyl), C(=O)(CrCe haloalkyl), C(=O)O(CrCe haloalkyl), C(=O)(CrCe cycloalkyl), C(=O)O(CrCe cycloalkyl), C(=O)(CrCe alkenyl), C(=O)O(C₂-C_e alkenyl), (CrCe aikyljOtCi-Ce alkyl), (CrCe alkylJSfC^ alkyl), C(=O)(CrCe alkyl)C(=O)O(CrCe alkyl), phenyl, phenoxy, substituted phenyl and substituted phenoxy, wherein such substituted phenyl and substituted phenoxy hâve one or more substituents independently selected from H, F, Cl, Br, I, CN, NCb, CrCe alkyl, CrCe haloalkyl, Cr Ce cycloalkyl, CrCe halocycloalkyl, CrCe cycloalkoxy, CrCe halocycloalkoxy, CrCe alkoxy, CrCe haloalkoxy, CrCe alkenyl, C_rCe alkynyl, S(=O)_n(C₁-C_e alkyl), S(=O)_n(CrCe haloalkyl), OSO₂(CrCe alkyl), OSO₂(CrCe haloalkyl), C(=O)H, C(=O)NR‘R^y> (C_rCe alkyONR-R*. C(=O)(CrCe alkyl), C(=O)O(CrCe alkyl), C(=O)(C,-Ce haloalkyl), C(=O)O(C_rCe haloalkyl), C(=O)(CrCe cycloalkyl), C(=O)O(CrCe cycloalkyl), C(=O)(C₁-C_e haloalkyl), C(=O)(C2-Ce alkenyl), C(=O)O(CrCe alkenyl), (CrCe alkyl)O(CrCe alkyl), (C,-Ce alkyl)S(CrCe alkyl), C(-O)(CrCe alkyl)C(=O)O(CrCe alkyl), phenyl, and phenoxy);

(D) R¹ Is selected from H, CrCe alkyl, C3-Ce cycloalkyl, CrCe alkenyl, CrCe alkynyl, S(=0)n(Cr C« alkyl), C(=O)NR^xR^y, (CrCe alkyl)NR^xR^y, C(=O)O(CrCe alkyl), C(=O)(CrCe cycloalkyl), C(=0)0(CrCe cycloalkyl), C(=0)(CrCe alkenyl), C(=0)0(CrCe alkenyl), (Ci-Ce alkyOO(CrCe alkyl), (C_rCe alkyf)OC(=O)(C_rCe alkyl), (Cj-Ce alkyt)S(CrCe alkyl), (C_rCe alkyl)OC(=O)O(CrCe alkyl), wherein each alkyl, cycloalkyl, cycloalkoxy, alkoxy, alkenyl, and alkynyl are optionally substituted with one or more substituents Independently selected from F, Cl, Br, I, CN, N0₂, oxo, CrCe alkyl, C_rCe haloalkyl, C₃-Ce cycloalkyl, CrCe halocycloalkyl, CrCe cycloalkoxy, CrCe halocycloalkoxy, C,-Ce alkoxy, CrCe haloalkoxy, S(=O)_n(Ci-Ce alkyl), S(=O)_n(CrCe haloalkyl), OSO₂(Ci-Ce alkyl), OSO₂(CrCe haloalkyl), C(=0)NR^xR^y, (CrCe alkyl)NR^xR^y, C{=O)(CrCe alkyl), C(=O)O(Ci-Ce alkyl), C(=O)(Ci-Ce haloalkyl), C(=O)O(C_rCe haloalkyl), C(=0)(CrCe cycloalkyl), C(=0)0(CyCe cycloalkyl), C(=0)(CrCe alkenyl), C(=0)0(CrCe alkenyl), (Ci-Ce alkyl)O(C_rCe alkyl), (C_rCe alkyl)S(CrC« alkyl), C(=0)(CrC« alkyl)C(=O)O(CrCe alkyl), phenyl, and phenoxy;

(E) R² Is selected from (K), H, Ci-Ce alkyl, CrCe cycloalkyl, CrCe alkenyl, CrCe alkynyl, C(=0)(Ci-Ce alkyl), (CrCe alkyl)0(Ci-C6 alkyl), (CrCe alkyl)S(CrCe alkyl), Ci-Ce alkylphenyl, CrCe alkyl-O-phenyl, C(=0)(Het-1), (Het-1), (CrCealkylHHeU), CrCe alkyl-O-C^OJCrCe alkyl, 0,-Ce alkyl-O-C(=O)(C1-Cfl alkyl), C^alkyl-O-C^OJO^-Ce alkyl, C1-Cealkyl-0-C(=0)N(R^xR^y)l CrCe alkylC(=O)N(R^x)C1-Ce alkyf-(Het-1 ). CrCealkylC(=0)(Het-1), C1-CealkylC(=O)N(R^x)C1-Ce alkyl(N(R')(R^y))(C(=O)OH), CrCealkylC(=O)N(R^x)CrCe alkylN(R^x)(R^y), CrCealkylC(=O)N(R^x)CrCe alkylN(R^x)C(=O)-O-Ci-Ce alkyl, C1-CealkylC(=O)N(R^x)C,-Cealkyl(N(R^x)C(=O)-O-CrCfl alkyl)(C(=O)OH), C,-CealkylC(=0)(Het-1)C(=0)-O-Ci-Cfl alkyl, C,-Cealkyl-O-C(=O)-O-Ci-Ce alkyl, CrCe alkyf-O-C(=O)CrCe alkyl, CrCealkyl-O-C(=O)CrCfl cycloalkyl, C_rCealkyl-O-C(=0)(Het-1 ), CrCealkyl-O-C(=0)Ci-Ce alkyl-N(R^x)C(=0)-O-Ci-Ce alkyl, CrC« alkyl-NR^xR^y, (CrCe alkyl)S-(Het-1) orCrCealkyl-O-fHeU), wherein each alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, and (Het-1) are optionally substituted with one or more substituents Independently selected from F, Cl, Br, I, CN, N0₂, NR^xR^y, CrCe alkyl, CrCe haloalkyl, CrCe cycloalkyl, CrCe halocycloalkyl, CrCe cycloalkoxy, Cy-Ce halocycloalkoxy, CrCe alkoxy, CrCe haloalkoxy, CrCe alkenyl, CrCe cycloalkenyl, CrCe alkynyl, CrCe cycloalkynyl, S(*O)_n(CrCe alkyl), S(=0)_n(CrCe haloalkyl), 0S0₂(CrCe alkyl), 0S0₂(CrCe haloalkyl), C(=0)H, C(=0)0H, C(=0)NR^xR^y, (Ci-Ce alkyl)NR^xR^y, C(=0)(CrCe alkyl), C(=0)0(CrCfl alkyl), C(=0)(CrCe haloalkyl), C(=0)0(CrCe haloalkyl), C(=0)(CrCe cycloalkyl), C(=0)0(CrCe cycloalkyl), C(=0)(CrCe alkenyl), C(=0)0(CrCe alkenyl), (Ci-Ce alkyl)O(Ci-Ce alkyl), (Ci-Ce a!kyl)S(CrCe alkyl), C(=O)(C_rCe a1kyDC(=O)O(CrCe alkyl), phenyl, phenoxy, Si(C_rC6 alkyf)₃, S(=O)_nNR^xR^v, or (Het-1);

(F) R³ Is selected from phenyl, CrCe alkylphenyl, CrCe alkyl-O-phenyl, CrCe alkenyl-O-phenyl, (Het-1), CrCe alkyl(Het-l), or C_rCe alkyl-O-(Het-l), wherein each alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, and (Het-1) are optionally substituted with one or more substituents Independently selected from F, Cl, Br, I, CN, NO₂, NR^xR^y, CrCe alkyl, Ca-Ce cycloalkyl, CrCe halocydoalkyl, CrCe cycloalkoxy, CrCe halocycloalkoxy, Ci-Ce alkoxy, CrCe haloalkoxy, CrCe alkenyl, CrCe cycloalkenyl, CrCe alkynyl, CrCe cycloalkynyl, S(=O)n(C1-Ce alkyl), S(=O)n(CrCe haloalkyl), OSO2(CrCe alkyl), OSO2(CrCe haloalkyl), C(=O)H, C(=O)NR’R^y, (CrCe alkyl)NR^xR^y, C(=O)(C₁-C_e alkyl), 0(=0)0(0,-^ alkyl), 0(=0)(0,-0, haloalkyl), 0(=0)0(0,^ haloalkyl), C(=O)(CrCe cycloalkyl), C(=O)O(CrCe cycloalkyl), C(=0)(CrC_e alkenyl), C(=O)O(CrCe alkenyl), O(C,-Ce alkyl), S(C_rCe alkyl), 0(=0)(0,-0« alkyl)C(=O)O(C₁-C_e alkyl), phenyl, phenoxy, and (Het-1 );

(G) R⁴ Is selected from (K), H, or C_rCe alkyl;

(H) MisNorC-R®, wherein R^s is selected from H, F, Cl, Br, I, CN, NO2, CfC, alkyl, CrCe haloalkyl, CrCe cycloalkyl, Cs-Ce halocydoalkyl, S(=O)n(C1-Ce alkyl), S(=O)n(C1-Ce haloalkyl), C(=O)NR^xR^y, C(=O)(C,-Ce alkyl), C(=O)O(CrCe alkyl), C(=O)(CrCe haloalkyl), C(=O)O(C_rCe haloalkyl), C(=O)(C₃-Ce cydoalkyl), C(=O)O(CrCe cydoalkyl), C(=0)(CrCe alkenyl), C(=0)0(CrCe alkenyl), or phenyl;

(i) (1) Q¹ is seleded from O or S, (2) Q³ is seleded from O or S;

(J) R^x and R^y are Independently selected from H, CrCe alkyl, CrCe haloalkyl, CrCe cydoalkyl, CrCe halocydoalkyl, CrCe alkenyl, CrCe alkynyl, S(=O)_n(C₁-C_e alkyl), S(=O)_n(CrCe haloalkyl), OSO₂(Ci-Ce alkyl), OSO₂(C,-C_e haloalkyl), C(=O)H, C(=O)(CrCe alkyl), C(=0)0(CrC_e alkyl), C(=O)(CrCe haloalkyl), 0(=0)0(0,-0, haloalkyl), C(=0)(C_rCe cydoalkyl), Ct=O)O(CrCe cycloalkyl), C(=O)(CrCg alkenyl), C(=0)0(CrCg alkenyl), (Ct-Cg alkyl)O(Ci-Ce alkyl), (0,-0« alkylJSiCrCe alkyl), C(=O)(Ct-Cg alkyl)C(=O)O(Ct-Ce alkyl), and phenyl, wherein each alkyl, cycloalkyl, cycloalkoxy, alkoxy, alkenyl, alkynyl, phenyl, phenoxy, and (Het-1 ), are optionally substituted with one or more substituents Independently selected from F, Cl, Br, I, CN, N0₂, oxo, 0,-0« alkyl, Ct-Cg haloalkyl, CrCg cycloalkyl, Cs-Cg halocycloalkyl, Ca-Ce cycloalkoxy, Cs-Cg halocycloalkoxy, Ct-Cg alkoxy, Ct-Cg haloalkoxy, CrCg alkenyl, CrCg cycloalkenyl, CrCg alkynyl, CrCg cycloalkynyl, S(=O)_n(Ci-Cg alkyl), S(=O)_n(C,-Cg haloalkyl), OSO₂(Ci-Cg alkyl), OSO₂(Ct-Cg haloalkyl), C(=O)H, C(=O)OH, C(=O)(C,-Cg alkyl), C(=O)O(C_rCg alkyl), C(=O)(Ct-Cg haloalkyl), C(=O)O(C_rCg haloalkyl), C(=O)(C3-Cg cycloalkyl), C(=0)0(C3-C_ecycloalkyl), C(=0)(CrC_e alkenyl), C(=O)O(CrCg alkenyl), (Ct-Cg alkyt)O(Ci-Cg alkyl), (Ct-Cg alkyl)S(Ci-Cg alkyl), C(=O)(Ci-Cg alkyl)C(=O)O(Ct-Ce alkyl), phenyl, halophenyl, phenoxy, and (Het-1), or R* and R^v together can optionally form a 5- to 7-membered saturated or unsaturated cyclic group which may contain one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and where said cyclic group may be substituted with F, Cl, Br, I, CN, oxo, thloxo, Ct-Cg alkyl, Ct-Cg haloalkyl, CrCg cycloalkyl, CrCg halocycloalkyl, CrCg cycloalkoxy, CrCg halocycloalkoxy, Ct-Cg alkoxy, Ci-Cg haloalkoxy, CrCg aîkenyl, CrCg cycloalkenyl, CrCg alkynyl, Ca-Cg cycloalkynyl, S(=O)_n(C_rCe alkyl), S(=O)_n(C,-Cg haloalkyl), OSO₂(Ct-Cg alkyl), OSO₂(Ct-Cg haloalkyl), C(=O)(Ct-Cg alkyl), C(=O)O(C,-Cg alkyl), C(=O)(Ct-Cg haloalkyl), C(=O)O(Ci-Cg haloalkyl), C(=0)(CrCg cycloalkyl), C(=0)0(CrC_e cycloalkyl), C(=0)(CrCg alkenyl), C(=0)0(CrCg alkenyl), (Ct-Cg alkyl)O(C,-Cg alkyl), (Ct-Cg alkyl)S(C,-C_e alkyl), C(=O)(C,-Cg aikyl)C(=O)O(Ci-Ce alkyl), phenyl, substituted phenyl, phenoxy, and (Het-1 );

(K) R² and R⁴ along with C^K(Q²)(N), form a 4- to 7-membered saturated or unsaturated, hydrocarbyl cyclic group, which may contain one or more further heteroatoms selected from nitrogen, sulfur, and oxygen, wherein said hydrocarbyl cyclic group may optionally be substituted with R^e and R⁷, wherein R® and R⁷ are independently selected from H, F, Cl, Br, I, CN, Ct-Cg alkyl, oxo, thioxo, Ci-Cg haloalkyl, CrCg cycloalkyl, CrCg halocycloalkyl, CrCg cycloalkoxy, CrCg halocycloalkoxy, Ct-Cg alkoxy, Ct-Cg haloalkoxy, CrCg alkenyl, CrCg cycloalkenyl, CrCg alkynyl, CrCg cycloalkynyl, S(=O)_n(C₁-C_e alkyl), S(=O)_n(Ct-Cg haloalkyl), OSO₂(C,-Cg alkyl), OSO₂(C_rCg haloalkyl), C(=O)(Ct-Cg alkyl), C(=O)O(Ct-Cg alkyl), C(=O)(C_rCe haloalkyl), C(=O)O(Ct-Cg haloalkyl), C(=0)(CrCg cycloalkyl), C(=0)0(CrC_e cycloalkyl), C(=0)(CrCg alkenyl), C(=0)0(CrCg 8 alkenyl), (0,-0, alkyf)O(C,-C, alkyl), (0,-0« alkyf)S(Ci-C, alkyl), 0(=0)(0,-0, alkyt)C(=O)O(C,-C, alkyl), phenyl, substituted phenyl, phenoxy, or (Het-1);

(L) (Het-1) Is a 5- or 6-membered, saturated or unsaturated, heterocyclic ring, containing one or more heteroatoms Independently selected from nitrogen, sulfur or oxygen, wherein said heterocyclic ring may also be substituted with one or more substituents independently selected from H, F, Cl, Br, I, CN, N0₂, oxo, C,-C_e alkyl, 0,-0, haloalkyl, Cj-C, cycloalkyl, C3-C, halocycloalkyl, CrC, cycloalkoxy, C3-C, halocycloalkoxy, Ci-C, alkoxy, Ci-C, haloalkoxy, CrC, alkenyl. CrC, alkynyl. S(=O)_n(C,-C, alkyl), S(=O)_n(C,-C, haloalkyl), OSO₂(C,-C, alkyl), OSO₂(C,-Ce haloalkyl). C(=O)NR¹'R^¥, (0,-0, alkylJNR-R*, 0(=0)(0,-0, alkyl), 0(=0)0(0,-0, alkyl), 0(=0)(0,-0, haloalkyl). 0(=0)0(0,-0, haloalkyl), 0(=0)(03-0, cycloalkyl), 0(=0)0(03-0, cycloalkyl). 0(=0)(0,C, alkenyl), Ο(=Ο)Ο(ΟγΟ, alkenyl). (0,-C, alkyl)O(Ci-C, alkyl), (0,-C, alkyJ)S(Ci-C, alkyl), 0(=0)(0,-0, alkyJ)C(=O)O(Ci-C, alkyl), phenyl, phenoxy, substituted phenyl and substituted phenoxy, wherein such substituted phenyl and substituted phenoxy hâve one or more substituents independently selected from H, F, Cl, Br, I, CN, N0₂, 0,-C, alkyl, 0,-C, haloalkyl, CrC, cycloalkyl, 0,-0, halocycloalkyl, CrC, cycloalkoxy, C3-C, halocycloalkoxy, 0,-C, alkoxy, 0,-C, haloalkoxy, Cr C, alkenyl, CrC, alkynyl, S(=O)_n(Ci-C, alkyl), S(=0)n(CrCe haloalkyl), OSO₂(Ci-C, alkyl), OSO₂(C,-C, haloalkyl). C(=O)H, C(=O)NR^ÏR^¥ (0,-C, alkylJNR-R* 0(=0)(0,-0, alkyl), 0(=0)0(0,C, alkyl), 0(=0)(0,-0, haloalkyl), 0(=0)0(0,-0, haloalkyl), 0(=0)(03-0, cycloalkyl), 0(=0)0(03-0, cycloalkyl), 0(=0)(02-0, alkenyl), 0(=0)0(0,-0, alkenyl), (0,-C, alkyl)O(C,-C, alkyl), (0,-C, alkyf)S(Ci-C, alkyl), phenyl, and phenoxy, and (M) n is each Individually 0,1, or 2.

Many of the molécules of this invention may be depicted in two or more tautomeric forms such as when R¹, R², or R⁴, Is H (see for example, “Scheme TAU* below). For the sake of slmplifying the schemes, ail molécules hâve been depicted as existing as a single tautomer. Any and ail alternative tautomers are Included within the scope of this Invention, and no Inference should be made as to whether the molécule exists as the tautomeric form in which it is drawn.

“Scheme TAU

ln another embodiment Ar¹ Is a substituted phenyl.

In another embodiment Ar¹ Is a substituted phenyl that has one or more substituents selected from C_rCe haloalkyl and C_rC_e haloalkoxy.

In another embodiment Ar¹ Is a substituted phenyl that has one or more substituents selected from CF₃, OCF₃, and OC^Fj.

In another embodiment Het is selected from benzofuranyl, benzoisothiazolyt, benzoisoxazolyl, benzoxazolyt, benzothlenyl, benzothiazolyt dnnolinyl, furanyl, indazolyl, indolyt, imidazoiyl, Isoindolyt, Isoqulnolinyl, isothiazoiyl, Isoxazoiyl, oxadiazoiyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyt, pyridyt, pyrimldinyt, pyrrolyl, quinazollnyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazollnyl, thiazoiyl, thlenyt, triazinyl, triazolyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyt, tetrahydropyranyl, 1,2,3,4-tetrahydroqulnolinyl, 4,5-dihydro-oxazolyt, 4,5-dihydro-IH-pyrazolyl, 4.5-dihydro-lsoxazolyl, and 2,3-dihydro[1,3,4]-oxadiazolyl.

In another embodiment Het Is triazolyl.

In another embodiment Het is 1,2,4 triazolyl.

In another embodiment Het is oxadiazoiyl.

In another embodiment Het is 1,3,4 oxadiazoiyl.

In another embodiment Het Is pyrazolyl.

In another embodiment Ar² Is phenyl.

In another embodiment Ar² Is a substituted phenyl.

in another embodiment Ar² is a substituted phenyl that has one or more substituents selected from Ci-Ce alkyl.

In another embodiment Ar² ls a substituted phenyl that has one or more substituents wherein said substituent ls CH₃.

In another embodiment R¹ ls H.

In another embodiment R² ls (K), H, CrCe alkyl, Ci-Cealkyl-O-C^OJCf-Ce alkyl, 0,-CealkylO-C(=O)N(R^KR^y), or (CrCe alkyl)S-{Het-1 ).

In another embodiment R² ls (K), H, CH₃, 0,-Ce alkyl, CH₂OC(=O)CH(CH₃)₂₁CH₂OC(=O)N(H)(C(=O)OCH₂Ph), orCH₂S(3,4,5-trimethoxy-2-tetrahydropyran).

In another embodiment R³ ls substituted phenyl.

in another embodiment R³ ls substituted phenyl wherein said substituted phenyl has one or more substituents selected from F, Ci, CrCe alkyl, Cs-Ce cycloalkyl, Ci-Ce alkoxy, and phenyl.

In another embodiment R³ is substituted phenyl wherein said substituted phenyl has one or more substituents selected from F, CH₃, 2-CH(CH₃)₂, CHfCHsJÎC^Hs), OCH₃₁ and phenyl.

In another embodiment R³ ls substituted phenyl wherein said substituted phenyl has more than one substituent and at ieast one pair of said substituents are not ortho to each other.

In another embodiment R³ ls CpCe alkylphenyl.

In another embodiment R³ is (Het-1).

In another embodiment R⁴ ls H.

In another embodiment M ls N.

In another embodiment M is CR^S wherein R⁵ is selected from H, CN, and 0(=0)(0,-(^ alkyl).

In another embodiment Q¹ is O.

In another embodiment Q² Is S.

In another embodiment Q² Is O.

In another embodiment R² and R* are (K) wherein R² and R⁴ along with C^X(Q²)(N^X), form a 4~ to 7-membered saturated or unsaturated, hydrocarbyl cyclic group.

In another embodiment R² and R⁴ are (K) wherein R² and R⁴ along with C^X(Q²)(N^X), form a

4- to 7-membered saturated or unsaturated, hydrocarbyl cyclic group, wherein said hydrocarbyl cyclic group Is substituted with oxo or CrCe alkyl.

In another embodiment R² and R⁴ are (K) wherein R² and R⁴ along with C^X(Q²)(N^X), form a 4- to 7-membered saturated or unsaturated, hydrocarbyl cyclic group, wherein the Iink* between Q² and N^x Is CH₂C(=O), CH₂CH₂, CH₂CH₂CH₂, or CH₂CH(CH₃).

The molécules of this Invention will generally hâve a molecular mass of about 400 Daltons to about 1200 Daltons. However, It Is generally preferred If the molecular mass Is from about 300 Daltons to about 1000 Daltons, and It Is even more generally preferred If the molecular mass Is from about 400 Daltons to about 750 Daltons.

PREPARATION OF TRIARYL-INTERMEDIATES

Molécules of this Invention can be prepared by making a triaryi Intermediate, Af-Het-Ar², and then linklng it to a desired Intermediate to form a desired compound. A wide variety of triaryi Intermediates can be used to préparé molécules of this Invention, provided that such triaryi intermediates contain a suitable functional group on Ar² to which the rest of the desired Intermediate can be attached. Suitable functional groups Include an amino or isocyanate or a carboxyl group. These triaryi Intermediates can be prepared by methods previously described in the chemical literature, including Crouse, et al., PCT Int. Appl. Pubi. W02009/102736 A1 (the entire disclosure of which Is hereby Incorporated by référencé).

PREPARATION OF UREA-LINKED COMPOUNDS

Thiobiurets (thio-bisureas) and biurets can be prepared according to Schéma 1, Scheme 2, and Scheme 3, described as foliows. S-R² thiourea precursors (3) are prepared from the corresponding thiourea (1) by treatment with R²-X, where X is a halogen or methanesulfonate or a similar displaceable group. These are usually isolated as their hydrohalide (methanesulfonate) salts. Subséquent treatment of the S-R² thiourea precursors (3) with either an isocyanate (4) (see, for example, Pandey, A. K.; et. al., Ind J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. (1982), 5 21 B(2), 150-2) or with a p-nitrophenyl carbamate, such as (5), In the presence of a base, such as triethylamine or potassium carbonate or césium carbonate, results in formation of an S-alkyl thiobiuret (6).

Scheme 1

H-X

. .

When R¹ is -CHiOC(O)alkyl, treatment with ethanolic HCl at températures from about 0 *C to about 50 C, results in removal of R² and génération of the thiobiuret (7) (Scheme 2). Under more prolonged heating, for example, by heating In ethanolic HCl to the reflux température for from about 1 to about 24 hours, the thiobiuret is converted into a biuret (8), with oxygen repladng the 15 sulfur atom.

’ Scheme 2

HCl, EtOH

20-70 °C

O OH

Â Ά N N NH H A,

An alternative process to form thiobiurets has been described by Kaufmann, H.P.; Luthje, K. (Archiv Pharm. und Ber. Deutschen Pharm, (1960), 293,150-9) and Oertel, G., et al.(Farb. Bayer,

DE 1443873 A19681031 (1972). A carbamoyl isothiocyanate (9) is treated with an équivalent of an aniline to form (7) (Scheme 3). Yet another route to thiobiurets involves treatment of an N-aryl urea with R³-NCS (N. Siddiqul, et. al., Eut. J. Med. Chem., 46 (2011), 2236-2242). Another route to blurets (8) involves treatment of an N-aryl urea with R³ isocyanate (Briody, et. al., J. Chem. Soc., Perk. 2,1977, 934-939).

Scheme 3

O ^ArtsHet^Ar^N^NCS

O

Ar¹ Ar² JL ^A 'Het 'N^NH₂

H

NH₂

R³

NCS

I

R³

O

ArL Ar². A Het N NH₂H

SH

NH

R³ ^Ar'-H=t-^A,ÎN^AN’^I;

H

O

Ar¹. ,Αγ² JL <L. Het N N H

O

Ar¹. ,Αι² JLA Het N N H

SH

NH

R³

OH

NH

R³

Thiobiurets (7) can be converted Into a variety of cyclized analogs (10), by treatment with, for example, vicinal dihalides (for example, 1-bromo-2-chloroethane, to form 2-imino-1,3-thlazolines Ί5 (10a)), or with methyl bromoacetate (to form 2-ïmino 1,3-thiazolin-4-ones (10b)), or with D-halo ketones (to form 2-lmino-1,3-thiazoles (10c)), as depicted in Scheme 4. A base such as potassium carbonate or sodium acetate, in a protic solvent or aprotic solvent, at températures between about 0 °C and about 100’C, can be used. Using conditions described above, it can be seen that other riqg stzes and substitutions can be envisioned as well; the corresponding six-membered ring analog (10d), for example, can be prepared starting with a 1,3-dihalopropane precursor.

Scheme 4 , , ^{0 S} ^Arx„ „^Ad _{M Het} N N

NH R³ ^6 R-7 .

BrCHCHCl ^Ar\,^ ---------»_ Het

K2CO3, butanone

R⁶

O S V/

H

R⁷

R³

10a

O ^BrvA _RZ^OMe

-----►

NaOAc, EtOH

O ^Αγ,„'^Αγ*χτΑ<Α

Het N N H

R⁶S

N ⁰

R³

10b

R⁶ R⁷

-----►

NaOAc, EtOH

O

Het N N H

10c

R⁶S

N ^R?

R³

K₂CO₃, butanone

R⁶o S^T „7

Ar< .Ar² U A >“^R

Hét 'iAV H _R3 lOd

An alternative route to analogs of Formula (10b) Is described In Scheme 5. Treatment of 2* imino-1,3-thlazolln-4-one (11) with an aryl isocyanate or with intermediate (5) (Scheme 1), In the 5 presence of an amine base such as triethylamine, leads to the synthesis of (10b). Other routes to (10b) Indude addition of carbonyldiimidazole to (11) to produce an Intermediate (12a), or addition of 4-nitrophenyl chloroformate to form (12b). Either (12a) or (12b) can then be made to react with an aniline Ar’-Het-A^-NHj to generate (10b).

Scheme 5

S

H₂N NH R³1

R⁶

BrCHCO₂Me NaOAc, EtOH _s Λ⁶ΗΝ^Ύ

NH CO₂Me i

R³

Carbonyldiimidazole (CDI)

R⁶

O S

Art Ar³ Jl, <4 O ^SHét 'N^N^N ^UH jp

10b

Ar’-Het-Ar²-NH₂

R⁶

O S*<

⁰

V à³

12a

I

R⁶

S

HN^N ⁰

R³

II

p-nitrophenyl chloroformate

O₂N

R⁶

O S~< cASS

R³

12b

Another route to 1-(3-aryl thiazolidin-2-ylidene)-3-aryl ureas (10a) is shown in Scheme 6. Treatment of an aryl cyanamlde (12) with a thiirane in the presence of a base such as potassium 5 carbonate ylelds the 2-lmino-1,3-thlazoline (14). The synthesis and subséquent acylation of 3-aryl24minothiazolidines by this route is described by F. X. Woolard in US 4,867,780 and référencés contained therein. Subséquent treatment of (14) with carbonyldiimidazole (to form 15a) or 4nitrophenyl chloroformate (to form 15b), followed by addition of an aniline results in formation of (10a). Altematively, reaction of (14) with an aryl isocyanate or 4-nltrophenyl carbamate (5) also 10 produces (10a).

Scheme 6

10a

NH CNBr •₃ ² --------► ^R NaOAc, EtOH

ISa^T^ 1-imîdazolyl 15b, T ^β 4-nitrophenoxy

By using the protocois described in Schemes 4 through 6, It can be seen that other analogs containing 4~, 5-, and 6-membered rings, and containing a variety of substitution patterns, can be produced. Other heterocyclic Systems containing an exo-lmino group are known, Including but not 5 limited to, 2-lmlno thiadiazoiinones (16) (see Scheme 7); or 2-imlno oxadiazolinones (17) (Syn.

Comm., 2002,32(5), 803-812); or 2-lmlno oxazolinones (18); or 2-imlno thladlazoies (19). These can also be used to prépare molécules (20)-(23), by appropriate substitution of precursors In the procedures described ln Scheme 5 and Scheme 6.

Scheme 7

R⁶Q-N HN^N^⁰	R⁶s—( htZn ⁰i	R⁶ W hn^nⁿkl
R’	R³	R³
16, Q = S 17, Q = O	18	19
I Scheme 5 or 6
R⁶/	R⁶	R⁶
s^-N^° 0 '_R3 Ar^NH / Het	Ο^θ 0 , y-N R3 Ar*'NH Ar’-Het	S^N 0 'Hj 5-N _r3 Ar*-NH Ar’-Het
20, Q = S 21,0 = 0	22	23

Malonyl monothloamldes ((25) and (26)) and malonyl diamldes (29) can be prepared as described In Scheme 8. Condensation of a D-ketoanilide or D-cyanoanilide (24) with R’-NCS 5 résulte In formation of 2-acyl malono-monothioamide (25). When R⁵ Is an acetyl group, déacylation occurs on refluxing In EtOH to form the malono-monothioamide (26). Thioamides can be cyclized In a manner simllar to that described in Schemes 5 and 6, to produce cyclic analogs (27). The dlamide (29) can be prepared from the correspondîng monocarboxyiic acid (28), by means of dicyclohexyl carbodiimide-1-hydroxy 7-azabenzotriazole coupling conditions, (for example, see

Jones, J., In: The Chemical Synthesis of Peptides. Int. Ser. of Monographs on Chemistry, Oxford Unlv. (Oxford. 1994), 23).

Scheme 8 , O

Ar’_{s x}Ar^ JL R³Hét

H

NCS i

R³

EtOH, reflux _ _ (forR’-COCH]) Ar'

N H i O SH

K₂CO₃, DMF ^Hét N^S^NH ---* ^H R⁵ R³

O SH BrCH,CO,Me ₀ , »_αλΛ<.

^Ar'HÎ. H

NH

R³ ^Ar'Héi^A'^ÎN^Ar^A'OH

H _R5

HOAt

---->

EDCl . , ⁰ OH ^Ar'H«^AP'N'VNH

H Rî R³

Further modifications by alkylation of the NH group of analogs such as (6), (1 Oa), (1 Ob), (10c), (20)-(23), and (27) can be effected by treating the appropriate molécule with an alkylating 5 agent, R¹-X, where X is a halogen or methanesulfonyl group, or other similar leaving group (Scheme 9). The reaction requires use of a strong base such as sodium hydride (NaH) or potassium hexamethyldisilazane, In an aprotic solvent such as tetrahydrofuran or N,Ndimethylformamlde.

	Scheme 9
r2	n2 pi Y ⁰ Q A —---- ^Αγ'_η'^Αγ?ν^Λν^Λν'^κ NaH, THF ^Het _r3

6,10a, 10b, 10c, 20-23,27

Analogs wherein R¹ is not H may also be prepared as in shown in Scheme 10. Alkylation of Ar’-Het-A^-NHj, and conversion into thlourea (31), can be accomplished by a variety of known methods. For example, réaction with formaldéhyde and benzotriazole, followed by réduction with sodium borohydride, generates the N-methyl analog (30). Conversion to (31) can be accomplished 19 by treatment with thiophosgene and ammonia, or with benzoyl isothiocyanate followed by basecatalyzed cleavage of the benzoyl group. Treatment of (31) with oxalyl chloride and triethylamine, under conditions first described by J. Goerdeler and K. Jonas (Chem. Ber., 1966,99(11), p. 35723581), results in formation of a 2-amino-1,3-thiazolin-4,5-dione (32). Pyrolysîs of this Intermediate In 5 refluxing toluene then générâtes an N-carbonyl Isothiocyanate (33), which on treatment with an amine R’-NH₂ forms the thiobiuret (7b, R¹ = CH₃). Thiobiurets where R¹ Is not H can then be further elaborated using conditions described In Scheme 4, to form cyciic analogs such as 10e.

Scheme 10

Ar’ Ar² L benzotnazole, HCHO _Afi _AJ

Hét NH₂ ---------- Het NH

2.NaBH₄ CH₃

O ³⁰

Oxalyl chloride ?θ _A.

^Ar Het CH₃

1. benzoyl isothiocyanate

2. NaOH i , ^s

Arl Λ

Het N NH₂ ch₃

EtjN

Toluene

100°C _A, afZncs ^Ar Het bi₃

O aA_n ^KncsAr’-Het tH₃ r³-nh₂

HS >-N _R3 Ar²^ Ar^l'Het ^CH3

7b

R⁶

BrÔHCO₂Me

NaOAc

Ar’-Het ³³ R‘

S O Q Xn R3 Ar^N J ch₃

10e

An aryl isocyanate, Ar’-Het-Ar^-NCO, can also be treated directly with an N-aryl thiourea In the presence of a catalytic amount of base such as césium carbonate or sodium hydride, resulting in the formation of a thiobiuret (7) (Scheme 11).

Scheme 11

S ^Ar'HéÎ^Ar*N*^C'°^{+ HînX}

Cs₂CO₃NH ----‘ _R3 or NaH

O

Ar¹. XxAxÂ Het N N

H

SH

NH

R³

A method to préparé 2,4-triazoles (36), wherein Ar¹ Is a 4(haloalkoxy)phenyl or a 4-(haloalkyl)phenyl group, Involves coupllng of a 1-(4-haloalkoxy)phenyl-3bromo-1,2,4-triazole or a 1-(4-haloalkyl)phenyl-3-bromo-1,2,4-triazole (35, Schéma 12) with an aryl boronic add or aryl boronic ester, under Suzuki conditions. The Intermediates (35) In tum can be prepared by reacting 3-bromo -1H-1,2,4-triazole (Kroeger, C. F.; Miethchen, R., Chemlsche Berichte (1967), 100(7), 2250) (however 3-chloro-1H-1,2,4-triazole may be used) with a 4haloalkoxy-1-halobenzene (where halo = Independently I or Br or Cl or F), In the presence of a métal catalyst such as Cul or Cu₂O, and a base such as Cs₂CO₃, K3PO4, or K₂CO_3l with or without an added ligand such as qulnolin-8-ol, or Ν,ΛΓ-dimethyl ethylenediamlne or other 1,2-dlamines, or 10 glydne, In a polar aprotlc solvent such as acetonitrile, DMF or DMSO at températures between about 70 and 150 °C.

Scheme 12

Catalyst, _f ^Ha! ₊ z,^Ny^BrorCI ligand ^Ar HN'N

^..Br or Cl N-N

Ar¹' , Catalyst ^{35 +} (RO)₂B-^A? -----Ar* n-n

We also disdosed novel 1-Ar¹-3-bromo-1,2,4-triazoies, wherein Ar¹ is 4-(Ci-C_e-alkyl)phenyl₁15 4-(Ct-Ce-haloalkyl)phenyl, 4-(CrCe alkoxy)phenyl, 4-(C₁-C_e-haloalkoxy)phenyl, 4-(C_rCe alkylthlo)phenyl, or 4-(C_rCe-haloalkylthlo)phenyl, as useful intermediates for the préparation of many of the molécules daimed In this Invention (préparation Is described In Scheme 12.

EXAMPLES

The examples are for Illustration purposes and are not to be construed as limiting 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 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 MDL ISIS™/Draw 2.5, ChemBioDraw Ultra 12.0 or ACD Name Pro. If such programs are unable to name a molecuie, the molécule Is named using conventional naming rules. ¹H NMR spectral data are in ppm (δ) and were recorded at 400 MHz, unless otherwise stated.

Exemple 1. Préparation of (E)-((N'-(4-methoxy-2-methylphenyl)-N-((4-(1-(4(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yt)phenyl)carbamoyl)carbamimtdoyl)thio) methyl Isobutyrate (Molecuie A1).

OMe

Step 1.2-Methyl-4-methoxyphenyl thiourea (0.5 grams (g), 2.55 millimoles (mmol)) and bromomethyl Isobutyrate were combined in 5 mL of acetone at ambient température, and the solution was allowed to stir for 18 hours (h). The solution was then cooled to 0 °C and the resulting solid was filtered and air-dried to give (E)-(N’-(4-methoxy-2-methylphenyl)carbamimidoylthio)methyl isobutyrate HBr (B1) (0.83 g, 82%): mp 127-130 °C; Ή NMR (CDCI₃) δ 11.34 (s, 1H), 10.29 (s, 1 H), 8.32 (s, 1 H). 7.09 (d, J - 8.7 Hz, 1 H), 6.79 (d, J = 2.8 Hz, 1 H), 6.74 (dd, J = 8.7, 2.8 Hz, 1 H),

3.81 (s, 3H), 2.69 (heptet, J - 7.0 Hz, 1 H), 2.31 (s, 3H), 1.22 (d, J = 7.0 Hz, 6H); ESIMS m/Z 297 ([M+H]*).

Step 2. The Intermediate from Step 1 (0.40 g, 1.06 mmol) was dissolved in tetrahydrofuran (THF; 7 mL), and 4-nitrophenyl 4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2_l4-triazol-3-yl)phenylcarbamate (0.50 g, 1.06 mmol) was added. To this suspension was added N-ethyl-N-lsopropylpropan-2-amine (Hûnig’s base; 0.25 g, 1.9 mmol), and the solution was allowed to stir at ambient température for 2 h. Evaporation of volatiles left a gummy oll which was purified by chromatography on silica gel. Elution with 0-50% ethyl acetate (EtOAc)-hexanes gave the title compound (425 mg, 61%) as a white solid: mp 160-164 °C; ¹H NMR (CDCI₃) δ 11.24 (s, 1H), 8.64 (s, 1H), 8.17 (d, J= 8.7 Hz, 2H),

7.92 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.41 (s, 1 H), 7.12 (d, J =

8.6 Hz, 1H), 6.79 (d, J = 2.8 Hz. 1H), 6.74 (dd. J = 8.4,3.1 Hz. 1H). 5.65 (s. 2H). 3.82 (s. 3H). 2.59 (heptet, J = 7.0 Hz, 1H), 2.27 (s. 3H). 1.18 (d, J= 7.0 Hz, 6H); ESIMS m/z 627 ([M+H]*).

Moiecules A54-A62 In Table 1 were made In accordance with the procedures disclosed In Example 1. The following moiecules (Examples 2-10) were prepared according to the conditions described In Example 1.

Example 2. (Z)-M ethyl N-(4-methoxy-2-methylphenyl)-M-((4-(1-(4-(trlfluoromethyl)phenyl)-1H-

1,2,4-trlazol-3-yl)phenyl)carbamoyl)carbamimldothioate (Molécule A2).

OMe

The title molécule was Isolated as a white solid; 38 mg (11%), mp 172-175 °C; 'H NMR (CDCI₃) δ 11.29 (s, 1H), 8.64 (s, 1H), 8.17 (d, J = 8.7 Hz. 2H). 7.92 (d, J= 8.5 Hz, 2H), 7.80 (d, J-8.5 Hz, 2H), 7.66 (d. J= 8.7Hz, 2H). 7.33 (s, 1H), 7.16(d, J= 8.6 Hz. 1H), 6.80 (d, J= 2.9Hz. 1H). 6.75 (dd, J- 8.6,2.8 Hz, 1H), 3.82 (s, 3H). 2.38 (s. 3H). 2.30 (s. 3H); ESIMS m/z 541 ([M+H]*).

Example 3. (E)-(V-(2_I6-Dimethylphenyl)-N-(4-(1-(4^trlfluoromethyl)phenyl)-1H-1,2,4-trlazol-3yl)phenylcarbamoyl) carbamimldoylthlo) methyl Isobutyrate (Molécule A3).

Step I.The Intermediate (E)-(M-(2,6-dimethylphenyl)carbamimidoylthio)methyl Isobutyrate HBr (B2), was prepared from 1-(2,6-dimethylphenyl thlourea) using conditions described In Example 1.

mp 129-131 °C; ¹H NMR (CDCI₃) □ 11.51 (s, 1H), 10.45 (s, 1 H). 8.25 (s, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.12 (d, J =7.4 Hz, 2H), 5.59 (s, 2H), 2.69 (heptet, J = 7.0 Hz, 1H), 2.30 (s, 6H), 1.23 (d, J = 7.0 Hz, 6H); ESIMS m/z 280 ([M+H]*).

Step 2. Molécule A3 was prepared In a manner similar to that described In Example 1: 575 mg (59%)ofawhitesolid,mp 173-176 °C; ¹H NMR(CDCI₃)511.21 (s, 1H), 8.65(s, 1H), 8.18(d, J =

8.7 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.20 (m, 1H), 7.14 - 7.04 (m, 2H), 5.65 (s, 2H), 2.59 (heptet, J = 7.0 Hz. 1H), 2.29 (s, 6H). 1.18 (d, J = 7.0 Hz. 6H); ESIMS m/z 611 ([M+H]*).

Example 4. (£)-(//-(2,6-Dimethylphenyl)-N-(4-{1-(4-{trifluoromethyoxy)phenyl)-1W-1,2,4triazol-3-y1)pheny1carbamoy1) carbamlm1doy1thlo)methyl Isobutyrate (Molécule A4).

O

Molécule A4 was prepared In a manner similar to that described In Example 1:860 mg (52%) of a white solid, mp 148-151 °C; ¹H NMR (CDCI₃) δ 11.21 (s, 1H), 8.55 (s. 1H). 8.17 (d, J = 8.7 Hz, 2H),

7.81 (d, J = 8.7 Hz, 2H), 7.67 (d. J = 8.7 Hz, 2H), 7.42 (br s, 1 H), 7.39 (d, J = 8.7 Hz, 2H), 7.21 7.10 (m. 3H), 5.65 (s, 2H), 2.67 - 2.52 (m, 1 H), 2.29 (s, 6H), 1.18 (d, J = 7.0 Hz, 6H); ESIMS m/z 627 ([M+H]*).

Example 5. (Z)-((N-(2-lsopropylphenyl)-//-((4-(1-(4-(tr1fluoromethoxy)phenyl)-1H-1,2,4-triazol3-yl)phenyl)carbamoy1) carbamlmldoy1)thlo)methy1 Isobutyrate (Molécule A5).

Step 1. The Intermediate (E)-{V-{2-isopiOpy1pheny1)carbamimidoy1thio)methy1 Isobutyrate HBr (B3), was prepared from 1-(2-lsopropy1phenyl thiourea) using conditions described ln Example 1; mp 80-85 °C; Ή NMR (CDCI₃) □ 11,70 (s, 1H), 10.45 (s, 1H), 8.27 (s, 1H), 7.47-7.36 (m, 1H), 7.23 m, 1H), 7.15 (d, J = 7.4 Hz, 2H), 5.59 (s, 2H), 3.17 (m, 1H), 2.69 (heptet, J= 7.0 Hz, 1H), 1.26 (d, J = 6.9 Hz, 3H), 1.22 (d. J= 6.9 Hz, 3H); ESIMS m/z 295 «M+H]*).

Step 2. Molécule A5 was prepared ln a manner similar to that described ln Example 1:382 mg (62%) of a white solid, mp 141-143 °C; Ή NMR (CDCI₃) δ 11.54 (s, 1H), 8.55 (d, J= 3.7 Hz, 1H), 8.16 (d, J= 8.6 Hz, 2H), 7.80 (d, J= 9.1 Hz, 2H). 7.67 (d, J= 8.6 Hz, 2H), 7.46 - 7.32 (m, 5H), 7.23 - 7.16 (m, 2H), 5.67 (s, 2H), 3.25 - 3.10 (m, 1H), 2.65 - 2.52 (m, 1H), 1.24 (d, J= 6.9 Hz, 6H), 1.17 (d, J = 7.0 Hz, 6H); ESIMS m/z 641 ([M+H]*).

Example 6. (Z)-((AH2-lsopropylphenyl)-N^,-((4-(1’(4-(pentafluoroethoxy)phenyl)-1H-1,2,4triazol-3-yi)phenyi)carbamoyl) carbamlmldoyl)thlo)methyl isobutyrate (Molécule A6).

Molécule A6 was prepared ln a manner similar to that described In Example 1:300 mg (45%) of a white solid, mp 154-156^eC; Ή NMR (CDCI₃) δ 11.54 (s, 1H), 8.56 (d, J=3.7 Hz, 1H), 8.17 (d, J =

8.7 Hz, 2H), 7.81 (d. J= 9.1 Hz, 2H), 7.67 (d, J= 8.7 Hz, 2H), 7.46-7.33 (m, 5H), 7.24-7.19 (m, 2H), 5.67 (s, 2H), 3.29 - 3.08 (m, 1 H), 2.66 - 2.50 (m, 1 H), 1.24 (d, J = 6.9 Hz. 6H), 1.17 (d, J = 7.0 Hz, 6H); ESIMS m/z 691 ([M+H]*).

Example 7. (Ê)-(N’-(2₍6-Dlmethyl-4-methoxyphenyl)-N-(4-(1-(4-(trifluoromethyoxy)phenyl)-1 H-

1,2,4-triazol-3-yl)phenylcarbamoy!) carbamlmldoylthlo)methyl isobutyrate (Molécule A7).

Step 1. The Intermediate (E)-(N'-{2₁6xjimethyl-4-methoxyphenyl)carbamlmldoylthlo)methyl Isobutyrate HBr(B4), was prepared from 1-(2,6-dimethyl-4-methoxyphenyl thlourea) using conditions described In Step 1 of Example 1: mp 152-154 °C; ¹H NMR (CDCIj) □ 6.62 (s, 2H), 5.59 (s, 2H), 3.79 (s, 3H), 2.68 (heptet, 7 = 7.0 Hz, 1H), 2.25 (s, 6H), 1.22 (d, J= 7.0 Hz,, 6H); ESIMS mZr311 ([M+H]*).

Step 2. Molécule A7 was prepared In a manner slmllarto that described In Example 1:955 mg (71%) of a white solid, mp 148-151 °C; ’H NMR (CDCI₃) δ 11.03 (s, 1H), 8.55 (s, 1H), 8.16 (d, J =

8.7 Hz, 2H), 7.80 (d, 7 = 9.1 Hz, 2H), 7.67 (d, 7= 8.7 Hz, 2H), 7.39 (m, 3H), 6.64 (s, 2H), 5.64 (s, 2H), 3.80 (s, 3H), 2.59 (heptet, 7= 7.0 Hz, 1 H), 2.25 (s, 6H), 1.17 (d, 7= 7.0 Hz, 6H); ESIMS m/z 657 ([M+H]*).

Example 8. (Z)-((N-(2,6-Dlmethy1phenyl)-A/*-((4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol· 3-yl)phenyl)carbamoyl) carbamlmldoyl)thlo)methyl 2-(((benzyloxy)carbony1)amlno)acetate (Molécule A8).

The Intermediate, ((A/-(2,6-dimethylphenyl)carbamlmldoyl)thio)methyl 2(((benzyloxy)carbonyl)amlno)acetate HCI (B5), was prepared as described In Step 1 of Example 1, and was used without purification. Molécule A8 (30 mg. 15%) was Isolated as a white solid, mp 142-148 °C; ’H NMR (CDCI₃) δ 11.26 (s, 1H), 8.64 (s, 1 H). 8.16 (d. J= 8.4 Hz, 2H), 7.91 (d, 7 = 8.2 Hz, 2H), 7.79 (d, 7 = 8.5 Hz, 2H), 7.71 (d, 7= 8.1 Hz, 2H), 7.54 (s, 1H), 7.34 (m, 5H), 7.15 (m, 3H), 5.69 (s, 2H), 5.23 (s, 1 H), 5.13 (s, 2H), 4.02 (d, 7= 5.7 Hz, 2H), 2.29 (s, 6H); ESIMS m/z 732 ([M+H]*).

Example 9. (E)-((N^,-(4-Methoxy-2,6-dlmethylpheny1)-N-((4-(1-(4-(trifluoromethyl)phenyl)-1H·

1,2,4-trlazol-3-y1)pheny!)carbamoyl) carbamlmldoy!)thlo)methy! 2(((benzyloxy)carbonyl)amlno)acetate (Molécule A9).

The Intermediate, ((N-(2₁6-dimethy1-4-methoxypheny1)carbamimidoy1)thio)methy12(((benzyloxy)carbonyl)amlno)acetate HCI (B6), was prepared as ln Step 1 of Example 1, and was used without purification. Molécule A9 (330 mg, 46 %) was Isolated as a white solid, mp 142-148 ®C; Ή NMR (CDCi₃) δ 11.07 (s, 1H), 8.55 (s, 1H), 8.15 (d, J= 8.5 Hz, 2H), 7.80 (d, J= 8.8 Hz, 2H), 7.70 (d, J= 8.4 Hz, 2H), 7.52 (d, J= 3.1 Hz, 1H), 7.44 - 7.31 (m, 7H), 6.64 (s, 2H). 5.67 (s, 2H), 5.23 (s, 1H), 5.12 (s, 2H), 4.02 (d, J = 5.8 Hz, 2H), 3.80 (s, 3H), 2.21 (s, 6H); ESIMS m/z 778 ([M+H]*).

Exemple 10. (Z)-(((2S,3R,4R,5S,6S)-3,4,5-Trimethoxy-6-methyltetrahydro-2H-pyran-2yi)thlo)methyl N-(4-methoxy-2-methylphenyl)-N'-((4-(1-(4-(trlfluoromethoxy)phenyl)-1H-1,2,4trlazol-3-yl)phenyl)carbamoyl) carbamlmldothloate (Molécule A10).

The intermediate, (((2S,3R,4R,5S,6S)-3,4₁5-trimethoxy-6-methyltetrahydro-2H-pyran-2y1)thio)methyl (4-methoxy-2-methylpheny1)carbamimidothioate HCl (B7), was prepared as ln Step 1 of Example 1, and was used without purification. Molécule A10 (240 mg, 43 %) was Isolated as a white solid, mp 128-132 °C; ’H NMR (CDCI₃) δ 11.19 (s, 1 H), 8.56 (s, 1 H), 8.15 (d, J = 8.4 Hz, 2H), 7.80 (J = 8.4Hz, 2H), 7.66 (d, J= 8.5 Hz, 2H), 7.38 (d, J= 8.3 Hz, 2H), 7.14 (d, J= 8.6 Hz. 1H),

6.82 - 6.69 (m, 3H), 5.69 (s, 1 H), 4.46 (d, J = 13.9 Hz, 1 H), 4.05 (d, J = 13.9 Hz, 1 H), 3.91 (dd, J = 9.3,6.2 Hz, 1H), 3.81 (s, 3H), 3.67 (dd, J= 3.2,1.5 Hz, 1 H). 3.56 (s, 3H), 3.46 s, 3H), 3.44 (s, 3H), 3.38 (dd, J= 9.3, 3.3 Hz, 1H), 3.21 (t, J= 9.3 Hz, 1H), 2.29 (s, 3H). 1.32 (d, J = 6.1 Hz, 3H); ESIMS m/z 777 ([M+H]*).

Example 11. Préparation of N-[[(2,6-dlmethylphenyf)amlno]thioxomethy!]-N^,-(4-(1-(4(trif1uoromethyoxy)pheny1)-1H-1,2,4-triazol-3-yl)phenyf urea (Molécule A11).

To a solution of Molécule A4 (660 mg, 1.05 mmol) In 75 mL of MeOH was added 20 mL of 1 N HCl , and the resulting solution was heated at 55 °C for 36 h. The cooled solution was then diluted with another 50 mL of water and the resulting white solid was filtered and air-drled to give 470 mg (81%) of the title compound, mp 233-235 °C. ¹H NMR (CDCI₃) δ 8.54 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.79 (d, J= 9.1 Hz, 2H), 7.62 (d, J= 8.8 Hz, 2H), 7.44 - 7.29 (m, 4H), 7.22 (d, J= 7.5 Hz, 2H), 4.01 (s, 2H), 2.17 (s, 6H); ESIMS m/z 527 ([M+H]*).

Compounds A44 and A49-A52 In Table 1 were made in accordance with the procedures disclosed In Example 11.

Example 12. Préparation ofN-[[(2,6-dlmethyfphenyl)amlno]thioxomethy1]-N’-(4-(1-(4(trif1uoromethyl)phenyf)-1H-1,2,4-trlazol-3-y1)pheny! urea (Molécule A12).

To a solution of Molécule A3 (125 mg, 0.203 mmol) In 5 mL of MeOH was added 0.5 mL of 7 N NH₃In MeOH. The resulting solution was allowed to stir at ambient température for 16 h. The solution was concentrated and chromatographed (0-100% EtOAc-hexanes) to give 28 mg (27%) of the thiobiuret as a white solid, mp 204-212 °C. ’H NMR (DMSO-d_e) δ 11.30 (s. 1H), 10.20 (s, 1H), 9.52 (s, 1H), 9.51 (s, 1 H>, 8.19 (d, J = 8.4 Hz, 2H), 8.11 (d, J - 8.7 Hz, 2H), 7.99 (d, J-8.6 Hz, 2H),

7.62 (d, J = 8.8 Hz, 2H), 7.20 - 7.09 (m, 3H). 2.20 (s, 6H); ESIMS m/z 511 ([M+H]*).

Example 13. Préparation of 1-(2-lsopropylphenyl)-3-[[4-[1-[4-(trlfluoromethoxy)phenyl]-1,2,4triazol-3-yl]phenyl]carbamoyl]urea (Molécule A13).

Molécule A5 (500 mg, 0.78 mmol) was added to 10 mL of THF and 2 mL of 1 N HCl and the solution was stirred for 24 h. The solution was then partitioned between EtOAc (30 mL) and saturated NaHCO₃ solution (15 mL). Séparation and drying of the organic layer followed by removal of the solvent gave a crude solid which was chromatographed on silica gel to fumish 160 mg (38%) of the title compound as a white solid; mp 300 ’C (dec); ¹H NMR (DMSO-d_e) δ 9.86 (s, 1H), 9.57 (s, 1H), 9.37 (d, J = 13.8 Hz, 2H), 8.15 - 7.98 (m, 4H), 7.74 (dd, J= 7.9,1.5 Hz, 1H), 7.67-7.53 (m, 4H), 7.33 (dd, J = 7.5,1.8 Hz, 1 H), 7.24 - 7.06 (m, 2H), 3.20 - 2.99 (m, 1 H), 1.22 (d, J = 6.8 Hz, 6H).; ESIMS m/z 525 ([M+H]*).

Example 14. Préparation of (Z)-1-(3-(2,6-dlmethylphenyl)-4-oxothlazolldln-2-ylldene)-3-(4-(1(4-(trifluoromethoxy)phenyl)-1H-1,2,4-trlazo1-3-yl)phenyl)urea (Molécule A14).

To a suspension of Molécule A11 (200 mg, 0.38 mmol) In 5 mL of EtOH was added sodium acetate (200 mg, 2.43 mmol) and methyl bromoacetate (0.14 g, 0.91 mmol), and the solution was heated at 60 ®C for 3 h. The cooled solution was then diluted with 2 mL of water and the resulting white solid was filtered and alr-dried to give 142 mg (64%) of the title compound, mp 190-196 ’C. ¹H NMR (CDCI₃) δ 8.54 (s, 1H), 8.12 (d, J- 8.7 Hz, 2H), 7.79 (d, J = 9.1 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H). 7.44 - 7.29 (m, 4H), 7.22 (d, J = 7.5 Hz, 2H), 4.01 (s, 2H), 2.17 (s, 6H); ESIMS m/z 567 ([M+H]*).

Compounds A35-A37, A65, A66, A69, A74-A77, A85-A88, A92-A95, A103-A105, A108A111, A115, A117, A120-A121, and A125 In Table 1 were made In accordance with the procedures disclosed In Example 14.

Example 15. Préparation of (Z)-2-((2₎6-dimethylphenyl)!m!no)-N-(4-(1-(4(trifluoromethoxy)phenyl)-1H-1,2,4-triazo!-3-yl)phenyl)thlazoildlne-3-carboxam!de (Molécule

A15).

To a solution of Molécule A11 (350 mg, 0.665 mmol) In 7 mL of acetone was added potassium carbonate (200 mg, 1.44 mmol) and 1-chloro-2-bromoethane (0.20 g, 1.40 mmol), and the solution was heated at 50 °C for 5 h. The cooled solution was adsorbed onto siiica gel and chromatographed (0-80% EtOAo-hexanes) to give 99 mg (26%) of Molécule A15: mp 145-150 °C. ’H NMR (CDCIj) δ 8.51 (s, 1H), 8.07 (d, J= 7.9 Hz, 2H), 7.81 - 7.74 (m, 2H), 7.59 (d, J= 6.8 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 7.19 (m, 3H), 7.12 (s, 1H), 3.81 (t, J = 7.7 Hz, 2H), 3.37 (t, J= 7.6 Hz, 2H), 2.23 (s, 6H); ESIMS m/z 553 ([M+H]*).

Example 16. Préparation of (Z)-2-((2_l6-dimethylphenyl)im!no)-N-(4-(1-(4(trffluoromethoxy)phenyl)-1H-1,2,4-triazol-3-y1)pheny1)-1,3-thlazlnane-3-carboxamlde (Molécule A16).

To a solution of Molécule A11 (150 mg, 0.28 mmol) in 5 mL of acetone was added potassium carbonate (150 mg, 1.08 mmol) and 1-ch!oro-3-bromopropane (0.16 g, 1.00 mmol), and the solution was heated at 50 °C for 5 h. The cooled solution was adsorbed onto silica gel and chromatographed (0-70% EtOAo-hexanes) to give 22 mg (12%) of the thiazinane: mp 121-125 °C. ¹H NMR (CDCIj) δ 12.81 (s, 1H), 8.54 (s, 1H), 8.16-8.09 (m, 2H), 7.79 (d, J= 9.2 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.18 - 6.96 (m, 3H), 4.22 - 4.09 (m, 2H), 3.00 (t, J = 6.9 Hz, 2H), 2.25 - 2.13 (m, 8H); ESIMS m/z 567 ([M+H]*).

Compounds A39 and A41 in Table 1 were made in accordance with the procedures dlsdosed In Example 16.

Example 17. Préparation of (Z)-2-((2,6-dImethylpheny1)lmlno)-N-{4-(1-{4(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-y1)pheny1)thlazolidine-3-carboxamlde (Molecuie

A17).

To a solution of Molecuie A11 (150 mg, 0.28 mmol) ln 5 mL of acetone was added potassium carbonate (100 mg, 0.72 mmol) and 1,2-dibromopropane (0.07 g, 1.20 mmoi), and the solution was heated at 50 °C for 12 h. The cooled solution was adsorbed onto silica gel and chromatographed (0-80% EtOAo-hexanes) to give 29 mg (18%) of the title compound as a light tan solid; mp 105-115 ®C. Ή NMR (CDClj) δ 8.52 (s, 1H), 8.07 (d, J = 8.3 Hz, 2H), 7.83-7.73 (m, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.37 (d. J= 8.3 Hz, 2H), 7.20 (m, 4H), 4.24 (dd, J= 14.5,6.6 Hz, 1H), 3.58 - 3.41 (m, 4H), 3.02 (dd, J= 11.0,8.6 Hz, 1H), 2.25 (s, 3H), 2.21 (s, 3H), 1.21 (d, 6.4 Hz, 3H).; ESIMS m/z567 ([M+H]*).

Compounds A38 and A40 ln Table 1 were made In accordance with the procedures disclosed In Example 17.

Example 18. Préparation of (Z)-1-(3-(2-{sec-butyl)pheny1)-4-oxothlazolldln-2-ylldene)-3-{4-(1(4-(trif1uoromethoxy)phenyi)-1H-1,2,4-triazol-3-yi)phenyi)urea (Molecuie A18).

To a solution of 1-(2-(seobutyl)phenylthïourea (1.40 g, 6.72 mmol) suspended ln 5 mL of acetone was added methyl bromoacetate (1.23 g, 1.20 mmol), and the solution was allowed to stir at ambient température for 18 h. The solution was then diluted with 8 mL of diethyl ether and, after stirring for 30 min, the solvent was carefully decanted from a gummy oil. The Intermediate, methyl

2-((N-(2-(sec-buty1)phenyl)carbamimIdoyl)thïo)acetate HBr (B8), was dissolved In 8 mL of dry tetrahydrofuran and 4-nltrophenyl (4-(1-(4-(trifluoromethoxy)pheny!)-1H-1,2,4-triazol-3yl)pheny!)carbamate (3.26 g, 6.72 mmol) was added, followed by HQnlg's base (2.6 g, 20 mmol). The solution was allowed to stir at ambient température for 3 h, then It was concentrated and the residue chromatographed (silica gel, 0-70% EtOAc-hexanes) to give 730 mg (18%) of the title compound as a solid, mp 169-177 °C; ¹H NMR (400 MHz, CDCI₃) δ 8.53 (s, 1H), 8.12 (d, J- 8.7 Hz, 2H), 7.81 - 7.74 (m, 2H), 7.63 - 7.56 (m, 2H), 7.52 (m, 1H), 7.45 (d, J =7.9 Hz, 1H), 7.41 7.32 (m, 3H). 7.28 (s, 1H), 7.11 (d, J =7.9 Hz,1H), 4.03-3.95 (m, 2H), 2.43 (dd, J= 13.5, 6.8 Hz, 1H), 1.73 -1.56 (m, 2H), 1.20 (overlapplng d, J= 7.6 Hz, 3H), 0.78 (overlapplng t, J= 7.4 Hz, 3H); ESIMS m/z 594 ([M+H]*).

The following molecuie was prepared according to the conditions described In the prevlous example.

Example 19. Préparation of (Z)-1-{3-{2-lsopropylphenyl)-4-oxothlazolldln-2-ylldene)-3-(4-(1-(4(trifluoromethoxy)phenyl)-1 H-1,2,4-trlazol-3-yl)phenyl)urea (Molecuie A19).

From 0.70 g (2.0 mmol) of the Intermediate (£)-methy! 2-((/7-(2lsopropylphenyl)carbamimldoyl)thlo)acetate, HBr (B9) and 850 mg (1,75 mmol) of 4-nltrophenyl (4(1-(4-(trifluoromethoxy)pheny!)-1H-1,2,4-trlazol-3-y!)phenyl)carbamate was obtained 320 mg (31%) of Molecuie A19 as a lîght tan solid, mp 180-183 °C; ’H NMR (CDCl₃) δ 8.53 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.80 - 7.74 (m, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.54 - 7.45 (m, 2H), 7.40 - 7.34 (m, 3H), 7.32 (s, 1H), 7.10 (d. J= 7.5 Hz, 1 H), 3.98(d, J= 2.5 Hz, 2H), 2.73 (heptet, J-6.9 Hz, 1H), 1.22 (dd, J= 6.8, 5.0 Hz, 6H); ESIMS m/z 581 ([M+H]*).

Example 20. Préparation of (E)-3-hydroxy-2-((2-lsopropylphenyl)carbamothloyl)-N-{4-(1-{4(trifluoromethoxy)phenyl)’1 H-1,2,4-triazol-3-yl)phenyl)but-2-enamlde (Molecuie A20).

Step 1. A solution of 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (1.0 g, 3.12 mmol) and t-butyt acetoacetate (0.494 g, 3.12 mmol) In 8 mL of toluene was heated at 90 °C for 2 h, then cooled. The resuiting solid was filtered and air-dried to give 1.12 g (89%) of 3-oxo-N-(4-(1(4-(trifluoromethoxy)phenyl)-1H-1,2_l4-triazol-3-yl)phenyl)-butanamide as a tan solid (B10); mp 159164 ^eC. Ή NMR (CDCi3) δ 9.35 (s, 1H), 8.55 (s, 1H), 8.19- 8.09 (d, J-8.7 Hz, 2H), 7.83-7.74 (d, J - 9.1 Hz, 2H), 7.74 - 7.63 (d, J = 8.7 Hz, 2H), 7.43 - 7.32 (d, J - 8.3 Hz, 2H), 3.62 (s, 2H), 2.34 (s, 3H); ¹³C NMR (101 MHz, CDCI3) δ 205.34, 163.43, 163.02, 148.34, 141.49, 138.84, 135.55, 127.37,126.50,122.37,121.67,121.16,120.03,49.56, 31.36; ESIMS m/z 581 ([M+H]*).

Step 2. A portion of the solid from Step 1 (0.50 g, 1.24 mmol) was dissolved In 5 mL of dry N,Ndimethylformamlde (DMF) and stirred at ambiant température whlle potassium carbonate (0.25 g, 1.81 mmoi) and 24sopropylphenyl isothiocyanate (0.25 g, 1.41 mmol) were added. The solution was stirred for 18 h, then it was poured into 15 mL of water, extracted with ether, and the solvent evaporated. Chromatography of the crude product (0-70% EtOAc-hexanes) gave 350 mg of the titie compound as an off-white solid. mp 141-144 °C. ¹H NMR (400 MHz, CDCI₃) δ 15.35 -14.58 (m, 1H), 10.93 (s, 1H), 8.57 (m, 3H), 8.31 - 8.11 (m, 6H), 7.71 (m, 12H), 7.56-7.30 (m, 15H), 5.35 (s, 1H), 3.02 (heptet, J = 6.9 Hz, 1H), 2.52 (s, 3H), 1.35 -1.11 (m, 6H); ESIMS m/z 582 ([M+H]*.).

Example 21. Préparation of 3-((2-lsopropylphenyl)amlno)-3-thloxo-N-(4-(1-(4(trifIuoromethoxy)phenyl)-1H-1,2,4-trlazol-3-y1)pheny1)propanamlde (Molécule A21).

Molécule A20 (0.410 g, 0.71 mmol) was heated In 5 mL of MeOH for 90 min, then it was cooled, concentrated and chromatographed (0-70% EtOAc-hexanes) to give 288 mg (75%) of Moiecule A21 as a yellow soüd, mp 173-178 °C. Ή NMR (CDCI₃) δ 10.46 (S, 1H), 8.57 (s, 1H), 8.38 (s,1H), 8.19 (d, J = 8.7 Hz, 2H), 7.80 (d, J = 9.1 Hz, 2H), 7.67 (d, J =8.8 Hz, 2H), 7.47 - 7.31 (m, 6H), 4.10 (s, 2H), 3.04(heptet, J-6.7 Hz, 1H), 1.22 (d, J = 6.9Hz, 6H); ESIMS m/z540([M+H]*).

The conditions described in Exemples 20 and 21 were used to préparé the molécules In Examples 22 and 23.

Example 22. Préparation of 3-thloxo*3-(o-toiylamlno)-A/-(4-(1-(4-(trlfluoromethoxy)phenyl)-1H1,2,4-triazoi-3-y1)phenyl)propanamlde (Molecuie A22).

Using 2-methylpheny! Isothiocyanate In place of 2-isopropylpheny! Isothiocyanate In Step 2 of Example 20, there was obtained 33 mg (52%) of Molecuie A22; ’H NMR (CDCI₃) δ 10.76 (s, 1H), 8.84 (s, 1 H), 8.56 (s, 1 H), 8.15 - 8.13 (d, J - 8.4 Hz, 2H), 7.81-7.74 (m, 3H), 7.66 - 7.33 (d, J - 8.4 Hz, 2H), 7.58 - 7.50 (m, 1 H), 7.43 - 7.20 (m, 4H), 4.10 (s, 2H), 2.28 (s, 3H); ESIMS m/z 511 ([M+H]*).

Exemple 23. Préparation of 3-((2,6-dimethylphenyl)amlno)-3-thloxo-N-(4-{1-(4(trifluoromethoxy)phenyl)-1 H-1,2,4-triazoi-3-yl)phenyl)propanamlde (Molecuie A23).

Using 2,6-dimethyiphenyl isothiocyanate In place of 2-isopropylpheny! Isothiocyanate in Step 2 of Example 20, there was obtained 185 mg (41%) of Molecuie A23 as a light yellow solid, mp 178-182 °C; ’H NMR (CDCI₃) δ 10.41 (s, 1H), 8.88 (s. 1H), 8.58 (s,1H), 8.15 (d, J= 8.7 Hz, 2H), 7.85-7.76 (m, 2H), 7.65 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.22 - 6.99 (m, 3H), 4.14 (s, 2H), 2.22 (s, 6H); ESIMS m/z 526 ([M+H]*).

Example 24. Préparation of (Z)-2-(3-(2-lsopropylphenyl)-4-oxothlazolldln-2-ylldene)-N-(4-(1(4-{tr1fluoromethoxy)phenyl)-1 H-1,2,4-triazoI-3-yi)phenyi)acetamlde (Molecuie A24).

Molécule A21 (0.031 g, 0.057 mmol) was dissolved in 4 mL of EtOH and treated with 20 mg (0.13 mmol) of methyl bromoacetate and 20 mg (0.24 mmol) of sodium acetate, and the solution was heated to reflux for 2 h. The solution was then cooled, concentrated and chromatographed (0-70% EtOAc-hexanes) to give 27 mg (73%) of Molécule A24 as a tan solid. mp >250 °C (dec). ¹H NMR (CDCI₃) δ 8.53 (s, 1H), 8.13 - 8.07 (m, 2H), 7.81 - 7.76 (m, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.53 (d, J - 3.9 Hz, 2H), 7.42 - 7.33 (m, 2H), 7.23 - 7.16 (m, 1H), 7.13 (d, J = 7.7 Hz, 1H), 6.97 (s, 1H), 5.01 (s, 1H), 3.91 (s, 2H), 2.83 - 2.68 (m, 1H), 1.31 -1.16 (m, 6H); ESIMS m/z 580 ([M+H]*).

Example 25. Préparation of (Z)-2-cyano-3-((2-lsopropylpheny1)amIno)-3-mercapto-N-(4-(1-(4(trlfluoromethoxy)phenyl)-lH-1_t2,4-trlazol-3-y1)pheny1)acrylamlde (Molécule A25).

Step 1. Cyanoacetic add (0.30 g, 3.53 mmol) and 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4triazo!-3-yl)aniline (1.00 g, 3.12 mmol) were dissolved In 30 mL of dichloromethane, and then dicydohexylcarbodiimlde (0.695 g, 3.37 mmol) was added In one portion as a solid. The solution was allowed to stir for 2 h, then the solvent was removed and the residue was heated in 75 mL of EtOAc, cooled and filtered to remove dicyclohexyl urea. The filtrate was concentrated and the solid was recrystallized from EtOH to give 0.82 g (66%) of 2-cyano-N-(4-(1-(4-(trifluoromethoxy)phenyl)1H-1,2,4-triazol-3-yl)phenyl)acetamlde (B11 ) as a white solid, mp 250-252 °C. Ή NMR (DMSO-d_a) δ 10.51 (s, 1H), 9.39 (s, 1H), 8.13-8.00 (m, 4H), 7.75 - 7.66 (m, 2H), 7.62 (d, 8.3 Hz, 2H),

3.95 (s, 2H). ESIMS m/z 388 (M+H).

Step 2. The cyanoacetanilide from Step 1 (0.30 g, 0.775 mmol) and 2-isopropylphenyl isothiocyanate (0.16 g, 0.903 mmol) were dissolved in 5 mL of DMF and stirred under N₂ while NaH (60%; 62 mg, 1.55 mmol) was added In one portion. The solution was allowed to stir at ambient température for 1 h, then it was poured Into 20 mL of 1 N HCl. The gummy solid was collected and crystallized from EtOH/water to give 0.32 g (71%) of the title compound as a light yellow solid, mp 159-162°C. ’H NMR(CDCI₃) δ 12.56 (s, 1H), 8.56 (s, 1H), 8.18 (d, J= 8.7 Hz, 2H), 7.85-7.77(m, 35

2H), 7.68 - 7.60 (m, 3H), 7.45 -7.36(m. 4H), 7.32 - 7,27 (m, 1H), 7.20 (d, J = 7.7 Hz, 1H), 4.42 (s, 1H), 3.11 (heptet, J= 6.9 Hz, 1H), 1.26 (d, J= 6.9 Hz, 6H); ESIMS m/z 565 ([M+H]*).

The following molécules (Examples 26-30) were prepared according to the procedure described In the previous Example.

Example 26. (Z)-2-Cyano-3-mercapto-3-((4-methoxy-2-methylphenyl)amlno)-N-{4-(1-{4~ (trlfluoromethoxy)phenyl)-1H-1,2,4-triazol-3-y1)phenyl)acrylamlde (Molécule A26).

Molécule A26 was Isolated as a light yellow solid, 103 mg (58%), mp 174-177 °C; ¹H NMR (CDCI3) δ 12.27 (s, 1H), 8.56 (s, 1H), 8.18 (d, J= 8.7 Hz, 2H), 7.80 (d. J= 9.1 Hz, 2H). 7.63 (d, J = 8.9 Hz, 2H), 7.61 (s, 1 H), 7.39 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1 H), 6.92 - 6.73 (m, 2H), 4.40 (s, 1H), 3.83 (s, 3H), 2.28 (s, 3H); ESIMS m/z 567 ([M+H]*).

Example 27. (Z)-3-([1,r-Biphenyl]-2-ylamlno)-2-cyano-3-mercapto-AF{4-(1-{4(trifluoromethoxy)phenyl)-1 W-1,2,4-trlazol-3-yl)pheny1)acrylam1de (Molécule A27).

Molécule A27 was isolated as a light yellow solid, 60 mg (32%), mp 162-166 °C; ¹H NMR (CDCI₃) δ 12.52 (s, 1H), 8.55 (s, 1H), 8.15 (d, 8.6 Hz, 2H), 7.80 (m, 3H), 7.57-7.28 (m, 13H), 4.29 (s,

1H); ESIMS m/z 599 ([M+H]*).

Example 28. (Z)-2-Cyano-3-mercapto-3-{(2,6-dlmethylphenyl)amlno)-N-(4-(1-{4(trlfluoromethoxy)pheny1)-1 H-1,2,4-trlazol-3-yl)pheny1)acrylamIde (Molécule A28).

Molécule A28 was Isolated as a light yellow solid, 103 mg (59%), mp 196-199 ®C; ’H NMR (CDCI₃) δ 12.24 (s, 1H), 8.58 (s. 1H), 8.18 (d. J= 8.8 Hz. 2H), 7.80 (d, J= 9.1 Hz, 2H). 7.64 (d, J= 8.7 Hz. 2H), 7.42 - 7.33 (m, 2H), 7.23 (m, 1H). 7.17 (d, J = 7.7 Hz, 2H), 4.30 (s, 1H), 2.28 (s, 6H); ESIMS m/z 551 ([M+H]*).

Example 29. (Z)-2-Cyano-3-mercapto-3-(o-toly1amlno)-N-(4-(1-(4-(trifluoromethoxy)phenyl)1H-1,2,4-tr1azol-3-yl)phenyl)acrylamlde (Molécule A29).

Molécule A29 was Isolated as a light yellow solid, 121 mg (71 %), mp 157-160 °C; ’H NMR (CDCI₃) δ 12.51 (S, 1H). 8.56 (s, 1H), 8.18 (d, J = 8.8 Hz. 2H), 7.84 - 7.73 (m, 2H), 7.67-7.60 (m, 3H), 7.39 (d, J = 8.3 Hz, 2H), 7.32 (m, 3H), 7.23 (m. 1H). 4.42 (s, 1H), 2.33 (s, 3H); ESIMS m/z 537 ([M+H]*).

Example 30. (Z)-2-Cyano-3-((2,6-dlfluorophenyl)amlno)-3-mercapto-W-(4-(1-{4(trifluoromethoxy)pheny1)-1H-1,2,4-triazol-3-yl)phenyl)acrylamlde (Molécule A30).

Molécule A30 was isolated as a light yellow solid, 53 mg (28 %), mp 135-142 °C; ’H NMR (CDCI₃) δ 12.31 (s, 1H), 8.84-8.50 (m, 1H). 8.19 (dd, J = 13.9,7.1 Hz, 2H). 7.80 (m, 2H), 7.65 (m, 2H). 7.39 (m, 3H), 7.14-8.86 (m, 3H). 4.97-4.11 (m. 1 H); ESIMS m/z 559 ([M+H]*).

Example 31. (Z)-2-Cyano-2-(3-(2-lsopropy1pheny1)-4-oxothlazolldin-2-ylidene)-N-{4-(1-{4(trlfluoromethoxy)phenyi)-1 H-1,2,4-trlazol-3-yl)phenyl)acetamlde (Molécule A31 ).

Molécule A25 (0.058 g, 0.103 mmol) was dissolved In 3 mL of EtOH and treated with 35 mg (0.23 mmol) of methyl bromoacetate and 30 mg (0.37 mmol) of sodium acetate, and the solution was heated to reflux for 1 h. The solution was then cooled and the solid product was filtered and airdried to give to give 46 mg (71%) of the thiazolinone as a light tan solid, mp 250-255 °C; ¹H NMR (CDC!₃) δ 8.55 (s, 1H), 8.16 (d, J= 8.8 Hz, 2H), 7.95 (s, 1H), 7.79 (d, J= 9.1 Hz, 2H), 7.62 (d, J = 8.8 Hz, 3H), 7.53 (dd, J= 7.8,1.2 Hz, 1H), 7.42-7.34 (m, 3H), 7.18 (dd, J= 7.9,1.2 Hz, 1H), 3.92 (d, J = 1.3 Hz, 2H), 2.71 (heptet, J= 6.8 Hz. 1 H). 1.33 (d, 6.9 Hz, 3H), 1.23 (d, J - 6.8 Hz, 3H);

ESIMS m/z 605 ([M+H]*).

Example 32. Préparation of (Z)-3-{2,6-dlmethy!pheny!amlno)-3-hydroxy-l-(4-(1-(4(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylamlde (Molécule A32).

Step 1. To a stirred solution of 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1_l2,4-triazol-3-y1)anîline (0.19 g; 0.593 mmol) and mono-benzyl malonlc acid (0.138 g: 0.712 mmol) dissolved ln DMF (6 mL) was added 1-hydroxy-7-azabenzotriazo!e (HOAt, 0.5 M ln DMF; 2.14 mL; 1.068 mmol), followed by 1(3-dimethylamlnnopropyl)-3-ethylcarbodiimlde hydrochloride (EDCI; 0.21 g; 1.068 mmol) and Nmethyl morpholine (0.46 mL; 4.15 mmol). The mixture was stirred ovemight. Water (25 mL) was then added and the solution was extracted with EtOAc (3 x 10mL). The organic solution was washed with water (5x10 mL) and brine (10 mL), followed by drying over MgSO<, filtration and concentration. The residue was applled to a 1 g Isolute SCX-2 column and eluted with a 9:1 CHCh/MeOH solution to afford the expected amide (B12), contaminated with about 10% of the dimethyl amide of the starting oxo-propanoic add (0.26 g; 88%). ’H NMR (CDCI₃) δ 9.35 (s, 1H), 8.55 (s, 1H), 8.15 (d. J= 8.7 Hz, 2H), 7.78 (d, J= 9.0 Hz, 2H), 7.67 (d, J = 8.7 Hz. 2H), 7.35 (m, 7H), 5.23 (s, 2H), 3.54 (s. 2H). ^,3C NMR (101 MHz, CDCI₃) δ 169.59,167.45,162.84,141.53, 138.91,135.58,134.81,128.77,128.60,128.52,128.41,128.36,127.37,122.39,121.17,119.97, 67.65, 41.76, 35.58. ESIMS m/z 496 ([M+H]*)

Step 2. The benzyl ester from Step 1 (0.26 g; 0.524 mmol) was dissolved In 4 mL of MeOH and eluted through the H-Cube hydrogenator at 50 °C (1 mL/min) using a 10% Pd/C cartridge as the catalyst. The MeOH was concentrated and the crude acid was dried under hïgh vacuum ovemight. The add (B13) (0.162 g; 76%). was used directly In the next step ¹H NMR (DMSO-d_e) δ 10.35 (s, 1H), 9.38 (s. 1H), 8.06 (dd, 8.9, 3.3 Hz, 4H). 7.74 (d, 8.8 Hz, 2H), 7.62 (d, J= 8.4 Hz, 2H),

7.37 (s, 1H), 3.39 (s, 2H). ESIMS m/z 406 ([M+H]*)

Step 3. To a solution of the carboxylic add from Step 2 (62 mg; 0.153 mmol) and 2,6-dimethyl aniline (20 üL; 0.153 mmol) In DMF (1.6 mL) was added HOAt (0.5 M In DMF; 0.55 mL; 0.275 mmol), EDCI HCl (53 mg; 0.275 mmol) and N-methyl morphoiine (0.18 mL; 1.068 mmol). The reaction was stirred at room température ovemight. The solution was diluted with water and extraded with EtOAc. The organic solution was washed with water (5x) and brine. The solution was then dried over MgSO<, filtered and concentrated. The residue was purified via radial chromatography using a 97.5:2.5 ratio of CHCIj/MeOH as the eluent (R< - 0.2). The fraction containing the product was contamlnated with the dimethyl amlde of the starting carboxylic add.

This mixture was purified via reverse phase chromatography using CH₃CN/H₂O gradient to give the pure desired diamide (9 mg; 12%). ¹H NMR (CDCI3, mixture of résonance forms, major reported) δ 10.53 (s, 1H), 9.71 (s, 1H), 8.55 (s, 1H), 8.13 (m, 3H), 7.79 (d, J= 9.1 Hz, 2H), 7.71 (d, J~ 8.7 Hz, 1H), 7.65 (d, J- 8.7 Hz, 1H), 7.37 (d, J- 8.3 Hz, 2H), 7.12 (m, 1H), 3.49 (s, 2H), 3.12 (s, 3H), 3.04 (s, 3H). ESIMS m/z 509 ([M+H]*)

Example 33. Préparation of (Z)-3-hydroxy-3-(4-methoxy-2-methylpheny1amlno)-A/-(4-(1-(4(trlfluoromethoxy)phenyl)-1H-1,2,4-trlazol-3-yl)phenyl)acrylamlde (Molécule A33).

OMe

Using Step 3 of the above procedure, and repladng 2,6-dimethylaniline with 2-methyl-4methoxyaniline, there was obtained 83 mg (56%) of the diamide as a tan solid, mp 168-171 °C. ’H NMR (DMSO-d_e) δ 10.39 (s, 1H), 9.48 (s, 1H), 9.38 (s, 1H), 8.07 (d, J= 8.9 Hz, 4H), 7.77 (d, J8.8 Hz, 2H), 7.62 (d, J= 8.3 Hz, 2H), 7.28 (d, J= 8.7 Hz, 1H), 6.81 (d, J= 2.8 Hz, 1H), 6.74 (dd, J8.7, 2.9 Hz, 1H), 3.73 (s, 3H), 3.51 (s, 2H), 2.21 (s, 3H). EIMS 525 (M*).

Example 34. Préparation of (Z)-3-hydroxy*3-(2-lsopropyl-4-methoxyphenylamlno)-N-(4-(1-(4(trlfluoromethoxyJphenyO-IH-I.Z^trlazol'S-ylJphenylJacrylamlde (Molécule A34).

Using Step 3 of the above procedure, and repladng 2,6-dimethylaniline with 2-isopropyl-4methoxyanlline, there was obtained 38 mg (36%) of the dlamide. 'H NMR (CDC1₃) δ 9.81 (s, 1H), 8.92 (s, 1H), 8.58 (s, 1H), 8.12 (d, J = 8.6 Hz, 2H). 7.79 (d, J = 9.0 Hz, 2H), 7.69 (d, J= 8.7 Hz, 2H), 7.50 - 7.10 (m, 3H), 6.84 (d, J~ 2.8 Hz, 1H), 6.72 (dd, J = 8.7,2.9 Hz, 1H), 4.02 (s, 3H), 3.80 (S, 2H), 3.08 (dt, J = 13.6,6.8 Hz, 1H), 1.20 (d, 6.9 Hz, 6H). ¹³C NMR (101 MHz, CDCI₃) δ

166.81,166.13,162.98,158.40,144.30,141.54,139.02,135.54,127.30,127.05,126.87,126.52, 126.30,122.36,121.13,120.10,111.97,110.85,56.04, 55.36,44.26,28.37,23.06. ESIMSm/z553 ([M+H]*)

Example 35. Préparation of 4-fluoro-2-nitro-1-(prop-1-en-2-yl)benzene (B14)

To 1-chloro-4-fluoro-2-nltrobenzene (1.03 g, 5.87 mmol) In a 100 mL round-bottomed flask equipped with a stir bar and nitrogen was added sodium carbonate (0.746 g, 7.04 mmol), dioxane (23.47 ml) and water (5.87 ml). To this was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2dioxaborolane (1.323 ml, 7.04 mmol) followed by bls(trlphenylphosphine)pal1adium(l1)ch1oride (0.329 g, 0.469 mmol). The reaction mixture was evacuated and backfilled with nitrogen (3x). The reaction was heated to 80 °C ovemight. The réaction was determined to be complété by TLC (10% EtOAc/Hex). The reaction was cooled, filtered through Celite, washed with EtOAc and concentrated. The residue was taken up in dichloromethane, poured through a phase separator and concentrated. Purification by flash column chromatography provided the title compound 4fluoro-2-nitro-1-(prop-1-en-2-y1)benzene (0.837 g, 75%) as a yellow oil: IR (thin film) 3091 (w), 2979 (w), 2918 (w), 1642 (w), 1530 (s), 1350 (s) cm·’; ¹H NMR (400 MHz, CDCI₃) δ 7.60 (dd, J ~ 8.2, 2.5 Hz, 1H), 7.37 - 7.21 (m, 2H), 5.19 (p, J = 1.5 Hz, 1H), 4.97 - 4.89 (m, 1 H), 2.11 - 2.04 (m, 3H); ¹³C

NMR (101 MHz, CDCI₃) δ 160.96 (d, 7«= = 250.8 Hz), 148.46,141.88,135.18 (d, J_Cf ~ 4.1 Hz), 132.09 (d, 7cf= 7.8 Hz), 119.98 (d, 7cf = 20.9 Hz), 115.99,111.63 (d, 7^ = 26.4 Hz), 23.35.

The following molécules (B15 and B16) were made in accordance with the procedures disclosed in Exampie 35.

1-Fluoro-3-nltro-2-(prop-1-en-2-y!)benzene (B15)

IR (thln film) 3091 (w), 2978 (w), 2922 (w), 1645 (w), 1528 (s), 1355 (s) cm’¹; ¹H NMR (400 MHz, CDCI3) δ 7.64 (dt, 7= 8.1,1.2 Hz, 1H), 7.39 (td, 7= 8.2,5.4 Hz, 1H), 7.31 (td, 7= 8.5,1.2 Hz, 1H), 5.28 (p, 7= 1.5 Hz, 1H), 4.91 (p, 7= 1.0 Hz, 1H), 2.16 (t, 7= 1.3 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) δ 159.59 (d, J_CF = 249.3 Hz), 149.81,136,14,128.57 (d, J_CF = 9.0 Hz), 127.02 (d, J_CF = 22.0 Hz), 119.84 (d, Jcf- 23.4 Hz), 119.41 (d, Jcf - 3.6 Hz), 117.25, 23.10 (d, 7_CF = 1.9 Hz).

4-Fluoro-1-nltro-2-(prop-1-en-2-y!)benzene (B16)

IR (thln film) 3085 (w), 2979 (w), 2919 (w), 1617 (m), 1580 (s), 1523 (s), 1344 (s) cm’¹; Ή NMR (400 MHz, CDCI₃) δ 7.96 (dd, 7 = 9.0, 5.1 Hz, 1 H), 7.08 (ddd, 7 = 9.0,7.4,2.8 Hz, 1H), 7.02 (dd, 7 =

8.7, 2.8 Hz, 1 H), 5.20 (p, J ~ 1.5 Hz, 1 H), 4.96 (p, 7 = 1.0 Hz, 1 H), 2.11 - 2.06 (m, 3H).

Example 36. Préparation of 5-fluoro*2-lsopropylanlllne (B17)

NH·

To 4-fluoro-2-nltro-1-(prop-1-en-2-yl)benzene (0.837 g, 4.62 mmol) in a 250 mL roirnd-bottomed flask equipped with a stir bar and rubber septum was added EtOAc (46.2 ml) followed by palladium on carbon (0.983 g, 0.462 mmol). The reaction was evacuated and purged with hydrogen (balloon) (2x) and stirred under hydrogen at room température ovemight. The reaction was determlned to be complété by TLC (10% EtOAc/Hex). The mixture was filtered through Celite, washed with EtOAc and concentrated. 5-F1uoro-2-lsopropylaniline (673 mg, 4.40 mmol, 95%) was obtained as a clear and yellow oil: IR (thin film) 3480 (w), 3390 (w), 2962 (m), 2872 (w), 1622 (m), 1504 (s), 1431 (m) cm'¹; ¹H NMR (400 MHz, CDC!3) C 7.05 (dd, J = 8.5, 6.4 Hz, 1H), 6.45 (td. J - 8.5,2.6 Hz, 1H), 6.37 (dd, J = 10.6, 2.6 Hz, 1H), 3.74 (bs, 2H), 2.83 (hept, J-6.8 Hz, 1H), 1.24 (d, J= 6.8 Hz, 6H); ¹³C NMR (101 MHz, CDCI3) δ 161.75 (d, Jcf “ 241.3 Hz), 144.76 (d, Jcf= 10.3 Hz), 128.11 (d, Jcf = 2.8 Hz), 126.53 (d, Jcf = 9.6 Hz), 105.06 (d, Jcf = 20.7 Hz), 102.26 (d, Jcf = 24.2 Hz), 27.27.22.35.

The following molécules were made in accordance with the procedures disclosed In Example 36.

3- Fluoro-2-lsopropylanlllne (B18)

IR (thin film) 3478 (w), 3386 (w), 2963 (m), 2934 (w), 2934 (w), 1624 (s), 1466 (s), 1453 (s) cm*¹: Ή NMR (400 MHz, CDCI3) δ 6.92 (td, J= 8.1,6.1 Hz, 1 H). 6.44 (ddd, J= 10.4, 8.1,1.1 Hz, 2H), 3.72 (bs, 2H), 3.06 (heptd, J- 7.1,1.3 Hz, 1H), 1.35 (dd, J = 7.1,1.5 Hz, 6H); ¹³C NMR (101 MHz, CDCI3) δ 162.83 (d, Jcf = 243.4 Hz), 145.29 (d, Jcf = 8.8 Hz), 127.08 (d, Jcf - 11.2 Hz), 119.64 (d, Jcf 16.1 Hz), 111.77 (d, Jcf = 2.3 Hz), 106,47 (d, Jcf « 24.2 Hz), 25.65,20.97 (d, J cf= 3.8 Hz).

4- Fluoro-2*lsopropy!anll!ne (B19)

F

IR (thin film) 3455 (w), 3373 (w), 2962 (m), 2870 (w), 1625 (w), 1609 (w), 1497 (s). 1429 (m) cm*¹: Ή NMR (400 MHz. CDC1₃) δ 6.85 (dd, J= 10.3, 2.9 Hz, 1H), 6.72 (td, J= 8.3, 2.9 Hz, 1H), 6.60 42 (dd, J- 8.6, 5.1 Hz, 1H), 3.49 (bs, 2H), 2.88 (hept, 6.81H), 1.24 (d, J = 6.8 Hz, 6H); ¹³C NMR (101 MHz, CDCI₃) δ 156.92 (d, Je? - 235.0 Hz), 139.17 (d, Je? = 2.1 Hz), 134.61 (d, Je? = 6.2 Hz), 116.55 (d, Jcf = 7.5 Hz), 112.69 (d, Jcf = 22.5 Hz), 112.17 (d, 22.4 Hz), 27.90,22.11.

Example 37. Préparation of N-((2-cyclopropy1pheny1)carbamothloy1)benzamlde (B20)

To 2-cyclopropylaniline (498 mg, 3.74 mmol) in acetone (10 mL) was added benzoyl Isothiocyanate (0.53 mL, 3.93 mmol) and the mixture was heated at 50 *C for 8 hours. The reaction mixture was concentrated to provide N-((2-cyclopropylphenyl)carbamothloy1)benzamide as a orange oil (1.249 g, 100%): ’H NMR (400 MHz, CDCI₃) δ 12.59 (s, 1H), 9.14 (s, 1H), 8.07 (dd, 7.8,1.3 Hz, 1H),

7.92 (dd, J = 8.4,1.2 Hz, 2H), 7.69 - 7.63 (m, 1 H), 7.59 - 7.52 (m, 2H), 7.31 - 7.26 (m, 1 H), 7.23 (td, J= 7.5,1.5 Hz, 1H), 7.13 (dd, J = 7.6,1.5 Hz, 1H), 1.95 (qt, J= 12.3,4.4 Hz, 1H), 1.09-1.01 (m, 2H), 0.76 - 0.69 (m, 2H); ¹³C NMR (101 MHz, CDCI₃) δ 178.70,166.72,137.59,137.06,133.71,

131.72,129.22,127.51,127.20,126.93,126.12,125.26,11.72,7.03; ESIMS m/z 295 ([M-H]').

The following molecuies were made In accordance with the procedures disclosed In Example 37.

N-((2-chloro-6-!sopropyiphenyl)carbamoth!oyl)benzamide (B21) .Cl

Mp 177-181 °C; ¹H NMR (400 MHz, CDCi₃) δ 11.92 (s, 1H), 9.25 (s, 1H), 7.98 - 7.89 (m, 2H), 7.72 7.62 (m, 1H). 7.62 - 7.51 (m, 2H), 7.40 - 7.28 (m, 3H), 3.17 (hept, J= 6.0 Hz, 1H), 1.33 (d, J= 6.8 Hz, 3H), 1.21 (d, J= 6.9 Hz, 3H): ESIMS m/z 333 ([M+H]*).

N-((5-fluoro-2-lsopropylpheny1)carbamothloyl)benzamlde (B22)

Mp 134 °C (dec.); Ή NMR (400 MHz, CDCI₃) δ 12.31 (s, 1H), 9.17 (s, 1 H), 7.96 - 7.87 (m, 2H), 7.73-7.62 (m, 1H), 7.61 -7.49(m, 3H), 7.33 (dd, J = 8.8,6.1 Hz, 1H), 7.03 (td, J- 8.3, 2.8 Hz, 1H), 3.13 (hept, 6.9 Hz, 1H), 1.27 (d, J = 7.0 Hz, 6H); ESIMS m/z 315 ([M-H]).

A/-((2-lsopropyl-5-methylphenyl)carbamothloyl)benzamlde (B23)

Ή NMR (400 MHz, CDCI₃) δ 12.14 (s, 1 H), 9.16 (s, 1H), 7.97 - 7.87 (m, 2H), 7.73 - 7.61 (m, 1H), 7.61 - 7.50 (m, 2H), 7.42 - 7.34 (m, 1H), 7.31 - 7.23 (m, 1 H), 7.16 (dd, J = 7.9,1.8 Hz, 1H), 3.11 (hept, J= 6.9 Hz, 1H), 2.36 (s, 3H), 1.26 (d, J = 6.9 Hz, 6H); ’³C NMR (101 MHz, CDCI₃) δ 180.23, 166.97,140.94,136.03,134.89,133.75,131.67,129.22,129.20,127.71,127.55,126.01, 28.17, 23.38,20.90; ESIMS m/z 311 ([M-H]).

N-((2-lsopropyl-4-methylphenyl)carbamothloyl)benzamlde (B24)

Mp 136 “C (dec.); ’H NMR (400 MHz, CDCI₃) δ 12.11 (s, 1H), 9.17 (s, 1H), 7.97 - 7.86 (m, 2H), 7.72- 7.61 (m, 1H), 7.60-7.49 (m, 2H), 7.44 (d, J- 8.0 Hz, 1H), 7.18 (d, J= 1.9 Hz, 1H), 7.09 (dd, J- 8.1, 2.0 Hz, 1H), 3.11 (hept. J = 6.8 Hz, 1H), 2.38 (s, 3H), 1.27 (d, J= 6.9 Hz, 6H); ESIMS m/z 311 ([M-H]*).

N-((2-lsopropyl-3-methylphenyl)carbamothloyl)benzamlde (B25)

Ή NMR (400 MHz, CDCI₃) δ 12.12 (s, 1H), 9.18 (s, 1 H), 7.99 - 7.86 (m, 2H), 7.71 - 7.60 (m, 1H), 7.60 - 7.50 (m, 2H). 7.32 (dd, J= 6.6. 2.8 Hz, 1H), 7.21 - 7.09 (m, 2H), 3.46 - 3.31 (m, 1H), 2.42 (s, 3H), 1.37 (d, J = 7.2 Hz, 6H); ¹³CNMR(101 MHz, CDCI₃) δ 180.41,166.88,141.79.137.22,

136.15,133.76,131.65,130.94,130.53,129.23,127.57,126.02,28.69,21.17,21.05; ESIMS m/z

311 ([Μ-ΗΓ).

N-((3-fluoro-2-lsopropylphenyl)carbamothloyl)benzamlde (B26)

’H NMR (400 MHz, CDCI₃) δ 12.11 (s, 1 H). 9.20 (s, 1H), 8.00 - 7.85 (m, 2H), 7.73 - 7.62 (m, 1H), 7.62 - 7.50 (m. 2H), 7.32 - 7.18 (m, 2H), 7.11 - 6.98 (m, 1H), 3.27 - 3.14 (m, 1H), 1.38 (dd, J = 7.1, 1.4 Hz, 6H); ¹³C NMR (101 MHz, CDCI₃) δ 180.87,167.04,162.36 (d, J& - 247.2 Hz), 136.61 (d, J& = 8.8 Hz), 133.88,132.02 (d, Je? = 15.2 Hz), 131.50,129.27,127.57,127.06 (d, Jqf = 10.2 Hz), 123.77 (d, 3.0 Hz), 116.04 (d, Jcf = 23.5 Hz), 27.36,21.35, 21.31; ESIMS m/z 315 ([M15 HJ*)N-((4-fluoro-2-lsopropylphenyl)carbamothloyl)benzamlde (B27)

Mp 96-102 °C; Ή NMR (400 MHz, CDCI₃) δ 12.11 (s, 1H), 9.18 (s, 1H), 7.97 - 7.87 (m, 2H), 7.73 20 7.63 (m, 1 H). 7.60 - 7.48 (m, 3H), 7.07 (dd, J = 10.0,2.9 Hz, 1 H), 6.97 (ddd, J = 8.7,7.7,2.9 Hz,

H), 3.20 - 3.06 (m. 1 H), 1.27 (d, J = 6.8 Hz, 6H); ESIMS m/z 315 ([M-H]).

N-((1-lsopropyl-1 H-pyrazol-5-yl)carbamothloy1)benzamlde (B28)

’H NMR (400 MHz, CDCI₃) δ 12.37 (s, 1H), 9.24 (s, 1H), 7.97 - 7.85 (m, 2H), 7.75 - 7.83 (m, 1 H), 7.58 (ddd, J= 7.8, 5.9,2.4 Hz, 3H), 8.58 (d, J = 1.9 Hz, 1 H), 4.49 (hept, J= 8.8 Hz, 1H), 1.54 (d, J = 6.7 Hz, 6H); ’³C NMR (101 MHz, CDCI₃) δ 179.82,167.18,138.45,134.40,134.13,131.16, 129.37,127.58,101.12,49.79,22.33; ESIMS m/z 289 ([M+H]*).

N-((3-lsopropylphenyl)carbamothloyl)benzamlde (B29)

Λ ’H NMR (400 MHz, CDCI₃) δ 12.57 (s, 1H), 9.05 (s, 1H), 7.96 - 7.84 (m, 2H), 7.72 - 7.49 (m, 5H), 7.35 (t, J =7.8 Hz, 1H), 7.15 (dt, J = 7.7,1.3 Hz, 1H), 2.95 (hept, J = 6.9 Hz, 1H), 1.28 (d. J = 8.9 Hz. 6H); ¹³C NMR (101 MHz, CDCI₃) δ 178.05, 166.86,149.90,137.52,133.75,131.70,129.25, 128.73,127.48,125.11,122.10,121.43, 34.04, 23.87; ESIMS m/z 299 ([M+H]*).

Example 38. Préparation of 1-(2-cyciopropylphenyl)thlourea (B30)

To N-((2-cydopropylphenyl)carbamothioyl)benzamide (1.210 g, 4.08 mmol) In MeOH (10 mL) was added 2 N NaOH (4.1 mL, 8.17 mmol) and stirred at 85 *C for 3 hours. The reaction was cooled, neutralized with 2 N HCl, and half of the reaction volume was evaporated under a stream of nitrogen. A yellow predpltate formed that was filtered, rinsed with water and dried in the vacuum oven to give 1-(2-cydopropylphenyl)thiourea as a yellow solid (444.5 mg, 56%); mp 152 -154 *C; ’H NMR (400 MHz, CDCI₃) δ 7.75 (s, 1H), 7.31 - 7.27 (m, 1H), 7.26 - 7.22 (m, 2H), 7.00 (d, J= 7.4 Hz, 1H), 5.95 (s, 2H), 1.99 (tt, J= 8.4. 5.3 Hz, 1H), 1.06 (ddd, J= 8.4, 6.3,4.5 Hz, 2H), 0.69 (dt, J= 8.4,4.8 Hz, 2H); ’³C NMR (101 MHz, CDCl₃) δ 182.10,140.33,135.18,128.81,126.96,126.45, 128.04,10.95, 8.39; ESIMS m/z 193 ([M+H]*).

The foliowing molécules were made In accordance with the procedures disclosed in Example 38.

1-(2-Chloro-6-lsopropylphenyl)thlourea (B31)

Ή NMR (400 MHz, CDCi₃) δ 7.63 - 7.52 (m, 1H), 7.40 - 7.29 (m, 3H), 5.30 (bs, 2H), 3.24 (hept, J~

6.9 Hz, 1H), 1.34-1.11 (m, 6H); ⁿC NMR (101 MHz, CDCI₃) δ 182.68,149.91,133.87,130.66. 130.41,128.07,125.63,29.11,24.11; ESIMS m/z 227 ([M-H] ).

1-(5-F1uoro-2-lsopropylphenyl)thlourea (B32)

F

’H NMR (400 MHz, CDCI₃) δ 7.89 (s, 1 H), 7.37 (dd, J = 8.8, 6.1 Hz, 1 H). 7.13 - 7.05 (m, 1H), 6.97 (dd, J= 8.8,2.7 Hz, 1H), 5.98 (s, 2H), 3,16 (hept, J - 6.9 Hz, 1H), 1.21 (d, J- 6.9 Hz, 6H); ^1flF

NMR (376 MHz, CDCI₃) δ -114.00; ESIMS m/z 211 ([M-H]j.

-(2-lsopropyl-5-methylphenyl)thlourea (B33)

¹H NMR (400 MHz, CDCI3) δ 7.58 (s, 1H), 7.29 (d, J- 8.0 Hz, 1H), 7.18 (dd, J = 8.1,1.9 Hz, 1 H), 7.05 - 6.99 (m, 1H), 6.33 - 5.36 (m, 2H), 3.13 (hept, J ~ 6.9 Hz, 1H), 2.45-2.23 (m, 3H), 1.29-1.10 (m, 6H); ¹³C NMR (101 MHz, CDCI3) δ 182.36,143.05,137.35,132.92,130.29,127.99,127.20, 27.94,23.54,20.74; ESIMS m/z 207 ([Μ-ΗΓ).

1-(2-lsopropyl-4-methylphenyl)thlourea (B34)

’H NMR (400 MHz, CDCI₃) δ 7.64 - 7.51 (m, 1H), 7.21 - 7.17 (m, 1H), 7.13 - 7.02 (m, 2H), 6.35 5.31 (m, 2H), 3.14 (hept, J= 6.9 Hz, 1H), 2.37 (s, 3H), 1.21 (d. J= 6.9 Hz, 6H); ¹³C NMR (101 MHz, CDCI₃) δ 182.50,146.05,139.59,130.49,128.03,127.94,127.52, 28.18, 23.49, 21.37; ESIMS m/z 207 ([M-HT).

1-{2-lsopropyl-3-methylphenyl)thlourea (B35)

¹H NMR (400 MHz, CDCI₃) δ 7.52 (d, J = 4.2 Hz, 1 H), 7.20 - 7.12 (m, 2H>. 7.05 (dd, J = 6.6, 2.7 Hz, 1H), 6.34 - 5.05 (m. 2H), 3.40 (hept, J= 7.3 Hz, 1H), 2.41 (s, 3H), 1.33 (d, J= 7.2 Hz, 6H); ¹³C NMR (101 MHz, CDClj) δ 182.09, 143.68,138.60, 134.25,131.94,127.11,126.66, 28.66, 21.00, 20.92; ESIMS m/z 209 ([M+H]*).

1-(3-Fluoro-2-Isopropylphenyf)thIourea (B36)

¹H NMR (400 MHz, CDCI3) δ 7.74 - 7.56 (m, 1H), 7.32 - 7.19 (m, 1H), 7.13 - 7.01 (m, 2H), 6.41 5.27 (m, 2H), 3.35- 3.17 (m, 1H), 1.33 (dd, J = 7.1,1.3 Hz, 6H); ^ieF NMR (376 MHz, CDCI3) δ 110.45; ESIMS m/z 211 ([M-H]*).

1-{4-Fluoro-24sopropylphenyl)thlourea (B37)

¹H NMR (400 MHz, CDCI₃) δ 7.59 - 7.42 (m, 1H), 7.25 - 7.18 (m, 1H), 7.12 - 7.05 (m, 1 H), 7.02 6.91 (m, 1H), 6.33 - 5.27 (m, 2H), 3.24 - 3.08 (m, 1H), 1.22 (d, J- 6.8 Hz, 6H); ¹⁹F NMR (376 MHz, CDClj) δ -110.29; ESIMS m/z 211 ([M-H]*).

1-(1-lsopropy!-1 H-pyrazoî-5-y1)thlourea (B38) ¹H NMR (400 MHz, DMSO-de) δ 9.35 (s, 1 H), 8.07 (s, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.10 (s, 1 H), 6.07 (d, J= 1.9 Hz, 1H). 4.36 (hept, J= 6.6 Hz, 1H), 1.33 (d, J-6.6 Hz, 6H): ¹³CNMR(101 MHz, DMSO-de) δ 183.02,137.47.135.00,102.00.48.12.22.27; ESIMS m/z 185 ([M+H]*).

1-(3-tsopropylphenyl)thlourea (B39)

Ή NMR (400 MHz. CDCI₃) δ 7.99 (s, 1H), 7.36 (t, J-7.8 Hz, 1H), 7.20 (dt, J-7.8,1.4 Hz, 1 H),

7.12 - 7.02 (m, 2H). 6.11 (s. 2H), 2.92 (hept, J= 6.9 Hz, 1H), 1.25 (d, J- 7.0 Hz. 6H); ¹³C NMR (101 MHz. CDCl₃) δ 181.65.151.61,136.18,130.11,126.13,123.17,122.40, 33.98,23.83; ESIMS m/z 195 ([M+H]*).

Example 39. Préparation of N-[[(2-lsopropy1lpheny1)amlno]thIoxomethyl]-N’-(4-(1-(4(trifluoromethy1)phenyl)-1H-1,2,4-trlazol-3-yl)phenyl urea. (Molécule A48)

To a round bottom flask was added 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoyl azide (300 mg, 0.802 mmol). The flask was evacuated/backfilled with N₂. then toluene (20.0 mL) was added, followed by 1-(2-lsopropylphenyl)thiourea (30 mg, 0.154 mmol). The reaction mixture was heated to 100 *C for 1 h. the reaction was then cooled to 50 *C and stirred for an additional 1

h. The reaction mixture was then cooled to 35 *C. THF (1 mL) was added, followed by sodium hydrlde (32.1 mg, 0.802 mmol) in one portion. Vigorous bubbling occurred, and the reaction mixture tumed yellow. The reaction mixture was stirred at 35 *C for an additional 15 min. The reaction mixture was cooled to room température, poured over Ice water, extracted with Et₂O, dried, and concentrated onto silica. The crude residue was purifîed via flash chromatography (silica/EtOAc/hexanes) to yield the titie compound as a white solid (57 mg, 0.104 mmol, 13%): mp 201-203 ’C; ¹H NMR (400 MHz, CDCi3) δ 8.57 (s, 1H), 8.16 (m, 2H), 7.80 (m, 3H), 7.56 (d, J = 8.3 Hz, 2H). 7.40 (ddt, J= 8.0, 6.7,1.7 Hz, 2H), 7.28 (dt, J = 6.8,1.8 Hz, 2H), 7.23 (m, 2H), 3.16 (dp, J = 16.4, 6.9 Hz, 3H). 1.22 (d, J= 6.9 Hz, 6H); ^ieF NMR (376 MHz, CDCI3) δ -58.02; EIMS m/z 542 ([M+2]).

Molécules A46, A63, A64, A67, A68, A70-A73. A78-A84, A89, A97-A101, A106, A107, A112, A113, A116, A118 and A119 ln Table 1 were made either ln accordance with the procedures disclosed ln Exemple 39 or by the procedure described ln Example 53.

Example 41. Préparation of N-[[(2-methyl-4-methoxypheny1)amino]oxomethy1]-N’-(4-(1-(4(trifluoromethyl)phenyl)-1H-1,2,4-trlazol-3-yl)pheny1 urea (Molécule A53).

ln a 100 mL round-bottomed flask were added 1-(4-(1-(4-(trifluor^omethoxy)phenyl)-1/-/-1l2l4-triazor 3-yl)phenyl)urea (200 mg, 0.551 mmol) and 14socyanato-4-methoxy-2-methyibenzene (135 mg, 0.826 mmol) ln dioxane (10 mL). The vessel was heated at 100 °C for 2 hours before the contents were cooled and the solvent removed under reduced pressure. The residue was suspended ln DCM and purified via normal phase chromatography (silica gel; hexanes/EtOAc) to afford the titie product as a white solid (30 mg): mp 213-233 °C; ¹H NMR (400 MHz, DMSO-de) δ 10.71 (s, 1 H), 10.34 (s, 1H), 10.13 (s. 1H), 9.39 (s, 1 H), 8.08 (m, 4H), 7.70 - 7.57 (m, 4H), 7.26 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 2.9 Hz, 1H), 6.81 (dd, J = 8.7, 2.9 Hz, 1H), 3.75 (s, 3H), 2.20 (s, 3H); EIMS m/z 527 ([M+H]*).

Example 42. Préparation of (E)-methyl 4-(3-(dImethylamlno)acryloyl)benzoate (B40)

A mixture of methyl 4-acetylbenzoate (5.00 g, 28.1 mmol) In DMF-DMA (38 mL, 284 mmol) was heated at 105 *C for 20 hours. The reaction was cooled, concentrated, and used crude In the next reaction.

Example 43. Préparation of methyl 4-(1H-pyrazol*3-yl)benzoate (B41)

To a solution of crude (£)-methy14-(3-(dimethy1amino)acry!oy1)benzoate (28.1 mmol) In EtOH (100 mL) was added hydrazine monohydrate (1.50 mL, 30.9 mmol) and the reaction was heated at 50 ’C for 24 hours. The reaction température was then Increased to 60 ’C for 24 hours. Additlonal hydrazine monohydrate (1.5 mL) was added, and the reaction was heated at 60 ’C for an additional 6 hours. The reaction was cooled, concentrated, and dried In a vacuum oven at 45 ’C ovemight to yield methyl 4-(1H-pyrazol-3-yl)benzoate as an orange solid (8.15 g, quantitative): mp 106 ’C (dec); ¹H NMR (400 MHz, CDCI3) δ 8.15 - 8.05 (m, 2H). 7.91 - 7.83 (m, 2H), 7.65 (d, J - 2.4 Hz, 1H), 6.71 (d. J- 2.3 Hz, 1H), 3.94 (s, 3H); ¹³C NMR (101 MHz, CDCI3) δ 166.91,136.89,131.83, 130.13,129.37,125.50,103.35, 52.14,22.46; EIMS m/z 202.

Example 44. Préparation of 4-(1-(4-(trlfluoromethoxy)phenyl)-1H-pyrazol-3-yl)benzolc acid (B42)

HO .0

Methyl 4-(1H-pyrazol-3-yl)benzoate (2.00 g, 9.89 mmol), 1-brorno-4-(trifluoromethoxy)benzene (2.38 g, 9.88 mmol), copper (I) lodide (0.28 g, 1.47 mmol), 8-hydroxyquinoline (0.21 g, 1.45 mmol), and césium carbonate (6.47 g, 19.86 mmol) In DMF/water (11:1) was heated at 120 ’C for 20 hours. The reaction was cooled, diluted with water and EtOAc, and decanted from the copper solids. The mixture was extracted three times with EtOAc (3 x 150 mL) and the combined organic layers washed with water. The organic layers were dried over anhydrous sodium sulfate, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-10% MeOH/dichloromethane) gave 4-(1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)benzoic add as a brown solid (580 mg, 16%): ’H NMR (400 MHz, CDCIj) δ 8.19 (d, J= 7.7 Hz. 2H), 8.03 (d, J= 7.7 Hz, 2H), 7.98 (d, J =

2.5 Hz. 1H), 7.85 — 7.79 (m. 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.88 (d, J= 2.5 Hz, 1 H); ”F NMR (376 MHz, CDCI₃) δ -58.05; ESIMS m/z 349 ([M+H]*).

Example 45. Préparation of 4-(1-(4-(trlfIuoromethoxy)phenyl)-1H-pyrazol-3-yl)benzoyl azide (B43)

To4-(1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)benzoic add (0.58 g, 1.67 mmol) in Isopropanol (10.7 mL) was added triethylamine (0.30 mL, 2.17 mmol) and diphenylphosphoryl azide (0.47 mL, 2.17 mmol) and the reaction was stirred at room température for 16 hours. The orange predpitate that had formed was filtered through a fritted glass funnel, rinsed with Isopropanol, and dried in a vacuum oven to provide 4-(1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3yl)benzoyl azide as an orange solid (188 mg, 30%): ’H NMR (400 MHz, DMSO-tf_e) δ 8.69 (d, J =

2.6 Hz, 1H), 8.17 - 8.11 (m, 2H), 8.09 - 8.04 (m. 4H), 7.57 (d, J - 8.4 Hz, 2H), 7.24 (d, J = 2.6 Hz, 1H); ”F NMR (376 MHz, DMSO-cf_e) δ -56.97; ESIMS m/z 374 ([M+H]*).

Example 46. Préparation of N-[[(2-lsopropyllphenyl)amlno]thloxomethyl]-N^I-((4-(1-(4(trifiuoromethoxy)phenyl)-1H'pyrazol-3-yl)phenyl))urea (Molécule A114)

A solution of 4-(1-{4-(trifluoromethoxy)phenyl)-1H-pyrazo1-3-yl)benzoyl azide (186 mg, 0.50 mmol) in DCE (2.5 mL) was heated at 80 *C for 2 hours. The reaction was cooled to room température and 1-(2-lsopropylphenyl)thlourea (97 mg, 0.50 mmol) and césium carbonate (170 mg, 0.52 mmol) were added. The mixture was stirred at room température for 3 days. The reaction was diluted with EtOAc and transferred to a separatory funnel containing water. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over anhydrous sodium sulfate, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-20% EtOAc/B, where B = 1:1 dichloromethane/hexanes) provided a yellow solid that contained a 10% Impurity by LC/MS. Reverse-phase flash chromatography (0-100% acetonltrile/water) provided the title compound as a white solid (36.5 mg,13%): mp 131 ’C (dec); Ή NMR (400 MHz, CDCI₃) δ 11.98 (s, 1H), 10.56 (s, 1H), 8.16 (s, 1 H). 7.93 (d, J = 2.5 Hz, 1H), 7.86 (d, J - 8.5 Hz, 2H), 7.83 - 7.76 (m, 2H), 7.47 (d, J7.9 Hz, 2H), 7.43 - 7.35 (m, 3H), 7.35 - 7.27 (m, 3H), 6.76 (d, J = 2.5 Hz, 1 H), 3.15 (dt, J = 13.7,

6.8 Hz, 1H), 1.26 (d, J = 6.5 Hz, 6H); ¹®F NMR (376 MHz, CDCI₃) δ -58.06; ESIMS m/z 540 «M+H]*).

Example 47. Préparation of ethyl 4-(perfluoroethoxy)benzoate (B44)

O’ '0

To an oven-dried 500-mL round bottom flask equipped with a stirring bar was added 1-bromo-4(perfluoroethoxyjbenzene (9.35 g, 32.1 mmol) and anhydrous THF (200 mL). The flask was placed under nitrogen and cooled In an Ice bath for 10 min. A solution of 1.3 M isopropylmagneslum chloride-lithlum chloride complex (30 mL, 38.6 mmol) was added over 15 min. The Ice bath was removed after 1 hour, and the reaction was warmed to room température and stirred ovemight. GC/MS showed the presence of starting material. The reaction was cooled In an Ice bath and 1.3 M Isopropylmagneslum chloride-lithium chloride complex (5 mL) was added. The ice bath was removed after 20 min and stirred at room température for 9 hours. Ethyl chloroformate (3.4 mL, 35.3 mmol) was added in a slow, steady stream. The reaction was warmed slightly during the addition and was stirred at room température overnight. The reaction was diluted with EtOAc and washed with saturated aqueous ammonium chloride. The aqueous layer was extracted three times with EtOAc. The organic layers were dried over anhydrous sodium sulfate, fiitered, and concentrated to give a yellow liquid, which was purified by flash chromatography (0-0,0-4,4-10% EtOAc/hexanes) to provide ethyl 4-(perfluoroethoxy)benzoate as a yellow liquid (4.58 g, 50%); ’H NMR (400 MHz, CDCI₃) δ 8.10 (d, J = 8.8 Hz, 2H). 7.28 (d, J = 8.7 Hz, 2H), 4.39 (q, J= 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H>; ”F NMR (376 MHz, CDCI₃) δ -86.05, -87.84; ESIMS m/z 284 ([M+H]*).

Example 48. Préparation of 4-(perfluoroethoxy)benzohydrazlde (B45)

To a solution of ethyl 4-(perfluoroethoxy)benzoate (4.58 g, 16.1 mmol) in EtOH (16 mL) was added hydrazine monohydrate (1.96 mL, 40.3 mmol) and the réaction was heated at 85 *C for 36 hours. The réaction was cooled and poured into ice water (100 mL). A white gel-solid formed and was fiitered through a Büchner funnel under vacuum. The solid was dried In a vacuum oven at 45 *C overnight to provide 4-(perfluoroethoxy)benzohydrazide as an off-white solid (3.177 g, 73%): mp 117-119.5 *C; ’H NMR (400 MHz, CDCl₃) δ 7.83-7.76 (m, 2H). 7.36 (s, 1 H). 7.31 (d, J= 8.8 Hz, 2H), 4.13 (s, 2H); ”F NMR (376 MHz, CDCI₃) δ -86.01, -87.83; ESIMS m/z 269 [(M-Hp).

Example 49. Préparation of 2-(4-(perfluoroethoxy)phenyl)-1_l3,4-oxadiazole (B46)

A mixture of 4-(perfluoroethoxy)benzohydrazide (3.17 g, 11.7 mmol) in trimethyl orthoformate (11.6 mL, 106 mmol) and acetlc add (0.13 mL, 2.35 mmol) was heated at 120 °C for 5 hours. The reaction was diluted with MeOH (15 mL) and poured into a beaker containing Ice water (150 mL). The white predpitate was vacuum fiitered and dried In a vacuum oven to provide 166 mg of 2-(4(perfluoroethoxy)phenyl)-1,3,4-oxadiazole as an off-white solid. An orange predpitate had formed In the aqueous filtrats and was collected by vacuum filtration and adsorbed onto silica gel.

Purification by flash chromatography (0 - 40% EtOAc/hexanes) provided 2.02 g of 2-(4-(perfluoroethoxy)pheny1)-1,3,4-oxadiazole as an off-whlte solid giving a combined yield of 2.188 g (87%): mp 87-89 ’C; ¹H NMR (400 MHz, CDCIj) δ 8.49 (s, 1H), 8.28-8.05 (m, 2H), 7.40 (d, J= 8.9 Hz, 2H); ”F NMR (378 MHz, CDQ₃) δ -85.98, -87.82; ESIMS m/z 280 ([M+H]*).

Example 50. Préparation of methyl 4-(5-(4-(perfluoroethoxy)pheny1)-1,3,4-oxadlazol-2yl)benzoate (B47)

A mixture of 2-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazoie (2.186 g, 7.80 mmol), methyl 4lodobenzoate (3.07 g, 11.70 mmol), copper(l) Iodide (0.28 g, 1.47 mmol), 1,10-phenanthroline (0.30 g, 1.87 mmol), and césium carbonate (2.54 g, 7.80 mmol) In anhydrous DMSO (20 mL) was heated at 100 ’C for 18 hours. The reaction was cooled, diluted with water, and extracted three times with EtOAc. The organic layers were dried over anhydrous sodium sulfate, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-50% EtOAc/hexanes) provided methyl 4-(5-(4(perfluorœthoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoate as a white solid (1.08 g, 33%); mp 185-191 ’C; ¹H NMR (400 MHz, CDCIj) δ 8.25 - 8.19 (m, 6H), 7.41 (t, J= 9.4 Hz, 2H), 3.98 (s, 3H); ^1#F NMR (378 MHz, CDCIj) δ -85.98, -85.98, -87.79; ESIMS m/z 415 ([M+H]*).

Example 51. Préparation of 4-{5-(4-(perfluoroethoxy)phenyl)-1₎3,4-oxadlazol-2-y1)benzolc acid (B48) ,o

OH

To methyl 4-(5-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoate (1.07 g, 2.58 mmol) was added MeOH (28 mL) (starting material remalned partlaliy Insoluble). A solution of 2 N NaOH (5.2 mL, 10.33 mmol) was added, and the reaction was stirred at room température for 18 h. Stirring had become hlndered ovemight due to the formation of solid. LC/MS showed 25% conversion to product. The reaction mixture was diluted with MeOH and additional 2 N NaOH (20 mL) was added and the reaction was heated to 45 ’C for 24 h. The reaction was cooled and neutraiized with 2 N

HCl (20 mL). Some of the MeOH was concentrated off in vacuo, causing the product to predpitate. The white predpitate was vacuum filtered and dried In a vacuum oven at 45 °C to provide 4-(5-(4(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoic add as a white solid (760 mg, 90% purity, 66%); mp 301-307 *C; Ή NMR (400 MHz, DMSO-d_e) δ 13.40 (s, 1H). 8.34 - 8.26 (m, 4H), 8.18 (d,

8.6 Hz, 2H), 7.68 (d, J= 8.8 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d_e) δ-85.25, -86.89; ESIMS m/z 401 ([M+H]*).

Example 52. Préparation of 4-(5-(4-(perfluoroethoxy)pheny1)-1,3,4-oxadiazol-2-y1)benzoy1 azide (B49)

To a solution of 4-(5-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yi)benzoic add (217 mg, 0.54 mmol) in Isopropanol (5.4 mL) was added triethylamine (0.09 mL, 0.65 mmol) and diphenyl phosphorazidate (0.13 mL, 0.60 mmol) and the reaction was stirred at room température for 16 hours. The white predpitate that had formed was filtered and dried in a vacuum oven to provide 4(5-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoyi azide as a white solid (145 mg, 63%); mp 140 *C (dec); ’H NMR (400 MHz, DMSO-d_e) δ 8.32 (m, 4H), 8.24 - 8.17 (m, 2H), 7.68 (d, J = 8.9 Hz, 2H); F NMR (376 MHz, DMSO-d_e) δ -85.25, -86.89; ESIMS m/z 426 ([M+H]*).

Example 53. Préparation of N-[[(2-lsopropyliphenyl)amlno]thloxomethy1]-Ar-((4-(5-{4(perfluoroethoxy)phenyl)-1,3,4-oxadIazoi-2-yi)phenyi))urea (Molécule A96)

A solution of 4-(5-(4-(perfluoroethoxy)phenyi)-1,3_t4-oxadiazol-2-yl)benzoyl azide (278 mg, 0.65 mmol) In DCE (3.3 mL) was heated at 80 ’C for 3 hrs. The reaction was cooled to room température and 1-(2-lsopropyiphenyl)thiourea (131 mg, 0.67 mmol) followed by césium carbonate (243 mg, 0.75 mmol) were added. The reaction mixture was stirred at room température for 18 hours. The reaction was diluted with EtOAc and transferred to a separatory funnel containing aqueous sodium bicarbonate. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over anhydrous sodium sulfate, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-20% EtOAc/B, where B = 1:1 dlchloromethane/hexanes) provided the title compound as a white powder (43 mg, 11%); mp 219 ’C (dec); ¹H NMR (400 MHz, DMSO-d_e) δ 11.61 (s, 1H), 10.25 (s, 1H), 9.71 (s, 1H), 8.30-8.22 (m, 2H), 8.14 (d, J = 8.8 Hz, 2H), 7.71 (d, J~

8.8 Hz, 2H), 7.66 (d, J- 8.7 Hz, 2H), 7.39 (dd, J- 10.3, 3.9 Hz, 2H), 7.27 (ddd, J= 13.5,10.6,6.1 Hz, 2H), 3.07 (heptet. J- 6.8 Hz, 1H), 1.20 (d, J= 6.9 Hz, 6H); «F NMR (376 MHz. DMSO-d_e) δ 85.25, -86.89; ESIMS m/z 590 ([M-H]').

Example 54. Préparation of (Z)-1-(3-(2-lsopropylphenyl)-4-oxothlazolldln-2-y1ldene)-3-(4-(5-(4(perf1uoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)phenyl)urea (Molécule A102)

To the thiobluret (135.5 mg, 0.23 mmol) and sodium acetate (80 mg, 0.98 mmol) In éthanol (3 mL) was added methyl 2-bromoacetate (0.05 mL, 0.49 mmol) and the reaction was heated at 65 ’C for 4 hours. The reaction was diluted with water, and the precipltate was filtered and dried In a vacuum oven. The material was purified by flash chromatography (0 - 20% EtOAc/B, where B = 1:1 dichloromethane/hexanes) to provide (Z)-1-(3-(2-isopropylphenyl)-4-oxothlazolidin-2-ylidene)-3-(4(5-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)phenyl)urea as a yellow solid (56 mg, 38%): mp 244-247 ’C; ¹H NMR (400 MHz, CDCI₃) δ 8.21 - 8.15 (m, 2H), 8.06 (d, J = 8.8 Hz. 2H), 7.68 (d. J =

8.8 Hz. 2H), 7.56-7.49 (m, 2H), 7.38 (m, 4H), 7.10 (d, J- 7.5 Hz, 1H), 4.01 (d, J~ 2.8 Hz, 2H), 2.77 - 2.66 (m, 1H), 1.22 (dd, J-6.8, 3.1 Hz, 6H); ¹⁹F NMR (376 MHz. CDCI₃) δ-85.96, -87.77; ESIMS m/z 632 ([M+H]*).

The following molécules were made In accordance with the procedures disclosed In Example 1, Stepl.

(E)-((N^,-(4-methoxyphenyl)carbamlmldoyl)thlo)methyl Isobutyrate hydrobromide (B50)

Mp 129-130 ’C; Ή NMR (DMSO-cf_e) δ 9.47 (s, NH), 7.23 (s, 2H), 7.07 (d, J - 8.9 Hz, 2H), 6.90 (d, J = 9.0 Hz, 1H), 5.76 (s, 2H), 3.79 (s, 3H), 3.74 (s, 1H), 2.65 (dd, J = 12.0, 5.1 Hz, 1H), 1.13 (d, J = 7.0 Hz, 6H); ESIMS m/z 283 ([M+H]*).

(E)-((N*-mesltylcarbamlmldoyl)thlo)methyl Isobutyrate hydrobromlde (B51)

Mp 189-191 ’C; ’H NMR (DMSO-cf_e) δ 11.26 (s, 1H), 9.82 (s, 1H), 8.96 (s, 1H), 7.06 (s, 2H), 5.85 (s, 2H), 2.73 - 2.54 (m, 1H), 2.29 (s, 3H), 2.11 (d, J= 18.4 Hz, 6H), 1.13 (d, J = 7.0 Hz, 6H); ESIMS m/z 295 ([M+H]*).

(E)4(V-(2,6-dlfJuorophenyl)carbamlmldoyl)thlo)methyl Isobutyrate hydrobromlde (B52)

’H NMR (400 MHz, CDO₃) δ 11.25 (s. 1H), 10.46 (s, 1H), 9.17 (s, 1H), 7.45 (s, 1H), 7.05 (t, J-8.1 15 Hz, 2H), 5.78 (s, 2H), 2.76-2.64 (m, 1H), 1.29-1.14 (m, 6H).

(E)-[(W-(o-tolyl)carbamlmldoyl)thlo)methyl Isobutyrate hydrobromlde (B53)

O —Ç H₂N HBr ’H NMR (DMSO-de) δ 11.50(s, 1H), 10.28 (s, 1H), 8.48 (s, 1H), 7.43-7.07 (m, 4H), 5.65 (s, 2H), 20 2.69 (s, 1 H), 2.37 (s, 3H), 1.22 (d, J = 7.0 Hz, 6H); ESIMS m/z 295 ([M+H]*).

(EH(N*-(2-ethylphenyl)carbamlmldoyl)thlo)methyl Isobutyrate hydrobromlde (B 54)

’H NMR (DMSO-d_e) δ 11.51 (s, 1H), 10.30 (s, 1H), 8.49 (s, 1H), 7.43 - 7.31 (m, 2H), 7.27 - 7.15 (m, 1H), 5.66 (s, 2H), 2.81 - 2.61 (m, 3H), 1.27 -1.21 (m, 9H); ESIMS m/z 295 ([M+H]*).

(E)-((N*-(2_t6-dlchloropheny1)carbamlmldoy1)thlo)methyl Isobutyrate hydrobromlde (B55)

’H NMR (400 MHz, CDCI₃) δ 11.48 (s, 1 H), 10.55 (s, 1H), 9.05 (s, 1H), 7.47 - 7.41 (m, 2H), 7.36 (dd, J= 9.2,6.9 Hz, 1H), 5.75 (s, 2H), 2.69 (m, 1 H). 1.25 -1.18 (m, 6H); ESIMS m/z 322 ([M+H]*).

(£)-((/7-(2-ethyl-6-methy1pheny1)carbamimldoy1)thlo)methyl Isobutyrate hydrobromlde (B56)

’H NMR (400 MHz, CDCI₃) δ 11.17 (s, 1H), 10.20 (s, 1H), 8.67 (s, 1H), 7.32 - 7.27 (m, 1 H), 7.1815 7.08 (m, 2H), 5.71 (s, 2H), 2.71-2.56 (m, 3H), 2.30 (s, 3H), 1.26-1.18 (m, 9H); ESIMS m/z 295 ([M+H]*).

(£)-((//-(2-(sec-butyl)phenyl)carbamlmldoyl)thlo)methyl Isobutyrate hydrobromlde (B57)

HBr ’H NMR (400 MHz, CDClj) 7.46 - 7.39 (m, 1H), 7.37 - 7.32 (m, 1 H), 7.23 (t, J ~ 7.1 Hz, 1H), 7.17 (d, J- 7.6 Hz, 1H), 5.64 (s, 2H), 2.92 (dd, J= 13.9,7.0 Hz, 1H), 2.68 (dt, 14.0,7.0 Hz, 1H), 1.70 -1.60 (m, 2H), 1.23 (t, J- 6.7 Hz, 9H), 0.84 (t, J - 7.4 Hz, 3H); ESIMS m/z 332 ([M+Na]*).

Example 55. Préparation of 1-(4-(perfluoropropyl)phenyl)-3-(p-tolyl)-1H-1,2,4-triazole (B58)

Heptafluoropropyl-1-lodopropane (3.14 g, 10.6 mmol), 1-lodo-4-bromobenzene (2.0 g, 7.07 mmol), and copper (powder: 1.123 g, 17.7 mmol) were combined in 16 mL of DMSO In a 20 mL microwave tube, and the solution was stirred and heated at 175 *C for 90 min. The cooled solution was then extracted with 2 X 30 mL of hexanes, and the combined organic layer was washed with water, dried and concentrated to give 2.0 grams of a yellow oil. This crude material, which conslsted of a mixture of 4-heptafluoropropy!-iodobenzene and 4-heptafluoropropy!-bromobenzene, was combined with 3-(p-tolyl)-1H-1,2,4-triazole (1.0 g, 6.28 mmol), césium carbonate (6.14 g, 18.9 mmol), Cul (0.12 g, 0.63 mmol), and quinolin-8-ol (0.091 g, 0.63 mmol) In 16 mL of 90:10 DMFwater, and the solution was heated to 125 *C for 8 hrs. The cooled solution was then poured onto 60 mL of a 2N aqueous NH«OH solution, and the resulting predpltate was filtered and alr-dried. This material was heated In 50 mL of MeOH, filtered, and the filtrate diluted with 30 mL of water. The resulting solid was Filtered and alr-dried to give 1-(4-(perfluoropropyl)pheny!)-3-(p-tolyl)-1H1,2,4-triazoie as a white solid (1.03 g, 39%): mp 140-143 °C; ’H NMR (400 MHz, CDClj) δ 8.66 (s, 1 H), 8.10 (d, J = 8.1Hz, 2H), 7.94 (d, J = 8.9 Hz, 2H), 7.76 (d, J- 8.5 Hz, 2H), 7.30 (dt, J= 8.0, 0.7 Hz, 2H), 2.43 (s, 3H); ESIMS m/z 405 ([M+H]*).

Example 56. Préparation of 4-(1-(4-(perfluoropropyt)phenyl)-1H-1,2,4-trlazol-3-yt)benzolc acid (B59)

A solution of the toiyl triazoie (1.0 g, 2.48 mmol) In 6 mL of AcOH was heated to 60 °C, and ceric ammonium nitrate (4.50 g, 8.21 mmoi) in 3 mL of water was added over 10 minutes. Heating was continued for 1 hr, then the solution was cooled and diluted with 30 mL of water. The liquid was decanted from a light yellow gummy solid which formed over 30 min. This residue was then combined with 10 mL of dloxane and 3 mL of 50% aqueous KOH, and heated at 75-80 °C for 2 hrs. The solution was cooled and diluted with 20 mL of water. The resulting solid was filtered and then re-dissolved In 15 mL of acetonitrile, and sodium bromate (1.12 g, 7.44 mmol) and sodium bisulfite (0.298 g, 2.48 mmol) were added. The solution was heated at reflux for 2 hr, then cooled and diluted with 10 mL of water. A white precipitate formed, which was filtered and air-dried to give 4-(1(4-(perfIuoropropyl)phenyl)-1H-1,2,4-triazol-3-yl)benzoic add as a white powder (472 mg, 41 %): mp 225 *C; ’H NMR (400 MHz, DMSO-d_e) δ 9.60 (s, 1H), 8.29 - 8.20 (m, 4H), 8.13 - 8.06 (m, 2H), 7.96 (d, J= 8.7 Hz, 2H); ESIMS m/z 434 ([M+H]*).

Example 57. Préparation of 4-(1-(4-(perfluoropropy1)pheny1)-1H-1_l2,4-trlazol-3-yl)benzoy1 azlde (B60)

4-(1-(4-(Perfluoropropyl)phenyl)-1H-1,2,4-triazol-3-yl)benzolc add (400 mg, 0.92 mmol) was dissolved In 7 mL of Isopropanol and treated with dlphenylphosphoryl azlde (0.300 g, 1.09 mmol) and triethylamlne (0.200 g, 2,0 mmol). The solution was allowed to stirfor6 h, then It was cooled to 0 *C and the resulting sdid was filtered, washed with a minimum amount of Ÿ’rOH, and dried under high vacuum to give the azlde as an off-whlte solid (0.120 g, 30%). This solid was not further characterized, but used directly in the subséquent Curtius rearrangement to préparé molécule A113, using conditions described In Example 39.

Example 58. Préparation of (Z)-1-(3-mesltyl-4-methylthlazol-2(3W)-ylldene)-3-(4-(1-(4(tri fluoromethoxy)phenyl)-1H-1,2,4-trlazol-3-yi)phenyl)urea (Molécule A43)

To free thiobluret (100 mg, 0.185 mmol) In 3 mL of butanone was added triethylamlne (0.052 mL, 0.370 mmol) followed by chloroacetone (0.021 mL, 0.259 mmol). The solution was heated at reflux 61 for 20 hrs, then It was cooled, diluted with 20 mL of CH₂CI₂, washed with water (10 ml), dried and concentrated In vacuo. Chromatography (silica, 0-100% EtOAc-hexanes) fumished the desired product as a viscous yellow oll (0.92 g, 84%); ’H NMR (400 MHz, CDCI₃) δ 8.55 (s, 1H), 8.17 (d, J = 8.7 Hz, 2H), 7.85 - 7.68 (m, 5H), 7.37 (d, J = 8.3 Hz, 2H), 7.02 (s, 2H), 6.35 (d, J = 0.9 Hz, 1H),

2.43 (s, 3H), 2.34 (s, 3H), 2.17 (s, 6H); ”F NMR (376 MHz, CDCI₃) □ -58.01 (s); ESIMS m/z 579 ([M+H]*).

Molécule A42 In Table 1 was made In accordance with the procedures disclosed In Example 58.

Example 59. Préparation of 3-bromo-1-(4-(trlfluoromethoxy)pheny1)-1H-1,2,4-trlazole (B61)

To a 250 mL reaction flask was added 3-bromo-1H-1,2,4-triazole (5 g, 33.8 mmol), copper(l) lodide (0.644 g, 3.38 mmol) and césium carbonate (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with N₂, then DMSO (33.8 ml) and 1-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100 ’C for 20 h. The reaction was cooled to room température, diluted with EtOAc and filtered through a plug of Celite. The Celite was further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash chromatography (silica/EtOAc/Hex) yielded 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole as an off white solid (3.78 g, 12.27 mmol, 72.6%): mp 69-70 *C; ’H NMR (400 MHz, CDCI₃) δ 8.44 (s, 1H), 7.70 (d, J- 8.9 Hz, 2H), 7.38 (d, J= 8.5 Hz, 2H); ”F NMR (376 MHz, CDCI₃) δ-58.04; EIMS m/z307.

Example 60. Préparation of methyl 2-methyl-4-(1-(4-(trlfluoromethoxy)phenyl)-1H-1_l2_l4trlazol-3-yl) benzoate (B62)

To 3-bromo-1-(4-(trinuoromethoxy)phenyl)-1H-1,2,4-triazole (0.496 g, 1.609 mmol), methyl 2methyl-4-{4,4,5,5-tetramethyl-1,3,2-dioxaborDlan-2-yl)benzoate (0.466 g, 1.689 mmol), sodium bicarbonate (0.405 g, 4.83 mmol) and tetrakls(triphenylphosphlne)palladium (0.186 g, 0.161 mmol) In a 2.0 mL microwave vlal was added dioxane (6 mL) and water (1.5 mL). The reaction was capped and placed on a Biotage® Initiator microwave reactorfor 30 min at 140 °C. The reaction mixture was then diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO₄, filtered and concentrated. Purification by flash column chromatography provided the title compound as a white solid (0.376 g, 0.997 mmol, 62%): Ή NMR (400 MHz, CDCI₃) δ 8.59 (s, 1H), 8.10 (dt, J- 1.6, 0.7 Hz, 1H), 8.098.00 (m, 2H), 7.84 - 7.78 (m, 2H), 7.44 - 7.37 (m, 2H), 3.93 (s, 3H), 2.70 (s, 3H); ¹⁰F NMR (376 MHz, CDCI₃) δ -58.02; ESIMS m/z 378 ([M+H]*).

Example 61. Préparation of 2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1W-1,2,4-tr1azol-3yl)benzolc acid (B63)

OH

To two batches of methyl 2-methyl-4-(1-(4-(trifluorDmethoxy)phenyl)-1H-1₍2,4-triazol-3-yl)benzoate (0.452 g, 1.198 mmol) in a 250 mL round-bottomed flask equipped with a stir bar was added MeOH (12 ml), THF (12 ml) and 2N sodium hydroxide (5.99 ml, 11.98 mmoi). The reaction was stirred ovemight The reaction mixture was diluted with water and addified with 1N HCl. The solid was extracted with EtOAc (3x). The organic layer was dried over MgSO₄, filtered and concentrated provlding the title compound as a yellow solid (0.412 g, 1.134 mmol, 95%): ’H NMR (300 MHz, DMSO-d_e) δ 12.94 (s, 1H), 9.43 (s, 1H), 8.14 - 8.03 (m, 2H), 8.03 - 7.89 (m, 3H). 7.61 (d, J = 8.7 Hz, 2H), 2.60 (s, 3H); ”F NMR (376 MHz, DMSO-d_e) δ -56.95; ESIMS m/z 364 ([M+H]*).

Exemple 62. Préparation of 2-methy!-4-(1-(4-(trifluoromethoxy)phenyl)-1W-1,2,4-tr1azol-3yljbenzoyl azlde (B64)

To 2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2.4-triazo!-3-yl)benzoic add (0.412 g, 1.134 mmol) ln a 100 mL round-bottomed flask equipped with a stlr bar under N₂ was added Isopropyl alcohol (11 mL), triethylamine (0.205 ml, 1.474 mmol) and dlphenyl phosphorazldate (0.319 ml, 1.474 mmol). The reaction was stirred at room température ovemight. The résultant solid was filtered, washed with Isopropyl alcohol followed by hexanes and dried under vacuum provldlng the title compound as a white solid (0.294 g, 0.757 mmol, 67%): ¹H NMR (300 MHz, CDC!3) δ 8.60 (s, 1 H), 8.13 (s, 1H), 8.11 - 8.02 (m, 2H), 7.84 - 7.77 (m, 2H), 7.40 (d, J = 8.6 Hz, 2H), 2.74 (s, 3H); ¹⁹F NMR (376 MHz, CDCI3) δ -58.02; ESIMS m/z 389 ([M+H]*).

Example 63. Préparation ofA/-[[(2-lsopropyllphenyl)amlno]thloxomethyl]-A/'-(2-methyl(4-(1-(4(trlfluoromethoxy)phenyl)-1H-1,2,4-trlazol-3-y1)phenyl))urea (Molécule A122)

To2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoyl azide (0.294 g, 0.757 mmol) ln a 25 mL vlal equipped with a stir bar and a Vigreux column was added 1,2-dichloroethane (4 ml). The reaction was heated to 80 *C. Following Isocyanate formation the reaction was cooled to room température. To the reaction was added 1-(2-isopropylphenyl)thlourea (0.162 g, 0.833 mmol) and césium carbonate (0.271 g, 0.833 mmol). The reaction was stirred ovemight. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSOi, filtered and concentrated. Purification by flash column chromatography provided the title compound as a white solid (0.243 g, 0.438 mmol, 58%): ’H NMR (400 MHz, DMSO-dj) δ 11.74 (s, 1H), 10.71 (s, 1H). 9.39 (s, 1H), 8.83 (s, 1H), 8.13-8.04 (m, 2H), 8.04-7.88 (m, 3H), 7.68-7.56 (m, 2H), 7.47 - 7.35 (m, 2H), 7.35 - 7.27 (m, 1 H), 7.27 - 7.21 (m, 1 H), 3.06 (hept, J = 6.8 Hz, 1 H), 2.37 (s, 3H), 1.19 (d, J= 6.8 Hz, 6H); ^WF NMR (376 MHz, DMSO-d_e) δ -56.97; ESIMS m/z 555 ([M+H]*).

Example 64. Préparation of (Z)-1-(3-(2-lsopropylphenyl)-4-oxothlazolldln-2-ylldene)-3-(2methy!-4-(1-(4-(trlfluoromethoxy)phenyl)-1 H-1,2,4-trlazol-3-y1)phenyl)urea (Molécule A123)

To N-[[(2-isopropy1lphenyl)amino]thloxomethyl]-N’-(2-methy1(4-(1-(4-{trifluoromethoxy)phen-yl)-1 Η~ 1,2,4-triazol-3-yl)pheny1))urea (0.193 g, 0.348 mmol) In a 25 mL vial equlpped with a stir bar and Vigreux column was added sodium acetate (0.114 g, 1.392 mmol), EtOH (4 ml) and methyl 2bromoacetate (0.068 ml, 0.696 mmol). The reaction was stirred at 60 ’C ovemlght. The reaction was cooled and the solid was filtered, washed with EtOH, followed by diethyl ether and dried under vacuum providing the title compound as a white solid (0.124 g, 0.209 mmol, 60%): ¹H NMR (400 MHz, CDCI₃) δ 8.53 (s, 1 H), 8.18 (d, J= 8.6 Hz, 1H), 8.06 - 8.01 (m, 1H), 7.98 (s, 1H), 7.82 - 7.76 (m, 2H), 7.53 - 7.48 (m, 2H), 7.41 - 7.34 (m, 3H), 7.13 - 7.06 (m, 2H), 3.99 (s, 2H), 2.73 (hept, J = 6.8 Hz, 1H), 2.25 (s, 3H), 1.27-1.22 (m, 6H); ”F NMR (376 MHz, CDCI₃) δ -58.03; ESIMS m/z 595 ([M+H]*).

Example 65. Préparation of N-((1H-benzo[d][1,2,3]trlazol-1-yl)methyl)-4-(1-(4(trlfluoromethoxy)phenyl)-1H-1,2,4-trlazol-3-yl)anlllne (B65)

To a 100 mL flask was added benzotriazole (2.083 g, 17.5 mmol) and 4-(1-(4(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-y1)anlline (5.6 g, 17.5 mmol), and the solids were melted with a heat gun. EtOH (26 mL) was qulckly added and the mixture was stirred while formaldéhyde (1.3 mL of a 37% aqueous solution, 47.2 mmol) was added via syringe. The solution was allowed to stir at amblent température for 30 min, then It was warmed to 40 °C for another 30 min, then allowed to cool to amblent température before collectlng the solid product by vacuum filtration. After washlng the solid with EtOH and hexanes, there was obtained crude N-((1H-benzo[d][1,2,3]triazol1-yl)methyl)-4-(1-(4-{trifluoromethoxy)pheny1)-1H^L1,2,4-triazol-3-y1)aniline_l which was used diredly without further purification (3.79 g, 49%): Ή NMR (400 MHz, CDCI₃) δ 8.49 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.02 (d, J= 8.7 Hz, 2H),7.76 (d, J= 9.0 Hz, 2H), 7.64 (d. J= 8.3 Hz. 1 H). 7.48 (ddd. J = 8.3,7.0,1.0 Hz, 1 H), 7.40 - 7.33 (m, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.15 (d, J = 7.2 Hz, 2H), 5.07 (t, J =7.1 Hz, 1H).

Example 66. Préparation of N-methy1-4-(1-{4-(trlfluoromethyl)pheny1)-1H-1,2₍4-trlazol-3yl)anillne (B66)

To a solution of N-((1H-benzo[d][1,2,3]tιiazol-1-yl)methyl)-4-(1-(4-(trifluoromethoxy)phenyl)-1H1,2_>4-triazol-3-yl)anilinθ (3.78 g, 8.37 mmol) In THF (25 mL) was added sodium borohydride (0.475 g, 12.56 mmol), slowly with stirring under N₂. The solution was allowed to stir at ambient température for 1 h, then It was heated to reflux for 3.5 h. After cooling to ambient température, the solution was poured onto water (25 mL) and extracted with 50 mL of ether (2x). Drylng and concentration of the organic layer fumished N-methyl-4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2_l4triazol-3-yl)aniline as an orange solid (2.49 g, 86%): mp 106-113 ’C; ESIMS m/z 335 ([M+H]*).

Example 67. Préparation of W-(methyl(4-(1-(4-(trlfluoromethoxy)phenyl)-1H-1,2,4-trlazol-3y1)phenyl)carbamothioyl)benzamlde (B67)

To a solution of of N-methyl-4-(1-(4-(trifluoromethyl)phenyl)-1H-1_l2,4-triazol-3-yl)anlline (2.0 g, 5.98 mmol) In acetone was added benzoyl Isothlocyanate (0.847 g, 6.28 mmol) via syringe, and the solution was heated at 50 *C for 8 h, Jhen the solution was cooled and concentrated ln vacuo to give N-(methyl(4-(1 -(4-(trifluoromethoxy)phenyl)-1 H-1,2,4-triazol-3yl)phenyl)carbamothloyl)benzamlde as a yellow solid (2.9 g, 96%); mp 166-169 ’C; ’H NMR (400 MHz, CDCI₃) δ 8.53 (s, 1H), 8.36 (s, 1H), 8.20 (d. J- 8.6 Hz, 2H), 7.76 (d, J - 9.0 Hz, 2H). 7.60 (d, J-7.5 Hz, 1H), 7.52 - 7.42 (m. 4H), 7.38 (dt, J = 8.0,1.0 Hz, 2H), 3.82 (s, 3H); ESIMS m/z 497 ([M+H]*).

Exemple 68. Préparation of 1-methyl-1-(4-(1-{4-(trifluoromethoxy)phenyi)-1H-1,2,4-triazoi-3yi)phenyl)thiourea (B68)

To a 100 mL round bottom flask containing MeOH (23 mL) was added W-(methyi(4-(1-(4(trifluoromethoxyJphenyiï-IH-I^Atriazol-S-ylJphenyiJcarbamothioyiJbenzamide (2.8 g, 5.63 mmol) and sodium hydroxide (5.6 mL of a 2 N solution, 11.3 mmol), and the solution was heated at 65 *C for 3.5 hours. Another 20 mL (40 mmol) of 2N NaOH was then added and heating was continued for 6 hours. Upon cooling the solution was neutralized by addition of 2N HCl, and the resulting yeliow solid was collected by vacuum filtration to give 1-methyl-1 -(4-(1 -(4-{trifluoromethoxy)phenyi)1H-1,2,4-triazol-3-yl)phenyi)thiourea as a yeliow solid (1.073 g, 47%): mp 142-152 ’C; ’H NMR (400 MHz, CDCIj) δ 8.59 (s, 1H), 8.36 - 8.24 (m, 2H), 7.81 (d, J= 9.0 Hz, 2H), 7.46-7.33 (m, 4H), 5.62 (s. 2H), 3.73 (s. 3H); ESIMS m/z 393 ([M+H]*).

Example 69. Préparation of 2-(methyl(4-(1-(4-(trlfluoromethoxy)phenyl)-1H-1,2,4-triazol-3yl)phenyl)amlno)thlazole-4,5-dlone (B69)

To a flask containing EtOAc (30 mL) was added 1-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H· 1,2,4-triazol-3-yl)phenyl)thiourea (0.600 g, 1.52 mmol) and triethylamine (510 DI, 3.66 mmol). A solution of oxaiyl chioride (467 mL, 5.34 mmol) In EtOAc (24 mL) was added and the solution was stirred at ambient température for 15 min. Evaporation of solvent in vacuo left a white-yellow solid which was dissolved in 50 mL of dichloromethane and washed with water (3 X 25 mL). The organic layer was dried (MgSO<) and concentrated to fumish 2-(methyl(4-(1-(4-(trifluoromethoxy)phenyl)1H-1,2,4-triazo!-3-yl)phenyl)amlno)thlazole-4,5-dione as an orange solid (632 mg, 92%): mp 114118 *C; ’H NMR (400 MHz, CDCIj) δ 8.62 (s, 1H), 8.36 (d, J =8.7 Hz, 2H), 7.82 (d, J = 9.1 Hz, 2H), 7.50 - 7.34 (m, 4H), 3.82 (s, 3H); ESIMS m/z 448 ([M+H]*).

Example 70. Préparation N-[[(2-lsopropy1lphenyl)amlno]thloxomethy1]-N-methy1-N’-(4-(1-(4(trifluoromethoxy)phenyl)-1H-1,2,4-triazo1-3-yl)pheny1))urea (A124)

A solution of 2-(methyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3yl)phenyl)amlno)thlazole-4,5-dione (615 mg, 1.33 mmol) in toluene (16 mL) was heated to 100 *C for 25 min, then cooled to 0 *C and 2-isopropylaniline (0.212 mL, 1.51 mmol) in acetone (4 mL) was added under N₂. After 2 h, the solution was allowed to warm to amblent température and then concentrated. Purification by flash column chromatography (EtOAc-hexanes) fumlshed Ν-Π(2isopropyllphenyl)amlno]thloxomethyl]-Ar-methyl-//-(4-(1 -(4-(trifluoromethoxy)phenyl)-1 H-1,2,4triazol-3-yl)phenyl))urea as a light orange oil (300 mg, 40%); ’H NMR (400 MHz, CDCI₃) δ 12.03 (s, 1 H), 8.60 (s, 1H), 8.36 (d, J =8.7 Hz, 1 H), 7.89 (s, 1 H), 7.81 (d,J=9.1 Hz, 1 H), 7.52-7.48 (m, 1H), 7.46 (d, J= 8.7 Hz, 1 H), 7.41 (dt, J= 7.9,1.0 Hz, 2H), 7.36 (dd, J= 7.8,1.7 Hz, 1H), 7.30 (td, J =7.5,1.5 Hz, 1 H), 7.25-7.20 (m, 1H), 3.40 (s, 3H), 1.27 (d, J= 6.9 Hz, 6H); ESIMS m/z 555 ([M+Hf).

Example 71. Préparation (Z)-3-(3-(2-lsopropylpheny1)-4-oxothlazolldln-2-ylldene)-1-methy1-1(4-(1-(4-(trifluoromethoxy)pheny1)-1H-1,2,4-triazol-3-y1)pheny1)urea (A125)

Conditions described In Example 14 were used to convert A/-[[(2lsopropyllphenyl)amlno]thloxomethyl]-N-methyl-Ar-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4triazol-3-yl)phenyl))urea Into (Z)-3-(3-(2-lsopropylphenyl)-4-oxothlazolldin-2-ylïdene)-1 -methyl-1-(4(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)urea, which was lsolated as a yellow oil (19 mg, 34%): δ ’H NMR (400 MHz, CDCI₃) δ 8.58 (s, 1H), 8.17 (s, 1H), 7.83 (d, J= 8.9 Hz, 2H), 68

7.73 (d, J= 8.1 Hz, 2H), 7.42 (d, J- 8.8 Hz, 3H), 7.22 (d, J- 7.6 Hz, 1H), 7.17-7.07 (m, 1H), 6.85 (dd, J- 28.9, 8.0 Hz, 2H), 3.95 (d, 2.5 Hz, 3H), 3.37 (s, 2H), 2.50 (d, 7.1 Hz, 1H), 1.05 (d, J = 6.9 Hz, 3H), 0.79 (d, J - 6.8 Hz, 3H); ESIMS m/z 595 ([M+H]*).

Table 1: Structures for Compounds

No.	Structure
A1	A.
A2	__ zx ⁰ G
A3
A4

A11
A12
A13
A14	'Ά-,ον*
A15	^sxZ

A16	;<©τνΟ·“ί·“Ρ Ύτ
A17	Ύτ
A18	><^οΌ·^_ΓοΎ^Ν^ο^
A19	^^Ν=^/
A20	HS Η ΐ Fjccr^ °

A21	_FJcoO ^N^hi 0
A22	f=N 0 ^HS _L . ,χτ’’^ΛΟτΥτ5
A23	n ^HSv ^H 1 rVzx V^VS i^Y’srw-'™ -AJ FjCO^^
A24	s^yo ,,^^ο
A25	r* 0 ^HL V f₃co^> ^^''h cn

A26	ο V 1 \|<^^NN^?\₌-/'^nh CN FjCtr^
A27	HS « FjCO'^^
A28	HS h I r^yN'NX-:/ ^NH CnX^ f₃co'^⁵^
A29	rN o ^HS\ i /^S-N K/^nhI F.CO'CX ^N W'tPcN 0
A30	ry^N N^fY_N>-c^NHA FjCoA>> CN IJ

A31	/=N O FjCO^tA CN
A32	r. o ^houB / f,coXX 'AîJO
A33	r^N _v o ^H0\ H /
A34	/=N o ^H9 H ^OMc
A35	..Xr^A O-

A61	0 / F ^HNkU
A62	W HN O OMe
A63	ΗίοΌ'^Ν'^Ν ^>^0~[;Λ=<^5Η?
A64	F₁CoO”^N'^N''ⁱ^^j\|X_w,^!!H Q Ό
A65	^iHa

A66
A67	F₁C0-O'^N'N^<UO'_tj'<_N=(;^EH V X
A68	Xk
A69	S^Y° >^CH3 ΥΉ yrvÇ * ^yw>T v u_N ^z \=/
A70	y
A71	XT

A72
A73	ΎΧ
A74	0¾
A75	^;/°Ο „ 0¾^ ^γνζγΛ kJ ^=⁷
A76	F 0 ^CHa ’W/ï) Sj ^=⁷ _Ci

A77
A78	F_Jco-O''^N<kO-_t\|X_N=<F^H α ù.
A79	f.co-0'^^<>'0'[\|Ah^PH I ⁿv^f
A80
A81

A82	^Η HaC^CHj
A83	H_aC _ F _ /=^N. _ η rîl ^H HjC^CH,
A84	^H HjC^Hj
A85	^H α—ΛΛ
A86	F?

A87	HjC
A88	ο CHj
A89	ÇHj
A92	Ύχι viys Αη>” η,
A93	^fV°t1 ypÆ ^q-O-^nV

A94	YVi vPÇ-S
A95	^{F N} O
A96	^H H₃C^CH₃
A97
A98	HS CJ

^CHÛ^ N-f o oA/^S	εοι-ν
uif¹ '	20IV
	10IV
<hA	00IV
	66V

A104	P /γ0^-ο^^~0-^<!Η· Η.Γ
A105	r^N\_^=\ W~V<O p ^'>r\J-^m (j
A106	^h HjC^CHj
A107	^H h₃c'x:h₃
A108	^H cv O/'CHj

A109
A110	M 9\ A~N pHj rA/=\ Sh _F O £>k₀XJ >>-CH>
A111	» - v^'G³'⁰· F r-YQ~O-^{NM N} Q p>U0A^J _α
A112
A113	F ^H H,C CH,

	9HV
	ZI4V
	91IV
^CH3-/ H-f Λ 'ΗΟΟ^φχδ	SHV
	niv

	εει-ν
	ZZIV
	IZLV
^j‘‘t‘O^f-Cr’ti	oztv
	6UV

A124
A125

Table 2: Analytlcal Data for Compounds In Table 1.

No.	Appearanc e	Mp (’C)	ESIMS m/z	’H NMR (□)’	”C NMR or”F NMR(û)
A1		160- 164	627 (M+H)	11.24 (S.1H), 8.64 (s, 1H), 8.17 (d, J = 8.7 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.67 (d, J =8.7 Hz, 2H), 7.41 (s, 1H), 7.12 (d, J = 8.6 Hz, 1H), 8.79 (d, J = 2.8 Hz, 1H), 6.74 (dd, J = 8.4,3.1 Hz, 1H), 5.65 (s, 2H), 3.82 (s, 3H), 2.59 (heptet, J = 7.0 Hz, 1H), 2.27 (s, 3H), 1.18 (d, J =7.0 Hz, 6H)

A2		172- 175	541 (M+1)	11.34 (s, 1 H), 10.29 (s, 1H), 8.32 (s, 1 H), 7.09 (d, 7 =8.7 11.29 (s, 1H), 8.64 (s,1H), 8.17 (d, 7 = 8.7 Hz, 2H), 7.92 (d, 7 =8.5 Hz, 2H), 7.80 (d,7 = 8.5 Hz, 2H), 7.66 (d, 7 = 8.7 Hz, 2H), 7.33 (s, 1 H), 7.16 (d, 7= 8.6 Hz, 1H), 6.80 (d, 7 = 2.9 Hz, 1H), 6.75 (dd, 7 = 8.6,2.8 Hz, 1 H), 3.82 (s, 3H), 2.38 (s, 3H). 2.30 (s, 3H)
A3		173- 176	611 (M+H)	11.21 (s, 1H), 8.65 (s, 1H), 8.18 (d, 7= 8.7 Hz, 2H). 7.92 (d, 7“ 8.4 Hz, 2H), 7.80 (d, 7 = 8.5 Hz, 2H), 7.68 (d, 7 = 8.7 Hz, 2H), 7.20 (m,1H), 7.14-7.04 (m, 2H), 5.65 (s, 2H), 2.59 (heptet, 7= 7.0 Hz, 1H), 2.29 (s, 6H), 1.18 (d, 7 = 7.0 Hz, 6H)

A4		148- 151	627 (M+1)	11.21 (s. IH). 8.55 (s, 1 H), 8.17 (d, J = 8.7 Hz, 2H), 7.81 (d, J- 8.7 Hz, 2H),7.67(d, J = 8.7 Hz, 2H), 7.42 (br s, 1H), 7.39 (d, J =8.7 Hz, 2H), 7.21-7.10 (m, 3H), 5.65 (s, 2H), 2.67 -2.52(m, 1H), 2.29 (s, 6H), 1.18 (d, J= 7.0 Hz, 6H)
A5		141- 143	640	11.54 (s, 1H), 8.55 (d, J = 3.7 Hz, 1 H), 8.16 (d, J =8.6 Hz, 2H), 7.80 (d, J =9,1 Hz, 2H), 7.67 (d, J =8.6 Hz, 2H), 7.46-7.32 (m,5H), 7.23-7.16 (m, 2H), 5.67 (s, 2H), 3.25-3.10 (m, 1 H), 2.65-2.52 (m,1H), 1.24 (d, J =6.9 Hz, 6H), 1.17 (d, J= 7.0 Hz, 6H)

A6		154- 156	691 (M+1)	11.54 (s, 1 H), 8.56 (d, J =3.7 Hz, 1 H), 8.17 (d, J =8.7 Hz, 1H), 7.81 (d, J = 9.1 Hz, 1 H), 7.67 (d, J =8.7 Hz, 1 H). 7.46 - 7.33 (m, 3H), 7.24-7.19 (m, 1H), 5.67 (s, 2H), 3.29-3.08 (m, 1H), 2.66-2.50 (m,1H), 1.24 (d, J =6.9 Hz, 3H), 1.17 (d, J =7.0 Hz, 3H)
A7		148- 151	657 (M+1)	11.03 (s,1H), 8.55 (s, 1H), 8.16 (d,J= 8.7 Hz, 2H), 7.80 (d, J = 9.1 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.39 (m, 3H), 6.64 (s, 2H), 5.64 (s, 2H), 3.80 (s, 3H), 2.59 (heptet, J =7.0 Hz, 1H), 2.25 (s, 6H), 1.17 (d, J = 7.0 Hz, 6H)

A8		142- 148	732 (M+1)	11.26 (s, 1H), 8.64 (s, 1H), 8.16 (d, J =8.4 Hz. 2H), 7.91 (d. J- 8.2 Hz, 2H), 7.79 (d, J - 8.5 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.54 (s, 1H), 7.34 (m„ 5H), 7.15 (m, 3H), 5.69 (s, 2H), 5.23 (s, 1H), 5.13 (s, 2H), 4.02 (d, J =5.7 Hz. 2H), 2.29 (s, 6H)
A9		142- 148	778.5 (M+1)	11.07 (s, 1H), 8.55 (s. 1H), 8.15 (d. J =8.5 Hz, 2H),7.80(d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 3.1 Hz, 1H), 7.447.31 (m, 7H), 6.64 (s, 2H), 5.67 (s, 2H), 5.23 (s.1H), 5.12 (s. 2H), 4.02 (d, J =5.8 Hz, 2H), 3.80 (s, 3H), 2.21 (s, 6H)

A10		128- 132	777 (M+1)	11.19 (s, 1H). 8.56 (s, 1H), 8.15 (d, J =8.4 Hz, 2H), 7.80 (J = 8.4Hz, 2H), 7.66 (d, J= 8.5 Hz, 2H). 7.38 (d, J = 8.3 Hz, 2H), 7.14 (d, J =8.6 Hz, 1H), 6.826.69 (m, 3H). 5.69 (s, 1H), 4.46 (d, J= 13.9 Hz, 1H), 4.05 (d, J = 13.9 Hz, 1H), 3.91 (dd, J =9.3, 6.2 Hz, 1H), 3.81 (s, 3H). 3.67 (dd, J = 3.2,1,5 Hz, 1 H), 3.56 (s, 3H), 3.46 s, 3H), 3.44 (s, 3H), 3.38 (dd, J =9.3,3.3 Hz, 1H), 3.21 (t. J =9.3 Hz, 1H). 2.29 (s, 3H), 1.32 (d, J =6.1 Hz. 3H)
A11		233- 235	527 (M+H)	8.54 (s, 1 H), 8.12 (d, J = 8.7 Hz, 2H), 7.79 (d, J =9.1 Hz, 2H), 7.62 (d, J =8.8 Hz, 2H), 7.44 - 7.29 (m,4H), 7.22 (d, J =7.5 Hz, 2H), 4.01 (s, 2H), 2.17 (s, 6H)

A12	204- 212	511 (M+H)	11.30 (s, 1 H), 10.20 (s, 1H), 9.52 (s, 1H), 9.51 (s, 1H), 8.19 (d. J =8.4 Hz, 2H), 8.11 (d,J = 8.7 Hz, 2H), 7.99 (d, J = 8.6 Hz, 2H), 7.62 (d, J =8.8 Hz, 2H), 7.13 (m, 3H), 2.20 (s, 6H)
A13	300 (dec)	525 (M+H)	(DMSO-d_e) δ 9.86 (s, 1H), 9.57 (s, 1H), 9.37 (d, J = 13.8 Hz, 2H), 8.15-7.98 (m, 4H), 7.74 (dd, J = 7.9,1.5 Hz, 1H), 7.67-7.53 (m, 4H), 7.33 (dd,J = 7.5,1.8 Hz, 1 H), 7.247.06 (m, 2H), 3.202.99 (m, 1 H), 1.22 (d,J = 6.8 Hz, 6H)
A14	190- 196	567 (M+H)	8.54 (s, 1 H), 8.12 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 9.1 Hz, 2H), 7.62 (d, J =8.8 Hz, 2H), 7.44 - 7.29 (m, 4H), 7.22 (d, J = 7.5 Hz, 2H), 4.01 (s, 2H), 2.17 (s, 6H)

A15	145- 150	553 (M+H)	8.51 (s, 1H), 8.07 (d, J = 7.9 Hz, 2H), 7.81 - 7.74 (m, 2H), 7.59 (d, J = 6.8 Hz, 2H), 7.36 (d, J =8.3 Hz, 2H), 7.19 (m, 3H), 7.12 (s, 1 H). 3.81 (t, J = 7.7 Hz, 2H), 3.37 (t, J =7.6 Hz, 2H), 2.23 (s, 6H)
A16	121- 125	567 (M+H)	12.81 (s, 1H), 8.54 (s, 1H), 8.16-8.09 (m, 2H), 7.79 (d, J = 9.2 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.186.96 (m, 3H), 4.22- 4.09 (m, 2H), 3.00 (t, J = 6.9 Hz, 2H), 2.25- 2,13 (m, 8H)
A17	105- 115	567 (M+H)	8.52 (s, 1H), 8.07 (d, J = 8.3 Hz. 2H), 7.837.73 (m, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.37 (d, J =8.3 Hz, 2H), 7.20 (m, 4H), 4.24 (dd,J = 14.5, 6.6 Hz, 1H), 3.58 -3.41 (m, 4H), 3.02 (dd, J= 11.0, 8.6 Hz, 1H), 2.25 (s, 3H), 2.21 (s, 3H), 1.21 (d,J=6.4 Hz, 3H)

A18		169- 177	594 (M+H)	8.53 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.81 7.74 (m, 2H), 7.63- 7.56 (m, 2H), 7.52 (m, 1H), 7.45 (d, J =7.9 Hz, 1H), 7.41-7.32 (m, 3H), 7.28 (s, 1 H), 7.11 (d. J =7.9 Hz,1 H), 4.03 - 3.95 (m, 2H), 2.43 (dd, J =13.5,6.8 Hz, 1H), 1.73-1.56 (m, 2H), 1.20 (overiapping d, J = 7.6 Hz, 3H), 0.78 (overiapping t, J = 7.4 Hz, 3H)
A19		180- 183	581 (M+H)	8.53 (s, 1 H), 8.12 (d, J = 8.7 Hz. 2H). 7.807.74 (m, 2H), 7.60 (d. J = 8.8 Hz. 2HJ.7.547.45 (m. 2H). 7.407.34 (m, 3H), 7.32 (s, 1H). 7.10 (d, J = 7.5 Hz. 1H), 3.98 (d. J = 2.5 Hz, 2H), 2.73 (heptet, J = 6.9 Hz, 1H), 1.22 (dd, J =6.8, 5.0 Hz. 6H)

100

Α20	141- 144	582 (M+H)	15.35-14.58 (m, 1H), 10.93 (s, 1H), 8.57 (m, 3H), 8.31-8.11 (m. 6H), 7.71 (m, 12H), 7.56 - 7.30 (m, 15H). 5.35 (s,1H), 3.02 (heptet, J - 6.9 Hz. 1 H), 2.52 (s, 3H). 1.35 -1.11 (m, 6H)
Α21	173- 178	540 (M+H)	10.46 (s, 1 H), 8.57 (s, 1H). 8.38 (s,1H), 8.19 (d, J = 8.7 Hz, 2H), 7.80 (d, J =9.1 Hz. 2H), 7.67 (d, J =8.8 Hz, 2H), 7.47 - 7.31 (m, 6H), 4.10 (s. 2H), 3.04 (heptet, J- 6.7 Hz, 1 H). 1.22 (d, J = 6.9 Hz, 6H)
Α22		511 (M+H)	10.76 (s, 1H), 8.84 (s, 1 H). 8.56 (s, 1H), 8.15 - 8.13 (d, J =8.4 Hz, 2H), 7.81-7.74 (m, 3H), 7.66-7.33 (d, J =8.4 Hz, 2H), 7.58-7.50 (m, 1 H), 7.43-7.20 (m, 4H), 4.10 (s, 2H). 2.28 (s, 3H)

ΙΟΙ

A23	178- 182	526 (M+H)	10.41 (s.1H), 8.88 (s, 1H), 8.58 (s,1 H), 8.15 (d, J =8.7 Hz, 2H), 7.85- 7.76 (m, 2H), 7.65 (d, J= 8.7 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.22-6.99 (m,3H), 4.14 (s, 2H), 2.22 (s, 6H)
A24	250 (dec)	580 (M+H)	8.53 (s, 1H), 8.13 — 8.07 (m, 2H), 7.81 - 7.76 (m, 2H), 7.61 (d, J = 8.6 Hz, 2H). 7.53 (d, J = 3.9 Hz, 2H), 7.42 — 7.33 (m, 2H), 7.23 — 7.16 (m, 1H),7.13(d, J = 7.7 Hz, 1H), 6.97 (s, 1H), 5.01 (s, 1H), 3.91 (s, 2H), 2.83-2.68 (m, 1H), 1.31-1.16 (m, 6H)
A25	159- 162	565 (M+H)	12.56 (s, 1 H), 8.56 (s, 1H), 8.18 (d, J= 8.7 Hz, 2H), 7.85 - 7.77 (m, 2H), 7.68-7.60 (m, 3H),7.45-7.36(m, 4H), 7.32 - 7.27 (m, 1H), 7.20 (d, J =7.7 Hz, 1H), 4.42 (s, 1H), 3.11 (heptet, J = 6.9 Hz, 1H), 1.26 (d, J = 6.9 Hz. 6H)

102

A26	174- 177	567 (M+H)	12.27 (s, 1H), 8.56 (s, 1H), 8.18 (d, J =8.7 Hz, 2H), 7.80 (d, J = 9.1 Hz, 2H), 7.63 (d, J - 8.9 Hz, 2H), 7.61 (s, 1H), 7.39 (d, J =8.3 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H), 6.92- 6.73 (m, 2H), 4.40 (s, 1H), 3.83 (s, 3H), 2.28 (s, 3H)
A27	162- 166	599 (M+H)	12.52 (s, 1 H), 8.55 (s, 1H), 8.15 (d, J = 8.6 Hz, 2H), 7.80 (m, 3H), 7.57-7.28 (m, 13H), 4.29 (s, 1H)
A28	196- 199	551 (M+H)	12.24 (s, 1H), 8.56 (s, 1H), 8.18 (d, J =8.8 Hz, 2H), 7.80 (d, J = 9.1 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 7.427.33 (m, 2H), 7.23 (m, 1H), 7.17 (d, J =7.7 Hz, 2H), 4.30 (s, 1H), 2.28 (s, 6H)

103

A29	157- 160	537 (M+H)	12.51 (s, 1H), 8.56(2, 1H), 8.18 (d, J =8.8 Hz, 2H), 7.84-7.73 (m,2H), 7.67-7.60 (m, 3H), 7.39 (d, J = 8.3 Hz, 2H), 7.32 (m, 3H), 7.23 (m, 1H), 4.42 (s, 1H), 2.33 (s, 3H)
A30	135- 142	559 (M+H)	12.31 (s, 1H), 8.648.50 (m. 1H), 8.19 (dd, J= 13.9, 7.1 Hz, 2H), 7.80 (m, 2H), 7.65 (m, 2H), 7.39 (m, 3H), 7.14 - 6.86 (m, 3H), 4.97 - 4.11 (m, 1H)
A31	250- 255	605 (M+H)	8.55 (s, 1H), 8.16 (d, J = 8.8 Hz, 2H). 7.95 (s, 1H), 7.79 (d, J= 9.1 Hz, 2H), 7.62 (d, J = 8.8 Hz. 3H), 7.53 (dd, J = 7.8,1.2 Hz, 1 H), 7.42 -7.34 (m, 3H), 7.18 (dd, J = 7.9,1.2 Hz, 1H), 3.92 (d, J =1.3 Hz, 2H), 2.71 (heptet, J = 6.8 Hz, 1 H), 1.33 (d, J =6.9 Hz, 3H), 1.23 (d, J =6.8 Hz, 3H)

104

A32			509 (M+H)	10.53 (s. 1H). 9.71 (s. 1H), 8.55 (s, 1H), 8.13 (m, 3H), 7.79 (d, J - 9.1 Hz, 2H), 7.71 (d, J = 8.7 Hz, 1H), 7.65(d, J =8.7 Hz. 1H), 7.37 (d, J =8.3 Hz. 2H), 7.12 (m, 1H), 3.49 (s, 2H). 3.12 (s, 3H). 3.04 (s, 3H)
A33		168- 171	525 (M+H)	10.39 (s, 1H), 9.48 (s, 1H), 9.38 (s, 1H), 8.07 (d, J =8.9 Hz, 4H), 7.77 (d, J =8.8 Hz, 2H), 7.62 (d, J= 8.3 Hz, 2H), 7.28 (d, J = 8.7 Hz, 1H). 6.81 (d, J = 2.8 Hz, 1H), 6.74 (dd, J =8.7,2.9 Hz, 1H), 3.73 (s, 3H), 3.51 (s, 2H), 2.21 (s, 3H)

105

A34			553 (M+H)	9.81 (s, 1H), 8.92 (s, 1H), 8.58 (s, 1H), 8.12 (d, J =8.6 Hz, 2H), 7.79 (d, J = 9.0 Hz, 2H), 7.69 (d, 7=8.7 Hz, 2H), 7.50-7.10 (m, 3H), 6.84 (d,7 = 2.8 Hz, 1H), 6.72 (dd, 7 = 8.7, 2.9 Hz, 1H), 4.02 (s, 3H), 3.80 (s, 2H), 3.08 (dt,7=13.6, 6.8 Hz, 1 H), 1.20 (d, 7 = 6.9 Hz. 6H)	¹³CNMR(101 MHz, CDCI3) δ 166.81,166.13, 162.98,158.40, 144.30,141.54, 139.02,135.54, 127.30,127.05, 126.87,126.52, 126.30,122.36, 121.13,120.10, 111.97,110.85, 56.04, 55.36, 44.26, 28.37, 23.06
A35			567 (M+1)	8.53 (s, 1 H). 8.138.07 (m. 2H), 7.807.74 (m,2H). 7.63- 7.55 (m, 2H), 7.49 (d, 7 = 4.5 Hz, 1H), 7.487.41 (m, 2H), 7.38- 7.35 (m, 3H), 7.12 (dd, 7=7.8,1.2 Hz, 1H), 3.97 (d, 7= 2.0 Hz, 2H), 2.49 (q, 7 = 7.6 Hz, 2H). 1.20 (t, 7= 7.6 Hz, 3H)	^ieF NMR (376 MHz, CDClj) □ -58.02 (s)

106

A36	262- 266	581 (M+1)	8.53 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.78 (d, J =9.1 Hz, 2H), 7.61 (d, J =8.8 Hz, 2H), 7.47 (s, 1 H), 7.37 (d, J = 8.4 Hz, 2H), 7.02 (s, 2H), 3.98 (s, 2H), 2.35 (s, 3H), 2.12 (s, 6H)
A37		595 (M+1)	8.53 (s, 1H), 8.148.09 (m, 2H), 7.80 7.76 (m, 2H), 7.647.58 (m, 2H), 7.45 (s, 1H), 7.37 (d, J =8.3 Hz, 2H), 7.01 (s, 2H), 4.15 (q, J =7.3 Hz, 1H), 2.36 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H), 1.77 (d, J =7.3 Hz, 3H)	^ieF NMR (376 MHz, CDClj) □ -58.02 (s)
A38		595 (M+1)	8.51 (s, 1 H), 8.06 (d.J = 8.1 Hz, 2H), 7.79- 7.75 (m, 2H), 7.60 (t, J = 8.4 Hz, 2H), 7.36 (d, J=8.4Hz,2H), 7.19 (s, 1H), 6.97 (d, J = 7.4 Hz, 2H), 3.95 (m, 1H), 3.45 (dd, J =11.0,7.3 Hz, 1H), 3.10-2.97 (m, 1H), 2.33 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H), 1.63-1.44 (m, 2H), 0.89 (m, 3H)	¹⁹F NMR (376 MHz, CDClj) □ □□□□-58.03 (s)

107

A39			581 (M+1)	8.51 (s, 1H), 8.03 (s, 2H), 7.80 - 7.75 (m, 2H), 7.55 (s, 2H), 7.36 (d, 7=8.6 Hz, 2H), 7.15 (m, 3H), 6.86 (br s, 1H.NH), 3.33 (d,7 = 9.7 Hz, 2H), 3.032.80 (m, 2H), 2.54 (dd, 7= 10.1, 4.2 Hz, 1 H), 2.24 (s, 6H), 1.17 (d, 7 = 6.6 Hz, 3H)	¹⁹F NMR (376 MHz, CDCI3) □ -58.03 (s)
A40			581 (M+1)	12.37 (s. 1 H), 8.54 (s, 1H), 8.13 (d, 7= 4.8 Hz. 2H), 7.79 (d, 7 = 4.7 Hz, 2H), 7.64 (d, 7 = 4.8 Hz, 2H), 7.37 (dd, 7= 4.6,1.1 Hz, 2H), 6.93 - 6.92 (m, 2H), 5.26 (t, 7= 6.5 Hz, 2H), 3.46 (d,7=3.8 Hz, 1H), 2.30 (s, 3H), 1.26 (t, 7= 7.1 Hz, 6H), 2.16-2.16 (m, 3H)	¹⁹F NMR (376 MHz, CDCI3) □ -58.02 (s)

108

A41		595 (M+1)	8.51 (s, 1H), 8.02 (m, 2H), 7.81 - 7.74 (m, 3H), 7.56 (s, 1H), 7.36 (m, 3H), 6.94 (br s, 2H). 3.32 (m, 2H), 2.95 (dd, J =3.7,1.8 Hz, 1H), 2.87 (dd, J =12.3, 10.4 Hz, 1H), 2.58- 2.44 (m,1H), 2.33 (s, 3H), 2.19 (s, 6H), 1.16 (d, J =6.6 Hz, 3H)	^,eF NMR (376 MHz, CDCI3) □ -58.03 (s)
A42	190- 200	565 (M+1)	8.55 (s, 1H), 8.21- 8.12 (m, 2H), 7.88- 7.66 (m, 4H), 7.41 7.35 (m, 2H), 7.30 (dd, J =8.3, 6.7 Hz, 1H), 7.22 (d, J= 7.6 Hz, 2H), 6.36 (d, J =1.0 Hz, 1H), 2.44 (s, 3H), 2.22 (s, 6H)
A43		579 (M+1)	8.55 (s, 1H), 8.17 (d, J = 8.7 Hz, 2H), 7.85- 7.68 (m,4H), 7.37 (d, J = 8.3 Hz, 2H), 7.02 (s, 2H), 6.35 (d, J =0.9 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 3H), 2.17 (s, 6H)	F NMR (376 MHz, CDCI3) □ -58.01 (s)

109

A44		239- 246	597 (M+1)	6.57 (s,1H), 6.55 (s, 1H), 6.14 (d, J =6.6 Hz, 2H), 7.60 (d, J =9.0 Hz, 2H), 7.63 (d. J = 6.6 Hz, 2H), 7.43 - 7.35 (m, 2H), 6.75 (s, 2H), 4.00 (s, 2H), 3.65 (s. 3H), 2.14 (s,6H)
A46	white solid	168- 190	527 ([M+H]*)	6.57 (s, 1H), 6.17 (m, 1H), 7.61 (m, 2H), 7.61 (d, J =30.5 Hz, 3H), 7.34 (m, 6H), 7.24 (m, 3H), 2.67 (qd, J =7.5, 4.1 Hz, 2H), 1.23 (td, J = 7.5, 6.5 Hz, 3H)	”F NMR (376 MHz, CDCI3) δ -56.03
A46	White Solid	201- 203		6.57 (s, 1H), 6.16 (m, 2H), 7.60 (m, 3H), 7.56 (d, J = 6.3 Hz, 2H), 7.40 (ddt, J = 6.0, 6.7, 1.7 Hz, 2H), 7.26 (dt, J = 6.6,1.6 Hz, 2H), 7.23 (m, 2H), 3.16 (dp, J = 16.4, 6.9 Hz, 3H), 1.22 (d, J =6.9 Hz, 6H).	”F NMR (376 MHz, CDCI3) δ -56.02

110

A49	190- 193	541 (M+1)	(DMSO-d_e) δ 11.23 (s, 1H), 10.18 (s, 1H), 9.57 (s, 1H), 9.39 (s, 1H), 8.15-7.95 (m, 4H), 7.62 (dd, J =8.1, 6.0 Hz, 4H), 6.92 (s, 2H), 2.25 (s, 3H), 2.15 (s. 6H)
A50	260 (dec)	557 (M+1)	8.57 (s,1H), 8.15(d, J = 8.6 Hz, 2H), 7.85- 7.76(m, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.39 (d, J =8.3 Hz, 2H), 6.69 (s, 2H), 3.82 (s. 3H), 2.26 (s, 6H)
A51	210- 212	497 (M+1)	(DMSO-d_e) δ 9.85 (s, 1H), 9.66 (s, 1H), 9.39 (s, 1H), 9.39 (s, 1H), 8.08 (t, J = 2.5 Hz, 2H), 8.06 (d, J =3.0 Hz, 2H), 7.90 (d, J =7.9 Hz, 1H), 7.65-7.59 (m, 4H), 7.26-7.14 (m. 2H), 7.03 (t, J =7.4 Hz, 1H), 2.28 (s, 3H)

111

A52		245- 255	511 (M+1)	(DMSO-d_e) δ 9.82 (s, 1H), 9.63 (s. 1H). 9.44 -9.35(m, 2H), 8.188.06 (m, 5H), 7.86 (d, J = 7.0 Hz, 1H), 7.647.60 (m, 3H), 7.22 (dd, J =19.2,7.7 Hz, 2H), 7.10 (dd, J = 7.4,1,2 Hz,1H), 2.63 (d, J = 7.5 Hz, 2H), 1.19 (t, J = 7.5 Hz. 3H).
A53		231- 233	527 (M+1)	(DMSO-d_e) δ 10.71 (s, 1H), 10.34 (s, 1H), 10.13 (s, 1 H), 9.39 (s. 1H), 8.08 (m, 4H), 7.70 -7.57 (m,4H), 7.26 (d, J = 8.7 Hz, 1H), 6.87 (d, J =2.9 Hz, 1 H), 6.81 (dd, J =8.7,2.9 Hz, 1H), 3.75 (s, 3H), 2.20 (s, 3H)

112

A54			655 (M+1)	11.57 (s, 1H), 8.55 (s, 1H). 8.16 (d, J =8.6 Hz, 2H), 7.82 - 7.78 (m, 2H), 7.70 - 7.64 (m, 2H), 7.46 (s. 1 H). 7.42-7.35 (m,4H), 7.30 (d. J =7.3 Hz, 1 H), 7.22 (d, J =3.0 Hz, 1H), 5.67 (d, J = 4.1 Hz, 2H), 2.92 (d. J = 7.0 Hz, 1H), 2.692.50 (m, 1H), 1.631.55 (m, 2H), 1.26- 1.16 (m, 9H), 0.63 (d, J = 7.4 Hz. 3H)	F NMR (376 MHz, CDCI3) □□□□-58.02 (s)
ASS			641 (M+1)	8.56 (s, 1H), 8.16 (d. J = 8.9 Hz, 2H), 7.82 7.79 (m, 2H), 7.67 (d, J = 8.5 Hz. 2H), 7.43 (s, 1H), 7.39 (d. J =8.4 Hz, 2H), 7.24 (d, J = 7.5 Hz, 1 H), 7.167.10 (m, 3H), 5.65 (s, 2H), 2.62 (m, 3H), 2.29 (s, 3H), 1.22-1.15 (m, 9H)

113

A56		106- 109	643 (M+1)	11.22 (s, 1 H), 8.57 (s. 1H), 8.17-8.15 (m. 2H), 7.84-7.79 (m, 2H), 7.66 (d, J =8.5 Hz, 2H). 7.41-7.37 (m, 2H), 7.12 (d, J = 8.6 Hz, 1H), 6.92 — 6.88 (m, 2H), 6.77 (d, J = 12.5 Hz, 1H), 5.65 (s, 2H), 3.82 (s, 3H), 2.58 (dq, J= 14.0, 7.0 Hz, 1H), 2.27 (s, 3H), 1.18 (d, J= 7.0 Hz, 6H)
A57		132- 137	627 (M+1)	8.59 (s, 1H), 8.208.09 (m,4H), 7.86- 7.80 (d, J =8.4 Hz, 2H), 7.65 (d, J =8.6 Hz, 2H), 7.48 (s, 1 H). 7.39 (d, J =8.4 Hz, 2H), 7.30 (s, 1H), 7.23 (s, 1H), 6.97-6.64 (m, 2H), 5.67 (s, 2H), 2.63 (m, 2H), 1.24-1.17 (m, 9H)

114

A58		668 (M+1)	11.23 (s, 1H). 8.56 (s, 1H). 8.46 (s. 1H). 8.17 -8.13 (m, 3H), 7.80 (q. J- 3.7 Hz. 2H), 7.68 — 7.60 (m, 2H), 7.39- 7.36 (m, 4H). 7.07 (t. J = 8.1 Hz, 1H), 5.48 (s, 2H), 2.77- 2.62 (m, 1H). 1.27-1.24 (m, 6H)
A59	125- 129	641 (M+1)	(DMSO-d_e) 10.92 (s. 1H). 9.82 (s, 1H), 9.37 (S.1H), 8.13-8.10(m, 2H). 7.84 (s, 2H). 7.62 (d, J = 8.6 Hz, 2H), 6.97 (s. 2H). 6.91 (d, J = 8.8 Hz, 3H), 5.74 (s. 2H), 2.62-2.56 (m, 1H), 2.26 (s, 3H), 2.15 (s, 6H), 1.08-1.06 (m, 6H)
A60	120- 125	613 (M+1)	8.57 (s, 1 H), 8.14 (d, J = 8.6 Hz, 2H), 7.82- 7.78 (m, 2H). 7.66 (d, J = 8.6 Hz, 2H), 7.54 (s, 1H), 7.38 (d, J =8.5 Hz, 2H), 7.29 (t. J =4.0 Hz, 1 H), 7.23 (d, J = 2.6 Hz, 2H). 5.67 (s, 2H), 2.67-2.47 (m, 1H), 2.31 (s, 3H), 1.22 -1.11 (m, 6H)

115

A61		165- 170	635 (M+1)	(DMSO-de) 9.37 (s, 1H), 8.06 (d, J =9.1 Hz, 6H), 7.62 (d. J = 8.4 Hz, 4H). 7.19 (s, 3H), 5.78-5.66 (m, 1H), 5.62 (s, 2H), 2.67 (s,1H), 1.06 (d, J =7.0 Hz, 6H)
A62		155- 157	629 (M+1)	8.55 (s, 1H), 8.16 (d, J = 8.7 Hz, 2H), 7.80 (d, J = 9.1 Hz, 2H), 7.66 (d. J = 8.6 Hz, 2H), 7.40 (s, 3H), 7.18 (d, J = 8.8 Hz, 2H), 6.90 (d, J =8.9 Hz, 2H), 5.66 (s, 2H), 3.83 (s, 3H), 2,67-2.51 (m, 1H), 1.19 (d, J = 7.0 Hz, 6H)
A63	White Solid	197 (dec)	539 ([M+H]*)	(DMSO-d_e) δ 12.03 (s, 1H), 10.21 (s, 1H), 9.56 (s, 1H). 9.39 (s, 1H), 8.13-8.03 (m, 4H),7.79(d, J = 7.1 Hz, 1H), 7.62 (t, J = 7.9 Hz, 4H), 7.28-7.16 (m, 2H), 7.09 (d, J= 7.0 Hz, 1 H), 1.97- 1.81 (m, 1 H), 1.020.91 (m, 2H), 0.72- 0.62 (m, 2H)	^ieF NMR (376 MHz, DMSO-d_e) δ -56.96

116

A64	White Solid	185 (dec)	541 ([M+H]*)	(DMSOO δ 11,78 (s, 1 H), 10.21 (s,1H), 9.54 (s, 1 H), 9.39 (s, 1H), 8.16-7.98 (m, 4H), 7.68 - 7.52 (m, 5H). 7.36-7.17 (m, 3H), 2.59 - 2.52 (m, 2H), 1.67-1.43 (m, 2H), 0.91 (t, J =7.3 Hz, 3H)	”F NMR (376 MHz, DMSO-de) δ -56.96
A65	White Solid	175- 178	553 ([M+H]*)	8.53 (s, 1H), 8.12 (d, J = 8.6 Hz, 2H). 7.78 (d, J=8.9Hz, 2H), 7.61 (d, J =8.6 Hz. 2H), 7.43-7.39 (m, 6H), 7.15 (d, J =7.4 Hz, 1H), 3.99 (s, 2H), 2.20 (s, 3H)	”F NMR (376 MHz, CDCI₃) δ -58.03
A66	White Solid	178- 181	579 «M+H]*)	8.54 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.81 7.75 (m, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.45 (t, J = 7.0 Hz, 1H), 7.36 (dd, J =14.3,6.6 Hz, 4H), 7.24-7.13 (m, 2H), 4.00 (s, 2H), 1.73 (dd, J=11.3, 5.8 Hz, 1H), 0.91 -0.85(m, 2H), 0.74 - 0.59 (m, 2H)	^1flF NMR (376 MHz, CDCI3) δ -58.03

117

A67	Off-White Sticky Solid		555 ([M+H]*)	(DMSO-de) δ 11.77 (s, 1 H), 10.25 (s, 1H), 9.56 (s, 1 H), 9.39 (s, 1H), 8.18-7.97 (m, 4H), 7.61 (dd. J =11.2, 6.7 Hz, 4H), 7.53 - 7.38 (m, 1H), 7.38- 7.21 (m, 3H), 1.36(s, 9H)	^ieF NMR (376 MHz, DMSO-d_e) δ -56.96
A68	White Solid	201 (dec)	525 ([M-HD	(DMSO-d_e) δ 11.64 (s, 1H), 10.16 (s, 1 H), 9.53 (s, 1H), 9.39 (s, 1H), 8.14-8.01 (m, 4H). 7.61 (dd, J =12.1, 5.2 Hz, 4H), 7.44 (d, J = 6.0 Hz, 1H), 7.10 (s, 1H), 7.04 (d, J =8.0 Hz, 1H), 2.29 (s, 3H), 2.21 (s, 3H)	^ieF NMR (376 MHz, DMSO-d_e) δ -56.96
A69	White Solid	144- 147	581 ([M+HD	8.54 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 9.0 Hz, 2H), 7.61 (d, J =8.7 Hz, 2H), 7.42 (ddd, J= 24.5, 14.6, 6.9 Hz, 6H), 7.13 (d, J= 7.8 Hz, 1H), 3.99 (d, J =2.5 Hz, 2H), 2.48-2.39 (m, 2H), 1.62 (dt, J= 15.4, 7.6 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H)	F NMR (376 MHz, CDCI₃) δ -58.03

118

A70	White Solid	203 (dec)	545 ([MΗΓ)	(DMSO-d_e) δ 11.42 (s, 1 H), 10.32 (s, 1H), 9.51 (s, 1H), 9.39 (s, 1 H), 8.08 (ddd, J = 10.2, 7.2, 5.0 Hz, 4H), 7.66-7.58 (m, 4H), 7.39 (t, J = 4.7 Hz, 1H), 7.27 (d, J =5.4 Hz, 2H), 2.27 (s, 3H)	”F NMR (376 MHz, DMSO-d_e) δ-56.96
A71	White Solid	217 (dec)	525 ([M-HD	(DMSO-de) δ 11.64 (s, 1H), 10.17 (s, 1H). 9.54 (s. 1H), 9.39 (s, 1H), 8.14-8.03 (m, 4H), 7.62 (t, J =7.7 Hz, 4H), 7.30 (t, J =4.6 Hz, 1H), 7.13 (d, J =4.8 Hz, 2H). 2.29 (s. 3H), 2.13 (s, 3H)	”F NMR (376 MHz, DMSO-d_e) δ -56.96
A72	White Solid	205 (dec)	545 ([M-HD	(DMSO-d_e) δ 11.81 (s. 1H), 10.28 (s, 1H), 9.53 (s, 1 H), 9.38 (d,J = 4.6 Hz, 1H), 8.17- 7.95 (m, 5H), 7.61 (dd, J =11.2, 4.4 Hz, 4H), 7,38-7.21 (m, 2H), 2.24 (s, 3H)	”F NMR (376 MHz, DMSO-de) δ -56.96

119

A73	White Solid	195 (dec)	545 ([M-HD	(DMSO-d_e) δ 12.00 (s, 1 H), 10.32 (s, 1H), 9.54 (s, 1 H), 9.39 (s, 1H), 8.12-8.03 (m, 4H), 7.89 (d, J = 8.2 Hz, 1H), 7.61 (dd, J = 11.6,4.7 Hz, 4H), 7.41 (d, J= 1.2 Hz, 1H), 7.21 (d, J =8.3 Hz, 1H), 2.33 (s, 3H)	”F NMR (376 MHz, DMSO-cf_e) δ -56.96
A74	Tan Solid	134 (dec)	587 ([M+H]*)	8.54 (s, 1 H). 8.13 (d, J = 8.7 Hz, 2H), 7.82- 7.76 (m, 2H), 7.62 (d. J = 8.7 Hz, 2H), 7.45- 7.28 (m, 6H), 4.02 (d, J - 8.0 Hz, 2H), 2.24 (s, 3H)	”F NMR (376 MHz, CDCIj) δ -58.03
A75	Pale Yellow Solid	188- 191	567 ([M+H]*)	8.54 (s, 1 H), 8.12 (d, J = 8.7 Hz, 2H), 7.79 (d, J =9.0 Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H), 7.41 - 7.27 (m, 5H), 7.01 (d, J = 7.3 Hz, 1H). 3.99 (d, J =1.3 Hz, 2H), 2.38 (s, 3H), 2.07 (s, 3H)	”F NMR (376 MHz, CDCI₃) δ -58.03

120

A76	Yellow Powder	134 (dec)	587 ([M+H]*)	8.54 (s, 1 H), 8.14 (d, J = 8.7 Hz, 2H), 7.79 (d, J =9.0 Hz, 2H), 7.63 (d, J =8.8 Hz, 2H), 7.37 (m, 5H),7.18(d, J = 2.1 Hz, 1H), 3.99 (s, 2H), 2.16 (s,3H).	¹⁹F NMR (376 MHz, CDCI₃) δ -58.03
A77	Yellow Solid	184- 186	587 ([M+H]*)	8.54 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.79 (d, J =9.0 Hz, 2H), 7.61 (d, J =8.8 Hz, 2H), 7.46-7.35 (m, 3H), 7.32 (s, 1 H), 7.25 (s, 1H), 7.18 (d. J =8.0 Hz, 1H), 3.99 (q, J = 18.1 Hz, 2H), 2.45 (s, 3H)	¹⁹F NMR (376 MHz, CDCI3) δ -58.03
Α7Θ	White Solid	211 (dec)	565 ([M-H)D	(DMSO-de) δ 12.07 (s. 1 H), 10.41 (s, 1H), 9.54 (s, 1 H), 9.39 (s, 1H), 8.15-8.01 (m, 5H), 7.77 (d, J =2.4 Hz, 1H), 7.62 (dd, J = 8.6, 6.9 Hz, 4H), 7.50 (dd, J =8.7, 2.4 Hz, 1H)	¹⁹F NMR (376 MHz. DMSO-d_e) δ-56.96

121

A79	White Solid	225 (dec)	531 ([M+H]*)	(DMSO-d_e) δ 11.72 (s, 1 H), 10.26 (s, 1H), 9.53 (s, 1 H), 9.39 (s, 1H). 8.14-8.04 (m, 4H). 7.62 (dd, J= 8.4, 6.1 Hz, 4H), 7.41 (d, J = 8.0 Hz, 1 H), 7.35- 7.22 (m, 1H), 7.14 (t, J = 8.7 Hz, 1H), 2.15 (s, 3H)	¹⁰F NMR (376 MHz, DMSO-d_e) δ-56.96, - 115.93
A80	White Solid	222 (dec)	513 ([M+H]*)	(DMSO-de) δ 11.71 (s, 1H), 10.17 (s, 1H), 9.52 (s, 1H), 9.37 (d.J = 0.9 Hz, 1 H), 8.13- 7.98 (m, 4H), 7.59 (dd, J =8.4, 5.4 Hz, 5H), 7,33-7.14 (m, 3H), 2.24 (s, 3H)
A81	White Solid	283 (dec)	575 ([M]*)	(DMSO-de) δ 11.42 (s, 1H). 10.34 (s, 1H), 9.52 (s, 1 H), 9.39 (s, 1H), 8.13-8.03 (m, 4H), 7.67-7.57 (m, 4H), 7.43-7.33 (m, 3H), 3.06 (hept, J =6.8 Hz, 1 H), 1.24 (d, J = 6.9 Hz, 3H). 1.15 (d, J = 6.9 Hz, 3H)

122

A82	White Solid		559 (ΙΜ+ΗΓ)	(DMSO-d_e) δ 11.76 (s, 1H), 10.29 (s, 1 H). 9.54 (s, 1H), 9.39 (s. 1H), 8.15-8.03 (m, 4H), 7.61 (ddt, J = 9.3, 6.9,1.8 Hz. 4H), 7.457.35 (m, 2H), 7.15 (td. J =8.5, 2.8 Hz. 1 H), 3.04 (hept, J=7.0Hz, 1H), 1.23-1.16 (m, 6H)	”F NMR (376 MHz. DMSO-d_e) δ-56.96, -116.95
A83	White Solid		555 ([M+H]*)	(DMSO-d_e) δ 11.62 (s. 1 H), 10.20 (s, 1H), 9.53 (s, 1H), 9.39 (s, 1H), 8.13-8.03 (m, 4H), 7.67-7.56 (m. 4H), 7.26 (d, J =8.0 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.157.08 (m, 1 H), 3.072.95 (m. 1H), 2.28 (s. 3H). 1.17 (d, J = 6.9 Hz, 6H)	F NMR (376 MHz, DMSO-d_e) δ -56.96

123

A84	White Solid		555 ([M+H]*)	(DMSO-d_e) δ 11.58 (s, 1H), 10.18 (s, 1H), 9.53 (s, 1H), 9.39 (s. 1H), 8.13-8.02 (m. 4H), 7.67-7.55 (m. 4H), 7.26 (d. J =8.0 Hz, 1 H), 7.17 (d. J = 2.0 Hz, 1 H), 7.097.01 (m,1H), 3.01 (hept, J = 6.9 Hz, 1H), 2.32 (s, 3H), 1.18 (d. J = 6.9 Hz. 6H)	F NMR (376 MHz, DMSO-de) δ-56.96
A85	Light Yellow Solid	179 (dec)	616 ([M+H]*)	8.54 (s, 1H), 8.16- 8.10 (m, 2H),7.827.75 (m, 2H), 7.65 7.59 (m, 2H), 7.497.42 (m. 2H). 7.39 (ddd, J =8.2, 5.4,1.8 Hz, 3H). 7.31 (s. 1H). 4.05 (d, J =18.1 Hz, IH), 3.99 (d, J =18.1 Hz, 1H), 2.77 (hept, J = 6.9 Hz, 1H), 1.22 (t. J = 6.8 Hz, 6H)

124

A86	Yellow Solid	206- 208	599 ([M+H]*)	8.54 (s, 1 H), 8.178.09 (m, 2H), 7.827.75 (m, 2H), 7.66- 7.57 (m, 2H), 7.46 (dd, 7 = 8.9, 5.9 Hz, 1 H), 7.41-7.34 (m, 2H), 7.31 (s, 1H), 7.257.18 (m, 1 H), 6.86 (dd, 7=8.6,2.7 Hz, 1H), 4.05-3.99 (m, 1H), 3.99-3.94 (m, 1H), 2.68 (hept, 7 = 6.8 Hz, 1H), 1.20 (d, 7= 6.8 Hz, 6H)
A87	Grey Solid		595 ([M+H]*)	8.54 (d, 7= 1.1 Hz, 1H), 8.13 (d, 7= 8.3 Hz, 2H), 7.82-7.76 (m, 2H), 7.61 (d,7= 8.3 Hz, 2H), 7.43 - 7.30 (m, 5H), 6.92 (s, 1H), 3.98 (d, 7 =3.2 Hz, 2H), 2.75 - 2.61 (m, 1H), 2.39 (s, 3H), 1.20 (t, 7= 6.6 Hz, 6H)	F NMR (376 MHz, CDClj) δ -58.03

125

A88	Light Yellow Solid		595 ([M+H]*)	8.53 (s.1H), 8.158.09 (m, 2H), 7.81 7.75 (m, 2H). 7.63 - 7.57 (m, 2H), 7.41- 7.32 (m, 3H), 7.29 (d, J = 1.9 Hz, 1 H), 7.17 (dd, 7=8.3,1.9 Hz, 1H), 6.99 (d, 7=8.0 Hz, 1H), 4.04-3.90 (m, 2H), 2.68 (hept, 7 = 6.9 Hz, 1H), 2.45 (s, 3H), 1.24-1.15 (m, 6H)	¹⁹F NMR (376 MHz, CDCIj) δ -58.03
ΑΘ9	White Solid	292 (dec)	531 ([M+H]*)	(DMSO-de) δ 11.96 (s, 1 H), 10.31 (s, 1H), 9.53 (s, 1 H), 9.39 (s, 1H), 8.18-8.00 (m, 4H), 7.87 (d, 7 = 5.7 Hz, 1 H), 7.61 (dd, 7 = 11.6, 4.8 Hz, 4H), 7.21 (dd,7=10.4, 8.5 Hz, 1H), 7.13 (d, 7 =5.3 Hz, 1H), 2.31 (s, 3H)	F NMR (378 MHz, DMSO-d_e) δ-56.96,-128.73
A92	Pink Solid	121 (dec)	607 ([M]*)	8.54 (s, 1H), 8.14 (d, 7 = 8.7 Hz, 2H), 7.82- 7.77 (m, 2H), 7.64 - 7.60 (m,3H), 7.44 (dd, 7=8.5, 2.3 Hz, 1 H), 7.38 (d, 7 =8.4 Hz, 2H), 7.31 (s, 1H), 7.28 -7.24 (s, 1H), 4.09- 3.91 (m, 2H)	^WF NMR (378 MHz, CDCIj) δ -58.03

126

A93	Off-White Solid	138 (dec)	571 ([M+H]*)	8.54 (s, 1H),8.13(d,J = 8.7 Hz, 2H), 7.81 7.76 (m, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.41 7.30 (m,4H), 7.21 (t, J - 8.8 Hz, 1H), 7.01 6.96 (m, 1H),4.00(d,J = 1.1 Hz, 2H), 2.11 (d, J =1.8 Hz, 3H)	”F NMR (376 MHz, CDCh) C -58.03, -113.60
A94	Off-White Powder	168- 172	571 ([M+H]*)	8.54 (s, 1H), 8.15- 8.10 (m, 2H), 7.81 - 7.76 (m,2H), 7.64- 7.59 (m, 2H), 7.41 - 7.33 (m, 3H), 7.32- 7.27 (m, 1 H), 7.20- 7.12 (m, 1 H), 7.09 (dd, J= 6.8.1.7 Hz, 1H). 4.08 - 3.90 (m, 2H), 2.41 (s, 3H)	¹⁹F NMR (376 MHz, CDClj) δ -58.03, -124.58
A95	Off-White Oil		595 ([M+H]*)	8.54 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 9.1 Hz, 2H), 7.64 (dd, J- 19.6,8.5 Hz, 3H), 7.49 (dd, J =15.0, 7.6 Hz, 1H), 7.41 7.32 (m, 4H), 7.01 - 6.91 (m, 1H), 3.93 (s, 2H), 1.35 (s, 9H)	¹⁹F NMR (376 MHz, CDCIa) C -58.03

127

A96	White Powder	219 (dec)	590 (ΙΜ-ΗΓ)	(DMSO-d_e) C 11.61 (s, 1H). 10.25 (s, 1H), 9.71 (s, 1H), 8.30- 8.22 (m, 2H), 8.14 (d, J - 8.8 Hz, 2H), 7.71 (d, J =8.8 Hz, 2H), 7.66 (d, J =8.7 Hz, 2H), 7.39 (dd, J= 10.3,3.9 Hz, 2H), 7.27 (ddd, J13.5,10.6,6.1 Hz, 2H), 3.07 (dt, J = 13.8, 6.8 Hz, 1 H), 1.20 (d, J = 6.9 Hz, 6H)	¹⁹F NMR (376 MHz, DMSO-de) C-85.25, -86.89
A97	White Solid	288 (dec)	541 ([M+H]*)	(DMSO-d_e) C 11.35 (s, 1H), 10.21 (s, 1H), 9.52 (s, 1H), 9.39 (s, 1H), 8.17-7.98 (m, 4H), 7.62 (dd, J= 8.4, 5.5 Hz, 4H), 7.26 7.08 (m, 3H), 2.58- 2.52 (m, 2H), 2.21 (s, 3H), 1.16 (t, J = 7.6 Hz, 3H)	^ieF NMR (376 MHz, DMSO-de) C -56.96

128

A98	White Solid	275- 280	541 (\|M-HT)	(DMSO-de) δ 11.55 (s, 1H). 10.17 (s, 1H). 9.55 (s, 1 H), 9.41 (s, 1H), 8.14-8.06 (m, 4H), 7.63 (dd, J = 12.3, 5.4 Hz, 4H), 7.41 (d, J = 8.7 Hz, 1 H), 6.89 (d, J = 2.8 Hz, 1H), 6.82 (dd, J = 8.7,2.9 Hz, 1H), 3.79 (s, 3H), 2.24 (s, 3H)	F NMR (376 MHz, DMSO-d_e) δ-56.96
A99	White Solid	198 (dec)	561 ([M-HD	(DMSO-de) δ 12.46 (s, 1H), 10.25 (s, 1H), 9.52 (s, 1H), 9.39 (s, 1H), 8.75 (d, J = 2.6 Hz, 1H), 8.16-7.97 (m, 4H), 7.71 - 7.44 (m, 4H), 7.27 (dd, J = 8.8, 2.6 Hz, 1H), 7.16 (d, J =8.9 Hz, 1 H), 3.90 (s, 3H)	F NMR (376 MHz, DMSO-d_e) δ-56.96
A100	White Solid	200 (dec)	525 ([M-HD	(DMSO-d_e) δ 12.05 (s. 1H), 10.11 (s, 1H), 9.54 (s, 1 H), 9.39 (s, 1H), 8.14-8.01 (m, 4H), 7.61 (dd, J =11.8, 5.0 Hz, 4H), 7.31 (s, 2H), 6.90 (s, 1H), 2.29 (s, 6H)	”F NMR (376 MHz, DMSO-d_e) δ -56.96

129

A101	White Solid	251 (dec)	587 (ΙΜ-ΗΓ)	(DMSO-de) δ 11.68 (s, 1 H), 10.19 (s, 1 H). 9.51 (s, 1H), 9.39 (s, 1H). 8.14-8.01 (m, 4H). 7.60 (dd. J =16.8. 8.6 Hz, 4H), 7.557.49 (m, 1H), 7.33- 7.15 (m. 8H), 3.97 (s, 2H)	¹⁹F NMR (376 MHz, DMSO-d_e) δ-56.96
A102	Yellow Solid	244- 247	632 ([M+H]*)	(DMSO-d_e) δ 8.21 8.15 (m, 2H), 8.06 (d, J = 8.8 Hz, 2H), 7.68 (d, J =8.8 Hz, 2H), 7.56- 7.49 (m, 2H), 7.38 (ddd, J =10.0, 8.8,3.9 Hz, 4H), 7.10 (d, J = 7.5 Hz, 1H), 4.01 (d, J = 2.8 Hz, 2H), 2.772.66 (m. 1H). 1.22 (dd, J =6.8, 3.1 Hz, 6H)	¹⁹F NMR (376 MHz, CDClj) δ -85.96, -87.77

130

A103	Off-White Solid	145 (dec)	581 ([M+H]*)	(DMSO-d_e) δ 8.54 (s, 1H), 8.13 (d, J =8.7 Hz, 2H), 7.82 - 7.76 (m, 2H), 7.62 (d, J8.7 Hz, 2H), 7.44 (dd, J = 8.9,2.6 Hz, 1H), 7.40 - 7.34 (m, 3H), 7.22 (d, J = 2.6 Hz, 1 H), 7.00 (d, J =8.9 Hz, 1H), 3.96 (q, J =18.0 Hz, 2H), 3.82 (s, 3H), 3.79 -3.66 (m, 2H), 1.25 (t, J =7.0 Hz, 3H)	^ieF NMR (376 MHz, CDCI₃) δ -58.03
A104	Off-White Solid	192 (dec)	567 ([M+H]*)	8.54 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.81 - 7.76 (m, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.2 Hz, 3H), 7.14 (s,1H), 6.88 (s, 2H), 3.95 (s, 2H), 2.40 (s, 6H)	¹⁹F NMR (376 MHz, CDCI₃) δ -58.03
A105	Off-White Solid	140 (dec)	629 ([M+H]*)	8.54 (s, 1H), 8.14 (d, J = 8.7 Hz, 2H), 7.82- 7.76 (m, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.52 7.36 (m, 5H), 7.267.23 (m, 3H), 7.21- 7.09 (m, 4H), 3.91 (d, J = 4.2 Hz, 2H), 3.75 (d, J =17.9 Hz, 1H), 3.52 (d, J= 18.0 Hz, 1H)	^1SF NMR (376 MHz, CDCI₃) δ -58.02

131

A106	White Solid	555 ([M+H]*)	(DMSO-d_fl) δ 11.62 (s, 1H), 10.21 (s, 1H), 9.55 (s, 1H), 9.38 (s, 1H), 8.14-7.96 (m, 4H), 7.61 (t, J = 9.3 Hz, 4H), 7.21 - 6.87 (m, 3H), 3.31-3.27 (m, 1H). 2.37 (s, 3H), 1.27 (d, J= 7.1 Hz, 6H)	”F NMR (376 MHz, DMSO-d_e) δ -56.96.
A107	White Solid	559 ([M+H]*)	(DMSO-de) δ 11.56 (s, 1 H), 10.27 (s, 1H), 9.52 (s, 1H), 9.39 (s, 1H), 8.14-8.02 (m, 4H), 7.67-7.56 (m, 4H), 7.28 (td, J =8.1, 6.0 Hz, 1H), 7.187.08 (m, 2H), 3.13 (hept, J= 7.0 Hz, 1H), 1.30 (dd, J = 7.0,1.3 Hz, 6H)	¹⁹F NMR (376 MHz, DMSO-de) δ-56.96, -114.66
A108	Light Yellow Solid	595 ([M+H]*)	8.54 (s, 1H), 8.178.07 (m, 2H), 7.82 7.75 (m, 2H), 7.647.58 (m, 2H), 7.42 - 7.38 (m, 1H), 7.38- 7.34 (m, 2H), 7.30 (dd, J =7.4, 5.7 Hz, 2H), 6.94-6.86 (m, 1H), 4.03 - 3.92 (m, 2H), 3.08-2.95 (m, 1H), 2.53 (s, 3H), 1.32- 1.27 (m, 6H)	¹⁹F NMR (376 MHz, CDCIj) δ -58.03

132

A109	White Solid		599 ([M+H]*)	6 8.54 (s, 1 H), 8.178.10 (m, 2H), 7.827.75 (m, 2H), 7.66 - 7.58 (m, 2H), 7.41 - 7.36 (m, 2H), 7.36 - 7.30 (m, 2H), 7.24- 7.16 (m,1 H), 6.91 (dd, J= 7.8,1.1 Hz, 1H), 4.06-3.93 (m,2H), 2.68 (hept, J =6.9 Hz, 1 H), 1.37-1.28 (m, 6H)	¹F NMR (376 MHz, CDCI₃) 6 -58.03, -111.63
A110	Yellow Solid	138 (dec)	581 ([M+H]*)	8.54 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.81 - 7.76 (m, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 9.2 Hz, 3H), 7.06 (d, J = 8.3 Hz, 1H), 6.92 - 6.85 (m, 2H), 3.97 (s, 2H), 3.86 (s, 3H), 2.16 (s, 3H).	^ieF NMR (376 MHz, CDCh) δ -58.03

133

A111	Off-white Solid	146 (dec)	603 ([MD	6 8.54 (s, 1H), 8.13 (d, J =8.7 Hz. 2H), 7.79 (d. J = 9.0 Hz, 2H), 7.63 (d, J =8.8 Hz, 2H), 7.44 (dd. J =8.9. 2.6 Hz. 1H), 7.42- 7.32 (m, 3H). 7.22 (d, J = 2.6 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 3.96 (q, J =18.0 Hz, 2H). 3.82 (s, 3H)	”F NMR (376 MHz, CDCIj) 6 -58.03
A112	White Solid	197 (dec)	591 ([M+H]*)	(DMSO-d_e) 611.67 (s, 1 H), 10.22 (s, 1 H), 9.54 (s, 1H), 9.40 (s, 1H), 8.13-8.05 (m, 4H), 7.62 (t, J = 8.6 Hz, 4H), 7.39 (t, J =8.6 Hz, 2H), 7.31 (t, J =6.9 Hz, 1H), 7.25 (dd, J =10.5, 4.5 Hz, 1H), 3.13- 2.96 (m, 1 H), 1.20 (d, J = 6.9 Hz, 6H)	^1BF NMR (376 MHz, DMSO-d_e) 6-85.18, -86.91

134

A113	Off-white Solid	192 (dec)	625 ([M+H]*)	(DMSO-de) δ 11.67 (s. 1H), 10.22 (s, 1H), 9.55 (s, 1 H), 9.53 (s, 1H), 6.22 (d,7=8.8 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 7.62 (d, 7=8.8 Hz, 2H), 7.39 (dd,7=12.6,4.7 Hz, 2H), 7.31 (t, 7= 6.8 Hz, 1H), 7.27-7.21 (m, 1H), 3.06 (dt,7=13.7, 6.8 Hz, 1H), 1.20 (d, 7 = 6.9 Hz. 6H)	”F NMR (376 MHz, DMSO-de) δ -79.37, -79.40, -79.42, -110.35, -110.37, -125.95
A114	White Solid	131 (dec)	540 ([M+H]*)	δ 11.98 (S, 1H), 10.56 (s, 1H), 8.16 (s, IH), 7.93 (d, 7= 2.5 Hz, 1 H), 7.86 (d, 7= 8.5 Hz, 2H), 7.83-7.76 (m, 2H), 7.47 (d,7 = 7.9 Hz, 2H), 7.437.35 (m, 3H). 7.357.27 (m, 3H), 6.76 (d, 7 = 2.5 Hz, 1H), 3.15 (dt, 7=13.7,6.8 Hz, 1H). 1.26 (d, 7 = 6.5 Hz, 6H)	^ieF NMR (376 MHz, CDClj) δ -58.06

135

A115	Off-white Solid	193- 199	631 ([M+H]*)	δ 8.55 (d, J =3.8 Hz, 1H), 8.13 (d, J =8.7 Hz, 2H), 7.83-7.77 (m,2H), 7.61 (d, J8.8 Hz, 2H), 7.537.50 (m, 2H), 7.41 7.31 (m. 4H), 7.10 (d. J = 7.5 Hz, 1H), 4.00 (d, J =2.5 Hz, 2H), 2.782.65 (m, 1H), 1.22 (dd, J =6.8, 4.6 Hz, 6H)	¹⁸F NMR (376 MHz, CDCI₃) δ -85.90, -87.85
A116	White Solid		559 ([M+H]*)	(DMSO-de) δ 11.56 (s, 1H), 10.24 (s, 1H), 9.53 (s, 1 H), 9.39 (s. 1H), 8.12-8.04 (m, 4H), 7.65-7.58 (m, 4H), 7.39 (dd, J =8.8, 5.6 Hz, 1H),7.19(dd, J = 10.4, 3.0 Hz, 1H), 7.07 (td, J =8.4,3.0 Hz, 1H), 3.03 (hept, J- 7.1 Hz, 1H), 1.19 (d, J = 6.9 Hz, 6H)	”F NMR (376 MHz, DMSO-d_e) δ -56.96, - 114.07

136

A117	White Solid		599 ([M+H]*)	8.54 (s, IH), 8.16- 8.10 (m, 2H), 7.82- 7.76 (m,2H), 7.65- 7.58 (m, 2H), 7.42 - 7.35 (m, 2H), 7.31 (s, 1H), 7.17 (dd, J =9.9, 2.6 Hz, 1 H), 7.127.01 (m, 2H), 4.053.91 (m, 2H), 2.762.61 (m, 1H), 1.24- 1.17 (m, 6H)	¹⁰F NMR (376 MHz, CDCI₃) δ -58.03, - 110.25
A118	White Solid		541 ([M+H]*)	(DMSO-d_e) δ 12.09 (s. 1 H), 10.15 (s, 1 H), 9.55 (s. 1 H), 9.39 (s. 1H), 8.13-8.01 (m, 4H), 7.69 - 7.58 (m, 4H), 7.58-7.47 (m, 2H), 7.32 (t, J =7.8 Hz, IH), 7.14 (d, J =7.7 Hz. 1H), 2.91 (hept, J = 6.9 Hz, 1H), 1.22 (d,J = 7.0 Hz, 6H)	¹⁹F NMR (376 MHz, DMSO-de) δ -56.96

137

A119	White Solid	531 ([M+H]*)	(DMSO-d_e) δ 11.58 (s. 1 H). 10.46 (s.1H), 9.52 (s, 1H), 9.39 (s, 1H), 8.14-8.03 (m, 4H), 7.67 - 7.56 (m, 4H), 7.45 (d, J =1.9 Hz. 1H), 6.29 (d. J= 1.9 Hz, 1 H). 4.39 (hept, J =6.5 Hz, 1H), 1.39 (d, J =6.6 Hz, 6H)	^1,F NMR (376 MHz, DMSO-d_e) δ -56.96
A120	White Solid	581 ([M+H]*)	8.54 (d, J =0.9 Hz, 1 H), 8.13 (d, J = 8.5 Hz, 2H), 7.83 - 7.74 (m. 2H). 7.62 (d,J = 8.5 Hz, 2H), 7.47 (t, J = 7.7 Hz, 1 H), 7.37 (dd, J = 10.6, 3.8 Hz, 4H), 7.14-7.06 (m. 2H), 3.97 (s, 2H), 3.00 (hept, J =7.0 Hz, 1H), 1.31 (d, J =6.9 Hz, 6H)	”F NMR (376 MHz, CDCIj) δ -58.03
A121	White Solid	571 ([M+H]*)	8.54 (s, 1H), 8.21 - 8.11 (m, 2H), 7.84- 7.75 (m, 2H), 7.71 (d, J = 2.0 Hz,1H), 7.68- 7.59 (m, 2H), 7.38 (d, J = 7.8 Hz, 3H), 6.26 (d. J =2.0 Hz, 1H), 4.00 (s, 2H), 3.78 - 3.67 (m, 1 H), 1.52 (d, J = 6.6 Hz, 3H), 1.47 (d, J = 6.6 Hz, 3H)	”F NMR (376 MHz, CDCIj) δ -58.03

138

A122	White Solid		555 [(M+H]*)	(DMSO-de) δ 11.74 (s, 1H), 10.71 (s, 1H), 9.39 (s, 1 H), 8.83 (s, 1H), 8.13-8.04 (m, 2H), 8.04-7.88 (m, 3H), 7.68-7.56 (m, 2H), 7.47 - 7.35 (m, 2H), 7.35-7.27 (m, 1H), 7.27-7,21 (m, 1H), 3.06 (hept, J =6.8 Hz, 1H), 2.37 (s, 3H), 1.19 (d, J =6.8 Hz, 6H)	”F NMR (376 MHz, DMSO-d6) δ -56.97
A123	White Solid		595 ([M+H]*)	8.53 (s, 1H). 8.18 (d, J = 8.6 Hz, 1 H), 8.068.01 (m, 1H), 7.98 (s, 1H), 7.82 - 7.76 (m, 2H), 7.53-7.48 (m, 2H), 7.41-7.34 (m, 3H), 7.13-7.06 (m, 2H), 3.99 (s, 2H), 2.73 (hept, J = 6.8 Hz, 1H), 2.25 (s, 3H), 1.27- 1.22 (m,6H)	”F NMR (376 MHz, CDCIa) δ -58.03

139

A124	Orange gummy oil		555 ([M+H]*)	12.03 (s,1H), 8.60 (s, 1H), 8.36 (d, J =8.7 Hz, 1H), 7.89 (s, 1 H), 7.81 (d, J = 9.1 Hz, 1H), 7.52-7.48 (m, 1H), 7.46 (d, J = 8.7 Hz, 1 H), 7.41 (dt, J = 7.9,1.0 Hz, 2H), 7.36 (dd, J =7.8,1.7 Hz, 1H), 7.30 (td, J =7.5, 1.5 Hz, 1H), 7.25- 7.20 (m, 1H). 3.40 (s, 3H), 1.27 (d, J = 6.9 Hz, 6H)
A125	Yellow oil		595 ([M+H]*)	8.58 (s, 1 H), 8.17 (s, 1 H), 7.83 (d, J =8.9 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.8 Hz, 3H), 7.22 (d, J =7.6 Hz, 1H), 7.177.07 (m,1H). 6.85 (dd, J =28.9,8.0 Hz, 2H). 3.95 (d, J =2.5 Hz, 3H), 3.37 (s, 2H), 2.50 (d, J = 7.1 Hz, 1H), 1.05 (d, J = 6.9 Hz. 3H), 0.79 (d, J =6.8 Hz, 3H

• AI! ’H NMR data measured in CDCI₃ at 400 MHz unless otherwise noted

Example A: Bioassays on Beet Armyworm (BAW”) and Corn Earworm (“CEW”)

140

BAW has few effective parasites, diseases, or predators to lower Its population. BAW Infests many weeds, trees, grasses, legumes, and field crops. In various places, It Is of économie concem upon asparagus, cotton, com, soybeans, tobacco, alfalfa, sugar beets, peppers, tomatoes, potatoes, onlons, peas, sunflowers, and citrus, among other plants. CEW Is known to attack com and tomatoes, but it also attacks artlchoke, asparagus, cabbage, cantaloupe, collards, cowpeas, eu eu m bers, eggplant, lettuce, lima beans, melon, okra, peas, peppers, potatoes, pumpkln, snap beans, spinach, squash, sweet potatoes, and watermelon, among other plants. CEW Is also known to be résistant to certain Insecticides. Consequently, because of the above factors control of these pests is Important. Furthermore, molecuies that control these pests (BAW and CEW), which are 10 known as chewing pests, are useful in controlling other pests that chew on plants.

Certain molecuies disclosed in this document were tested against BAW and CEW using procedures described in the following examples. In the reporting of the results, the “BAW & CEW Rating Table was used (See Table Section).

BlOASSAYS ON BAW (Spodoptera exlgua)

Bioassays on BAW were conducted using a 128-well diet tray assay. one to five second Instar BAW larvae were placed In each well (3 mL) of the diet tray that had been prevlously filled with 1 mL of artifidal diet to which 50 pg/cm² of the test compound (dissoived in 50 pL of 00:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays 20 were covered with a dearself-adheslve cover and held at 25 ’C, 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae In each well; activity in the eight wells was then averaged. The results are Indicated in the table entitled “Table ABC: Bioiogicai Results* (See Table Section).

Bioassays on CEW (Hellcoverpa zea)

Bioassays on CEW were conducted using a 128-well diet tray assay. one to five second Instar CEW larvae were placed In each well (3 mL) of the diet tray that had been prevlously filled with 1 mL of artifidal diet to which 50 pg/cm² of the test compound (dissoived in 50 pL of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays 30 were covered with a dear self-adhesive cover and heldat25°C, 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae In each well; activity in the eight wells was then

141 averaged. The results are Indicated ln the table entitled Table ABC: Blologlcal Results’ (See Table Section).

Example B: Bioassays on Green Peach Aphid (“GPA”) (Myzus perslcae).

GPA is the most sïgnificant aphid pest of peach trees, causlng decreased growth, shriveling of the ieaves, and the death of various tissues. It is also hazardous because It acts as a vector for the transport of plant viruses, such as potato virus Y and potato ieafroll virus to members of the nlghtshade/potato family Solanaceae, and various mosaic viruses to many other food crops. GPA attacks such plants as broccoii, burdock, cabbage, carrot, cauliflower, dalkon, eggplant, green beans, iettuce, macadamla, papaya, peppers, sweet potatoes, tomatoes, watercress, and zucchinl, among other plants. GPA also attacks many omamentai crops such as carnation, chrysanthemum, flowering white cabbage, poinsettia, and roses. GPA has deveioped résistance to many pesticides. Consequentiy, because of the above factors control of this pest is important. Furthermore, molécules that control this pest (GPA), which Is known as a sucking pest, are usefül in controlling other pests that suck on plants.

Certain molécules disclosed ln this document were tested against GPA using procedures described in the following example, ln the reporting of the results, the GPA Ratlng Table’ was used (See Table Section).

Cabbage seedlings grown ln 3-inch pots, with 2-3 small (3-5 cm) true ieaves, were used as test substrate. The seedlings were Infested with 20-50 GPA (wingless adult and nymph stages) one day prior to chemical application. Four pots with Individual seedlings were used for each treatment Test compounds (2 mg) were dissolved ln 2 mL of acetone/MeOH (1:1) solvent, forming stock solutions of 1000 ppm test compound. The stock solutions were diluted 5X with 0.025% Tween 20 ln H₂O to obtain the solution at 200 ppm test compound. A hand-held aspirator-type sprayer was used for spraying a solution to both sides of cabbage ieaves untii runoff. Référencé plants (solvent check) were sprayed with the diluent only containing 20% by volume of acetone/MeOH (1:1) solvent. Treated plants were heid in a holding room for three days at approximately 25 ’C and ambient relative humidity (RH) prior to grading. Evaluation was conducted by counting the number of live aphlds per plant under a microscope. Percent Control was measured by using Abbott’s correction formula (W.S. Abbott, A Method of Computing the Effectiveness of an Insecticide J. Econ. Entomoi. 18 (1925), pp.265-267) as foliows.

Corrected % Control = 100 * (X - Y) / X

142 where

X = No. of live aphids on solvent check plants and

Y b No. of live aphids on treated plants

The results are Indicated In the table entltled Table ABC: Biological Results” (See Table Section).

Example C: BiOASSAYS on Yellow Fever Mosquito YFM (Aedes aegypti).

YFM prefers to feed on humans during the daytime and Is most frequently found In or near human habitations. YFM Is a vectorfor transmitting severai diseases. It Is a mosquito that can spread the dengue fever and yellow fever vlruses. Yellow fever is the second most dangerous mosqulto-bome disease after malaria. Yellow fever is an acute viral hémorrhagie disease and up to 50% of severely affected persons without treatment wiil die from yellow fever. There are an estimated 200,000 cases of yellow fever, causlng 30,000 deaths, worldwide each year. Dengue fever Is a nasty, viral disease; it is sometimes called breakbone fever or break-heart fever because of the intense pain it can produce. Dengue fever kilis about 20,000 people annually. Consequently, because of the above factors control of this pest Is important. Furthermore, molécules that control this pest (YFM), which is known as a sucklng pest, are useful In controlling other pests that cause human and animal suffering.

Certain molécules disclosed in this document were tested against YFM using procedures described In the following paragraph. In the reporting of the resuits, the YFM Ratlng Table was used (See Table Section).

Master plates containing 400 Dg of a molecuie dissolved in 100 □!_ of dimethyl sulfoxlde (DMSO) (équivalent to a 4000 ppm solution) are used. A master plate of assembled molécules contains 15 DL per well. To this plate, 135 DL of a 90:10 wateracetone mixture Is added to each well. A robot (Biomek® NXP Laboratory Automation Workstation) Is programmed to dispense 15 □L aspirations from the master plate into an empty 96-weli shaflow plate (daughter* plate). There are 6 reps (daughter plates) created per master. The created daughter plates are then immediateiy infested with YFM larvae.

The day before plates are to be treated, mosquito eggs are piaced in Miilipore water containing liver powder to begin hatching (4 g. into 400 ml). After the daughter plates are created using the robot, they are Infested with 220 □!_ of the liver powder/larval mosquito mixture (about 1 day-old larvae). After plates are Infested with mosquito larvae, a non-evaporative lid is used to

143 cover the plate to reduce drying. Plates are held at room température for 3 days prior to grading. After 3 days, each well is observed and scored based on mortality.

The results are Indicated in the table entitled Table ABC: Blologlcal Results (See Table Section).

PEST1CIDALLY ACCEPTABLE ACID ADDITION SALTS, SALT DERIVATIVES, SOLVATES, ESTER DERIVATIVES, POLYMORPHS, ISOTOPES AND RADIONUCLIDES

Molécules of Formula One may be formulated Into pestiddally acceptable add addition salts. By way of a non-limiting example, an amine fonction can form salts with hydrochloric, hydrobromic, sulforic, phosphoric, acetic, benzolc, dtric, malonic, salicylic. malic, fumaric. oxalic, sucdnic, tartaric, lactic, gluconic, ascorblc, maleic, aspartic, benzenesuifonlc, methanesulfonic, ethanesulfonic, hydroxymethanesulfonlc, and hydroxyethanesulfonic acids. Additionally, by way of a non-limiting example, an add fonction can form salts Induding those derived from alkali or alkaline earth metais and those derived from ammonia and amines. Examples of preferred cations Indude sodium, potassium, and magnésium.

Molécules of Formula One may be formulated Into sait dérivatives. By way of a non-limiting example, a sait dérivative can be prepared by contacting a free base with a suffident amount of the desired add 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 pestidde, 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 remalns intact after the non-complexed solvent Is removed. These complexes are often referred to as solvatés. However, It is partlcularly 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 molécules disdosed In this document Is applied.

Molécules of Formula One may be made as various crystal polymorphs. Polymorphlsm Is Important In the development of agrochemlcals slnce different crystal polymorphs or structures of the same molécule can hâve vastly different physical properties and biologlcal 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 ’H.

144

Molécules of Formula One 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 appredated by those skilled In the art that one stereoisomer may be more active than the other stereoisomers. Individuai stereoisomers may be obtained by known sélective synthetlc procedures, by conventional synthetic procedures using resolved starting materials, or by conventional résolution procedures. Certain molécules disclosed In this document can exist as two or more isomers. The various Isomers include géométrie Isomers, dlastereomers, and enantiomers. Thus, the molécules disclosed In this document Include géométrie Isomers, racemic mixtures, Individuai stereoisomers, and optlcally active mixtures. It will be appredated by those skilled In the art that one Isomer may be more active than the others. The structures disdosed in the présent disdosure are drawn In only one géométrie form for darity, but are Intended to represent ail géométrie forms of the molécule.

COMBINATIONS

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 compounds having acariddal, alglddal, avlcidal, bactericidal, fungiddal, herbiddal, insecticidal, mollusdddal, nematlddal, rodentiddal, or viruddal properties. Additionally, the molécules of Formula One may also be used In combination (such as, in a compositional mixture, or a simultaneous or sequential application) with compounds that are antifeedants, bird repelients, chemosterilants, herbldde safeners, Insect attractants, Insect repelients, mammal repelients, mating disrupters, plant activators, plant growth regulators, or synergists. Examples of such compounds in the above groups that may be used with the Moiecuies of Formula One are - (3-ethoxypropy!)mercury bromide, 1,2-dichloropropane, 1,3-dichloropropene, 1-methylcydopropene, 1-naphthol, 2(octylthlo)ethanol, 2,3,5-tri-lodobenzoic add, 2,3,6-TBA, 2,3,6-TBA-dimethyIammonium, 2,3,6-TBAlithlum, 2,3,6-TBA-potassium, 2,3,6-TB A-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl, 2.4.5-T-2ethylhexyl, 2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T-butotyl, 2,4,5-T-butyl,

2.4.5- T-lsobuty!, 2,4,5-T-lsoctyl, 2,4,5-T-lsopropyl, 2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T-sodium,

2.4.5- T-triethyIammonium, 2,4,5-T-trolamlne, 2,4-D, 2,4-D-2-butoxypropyl, 2,4-D-2-ethy!hexyl, 2,4D-3-butoxypropyl, 2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium, 2,4-DB

145

Isoctyl, 2,4-DB-potasslum, 2,4-DB-sodium, 2,4-D-butotyl, 2,4-D-butyl, 2,4-D-diethylammonlum, 2,4D-dimethylammonium, 2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethyl,

2.4- D-heptylammonium, 2,4-D-isobutyl, 2,4-D-lsoctyl, 2,4-D-isopropyl, 2,4-D-isopropylammonium,

2.4- D-lithlum, 2,4-D-meptyl, 2,4-D-methy!, 2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl,

2.4- D-sodîum, 2,4-D-tefuryl, 2,4-D-tetradecylammonlum, 2,4-D-triethylammonium, 2,4-D-tris(2hydroxypropy!)ammonium, 2,4-D-trolamlne, 2iP, 2-methoxyethylmercury chioride, 2-phenylphenoi,

3.4- DA, 3,4-DB, 3,4-DP, 4-aminopyridine, 4-CPA, 4-CPA-potasslum, 4-CPA-sodium, 4-CPB, 4CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyqulnoiine sulfate, 8-pheny!mercurioxyquinoiîne, abamectin, absclsic acid, ACC, acephate, acequlnocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprofe, acibenzolar, acibenzolar-S-methyl, acifluorfen, aclfluorfen-methyl, adfluorfen-sodium, adonifen, acrep, acrinathrin, acrolein, acrylonitriie, acypetacs, acypetacscopper, acypetacs-zinc, alachlor, alanycarb, albendazole, aldicarb, aidimorph, aldoxycarb, aldrin, aliethrin, allidn, aliidochlor, allosamidin, alloxydim, alloxydïm-sodium, allyl alcohol, allyxycarb, alorac, a/pha-cypermethrin, a/pha-endosulfan, ametoctradin, ametridione, ametryn, amlbuzin, amlcarbazone, amlcarthiazoi, amidithion, amldoflumet, amidosuifuron, amlnocarb, amlnocyclopyrachlor, amlnocyclopyrachlor-methyl, aminocydopyrachfor-potassium, aminopyralid, aminopyralid-potassium, aminopyralid-tris(2-hydroxypropyl)ammonium, amiprofos-methyl, amiprophos, amisuibrom, amiton, amiton oxalate, amitraz, amitroie, ammonium sulfamate, ammonium α-naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anllazine, anllofos, anisuron, anthraqulnone, antu, apholate, aramlte, arsenous oxide, asomate, aspirin, asulam, asulam-potasslum, asulam-sodium, athidathlon, at raton, atrazlne, aureofungln, avigiydne, avlglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azlnphos-ethyl, azlnphos-methyl, azlprotryne, azithiram, azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosiiicate, barium polysulfide, barthrin, BCPC, beflubutamld, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazoiin-ethyl, benazolin-potassium, bencarbazone, bendothiaz, bendiocarb, benfluralin, benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, bensulfuronmethyi, bensuiide, bensultap, bentaiuron, bentazone, bentazone-sodium, benthlavalicarb, benthiavalicarb-lsopropyl, benthiazole, bentranil, benzadox, benzadox-ammonium, benzalkonlum chioride, benzamacril, benzamacrii-isobutyl, benzamorf, benzfendîzone, benzlpram, benzoblcyclon, benzofenap, benzofluor, benzohydroxamic add, benzoximate, benzoylprop, benzoylprop-ethyl, benzthlazuron, benzyl benzoate, benzyladenlne, berberlne, berberine chioride, befa-cyfluthrin, befa-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox, bifenthrin, bifujunzhl, bllanafos, biianafos-sodium, binapacryl, bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin,

146 bloresmethrin, blphenyl, bisazir, bismerthiazol, bispyribac, blspyribac-sodium, bistrifluron, bltertanol, blthlonol, blxafen, blastiddin-S, borax, Bordeaux mixture, boric acid, boscalid, brasslnolide, brassinolide-ethyl, brevicomin, brodifacoum, brofenvalerate, brofluthrinate, bromadl, bromadllithlum, bromadl-sodium, bromadiolone, bromethaiin, bromethrin, bromfenvinfos, bromoacetamlde, bromobonll, bromobutide, bromocyclen, bromo-DDT, bromofenoxlm, bromophos, bromophos-ethyt, bromopropylate, bromothalonil, bromoxynll, bromoxynil butyrate, bromoxynll heptanoate, bromoxynil octanoate, bromoxynll-potasslum, brompyrazon, bromuconazole, bronopol, bucarpolate, bufencarb, bumlnafos, bupirimate, buprofezin, Burgundy mixture, busulfan, butacarb, butachlor, butafenadl, butamifos, butathlofos, butenachlor, butethrin, buthldazoie, buthlobate, buthluron, butocarboxim, butonate, butopyronoxyl, butoxycarboxlm, butraiin, butroxydim, buturon, butylamlne, butylate, cacodyllc add, cadusafos, cafenstrole, calcium arsenate, calcium chlorate, caldum cyanamide, calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor, capta fol, captan, carbamorph, carbanoiate, carbaryl, carbasulam, carbendazim, carbendazim benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone-ethyl, carpropamld, cartap, cartap hydrochloride, carvacrol, carvone, CDEA, celloddin, CEPC, ceralure, Cheshunt mixture, chlnomethionat, chitosan, chlobenthiazone, chlomethoxyfen, chloralose, chloramben, chloramben-ammonlum, chloramben-dioiamine, chloramben-methyl, chloramben-methylammonium, chioramben-sodium, chloramine phosphorus, chloramphenicol, chloraniformethan, chloranii, chloranocryl, chlorantraniliprole, chlorazifop, chlorazlfop-propargyl, chlorazlne, chlorbenslde, chlorbenzuron, chlorbicyden, chiorbromuron, chlorbufam, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chiorfenac, chlorfenac-ammonium, chiorfenac-sodium, chlorfenapyr, chlorfenazole, chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide, chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren, chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequat chloride, chlomidine, chlomitrofen, chlorobenzilate, chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron, chloroneb, chlorophadnone, chlorophadnone-sodium, chloropicrin, chloropon, chloropropylate, chlorothalonll, chlorotoluron, chloroxuron, chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chiorpyrifos, chlorpyrifosmethyl, chiorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos, chlozoiinate, choline chloride, chromafenozide, dnerin I, dnerin II, dnerins, cinidonethyl, cinmethylin, dnosulfuron, dobutide, dsanllide, dsmethrin, dethodim, dimbazole, diodinate, clodinafop, dodinafop-propargyl, cloethocarb, clofencet, dofencet-potassium, dofentezlne, clofibric

147 add, dofop, clofop-isobutyl, clomazone, domeprop, doprop, cloproxydim, dopyralid, dopyralidmethyl, dopyralid-olamine, dopyraiid-potassium, dopyralid-tris(2-hydroxypropyl)ammonium, doquintocet, doqulntocet-mexyl, cloransulam, cloransulam-methyl, dosantel, clothîanldin, dotrimazole, doxyfonac, cloxyfonac-sodium, CMA, codlelure, colophonate, copper acetate, copper acetoarsenlte, copper arsenate, copper carbonate, baslc, copper hydroxlde, copper naphthenate, copper oleate, copper oxychloride, copper silicate, copper sulfate, copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl, coumlthoate, coumoxystrobtn, CPMC, CPMF, CPPC, credazine, cresol, crimldine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure, cufraneb, cumyfuron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamld, cybutiyne, cyclafuramld, cydanilide, cyclethrin, cydoate, cydoheximlde, cycloprate, cycloprothrin, cydosulfamuron, cydoxydim, cyduron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofopbutyl, cyhalothrin, cyhexatin, cymlazole, cymiazole hydrochloride, cymoxanil, cyometrlnil, cypendazole, cypermethrln, cyperquat, cyperquat chioride, cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromld, cyprosulfamlde, cyromazine, cythioate, daimuron, dalapon, dalapon-caldum, dalapon-magnesium, dalapon-sodium, daminozide, dayoutong, dazomet, dazomet-sodium, DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic add, delachlor, deltamethrin, demephion, demephion-O, demephionS, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyf, demeton-S-methylsulphon, desmedipham, desmetryn, d-fanshiluquebingjuzhl, diafenthiuron, dialifos, di-allate, diamidafos, diatomaceous earth, diazinon, di butyl phthaiate, dibutyl sucdnate, dicamba, dicamba-diglycolamlne, dicamba-dimethylammonlum, dicamba-dioiamine, dicambaIsopropylammonium, dicamba-methyl, dicamba-olamlne, dicamba-potasslum, dicamba-sodium, dicamba-trolamine, dicapthon, dlchlobenll, dichlofenthion, dichlofiuanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyf, dichlormate, dichlormid, dichlorophen, dichlorprop, dichlorprop-2-ethylhexyl, dichlorprop-butotyl, dichlorprop-dimethyfammonium, dichlorprop-ethylammonium, dichlorprop-lsoctyl, dichlorprop-methyf, dichlorprop-P, dîchlorprop-P-2ethylhexyl, dlchlorprop-P-dimethytammonlum, dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline, didobutrazol, didocymet, dîdofop, didofop-methyf, diclomezine, diclomezine-sodium, didoran, didosulam, dicofol, dicoumarol, dicresyl, dicrotophos, dicydanil, dîcydonon, dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl, diethatyl-ethyl, diethofencarb, dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole, difenopenten, difenopenten-ethyf, difenoxuron, difenzoquat, difenzoquat metilsulfate, difethiaione, diflovidazln, diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium, diflumetorim,

148 dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin, dimefox, dimefuron, dimeplperate, dlmetachlone, dimetan, dimethacarb, dimethachlor, dimethametryn, dimethenamld, dimethenamidP, dimethipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate, dimethylvlnphos, dimetilan, dimexano, dimldazon, dimoxystrobin, dinex, dinex-didexine, dingjunezuo, diniconazoie, diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb acetate, dinosebammonium, dinoseb-diolamlne, dinoseb-sodium, dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, diphadnone, dlphadnone-sodium, diphenamid, diphenyt sulfone, diphenylamine, dipropalin, dipropetryn, dipyrithlone, diquat, diquat dibromide, dispariure, disul, disulfiram, disulfoton, disulsodium, ditalimfos, dithlanon, dithicrofos, dîthloether, dithiopyr, diuron, d-limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potasslum, DNOC-sodium, dodemorph, dodemorph acetate, dodemorph benzoate, dodlcln, dodidn hydrochloride, dodidn-sodlum, dodine, dofenapyn, dominicalure, doramectin, drazoxolon, DS MA, dufulin, EBEP, EBP, ecdysterone, edifenphos, eglinazlne, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothal, endothal-diammonlum, endothal-dipotassium, endothal-disodium, endothlon, endrin, enestroburin, EPN, epocholeone, epofenonane, epoxlconazole, eprinomectin, epronaz, EPTC, erbon, ergocaldferol, erlujixiancaoan, esdépalléthrine, esfenvalerate, esprocarb, etacelasii, etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsuifuronm ethyl, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethlolate, ethion, ethiozin, ethlprole, ethlrimol, ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen, ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl α-naphthaleneacetate, ethyl-DDD, ethylene, ethylene dibromide, ethylene dichloride, ethylene oxide, ethylîdn, ethylmercury 2,3dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercury bromlde, ethylmercury chloride, ethylmercury phosphate, etinofen, etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrlmfos, eugenol, EXD, famoxadone, famphur, fenamldone, fenamlnosulf, fenamlphos, fenapanll, fenarimol, fenasulam, fenazaflor, fenazaquln, fenbuconazoie, fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos, fendorim, fenethacarb, fenfluthrin, fenfuram, fenhexamld, fenltropan, fenltrothlon, fenjuntong, fenobucarb, fenoprop, fenoprop-3-butoxypropyl, fenopropbutometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-lsoctyl, fenoprop-methyl, fenoproppotasslum, fenothlocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpldonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamlne, fenpyroximate, fenridazon, fenridazon-potasslum, fenridazonpropyl, fenson, fensulfothlon, fenteracol, fenthiaprop, fenthlaprop-ethyl, fenthlon, fenthlon-ethyl,

149 fentin, fentin acetate, fentin chloride, fentin hydroxlde, fentrazamide, fentrifanil, fenuron, fenuron TCA, fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil, flamprop, flamprop-isopropyl, flamprop-M, flamprop-methyl, flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, flocoumafen, flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl, fluazifop-P, fluazifop-P-butyl, fluazînam, fluazolate, fluazuron, flubendiamide, flubenzimlne, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludioxonll, fluenetil, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin, flumldorac, flumiclorac-pentyl, flumloxazin, flumipropyn, flumorph, fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamld, fluoroacetamlde, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluorolmide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropadl, flupropadine, flupropanate, flupropanate-sodium, flupyrsulfuron, flupyrsulfuron-methyl, flupyrsulfuron-methyl-sodium, fluquinconazole, flurazoie, flurenol, flurenol-butyl, flurenol-methyl, fluridone, flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimldol, flursulamid, flurtamone, flusllazole, flusulfamlde, fluthlacet, fluthlacetmethyl, flutianii, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafen-sodlum, fonofos, foramsulfuron, forchlorfenuron, formaldéhyde, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl, fosetyl-alumlnium, fosmethllan, fosplrate, fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaomi, funalhecaoling, fuphenthlourea, furalane, furalaxyt, furamethrin, furametpyr, furathiocarb, furcarbanil, furconazole, furconazole-ds, furethrin, furfural, furilazole, furmecydox, furophanate, furyîoxyfen, gamma-cyhalothrin, gamma-HCH, genit, glbberellic add, glbberellins, gliftor, glufoslnate, glufoslnate-ammonium, glufosinate-P, glufosinateP-ammonlum, glufosinate-P-sodium, glyodin, glyoxime, glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium, glyphosate-lsopropylammonium, glyphosate-monoammonlum, glyphosate-potasslum, glyphosate-sesqulsodium, glyphosate-trimesium, glyphosine, gossyplure, grandlure, griseofuivin, guazatine, guazatlne acétates, halacrinate, halfenprox, halofenozide, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyi, haloxyfopmethyl, haloxyfop-P, haioxyfop-P-etotyl, haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargïl, heterophos, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, hexaflurate, hexalure, hexamlde, hexazinone, hexytthiofos, hexythiazox, HHDN, holosulf, huancalwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanlde, hydroprene, hymexazol, hyqulncarb, IAA, IB A, icaridin, imazalil, imazalil nitrate, Imazalil

150 sulfate, imazamethabenz, Imazamethabenz-methyl, Imazamox, imazamox-ammonium, Imazaplc, Imazaplc-ammonlum, Imazapyr, Imazapyr-lsopropylammonlum, Imazaquln, Imazaquln-ammonium, imazaquin-methyl, Imazaquin-sodium, Imazethapyr, Imazethapyr-ammonium, Imazosulfuron, Imîbenconazole, Imlcyafos, Imldadoprid, Imldaclothlz, iminoctadine, Iminoctadine triacetate, Imlnoctadine trîalbesllate, Imlprothrin, Inabenfide, Indanofan, Indaziflam, Indoxacarb, Inezin, lodobonll, lodocarb, lodomethane, lodosulfuron, lodosulfuron-methyl, lodosulfuron-methyl-sodium, loxynil, loxynil octanoate, ioxynii-lithium, loxynll-sodium, Ipazine, Ipconazole, Ipfencarbazone, Iprobenfos, Iprodione, Iprovalicarb, Iprymldam, Ipsdienol, Ipsenol, IPSP, Isamldofos, Isazofos, Isobenzan, isocarbamld, Isocarbophos, Isocil, Isodrin, Isofenphos, Isofenphos-methyl, Isolan, isomethiozin, isonoruron, Isopolinate, Isoprocarb, Isopropalin, Isoprothiolane, isoproturon, isopyrazam, Isopyrimol, Isothloate, Isotlanil, Isouron, Isovaledione, Isoxaben, Isoxachlortole, Isoxadifen, isoxadifen-ethyl, Isoxaflutole, isoxapyrifop, Isoxathion, Ivermectin, Izopamfos, japoniiure, japothrins, ja s mol in I, jasmolin II, jasmonlc add, jiahuangchongzong, jiajlzengxlaolln, jiaxiangjunzhl, jiecaowan, jiecaoxl, jodfenphos, juvénile hormone I, juvénile hormone II, juvénile hormone III, kadethrin, karbutilate, karetazan, karetazan-potasslum, kasugamycln, kasugamycln hydrochloride, kejunlin, kelevan, ketosplradox, ketospiradox-potassium, klnetin, klnoprene, kresoxîm-methyl, kuicaoxi, lactofen, iambda-cyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lindane, llneatin, linuron, lirimfos, litlure, looplure, lufenuron, Ivdingjunzhl, Ivxlancaolin, lythldathion, MAA, malathlon, maleic hydrazide, malonoben, maltodextrin, ΜΑΜΑ, mancopper, mancozeb, mandipropamld, maneb, matrine, mazidox, MCPA, MCPA-2-ethylhexyl, MCPA-butotyl, MCPAbutyl, MCPA-dimethylammonlum, MCPA-diolamlne, MCPA-ethyl, MCPA-lsobutyl, MCPA-lsoctyl, MCPA-lsopropyl, MCPA-methyl, MCPA-olamine, MCPA-potasslum, MCPA-sodium, MCPAthïoethyf, MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil, mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl, mecopropdimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-lsoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl, mecoprop-P-dimethylammonlum, mecoprop-P-lsobutyl, mecoprop-potasslum, mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform, medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr, mefenpyr-diethyl, mefluldide, mefluldide-diolamlne, mefluldide-potasslum, megatomoic add, menazon, mepanlpyrim, meperfluthrin, mephenate, mephosfblan, mepiquat, mepiquat chloride, mepiquat pentaborate, mepronll, meptytdinocap, mercuric chloride, mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron, mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumlzone, metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonlum, metamlfop, metamltron, metam-potassium, metam-sodium, metazachlor, metazosulfuron, metazoxolon,

151 metconazole, metepa, metflurazon, methabenzthiazuron, methacrifos, methaipropalin, methamldophos, methasulfocarb, methazole, methfuroxam, methîdathlon, methlobencarb, methiocarb, methiopyrisulfuron, methiotepa, methiozolin, methluron, methocrotophos, methometon, methomyl, methoprene, methoprotryne, methoquin-butyl, methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methyi apholate, methyi bromlde, methyi eugenol, methyi lodide, methyi Isothlocyanate, methylacetophos, methylchloroform, methyldymron, methylene chloride, methylmercury benzoate, methylmercury dicyandiamlde, methylmercury pentachlorophenoxlde, methylneodecanamide, metiram, metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb, metominostrobln, metosulam, metoxadlazone, metoxuron, metrafenone, metribuzin, metsulfovax, metsuifuron, metsulfuron-methyl, mevinphos, mexacarbate, mleshuan, milbemectin, mllbemydn oxlme, milneb, mlpafox, mlrex, MNAF, moguchun, molinate, molosultap, monalide, monisouron, monochloroacetic add, monocrotophos, monolinuron, monosulfuron, monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquat dichloride, moroxydine, moroxydine hydrochloride, morphothlon, morzid, moxidectin, MSMA, muscalure, mydobutanil, mydozolln, N-fethytmercuryj-p-toluenesulphonanilide, nabam, naftaiofos, naied, naphthalene, naphthaieneacetamide, naphthalic anhydride, naphthoxyacetic adds, naproaniiide, napropamide, naptalam, naptalam-sodium, natamydn, neburon, nidosamide, nidosamide-olamine, nicosuifuron, nicotine, nifluridide, nipyradofen, nitenpyram, nlthiazine, nitraiin, nitrapyrin, nltrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothai-isopropyl, norbormide, norflurazon, nomicotine, noruron, novaluron, novlflumuron, nuarimoi, OCH, octachlorodipropyl ether, octhilinone, ofurace, omethoate, orbencarb, orfralure, ortho-dichlorobenzene, orthosulfamuron, oryctalure, orysastrobln, oryzalin, osthol, ostramone, oxabetrinll, oxadlargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon, oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone, oxinecopper, oxolinic add, oxpoconazole, oxpoconazole fumarate, oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen, oxymatrine, oxytetracydine, oxytetracydine hydrochloride, paciobutrazol, paichongding, para-dichiorobenzene, parafluron, paraquat, paraquat dichloride, paraquat dimetilsulfate, parathlon, parathlon-methyl, parinoi, pebuiate, pefurazoate, peiargonic add, penconazoie, pencycuron, pendimethalin, penflufen, penfluron, penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin, pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, phenazine oxide, phenlsopham, phenkapton, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercury dérivative of pyrocatechoi, phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim, phosalone, phosdiphen, phosfoian, phosfolan-methyl, phosglydn, phosmet, phosnlchior, phosphamidon.

152 phosphlne, phosphocarb, phosphores, phostin, phoxim, phoxim-methyi, phthalide, picloram, picloram-2-ethylhexyl, pldoram-lsoctyl, plcioram-methyi, picloram-olamlne, pidoram-potassium, plcloram-triethylammonium, picloram-tris(2-hydroxypropyî)ammonium, picolinafen, picoxystrobin, plndone, pindone-sodium, plnoxaden, piperalin, piperonyl butoxide, piperonyi cyclone ne, piperophos, piproctanyl, piproctanyl bromide, piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl, pirimiphos-methyî, plifenate, polycarbamate, polyoxins, polyoxorim, polyoxorimzinc, polythïalan, potassium arsenlte, potassium azide, potassium cyanate, potassium gibbereliate, potassium naphthenate, potassium polysulfide, potassium thiocyanate, potassium anaphthaleneacetate, pp’-DDT, prallethrin, precocene I, precocene II, precocene III, pretilachlor, primidophos, primisulfuron, primisulfuron-methyl, probenazole, prochloraz, prochloraz-manganese, proclonol, procyazine, procymidone, prodlamine, profenofos, profluazol, profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl, prohexadione, prohexadione-caldum, prohydrojasmon, promacyl, promecarb, prometon, prometryn, promurit, propachlor, propamidine, propamldine dihydrochloride, propamocarb, propamocarb hydrochloride, propanil, propaphos, propaquizafop, propargite, proparthrin, propazlne, propetamphos, propham, propiconazole, propineb, propisochlor, propoxur, propoxycarbazone, propoxycarbazone-sodium, propyl Isome, propyrisulfuron, propyzamide, proquinazid, prosuier, prosulfaiin, prosuifocarb, prosulfuron, prothidathlon, prothiocarb, prothiocarb hydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute, proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid, pyraclofos, pyraclonll, pyraclostrobin, pyraflufen, pyraflufen-ethyl, pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin il, pyrethrins, pyribambenz-lsopropyi, pyribambenz-propyi, pyribencarb, pyribenzoxlm, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyi, pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluqulnazon, pyriftalid, pyrimethanil, pyrimldifen, pyriminobac, pyriminobac-methyi, pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, pyrithlobac, pyrithiobac-sodium, pyrolan, pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassla, quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl, qulnazamid, quinclorac, qulnconazole, qulnmerac, quinodamlne, quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, qulzalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, quIzalofop-P-tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide, rebemide, resmethrin, rhodethanil, rhodojaponln-lll, ribavlrin, rimsulfuron, rotenone, ryania, saflufenadl, saljunmao, saisentong, salicylanilide, sangulnarine, santonin, schradan, scilliroside, sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz, semiamitraz chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolïn, siduron, siglure, silafluofen, silatrane, silica 153 gel, silthiofam, slmazlne, simeconazole, simeton, simetryn, sintofen, SMA, S-metolachlor, sodium arsenlte, sodium azlde, sodium chlorate, sodium fluoride, sodium fluoroacetate, sodium hexafluorosllicate, sodium naphthenate, sodium orthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide, sodium thiocyanate, sodium a-naphthaleneacetate, sophamide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, splroxamlne, streptomycin, streptomycin sesquisulfate, strychnine, sulcatol, sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram, sulfluramld, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric add, sulfuryl fluoride, sulglycapin, sulprofos, sultropen, swep, fau-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonlum, TCA-calcIum, TCA-ethadyf, TCA-magneslum, TCA-sodium, TDE, tebuconazole, tebufenozlde, tebufenpyrad, tebufloquln, tebuplrimfos, tebutam, tebuthiuron, tedoftalam, tecnazene, tecoram, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim, terallethrin, terbadl, terbucarb, terbuchlor, terbufos, terbumeton, terbuthylazine, terbutryn, tetcyclads, tetrachloroethane, tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin, tetramethyîfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate, thenylchlor, theta-cypermethrin, thlabendazole, thladoprid, thladifluor, thiamethoxam, thlapronil, thiazafluron, thlazopyr, thlcrofos, thicyofen, thldiazimin, thldlazuron, thlencarbazone, thlencarbazone-methyl, thifensulfuron, thlfensulfuron-methyl, thifluzamide, thlobencarb, thiocarboxime, thiochlorfenphim, thiocyclam, thiocydam hydrochloride, thiocyclam oxalate, thlodiazole-copper, thiodïcarb, thiofanox, thlofluoxlmate, thlohempa, thlomersal, thiometon, thionazin, thiophanate, thiophanate-methyî, thloquinox, thiosemlcarbazlde, thiosultap, thiosuitap-diammonium, thlosultap-disodium, thiosultapmonosodium, thiotepa, thiram, thuringiensln, tiadinli, tiaojiean, tiocarbazîl, tioclorim, tioxymid, tirpate, tolclofos-methyl, tolfenpyrad, tolytfluanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamlne, triacontanol, triadimefon, triadimenol, triafamone, tri-allate, triamlphos, triapenthenol, triarathene, triarimol, triasulfuron, triazamate, triazbutîl, triaziflam, triazophos, triazoxide, tribenuron, tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamlde, trichlorfon, trichlormetaphos-3, trichioronat, tridopyr, triclopyr-butotyl, triciopyr-ethyl, triclopyr-triethylammonium, tricydazole, tridemorph, tridiphane, trietazlne, trifenmorph, trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium, triflumizole, triflumuron, trifluralin, triflusulfuron, triflusulfuron-methyl, trifop, trifop-methyl, trifopsime, triforine, trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac, trinexapac-ethyl, triprene, tripropindan, triptolide, tritac, triticonazole, tritosulfuron, trunc-call, uniconazole, uniconazole-P, urbadde, uredepa, valerate, validamydn, valifenalate, valone, vamldothlon, vangard, vaniliprole, vemolate, vindozolin, warfarin, warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan,

154 xiwojunan, XMC, xytachlor, xylenols, xytylcarb, yishijing, zarilamid, zeatin, zengxlaoan, zetacypermethrin, zinc naphthenate, zinc phosphlde, zinc thlazole, zineb, ziram, zolaprofos, zoxamlde, zuomihuanglong, a-chlorohydrin, a-ecdysone, a-multistriatin, and a-naphthaleneacetlc add. For more Information consult the Compendium of Pesticide Common Names* located at http://www.alanwood.net/DestÎddes/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 recent éditions.

BIOPESTICIDES

Molécules of Formula One may also be used In combination (such as in a compositional mixture, or a slmultaneous or sequential application) with one or more biopestiddes. The term “biopesticide Is used for mlcrobial biological pest controi agents that are applied in a similar manner to chemical pestiddes. Commonly these are bacterial, but there are also examples of fungal controi agents, induding 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 mlcrobial agents. One well-known Insecticide example is Bacillus thuringlensls, a bacterial disease of Lepidoptera, Coleoptera, and Diptera. Because it has little effect on other organlsms, it is considered more envlronmentaity friendty than synthetic pesticides. Biological insectiddes Indude products based on:

1. entomopathogenic fungi (e.g. Metarhlzium anlsopliae);

2. entomopathogenic nematodes (e.g. Stelnernema feltlae); and

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

Other examples of entomopathogenic organlsms Indude, but are not limited to, baculoviruses, bacteria and other prokaryotic organlsms, fungi, protozoa and Microsproridia. Blologically derived insectiddes include, but not limited to, rotenone, veratridine, as well as microbial toxins; insect tolérant or résistant plant varieties; and organlsms modified by recombinant DNA technology to either produce insectiddes 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 biopestiddes in the area of seed treatments and soil amendments. The Manual of Biocontrol Agents glves a review of the avaiiable biological Insecticide (and other biology-based controi) products. Copping LG. (ed.) (2004). The Manual of BiocontrolAgents (formeriy the Biopesticide Manual) 3rd Edition. British Crop Production Coundl (BCPC), Famham, Surrey UK.

155

OTHER ACTIVE COMPOUNDS

Molécules of Formula One may also be used in combination (such as in a compositional mixture, or a slmultaneous or sequential application) with one or more of the following:

1. 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one;

2. 3-(4'-chlono-2_I4-dimethyl[1,r-biphenyl]-3-yl)-4-hydroxy-8-oxa-1-azaspiro[4_I5]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;

5. 3-chloro-/V2-[(1 S)-1 -methyl-2-(methylsulfonyl)ethyl]-N1 -[2-methyl-4-[1,2,2,2-tetrafluoro-1(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxamide;

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

7. 2-cyano-N-ethyl-3-methoxy-benzenesulfonamIde;

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

0. 2-cya no-3-fl uoromethoxy-N-ethyl-be nzenesu Ifonamide ;

10. 2-cyano-6-fluoro-3-methoxy-N,N-dimethyl-benzenesulfonamide;

11. 2-cyano-/V-ethyl-6-fluoro-3-methoxy-N-methyl-benzenesulfonamlde;

12. 2-cyano-3-difluoromethoxy-N,N-dimethylbenzenesulfon-amide;

13. 3-(difluoromethyl)-/V-[2-(3_l3-dimethylbutyl)phenyl]-1-methyl-1H-pyrazole-4-carboxamide;

14. N-ethy1-2,2-dimethylpropionamide-2-(2,6-dichloro-a,a,a-trifluoro-p-tolyl) hydrazone;

15. N-ethyl-2,2-dichlono-1 -methylcyclopropane-carboxamide’2’(2,6-dlchloro-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-chloropyridin-3-ylmethyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydro-1midazo[1,2-a]pyridin-

5-ol;

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

20. N-Ethyl-2,2-dichloro-1-methy1cyclopropanecarboxamide-2-(2,6-dichloro-a/pha,a/pha,a/phatrifluono-p-tolyl)hydrazone.

156

SYNERGISTIC MIXTURES

Moiecules of Formula One may be used with certain active compounds to form synergistic mixtures where the mode of action of such compounds compared to the mode of action of the moiecules of Formula One are the same, simllar, or different Examples of modes of action Include, but are not limited to: acetylchollnesterase Inhibitor, sodium channel moduiator; chitin blosynthesis Inhibitor; GABA and glutamate-gated chloride channel antagonist; GABA and glutamate-gated chloride channel agonist; acétylcholine receptor agonist; acétylcholine receptor antagonist; MET I Inhibitor; Mg-stimulated ATPase Inhibitor nicotinlc acétylcholine receptor; Midgut membrane disrupter; oxidative phosphorylation disrupter, and ryanodine receptor (RyRs). Generally, weight ratios of the moiecules of Formula One In a synergistic mixture with another compound are from about 10:1 to about 1:10, in another embodiment from about 5:1 to about 1:5, and in another embodiment from about 3:1, and In another embodiment about 1:1.

FORMULATIONS

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 emuislons, dusts, emuisifiable concentrâtes, fumlgants, gels, granules, microencapsuiations, seed treatments, suspension concentrâtes, suspoemulsions, tablets, water soluble liquids, water dlsperslble 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^e2, 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-solubie, water-suspendable, or emuisifiable formulations are either solids, usualiy known as wettable powders, or water disperslble granules, or iiquids usually known as emuisifiable concentrâtes, or aqueous suspensions. Wettable powders, which may be compacted to form water disperslble granules, comprise an intimate mixture of the pesticide, a carrier, and surfactants. The concentration of the pesticide is usualiy from about 10% to about 90% by weight. The carrier Is usualiy selected from among the attapulgite clays, the montmorillonite days, the diatomaceous earths, or the purified silicates. Effective surfactants, comprising from about 0.5% to about 10% of the wettable powder, are found among 157 sulfonated lignins, condensed naphthalenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and non-lonlc surfactants such as ethylene oxide adducts of alkyl phénols.

Emulsifiable concentrâtes of pesticides comprise a convenant concentration of a pesticide, such as from about 50 to about 500 grams per lîter of Iiquid dissolved In a carrier that Is either a water miscible solvent or a mixture of water-lmmiscible organic solvent and emulslfiers. Useful organic solvents Indude aromatlcs, espedally xylenes and petroleum fractions, espedally the hlghboiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as the terpenlc solvents Indudlng rosin dérivatives, aliphatic ketones such as cydohexanone, and complex aicohols such as 2-ethoxyethanoi. Suitable emulsifiers for emulsifiable concentrâtes are selected from conventional anionlc and non-lonic surfactants.

Aqueous suspensions comprise suspensions of water-lnsoluble pesticides dispersed in an aqueous carrier at a concentration In the range from about 5% to about 50% by weight. Suspendons are prepared by finely grinding the pesticide and vigorously 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 of the aqueous carrier. It is often most effective to grind and mix the pestldde at the same time by preparing the aqueous mixture and homogenlzlng It In an Implement such as a sand mlli, bail mil), or piston-type homogenizer.

Pestiddes may also be applied as granular compositions that are particularly useful for applications to the soll. Granular compositions usually contain from about 0.5% to about 10% by weight of the pestldde, dispersed In a carrier that comprises day or a similar substance. Such compositions are usually prepared by dissolving the pestidde In a suitable solvent and applying It to a granular carrier which has been pre-formed to the appropriate particle slze, 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 drylng to obtaln the desired granular parfide slze.

Dusts containing a pestidde are prepared by Intlmately mixing the pestidde In powdered form with a suitable dusty agricultural carrier, such as kaolin day, ground volcanlc rock, and the like. Dusts can suitably contain from about 1% to about 10% of the pestidde. They can be applied as a seed dresslng or as a foliage application with a dust blower machine.

It Is equally practical to apply a pestldde 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.

158

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

Pesticide balts 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. Balts may take the form of granules, gels, flowable powders, llquids, or solids. They can be used In pest harborages.

Fumigants are pesticides that hâve a relatively high vapor pressure and hence can exlst as a gas In suffident concentrations to kiil pests in soll or endosed spaces. The toxlcity of the fumigant Is proportlonal to Its concentration and the exposure time. They are charaderized by a good capadty for diffusion and act by penetrating the pest's respiratory System or being absorbed through the pest’s article. Fumigants are applied to control stored product pests under gas proof sheets, in gas sealed rooms or buildings or in spécial chambers.

Pestiddes can be microencapsulated by suspending the pestidde partides or dreplets In plastic polymers of various types. By aitering the chemlstry 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 govem the speed with which the active Ingrédient within is released, which in tum, affects the residual performance, speed of action, and odor of the product.

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

Another embodiment is an oil-ln-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 agriculturally active, and Is Indivldually coated with a monolamellar or oligolamellar layer comprising: (1) at least one non-lonlc lipophilie surface-active agent, (2) at least one non-ionlc hydrophilic surface-active agent and (3) at ieast one ionlc surface-active agent, wherein the globules having a mean partide diameter of less than 800 nanometers. Further information on the embodiment is disdosed In U.S. patent publication 20070027034 published February 1,2007, having Patent Application serial number 11/495,228. For ease of use, this embodiment will be referred to as OIWE’.

159

For further Information consult ’lnsect Pest Management’ 2nd Edition by D. Dent, copyright CAB International (2000). Additionally, for more detailed Information consult Handbook of Pest Control - The Behavior, Llfe History, and Control of Household Pests’ by 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 non-exhaustive and non-mutually exclusive list) wetters, spreaders, stickers, pénétrants, buffers, sequestering agents, drift réduction agents, compatibility agents, anti-foam agents, cieanlng agents, and emulsiflers. A few components are described forthwlth.

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 h 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 liqulds or suspension concentrâtes; and during mlxing 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 sulfosucdnate; alkyl phénol ethoxylates; and aliphatic alcohol ethoxylates.

A dispersing agent Is a substance which adsorbs onto the surface of particles and helps to preserve the state of dispersion of the particles and prevents them from reaggregating. Dispersing agents are added to agrochemical formulations to fadlitate dispersion and suspension during manufacture, and to ensure the 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 dispersing agents hâve the ability to adsorb strongly onto a partide surface and provide a charged or steric barrier to reaggregation of partides. The most commonly used surfactants are anlonlc, non-lonlc, or mixtures of the two types. For wettable powder formulations, the most common dispersing 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 are also used. Non-lonlcs such as alkylarylethylene oxide condensâtes and EO-PO block copolymers 160 are sometimes combined with anionics as dîspersing agents for suspension concentrâtes, tn recent years, new types of very high molecular weight polymeric surfactants hâve been developed as dîspersing agents. These hâve very long hydrophobie 'backbones' and a large number of ethylene oxide chains formlng the Teeth* of a 'comb’ surfactant. These high molecular weight polymers can give very good long-term stability to suspension concentrâtes because the hydrophobie backbones hâve many anchoring points onto the partide surfaces. Examples of dîspersing agents used In agrochemlcal 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.

An emulslfying agent Is a substance which stabîlizes a suspension of droplets of one liquid phase in another liquid phase. Without the emulsifying agent the two liquids would separate Into two Immlsdble liquid phases. The most commonly used emulslfier blends contain alkylphenol or aliphatic alcohol with twelve or more ethylene oxide units and the oil-soluble calcium sait of dodecytbenzenesuifonic add. A range of hydrophlle-lipophile balance (‘HLB’) values from 8 to 18 will normally provide good stable émulsions. Emulsion stability can sometimes be Improved by the addition of a small amount of an EO-PO block copolymer surfactant.

A solubîlizing agent Is a surfactant which will form mlcelles In water at concentrations above the critical micelle concentration. The mlcelles are then able to dissolve or solubilize water-insoiuble materials inside the hydrophobie part of the micelle. The types of surfactants usually used for solubllizatlon are non-lonlcs, sorbltan monooleates, sorbltan monooleate ethoxylates, and methyl oleate esters.

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

A carrier or diluent in an agriculture! formulation Is a material added to the pestidde to give a product of the required strength. Carriers are usually materials with high absorptive capadties, while diluents are usually materials with low absorptive capadties. Carriers and diluents are used In the formulation of dusts, wettable powders, granules and water-dispersible granules.

Organic solvents are used malnly In the formulation of emulslfiable concentrâtes, oii-lnwater émulsions, suspoemulslons, and ultra low volume formulations, and to a fesser extent, granular formulations. Sometimes mixtures of solvents are used. The first main groups of solvents 161 are aliphatic paraffinlc oils such as kerosene or refined paraffins. 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 emulslfied 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 mainiy In the formulation of suspension concentrâtes, émulsions and suspoemuislons to modify the rheology or flow properties of the liquid and to prevent séparation and settling of the dispersed particles or droplets. Thickenlng, gelling, and anti-settling agents generally fall into two categories, namely water-lnsolubie particulates and water-solubie polymers. It is possible to produce suspension concentrate formulations using clays and silicas. Examples of these types of materials, include, but are not limited to, montmorillonlte, bentonite, magnésium aluminum silicate, and attapulgite. Water-solubie polysaccharides hâve been used as thlckenlng-gelling agents for many years. The types of polysaccharides most commonly used are naturel extracts of seeds and seaweeds or are synthetic dérivatives of cellulose. Examples of these types of materials Inciude, but are not iimlted to, guar gum; locust bean gum; carrageenam; alginates; methyl cellulose; sodium carboxymethyl cellulose (SCMC); hydroxyethyl cellulose (HEC). Other types of anti-settling agents are based on modified starches, polyacrylates, polyviny! aicohol and polyethylene oxide. Another good anti-settling agent is xanthan gum.

Microorganisms can cause spoilage of formulated products. Therefore préservation agents are used to elimlnate or reduce their effect Examples of such agents inciude, but are not limited to: propionic acid and its sodium sait; sorbic add and its sodium or potassium salts; benzolc add and its sodium sait; p-hydroxybenzolc acid sodium sait; methyl p-hydroxybenzoate; and 1,2benzisothiazolin-3-one (BIT).

The presence of surfactants often causes water-based formulations to foam during mlxing 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 non-silicones. Silicones are usually aqueous émulsions of dimethyl polysiloxane, while the non-sliicone anti-foam agents are water-insoiuble oils, such as octanol and nonanoi, or silica. In both cases, the fonction of the anti-foam agent is to displace the surfactant from the alr-water interface.

‘Green* agents (e.g., adjuvants, surfactants, solvents) can reduce the overall environmental footprint of crop protection formulations. Green agents are biodégradable and generally derived

162 from naturel and/or sustainable sources, e.g. plant and animal sources. Spécifie examples are: vegetable oils, seed oils, and esters thereof, also alkoxylated alkyl polyglucosides.

For further information, see ’Chemistry and Technology of Agrochemical Formulations' edited by DA. 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 ln 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, iocusts, crickets, fleas, thrips, bristletails, mites, ticks, nematodes, and symphylans.

ln another embodiment, the molécules of Formula One may be used to control pests in the Phyla Nematoda and/or Arthropode.

ln another embodiment, the molécules of Formula One may be used to control pests ln the Subphyla Chellcerata, Myrlapoda, and/or Hexapoda.

In another embodiment, the molécules of Formula One may be used to control pests in the Classes of Arachnlda, S ym phyla, and/or Insecta.

ln 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., Unognathus spp., Pediculus spp., and Polyplax spp. A nonexhaustive list of particular species Indudes, but is not limited to, Haematopinus asinl, Haematopinus suis, Unognathus setosus, Unognathus ovillus, Pediculus humanus capltis, Pediculus humanus humanus, and Pthirus pubis.

ln anotherembodiment, 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, Acanthosceiides spp., Agiotes spp., Anthonomus spp., Apion spp., Apogonla spp., Aulacophora spp., Bruchus spp., Cerostema spp., Cerotoma spp., Ceutorhynchus spp., Chaetocnema spp., Colasp/s spp., Ctenicera spp., Curcuiio spp., Cyclocephala spp., Diabrotica spp., Hypera spp., Ips spp., Lyctus spp., Megascelis spp., Meligethes spp., Otiorhynchus spp., Pantomorus spp., Phyllophaga spp., Phyliotrata spp., Rhizotrogus spp., Rhynchites spp., Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophiius spp., and Tribolium spp. A non-exhaustive list of

163 particular specles Indudes, but Is not limited to, Acanthoscelldes obtectus, Agrilus planipennis, Anoplophora glabripennls, Anthonomus grandis, Ataenius spretulus, Atomaria linearis, Bothynoderes punctiventris, Bruchus pisorum, Caliosobruchus maculatus, Carpophiïus hemlpterus, Casslda vittata, Cerotoma trifurcata, Ceutorhynchus assimilis, Ceutorhynchus napi, Conoderus scalaris, Conoderus st/gmosus, Conotrachelus nanuphar, Cotinls nltlda, Crioceris asparagi, Cryptolestes ferruglneus, Cryptolestes pusillus, Cryptolestes turcicus, Cytindrocopturus adspersus, Deporaus marglnatus, Dermestes lardarius, Dermestes maculatus, Epilachna varivestis, Faustinus cubae, Hylobius pales, Hypera postica, Hypothenemus hampel, Lasioderma serricome, Leptlnotarsa decemlineata, Uogenys fuscus, Uogenys suturaiis, Ussorhoptrus oryzophilus,

Maecolaspis jolivetl, Melanotus commuais, Meiigethes aeneus, Melolontha meioiontha, Oberea brevis, Oberea linearis, Oryctes rhinocéros, Oryzaephilus mercator, Oryzaephilus surinamensîs, Ouléma melanopus, Ouléma oryzae, Phyllophaga cuyabana, Popillia Japonica, Prostephanus truncatus, Rhyzopertha domlnica,, Sitona lineatus, Sitophilus granarius, Sitophilus oryzae, Sitophilus zeamais, Stegobium paniceum, Tribolium castaneum, Tribolium confusum, Trogoderma 15 varlabile, and Zabrus tenebrbides.

In another embodiment, the molécules of Formula 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 Blattarla. A non-exhaustive list of particular spedes indudes, but Is not limited to, Blattella 20 germanlca, Blatte orlentalls, Parcoblatta pennsylvanlca, Periplaneta americana, Periplaneta australaslae, Periplaneta brunnea, Periplaneta fuliglnosa, Pycnoscelus surinamensîs, and Supalla longlpalpa.

in another embodiment, the molécules of Formula One may be used to control pests of the Order Dlptera. A non-exhaustive list of particular généra indudes, but is not limited to, Sectes spp., 25 Agromyza spp., Anastrepha spp., Anopheles spp., Bactrocera spp., Ceratitis spp., Chrysops spp., Cochliomyia spp., Contarinla spp., Cu/exspp., Daslneura spp.. Délia spp., Drosophile spp., Fannia spp., Hylemyla spp., Uriomyza spp., Musca spp., Phorbla spp., Tabanus spp., and Tipula spp. A non-exhaustive list of particular spedes Indudes, but Is not limited to, Agromyza frontelia, Anastrepha suspense, Anastrepha ludans, Anastrepha obliqa, Bactrocera cucurbitae, Bactrocera dorsalis, Bactrocera invadens, Bactrocera zoneta, Ceratitis capitata, Daslneura brassicae, Délia piatura, Fannia canîcularis, Fannia scalaris, Gasterophilus intestinalis, Gracillia perseae, Haematobia Irritans, Hypoderma lineatum, Uriomyza brassicae, Melophagus ovinus, Musca autumnalis, Musca domestica, Oestrus ovfs, Oscinella frit, Pegomya betae, Pslla rosae, Rhagoletis

164 cerasl, Rhagoletis pomonella, Rhagdetis mendax, Sitodiplosis mosellana, and Stomoxys calcitrans.

In another embodiment, the moiecules of Formula One may be used to control pests of the Order Hemlptera. A non-exhaustive list of particular généra Includes, but Is not limited to, Adalgas spp., Aulacaspis spp., Aphrophora spp., ApWs spp., Bemisia spp., Ceroplastas spp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp., Lepldosaphas spp., Lagynotomus spp., Lygus spp., Macrosiphum spp., Nephotettix spp., Nezara spp., Philaenus spp., Phytocoris spp., Piezodorus spp., Planococcus spp., Pseudococcus spp., Rhopalosiphum spp., Salssatia spp., Tharioaphis spp., Toumeyella spp., Toxoptera spp., Trialeurodas spp., Trlatoma spp. and Unaspfs spp. A non-exhaustive list of particular species Includes, but Is not limited to, Acrosternum hilare, Acyrthoslphon plsum, Aleyrodes proletella, Aleurodicus dispersus, Aleurothrixus floccosus, Amrasca biguttula biguttula, Aonldialla aurantii, Aphis gossypii, Aphis glycines, Aphis poml, Aulacorthum solanl, Bemisia argentifoliï, Bemisia tabad, Blissus leucopterus, Brachycorynella asparagl, Brevennla rahi, Brevicoryne brasslcae, Calocoris norvagicus, Ceroplastas rubans, Cimex hemlpterus, Cimex lectularius, Dagbertus fasclatus, Dicheiops furcatus, Diuraphls noxla, Dlaphorlna citri, Dysaphls plantaglnea, Dysdercus suturallus, Edassa meditabunda, Erlosoma lanlgarum, Eurygastar maure, Euschistus héros, Euschistus servus, Helopeltis antonil, Halopeltis theivora, Icerya purchasl, Idioscopus nîtidulus, Laodelphax striatellus, Leptocorisa oratorius, Leptocorisa varicomis, Lygus hesperus, Maconellicoccus hlrsutus, Macrosiphum euphorblae, Macrosiphum granarlum, Macrosiphum rosae, Macrosteles quadrilinaatus, Mahanarva frimbiolata, Metopolophlum dirhodum. Midis longlcornls, Myzus persicae, Nephotettix dndipes, Neurocolpus longirostris, Nezara vlridula, Nilaparvata lugans, Parlatorla pergandil, Parlatoria ziziphi, Peregrinus maldis, Phylloxéra vitifdiae, Physokermes piceae,, Phytocoris califomicus, Phytocoris relativus, Piezodorus guildinii, Poedlocapsus lineatus, Psallus vacdnicola, Pseudacysta perseae, Pseudococcus brevipes, Quadraspidiotus parnldosus, Rhopalosiphum maidis, Rhopalosiphum padi, Salssetia oleae, Scaptocoris castanea, Schizaphis graminum, Sltobion avenae, Sogatella furcifera, Trialeurodes vaporariorum, Trialeurodas abutiloneus, Unaspis yanonensis, and Zulia entrerriana.

In another embodiment, the moiecules of Formula One may be used to control pests of the Order Hymenoptera. A non-exhaustive list of particular généra Includes, but is not limited to, Acromyrmex spp., Atta spp., Camponotus spp., Dlprion spp.. Formica spp., Monomorium spp., Neodiprion spp., Pogonomyrmex spp., Po/istes spp., Sdenops/s spp., Vespula spp., and Xylocopa spp. A non-exhaustive list of particular species Includes, but Is not limited to, Athalia rosae, Atta

165 texana, Irldomyrmex humilis, Monomorium minimum, Monomorium pharaonis, Soienopsis Invicta, Soienopsis geminata, Soienopsis molesta, Soienopsis richtery, Soienopsis 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 Indudes, but is not limited to, Coptotermes spp., Comltermes spp., Cryptotermes spp., Heterotermes spp., Kalotermes spp., Incisitermes spp., Macrotermes spp,, Marginitermes spp., Microcerotermes spp., Procomitermes spp., Reticulitermes spp., Schedorhinotermes spp., and Zootermopsis spp. A non-exhaustive list of particular spedes Indudes, but is not limited to, Coptotermes curvignathus, Coptotermes frenchl, 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 Lepldoptera. A non-exhaustive list of particular généra indudes, but Is not limited to, Adoxophyes spp., Agrotis spp., Argyrotaenia spp., Cacoeda spp., Caloptilia spp., Chilo spp., Chrysodelxis spp., Colias spp., Crambus spp., Diaphania spp,, Diatraea spp., Earias spp., Ephestia spp., Eplmecls spp., Feltia spp., Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela spp., Uthocolletis spp., Loxagrotls spp., Malacosoma spp., Peridroma spp., Phyllonorycter spp., Pseudaletia spp., Sesamia spp., Spodoptera spp., Synanthedon spp., and Yponomeuta spp. A non-exhaustive list of particular spedes Indudes, but Is not limited to, Achaea janata, Adoxophyes orana, Agrotis Ipsllon, Alabama argiliacea, Amorbia cuneana, Amyelds transitella, Anacamptodes defectaria, Anarsia lineatella, Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archips rosana, Argyrotaenia citrana, Autographe gamma, Bonagota cranaodes, Borbo dnnara, Bucculatrix thurberlella, Capua reticulana, Carposina niponensis, Chlumetia transversa, Choristoneura rosaceana, Cnaphalocrocls medinalis, Conopomorpha cramerella, Cossus cossus, Cydia caryana, Cydia funebrana, Cydia molesta, Cydia nigricana, Cydia pomonella. Dama diducta, Diatraea saccharalis, Diatraea grandiosella, Earias Insulana, Earias vittella, Ecdytolopha aurantlanum, Elasmopalpus lignoselius, Ephestia cautella, Ephestia elutella, Ephestia kuehnlella, Epinotia aporema, Eplphyas postvittana, Erionota thrax, Eupoedlia ambiguella, Euxoa auxiliaris, Grapholita molesta, Hedylepta Indicata, Helicoverpa armigera, Helicoverpa zea, Heliothis virescens, Hellula undalis, Keiferla lycopersicella, Leucinodes orbonalis, Leucoptera coffeella, Leucoptera malifollella, Lobesia botrana, Loxagrotls albicosta, Lymantria dispar, Lyonetia clerkella,

166

Mahasena corbattl, Mamestra brasslcae, Maruca testulalis, Metlsa plana, Mythlmna unipuncta, Neoleuclnodes elegantalis, Nymphula depunctalis, Operophtera brumata, Ostrinla nubilalis, Oxydia vesulia, Pandemis cerasana, Pandemls heparana, Papllio demodocus, Pectinophora gossypîella, Peridroma saucia, Perileucoptera coffeella, Phthorimaea operculella, Phyllocnlstis citrella, Pieris rapae, Plathypena scabra, Plodia Interpunctella, Plutella xyiostella, Polychrosls viteana, Prays endocarpe, Prays olaae, Pseudaletia unipuncta, Pseudoplusia Includens, Rachiplusla nu, Sclrpophaga Incartulas, Sasamla Inferans, Sasamla nonagrloidas, Satora nitens, Sitotroga cerealella, Sparganothls pllleriana, Spodoptera exigua, Spodoptera fruglparda, Spodoptera aridanla, Theda basilides, Tineola blssalliella, Trichoplusia ni, Tuta absoluta, Zeuzera coffeae, and Zeuzera pyrina.

In another embodiment, the molécules of Formula One may be used to control pests ofthe Order Mallophaga. A non-exhaustive list of particular généra Includes, but is not limited to, Anaticola spp., Bovlcola spp., Chalopistes spp., Gonlodes spp., Manacanthus spp., and Trichodectes spp. A non-exhaustive list of particular species Includes, but Is not limited to, Bovlcola bovis, Bovlcola caprae, Bovicola ovis, Chalopistes meleagridis, Gonlodes dissimilis, Goniodes glgas, Menacanthus stramineus, Menopon gallinae, and Trichodectes canls.

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 africana, Gryllotalpa australes, Gryllotalpa brachyptera, Gryllotalpa hexadactyla, Locuste mlgratoria, Microcentrum retinarve, Schlstocerca gregaria, and Scudderla 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, Ctenocephalides canls, Ctenocaphalides felis, and Pulex Irritans.

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 indudes, but is not limited to, Caliothrips spp., Frankliniella spp., Sclrtothrips spp., and Thrips spp. A non-exhaustive list of particular sp. Indudes, but Is not limited to, Frankliniella fusca, Frankliniella occidentales, Frankliniella schultzei, Frankliniella Williams!, Heliothrips haemorrhoidalis, Rhiplphorothrlps cruentatus, Sclrtothrips citri, Sclrtothrips dorsales, and Taeniothrips rhopalantennalis, Thrips hawaiiensls, Thrips nlgropilosus, Thrips orientalis, Thrips tabacl.

167

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 Inciudes, 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 Acarlna. A non-exhaustive list of particular généra Inciudes, but Is not limited to, Acarus spp., Aculops spp., Boophllus spp., Demodex spp., Dermacentor spp., Epltrimarus spp., Eriophyes spp., Ixodes spp., Oligonychus spp., Panonychus spp., Rhizoglyphus spp., and Tetranychus spp. A non-exhaustive list of particular species Inciudes, but Is not limited to, Acarapis woodl, Acarus siro, Aceria mangiferae, Aculops lycopersici, Aculus pelekassi, Aculus schlechtendali, Amblyomma americanum, Brevlpalpus obovatus, Brevlpalpus phoenids, Dermacentor variabilis, Dermatophagoldes pteronysstnus, Eotetranychus carplni, Notoedres catl, Oligonychus coffeae, Oligonychus ilids, Panonychus dtri, Panonychus ulmi, Phyllocoptruta oleivora, Polyphagotarsonemus latus, Rhiplcephalus sangulneus, Sarcoptes scabiel, Tegolophus perseaflorae, Tetranychus urtlcae, and Varroa destructor.

In another embodiment, the molécules of Formula One may be used to control pest ofthe Order Symphyla. A non-exhaustive list of particular sp. inciudes, but is not limited to, Scutlgerella 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 indudes, but is not limited to, Aphelenchoides spp., Belonolaimus spp., Criconemella spp., Ditylenchus spp., Heterodera spp., Hirschmanniella spp., Hoplolaimus spp., Melddogyne spp., Pratylenchus spp., and Radopholus spp. A non-exhaustive list of particular sp. indudes, but is not limited to, Dirofilaria Immitis, Heterodera zeae, Meloldogyne incognita, Meloidogyne Javanica, Onchocerca volvulus, Radopholus similis, and Rotylenchulus renlformis.

APPLICATIONS

Molécules of Formula One are generally used in amounts from about 0.01 grams per hedare to about 5000 grams per hectare to provide control. Amounts from about 0.1 grams per

168 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 One 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 omamental 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 Indude areas where apples, corn, sunflowers, cotton, soybeans, canola, wheat, rice, sorghum, barley, oats, potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes, peppers, crudfers, 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 ammonium 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 Incapadtated In or around an area; or pests are exterminated, In whole, or In part, In or around an area. Of course, a combination 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.

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 1-methylcydopropene (also known as 1-MCP). Furthermore, such molécules may be used during times when pest activity Is low, such as before the plants that are growing begin to produce valuable agricultural commodities. Such times Indude the eariy planting season when pest pressure Is usually low.

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 pestidde when eating leaf, fruit mass, or extracting sap, that contains the pestidde. The molécules of Formula One can also be applied to the soil, and when applied In this manner, root and stem feedlng pests can be controlled. The roots can absorb a molécule taking It up Into the foliar portions of the plant to control above ground chewlng and sap feeding pests.

169

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

The molecuies of Formula One can be encapsuiated 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 mlcrometer 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 molecuies of Formula One may be désirable to contrat newly emerged larvae.

Systemic movement of pesticides in plants may be utiiized to control pests on one portion of the plant by appiying (for exampie by spraying an area) the molecuies of Formula One to a different portion of the plant. For exampie, contrai of folîar-feeding insects can be achieved by drip Irrigation or furrow application, by treating the soi! with for exampie pre- or post-pianting soit drench, or by treating the seeds of a plant before planting.

Seed treatment can be applied to ali types of seeds, including those from which plants genetlcally modified to express spedalized traits will germinate. Représentative examples indude those expressing proteins toxic to Invertebrate pests, such as Bacillus thuringiensis or other insectiddai toxins, those expressing herbicide résistance, such as “Roundup Ready seed, or those with stacked foreign genes expressing insectiddai toxins, herbidde résistance, nutritionenhancement, drought résistance, or any other benefidal traits. Furthermore, such seed treatments with the molecuies of Formula One may further enhance the ability of a piant to better withstand stressfui growing conditions. This results in a healthler, more vigorous plant, which can iead to higher yields at harvest time. Generally, about 1 gram of the molecuies of Formula One to about 500 g ram s per 100,000 seeds is expected to provide good benefits, amounts from about 10 grams to about 100 grams per 100,000 seeds is expeded to provide better benefits, and amounts from about 25 grams to about 75 grams per 100,000 seeds Is expeded to provide even better benefits.

it should be readily apparent that the molecuies of Formula One may be used on, in, or around plants genetîcally modified to express spedalized traits, such as Bacillus thuringiensis or other insectiddai toxins, or those expressing herbidde résistance, or those with stacked* foreign genes expressing insectiddai toxins, herbidde résistance, nutrition-enhancement, or any other benefidal traits.

170

The molécules of Formula One may be used for controlling endoparasites and ectoparasites in the veterinary medicine sector or in the field of non-human animai 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 dusting, 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 spedes.

The molécules of Formula One may also be used for controlling para si tic worms, espedally of the intestine, In the animais iisted above.

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.

Pests around the worid hâve been migratïng to new environments (for such pest) and thereafter becoming a new invasive spedes in such new environment. The molécules of Formula One may also be used on such new invasive spedes 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 growlng (e.g. pre-planting, planting, pre-harvesting) and where there are low levels (even no actual presence) of pests that can commerdally damage such plants. The use of such molécules in such area Is to benefit the plants being grown In the area. Such benefits, may indude, 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 pestidde can be used or sold commerdally, such pestidde undergoes iengthy évaluation processes by various govemmental 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 Worid Wide Web.

171

These govemmental 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 moiecule 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 moiecule 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 In this document are for convenlence only and must not be used to

Interpret any portion hereof.

TABLE SECTION

BAW & CEW Rating Table
% Control (or Mortality)	Rating
50-100	A
More than 0 - Less than 50	B
Not Tested	C
No activity noticed in this bioassay	D

GPA Rating Table
% Control (or Mortality)	Rating
80-100	A
More than 0 - Less than 80	B
Not Tested	C
No activity noticed ln this bioassay	D

172

YFM Ratlng Table
% Control (or Mortality)	Ratlng
80-100	A
More than 0 - Less than 80	B
Not Tested	C
No activity notlced In this bloassay	D

173

Table ABC: Biological Résulta

Molécule #	Ratlng YFM	Ratlng CEW	Rating BAW	Rating GPA
A1	C	A	A	D
A2	C	A	A	D
A3	A	A	A	D
A4	A	A	A	B
A5	C	A	A	C
A6	C	A	A	D
A7	C	A	A	B
A8	C	A	A	C
A9	C	A	A	B
A10	C	A	A	C
A11	C	A	A	B
A12	C	A	A	D
A13	C	A	A	C
A14	A	A	A	B
A15	A	A	A	D
A16	C	C	C	C
A17	C	C	C	C
A18	A	A	A	C
Α1Θ	C	A	A	C
A20	C	A	A	D
A21	C	A	A	C
A22	C	A	A	D

174

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Q

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Q

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CM

CO

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A51	C	A	A	C
A52	C	A	A	C
A53	C	D	D	C
A54	C	A	A	c
ASS	C	A	A	c
A56	C	A	A	c
A57	C	A	A	c
A58	C	A	A	c
A59	C	A	A	c
A60	C	A	A	c
A61	C	A	A	c
A62	A	A	A	D
A63	C	A*	A	C
A64	C	A*	A	C
A65	A	A*	A	c
A66	C	C	A	c
A67	C	A*	A	c
A68	C	A*	A	c
A69	A	A*	A	c
A70	C	A‘	A	c
A71	C	C	A	c
A72	C	A*	A	c
A73	C	A*	A	c
A74	C	A*	A	c
A75	C	A*	A	c
A76	C	A*	A	c

176

A77	B	A*	A	C
A78	C	c	D	C
A79	C	A‘	A	C
A80	B	A	A	C
A81	C	A	A	C
A82	C	A*	A	C
A83	C	C	A	C
A84	c	A”	A	C
A85	A	A”	A	C
A86	C	A”	A	C
A87	C	A*	A	C
A88	c	A*	A	C
A89	c	A*	A	C
A92	c	A*	A	C
A93	c	A*	A	C
A94	c	A*	A	C
A95	c	A*	C	C
A96	c	D	A	C
A97	c	A”	A	c
A98	c	A*	A	c
A99	c	C	D	c
A100	c	A*	A	c
A101	c	A*	A	c
A102	c	A*	C	c
A103	c	A*	A	c
A104	c	A”	D	c

177

A105	C	A*	A	C
A106	C	A*	A	C
A107	C	A*	A	C
A108	C	A*	A	C
A109	C	A’	A	C
A110	A	A’	A	D
A111	C ·	A*	A	C
A112	C	C	A	c
A113	C	D	A	c
A114	C	A‘	A	c
A115	C	A*	A	c
A116	C	A‘	A	c
A117	C	A*	A	c
A118	c	D	D	c
A119	c	B*	A	c
A120	c	D	D	c
A121	c	A*	A	c
A122	A	A*	A	c
A123	A	A*	A	c
A124	C	C	C	c
A125	C	^c	C	c

** Tested at 12.5 Cg/cm² * Tested at 0.5 ng/cm²

178

Claims

Claims

1. A composition comprising a molecuie having the following formula /Q²—R’

Formula One wherein:

(A) Ar¹ Is a substituted phenyl, preferably a substituted phenyl that has one or more substituents selected from C,-Ce haloalkyl and C,-Ce haloalkoxy*, (B) Het is selected from benzofuranyl, benzoisothlazolyl, benzolsoxazolyl, benzoxazolyl, benzothlenyl, benzothlazolyl dnnoiinyl, furanyl, Indazolyl, indolyl, Imldazolyl, Isolndolyl, Isoquinolinyl, Isothlazolyl, isoxazolyl, oxadtazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimldinyl, pyrrolyl, quinazolinyl, quinolinyl, qulnoxalinyl, tetrazolyl, thiazolinyl, thlazolyl, thienyl, triazinyl, triazolyl, piperazlnyl, plperidinyl, morpholinyl, pyrrolldinyl, tetrahyrirofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydro-quinolinyl, 4,5-dihydro-oxazolyl, 4,5-dihydro-1H-pyrazoly1,4,5-dihydro-lsoxazolyl, and 2,3-dîhydro-[1,3,4]-oxadiazolyl;

(C) Ar² Is phenyl;

(D) R¹ Is H;

(E) R² Is (K), H, 0,-Ce alkyl, or C,-Ce alkyi-O-C(=0)C,-Ce alkyl;

(F) R³ Is substituted phenyl wherein said substituted phenyl has one or more substituents selected from F, C,-C_e alkyl, C,-Ce alkoxy, and phenyl;

(G) R⁴ Is H;

(H) M Is N or CR® wherein R® Is selected from H, CN, and C(=O)(C,-Ce alkyl);

0) (D Q’iso (2) Q² Is S;

(K) R² and R⁴ are (K) wherein R² and R⁴ along with C^x(Q²)(N^>t), form a 4- to 7-membered saturated or unsaturated, hydrocarbyl cyclic group, wherein said hydrocarbyl cyclic group may be substituted with oxo or C,-Ce alkyl or wherein the Iink between Q² and N* Is CH₂C(=O), CH₂CH₂, CH₂CH₂CH₂, or CH₂CH(CH₃);

or wherein at least one of R¹, R², or R⁴, Is H and said molecuie exlsts as one or more tautomers.

179
2. A composition according to claim 1 wherein R³ is substituted phenyl wherein said substituted phenyl has more than one substituent and at least one pair of said substituents are not ortho to each other.
3. A composition according to claim 1 wherein said molécule Is selected from one of the following ____________________________________________________________

No. Structure A1 A- A2 A3 irO-’Ax.kiÿ A4 A5